Estrogen - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

ESTROGEN A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES J AMES N. P ...

Author: ICON Health Publications

10 downloads 800 Views 5MB Size Report

This content was uploaded by our users and we assume good faith they have the permission to share this book. If you own the copyright to this book and it is wrongfully on our website, we offer a simple DMCA procedure to remove your content from our site. Start by pressing the button below!

Report copyright / DMCA form

DOWNLOAD PDF

ESTROGEN A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

ii

ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright ©2004 by ICON Group International, Inc. Copyright ©2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Estrogen: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-84277-9 1. Estrogen-Popular works. I. Title.

iii

Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International, Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

iv

Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on estrogen. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

v

About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

vi

About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

vii

Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON ESTROGEN ................................................................................................. 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Estrogen ...................................................................................... 17 E-Journals: PubMed Central ....................................................................................................... 76 The National Library of Medicine: PubMed .............................................................................. 104 Academic Periodicals covering Estrogen ................................................................................... 152 Dissertations on Estrogen.......................................................................................................... 152 CHAPTER 2. NUTRITION AND ESTROGEN ..................................................................................... 153 Overview.................................................................................................................................... 153 Finding Nutrition Studies on Estrogen..................................................................................... 153 Federal Resources on Nutrition ................................................................................................. 161 Additional Web Resources ......................................................................................................... 161 CHAPTER 3. ALTERNATIVE MEDICINE AND ESTROGEN ............................................................... 165 Overview.................................................................................................................................... 165 The Combined Health Information Database............................................................................. 165 National Center for Complementary and Alternative Medicine................................................ 166 Additional Web Resources ......................................................................................................... 197 General References ..................................................................................................................... 209 CHAPTER 4. CLINICAL TRIALS AND ESTROGEN ........................................................................... 211 Overview.................................................................................................................................... 211 Recent Trials on Estrogen.......................................................................................................... 211 Keeping Current on Clinical Trials ........................................................................................... 224 CHAPTER 5. PATENTS ON ESTROGEN ........................................................................................... 227 Overview.................................................................................................................................... 227 Patents on Estrogen ................................................................................................................... 227 Patent Applications on Estrogen ............................................................................................... 241 Keeping Current ........................................................................................................................ 250 CHAPTER 6. BOOKS ON ESTROGEN ............................................................................................... 251 Overview.................................................................................................................................... 251 Book Summaries: Federal Agencies............................................................................................ 251 Book Summaries: Online Booksellers......................................................................................... 254 Chapters on Estrogen................................................................................................................. 254 CHAPTER 7. RESEARCHING MEDICATIONS .................................................................................. 263 Overview.................................................................................................................................... 263 U.S. Pharmacopeia..................................................................................................................... 263 Commercial Databases ............................................................................................................... 266 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 271 Overview.................................................................................................................................... 271 NIH Guidelines.......................................................................................................................... 271 NIH Databases........................................................................................................................... 273 Other Commercial Databases..................................................................................................... 277 The Genome Project and Estrogen ............................................................................................. 277 APPENDIX B. PATIENT RESOURCES ............................................................................................... 281 Overview.................................................................................................................................... 281 Patient Guideline Sources.......................................................................................................... 281 News Services and Press Releases.............................................................................................. 289 Newsletter Articles .................................................................................................................... 290 Finding Associations.................................................................................................................. 296 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 299

viii Contents

Overview.................................................................................................................................... 299 Preparation................................................................................................................................. 299 Finding a Local Medical Library................................................................................................ 299 Medical Libraries in the U.S. and Canada ................................................................................. 299 ONLINE GLOSSARIES................................................................................................................ 305 Online Dictionary Directories ................................................................................................... 306 ESTROGEN DICTIONARY......................................................................................................... 307 INDEX .............................................................................................................................................. 407

1

FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with estrogen is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about estrogen, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to estrogen, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on estrogen. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to estrogen, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on estrogen. The Editors

1

From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

3

CHAPTER 1. STUDIES ON ESTROGEN Overview In this chapter, we will show you how to locate peer-reviewed references and studies on estrogen.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and estrogen, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “estrogen” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

Gallbladder Disease and Use of Noncontraceptive Estrogens Source: Geriatric Medicine Today. 9(3): 56, 59-60, 62-63. March 1990. Summary: Epidemiologic data on the physiological effects of estrogen support the contention that use of postmenopausal estrogen increases the risk of gallbladder disease during periods of current use. This article reviews three studies in which ultrasound was used for the diagnosis of gallbladder disease. Results showed no association between estrogen use and an increased risk of gallstones, however, suggesting that estrogens may precipitate symptoms in women with gallstones or may lead to referral of such women for surgery. Topics include implications for prescribing estrogens universally; costs, including those of morbidity and mortality as well as financial costs of gallstone surgery; and the effect of the present standard of estrogen combined with

4

Estrogen

progestin on the risk of surgery for gallbladder disease in postmenopausal women. 1 table. 23 references. (AA-M). •

Etiological Role of Estrogen Status in Renal Stone Formation Source: Journal of Urology. 168(5): 1923-1927. November 2002. Contact: Available from Lippincott Williams and Wilkins. 12107 Insurance Way, Hagerstown, MD 21740. (800) 638-3030 or (301) 714-2334. Fax (301) 824-7290. Summary: Estrogen may protect against kidney stone formation since nephrolithiasis (kidney stones) is more common in men than in women. Moreover, the incidence of stones rises after menopause in women. This article reports on a study that examined the contribution of estrogen to kidney stone risk by comparing outpatient evaluations in the two genders, and in estrogen treated and untreated postmenopausal women. The authors reviewed the results of the initial evaluation of 1,454 adult calcium oxalate stone formers, including 1,050 men and 404 women. Of the postmenopausal women, 39 and 50 were estrogen treated and untreated, respectively. Compared with men, the daily excretion of urinary calcium, oxalate, and uric acid was lower in women. Women had lower saturations of calcium oxalate and brushite as well as lower excretion of undissociated uric acid. Compared with men, urinary calcium was lower in women until age 50 years, when it equaled that of men. Citrate was equal in the genders until age 60 years, when it tended to decrease in women. Compared with untreated postmenopausal women, those treated with estrogen had lower mean 24 hour calcium, lower mean 2 hour fasting urine calcium, and lower mean calcium oxalate saturation. The authors conclude that the lower risk of stone formation in women may be due to the lower urinary saturation of stone forming salts. Estrogen treatment may decrease the risk of stone recurrence in postmenopausal women by lowering urinary calcium and calcium oxalate saturation. 1 figure. 4 tables. 20 references.

•

Estrogen Replacement Therapy and Memory in Older Women Source: Journal of the American Geriatrics Society. 42(9): 919-922. September 1994. Summary: Research on Alzheimer's disease (AD) has considered estrogen deficiency as a risk factor for AD. This article compares the recall performance of postmenopausal women without dementia receiving hormone replacement therapy with that of similar postmenopausal women not receiving hormone replacement therapy. It describes a case-control study of 144 community-dwelling female volunteers aged from 55 to 93 years. Subjects were given a proper name recall test and a word recall test. They also completed an estrogen use questionnaire. Proper name recall was significantly better in those receiving hormone replacement therapy than those not receiving it. There also was significantly greater variance in the name recall scores of the group on hormone replacement therapy. For word recall, there was no significant difference between the two groups. An association existed between estrogen use and enhanced recall of proper names. Previous failures to find differences associated with estrogen use may reflect the memory measures used or an increased inter-individual variability of the estrogentaking group as observed in this study. 3 tables, 27 references. (AA-M).

•

Postmenopausal Estrogen Replacement Therapy and the Risk of Alzheimer's Disease: A Population-Base Case-Control Study Source: American Journal of Epidemiology. 140(3): 262-267. 1994.

Studies

5

Summary: Researchers compare the exposure of estrogen replacement therapy of 107 female Alzheimer's disease cases with 120 age- and sex-matched control subjects by using computerized pharmacy data. The study examines whether postmenopausal estrogen replacement therapy reduces the risk of AD in women. AD cases were obtained from the Alzheimer's Disease Patient Registry of the University of Washington, Seattle, Washington, which is based on the enumerated health plan population from 1987 to 1992. Enrolled in the Registry are newly recognized cases of probable AD. These cases are ascertained and evaluated according to standardized diagnostic criteria. The control subjects were selected from the same defined population by stratified random sampling. The authors find use of estrogens did not show an association with AD. Oral and vaginal estrogens yielded similar results. The researchers conclude there is no evidence that estrogen replacement therapy has an impact on the risk of AD in women. 5 tables, 24 references. (AA-M). •

Estrogen Replacement Therapy in Older Women: Comparisons Between Alzheimer's Disease Cases and Nondemented Control Subjects Source: Archives of Neurology. 51(9): 896-900. September 1994. Summary: Researchers conducted a case-controlled study of estrogen replacement therapy using hierarchical procedures to control potentially confounding effects of age and education. Researchers hypothesized that oral estrogen replacement therapy would be less common among older women meeting criteria for Alzheimer's disease (AD) than among older women without dementia. For women with AD, investigators hypothesized that estrogen users would perform better on a cognitive task than would nonusers. Subjects met clinical criteria for probable AD (n=143) or met criteria for control status (n=92). Seventy patients who subsequently died met histopathologic criteria for AD. Current use of estrogen replacement at the time of enrollment was reported by control subjects or by the primary caregivers of AD patients. Among cases, performances on a brief cognitive screening instrument were compared between 10 estrogen users and 128 nonusers. Patients with dementia and using estrogen did not differ significantly from those not using estrogen in terms of age, education, or symptom duration. However, their mean performance on a cognitive screening instrument was significantly better. Findings suggest that postmenopausal estrogen replacement therapy may be associated with a decreased risk of AD and that estrogen replacement may improve cognitive performance of women with AD. 2 tables, 41 references. (AA-M).

•

Role of Estrogen Supplementation in Lower Urinary Tract Dysfunction Source: International Urogynecology Journal. 12(4): 258-261. 2001. Contact: Available from Springer-Verlag New York Inc. 175 Fifth Avenue, New York, NY 10010. (212) 460-1500. Fax (212) 473-6272. Summary: The female lower urinary and genital tracts both arise from the primitive urogenital sinus and develop in close anatomical proximity. Sex hormones have a substantial influence on the female urinary tract throughout adult life, with fluctuations in their levels leading to macroscopic, histological, and functional changes. Urinary symptoms may therefore develop during the menstrual cycle, in pregnancy, and following menopause. This article explores the role of estrogen supplementation in lower urinary tract dysfunction. Estrogen deficiency, particularly when prolonged, is associated with a wide range of urogenital complaints, including frequency, nocturia (urinating at night), incontinence (involuntary loss of urine), urinary tract infections

6

Estrogen

(UTIs), and the 'urge syndrome.' Estrogen supplementation subjectively improves urinary stress incontinence, but there is no objective benefit when given alone; however, estrogen given in combination with phenylpropanolamine may be clinically more useful. Hormone replacement therapy (HRT) does appear to treat postmenopausal irritative urinary symptoms such as frequency and urgency, possibly by reversing urogenital atrophy, and there is also evidence to suggest that estrogens can provide prophylaxis against recurrent urinary tract infections. However, the 'best' type of estrogen, route of administration, and duration of therapy are at present unknown. 1 figure. 36 references. •

Exogenous Estrogen Exposures and Changes in Diabetic Retinopathy: The Wisconsin Epidemiologic Study of Diabetic Retinopathy Source: Diabetes Care. 22(12): 1984-1987. December 1999. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article describes a study that investigated whether the use of exogenous estrogen is associated with changes in the severity of diabetic retinopathy and the incidence of macular edema. The study population consisted of 10,135 people who had diabetes and received primary care in an 11-county area in southern Wisconsin from 1979 to 1980. This sample consisted of one group of women diagnosed with diabetes at less than 30 years old and used insulin and another group of women diagnosed with diabetes at 30 years old or older who had no criteria regarding therapy. Participants received standard examinations, medical interviews, and retinal photography from 1980 to 1982. Specific questions about exogenous hormone exposure were added to the study questionnaire at the first follow-up examination 4 years after the baseline examination. Change in the severity of retinopathy 6 and 10 years after the 4-year follow-up examination were examined regarding the use of oral contraceptives at the first followup examination in the younger-onset group and at 6 years after the first follow-up examination regarding hormone replacement therapy in the older-onset group. In the younger-onset group, the study found no significant associations among the use of oral contraceptives at the 4-year examination and progression of retinopathy, progression to proliferative retinopathy, or incidence of macular edema 10 years later. In addition, there was no evidence of a relationship between the use of oral contraceptives and subsequent incidence of hypertension during the same interval. For the older-onset group, the study found no association between the use of hormone replacement therapy and the retinal end points, nor an association with the development of hypertension 6 years after the 4 year followup retinopathy. Incidence of macular edema were unrelated to either type of estrogen exposure in univariable and multivariable analyses. The article concludes that the data are compatible with the hypothesis that the medications used by the study population do not affect the severity of diabetic retinopathy or macular edema. 5 tables. 29 references. (AA-M).

•

Serum Estrogen Levels, Cognitive Performance, and Risk of Cognitive Decline in Older Community Women Source: Journal of the American Geriatrics Society. 46(7): 816-821. July 1998. Summary: This article details a study that determined an association between serum estrogen levels, cognitive performance, and risk of cognitive decline in older women. Researchers designed a prospective cohort study with an average followup of 5 years to study women aged 65 and older who were controls in two ongoing studies of

Studies

7

osteoporotic fractures. Three cognitive tests were administered at study initiation and repeated 5 years later. Estrone and estradiol levels were determined by radioimmunoassay from baseline stored serum. Data showed that the characteristics of the women in the four serum estrogen quartiles did not differ, except that: weight after age 50 increased directly with higher quartile of serum estrogen, scores on cognitive function tests declined over the followup period; and the age-adjusted odds of cognitive decline did not vary across quartile of estrone or estradiol. The authors conclude that endogenous estrogens are not associated consistently with cognitive performance or risk of cognitive decline in older women. The worse performance on two cognitive tests among women with higher estrone levels was surprising and warrants further investigation. Discussed in Barrett-Connor, E. (Journal of the American Geriatrics Society. 46(7): 816-821. July 1998). 1 figure, 3 tables, 41 references. •

Postmenopausal Estrogen Replacement Therapy and the Risk of Alzheimer Disease Source: Archives of Neurology. 58(3): 435-440. March 2001. Summary: This article examines the effect of postmenopausal estrogen replacement therapy (ERT) on the risk of Alzheimer's disease (AD). Data were obtained from the United Kingdom's General Practice Research Database. The sample consisted of 112,481 women who had received at least one prescription for ERT (n=112,481) and 108,925 women who had never used ERT. All participants were born on or before January 1, 1950. A total of 59 newly diagnosed cases of AD and 221 matched controls were identified from the 2 cohorts. Fifteen of the newly diagnosed AD cases (25 percent) and 53 controls (24 percent) were current estrogen users. The adjusted odds ratio for all current estrogen users compared with nonusers was 1.18. The odds ratio for users who took estrogen for 5 years or longer compared with nonusers was 1.05. Odds ratios were similar for women who used estrogen alone and those who used combined estrogenprogestin treatment. In this study, the use of ERT by postmenopausal women was not associated with a reduced risk of developing AD. 4 tables, 28 references.

•

Hormone Replacement: More Than Just Estrogen Source: Diabetes Self-Management. 15(2): 58, 60-62. March-April 1998. Contact: Available from R.A. Rapaport Publishing, Inc. 150 West 22nd Street, New York, NY 10011. (800) 234-0923. Summary: This article focuses on the use of hormone replacement therapy following menopause to reduce the risk of heart disease in women, particularly women with diabetes. It describes the normal body changes that occur during menopause. Early signs of menopause include irregular periods, hot flashes, and night sweats. Menopause can also weaken the muscles and tissues of the vagina and the base of the bladder. The article identifies the potential benefits of hormone replacement therapy, including reducing the risk of heart disease and preventing osteoporosis. It highlights potential concerns about hormone replacement therapy, including impairing blood glucose control, affecting blood pressure, and increasing the risk of developing blood clots and breast and endometrial cancer. The article discusses the available choices for hormone replacement and stresses the need for women with diabetes to talk with a doctor about hormone replacement therapy. It also includes a list of organizations and books that provide information about menopause and the pros and cons of hormone replacement therapy.

8

•

Estrogen

Estrogen Replacement Therapy Source: Diabetes Self-Management. 9(3): 42-44. May-June 1992. Contact: Available from R.A. Rapaport Publishing Company. 150 West 22nd Street, New York, NY 10011. (800) 234-0923. Summary: This article provides facts about the benefits and risks of estrogen replacement therapy. The authors note that replenishing the body's store of estrogen and progesterone can effectively treat menopausal symptoms and may also decrease the risk of heart disease; however, there may be a link between estrogen therapy and certain forms of cancer. The article addresses typical changes during menopause, the long-term effects of menopause, estrogen replacement and diabetes, cancer concerns, and choosing a regimen (vaginal cream, skin patch, or oral pills).

•

Estrogen Replacement Therapy for Postmenopausal Women With Diabetes Source: Diabetes Spectrum. 10(3): 203-206. 1997. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article provides information about estrogen replacement therapy for postmenopausal women with diabetes. The author notes that studies in recent years have provided a wealth of information about the effects of estrogen replacement on disease prevention in predominantly healthy women. However, little information is available on the effects of estrogen replacement therapy on disease prevention among women with diabetes because they have been systematically excluded from the majority of early prospective trials. Topics with information specific to women with diabetes include estrogen effects on cardiovascular disease; lipid and lipoprotein abnormalities; effects of estrogen replacement on lipid, lipoprotein, and HbA1c concentrations; lipid oxidation; osteoporosis; estrogen replacement therapy in osteoporosis; and adverse effects, forms, and ongoing research of estrogen replacement therapy. The article notes that the impact of estrogen replacement therapy on the risk of developing breast cancer remains an area of intense debate. The author concludes that ongoing trials and the Women's Health Initiative will likely fill some of the important gaps in research knowledge pertaining to the long-term efficacy and safety of estrogen replacement therapy. 37 references. (AA-M).

•

Managing Menopause Without Estrogen Source: Diabetes Self-Management. 11(1): 38-42. January-February 1994. Contact: Available from R.A. Rapaport Publishing, Inc. 150 West 22nd Street, New York, NY 10011. (800) 234-0923. Summary: This article provides readers with an overview of hormone replacement therapy and a guide to nonhormonal therapy for managing menopause and preventing postmenopausal cardiovascular disease. The authors review the patients for whom nonhormonal therapy might be appropriate, cautioning that most of the nonhormonal treatment options have not yet been subjected to controlled scientific evaluations. The authors discuss symptoms and the recommended treatment options for each. Topics include hot flashes; sexual problems; urinary tract problems; and other menopausal symptoms, including irritability, mood swings, sleep disorders, and fluid retention. The article concludes with a discussion of cardiovascular disease and ways to minimize the potential for heart problems.

Studies

•

9

Prospective Study of Postmenopausal Estrogen Therapy and Subsequent Incidence of Non-Insulin-Dependent Diabetes Mellitus Source: Annals of Epidemiology. 2(5): 665-673. September 1992. Summary: This article reports on a study that examined the association between postmenopausal hormone use and the subsequent incidence of noninsulin-dependent diabetes mellitus (NIDDM) in a prospective cohort of 21,028 postmenopausal American women aged 30 to 55 years and free of diagnosed diabetes, cardiovascular disease, and cancer in 1976. During 12 years of follow-up (422,991 person-years), the researchers confirmed 1249 cases of NIDDM. Current users of postmenopausal hormones had a relative risk of NIDDM of 0.80 as compared with never users, after adjustment for age and body-mass index (BMI). Past users of these hormones had an age-and BMI-adjusted relative risk of 1.07. These results were not materially altered by multivariate adjustment for age, BMI, family history of diabetes, and coronary risk factors. The authors conclude that these prospective data indicate that postmenopausal hormone therapy is unlikely to be associated with a material increase in the incidence of NIDDM among women. 4 tables. 15 references. (AA-M).

•

Effect of Estrogen Use on Levels of Glucose and Insulin and the Risk of Type 2 Diabetes in American Indian Postmenopausal Women: The Strong Heart Study Source: Diabetes Care. 25(3): 500-504. March 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article reports on a study undertaken to examine the associations between estrogen use and levels of insulin and glucose, as well as the effect of estrogen use on the risk of type 2 diabetes. The report is based on 857 American Indian women who were both nondiabetic and postmenopausal at the baseline examination (1989 to 1992) and who completed a second examination (1993 to 1995) an average of 4 years later. The participants were divided into three groups: never, past, and current users based on their baseline estrogen use status. Postmenopausal estrogen use was associated with lower fasting glucose but higher 2 hour glucose levels compared with never users. Postmenopausal estrogen use was not significantly associated with the risk of type 2 diabetes compared with past and never users, based on the American Diabetes Association or World Health Organization definitions of diabetes. However, the risk of type 2 diabetes increased with increasing duration of estrogen use among current users. The authors conclude that these data suggest that estrogen use in American Indian postmenopausal women may relate to deterioration of glucose tolerance. Longer duration of estrogen use among current users may relate to an increased risk of type 2 diabetes. 3 tables. 26 references.

•

Effect of Estrogen Plus Progestin on Global Cognition Function in Postmenopausal Women. The Women's Health Initiative Memory Study: A Randomized Controlled Trial Source: JAMA. Journal of the American Medical Association. 289(20): 2663-2672. May 28, 2003. Summary: This article reports the effect of estrogen plus progestin on global cognitive function in postmenopausal women, using data from the Women's Health Initiative Memory Study (WHIMS). The WHIMS is a randomized, double-blind, placebocontrolled trial involving postmenopausal, community-dwelling women aged 65 years

10

Estrogen

or older. Of 4,894 eligible women who were free of probable dementia at baseline, 4,532 (92.6 percent) were enrolled in the estrogen plus progestin component of the trial. A total of 4,381 participants (96.7 percent) provided at least 1 valid cognitive function score between June 1995 and July 2002. Participants received one tablet daily containing either 0.625 mg of conjugated equine estrogen with 2.5 mg of medroxyprogesterone acetate (n=2,145) or placebo (2,236). Global cognitive function measured with the Modified Mini-Mental State Examination increased slightly over time in both groups. Women taking estrogen plus progestin had smaller average increases than those taking placebo, but the differences were not clinically important. However, more women in the estrogen plus progestin group had a clinically meaningful cognitive decline compared with the placebo group. Results do not support the use of estrogen plus progestin to protect cognition in older women. 4 figures, 4 tables, 58 references. •

Effects of Estrogen Treatment on Glutamate Uptake in Cultured Human Astrocytes Derived From Cortex of Alzheimer's Disease Patients Source: Journal of Neurochemistry. 80(5): 807-814. March 2002. Summary: This article reports the effects of estrogen treatment on glutamate uptake in cultured human astrocytes derived from the cortex of Alzheimer's disease (AD) patients. Estrogen is thought to protect against neurodegeneration through a variety of mechanisms including the activation of growth factors, control of synaptic plasticity, and reduction of response to various insults such as iron and glutamate. A growing body of evidence indicates an increased level of extracellular glutamate and a down regulation of glutamate transporters in AD. In the present study, glutamate uptake in astrocytes derived from AD patients was significantly lower than that from controls without dementia. Estrogen treatment increased glutamate uptake in a dose dependent pattern. Two glutamate transporters, GLT-1 and GLAST, were expressed in the astrocytes. Uptake regulation of the glutamate transporters was induced by estrogen treatment in AD astrocytes but not controls. These data suggest that the action of estrogen on glutamate uptake by astrocytes might contribute to its potential neuroprotective role in AD. 4 figures, 44 references. (AA-M).

•

Long-Term Estrogen Replacement Therapy in Female Patients With Dementia of the Alzheimer Type: 7 Case Reports Source: Dementia. 6(2): 99-107. March-April 1995. Summary: This article reports the results of a study of the efficacy of long-term, lowdose estrogen replacement therapy (ERT) among seven female patients with mild to moderate dementia related to Alzheimer's disease (DAT). Five of the patients had previously responded well to short-term ERT. The seven patients were 56 to 77 years of age. Therapeutic efficacy of estrogen was evaluated by psychometric assessments and a behavior rating scale. The psychometric assessments were performed once in 2-4 weeks. In four of the seven patients the psychometric assessment scores were elevated above pretreatment levels during ERT; termination of ERT resulted in a decrease in score. Geriatric rating scale scores and daily activities of the same four patients improved and cognitive functions were markedly improved throughout the treatment period. Two patients responded moderately well and another patient did not respond at all. The authors conclude that long-term, low-dose ERT improves cognitive function, dementia symptoms, and daily activities in women with mild to moderate DAT. However, the supplemental treatment with medroxyprogesterone acetate (a drug commonly used in ERT) seems to have an unfavorable effect on dementia symptoms and daily activities in these patients. 2 figures, 40 references.

Studies 11

•

Rethinking Estrogen and the Brain (editorial) Source: Journal of the American Geriatrics Society. 46(7): 918-920. July 1998. Summary: This editorial discusses the article by Yaffe, K., et al. (Journal of the American Geriatrics Society 46(7): 816-821. July 1998) that demonstrates that women with high endogenous estrone levels performed significantly worse on two of three cognitive function tests than women with lower levels of estrone. Estradiol levels were unrelated to change in test performance. The author concludes that this study of endogenous estrogen and change in cognitive function fails to support the hypothesis that estrogen preserves brain function. The author discusses how well the estrogen-memory data meet the standard epidemiologic criteria for causality, confounding factors, compliance bias, and misclassification bias, and concludes that enthusiasm for the neuroprotective effects of estrogen appear to have outrun the actual data. All observational studies have limitations, and clinical trials are small and few. The unexpected results highlight the need for some restraint until results are available from other clinical trials. 27 references.

•

Estrogen Makes the Brain a Sex Organ Source: Journal of Clinical Psychiatry. 58(10): 421-422. October 1997. Summary: This journal article briefly reviews recent advances in knowledge about understanding of the effects of estrogen on the brain. Estrogen is one of the agents currently under investigation for the prevention or treatment of Alzheimer's disease. It has well documented actions on several neurotransmitter systems, including serotonergic, adrenergic, and cholinergic pathways and receptors. However, findings from molecular neuroscience suggest that estrogen may not act like a traditional neurotransmitter. Its receptors are present in the cell nucleus of certain neurons, where they can directly influence the expression of genes in the central nervous system. In addition, estrogen can exert dramatic cyclical influences on synapses in certain neurons during the menstrual cycle, with early-cycle estrogen erecting synapses and late-cycle estrogen withdrawal dismantling them. 1 figure, 5 references.

•

Estrogen Replacement Therapy for Treatment of Mild to Moderate Alzheimer Disease: A Randomized Controlled Trial Source: JAMA. Journal of the American Medical Association. 283(8): 1007-1015. February 23, 2000. Summary: This journal article describes a multicenter, randomized, controlled trial of estrogen replacement therapy as a treatment for Alzheimer's disease (AD). The participants were 120 women with mild to moderate AD (Mini-Mental State Examination score between 12 and 28) who had had a hysterectomy. The women were randomly assigned to estrogen at 0.625 mg/d (n=42) or 1.25 mg/d (n=39), or to placebo (n=39) for 1 year; 97 women completed the trial. Participants were assessed at 2, 6, 12, and 15 months. The primary outcome measure was change on the Clinical Global Impression of Change (CGIC); other global scales and measures of mood, specific cognitive domains, motor function, and activities of daily living also were obtained. The CGIC at 12 months was similar for the two estrogen groups combined (5.1) and the placebo group (5.0). Eighty percent of those taking estrogen and 74 percent of those taking placebo worsened. Secondary outcome measures also showed no significant differences, with the exception of the Clinical Dementia Rating Scale, which suggested worsening among women taking estrogen. The study does not support a role for estrogen in the treatment of AD. The potential role of estrogen in the prevention of AD, however, requires further research. 3 figures, 3 tables, 49 references.

12

•

Estrogen

Estrogen Use and Early Onset Alzheimer's Disease: A Population- Based Study Source: Journal of Neurology, Neurosurgery and Psychiatry. 67: 779-781. 1999. Summary: This journal article describes a population-based study of the relationship between estrogen use and early onset Alzheimer's disease (AD). The sample consisted of women from two regions in the Netherlands who were diagnosed with early onset AD, and matched control subjects. The strength of the association between early onset AD and estrogen was studied using conditional logistic regression with adjustment for age and educational level. A significant inverse relationship was found between estrogen use and early onset AD (adjusted odds ratio of 0.34). When the analysis was limited to those without vascular pathology, the adjusted odds ratio was 0.16. The findings suggest that estrogen use may have a protective effect on early onset AD. The authors review several possible mechanisms for this effect. 2 tables, 23 references.

•

Longitudinal Effects of Estrogen Replacement Therapy on PET Cerebral Blood Flow and Cognition Source: Neurobiology of Aging. 21: 373-383. 2000. Summary: This journal article describes a study which used brain imaging technology to find evidence that the brains of post-menopausal women who receive estrogen replacement therapy (ERT) age differently and have significantly greater blood flow to areas involved in memory formation than the brains of women who do not receive hormone replacement. Participants were 28 cognitively healthy women, 12 were receiving ERT and 16 were not, all of whome were ages 55 or older. Positron emmission tomography scans were used to produce brain images as the participants rested and as they performed memory tasks for words and designs. These scans showed that over time, women taking ERT had increased blood flow in areas of the brain that form memory circuits and that show changes during the preclinical course of Alzheimer's disease. Researchers also found that overall, women using ERT scored higher on memory tests. Taken together, these findings suggest that ERT may protect against longitudinal changes in cognition.

•

Is There a Role for Estrogen Replacement Therapy in the Prevention and Treatment of Dementia? Source: Journal of the American Geriatrics Society. 44(7): 865-870. July 1996. Summary: This journal article describes how postmenopausal estrogen deficiency contributes to the neurodegenerative changes associated with aging and dementia. One part reviews evidence from animal studies concerning the effects of estrogen in the central nervous system (CNS) and the role of estrogen and neurotrophic factors as modulators of brain function. Another part reviews findings from studies concerning the effects of estrogen on cerebral blood flow and mental function, the role of estrogen deficiency in Alzheimer's disease (AD), and the role of estrogen in the treatment of dementia in humans. The evidence suggests that estrogen deficiency may contribute to the development of AD, although the neurodegenerative process probably precedes by many years the clinical presentation of the disease. However, the research has not established what factors contribute to the selective neuronal injury which, over time, eventually results in the cognitive impairment of AD. Estrogen's role in modifying this process also remains uncertain, although data from experimental animal models suggest that estrogen deficiency might selectively increase the vulnerability of estrogenresponsive neural elements and it may impair the brain's ability to adapt to the neuronal loss by stimulating axonal and synaptic regeneration. The limited epidemiologic data

Studies 13

and intervention trials, along with the data from animal studies, suggest that estrogen deficiency is not a cause of AD but perhaps one of several factors modifying the neuronal injury and loss leading to AD. 79 references. •

Effect of Estrogen on Brain Activation Patterns in Postmenopausal Women During Working Memory Tasks Source: JAMA. The Journal of the American Medical Association. 281(13): 1197-1202. April 7, 1999. Summary: This journal article describes the effects of estrogen on brain activation patterns in post-menopausal women during verbal and nonverbal working memory tasks. Forty-six postmenopausal women, aged 33 to 61 years, were enrolled in a randomized, double-blind, placebo-controlled trial. Women were randomly assigned to 21 days of treatment with conjugated equine estrogens (1.25 mg/d) or placebo, followed by a washout period of 14 days before crossover to the other treatment. Brain activation patterns were measured with functional magnetic resonance imaging during tasks involving verbal and nonverbal working memory. Treatment with estrogen increased activation in the inferior parietal lobule during storage of verbal material, whereas it decreased activation during storage of nonverbal material. Estrogen also produced a sharpening of the hemisphere encoding/retrieval asymmetry effect; it increased activation in the right superior frontal gyrus during retrieval tasks, with greater left hemisphere activation during encoding. Estrogen did not affect actual performance on the verbal and nonverbal memory tasks. The results suggest that it may be possible to affect functional brain organization in older women. 4 figures, 34 references. (AA-M).

•

Estrogen as a Psychotherapeutic Agent Source: Clinics in Geriatric Medicine. 14(1): 177-189. February 1998. Summary: This journal article discusses how hormone replacement therapy (HRT), specifically estrogen replacement therapy (ERT), may affect mood, behavior and cognition. Reproductive hormones are known to affect mood and the psychologic functioning of women after menopause. Research also suggests that ERT may help delay onset of and improve cognition in Alzheimer's disease (AD). The authors conclude that estrogen enhances mood and verbal memory in women; the estrogenic enhancement of mood may be dose-dependent; and estrogen as an antidepressant adjunct appears to facilitate the action of fluoxetine by modulating receptor activity, increasing the release of endogenous cathecolamines from the hypothalamus, and inhibiting monoamine oxidase activity. 64 references.

•

Estrogen Use, APOE, and Cognitive Decline Source: Neurology. 54: 1949-1953. May 2000. Summary: This journal article examines the effect of estrogen use on the association between apolipoprotein E4 (apoE4) and risk of cognitive decline. The sample consisted of 3,393 women age 65 years or older who were enrolled in a study on cardiovascular health. Cognitive testing was administered annually, and the 2,716 women who were tested on two or more visits were included in this analysis. Of these, 297 women were current estrogen users and 336 were former estrogen users. Over an average follow-up of 6 years, current users at baseline declined 1.5 points on the Modified Mini-Mental State Examination whereas never users declined 2.7 points. Women with one or more apoE4 alleles had greater cognitive decline than those without the allele. Estrogen use was associated with less cognitive decline in apoE4-negative women but not in apoE4-

14

Estrogen

positive women, but certain health risks with estrogen use such as carotid atherosclerosis were also noted by the researchers. 2 figures, 2 tables, 33 references. •

Endogenous Estrogen Levels and Alzheimer's Disease Among Postmenopausal Women Source: Neurology. 54: 833-837. February 2000. Summary: This journal article examines the relationship between endogenous estrogen levels and Alzheimer's disease (AD) among postmenopausal women. The study participants were an ethnically diverse sample of postmenopausal women, age 65 years or older, with or without AD, who were not currently taking estrogen replacement therapy. The patients with AD had lower estradiol levels than did the controls. AD patients also had lower levels of estrone, but the difference was not significant. The results suggest an association between endogenous estradiol levels and AD in postmenopausal women, but the directionality of the association could not be determined. 3 tables, 41 references.

•

Evaluating Estrogen for Alzheimer Disease Poses Ethical and Logistical Challenges Source: JAMA. Journal of the American Medical Association. 277(23): 1831-1833. June 18, 1997. Summary: This journal article explores the ethical questions raised by randomized, double-blind, placebo-controlled trials of estrogen for the prevention or treatment of Alzheimer's disease (AD). Two such national trials, the Women's Health Initiative and the Alzheimer's Disease Cooperative Study Unit, are currently underway. Both trials have had trouble recruiting participants and both raise questions about the ethics of giving postmenopausal women a placebo instead of a hormone that may prevent bone loss, heart disease, and AD. Many women are reluctant to volunteer for trials in which they may be given a placebo instead of estrogen. In addition, some ethicists argue that the evidence of estrogen's benefits is strong enough to raise serious ethical questions about giving postmenopausal women a placebo instead of the hormone. Others argue that randomized controlled trials are needed to provide the most reliable evidence of a drug's effects. One researcher has suggested that new research paradigms are needed for placebo-controlled trials of estrogen, especially for prevention trials that last many years and require large numbers of participants.

•

Use of Estrogen to Decrease Aggressive Physical Behavior in Elderly Men With Dementia Source: Journal of the American Geriatrics Society. 39(11): 1110-1112. November 1991. Summary: This journal article presents two case reports in which elderly men with dementia were successfully treated with estrogen to reduce their aggressive behavior. The first patient was treated for several medical conditions at a hospital and diagnosed with probable Alzheimer's disease. His physically aggressive behavior prevented successful placement in a nursing home, but a 2-week trial of estrogen resulted in calmer behavior. The second patient also had probable Alzheimer's disease as well as prostate cancer, and demonstrated aggressive behavior that was highly sexual in nature. Treatment with diethylstilbestrol resulted in a reduction both of physically aggressive behavior and growth of the patient's prostate cancer. Neither man suffered severe side effects. Only physically aggressive behavior was reduced; verbal aggression and physical and verbal repetitive behaviors were not controlled. The authors conclude that

Studies 15

this treatment may be valuable for a subset of elderly demented men who cannot be treated with more conventional methods. 33 references. •

Effect of Oestrogen During Menopause on Risk and Age at Onset of Alzheimer's Disease Source: Lancet. 348: 429-432. August 17, 1996. Summary: This journal article reports the effects of estrogen during menopause on the risk of Alzheimer's disease and age at onset. The study involved 1,124 older women who were initially free of Alzheimer's disease (AD), Parkinson's disease, or stroke; and who were taking part in a longitudinal study of aging and health in a New York City community. Overall, 156 (12.5 percent) of the women reported taking estrogen after the onset of menopause. The age at onset of AD was significantly later in women who had taken estrogen than in those who did not, and the relative risk of AD was significantly reduced (5.8 percent of estrogen users versus 16.3 percent of nonusers) even after adjustment for differences in education, ethnic origin, and apolipoprotein E gene status. Women who used estrogen for longer than 1 year had a greater reduction in risk. None of the women who were using estrogen at the start of the study has developed AD. The authors interpret these findings to suggest that estrogen use in postmenopausal women may delay the onset and decrease the risk of AD. 1 figure, 2 tables, 28 references.

•

Estrogen Boosts Resistance to Alzheimer's Source: Provider. p. 69-70. March 1997. Summary: This journal article reviews evidence that estrogen therapy may delay the onset of Alzheimer's disease (AD) and improve symptoms in older women. A 5-year study of older women at the Columbia-Presbyterian Medical Center, New York, found a lower incidence of AD and older age of onset among estrogen users compared1 with nonusers. In a study conducted by the Department of Veterans Affairs and the University of Washington, in Seattle, women with AD who received estrogen therapy showed improvements in memory function and attention span, which diminished after they stopped taking the drug. In one of the largest studies of the effects of estrogen, researchers at the University of Southern California School of Medicine in Los Angeles, found that higher doses and greater duration of estrogen use were associated with greater reductions of risk.

•

Estrogen Therapy in Postmenopausal Women: Effects on Cognitive Function and Dementia Source: JAMA. Journal of the American Medical Association. 279(9): 688-695. March 4, 1998. Summary: This journal article reviews research on the effects of estrogen replacement therapy on cognition and dementia in postmenopausal women. The authors performed a MEDLINE search of studies published from January 1966 through June 1997, reviewed bibliographies of identified articles, and consulted experts. Biochemical and neurophysiologic studies suggest several mechanisms by which estrogen may affect cognition, including promotion of cholinergic and serotonergic activity in specific brain regions, maintenance of neural circuitry, favorable lipoprotein alterations, and prevention of cerebral ischemia. Thirteen studies examined the effect of estrogen use on cognitive function in postmenopausal women without dementia. The findings suggest that estrogen improves cognitive performance in recently menopausal women, but there is no clear benefit in asymptomatic women. Meta-analysis of 10 studies of estrogen use

16

Estrogen

and dementia risk suggests a 29-percent decreased risk of developing dementia among estrogen users, but the study findings are heterogeneous. Four trials of estrogen use in women with Alzheimer's disease (AD) have been conducted and have had primarily positive results, but most were small, nonrandomized, uncontrolled, and of short duration. The authors conclude that large placebo-controlled trials are needed to determine estrogen's role in the prevention and treatment of AD and other dementias. 1 figure, 6 tables, 89 references. (AA-M). •

Role of Estrogen in the Treatment of Alzheimer's Disease Source: Neurology. 48(Supplement 7): S36-S41. May 1997. Summary: This journal article reviews the literature on the potential of estrogen in the treatment of Alzheimer's disease (AD). Estrogen affects neuronal function in those regions of the brain most sensitive to the neurodegenerative changes associated with AD. These effects, including increased regional blood flow, increased glucose transport, and reduction of the neurotoxic form of beta-amyloid, may slow the processes that contribute to neuronal injury. Estrogen also may facilitate neuronal repair by stimulating the expression of neurotrophins. These effects suggest that estrogen has the potential to influence the disease process associated with dementia of the Alzheimer's type. However, studies supporting its efficacy are limited in scope and experimental design; and the results of only two randomized, placebo-controlled trials have been published so far. Still, several consistent results have emerged. Some but not all AD patients demonstrate progressive improvement in cognitive function over the first 12 months of treatment, followed by a decline in cognitive performance, despite continued treatment, at a rate comparable to that in untreated patients. The author recommends that additional, appropriately designed trials are needed to demonstrate the efficacy of estrogen in the treatment of AD. 1 figure, 2 tables, 55 references.

•

Estrogen Replacement Therapy and Cognitive Decline in Older Community Women Source: JAGS. 47(5): 518-523. May 1999. Summary: This study evaluated the cross-sectional and longitudinal association of oral estrogen replacement therapy and cognitive function in a sample of older, nondemented women. A prospective cohort of 9,651 Caucasian women aged 65 years and older enrolled in the study and were evaluated twice by a modified Mini-Mental Status Exam (mMMSE), digit symbol substitution, and Trails B tests at 4 and 6 months. Researchers documented the history and current use of oral estrogen replacement therapy (ERT). Primary covariates of analysis consisted of age, educational attainment, and activity limitations; in addition, stroke and depression scores were adjusted in subsets of women with available data. Results show that current and past users of ERT had better initial scores on the mMMSE than never users, with better scores for current estrogen hormone users being most apparent among the older and less educated women. Educational attainment predicted both initial test scores and change scores and was, next to age, the most powerful predictor of cognitive function. Findings indicate oral ERT does not protect against age-related declines in cognitive function in older nondemented women, whereas formal education does protect, even if completed many years earlier. 5 tables, 15 references. (AA-M).

•

Estrogen Deficiency and Risk of Alzheimer's Disease in Women Source: American Journal of Epidemiology. 140(3): 256-261. 1994.

Studies 17

Summary: This study explored the possibility that a woman's estrogen loss, associated with menopause, may contribute to the development of Alzheimer's disease (AD). A case-control study nested within a prospective cohort study provided the relevant information. Researchers identified 138 female Leisure World (Silver Spring, MD) residents, who had died between 1981 and 1992, as having either AD or other dementia diagnoses likely to represent AD (senile dementia, dementia, or senility) mentioned on the death certificate. Four controls were matched individually by birth date and date of death to each case. Findings reveal the risk of AD and related dementia was less in estrogen users compared with nonusers. The risk decreased significantly with an increasing estrogen dosage and with increasing duration of estrogen use. Risk also was associated with variables related to endogenous estrogen levels; it increased with increasing age at menarche and decreased with increasing weight. This study suggests that the increased incidence of AD in older women may be due to estrogen deficiency and that estrogen replacement therapy may be useful for preventing or delaying the onset of this dementia. 2 tables, 33 references.

Federally Funded Research on Estrogen The U.S. Government supports a variety of research studies relating to estrogen. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to estrogen. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore estrogen. The following is typical of the type of information found when searching the CRISP database for estrogen: •

Project Title: ACTIONS OF ESTROGEN & ENVIRONMENTAL ESTROGENS ON NEURONS Principal Investigator & Institution: Belcher, Scott M.; Pharmacology & Cell Biophysics; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2005 Summary: (provided by applicant): The broad long-term goal of the proposed research is to understand the functions of 17beta-estradiol (estrogen; E2) and estrogen receptors (ERs) in the developing nervous system and to determine to what extent environmental estrogens influence these functions. E2 influences the development and function of many regions of the brain in both males and females. Thus, it is possible that other estrogenic compounds can impact development of the brain. Environmental estrogens, also known as "endocrine disrupters," are a diverse group of compounds that can mimic

2

Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

18

Estrogen

or antagonize the normal actions of E2. The extent to which environmental estrogens impact the developing nervous system is unclear. Proposed experiments employing primary cultures of neonatal rat cerebellar neurons and the developing cerebellum as models will address the following Specific Aims-Specific Aim 1: Determine whether E2 modulates cellular signaling in developing cerebellar neurons through rapid, nongenomic actions on MAPK signal transduction; Specific Aim 2: Determine the networks of estrogen responsive genes whose expression is modulated by E2 in cerebellar neurons; Specific Aim 3: Determine to what degree representative environmental estrogens mimic or inhibit the effects of E2 in developing cerebellar neurons. Specific Aims 1 & 2 test the hypothesis that E2 normally functions in developing neurons by rapidly modulating the activity of MAPK signaling, and also through genomic ERmediated mechanisms which together, modify expression of discrete networks of gene products. Specific Aim 3 will test the hypothesis that environmental estrogens influence developing neurons by modifying both MAPK signaling and genomic ER-mediated mechanisms, which results in altered networks of expressed genes. All three Specific Aims will be addressed through experiments using activation-state specific antisera to determine E2-mediated signaling pathways and by cDNA array and RT -PCR analysis of E2-responsive gene expression. From these results a neuronal "E2-signature cDNA array" will be developed and used in Aim 3 to determine how environmental estrogens influence E2-responsive gene expression in these developing neurons. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADENOCARINOMA OF THE LUNG IN WOMEN Principal Investigator & Institution: Schwartz, Ann G.; Associate Professor and Associate Dir.,; Internal Medicine; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 13-JUN-2001; Project End 31-MAY-2006 Summary: In 1998, 80,000 women in the US were diagnosed with lung cancer and incidence rates, particularly of adenocarcinoma, continue to increase among women. Many pieces of evidence suggest that there are gender differences in susceptibility to tobacco carcinogens. Several studies have shown that DNA adducts, p53 mutations, CYP1A1 expression in the lung, and GSTM1 null genotypes are more frequent in females than in males. Reasons for differential susceptibility by gender might be explained by variations in metabolic enzyme functioning or hormonal differences. Some of the same enzymes involved in the metabolism of carcinogens in tobacco smoke are involved in the metabolism of estrogen. The goals of the proposed study are two-fold. First, we will evaluate the role of tobacco smoke and estrogens in determining risk of adenocarcinoma of the lung among women. Secondly, we will evaluate the role of estrogen receptors and c-erbB-2 in lung tumors to further understand the pathways through which estrogen may be acting in the lung. The specific aims are: 1) To conduct a population-based case-control study of the contribution of tobacco exposure, estrogen use, and reproductive history in determining risk of adenocarcinoma of the lung in women. 716 cases will be identified through the Metropolitan Detroit Cancer Surveillance System of the Karmanos Cancer Institute (a SEER participant). An equal number of controls will be selected through random digit dialing. 2) To determine if genotype at the metabolic enzyme loci CYP1A1, CYP1B1, CYP17, CYP19, GSTM1, GSTP1, COMT, and NQO1 are associated with risk of adenocarcinoma of the lung in women. These enzymes are active in both the metabolism of tobacco smoke carcinogens and the synthesis and metabolism of estrogens. 3) To examine gene-gene and geneenvironment interactions, focusing on tobacco and estrogen effects. 4) To determine

Studies 19

estrogen receptor status (alpha and beta) and c-erbB-2 levels in the lung tumors of women with adenocarcinoma and evaluate risk associated with tobacco exposure, estrogen use, reproductive history, and genotype at metabolic enzyme loci by tumor characteristics. The proposed study represents a focused approach to defining the contribution of genes and environments in risk of adenocarcinoma of the lung in women. The interview component of the study will provide data about individually measured environmental risk factors. Genotypes have been chosen which impact on biologically effective dose of tobacco carcinogens and estrogens in the lung. The study of tumor characteristics will provide insight into mechanism of action. This large, population-based study should provide clues for important prevention and therapeutic strategies for lung cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALCOHOL AND HYPERPROLACTINEMIA Principal Investigator & Institution: Sarkar, Dipak K.; Professor Ii and Director; Animal Sciences; Rutgers the St Univ of Nj New Brunswick Asb Iii New Brunswick, Nj 08901 Timing: Fiscal Year 2003; Project Start 01-APR-1998; Project End 31-JAN-2008 Summary: (provided by applicant): There are several reports showing evidence for the existence of high levels of prolactin (PRL) in chronic alcoholic men and women. The study conducted by us during the past funded period provided data that suggest that chronic ethanol administration not only elevates plasma levels of PRL but also increases proliferation of pituitary lactotropes. We also found that ethanol affects the expression of estrogen-responsive hormones and polypeptides that promote growth and transformation of lactotropes. Hence, we hypothesized that, like estrogen, chronic ethanol might promote tumor development in lactotropes.The present proposal will address this issue by studying ethanol's in vivo and in vitro effects on lactotropic cell secretion, growth and transformation using the rat as an animal model. The proposed research will test the hypothesis that ethanol may cross-talk with estrogen receptors, an estrogen-responsive signaling cascade or estrogen-regulated cell-cell communication to control prolactin secretion and lactotropic cell proliferation. Specific proposal objectives are: (1) to evaluate the mechanisms of ethanol action on PRL gene transcription by determining the role of G protein-coupled D2 receptors and cAMP-PKA-CREB signaling, and the role of TGF-beta, estrogen receptors and p42/p44 MAP kinase; and (2) to determine the cellular action of ethanol on lactotrope proliferation by testing the role of estrogen receptors, G proteins, cAMP, PKA, PKC and MAPK in the ethanol actions. To study the mechanisms of ethanol action on lactotropes, we will pharmacologically and genetically manipulate the signal transduction systems, and measure the intracellular level of these signal transducers by histological, biochemical and molecular techniques.These studies have the potential to elucidate important cellular mechanisms underlying the ethanol effect on prolactinomas. Such knowledge will improve the understanding and management of hyperprolactinemia in alcoholic patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: LEUKOPLAKIA

ANIMAL

MODEL

OF

PROLIFERATIVE

VERRUCOUS

Principal Investigator & Institution: Murrah, Valerie A.; Diagnostic Scis/Gen Dentistry; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599

20

Estrogen

Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2004 Summary: (provided by applicant) Oral squamous cell carcinoma is a significant global health problem, comprising one of the ten most common cancers, worldwide. Over the past decade, there has been increased interest in viruses as etiologic agents for cancers of all types. Human papillomavirus (HPV) is the leading candidate for a role as a viral cofactor in oral cancer. In women, estrogen has been linked to multiple malignancies, including breast, cervical and uterine cancers, but, heretofore, estrogen has not been studied as a possible factor in oral cancer, despite the fact that well-recognized hyperplastic lesions of the oral cavity occur as a result of hormonal changes during pregnancy and puberty. We hypothesize that HPV and estrogen interact in the oral cavity to cause proliferative verrucous leukoplakia, an oral condition, seen predominantly in women, which is associated with a high prevalence of HPV infection and which ultimately eventuates in oral cancer. Interactions between HPV and estrogen in the pathogenesis of cervical cancer have been studied in a specific transgenic mouse model (K14-HPV16), in which a portion of the HPV16 genome is targeted to the progenitor compartment of the epithelium; by means of the keratin 14 promoter. Preliminary data on the oral cavity in this model strongly support its value for studies of the interactions between these two agents at this site as well. To that end, our specific aims are: 1) to determine whether estrogen can promote transformation of the oral epithelium to a premalignant or malignant phenotype in the K14-HPV16 transgenic mouse model, 2) to perform a prospective analysis of changes in biomarkers associated with proliferation and transformation in the oral epithelium of K14-HPV16 mice that have been exposed to estrogen in a longitudinal manner, and 3) to analyze changes in biomarkers in human specimens of proliferative verrucous leukoplakia to determine correlations with the mouse model. The proposed study is unique in that it addresses the question of estrogen and viral interaction as a possible etiology of oral cancer, an important issue which has not ever been investigated. We feel strongly that this knowledge will ultimately result in appropriate timing of specific interventional therapies and preventive strategies for proliferative verrucous leukoplakia and oral cancer in the future, and will address an oral health problem that is a significant women's health issue. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ASTROCYTE-NEURON INTERACTIONS AND GNRH NEURONAL FUNCTION Principal Investigator & Institution: Brann, Darrell W.; Associate Professor; Neurology; Medical College of Georgia 1120 15Th St Augusta, Ga 30912 Timing: Fiscal Year 2002; Project Start 01-APR-1997; Project End 31-MAR-2006 Summary: (Scanned from the applicant's description): Estrogen is well known to play a critical role in reproduction and to have important beneficial effects on the brain. The mechanism(s) underlying these important effects of estrogen are unknown and represent the focus of this grant application. Our major hypothesis is that astrocytes function to mediate, at least in part, the reproductive and beneficial effects of estrogen on the brain. Thus, we propose that astrocytes are capable of regulating the neurosecretion, neuronal connectivity and survival of GnRH and non-GnRH neurons and that these effects are primarily due to the ability of astrocytes to release transforming growth factor-beta (TGFbeta). Central to this proposed mechanism, is the hypothesis that 17beta-estradiol exerts regulatory control over astrocytes to stimulate release of TGFbeta. This putative 17beta-estradiol-astrocyte-TGF-beta signaling pathway could have important implications not only to reproduction, but could also provide a

Studies 21

conceptual framework to explain how estrogen may be beneficial in certain clinical situations such as stroke and Alzheimer's disease. Aim 1 would establish whether TGFbeta mediates the GnRH-releasing, neurite outgrowth and neuroprotective actions of hypothalamic astrocytes. This aim would characterize the different TGF-beta isoforms released by hypothalamic astrocytes, the degree of correlation between their levels and the functional effects of hypothalamic astrocyte-conditioned media (HA-CM), and perform causative studies to prove a role for TGFbeta. Aim 2 would characterize the recently discovered 17beta-estradiol-astrocyte-TGFbeta signaling pathway in the hypothalamus and establish the underlying mechanisms and functional implications of the pathway. This aim would determine the specific TGFbeta isoforms regulated by 17beta-estradiol, the functional importance of such regulation, whether it is ERalpha or ERbeta that mediates the 17beta-estradiol effects, and the applicability of the novel pathway to other clinically important estrogen target tissues, such as cortex and hippocampus, as well as to the human. Aim 3 will establish whether steroid hormones upregulate TGFbeta type I, II and/or III receptors in GnRH neurons during the time of the LH surge. Preliminary results showed a dramatic up-regulation of the TGFbeta type II receptor in the hypothalamus at the time of the LH surge induced by estrogen plus progesterone. This aim would confirm these preliminary observations and extend them by determining whether the up-regulation occurs in GnRH neurons, whether it is 17beta-estradiol or progesterone which is responsible for the effect, and determine if the steroid regulation extends to the type I and type III TGFbeta receptors as well. Aim 4 will establish the cell signaling mechanism utilized by HA-CM and TGFbeta to promote neurite outgrowth and exert neuroprotection on GnRH neurons. This study would examine the Ras-Raf-ERK pathway, with the hypothesis that this signaling pathway activates downstream mediators such as the neurite-outgrowth promoting factor, growth associated protein-43 (GAP-43), and the anti-apoptotic proteins bcl-2 and bcl-xl in order to promote neurite-outgrowth and survival of GnRH and non-GnRH neurons. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOLOGICAL MARKERS OF BREAST CANCER & TAMOXIFEN RESPONSE Principal Investigator & Institution: Weber, Barbara L.; Professor; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-JUL-2005 Summary: The overall goal of this Program Project is to increase our understanding of the contribution of estrogen to the development of breast cancer. We will address the use of breast cancer risk determinants in both African American and Caucasian women using a genetic, as well as a biochemical approach. We will address the issue of breast cancer risk determinants in both African American and Caucasian women using a genetic, as well as a biochemical approach. We also will evaluate the clinical utility of modifying breast epithelial exposure to estrogen by assessing the response of women at increased risk to the Selective Estrogen Receptor Modifier (SERM) Tamoxifen in two inter-related clinical trials. Thus the overall goals of the project are: 1) To develop a genetic model of breast cancer risk by analyzing a panel of proposed breast cancer susceptibility alleles related to hormone metabolism and response to DNA damage in African American and Caucasian women with breast cancer and a matched set of controls; 2) To develop a biochemical model of breast cancer risk by analyzing interindividual variability in estrogen metabolism in African American and Caucasian women with breast cancer and a matched set of controls, all of whom have been genotyped for the susceptibility alleles related to hormone metabolism; 3) To develop a

22

Estrogen

pharmacogenetic model of breast cancer risk by combining genotypic data on the proposed breast cancer susceptibility alleles with the biochemical risk profile developed by studying estrogen metabolism in cases vs. controls; 4) To evaluate the response of MRI-defined alteration in breast volume as endpoints; 5) To identify biologic markers of response to Tamoxifen using markers of oxidative damage in peripheral blood and immunohistochemical evaluation of regions of increased density seen with MRI. At the conclusion of this study, we will have developed a comprehensive model for breast cancer risk based on a range of measures of estrogen effect that is applicable to both African Americans and Caucasians and we will have tested the ability of Tamoxifen to alter surrogate measures of risk. In addition, we will have evaluated the ability of Tamoxifen to alter surrogate measures of risk. In addition, we will have evaluated the potential of MRI-detected breast changes as surrogate endpoints and accumulated data on a range of histopathologic lesions that may be used as surrogate endpoints as well. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOTRANSFORMATION OF ESTROGENS TO CARCINOGENIC QUINOIDS Principal Investigator & Institution: Bolton, Judy L.; Professor; Medicinal Chem & Pharmacognosy; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2002; Project Start 01-APR-1997; Project End 31-MAR-2006 Summary: There is a clear association between excessive exposure to estrogens and the development of cancer in several tissues including breast and endometrium. The risk factors for women developing these cancers are all associated with longer estrogen exposure; early menses, late menopause, and long term estrogen replacement therapy. The mechanism(s) of estrogen carcinogenesis is not known. The central hypothesis is that the formation of quinoids is an important mechanism of estrogen carcinogenesis. oQuinones are known metabolites of estrogens. These redox-active compounds have been shown to cause oxidative damage to cellular DNA. Furthermore, these o-quinones can alkylate DNA that may lead to genotoxicity. Our data also suggests that DNA damage may be potentiated by the presence of an estrogen receptor (ER). The specific aims are: 1. What is the predominant mechanism of catechol estrogen-induced DNA damage? Oxidation versus alkylation. Using synthetic oligonucleotides with defined sequences, we will explore the effect of time, concentration, sequence, and redox status on formation of each DNA lesion. Of special interest is the role of the estrogen responsive element since our hypothesis predicts that extensive damage should occur at estrogen sensitive genes. 2. Correlation between DNA damage and estrogen receptor status in cell lines. We will further investigate the role of ERa and/or ERb in mediating catechol estrogen-induced DNA damage and toxicity. The cell lines to be examined include tumorigenic and nontransformed human breast cell lines with no estrogen receptor or ERa or ERb. The comet assay will be employed to examine DNA single strand cleavage and oxidation and alkylation of DNA bases will be studied using LCMS-MS. 3. Evaluation of the binding affinity of catechol estrogens for ERa and ERb and the functional consequences of ER activation. We propose to evaluate the estrogenic potency of catechol estrogens and correlate these effects with the extent of DNA damage observed in Aims 1 and 2. The relative binding affinity of these compounds to ERa and ERb proteins will be measured using a competitive binding assay. These results will be compared to studies evaluating the ability of the catechol estrogens to transcriptionally activated ER WERE luciferase and ERb /ERE luciferase assays. Finally, we will study the modulation of certain estrogen responsive genes by catechol estrogens in the cell

Studies 23

lines described in Aim 2. 4. Role of quinoids in the carcinogenic effects of estrogens. We plan to further explore the relative ability of the catechol estrogens to induce cellular transformation in the non-transformed human breast epithelial cell lines discussed above. The transformed colonies will be implanted into athymic nude mice to establish their ability to induce tumor formation. Finally, to determine whether the parent estrogens are carcinogenic in vivo, ACT rats will be treated with estrogens and the mammary tissue will be analyzed for tumor formation. These data will determine the role of quinoids in the carcinogenic effects of estrogens and provide a basis for the development of estrogen replacement drugs devoid of carcinogenic activity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CELL GROWTH INHIBITION AND ESTROGEN ACTION Principal Investigator & Institution: Markaverich, Barry M.; Associate Professor; Molecular and Cellular Biology; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-AUG-1983; Project End 31-JUL-2002 Summary: The long-term objective of the proposed research is to define the mechanism by which methyl p-hydrophenylactate (MeHPLA) controls mammalian cell proliferation. Our laboratory identified MeHPLA as an endogenous ligand for nuclear type II [3H] estradiol binding sites and this bioflavonoid or tyrosine metabolite appears to inhibit cell proliferation through this binding interaction. Type II sites appear closely coupled to DNA replication and cellular proliferation, however, the precise function of this nuclear matrix protein in normal and abnormal cells is unknown. The goal of this project is to define the function of MeHPLA and type II sites in normal and malignant cells and to study type II gene structure and expression as it relates to hormonal (MeHPLA, estrogen, anti-estrogen) modulation of cellular proliferation. To accomplish these goals we have solubilized type II sites from rat uterine nuclear matrix and have purified the [3H] estradiol binding activity to near homogeneity to near homogeneity by dye ligand affinity chromatography (Affigel Blue) and HPLC. SDS-PAGE analysis of this highly purified material revealed a single 37 kDa protein which co-puries with the type II site [3H] estradiol binding activity. Affinity labeling studies indicate [3H] estradiol to the 37 kDa protein is blocked by the bioflavonoid luteolin and this protein is induced in the uterus by estrogen. Based upon our initial sequencing studies which have identified 10 amino acids of internal sequence, it appears that the 37 kDA protein may be unique. A major goal of this revised application is to obtain more exclusive amino acid sequence analysis of the 37 kDa protein to be used for the generation of oligonucleotide and anti- peptide antibody probes to the type II site (Specific Aim 1). These oligonucleotide probes and antibodies will be used to screen a cDNA library prepared from estrogen-treated rat uterine tissue to identify type II site cDNA sequences and characterizes the gene(s) (Specific Aim 2). The cDNA and antibody probes will also be utilized to study estrogen, MeHPLA, and anti-estrogen (tamoxifen, ICI-164, 384 ICI182,780) modulation of type II gene expression and subsequent effects on cell proliferation in the rat uterus and in MCF-7 (ER+) and MDA-468 ( ER-) human breast cancer cells in vitro (Specific Aim 3). The availability of these molecular probes will facilitate future structure/function analyses which will define ligand binding and/or other functional domains of this nuclear regulatory protein(s). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

24

•

Estrogen

Project Title: CORONARY ARTERY REGULATION BY CA2+SIGNALING & ESTROGEN Principal Investigator & Institution: Nelson, Mark T.; Professor and Chair; Pharmacology; University of Vermont & St Agric College 340 Waterman Building Burlington, Vt 05405 Timing: Fiscal Year 2002; Project Start 15-SEP-2000; Project End 31-JUL-2004 Summary: (Verbatim from the application): The cardioprotective effect of estrogen is complex, and incompletely understood. We have identified one potentially important action of physiological circulating estrogen on coronary arteries, which involved an elevation of basal nitric oxide release from the endothelium and an ensuing smooth muscle relaxation through activation of one type of calcium-sensitive (large conductance; BK) potassium channel in the smooth muscle. Our results indicate that estrogen causes fundamental alterations in Ca2+ signaling in the coronary endothelium, which leads to an elevation of nitric oxide production, which in turns alters Ca2+ signaling in the smooth muscle. This proposal focuses on novel, interlinked Ca2+ signaling mechanisms to explain the effects of estrogen and nitric oxide on coronary artery diameter. Specifically, Aim 1 will determine the mechanisms by which estrogen leads to an elevation of endothelial [Ca2+]i; Specific Aim 2 will explore positive feedback regulation of endothelial Ca2+ by local and global Ca2+ signaling from ryanodine receptors (RyRs) in the endoplasmic reticulum to small conductance calciumsensitive (SK) and BK channels; Specific Aim 3 will determine the negative feedback mechanisms by which endogenously produced nitric oxide activates RyRs and BK channels in coronary artery smooth muscle, with a focus on the key roles of phospholamban, which regulates SR Ca2+-ATPase activity, and on the beta-subunit of the BK channel. To address these issues, we have developed techniques to measure global and local calcium in the endothelium and smooth muscle of intact pressurized coronary arteries, including coronary arteries from phospholamban and beta-subunit gene-ablated mice, and developed novel, selective peptide inhibitors of cGMPdependent protein kinase. The proposed study should significantly deepen our understanding of the regulation of Ca2+ signaling in coronary arteries, and the important influences of physiological estrogen and nitric oxide on coronary artery function. This work should also suggest novel mechanisms for therapeutic interventions to mimic the beneficial effects of estrogen and nitric oxide on calcium signaling in coronary arteries. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: CORTISOL AND PLACENTAL ESTROGEN IN PROSTANOID SYNTHESIS Principal Investigator & Institution: Wu, Wen X.; Obstetrics and Gynecology; University of Oklahoma Hlth Sciences Ctr Health Sciences Center Oklahoma City, Ok 73126 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2006 Summary: (Scanned from the applicant's description): Fetal glucocorticoid (GC) induces premature labor in pregnant sheep in studies conducted in several laboratories throughout the world. However, pathways by which fetal cortisol triggers the subsequent interactive evolution of maternal and fetal endocrine changes are not clear. In particular, mechanisms that enhance uterine prostaglandin (PG) synthesis and output, and result in increased uterine activity and birth remain to be determined. While it has long been accepted that cortisol influences progesterone to estrogen conversion with resultant changes in uterine PG production (indirect pathway), we hypothesize

Studies 25

that cortisol also acts by an important additional pathway stimulating PG production directly (direct pathway). We propose studies to examine both the direction and indirect pathways of GC regulation of key enzymes of PG synthesis- PGH synthase (PGHS) and the critical post PGHS enzymes that determine the exact mix of POE2 and PGF2F2a produced. HYPOTHESIS: cortisol, both 1) directly and 2) indirectly (through estrogen) regulates activity of four key enzymes in PG synthesis: PGHS, POE2, isomerase (POES), PGF2a synthase (PGFS), and PG 9-keto reductase (PG9KR) in ovine fetal and maternal placenta, endometrium, myometrium, and cervix in a tissue- and regional- specific manner to initiate and maintain the several critical processes involved in labor. Nothing is known of regulation of PGES, PGFS or PG9KR. SPECIFIC AIMS: our two specific aims relate to the two component parts of our central hypothesis: We will use chronically instrumented adrenalectomized fetal sheep to evaluate the respective roles of cortisol acting (i) directly and (ii) indirectly through estrogen, in regulation of activity of PGHS, PGES, PGFS, and PG9KR in ovine fetal and maternal placenta, endometrium, myometrium and cervix in a tissue- and regional- specific manner. The chronically instrumented pregnant sheep and fetus have been studied extensively as a major model of parturition. To maximize information obtained, we have developed systems to interrogate the model at both the in vivo and in vitro levels. Our approach is to investigate time-related and tissue-specific events in pregnant animals undergoing specific experimental perturbations to determine critical steps in the direct and indirect pathways. For example, use of the estrogen receptor antagonist ICI 182780 addresses estrogen's role via the indirect pathway. The pathways whereby PG production is altered by cortisol and by estrogen are likely to operate in both sheep and primates. There is considerable evidence for both increased fetal adrenal function and increased estrogen in late gestation in primates including pregnant women. Simultaneous study of both pathways provides information critical to understanding of parturition across species. Premature labor is the major cause of perinatal mortality and morbidity. Better understanding of the mechanisms of term and preterm labor will provide evidence based, rational diagnosis and management. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DETERMINANTS OF TISSUE ESTRADIOL SENSITIVITY Principal Investigator & Institution: Santen, Richard J.; Professor of Medicine; Internal Medicine; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2002; Project Start 07-AUG-1994; Project End 31-JUL-2004 Summary: (Adapted from the applicant's abstract): The mechanisms allowing women with estrogen dependent breast cancer to respond to secondary hormonal therapies are incompletely understood. As a potential explanation, the applicant postulated that breast cancer cells adapt to estrogen deprivation by developing hypersensitivity and developed a model system demonstrating this phenomenon. Based on the results, the applicant suggested that hypersensitivity is not mediated primarily at the level of estrogen receptor transcription but rather involves up-regulation of growth factor signaling pathways. His working hypothesis is that growth factor and estrogen mediated events interact synergistically at the level of the cell cycle to mediate hypersensitivity. The proposed studies will further examine growth factor pathway upregulation and determine the specific mediators responsible. Based upon recent preliminary data, the applicant will also examine hypersensitivity and apoptosis. In his model, long term estrogen deprivation sensitizes cells to a paradoxic, stimulatory effect of estradiol on apoptosis. Accordingly, he plans to systematically examine this phenomenon and has envisioned a novel breast cancer treatment based upon his

26

Estrogen

findings. The strategy rests upon the concept that cell proliferation and apoptosis are intrinsically linked and regulated by survival factors. Certain proteins such as c-Myc, activated Ras, MAP kinase, and E2F1 and that a PI-3-kinase inhibitor can induce apoptosis. The integration of these concepts provides a rationale to "Kill" tumor cells with estrogen as part of a combined treatment strategy for breast cancer. This utilizes alternate cycles of therapy first to block cell proliferation with anti-estrogens and growth factor inhibitors and then to stimulate apoptosis with estradiol and PI-3-kinase inhibitors. Specific Aim 1 will demonstrate which growth factor mediated pathways are up regulated during adaptation to long term estradiol deprivation. Specific Aim 2 will delineate the separate mechanistic roles of c-Myc and the MAP kinase pathway on cell proliferation and on cell death. Specific Aim 3 will optimize the conditions for enhancing apoptosis and inhibiting cell proliferation in vitro. Specific aim 4 will demonstrate in an in vivo model that the strategy of alternate blockade of proliferation followed by stimulation of apoptosis results in greater tumor regression than with each intervention alone. The applicant expects these studies to be the basis for future clinical trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIET AND ESTROGEN RECEPTORS IN NORMAL MAMMARY TISSUE Principal Investigator & Institution: Trichopoulos, Dimitrios V.; Epidemiology; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2004 Summary: APPLICANT'S The major causes of a disease should be able to explain its dominant epidemiological patterns. Yet, with respect to breast cancer, there appears to be a major paradox. The role of endogenous estrogens in the etiology of breast cancer in women is well defined. However, differences between Caucasian and Asian women, with respect to estrogen production and blood levels, are not sufficiently large to explain the 5-fold difference in breast cancer incidence between these groups. Given the obligate role of estrogen receptors in estrogen response expression of these receptors in normal breast tissue could be a major determinant of breast cancer risk and an important explanatory factor of the marked variability in breast cancer incidence worldwide. A number of studies have indicated that breast cancer risk may be elevated when estrogen receptor expression is high, but exogenous determinants of estrogen receptor expression have not been identified. Diet in adult life does not appear to be a powerful determinant of breast cancer risk; however, consumption of vegetables, fruits, and olive oil are inversely associated with risk, whereas alcohol intake and perhaps saturated fat of animal origin may increase risk. Because food groups and nutrients may affect breast cancer risk, and expression of estrogen receptor-a (ER-a) in normal mammary tissue may modify this risk, we wish to investigate whether diet may affect the expression of ER-a in normal mammary epithelium. Specifically, we wish to investigate whether 1-) a diet high in fruits and vegetables or high in olive oil intake reduces ER-a expression in the mammary tissue, and 2-) whether a diet high in animal fat, in n-6 polyunsaturated fats, or alcohol consumption increases ER-a expression in mammary tissue. In the breast clinic of a major university hospital in Athens, Greece, some 4,000 women undergo annual mammography screening. Every year, more than 300 non-malignant breast biopsies are taken from these women. Thus, over a period of 18 months we estimate that biopsies from 440 women without breast cancer will be available. These women will be interviewed in person for demographic, socioeconomic, reproductive and biomedical variables, and they will complete a validated extensive

Studies 27

food frequency questionnaire. The percent of ER-a positive cells (ER-oc+ percent) will be determined through immunohistochemistry and through semi-quantitative PCR. All statistical analyses will conducted using linear models to determine the distribution of ER-a percent, by diet and other covariates. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIETARY METABOLITES

SOY/ISOFLAVONES AND

URINARY

ESTROGEN

Principal Investigator & Institution: Tseng, Marilyn M.; Fox Chase Cancer Center Philadelphia, Pa 19111 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2004 Summary: (provided by applicant): Research on potential cancer-protective effects of soy and isoflavones has led to an increase in the availability and consumption of soy products in the US. Yet conflicting scientific evidence raises the concern that high levels of intake might actually increase breast cancer risk. Whether current levels of soy and soy isoflavone intake are sufficiently high to affect breast cancer risk is unknown largely because of a lack of convenient, current, and validated methods of assessing intake. The objectives of the proposed study are to (1) evaluate the validity of overnight urine samples as a method of assessing soy isoflavone intake, and (2) examine associations between soy/isoflavone intake and urinary estrogen metabolites. Participants will be drawn from a program at Fox Chase Cancer Center for women at high breast or ovarian cancer risk. The study will include 50 women with either very high or low soy intake based on questionnaire data. Participants will complete a soyfood questionnaire and provide four 24-hour urine specimens over a one month period, with overnight samples collected in separate containers. Urines will be analyzed for isoflavones, primarily daidzein and genistein, and for estrogen metabolites including 2-, 4-, and 16alphahydroxy estrogens. Isoflavone levels in overnight urine samples will be evaluated for validity by examining their correlations with isoflavone levels in 24-hour urine specimens. We will use multiple linear regression to examine associations of soy/isoflavone intake with urinary estrogen metabolites. The proposed research will provide useful information towards assessment of soy/isoflavone intake in a non-Asian sample. It is also an opportunity to add to limited knowledge on soy/isoflavone intake and its association with urinary estrogen metabolites as markers of breast cancer risk. Findings from this research will contribute information towards a soy supplementation trial to evaluate modification of soy/isoflavone intake as a means of reducing risk of breast cancer, a disease for which few preventive measures are available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DNA SEQUENCES IMPACT ESTROGEN AND ANTIESTROGEN ACTIVITY Principal Investigator & Institution: Klinge, Carolyn M.; Associate Professor; Biochem and Molecular Biology; University of Louisville University of Louisville Louisville, Ky 40292 Timing: Fiscal Year 2002; Project Start 01-APR-1998; Project End 31-MAR-2003 Summary: Type I antiestrogens, e.g. tamoxifen (TAM), are used to prevent recurrence of estrogen-dependent disease in women with breast cancer and have beneficial agonist effects in other estrogen target tissues. TAM, and its metabolite 4-hydroxyTAM(4-OHT), compete with estradiol (E2) for binding to estrogen receptor (ER), activating the ER and enhancing its binding to specific DNA sites, estrogen response elements (ERE). The

28

Estrogen

precise molecular mechanisms allowing ERE-containing genes to be selectively responsive to estrogens versus ligands for other nuclear receptors and bind EREs, e.g., COUP-TF and retinoic acid receptors, are not well understood. Preliminary evidence suggests that the nature of the ERE sequence acts as an allosteric effector, altering ER conformation and thus modulating liganded-ER interaction with coactivators and components of the transcription initiation complex to regulate gene expression. The proposed studies will test the following hypotheses: 1) ERE sequence and that of its immediate adjacent sequences impact ER binding and conformation and impact ligand binding. I propose that ligand binding stability is important for maintaining ER in a conformation necessary for transactivation of target gene expression. Results will correlate DNA sequence, ligand binding stability, and alterations in ER sensitivity to trypsin digestion with transcriptional activation in transiently transfected cells. 2) The distance between ERE half-sites and the nature of immediately adjacent flanking sequences regulate ER versus type II nuclear or orphan receptor binding. Preliminary studies show ER binds more avidly to ERE half-sites located on opposite faces of the DNA helix. Results will provide detailed analysis of how ERE half-site spacing contributes to estrogen and antiestrogen action. 3) ER synergizes with Sp1 to regulate the transcription of two natural estrogen target genes: creatinine kinase B and lactoferrin by direct interactions that increase ER-ERE binding affinity and stability. Results will reveal the basis for how ER ligand and the sequence of the ERE and its surrounding nucleotides, impact ER conformation, ERE binding affinity, ER interaction with Sp1, and ligand- dependent induction of gene expression in vivo. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECT OF RALOXIFENE ON NEURONAL PHYSIOLOGY Principal Investigator & Institution: Audesirk, Teresa E.; Biology; University of Colorado at Denver P.O. Box 173364 Denver, Co 802173364 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: (provided by applicant): Selective estrogen receptor modulators (SERMs) are synthetic compounds that bind to genomic estrogen receptors (ER), mimicking estrogen in some tissues, and antagonizing it in others. The SERM raloxifene antagonizes estrogen in both the breast and uterus, conferring a degree of protection against breast and uterine cancers, while it serves as an estrogen agonist in lipid and bone metabolism, providing some protection against both osteoporosis and heart disease. In 1997, the U.S. FDA approved the use of raloxifene for the prevention of osteoporosis. As a result, raloxifene will soon be used by millions of postmenopausal women. There is a large and rapidly growing literature concerning the effects of b-estradiol on the brain, both on brain function generally (maintenance of cognitive abilities and protection against Alzheimer's disease) and on individual neurons (promotion of neurite outgrowth and dendritic spine production, nitric oxide synthase activation, and neuroprotection). A major gap in the current understanding of raloxifene is how it influences the brain. We will use cultured rat hippocampal and cortical neurons to accomplish the following aims: 1. To test the hypothesis that raloxifene will either mimic or antagonize the neuroprotective effects of b-estradiol against oxidative stress in vitro. 2. To test the hypothesis that raloxifene will mimic or antagonize the effects of b-estradiol on calcium levels in neurons. 3. To test the hypothesis that raloxifene will either reduce or enhance calmodulin activation. The SERM tamoxifen reduces calmodulin activity, suggesting that raloxifene should also be tested for this property. 4. To test the hypothesis that raloxifene will mimic or antagonize the effects of b-estradiol on nitric oxide synthase. The production of NO, which has been implicated in several aspects of neuronal

Studies 29

differentiation and learning, is enhanced by b-estradiol. This enhancement is blocked by the SERM tamoxifen. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECT OF SOYBEANS ON BONE AND THE REPRODUCTIVE TRACT Principal Investigator & Institution: Bahr, Janice M.; Professor; Animal Sciences; University of Illinois Urbana-Champaign Henry Administration Bldg Champaign, Il 61820 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-JUL-2004 Summary: (adapted from the applicant's abstract) Some postmenopausal women use hormone replacement therapy (HRT) to maintain bone. This treatment is, however, not acceptable to all women. An alternative approach is intake of foods rich in phytoestrogens - natural plant estrogens such as soybeans. The hypothesis is that soy protein protects against postmenopausal bone loss by slowing resorption and enhancing bone formation due to organ-selective estrogenic effects of the isoflavones genistein and daidzein. The applicant proposes four questions: 1. Efficacy: What is the effect of soy protein and soy isoflavones on bone formation and resorption? 2. Safety: Do soy isoflavones and estrogen have differential effects on bone and female reproductive tissues? 3. Safety: Do soy proteins or isoflavones antagonize the effects of endogenous estrogen on bone and the reproductive tract? 4. Mechanism: Do soy isoflavones differentially affect estrogen-dependent bone resorption and formation through estrogen receptor-mediated mechanisms? In vivo studies will use ovariectomized rats, an established model for osteoporosis, and intact rats. In vitro studies will use mouse calvarial explant culture and an estrogen receptor reporter system. To answer questions 1-3 ovariectomized and inteact rats will be fed diets of various concentrations of soy or isoflavones for 3 months. Measurements during and at termination of experiments are urinary deoxypyridine, an indicator of bone breakdown; bone mineral density; and bone formation by histomorphometry. The reproductive tract will be evaluated by histology and production of Complement C3 by the uterus and measurement of estradiol and luteinizing hormone in plasma. In vitro studies (question 4) will determine if isoflavones act through an ER and which subtypes, ERa or ERb. These studies are necessary to identify efficacious and safe alternative approaches to HRT readily accessible to all women. Knowledge of active agents and mechanism of action will allow standardization of soy supplements; identification of doses that maintain bone health without compromising other systems, e.g. reproductive; and assurance against interactions from like compounds in other drugs and food, including supplements. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: ENDOGENOUS/EXOGENOUS SEX HORMONES & CHD RISK FACTORS Principal Investigator & Institution: Barrett-Connor, Elizabeth L.; Professor and Chair; Family and Preventive Medicine; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 920930934 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: (provided by applicant): Coronary heart disease (CHD) is the most common cause of death in U.S. women. Observational studies consistently show that postmenopausal estrogen, with or without a progestin, reduces the risk of CHD, and there are several plausible mechanisms by which estrogen might protect the heart.

30

Estrogen

Nevertheless, clinical trials to date have not demonstrated cardioprotection. If hormone levels play a role in determining CHD risk in postmenopausal women and HRT is to be used as a means of reducing that risk, the interactions of endogenous hormones, HRT, and CHD risk factors need further definition, in particular the effect of covariates. Individual characteristics such as basal hormone levels, body size, past hormone use, and lifestyle decisions may modify responses to HRT. This proposal focuses on four questions: 1) what factors determine circulating sex hormone levels in postmenopausal women, 2) what factors determine changes in sex hormone levels in response to hormone replacement therapy (HRT), 3) do endogenous sex hormone levels influence CHD risk factors in postmenopausal women, and 4) do changes in sex hormone levels with HRT predict the effect of HRT on CHD risk factors. These questions will be addressed by analyzing existing data from the Postmenopausal Estrogen / Progestin Interventions Trial (PEPI), a 3-year, multi-center, double-blind, placebo-controlled trial designed to compare the effect of estrogen alone and 3 estrogen/progestin HRT regimens vs placebo on selected CHD risk factors. There were 875 participants. Serum sex hormone levels, CHD risk factors, and potential covariates (including demographic characteristics, anthropometric measurements, reproductive history and lifestyle variables), determined at baseline and at 24 or 36 months of treatment, will be considered in the analyses. Results of this study will help define the differences between women with regard to endogenous sex hormone levels and responses to HRT, and the relation of sex hormones to CHD risk factors. These observations may aid in deciding whether individual women should use HRT and, if so, which regimen would provide the most benefit with the least risk. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ESTOGENS, DIETARY ENERGY AND PITUITARY TUMORIGENESIS Principal Investigator & Institution: Shull, James D.; Professor; None; University of Nebraska Medical Center Omaha, Ne 681987835 Timing: Fiscal Year 2002; Project Start 15-AUG-1995; Project End 31-MAY-2004 Summary: Estrogens play a central role in the regulation of cell proliferation in numerous mammalian tissues and are inextricably implicated in the etiology of several major human cancers. The prolactin (PRL)-producing lactotroph of the rat anterior pituitary gland provides a valuable model for studying regulation of cell proliferation by estrogens. It is well established that estrogens stimulate lactotroph proliferation and induce development of PRL-producing pituitary tumors in several different inbred rat strains. Clinical observations indicate that estrogens act similarly in the human anterior pituitary gland. We have demonstrated that estrogens induce pituitary tumors in F344 and ACI rats by stimulating cell proliferation and inhibiting apoptosis. A 40 percent restriction of dietary energy consumption was demonstrated to virtually abolish estrogen induced pituitary tumorigenesis in the F344 rat, not by inhibiting estrogen induce cell proliferation, but by modulating the ability of estrogen to inhibit apoptosis. Interestingly, these effects of dietary energy restriction were not observed in the ACI rat strain, strongly suggesting that different molecular mechanisms regulate lactotroph proliferation and death in the F344 and ACI rat strains. Using a genetic approach, we demonstrated that the ACI alleles of at least 2 genes act in a dominant manner to confer the pituitary growth response of the ACI rat to estrogens. Herein we propose 4 specific aims to characterize further the genetic bases of estrogen induced pituitary tumor development in the ACI rat and to begin to elucidate the molecular mechanisms through which dietary energy restriction modulates, in a rat strain specific manner, the homeostatic equilibrium between proliferation and death in the lactotroph population.

Studies 31

Specific Aim 1 is to define the genetic bases underlying estrogen induced pituitary tumor development in the ACI rat strain. Specific Aim 2 is to map quantitative trait loci (QTL)that confer the tumorigenic response of the ACI rat pituitary gland to estrogen. Specific Aim 3 is to generate congenic rat strains which carry, on the BN genetic background, ACI alleles of QTL that confer the tumorigenic response of the pituitary gland to estrogen. Specific Aim 4 is to compare the effects of dietary energy restriction on the ability of administered estrogen to induce pituitary tumor development in F344, ACI and F344/ACI FI progeny. The research proposed herein will ultimately lead to the identification of genes that are involved in the regulation of lactotroph proliferation and death by estrogens and will reveal how the actions of these genes are modulated by dietary energy consumption. We believe that this new knowledge may have broad implications for other estrogen regulated cell populations and will thereby contribute significantly toward our efforts to prevent and treat cancers in which estrogens are etiologic factors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ESTROGEN AMPLIFIES THE VASODILATION OF ANGIOTENSIN(1-7) Principal Investigator & Institution: Brosnihan, K. Bridget.; Professor; Wake Forest University 2240 Reynolda Rd Winston-Salem, Nc 27106 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2003 Summary: Presently, there is limited information on the effects of estrogen on the development and progression of hypertension. The increased incidence of hypertension in women after age 50 suggests that endocrine changes associated with a decline in ovarian function play a role in the pathogenesis and clinical manifestations of hypertension. These issues have not been adequately addressed, and it is not clear whether estrogen is protective in regard to hypertension. Unquestionably, more than one system plays a role in the pathogenesis of hypertension. However, there are major derangements in the angiotensin system (RAS). We demonstrated in a model of postmenopausal chronic hormone replacement that estrogen (E2) both reduced the pressor response to angiotensin II (Ang II) and increased the magnitude of the vasodepressor actions of Ang-(1-7). Further, estrogen reduced angiotensin converting enzyme (ACE) mRNA in lung, kidney, and aorta, in conjunction with a decrease in ACE activity in tissues and serum, and in association with a reduction in circulating levels of Ang II and increased levels of Ang-(1-7). These findings provide the first evidence demonstrating that estrogen may be protective against hypertension by shifting the vasoconstrictor-vasodilator balance of the RAS. Our hypothesis is that estrogen contributes to the regulation of arterial pressure augmenting the local regional vasodilator contributions of Ang-(1-7) and diminishing the vasoconstrictor actions of Ang II. A critical component of this effect of estrogen may arise through its downregulation of angiotensin converting enzyme. We will determine the mechanism for these effects of estrogen by: 1) testing whether estrogen augments regional vasodilatory vascular reactivity to Ang-(1-7); (2) determining whether estrogen increases the affinity and number of the novel non-AT1/non-AT2 angiotensin receptor; 3) determining whether estrogen alters local angiotensin metabolism; and 4) testing whether estrogen reduces ACE mRNA through the classical estrogen-receptor, ERalpha, or the novel estrogen receptor, ERbeta. These novel studies will enhance our understanding of the role estrogen plays in promoting the paracrine production and participation of Ang-(17) in the regulation of regional vascular resistance, and may provide a new rationale for

32

Estrogen

the use of estrogen to prevent and treat cardiovascular disease in postmenopausal women. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRANSPORT

ESTROGEN

AND

AGING

EFFECTS

ON

TRANSVAGINAL

Principal Investigator & Institution: Gorodeski, George I.; Associate Professor; Reproductive Biology; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2003; Project Start 01-JUN-1999; Project End 31-MAY-2008 Summary: (provided by applicant): Our long-term objective is to understand the mechanisms that regulate the permeability of epithelia of the female reproductive tract. We have discovered that estrogen modulates the Resistance of the Lateral Intercellular Space (R-LIS) of human normal ectocervical-vaginal epithelial cells (ECVE), and decreases the paracellular resistance. The geometry of the lateral intercellular space (and the R-LIS) is determined by the shape of epithelial cells that define this space, and depends on the rigidity of the cytoskeleton. Based on novel preliminary results we advance our Maior Hypothesis that estrogen decreases the rigidity of the cytoskeleton by remodeling the cortical acto-myosin frame. The study has four Specific Aims: (1) To understand how estrogen remodels the cytoskeletal cortical acto-myosin frame. Our Hypothesis-A is that formation of a rigid cortical frame depends on the interaction of nonmuscle myosin IIB with cortical actin. We propose that estrogen remodels the cytoskeleton into a flexible structure by inducing disassembly of nonmusele myosin lIB from the cortical actin ring. (2) To understand the structural basis of the cortical actomyosin cytoskeletal ring in epithelial cells. Our Hypothesis-B is that in epithelial cells the stability of the cortical myosin-actin ring depends on the interaction of actin with homodimerized nonmuscle myosin IIB filaments. We propose that dedimerization of nonmuscle myosin IIB heavy chains inhibits myosin MgATPase activity, and leads to disassociation of nonmuscle myosin IIB from the cortical acto-myosin frame. (3) To understand the mechanism by which phosphorylation of nonmuscle myosin IIB heavy chains regulates MgATPase activity. Our Hypothesis-C is that that phosphorylation of nonmuscle myosin IIB heavy chains inhibits homodimerization of myosin filaments and blocks myosin MgATPase. The alternative hypothesis is that MgATPase can be regulated independent of dimerization, by phosphorylation of nonmuscle myosin lIB heavy chains directly at the motor domain. (4) To understand the signaling pathway of the estrogen-induced phosphorylation of nonmuscle myosin IIB heavy chains. Our Hypothesis-D is that the effect of estrogen is initiated by activation of the EGFR-MAPK pathway, and it involves casein kinase II (CKII) as the terminal kinase. The extended hypothesis postulates involvement of multimolecular complexes, including Rho-kinase and an unidentified phosphatase, as modulators of CKII-induced phosphorylation of nonmuscle myosin IIB heavy chains. Experiments will utilize tissues of human ectocervix and vagina obtained from women undergoing surgery, and cultures of human ECVE cells grown on filters. Health relatedness of the project: The results of the study may provide novel data about estrogen regulation of the permeability of the female reproductive tract epithelia, and improve our understanding of the physiology of reproduction: the pathophysiology of inflammatory and infectious disease in the genital tract; and for improving woman's health. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

Studies 33

•

Project Title: ESTROGEN AND SODIUM MODULATE HYPERTENSION IN AGING RATS Principal Investigator & Institution: Hinojosa-Laborde, Carmen; Associate Professor; Physiology; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 31-JAN-2007 Summary: (provided by applicant): The Dahl salt sensitive (S) rat will be studied as an animal model of post-menopausal hypertension to investigate the mechanisms responsible for the hypertension. The pressor systems that will be evaluated are the renin-angiotensin system (RAS) and the sympathetic nervous system (SNS). The role of estrogen, aging, and salt intake as modulators of these pressor systems via their effects on the nitric oxide (NO) system will be investigated. The first specific hypothesis is that the aging process with the accompanying loss of estrogen activity is associated with a down regulation of the nitric oxide system resulting in hypertension. To test this hypothesis, Specific Aim 1 of this study is to monitor blood pressure and the level of activation of the NO system in intact, ovariectomized (OVX), and OVX+estrogen-treated Dahl salt sensitive and Dahl salt-resistant (R) female rats as they age from 3 month to 2022 months of age. The second specific hypothesis is that the factors maintaining the hypertension associated with the loss of estrogen activity in Dahl S rats is determined by the level of salt intake. OVX performed at young, middle and old age will cause an increase in blood pressure, but the rise will be attenuated with increasing age. However, the level of blood pressure and the activity of the pressor systems contributing to hypertension will be higher pre-OVX because of the effects of aging on the RAS and SNS. Two specific aims will address this hypothesis. Specific Aim 2 will be to establish that the Dahl S elderly and OVX females maintained on low salt intake will become hypertensive as a result of an activation of the RAS. Estrogen administration will maintain activation of the NO system to suppress the RAS. Blockade of NO formation in low salt animals will increase RAS function, especially in the OVX+estrogen animals. Specific Aim 3 is to determine that high salt fed Dahl S elderly and OVX animals will develop a hypertension that is dependent on the activation of the SNS. As with the low salt animals, estrogen supplement will suppress the SNS stimulation through a NOmediated mechanism. Together these studies will provide evidence that the arterial pressure of the Dahl S rat is sensitive to the removal of estrogen through OVX or aging suggesting a useful model of post-menopausal hypertension. By investigating the relationship of estrogen, NO and salt, important new information will be gained in the mechanisms whereby estrogen provides protection against hypertension. Importantly, a greater understanding will be obtained addressing why the protection disappears with the aging process. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: ESTROGEN AND THE AGING BRAIN Principal Investigator & Institution: Morrison, John H.; Professor; Neurobiology; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 21-APR-1999; Project End 31-MAR-2004 Summary: The primary goal of this Program Project is to reveal the important interactions between the brain and female reproductive senescence, with particular attention to the impact of these evens on memory, cognition, and attention. While animal studies have demonstrated clearly that changes in circulating estrogen levels affect cellular and molecular attributes of certain neural circuits, the link between such

34

Estrogen

observations and the human data on peri- and post-menopausal memory impairment, beneficial neurobehavioral effects of estrogen replacement therapy (ERT), and potential decreased risk of Alzheimer's disease with ERT are far from clear. It is our strong conviction that the Program Project mechanism, as implemented in this proposal, is required to analyze the spectrum of mechanistic analyses from the in vitro level to an in depth structural and functional assessment of the effects of ERT on behaviorally characterized non-human primates. Though tight interactions between projects 1, 2, and 3, studies in rodents will extend from a) mechanistic analyses of estrogen's role in synaptogenesis and neurodegeneration to b) estrogen- and age-induced alterations in the circuits that directly control reproductive function and c) estrogen and age-induced plasticity in the circuits that mediate memory. The rodent analyses, particularly the in vitro studies of Project 1, will be a crucial testing ground for revealing novel molecular and cellular links to estrogen-brain interactions that could be pursued in the primate model. Core A as well as Projects 2, 3, 4, and 5 will converge on the non-human primate model. They will evaluate the structural (hippocampal, glutamate, cholinergic, basal forebrain, and dopaminergic mesocortical systems) and functional (behavioral assays of memory, cognition, and attention) consequences of ERT in young and aged Rhesus monkeys, as well as provide a detailed assessment of endocrine status and hypothalamic regulation of reproductive function. Rhesus monkeys of different ages that have been surgically ovariectomized with and without ERT as well as those that have transitioned through age-related menopause will be employed in this Program Project. These animals will be the object of detailed endocrine, neurobiological, and behavioral analyses in an integrated effort to reveal the effects of interactions of estrogen and aging in the brain. These studies will lay the groundwork for more informed approaches to ERT in humans in order to help ameliorate neurodegenerative processes, as well as to promote successful brain aging. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ESTROGEN DEPENDENCY OF UTERINE LEIOMYOMA Principal Investigator & Institution: Al-Hendy, Ayman; Obstetrics and Gynecology; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555 Timing: Fiscal Year 2003; Project Start 24-SEP-2003; Project End 31-JUL-2008 Summary: (provided by applicant): Uterine leiomyoma arise from the uterine smooth muscle compartment (myometrium) and are the most common gynecologic tumor in premenopausal women, occurring in up to 77% of all women. They are all significant cause of pelvic pain, menorrhagia, infertility, and pregnancy-related complications. These estrogen-dependent tumors are the leading indication for hysterectomy in reproductive age women. Currently, no medicinal therapy exists. Prolonged use of GnRH agonists, which can shrink tumors but induce a chemical menopause, is restricted due to serious side effects. The hormone-dependent phenotype of uterine leiomyoma suggests that interventions targeting the estrogen receptor (ER)-signaling pathway may have therapeutic efficacy. Proof-of-principal experiments have now established that treatment with anti-estrogen medications (e.g., tamoxifen and raloxifene) can significantly reduce tumor incidence, size, and proliferative index in the Eker rat, the only animal model known to acquire spontaneous uterine leiomyoma. Adenovirusmediated delivery of a mutated dominant-negative ER (Ad-ER-DN) inhibited cell proliferation and induced apoptosis in human and rat leiomyoma cell lines. In a pilot experiment, Ad-ER-DN injected directly intratumor in nude mice with pre- existing fibroids induced immediate arrest and regression of tumor growth due to extensive apoptosis. explants in nude In this project, we will (Specific Aim 1) determine if Ad-ER-

Studies 35

DN transduction inhibits endogenous ER signaling in estrogen-responsive rat and human leiomyoma cells, (Specific Aim 2) expand pilot results and evaluate the ability of Ad-ER-DN to ablate pre-established subcutaneous leiomyoma mice, and (Specific lira 3) conduct a pre-clinical trial to assess the ability of Ad-ER-DN to ablate uterine leiomyoma when delivered by direct intratumor injection in the immune-competent Eker rat. Tumor response will be correlated to proliferative and apoptotic indices, to markers of tumor angiogenesis, and to several estrogen-regulated genes. We will examine immune response and the safety of single vs. repeated recombinant adenovirus treatment alone or in combination with SERM (Raloxifene). Evident therapeutic potential aside, this project will add to our understanding of the molecular mechanisms of estrogen-dependence in this common uterine tumor. It will also show, in a wellcharacterized natural rat model, the effects of specific perturbing of ER signaling on several cellular functions (i.e., angiogenesis, apoptosis, and cell cycle). This knowledge will impact many other estrogen-related conditions (e.g., breast and endometrial cancer, cardiovascular disease, osteoporosis). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ESTROGEN EFFECTS ON AGE RELATED COGNITIVE DECLINE Principal Investigator & Institution: Gallagher, Michela; Professor; Psychology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-AUG-1998; Project End 31-JUL-2004 Summary: (Adapted from applicant's abstract): The long-term objective of this project is to evaluate the role of estrogen in modulating different types of memory and to understand the neural mechanisms underlying cognitive effects produced by estrogen as a function of aging. Ovarian steroids affect the brain throughout the life span and their effects are not limited to the areas primarily involved in reproduction, but also include the areas relevant to memory. Despite evidence that estrogen affects the brain, however, there have been no studies that directly test the effects of estrogen on memory as a function of aging. Our preliminary studies have indicated that ovariectomy (OVX) has a more rapid effect on cognition in older rats than in young. This has led to our main hypothesis that memory systems are more dependent on estrogens in aged rats. The main aims proposed in this application are to test the working hypothesis that with aging or long-term deficiency of estrogen, cognitive functions decline, and therefore, become more dependent on estrogens. Furthermore, it can be predicted that the types of memory that decline most with aging are most sensitive to estrogen. These studies will test these hypotheses in extended behavioral analyses that will produce detailed information on the interactions of aging and estrogen effects on cognition and the role of IGF-1 as a possible mediating mechanism for estrogen effects in the brain. The four specific aims that will be tested are whether 1) specific cognitive functions are more sensitive to estrogen, 2) with longer estrogen withdrawal cognition will decline more and effects of estrogen will depend upon the duration of the withdrawal, 3) estrogen effects differ as a function of aging, and 4) IGF-1 effects on NMDA receptors mediate the estrogen induced effects on cognition. The results of these studies will be the first to critically analyze the effects of estrogen on cognition as a function of aging, duration of estrogen deficiency and type of cognitive task and will also, test a potential neuroendocrine mechanism. Therefore, the data will be of importance in the understanding of age related changes in cognitive function and will have important clinical relevance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

36

•

Estrogen

Project Title: ESTROGEN EFFECTS ON ANXIETY RELATED NEURAL SYSTEMS Principal Investigator & Institution: Altemus, Margaret; Associate Professor; Psychiatry; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-JUL-2005 Summary: (Adapted from the Investigator's Abstract) This Mentored Clinical Scientist Development Award, a program of research and career development, is proposed to establish a foundation for future independent research in behavioral neuroscience, with a focus on reproductive hormones and emotional regulation. The research component of the proposal is a series of studies investigating the hypothesis that estrogen restrains fear associated behaviors. Clinical data indicates that reproductive hormones fluxes have profound effects on the course of anxiety disorders and depression, but the neurobiological determinants of these clinical observations are not well understood. The specific aims of the research plan are to: 1) study the effects of estrogen on a battery of behavioral tests of anxiety; 2) examine the effects of estrogen on glucocorticoid and stress induced enhancement of fear behaviors; 3) examine the effects of estrogen on extrahypothalamic CRH and glucocorticoid receptors, a neuroendocrine system known to modulate fear and anxiety and 4) define the anatomic sites of estrogen action on fear behaviors. Fear associated neural circuits involving the amygsala, bed nucleus of the stria terminalis, and medial prefrontal cortex will be studied using local administration of estrogen and estrogen antagonists. The training portion of this proposal consists of basic neuroscience coursework and seminars as well as hands-on instruction in behavioral analysis and functional neuroanatomic techniques. Studies of the effects of estrogen on anxiety related neural systems provides an opportunity for the investigator to expand her area of expertise from clinical neuroendocrinology and clinical psychiatry to behavioral neuroscience where the effects of hormones on brain function can be studied more directly. This field of investigation is likely to improve understanding and treatment of anxiety and affective disorders, both of which are widely prevalent, chronic public health problems. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: ESTROGEN EFFECTS ON CARDIOVASCULAR RESPONSE TO EXERCISE Principal Investigator & Institution: Kaufman, Marc P.; Professor of Internal Medicine & Human p; Internal Medicine; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 95616 Timing: Fiscal Year 2002; Project Start 01-FEB-2001; Project End 31-JAN-2006 Summary: (Applicant's abstract): Static and moderate dynamic exercise are known to increase heart rate, myocardial contractility, arterial blood pressure, breathing and muscle sympathetic nerve discharge. These effects, which are believed to increase the delivery of oxygen to metabolically active tissues (i.e., the exercising muscles), appear to be less in women than in men. This difference is often attributed to the effect of estrogen on neuronal function. Consequently, the aim of the experiments proposed in this application is to identify the effect of estrogen on "central command" and the muscle reflex, the two neural mechanisms responsible for evoking the autonomic responses to exercise. The proposed studies will be done in decerebrate unanesthetized female and male cats, which have been either ovariectomized or castrated, respectively two to four weeks prior to the experiment. In this preparation, the two neural mechanisms, central command and the muscle reflex, can be investigated separately without the influence of anesthesia. The effect of estrogen (i.e., 17-beta-estradiol) on the central command to

Studies 37

exercise will be studied while the cats are paralyzed with vecuronium, and will be evoked by both electrical and chemical stimulation of the hypothalamic and mesencephalic locomotor regions. Motoneuron discharge to agonist and antagonist hindlimb muscles will be recorded. The criterion for elicitation of central command will be "fictive locomotion." Likewise, the effect of estrogen on the muscle reflex will be studied, but the cats will not be paralyzed. The muscle reflex will be evoked both while the hindlimb muscles are freely perfused and while they are ischemic. Dose response relationships for the effect of estrogen on both the cardiovascular and respiratory responses to central command and the muscle reflex will be determined. Moreover, studies will be extended to estrogen pretreatment with timed release pellets implanted into castrated male cats and ovariectomized females. In addition, the effect of microinjections of 17beta-estradiol into the hypothalamic and mesencephalic locomotor regions will be determined because preliminary data suggest that central command, but not the muscle reflex, is responsible for the estrogen-induced attenuation of the cardiovascular and ventilatory responses to exercise. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ESTROGEN FUNCTION (PILOT)

EFFECTS

ON

VASCULAR

STRUCTURE

AND

Principal Investigator & Institution: Fentie, Ian H.; Meharry Medical College 1005-D B Todd Blvd Nashville, Tn 37208 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2007 Summary: Today, postmenopausal women are at greater risk than younger women for cardiovascular diseases, due, in part, to increased hypertension. Factors likely to cause vascular dysfunction in both men and women are an age related elastin decrease, apparently due to increased activity of vascular elastases. This, coupled with calcium enhanced cholesterol deposition on elastin fibers and cross-linking brought about by the Maillard reaction stabilization of collagen fibers further increase age related hypertension. Together these factors may contribute greatly to blood pressure increases in both men and women but do not explain postmenopausal blood pressure rate increases. The long term goal of this pilot project is development of an independent research program intended to evaluate the effects of estrogen and other steroids on hypertension, arterial stiffening and other aspects of cardiovascular disease. If successful, areas of intended study will include examination both animal and human vessels recovered from surgery and tissue culture studies of vascular endothelia from rat, pig and human sources. Vascular viscoelasticity and structure will be examined in estrogen replete or depleted animals. The hypothesis this project will test is that estrogen depletion compromises the structure and function of elastic and conducting arteries in middle-age spontaneously hypertensive female rats. We intend to elucidate the mechanisms underlying this derangement. Estrogen induced alteration in arterial elastin and the high affinity 67 kDa elastin-laminin receptor, both of which are intimately associated with cardiovascular disease and neoplasia will be quantified biochemically. Maillard reaction products will be quantified biochemically. Presence of structural change in elastic and conductive arteries from estrogen replete and estrogen depleted animals will be examined using immunohistochemical techniques, histology as well as biochemical techniques. Estrogen loss is known to increase blood pressure in "normal" and spontaneously hypertensive female rats. Further, loss of this steroid is known to increase stiffening in great vessels. Already, exciting pharmaceuticals are known to reverse the effects of the Maillard reaction. These compounds or modifications

38

Estrogen

of them may reduce arterial stiffening and improve future outcomes in hypertensive patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ESTROGEN MEDIATED NEURONAL PLASTICITY IN THE BRAIN Principal Investigator & Institution: Tuszynski, Mark H.; Associate Professor of Neurosciences; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 920930934 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 31-MAR-2003 Summary: Estrogen replacement therapy in elderly women has been reported to diminish the risk of developing Alzheimer's disease (AD) and to improve response to anti-cholinesterase therapy in women already diagnosed with AD. Further, recent evidence indicates that estrogen may modulate the expression of neuronal growth factors and their receptors in the brain. These findings suggest that neuronal plasticity in the brain may be modulated in part by estrogen-linked mechanisms. To investigate this possibility, our laboratory has explored interactions of estrogen-responsive neurons with growth factors and their receptors. We have found extensive co-expression of estrogen and neurotrophin systems in both cortical regions and forebrain projections to cortical regions in the brains of rodents and primates. Studies in this proposal will examine the effects of neuronal injury and estrogen loss on neural plasticity to test the hypothesis that estrogens modulate neural plasticity to test the hypothesis that estrogens modulate neural plasticity through interactions with neurotrophic factor systems in the brain. Mechanisms of such interactions will be elucidated. This work will build upon techniques and methods that are will-established in the PI's lab and that have led to useful insights into the nature of neurotrophin biology in the rodent and primate brains. The specific aims will be addressed: Aim 1: Do neuronal populations in the primate and rodent brains co-express estrogen receptors and neurotrophins or their receptors, reflecting co- modulation of these systems? Aim 2: What effects do natural fluctuations in estrogen levels exert on cortical synapse density and on expression of NGF, BDNF and neurotrophin receptors in the brain? Aims 3 and 4: What effect does estrogen loss exert on synapse density in cortical target regions, and on expression of neurotrophins and their receptors, in the brains of adult and aged rats (Aim 3) and in the brains of adult primates (Aim 4)? Aim 5: Do estrogens and growth factors act synergistically to enhance neural plasticity? These studies will provide insights regarding estrogen effects on going, cognition, and neurotrophic factors, leading to potential novel therapeutic approaches to AD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: ESTROGEN METABOLITES EFFECTS ON BONE Principal Investigator & Institution: Turner, Russell T.; Professor; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 01-AUG-1999; Project End 31-JUL-2004 Summary: A serious obstacle to the rational design of innovative approaches for preventing and/or treating osteoporosis is the idiopathic nature of postmenopausal bone loss. Menopause is the most important risk factor for osteoporosis. However, not all postmenopausal women develop osteoporotic fractures indicating that cessation of the menstrual cycle is insufficient to fully account for the disorder. Our working hypothesis is that the denovo production and metabolism of estrogens are among the most important factors influencing the rate of postmenopausal bone loss. Estrone (E1)

Studies 39

and its metabolites, 16alpha-Hydroxyl estrone ( (16alpha-OHE1) and 2-hydroxyesterone (2-OHE1), are the most abundant estrogens in postmenopausal women. 16alpha-OHE1 has been recently shown to be a negative risk factor (reduced risk) for postmenopausal bone loss, whereas 2-OHE1 has been positive risk factor (increased risk). 2-OHE1 does not have estrogenic activity in ovariectomized (OVX'd) rats. In contrast, 16alpha-OHE1 appears to be a tissue selective estrogen agonist with a profile of activity similar to the anti-breast drug tamoxifen; 16alpha-OHE1 is a much more effective estrogen agonist on bone and liver than on reproductive tissues. These observations suggest that differences in the skeletal activities on 2-OHE1 and 16-alpha-OHE1 are responsible for the observed association between bone mass and circulating levels of these metabolites in postmenopausal women. We propose to test this hypothesis in ovary intact and OVX'd rats. The specific aims are to determine the dose response effects of 2-OHE1 and 16alpha-OHE1 on the expression of immediate response genes in bone and other estrogen target tissues; and establish the long-term effects of the estrone metabolites on bone architecture, turnover and strength. The proposed research will characterize the probably cellular mechanisms of action. The results of these studies are likely to be relevant to women because of the similarity between postmenopausal bone loss and OVX-induced bone loss in rats, as well as the previous success the rat model has enjoyed for predicting the response of the human skeleton to estrogen agonists and markers to predict the rate of postmenopausal bone loss; 2) manipulation of estrone metabolism by changes in diet or by pharmacological intervention may be a valuable tool for reducing bone loss; and 3) analogs of 16alpha-OHE1 may be useful for prevention and treatment of postmenopausal osteoporosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ESTROGEN METABOLITES, RELATED GENES AND BREAST CANCER Principal Investigator & Institution: Shore, Roy E.; Professor; Environmental Medicine; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): The NYU Women's Health Study (NYUWHS) cohort has played a leading role in elucidating the associations of estrogens and androgens with breast cancer, based on blood samples that were obtained prospectively in 1985-91 from over 14,000 healthy women of ages 35-65. We now team up with another cohort from the Northern Sweden Health and Disease Study in Umea to address questions about the roles of estrogen metabolites in breast cancer. The proposed grant period would extend the NYUWHS follow-up to about 19 years on average and would permit the accrual of nearly 1,000 incident breast cancer cases, while the Umea study will have over 600 cases. The follow-up and cancer case ascertainment rates have been high in both studies. The study will investigate how much levels of estrogen metabolites which can be both estrogenic and genotoxic - affect breast cancer risk, and the degree to which functional polymorphisms in estrogen metabolism genes are predictive of estrogen metabolite levels and of breast cancer risk. We hypothesize that: Circulating levels of 16alpha-hydroxyestrone are positively associated with breast cancer risk, and the 2-hydroxyestrone to 16alpha-hydroxyestrone ratio is negatively associated with breast cancer; Genetic polymorphisms associated with altered activity of enzymes catalyzing 16alpha-hydroxylation (CYP3A4 and CYP3A5) and 4-hydroxylation (CYP1B1) are associated with breast cancer risk. Functional polymorphisms in the sulfotransferase and glucuronidase genes that diminish estrogen conjugation activity are associated with increased breast cancer risk. Over the last five years, the NYUWHS

40

Estrogen

cohort has been the basis for investigations, with a series of collaborators, of numerous risk factors for various cancers (breast, colorectal, endometrial, ovarian) e.g., IGF-I and its binding proteins; organochlorines; serum carotenoids, phytoestrogens, folate and homocysteine; polymorphisms in luteinizing hormone and DNA repair genes. The availability of serum specimens, DNA, and lifestyle and dietary data collected prospectively, combined with the extended followup and increasing numbers of cancers, will allow the study to continue to foster the investigation of various biological risk factors for a range of cancers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ESTROGEN PROTECTION OF THE LUNG: MECHANISMS AND PATHWAYS Principal Investigator & Institution: Said, Sami I.; Professor; Medicine; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: (provided by applicant): The broad objectives of this proposal are: to achieve better means of cell and tissue protection, and to gain a better understanding of cellprotective actions and functions of the female sex hormone estrogen. Specifically and near-term, we propose to examine the ability of estrogen to protect against certain forms of acute lung injury, and the mechanisms of this action. Specific objectives: 1) Document the protective properties of estrogen hormone against acute lung injury. Hypothesis: Already shown to be cytoprotective in neuronal cells and the cardiovascular system, estrogen is protective in the lung as well. This hypothesis will be tested in three models of injury: a) excitotoxicity, i.e., injury/cell death due to species overstimulation of NMDA receptors; b) oxidative stress, caused by the generation of reactive oxygen species (ROS) by the herbicide paraquat; and c) endotoxin shock, which leads to multiorgan dysfunction. Endpoints will be the speed of onset and the severity of highpermeability pulmonary edema in models a and b, and the survival time and organ damage, in model c. 2) Explore the mechanisms, sites, and pathways of lung protection by estrogen. Hypothesis: Acting at multiple sites, estrogen exerts anti-apoptotic (prosurvival), anti-inflammatory, anti-oxidant, and other beneficial effects. These possible sites and models of protection will be examined in the models of injury named above. We will evaluate: a) the specificity and nature of the effect (i.e., genomic vs. nongenomic); b) relative importance of different receptors (ER-alpha, ER-beta), membrane binding sites, and transduction pathways; c) the contribution of estrogeninduced upregulation of the expression of (VIP), which has known anti-injury and antiinflammatory properties; d) possible interactions and "transcription cross-talk" between estrogen and retinoic acid receptors, and d) anti-apoptotic and pro-survival activities of estrogen. The proposed work extends recent research on the protective effects of estrogen in the brain and the cardiovascular system. Preliminary data support the validity of the hypotheses underlying this project. This is the first, and probably the only, investigation of the female sex hormone estrogen as a lung-protective agent. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: ESTROGEN RECEPTOR VARIANCE AND CHD RISK IN HERS Principal Investigator & Institution: Herrington, David M.; Professor; Internal Medicine; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2002; Project Start 27-SEP-2002; Project End 31-MAY-2005

Studies 41

Summary: (provided by applicant): Estrogen raises HDL cholesterol levels - an effect that may account for the favorable association between hormone replacement therapy (HRT) and coronary heart disease (CHD) risk in postmenopausal women. Several lines of evidence suggest that genetic factors also influence HDL levels, although the precise genes involved have not yet been determined. Recent evidence from the Estrogen Replacement and Atherosclerosis (ERA) trial (N = 309) indicates that certain allelic variants in the estrogen receptor-alpha (ER-alpha) gene are associated with more than a twofold increase in estrogen's effects on HDL cholesterol. Women with the favorable genotype (ca. 20% of women) experienced a 26% increase in HDL with HRT compared with a 13% increase observed in the remaining women. However, this trial was too small to determine if these effects translate into an angiographic or clinical benefit. The Heart and Estrogen Replacement Study (HERS) was a large (N = 2763) randomized clinical endpoint trial of HRT for secondary prevention of CHD. This clinical trial cohort provides an ideal opportunity to confirm or refute the associations and interactions observed in the ERA trial with respect to lipids, and extend these observations to other estrogen-sensitive intermediate endpoints and clinical disease outcomes. Therefore, we propose to genotype HERS women with respect to several ER-alpha polymorphisms, and to examine the relationship between these ER-alpha genotypes, HRT use, change in HDL, and risk for CHD events. We will also examine the effects of ER-alpha polymorphisms on other plasma lipids, C-reactive protein, bone mineral density, risk for venous thromboembolic events, stroke, fractures, and all-cause mortality. Use of data and specimens from HERS is an efficient means to study the clinical impact of ER-alpha polymorphisms and possible modulation of estrogen action. If there are common polymorphisms in the ER-alpha gene that modify estrogen's effects on HDL and possibly other domains of estrogen action, this information could improve patients' and clinicians' ability to assess risks and benefits of HRT use. In addition, this information could lead to fundamentally important new knowledge about mechanisms of estrogen action, regulation of HDL cholesterol, and pathogenesis of CHD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ESTROGEN TRANSPARENCY

RECEPTORS

AND

MAINTENANCE

OF

LENS

Principal Investigator & Institution: Davis, Vicki; Pharmacology and Toxicology; Duquesne University 600 Forbes Avenue Pittsburgh, Pa 15282 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-JUL-2006 Summary: (provided by applicant): Epidemiological studies suggest that estrogen may protect against age-related cataracts. The discovery of ocular estrogen receptors (ER) indicates that estrogen protection may result from direct interactions with its receptors in the eye. Studies in our transgenic mouse model validate the concept that estrogen is beneficial for the eye; these mice express a repressor (ERdelta3) that inhibits estrogen action, leading to cortical cataract formation. Although the ERalpha and ERbeta protein and/or RNA have been detected in ocular tissues, there has been no confirmation that these receptors are functional, since there are no known estrogen responsive markers in the eye. Therefore, in this proposal, we will use several transgenic mouse models to investigate the function of ERalpha and ERbeta in the lens. Our specific aims will examine 2 critical questions important for understanding the role of estrogen and its receptors in normal lens physiology and cataractogenesis. 1) Can estrogen induce an ER-mediated response directly in the lens? 2) Are both ERalpha and ERbeta essential for maintenance of lens transparency? First, using ERIN transgenic mice, we will determine whether ERalpha, ERbeta, and ERdelta3 receptors can regulate expression of an

42

Estrogen

estrogen responsive reporter gene in the lens. The ERIN model expresses a betagalactosidase reporter under the control of 2 consensus estrogen response elements (ERE). The alphalERKO and betaERKO mice provide a means to segregate the individual ER subtypes to determine their individual roles in the lens. Therefore, the ERIN mice will be crossbred with alphaERKO, betaERKO, and ERdelta3 transgenic mice to document that each receptor influences estrogen responsive gene expression in the lens. Next, we will investigate if both ERalpha and ERbeta influence spontaneous and ERdelta3-induced cataract development. We will examine aging alphaERKO, betaERKO, and alphabetaERKO mice to determine if loss or each or both receptors induces lens opacity. To ascertain if cataracts occur in our ERdelta3 mouse model due to inhibition of ERalpha and/or ERbeta activity, the ERKO lines will be crossbred with the ERdelta3 mice. These studies will verify that ERalpha, ERbeta, and ERdelta3 are expressed and functional in the lens. In addition, we will establish if both ERalpha and ERbeta have essential roles in preserving lens transparency. The concept that estrogen can provide protection against age-related cataracts is promising. This study will provide the gateway for future studies to investigate how exposure to various estrogens influence risk of age-related cataracts and the potential of estrogens as a therapy for cataract prevention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ESTROGEN REDUCES VENOUS TONE IN EARLY HYPERTENSION Principal Investigator & Institution: Martin, Douglas S.; Basic Biomedical Sciences; University of South Dakota 414 E Clark St Vermillion, Sd 57069 Timing: Fiscal Year 2002; Project Start 15-SEP-2000; Project End 31-JUL-2004 Summary: (Verbatim from the application): Recent data from our laboratory indicated that venous tone is increased in the developmental stages of spontaneous hypertension in the rat. Since the increase in blood pressure in the initial stages of hypertension is characterized by an elevation of cardiac output, veins appear to play an important role in the initiation of the hypertensive process. The development of hypertension is sexually dimorphic. Considerable evidence suggests that estrogen attenuates the development of hypertension. Estrogen has been shown to affect vascular smooth muscle via both endothelial dependent and independent mechanisms and to modulate peripheral and central nervous system function. Veins possess functional estrogen receptors, high estrogen states are associated with changes in venous tone and estrogen modulates neural activity in brain regions involved in the control of venous tone. Thus, estrogen may modulate venoconstrictor tone during the developmental stages of hypertension via effects on venous smooth muscle and/or via effects on sympathetic outflow to veins. Accordingly, the proposed research is aimed at testing the general hypothesis that estrogen reduces venoconstrictor tone during the developmental stages of spontaneous hypertension. The specific aims of the research will be to determine if I) Estrogen reduces sympathetic venoconstrictor tone in young female SHR. II) Estrogen reduces venous tone via effects on venous smooth muscle responsiveness via an effect on the nitric oxide system, calcium channels or potassium channels. III) Estrogen alters the expression of key proteins involved in the control of venous tone. Experiments will be performed in spontaneously hypertensive (SHR) rats at 6-10 weeks of age, a time point when previous studies have shown elevated venous tone in SHR rats. MAP, HR, and mean circulatory filling pressure, an index of integrated venomotor tone will be measured in conscious rats to determine the effects of estrogen on overall venous tone. Isolated portal and mesenteric veins will be used to assess the effects of estrogen on venous smooth muscle responsiveness and the mechanisms underlying these effects.

Studies 43

Western blot techniques will be used to determine if estrogen affects venous tone by altering expression of key protein involved in venous control systems. These studies are expected to show that estrogen attenuates the development of hypertension by reducing venomotor tone and thereby, reduces a major factor contributing to the increase in cardiac output and blood pressure that initiates the hypertensive process. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ESTROGEN REGULATION OF THE REPRODUCTIVE AXIS Principal Investigator & Institution: Radovick, Sally M.; Section Chief; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2003; Project Start 28-APR-2003; Project End 31-MAR-2008 Summary: Estrogen regulates gene transcription by binding to high affinity nuclear receptors (ERs), which then recruit co-activator proteins to the transcription complex. Two isoforms of ER (ER-atpha and ER-beta), with variable tissue distribution, have been described. Estrogen is thought to regulate the neuroendocrine reproductive axis by binding to ERs found in the hypothalamus and pituitary. To begin to understand estrogen regulation in vivo, targeted disruption of ER-alpha was performed. ER-alpha knock-out mice display significant gonadal defects and impaired feedback regulation of the neuroendocrine axis. However, after detailed study of this animal model, controversies still exist as to the effect of estrogen on the axis, the mechanism of estrogen's effect (direct versus indirect), and the level of regulation (hypothalamic, pituitary, or both). The goal of this project, therefore, is to determine the mechanism of estradiol action on the hypothalamus and pituitary using both in vitro and in vivo studies. This proposal has three specific aims. In Aim 1, the mechanism of estrogen regulation of the GnRtt neuron in vitro will be determined. ER mutants and GnRH reporter constructs will be tested in GnRH-expressing cell lines. Binding of ER complexes and cofactors to putative negative estrogen response sites in the GnRH promoter will also be evaluated. In Aim 2, the role of ER-alpha [or ER-beta] in the GnRH neuron versus pituitary gonadotroph will be studied in vivo. A conditional knockout of the ER-alpha [or ER-beta] locus in either the GnRH neuron or pituitary gonadotroph will be induced using Cre-LoxP technology. Finally in Aim 3, the mechanism of central estrogen feedback will be determined using cell-specific targeting of a mutant ERs to either the GnRH neuron and/or pituitary gonadotroph. The ability of these transgenes to rescue the defect observed in ER-alpha knock-out mice will also be tested. This proposal will provide an understanding of the molecular mechanism of estrogen feedback on the central reproductive axis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: ESTROGEN USE IN PROTECTION FROM COGNITIVE DECLINE Principal Investigator & Institution: Rasgon, Natalie L.; Psychiatry and Behavioral Sci; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2003; Project Start 15-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): This is a new application for an R01 grant: "Estrogen use in protection from cognitive decline" designed to assess effects of estrogen replacement therapy among postmenopausal women at risk for cognitive decline. We have collected pilot data, which suggest that estrogen use among older persons at risk for Alzheimer's Disease may be protective of regional cerebral metabolism, as measured by position emission tomography with 18-fluorodeoxyglucose (FDG-PET). A total of 71 postmenopausal women ages 50-65, estrogen users, will be randomized to continue or

44

Estrogen

discontinue use and will be followed up to two years for changes in cerebral metabolism and cognitive performance. Subjects will undergo FDG-PET scans and neuropsychological assessments, initially and at the end of the two-year follow-up period. These procedures will allow us to evaluate regional, especially parietal, temporal, and posterior cingulate, cerebral glucose metabolism along with cognitive performance in postmenopausal women at baseline and upon random continuation vs. discontinuation of estrogen replacement therapy. Subjects who to discontinue estrogen use are hypothesized to show more evidence of decline than those who continue do. This project will expand current knowledge of effects of estrogen, by : (1) determining whether estrogen use among postmenopausal women at risk for cognitive decline is protective of brain metabolism; (2) identifying early predictors for cognitive decline; and (3) developing guidelines for estrogen use in postmenopausal women. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ESTROGEN, INFLAMMATION AND CARDIOVASCULAR RISK Principal Investigator & Institution: Reuben, David B.; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: (provided by applicant): The effects of exogenous estrogen on coronary heart disease are controversial. Substantial observational data support a protective effect and several randomized clinical trials have demonstrated that estrogen produces a more favorable lipid profile. Yet, when administered for secondary prevention in the Heart and Estrogen/Progestin Replacement Study (HERS) and Estrogen Replacement and Atherosclerosis (ERA) trials, estrogen had no overall benefit. In HERS, estrogen use was associated with an increase in early events but a late reduction in risk. These conflicting data suggest the need for additional exploration of the effect of estrogen on the risk factors and precipitants of coronary heart disease. Peripheral blood markers of inflammation, specifically C-reactive protein (CRP) and interleukins, have been increasingly recognized as predictors of cardiovascular events and suggest new pathophysiologic mechanisms. However, the effects of estrogen upon inflammatory markers and their subsequent impact upon endothelial function are still unclear. This study will use data from the NHLBI-funded Postmenopausal Estrogen Progestin Intervention (PEPI) randomized clinical trial to assess the effect of conjugated equine estrogens (CEE) with or without progestins upon two peripheral blood inflammatory markers, CRP and IL-6, and their subsequent effects on other cardiovascular risk factors. We will also examine the relation of exogenous CEE on sex hormone-binding globulin (SHBG), a hepatic protein whose production is independent of inflammation but is stimulated by CEE. Assays for IL-6, CRP, and SHBG will be performed on longitudinal stored serum samples and these results will be linked to extensive socio-demographic, lifestyle, and clinical information already collected in the PEPI clinical trial. We hypothesize that CEE will create unfavorable risk profiles of inflammatory markers (higher IL-6 and higher CRP) during the first year of therapy but these patterns will change toward more favorable profiles (lower IL-6 despite continued higher CRP) with continued treatment. We also hypothesize that the continued stimulation of CRP beyond the first year will be through a non- inflammatory effect on liver protein production (similar to estrogen's stimulation of sex hormone-binding globulin SHBG) rather than IL-6 mediated. These findings may provide substantial insight into why CEE appears to promote early but protect against late cardiovascular effects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

Studies 45

•

Project Title: OUTCOMES

ESTROGEN,

METABOLISM,

MENOPAUSE,

AND

HEALTH

Principal Investigator & Institution: Sowers, Maryfran R.; Professor; Epidemiology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2003; Project Start 15-FEB-2003; Project End 31-JAN-2007 Summary: (provided by applicant): Emerging information suggests that differential expression in estrogen metabolism generates differences in health outcomes. Observations from ethnic groups, particularly comparisons of Asians and Caucasians, have precipitated both interest and controversy about differences in estrogen metabolism and health status. The goal of this application is to assess the contribution of estrogen metabolites and xenoestrogens as well as their potential signaling pathways to selected subsequent human health measures in women transitioning the menopause. We will 1) examine whether smoking and diet influence estrogen metabolism; 2) assay for both estrogens and phenolic products that contribute to the total ligand load and determine if estrogen effects on measures of health status (absolute level at follow-up or change from baseline) are misattributed because of failure to account for estrogen mimics; 3) examine the interaction between the arylhydrocarbon receptor (ArH) and ER receptors to ascertain if this interaction modifies the association of estrogens to subsequent measures of health status (absolute level at follow-up or change from baseline); and 4) use follicular and luteal phase samples, collected longitudinally across the menopausal transition, to ascertain if the relative hormone differences in the menstrual cycle segments over time are related to health outcomes. The measures of health status to be evaluated include vasomotor symptoms (hot flashes), age at menopause, measures of lipids and thrombosis and bone mineral density. This application will use Repository serum and urine samples from an existing large study of African-American, Caucasian, Chinese, Hispanic and Japanese women at the midlife [Study of Women's Health Across the Nation (SWAN)]. Additionally, SWAN can provide the longitudinal data about both smoking and diet exposures and health outcomes measures without additional data collection. This is a unique opportunity to prospectively integrate lifestyle elements with measures of hormone metabolism pathways into a comprehensive examination of multiple human health effects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ESTROGEN, NADPH OXIDASE, AND NEUROTRAUMA Principal Investigator & Institution: Bruce-Keller, Annadora J.; Assistant Professor; Sanders-Brown Ky Res Ctr/Aging; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-MAY-2007 Summary: (provided by applicant): Traumatic brain injury (TBI) afflicts almost 500,000 Americans a year, but unfortunately, existing treatments have only minimal ability to prevent secondary brain damage accompanying traumatic brain injury. Epidemiological data that suggests that women fare better then men following TBI, but the basis for this difference is not understood. It is likely that action of female sex hormones, particularly estrogen, may have significant effects on the progression of brain injury, and recent data from our laboratory suggests that estrogen has potent anti-inflammatory properties that could account for its ability to attenuate traumatic brain injury. In particular, data indicates that estrogen is able to decrease oxidative burst activity and subsequent redoxbased inflammatory signaling in glial cells, thereby attenuating neurotoxic brain

46

Estrogen

inflammation. Therefore, it is proposed that estrogen acts to preserve brain function following TBI by decreasing both blood-brain barrier (BBB) breech and neuronal injury, and that these distinct endpoints are mediated by a single mechanism: modulation of the glial oxidative burst. Specific Aim 1 will test the hypothesis that estrogen is able to significantly attenuate oxidative burst activity in astrocytes, microglial cells, and endothelial cells both in vitro and in vivo, and will determine the role of estrogen receptors in this process through use of estrogen receptor knockout mice. Specific Aim 2 will test the hypothesis that by directly interfering with oxidative burst activity, estrogen blocks the release of matrix metalloproteinases and thus preserves blood-brain barrier integrity in mice following traumatic brain injury. Specific Aim 3 will build upon these studies by testing the hypothesis that by decreasing oxidative burst activity and redox signaling, estrogen blocks the formation of neurotoxic inflammatory mediators (excitotoxins and cytokines), culminating in decreased injury and increased recovery following traumatic brain injury. Completion of these studies will result in a thorough understanding of the mechanisms of estrogen-mediated neuroprotection in TBI and could highlight a novel target for therapeutic intervention following brain trauma in both women and men. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ESTROGEN-INDUCED NEUROPROTECTIVE MITOCHONDRIAL MECHANISM Principal Investigator & Institution: Brinton, Roberta Diaz.; Professor of Molecular Pharmacology And; Molecular Pharm & Toxicology; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2008 Summary: (provided by applicant): The long-term goal of our research program is to develop an estrogen replacement therapy that meets the unique requirements of the brain by activating estrogen-inducible mechanisms of memory and neuroprotection without activating mechanisms of proliferation within the uterus or breast. To achieve this long-term goal, multiple levels of mechanistic understanding of estrogen receptor function in brain must first be achieved. Towards elucidating mechanisms of estrogen promoted neuroprotection, we propose a model of estrogen-inducible proactive adaptation as a strategy whereby estrogen proactively protects neurons against insults of calcium dysregulation. The proposed model incorporates both novel mitochondria mechanisms of estrogen action and several existing estrogen-inducible pathways into a unified concept of proactive adaptation. Four specific aims are proposed. Specific Aim 1 will determine essential basics and generalizability of 17beta-estradiol (E2)-induced mitochondrial sequestration of calcium. Specific Aim 2 will investigate the impact of 17beta-estradiol on the threshold for mitochondrial Ca 2+ sequestration and the underlying mechanism for the shift in threshold. Specific Aim 3 will address the mechanism by which 17beta-estradiol protects against increased mitochondrial calcium load to prevent mitochondrial dysfunction. Specific Aim 4 will determine the mechanism underlying 17beta-estradiol regulation of Bcl-2 family of proteins. Throughout each of the specific aims, we will determine whether 17beta-estradiolinduced mitochondria mechanisms activated in vitro are present in vivo. Seven technological approaches will be extensively utilized: neuronal culture, fluorescent intracellular calcium imaging, biochemical analyses of enzyme activation, immunocytochemical protein labeling, Western blot, mitochondrial isolation and HPLC for polyamines. Mitochondrial function will be assessed within cultured hippocampal neurons and in mitochondria derived from adult rat hippocampal neurons. Results of

Studies 47

the proposed studies will provide a unified mechanistic model of estrogen-induced neuroprotection that incorporates both novel mitochondria mechanisms of estrogen action and estrogen-inducible MAPK, AKT and antiapoptotic pathways. From a clinical perspective, elucidation of the sites and targets of estrogen action should have a clear impact on both the use of estrogen replacement therapy for the prevention of neurodegenerative disease and the future design of target specific estrogens. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ESTROGENS AND INSULIN RESISTANCE IN WOMEN Principal Investigator & Institution: Olefsky, Jerrold M.; Professor; Medicine; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 920930934 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 31-MAY-2007 Summary: (provided by applicant): There are genetic and environmental causes of insulin resistance, and clearly these two inputs can be additive and interactive. A high fat intake is an important environmental factor which can cause, or exacerbate, insulin resistance and enhance the risk for the development of Type II diabetes. Our recent studies have shown that lipid/heparin infusions lead to insulin resistance in men, but not in pre-menopausal women. We also have preliminary data showing that postmenopausal women are fully susceptible to fat-induced insulin resistance and that estrogen replacement therapy re-establishes the protective state. In addition, we have conducted a series of studies in rats, demonstrating that estrogenization (endogenous or exogenous) will protect females from fat -induced insulin resistance. Based on these findings, we propose that men and non-replaced post-menopausal women will exhibit fat-induced insulin resistance, whereas, adequately estrogenized women will be protected. We will test these ideas, not only by employing the lipid/heparin infusion glucose clamp technique, but also by placing experimental subjects on control and high fat diets. It is also possible that adequate estrogen can ameliorate the effects of other physiologic causes of insulin resistance. Thus, we also will conduct studies to determine whether estrogenization can protect women from the insulin resistance induced by obesity and aging. Using muscle biopsy samples collected during the glucose clamp studies, we will conduct experiments aimed at identifying cellular mechanisms for these protective effects of estrogens. We also propose an extensive series of animal studies, in which we will explore in more detail the mechanisms of estrogen protection from fatinduced insulin resistance. We will conduct studies in normal male and female rats, ovariectomized rats, and old estrogen deficient female rats+/- treatment with estradiol, an estrogen antagonist, or estrogen receptor isoform specific agonists. Studies in mice with deletion of the alpha or beta forms of the estrogen receptor, as well as muscle specific estrogen receptor specific knockout animals are also proposed. We will also determine whether the fat cell secreted protein ACRP3O is modulated by estrogen status, and whether the insulin sensitizing effects of ACRP3O are responsible for the estrogen induced protection from insulin resistance. If the concepts contained in this application prove correct, then these findings could have significant implications concerning the mechanisms of insulin resistance as well as the treatment and possibly prevention of this disorder. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

48

•

Estrogen

Project Title: ESTROGENS CONSEQUENCES

FOR

ALCOHOLISM

&ITS

NEUROLOGICAL

Principal Investigator & Institution: Simpkins, James W.; Professor and Chair; Pharmacology & Neuroscience; University of North Texas Hlth Sci Ctr Fort Worth, Tx 761072699 Timing: Fiscal Year 2004; Project Start 15-FEB-2004; Project End 31-JAN-2009 Summary: (provided by applicant): Alcohol abuse causes increased mortality, neurological deficits and a huge cost to society to treat alcoholism, its social and medical consequences. Currently, there are no effective therapies for alcoholism and its neurological consequences. The present grant application proposes a research program to assess the efficacy of estrogens for treatment of the behavioral and neurological consequences of ethanol withdrawal (EW). Based upon our extensive preliminary data that indicate that estrogens reduce withdrawal signs, improve cerebellar-mediated behavioral outcomes and protect cerebellar Purkinje cells of ethanol withdrawn rats, we propose studies to further determine the efficacy and mechanisms of estrogen protection against EW-related neurobehavioral toxicity. We will achieve 5 specific aims in this grant. Specific Aim 1 will determine estrogen effects on the ethanol dependence and the EW phase. Male and female rats will be exposed to 17beta-estradiol (E2) during the dependence versus the withdrawal phase to determine the stage of dependence/withdrawal that is most responsive to estrogens. Specific Aim 2 will evaluate protective effects of nonfeminizing estrogens against neuronal and behavioral deficit in ethanol withdrawn rats. We will employ a novel estrogen, enatiomer-E2 that we have demonstrated to be neuroprotective in vitro and in vivo, but to lack estrogen receptor activity. Specific Aim 3 will determine if estrogens antagonize the pro-oxidant effects of EW by assaying an end product of lipid peroxidation product, malondialdehyde, in cerebellar tissue. Specific Aim 4 will determine if estrogen prevents oxidant-dependent nuclear factor-kappa B (NFrkappaB) activation in ethanol withdrawn rats. Specific Aim 5 will determine the role of estrogen-induced reduction in protein kinase activity and ERKI/2 phosphorylation in the estrogen blockade of nuclear translocation of NFrkappaB during EW. Collectively, the proposed studies will provide new knowledge on the mechanism of estrogen protection from the consequences of EW and determine if estrogens are potential pharmacotherapies for alcoholism and its consequences Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FEMALE SEXUALITY: MODULATION BY ESTROGEN AND ANDROGEN Principal Investigator & Institution: Wallen, Kim; Dobbs Professor of Psychology and Behavi; Psychology; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2006 Summary: (provided by applicant): The hypothesis is investigated that female sexual interest is stimulated by the neural actions of ovarian estrogens and that androgens regulate the bioavailability of these estrogens through interactions with sex hormone binding globulin (SHBG). Three projects, using a rhesus monkey model of endocrine function and behavior, investigate the hormonal basis of female sexual initiation. Project I investigates sexual initiation in females across the menstrual cycle, comparing the occurrence of female sexual initiation in a social group context during normal cycles treated with an androgen receptor blocker (flutamide) or an estrogen receptor blocker (tamoxifen). This will clarify whether androgens or estrogens act neurally to modulate

Studies 49

female sexual motivation. Project II tests the novel hypothesis that SHBG regulates bioavailable estrogens and androgens through these steroids' different affinities for SHBG. This project uses a monkey model of hormonal replacement therapy for reproductively prime females after surgical removal of their ovaries and tests the hypothesis that chronic estradiol (E2) ceases to effectively stimulate female sexual interest as estrogen is sequestered by SHBG. It further investigates whether an androgen, 5a-dihydrotestosterone (DHT), with a markedly higher affinity for SHBG than estradiol can acutely and rapidly reinstate female sexual interest by increasing free estradiol by displacing SHBG-bound estradiol. Ovariectomized females receiving chronic estradiol treatment mimicking mid-follicular estradiol levels will be observed for sexual initiation during chronic E2 treatment alone and following chronic E2 and an injection of DHT or E2. Concurrent administration of flutamide or tamoxifen with the estrogen or DHT will discriminate between behavioral changes resulting from the activation of neural androgen or estrogen receptors. The effects of these treatments on neuroendocrine function will also be investigated. Project III investigates whether common human hormonal replacement therapies of chronic estrogen, or chronic estrogen plus testosterone with or without concurrent progestin, can reinstate female sexual interest in reproductively prime ovariectomized female monkeys. The hypothesis will be tested that chronic progestin therapy reduces or eliminates the effectiveness of therapies that reinstate female sexual interest without progestin. These therapies will also be compared on their effects on neuroendocrine function. These studies will markedly increase our understanding of the role that ovarian steroids play in modulating women's sexuality. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FUNCTIONS OF ESTROGEN RECEPTOR COACTIVATORS IN BREAST TI Principal Investigator & Institution: Jeng, Meei-Huey; Associate Professor; Medicine; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2002; Project Start 22-JUL-1999; Project End 31-MAY-2004 Summary: Overexpression of estrogen receptor alpha (ERalpha) transcriptional regulators, such as AIB1 (coactivator amplified in breast cancer-1), has been demonstrated in many ERalpha-positive human breast cancer cell lines and tumors. Many transcriptional coactivators, including members of the Steroid Receptor Coactivator-1 family (SRC-1, GRIP1/TIF1/SRC-2, c/CIP/AIB1/SRC-3), can potentiate the estrogen-induced transcriptional activation of ERalpha target genes in transfection experiments. These findings, together with our recent data that mammary epithelial cells expressing SRC-1 are independent of these expressing ERalpha in normal breast, suggest a role for ERalpha coregulators in estrogen-stimulated breast cancer cell proliferation. The contributions of ERalpha coregulators in breast biology and estrogenmediated cell proliferation are not clear. We postulate that overexpression of SRC-1 family members contributes to estrogen-stimulated breast cancer cell proliferation. Our working hypotheses are: 1) SRC-1 family members act as coactivators for ERalpha and are segregated from ERalpha in normal epithelium; and 2) overexpression and colocalization of SRC-1 family members with ERalpha potentiates the transactivation function of ERalpha and estrogen-stimulated cancer cell proliferation. To integrate knowledge of cell signaling with whole organ biology, three aims are proposed to test the above hypotheses. In Aim 1, we will profile the expression and localization of ERalpha and SRC-1 family members during mammary gland development and compare

50

Estrogen

this to carcinogen-induced mammary tumors. The coactivators which are overexpressed in tumors, or segregated from ERalpha in normal mammary epithelium but colocalized with ERalpha in breast tumors, will be used for subsequent studies. In Aim 2, we will assess if overexpression or altered colocalization of SRC-1 family members can enhance in situ ERalpha transactivation function in normal breast. We will use our unique adenoviral approach to reconstitute ERalpha transactivation function in situ and deliver genes of interest locally into mammary epithelium in an intact microenvironment. In Aim 3, we will assess the contribution of SRC-1 family members to ERalpha transactivation function in modulating estrogen-stimulated cell proliferation and development of the mammary gland. These studies will provide a better understanding of the roles of transcriptional regulators of ERalpha in estrogen-regulated cell proliferation. The identification of abnormal expression and localization of these transcriptional regulators may lead to the development of new therapeutic targets and improved strategies for the prevention and treatment of breast cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENDER DIFFERENCES IN DRUG ABUSE Principal Investigator & Institution: Becker, Jill B.; Professor; Psychology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2003; Project Start 01-SEP-2000; Project End 31-MAY-2008 Summary: (provided by applicant): The onset of addiction to cocaine is more rapid in women than in men. Women begin using cocaine earlier, enter treatment at earlier ages, and are taking more cocaine at intake than men. Furthermore, cocaine cues induce more drug craving in female than male addicts. Basic research on the role of sex and ovarian hormones in the neurochemical and behavioral responses to acute and repeated exposure to cocaine is an important next step to enhance our understanding of the processes involved in gender differences in drug abuse. Experiments proposed will test the hypothesis that female rats are more susceptible to the behavioral effects of cocaine than are males because of organizational effects of gonadal hormones during development as well as activational effects of estrogen in adulthood. As a first step towards determining if there are organizational effects of gonadal hormones during prenatal development, we will look at whether there are sex differences in adulthood independent of circulating gonadal hormones in behavioral and neurochemical responses to cocaine. We will also investigate whether estrogen in adult females further enhances the induction and persistence of these measures. Finally, we will explore whether treatment can ameliorate these sex differences, experiments will test the hypothesis that progesterone can reverse the effect of estrogen on cocaine selfadministration. There are 5 specific aims which address these hypotheses: 1) To determine if there are sex differences in or hormonal influences on the persistence of behavioral sensitization to cocaine. 2) To determine if in females, estrogen enhances behavioral sensitization by potentiating the cocaine-stimulated increase in dopamine in dialysate from the dorsal striatum and nucleus accumbens acutely and after sensitization to cocaine. 3) To determine the effect of sex and gonadal hormones on reinstatement of cocaine self-administration. 4) To determine the effect of sex and gonadal hormones on acquisition of cocaine self-administration and breaking point after prior sensitization to cocaine. 5) To determine if progesterone can reverse the effects of estrogen on cocaine self-administration. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

Studies 51

•

Project Title: GENDER DEMYELINATION/REMYELINATION

SUSCEPTIBILITY

TO

Principal Investigator & Institution: Matsushima, Glenn K.; Microbiology and Immunology; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2003; Project Start 15-FEB-2003; Project End 31-JAN-2007 Summary: (provided by applicant): A number of autoimmune diseases show gender differences in susceptibility and severity. Multiple Sclerosis afflicts females at nearly twice the frequency as males; however, males tend to have a more severe disease profile and mortality. In our murine model of demyelination/remyelination that show features similar to MS, we find male mice that are chronically exposed to a neurointoxicant, cuprizone, undergo episodic demyelination/remyelination in the central nervous system. After a third episode of demyelination, male mice show grand mal seizures and die whereas females, although undergo similar episodic demyelination/remyelination, remain viable longer. This proposal investigates the role of estrogen, estrogen receptors and growth factors that may account for gender differences in seizures and demyelinating disease. We will study a plausible mechanism for the action of estrogen, test in vivo whether estrogen and IGF-1 can alter disease progression in male and female mice, and the role of estrogen receptors in gender differences. Our hope is to understand the interplay of these factors and elucidate mechanisms that may alter or ameliorate CNS demyelinating disease in both genders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE ACTIVATION BY ANTIESTROGENS USED IN CANCER THERAPY Principal Investigator & Institution: Kushner, Peter J.; Associate Research Biochemist; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2003; Project Start 08-JAN-1999; Project End 31-JAN-2008 Summary: (provided by applicant): Our long term objective is to understand the biochemical mechanisms and physiological significance of estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta) activation of gene expression at target genes with AP-1 or CRE sites (AP-1/CRE). Such AP1/CRE target genes, including cyclin D1, lack classical estrogen response elements (EREs) but are nonetheless induced by ER action. ERa activates AP-1/CRE primarily with estrogen and ERbeta, in contrast, only with antiestrogens. To understand how ERs work at AP- 1/CRE, we will exploit a mutation that makes both ERs selectively and dramatically superactive at AP-1/CRE sites and only with estrogen. ER induction of AP-1/CRE target genes may underlie some of the most profound effects of estrogen, those on cellular proliferation in the mammary gland and reproductive track. We find that the selectively superactive ERalpha, K206A, drives overexpression of cyclin D1 and hyper-proliferation in the genital track of transgenic female mice. K206A also drives overexpression of cyclin D1 in cultured cells, but the presence of ERa inhibits such activation. We thus wish to explore the hypothesis that ERa action at AP-1/CRE elements drives some of the proliferative effects of estrogen, especially in the mammary gland and reproductive track, and that the presence of ERbeta, by inhibiting activation of AP-1/CRE targets, modulates these effects. Our aims are: Aim 1. Determine the molecular mechanisms of ERalpha-estrogen activation and K206A super-activation at AP-1/CRE elements. Aim 2. Determine the physiological role of ERalpha activation of AP-1/CRE elements in the mammary gland.

52

Estrogen

Aim 3. Determine the mechanism whereby ERbeta inhibits the ability of ERalpha and ERalpha K206A to activate at AP-I/CRE with estrogen. Aim 4. Determine whether ERbeta, which inhibits ERbeta stimulation of cyclin D1 gene expression, also inhibits cellular proliferation mediated by ERalpha. If successful, these studies will test the hypothesis that ERalpha action at AP-1/CRE target genes mediates proliferation, and that ERbeta modulates such action. The knowledge gained will be greatly useful for developing a new generation of drugs to prevent estrogen induced cancers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC MECHANISMS OF ESTROGEN ATHEROPROTECTION Principal Investigator & Institution: Villablanca, Amparo C.; Internal Medicine; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 95616 Timing: Fiscal Year 2002; Project Start 01-JUN-1999; Project End 31-MAY-2004 Summary: The candidate is a Hispanic female (U.S. citizen) from Santiago, Chile. I am clinically trained in cardiovascular medicine and have interest and expertise in heart disease in women. As a newly promoted Associate Professor at the University of California, Davis I have prior research experience in cellular and molecular biology investigating the actions of vasoactive peptides in endothelial cell growth and function in vitro. My clinical interest in estrogen as a modulator of cardiovascular risk and mortality in women, leads me to now seek to extend my prior research work in a new research direction to investigate mechanisms of hormonal regulation of vascular gene expression in atheroprotection. I am at a critical juncture in my career where clinical responsibilities threaten my future research progress. I need and seek protected research time and additional research training under the guidance of a mentor in three areas: [1] the use of murine models of disease, [2] molecular genetics, and [3] physiologic studies to investigate functional significance of genetic changes. To attain this goal I have enlisted the help of Dr. Stephen Barthold as mentor and Dr. Beverly Paigen as comentor. Dr. Barthold is an expert in mouse biology and directs the UCDavis Center for Comparative Medicine which oversees the Mouse Biology Program. Dr. Paigen has expertise in murine models of atherosclerosis and is a senior research scientist at the Jackson Laboratories. Together, we propose a research development plan with five components: [1] didactic course work at UCDavis, [2] didactic and hand-on laboratory work at the Jackson Laboratory, [3] participation in research seminars and lectures, [4] attendance at National and International scientific meetings, and p5[ a state-of-the-art hands-on research program. The research development plan provides seamless integration with the research plan. The overall goal of the research proposal is to understand the action of estradiol, the estrogen receptor, and estrogen/receptor interactions on atheroprotection, vascular function and gene expression in mice. Previous studies suggest the possibility of both receptor-dependent and independent mechanisms of atheroprotection by estrogen, yet surprisingly, genetic mechanisms of atheroprotection by estrogen have not been investigated and a suitable atherogenic mouse model has not been developed. In conjunction with physiological studies we wish to use established mouse genetic models, and create new genetically engineered models, in order to investigate the overall hypothesis that: [1] The atheroprotective action of estrogen is mediated by the estrogen receptor, and [2] The beneficial effects of estrogen are accompanied by expression of estrogen-sensitive genes that regulate atheroprotection in the vascular wall. To investigate this hypothesis we will pursue the following specific aims: [1] Develop an estrogen receptor alpha deficient and sufficient mouse model of atherosclerosis and characterize it by quantitative histology of atheroma and vasomotor tone using aortic tension assays in vitro. [2] Use the model

Studies 53

developed in aim 1 to identify vascular genes that are up-regulated by estrogen by differential gene expression RNA fingerprinting by RT-PCR, and examine the role of selected other candidate genes that are likely to be influenced by estrogen (Ath 1, CASH, PAI-1, and aldose reductase) by Northern analysis. [3] Use molecular genetic methods for targeted deletion of mouse genes to determine the physiologic role of specific genes in newly created gene knock out mice, using the parameters optimized in Aim 1. The research and training environment available to the candidate for the conduct of these studies of vascular function and genetics is robust, the candidate's commitment is very strong, and the potential for success substantial. Advances in our basic understanding of mechanisms of hormone action could lead to more effective strategies for treatment of coronary artery disease in both men and women. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC POLYMORPHISMS BENIGN PROSTATIC HYPERPLASIA Principal Investigator & Institution: Roberts, Rosebud O.; Associate Professor; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 16-MAR-2002; Project End 31-JAN-2005 Summary: (provided by applicant) Benign prostatic hyperplasia (BPH) is the most frequent cause of lower urinary tract symptoms and office visits to urologists among elderly men. Despite this, little is known about the etiology and risk factors for BPH and the only proven risk factors for BPH to date are increasing age and an intact androgen metabolism. Estrogens have also been observed to act synergistically with androgens in the development of BPH. Recent studies suggest that the pathogenesis of BPH is related to a decrease in the serum androgen: estrogen ratio with increasing age. Serum hormone levels, however, have not been consistently associated with BPH risk, possibly because serum levels may not reflect intracellular hormone levels in prostate cells. Since hormone levels within prostate cells may reflect genetic variations, polymorphisms in genes that regulate intracellular androgen and estrogen levels in prostate cells may play an etiologic role in BPH. Several functionally significant polymorphisms have been described for genes that determine androgen and estrogen levels. These polymorphisms may alter the risk of BPH by altering hormone levels or by their effects on androgen and estrogen receptor-mediated events within the prostate. We propose to test the hypothesis that genetic polymorphisms in sex hormone receptors and sex hormone metabolizing enzymes are etiologic risk factors for BPH. In Specific Aim 1 we will test the association between genetic polymorphisms in androgen and estrogen receptor genes and measures of BPH obtained longitudinally in a cohort of men randomly selected from the community. In Specific Aim 2 we will test the association between polymorphisms in genes that encode enzymes involved in androgen and estrogen biosynthesis and activation and measures of BPH in the same cohort. We will evaluate the CYP11A1, CYP17, CYP19, 3Beta hydroxysteroid dehydrogenase, 17BETA hydroxysteroid dehydrogenase types 2,3, 5, and SRD5A2 genes. In SpecificAim 3 we will test the association between polymorphisms in genes that encode enzymes involved in estrogen bioactivation and inactivation and measures of BPH in the same cohort. These genes include CYP1A1, CYP1A2, CYP1B1, catechol 0-methyl transferase, sulfotransferase 1A1, and glutathione S-transferases (M1, P1, and T1). This communitybased cohort study should provide insights that should improve our understanding of the genetic control of hormonal mechanisms in the pathogenesis of BPH. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

54

•

Estrogen

Project Title: GENOTOXICITY OF ESTROGEN-AND ANTI-ESTROGEN-DNA ADDUCTS Principal Investigator & Institution: Shibutani, Shinya; Pharmacological Sciences; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2002; Project Start 13-MAY-1998; Project End 31-JUL-2007 Summary: (provided by applicant): Tamoxifen, an antiestrogen used in the endocrine therapy and chemoprevention of breast cancer, induces liver cancer in rodents and is associated with endometrial cancer in women. Estrogens also are implicated in the etiology of endometrial and breast cancer. The carcinogenicity of these agents may be mediated through their genotoxic effects. The goals of this research are to establish a mechanism for the genotoxicities of tamoxifen and estrogen and to find a safer alternative to tamoxifen. Oligodeoxynucleotides containing a single defined DNA adduct will be prepared by automated DNA synthesis. Using these site-specifically modified oligodeoxynucleotides, the mutagenic and repair potential of estrogen and anti-estrogen DNA adducts in mammalian cells will be determined. The three dimensional structure of tamoxifen- and estrogen adducts in DNA duplex also will be established, permitting us to understand the process of mutagenic and repair events which occur at lesion sites. Such modified oligodeoxynucleotides also will be employed as standards in ultrasensitive 32P-postlabeling and HPLC/electrochemical detector analyses designed to quantify DNA adducts and oxidatively damaged lesions in the tissues of rodents and monkeys treated with these drugs. Taken together, this information can be used to predict genotoxicity. Translational studies have been designed to detect adducts in the endometrial DNA of patients undergoing treatment with tamoxifen or toremifene. These experiments will provide biomarkers for molecular epidemiological studies and explore the relationship between tamoxifen therapy and the development of endometrial cancer in women treated with this drug. This research should lead to a safer alternative for women undergoing breast cancer therapy and for chemoprevention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: HAMSTER: A UNIQUE MODEL FOR STUDYING IMPLANTATION Principal Investigator & Institution: Paria, Bibhash C.; Pediatrics; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-JAN-2009 Summary: (provided by applicant): Ovarian progesterone is essential for implantation in all species studied. However, the requirement of embryonic estrogen in this process is still an unsettled issue, except in mice and rats in which embryos do not possess the machinery for estrogen synthesis. Implantation can occur in several species including hamsters and perhaps in humans in the absence of ovarian estrogen if progesterone is provided. However, our recent study shows that: (1) estrogen, but not progesterone, regulates the uterine expression of heparin binding EGF-like growth factor gene (Hegfl) in ovariectomized hamsters, and (2) Hegfl expression occurs in the uterine luminal epithelium surrounding the blastocyst at the time of implantation in the absence of circulating estrogen in progesterone-primed hypophysectomized pregnant hamsters. These results suggest that hamster blastocysts could be an alternative source of estrogen that acts locally to induce Hegfl gene expression in the uterus. Indeed, our preliminary experiments suggest the presence of cytochrome P450 aromatase protein in hamster morulae and blastocysts. Furthermore, the exposure of hamster morulae to a steroidal cytochrome P450 aromatase inhibitor in culture significantly inhibits the formation of

Studies 55

blastocysts. These observations together with our preliminary results of estrogen receptor-alpha expression in preimplantation hamster embryos and uterus at the time of implantation led us to postulate that this species does not depend on ovarian estrogen, but requires embryonic estrogen to initiate embryonic and uterine changes required for implantation. However, neither the synthesis nor the role of embryonic estrogen in blastocyst formation, uterine receptivity and implantation in hamsters has been resolved. Thus, our specific aims to study in hamsters: (1) Do hamster preimplantation embryos produce estrogen? (2) Is embryonic estrogen required for morula-blastocyst transformation? (3) Is embryonic estrogen required for the establishment of uterine receptivity for implantation? (4) Does systemic estrogen induce uterine receptivity and implantation in the absence of embryonic estrogen? We will use multiple approaches including RT-PCR, in situ hybridization, immunohistochemistry, immunofluorescence, Western blotting, embryo culture and transfer and others to accomplish our goals. With better understanding of the mechanisms of embryo development and uterine receptivity for implantation, issues concerning fertility and infertility in women will be more effectively managed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HORMONE REPLACEMENT THERAPY AND LARGE BOWEL CANCER RISK Principal Investigator & Institution: Newcomb, Polly A.; Member and Acting Head; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2002; Project Start 19-AUG-1998; Project End 31-MAY-2004 Summary: The benefits and risks of estrogen replacement therapy continue to confuse women and their physicians. Recent evidence suggests that estrogen replacement may be associated with reductions in large bowel cancer, a common disease among postmenopausal women. Further study of this potentially important association would provide more precise estimates of the magnitude of effect, identify salient patterns of use, and, importantly, supply insights into the biology of this tumor in women. A population-base case-control study is proposed to evaluate the association between postmenopausal hormones and the occurrence of colorectal cancer. This study will specifically assess use of estrogens with and without progestin, the duration and currency of hormone use, and inter-relationships with body mass. Additional aims of this study are to elucidate the mechanisms of this inverse association, specifically the relationship of HRT to hormone receptors and proliferation in the bowel, and to examine the modifying role of more common cancer susceptibility genes influencing the metabolism of estrogens. Over a three year period, interviews will be conducted with 1,100 women with newly diagnosed cancer of the colon or rectum selected from the population. In addition to the structured telephone interview, fixed diagnostic tissue will be obtained from 540 case in order to evaluate estrogen-receptor status and proliferation markers. Blood samples on a sample of 600 (most with diagnostic tissue) cases and 600 controls will be obtained for genetic studies of polymorphisms relevant to estrogen metabolism and function, specifically CYP17 and the estrogen receptor gene. The proposed study and its extensions should provide clear evidence for the degree to which HRT is protective against colorectal cancer and permit the determination of some of the relevant pathways for that protection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

56

•

Estrogen

Project Title: IMMUNOREGULATORY EFFECTS OF ESTROGEN IN EAE Principal Investigator & Institution: Offner, Halina; Professor; Neurology; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-JUL-2006 Summary: (provided by applicant): In patients with multiple sclerosis (MS), there is a distinct gender bias, with approximately twice as many affected females as males. Sex hormones may contribute to susceptibility or resistance to MS by influencing development and function of potentially pathogenic T cells specific for central nervous system (CNS) antigens, as well as regulatory T cells that might modify the course of disease. Previously, we reported that low doses of 17beta-estradiol (E2) can reduce severity of EAE by inhibiting activation, cytokine and chemokine production, and encephalitogenicity of murine T cells specific for myelin oligodendrocyte glycoprotein (MOG), proteolipid protein (PLP), or myelin basic protein (MBP), and by inhibiting I recruitment of inflammatory cells into the CNS. Of particular importance, estrogen treatment profoundly reduced intracellular production of TNF-alpha, known as a critical inflammatory cytokine in EAE and MS. Recent evaluation of E2 effects on EAE using microarray analysis of splenocyte gene expression confirmed potent inhibition of TNF-alpha, and further identified several previously unsuspected immune-associated candidate genes appearing to be strongly affected by E2 treatment in vivo. These modulatory effects of estrogen on pathogenic, recruited, and regulatory cells in EAE are likely mediated y direct interaction with estrogen receptors (ER), which include the classical ER-alpha and ER-beta that are internal f receptors (iER), and possibly membrane ERs (mER) that may be distinct from iERs. This proposal will test the hypothesis that modulation of EAE by estrogen involves receptor-mediated regulation of TNF-alpha and several other novel immunerelated genes, thereby inhibiting inflammatory effects of macrophages, dendritic cells and T cells and enhancing regulatory NKT cell activity. Our primary goals are to determine if the inhibitory effects of E2 on EAE can be observed in spontaneous EAE in the absence of regulatory T and NKT cells, and if inhibitory effects of E2 on EAE are mediated through iER-alpha and /or iERbeta, or in contrast, by neither of the classical iERs. Using newly developed ERalpha and ER-beta knockout mice we will for the first time associate E2- dependent regulation with either or both iERs, or alternatively with mER if E2 effects persist in double KO mice. Moreover, for each novel E2-affected gene implicated from the microarray analysis, we will investigate the cellular source, effects of E2 on transcription and protein production, and contribution to EAE induction in vivo. Genes found to be important in EAE will be further evaluated in blood cells from women with different levels of E2. The work proposed will identify key estrogen-sensitive genes, including TNFalpha, contributing to EAE induction and resistance. Changes in these genes can be followed during estrogen treatment as surrogate markers to verify effective doses of estrogen. From this research, we will develop a solid basis for using estrogen replacement therapy for MS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: INDUCTION OF BREAST CANCER IN MMTVNEU MICE Principal Investigator & Institution: Baldwin, William S.; Biological Sciences; University of Texas El Paso El Paso, Tx 79968 Timing: Fiscal Year 2002; Project Start 25-SEP-2001; Project End 31-JUL-2004 Summary: Environmental estrogens, such as PCBs, phthalates, and alkylphenols increase estrogen-responsive growth in vitro. This could play a role in the increase in

Studies 57

breast cancer incidence witnessed in developing countries since the industrial revolution. The objective of this study is to examine the carcinogenicity of the environmental estrogen, 4- nonylphenol, in a transgenic mouse model (MMTVneu) with a high propensity for developing primary tumors of the mammary glands and metastasis to the lung. Mice will be treated with 4-nonylphenol for 180- 200 days and then euthanized. Tumor incidence, number, proliferation and metastasis will be compared between treated and untreated mice to determine 4nonylphenol's effects on these parameters. Once a month during the study and following euthanasia, blood will be drawn and circulating estradiol levels will be examined for alterations caused by 4nonylphenol. Primary tumor tissue will be collected following euthanasia and examined for changes in cell cycle kinetics and production of estrogen response genes such as pS2 and TGFA3. Since 4nonylphenol has significantly greater effects on estrogen-responsive transcription than its estrogen receptor affinity would suggest and it alters steroidogenic P450 levels, it is our theory that 4-nonylphenol alters estradiol metabolism, inactivation and elimination. Therefore, livers will be collected from the mice and estradiol hydroxylation and conjugation will be investigated. Overall, the purpose of this study is to examine 4-nonylphenol's effects on breast cancer growth and its mechanism of action on the mammary tumor. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTERACTIONS BETWEEN DIETARY SOY COMPONENTS & TAMOXIFEN Principal Investigator & Institution: Zhou, Jin-Rong; Assistant Professor; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2002; Project Start 12-SEP-2001; Project End 31-MAY-2004 Summary: (provided by applicant): This proposal is focused on the interactive effects between soybean phytochemicals and tamoxifen (TAM) on breast cancer (BRCA). The hypothesis is that soy phytochemicals, especially soy isoflavone genistein, may counteract the inhibitory effect of TAM on estrogen-dependent BRCA, but may inhibit the growth of TAM-resistant BRCA and synergize the inhibitory effect of TAM on estrogen-independent BRCA. TAM has become the first-line treatment for estrogendependent BRCA, while its effect on estrogen-independent BRCA is limited. The positive response is usually of short duration, and most tumors eventually develop TAM-resistance. Soy phytochemicals, especially soy isoflavones, have anti-tumor activities. On the other hand, soy isoflavones are weak phytoestrogens and may interfere with TAM in competing with the binding sites of estrogen-receptors and modulate estrogen-mediated transcription. With more and more women are taking TAM and soy phytochemical supplements, it is imperative to evaluate the potential interactions between TAM and soy phytochemicals before any guideline and recommendations can be made. Our preliminary studies have found that soy isoflavone genistein counteracts the inhibitory effect of TAM on estrogen-dependent breast cancer cells, but may synergize the inhibitory effect of TAM on estrogen-independent breast cancer cells. Specific Aim 1 is to determine the combined effect of soybean components and TAM on the growth of estrogen-dependent human breast tumors. MCF-7 human BRCA cells will be implanted into mammary fat pad of immune deficient mice to develop estrogen-dependent breast tumor model to evaluate the interactive effects between a novel soy phytochemical concentrate or soy isoflavone genistin and TAM on MCF-7 tumor growth. Specific Aim 2 is to determine the effect of soybean bioactive components on the growth of TAM-resistant human breast tumors. A clinically relevant TAM-resistant human breast tumor model will be applied to evaluate the effects of

58

Estrogen

soybean components on the growth of TAM-resistant breast tumor. Specific Aim 3 is to determine the combined effect of soybean components and TAM on the growth of estrogen-independent human breast tumors. MDA-MB-435 human BRCA cells will be implanted into mammary fat pad of immune deficient mice to develop an estrogenindependent breast tumor model to evaluate the combined effects of soy components with TAM on estrogen-independent BRCA. A series of biomarkers will be determined to elucidate the possible mechanisms of action. We will first determine the biomarkers that are related to estrogen-pathways such as tumor expressions of ER(alpha), ER(beta) and serum levels of estrogens. We will then quantify tumor proliferation index by PCNA staining and apoptotic index by TUNEL assay. We will quantify tumor microvessel density (factor VIII staining) as an angiogenesis marker and the expression of angiogenesis factors, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). These in vivo bioassays and mechanistic studies will be expected to provide significant insight into the future consideration of potentiating the efficacy of TAM on BRCA treatment and prevention by soy bioactive component-containing supplements. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS AND NEURAL CONSEQUENCES OF ESTROGEN ACTION Principal Investigator & Institution: Sohrabji, Farida; Assistant Professor; Human Anatomy and Medical Neurobiology; Texas A&M University Health Science Ctr College Station, Tx 778433578 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 31-JAN-2006 Summary: (provided by the applicant): The overall goal of this research is to define the mechanisms and consequences of estrogens actions on the forebrain, which we will address in two specific aims. The first aim is to determine the cellular consequences of estrogen-mediated alterations in the ratio of neurotrophin receptors. In the adult forebrain, estrogen increases trk receptors and decreases p75, resulting in a favorable trk/p75 ratio, while in the reproductively senescent forebrain, estrogen replacement, paradoxically, results in an unfavorable trk/p75 ratio. While both neurotrophin receptors stimulate distinct and overlapping signaling pathways, the trks typically promote cell survival, while p75 may stimulate either cell survival or cell death. Here, our in vivo models will be used to assess how estrogen mediated changes in trk/p75 ratios will affect down-stream neurotrophin signaling and, consequently, cell fate, when challenged, in vivo, with neurotrophin stimulation or injury. The second aim is to test the hypothesis that expression/activation of the alpha form of the estrogen receptor (ER-alpha) is detrimental to cell health. Two estrogen receptors have been identified, although the specific contribution of each receptor to neural function is not clearly defined. Recent observations indicate that high ER-alpha expression is associated with decreased estrogen responsiveness on measures such as neurotrophin expression and cell survival. Estrogen receptor specific ligands, in conjunction with ex vivo and in vitro models, will be used to determine the contribution of each estrogen receptor to neurotrophin expression, signal transduction and cell death. These studies will also employ DNA microarray analysis, with the eventual goal of developing strategic gene arrays to facilitate rapid detection of estrogen-mediated cellular changes and to discriminate between the actions of receptor specific ligands. In view of the recent conflicting evidence regarding estrogen use and Alzheimer's disease, understanding the biology of estrogens actions are more critical now than ever. Moreover, identifying

Studies 59

hormone-stimulated pathways that initiate cell-degenerative events will be increasingly important to the development of target and receptor specific estrogenic compounds. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF HORMONE THERAPY IN POSTMENOPAUSAL WOMEN Principal Investigator & Institution: Newby, L K.; Medicine; Duke University Durham, Nc 27706 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-MAR-2004 Summary: The use of unopposed estrogen of combined estrogen/progestin therapy for primary and secondary prevention of coronary disease events in post- menopausal women is gaining favor in the United States. Support for this practice is based largely on epidemiological association of a reduction in the risk of death and non-fatal myocardial infarction in populations of women mostly without prior coronary artery disease who took estrogen for a variety of reasons. The effects of adding a progestin to estrogen are less well studied. Because the potential public health impact from treatment of postmenopausal women with hormone replacement therapy for prevention of coronary artery disease events is enormous, it is imperative to establish a fund of knowledge that supports and aids in the interpretation of clinical trials data to help establish the group or groups for whom treatment should be recommended and when it should be initiated. To accomplish these goals we propose: 1. Using non-invasive measurement of vascular reactivity, to quantify the effect on vascular endothelial function of the addition of progesterone to estrogen therapy in post-menopausal women with and without coronary artery disease. 2. To study the effect of various combinations of postmenopausal hormone therapy on the coagulation system. 3. To use accumulated clinical trials databases to study clinical factors that may influence the efficacy of hormone replacement therapy for secondary prevention of coronary artery disease in postmenopausal women. The propose work will provide additional understanding of the mechanism of estrogen action on endothelial function (which is postulated to be the major mechanism of the beneficial effects of estrogen) and the effects of adding progestins to estrogen replacement regimens. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: MODULATION OF ESTROGEN RECEPTOR FUNCTION BY BRCA1 Principal Investigator & Institution: Boyer, Thomas G.; Molecular Medicine; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): Our long-term goal is to understand how inactivation of the breast cancer susceptibility gene, BRCA1, leads to breast tumorigenesis. At the cellular level, BRCA1 ensures global genome stability by coupling DNA damage-induced signals to downstream responses, including DNA damage repair and cell-cycle checkpoint activation. Because the DNA damage-induced signaling pathways that converge on BRCA1 are conserved in most cell types, BRCA1 is likely to function ubiquitously in the maintenance of genome integrity. Nonetheless, germline inactivation of BRCA1 leads principally to cancer of the breast and ovary, and the underlying basis for its tissue-restricted tumor suppressor function remains poorly defined. Recently, we discovered a novel function for BRCA1 in suppressing the ligandindependent transcriptional activity of the estrogen receptor alpha (ERalpha), a principal determinant of the growth and differentiation of breasts and ovaries.

60

Estrogen

Importantly, we showed that clinically validated BRCA1 missense mutations abrogate this repression activity, suggesting that its ERalpha-specific repression function is important for the biological activity of BRCA1 in breast and ovarian tumor suppression. In human breast cancer cells, we observed an association between BRCA1 and ERalpha at endogenous estrogen-responsive gene promoters before, but not after, estrogen stimulation. Furthermore, we demonstrated that forced reduction of BRCA1 in estrogendependent human ovarian cancer cells could be correlated with increases in both the estrogen-independent transcription of ERalpha-target genes and estrogen-independent proliferation. We therefore hypothesize that BRCA1 represents a ligand-reversible barrier to transcriptional activation by unliganded ERalpha, and further, that mutational inactivation of BRCA1 promotes breast and ovarian epithelial cell proliferation through aberrant expression of estrogen-responsive genes. To confirm and extend this hypothesis, we propose the following aims. Aim 1 is to elucidate the mechanism by which BRCA1 represses the ligand-independent transcriptional activity of ERalpha. Aim 2 is to characterize the regulation of BRCA1-mediated ERalpha repression by both estrogen-dependent and estrogen-independent cell signals. Aim 3 is to establish the biological role of BRCA1 in the control of cellular proliferation through modulation of ligand-independent ERalpha activity. These studies should reveal novel insight into the tissue-specific tumor suppressor function of BRCA1 and provide defined molecular targets for future intervention in breast cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MODULATION OF VISCERAL FAT BY ESTROGENS AFTER MENOPAUSE Principal Investigator & Institution: Kohrt, Wendy M.; Professor; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 15-FEB-2000; Project End 31-JAN-2005 Summary: Excess abdominal visceral fat is associated with increased risk for coronary artery disease (CAD), Type 2 diabetes mellitus (DM), and hypertension. Although premenopausal women are largely protected against abdominal obesity, visceral fat accumulation increases after the menopause and there are concomitant deleterious changes in risk factors for CAD and Type 2 DM. Estrogen replacement attenuates increases in body weight and waist girth in postmenopausal women. However, it is not known whether estrogen use prevents or diminishes the visceral fat accumulation that occurs after menopause. It is possible that protective effects of estrogen on visceral fat metabolism contribute to the currently unknown component of the cardioprotective actions of estrogens. The specific aims of the proposed studies are to determine in postmenopausal women whether: 1) estrogen use augments reductions in visceral fat; 2) estrogen use attenuates increases in visceral fat; 3) changes in visceral adiposity are related to changes in whole body and regional resistance to the suppression of lipolysis by insulin and whether this relationship is altered by estrogens; and 4) changes in visceral adiposity are associated with changes in certain risk factors for CAD and Type 2 DM independent of an in addition to the effects of estrogen. An additional aim is to determine whether raloxifene exerts similar effects as estrogens on visceral fat. Faloxifene is a popular selective estrogen receptor modulator that is being promoted as a safer alternative to estrogen not only for its osteogenic effects but also for possible cardioprotective effects. To meet these aims, 108 healthy but overweight postmenopausal women, aged 50- 60 years, will be randomly assigned a placebo, estrogen, and weight reduction program and subsequent increases in adiposity will be

Studies 61

measured through a 12-month follow-up period during which time the hormone/drug treatment will continue. Changes in risk factors for CAD and Type 2 DM (blood lipids and lipoproteins, glucose tolerance, insulin resistance) in response to reductions and gains in visceral adiposity will be measured. Because insulin resistance is a prominent characteristic of abdominal obesity, the effects of estrogen/raloxifene and of changes in visceral, adiposity on the glucoregulatory and anti-lipolytic actions of insulin will be evaluated during hyper-insulinemic, euglycemic clamp procedures. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR MECHANISMS OF ESTROGEN NEUROPROTECTION Principal Investigator & Institution: Wang, Michael M.; Biological Chemistry; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 20-APR-2001; Project End 31-MAR-2006 Summary: We have demonstrated that female rats experience significantly decreased brain injury after experimental stroke compared to male rats. Ovariectomy eliminates the protection from stroke injury enjoyed by female rats, suggesting that female reproductive hormones are neuroprotective. Furthermore, we have shown that exogenous estrogen is neuroprotective in multiple models of stroke. Two estrogen receptors, ER-alpha and ER-beta, act in neurons via a number of mechanisms. Estrogen receptors directly regulate gene transcription and, in addition, trigger the MAP kinase signaling cascade. The present proposal focuses on the molecular mechanism of how estrogen protects the brain from stroke. The overall hypothesize of this proposal is that estrogen protects the brain during stroke by acting upon estrogen receptors within neurons of the brain. We will use a tissue culture model of neuronal injury to address several specific questions regarding estrogen's action on neurons. In Aim 1, we will determine whether estrogen receptors are necessary for estrogen-mediated protection by examining properties of neurons in which receptors have been inactivated. In Aim 2, we will evaluate whether activation of estrogen receptor-mediated transcription is sufficient for neuroprotection by utilizing molecular mutants of ER which constitutively activate estrogen signaling. In Aim 3, we will determine whether Src/Ras/MAP kinase activation, known to occur during estrogen stimulation of neurons, plays a role in protection. In Aim 4, we will ask whether our in vitro mechanism is valid in the intact animal using viral mediated gene transfer into an in vivo model of stroke. The mechanism of how estrogen affects stroke will perhaps foster development of novel treatments for stroke, and may influence hormone replacement regimens for postmenopausal women. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: ACTIONS

MOLECULAR

MECHANISMS

OF

ESTROGENS

VASCULAR

Principal Investigator & Institution: Clark, Kenneth E.; Professor; Obstetrics and Gynecology; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-JUL-2004 Summary: Although the uterine vascular effects of estrogen have been studied for over 70 years, the mechanism by which estrogen produces vasodilation remains unclear. Our laboratory was the first to show that a significant component of the uterine response to estrogen in the nonpregnant sheep is mediated by the release of nitric oxide (NO). We and others have shown that estradiol-17beta increases the expression and activity of endothelial nitric oxide synthase (eNOS) in the uterine circulation. However, it is not

62

Estrogen

currently clear how this occurs or if, in addition to eNOS, neuronal nitric oxide synthase (nNOS) or inducible nitric oxide synthase (iNOS) are also important in maintaining the sustained vasodilatory response seen after estrogen administration. Furthermore, it is not clear how estrogen modulates these NOS isoforms at the cellular and molecular level. Recently a new estrogen receptor, ERbeta has been isolated and emerging data suggest that this receptor may mediate a significant portion of the effects of estrogen in the vasculature. We hypothesize that uterine vasodilation produced by estradiol-17beta is mediated by specific interaction with both ERalpha and ERbeta, which subsequently activates eNOS (and potentially nNOS) via a nongenomic pathway, and iNOS via a genomic pathway, leading to increases in NO. The present application plans to evaluate the role of ER as a modulator of the NOS isoforms in the uterine circulation using a combination of physiologic and molecular endpoints. We will monitor the uterine hemodynamic responses to locally and systemically administered pharmacological antagonists that are selective for specific isoforms of NOS using a well-characterized ovine model. We intend to evaluate the expression of ERalpha and ERbeta in the ovine uterine vasculature and explore how estrogen alters eNOS, nNOS and NOS expression in endothelial cells and vascular smooth muscle. Finally we plan to determine if endogenous estrogen, acting through the uterine vascular NOS system, plays a critical role in increasing and maintaining uterine blood flow in late pregnancy. We believe that the information obtained in this revised application will provide new and important understanding into the mechanisms regulating vascular tone and hemodynamics in the uterine circulation in both the nonpregnant and pregnant animal. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NATURAL MUTATION AT THE COACTIVATOR BINDING SITE OF ER Principal Investigator & Institution: Nichols, Mark D.; Pharmacology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-JUN-2001; Project End 31-MAY-2004 Summary: (Scanned from the applicant's abstract) The coactivator binding site of the estrogen receptor (ER) must be generated by hormone binding to the ER, folding the Cterminal helix 12 over the ligand pocket and forming the interaction surface for the LXXLL motif of coactivator proteins, for estrogen hormone signals to properly activate responsive genes in target tissues. Antihormones block the action of estrogens by binding the ER LBD and misfolding helix 12 into a position that occludes coactivator binding. Similarly, the presence and abundance of specific coregulator gene products are also proposed to explain tissue-specific ligand differences, e.g. tamoxifen antagonism in breast and partial agonism in endometrium. Differential activity of estrogenic ligands, including selective estrogen receptor modulators (SEAMs), probably derive from varied cofactor interaction. Single amino acid changes in ER, some with significant phenotypic changes, currently remain under-evaluated. We have developed an assay in yeast to report normal, hormone-induced folding of the ER AF-2 that is very sensitive to mutationa' disruption. Using this assay, ER LBDs have been recovered from tissues and tumors that indeed show altered protein folding. In preliminary data from tumors so far analyzed, 3 have demonstrated changes in ER affecting the p160 coactivator binding site and tamoxifen folded structure. This proposal hypothesizes that significant alterations in estrogen stimulated transcription result from these naturally occurring changes in the estrogen receptor, its co-regulator proteins, or the interaction between them. This has important implications with respect to estrogen and antiestrogen functions in women, particularly those with cancers in estrogen responsive

Studies 63

tissues. The project aims are: 1) to determine mechanistic properties of the recovered estrogen receptors, using transcription assays in yeast and mammalian cells; 2) to test cofactor binding to recovered ER alleles with purified GST fusion proteins and in vitro transcription and translation experiments; 3) to isolate via RT-PCR and assay transcription with ER interacting! p160 coactivator clones SRC1, GRIP1, and NCOR cDNAs recovered from tissue samples, and 4) to isolate and identify further naturally occurring ER mutations in vivo, using assays sensitive to ER protein conformation of the AF-2 coactivator binding domain. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEUROCHEMICAL MECHANISMS OF VISCERAL PAIN Principal Investigator & Institution: Traub, Richard J.; Associate Professor; Oral & Craniofacial Biol Scis; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2003; Project Start 01-AUG-1999; Project End 31-MAY-2007 Summary: (provided by applicant): Irritable Bowel Syndrome (IBS) is characterized by abdominal pain in the absence of pathology. Epidemiological studies further show IBS is reported most often in menstruating women compared to post-menopausal women or men suggesting gonadal hormones could be a contributing factor. It was recently hypothesized that the pain of IBS could result from sensitization of visceral afferent fibers or hyperexcitability of dorsal horn neurons. Recent data suggests a role for spinal NMDA receptors in processing noxious and innocuous visceral stimuli and NMDA receptors in the brain are modulated by estrogen. The long-term goal of this application is to examine the effects of estrogen on spinal NMDA receptor-mediated processing of noxious and innocuous colorectal stimuli. We hypothesize that estrogen increases activity at spinal NMDA receptors in the absence and presence of colonic inflammation leading to colorectal allodynia and hyperalgesia. This modulation may result from alterations in NMDA receptor subunit composition or second messenger mediated phosphorylation. Using our model of colorectal distention (CRD), we will test these hypotheses by examining the effects of estrogen replacement in ovariectomized rats on visceral sensory processing in the spinal cord in the absence and presence of colonic inflammation, in the following specific aims: 1) Determine the effects of estrogen on responses to transient innocuous, noxious and inflammatory colorectal stimuli. Behavioral, immunocytochemical and electrophysiological studies will test the hypothesis that estrogen facilitates responses to CRD in the absence and presence of colonic inflammation. 2) Characterize the effects of estrogen on subpopulations of visceroceptive projection neurons using retrograde tract tracing and immunocytochemical localization of Fos expression. This will test the hypothesis that estrogen alters the percentage and segmental distribution of supraspinal projection neurons that respond to CRD in the absence and presence of colonic inflammation. 3) Determine if NMDA receptor-mediated modulation of viscerosensory processing is affected by ovariectomy and estrogen replacement. This will test the hypothesis that the modulation of responses to CRD by estrogen is due to altering activity at NMDA receptors. 4) Determine the mechanism(s) through which estrogen modulates CRDevoked NMDA receptor activity in the absence and presence of colonic inflammation. This will test the hypothesis that estrogen alters NMDA receptor subunit composition and/or modulates second messenger-mediated phosphorylation of tile NMDA receptor. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

64

•

Estrogen

Project Title: PHYSIOLOGY PROGESTERONE

OF

HYPOTHALAMIC

NEUROSTEROIDAL

Principal Investigator & Institution: Micevych, Paul; Professor; Neurobiology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): Neurosteroids, steroids synthesized in the brain, have been implicated in functions ranging from stress, depression, anxiety, to cognition. One neurosteroid is progesterone, a classic sex hormone involved in the regulation of reproduction. Although the CNS has the capacity to synthesize progesterone, to date it has appeared that only peripheral progesterone, from the ovaries and adrenals, regulates reproduction. Our preliminary studies have demonstrated that estrogeninduced hypothalamic progesterone synthesis is sufficient to initiate reproductive events necessary for ovulation and copulation. Estrogen stimulation of ovariectomized and adrenalectomized (ovx/adx) rats increased hypothalamic progesterone levels. In such animals, estrogen induced lordosis behavior and progesterone dependent proceptive behavior. Similarly, estrogen stimulation of ovx/adx rats induced a luteinizing hormone (LH) surge. In these rats, blocking 3beta-hydroxysteroid dehydrogenase (3beta-HSD), the enzyme that converts pregnenolone to progesterone, prevented the LH surge. Estrogen stimulates astrocytes in culture to synthesize progesterone, suggesting that glial cells may mediate estrogen-positive feedback. These data indicate that, absent the peripheral steroidogenic tissues, estrogen can induce progesterone dependent events by stimulating the synthesis of neurosteroidal progesterone. We propose to test the hypothesis: estrogen stimulates synthesis of hypothalamic progesterone that activates circuits regulating the LH surge and sexual behavior. Three experiments are proposed: First, using intact and ovx/adx rat models we will directly test whether the estrogen-induced LH surge is dependent on increased hypothalamic neurosteroidal progesterone. Second, we propose to determine whether estrogen increases the expression and/or activity of steroidogenic enzymes (P450 side chain cleavage and 3beta-HSD) needed to synthesize progesterone, in vitro and in vivo. Third, using the same intact and ovx/adx rat models, we will determine whether estrogen-induced hypothalamic progesterone is sufficient to facilitate sexual behavior. These studies will demonstrate the physiology of neurosteroidal progesterone and provide important new information about the mechanism of estrogen-positive feedback in the CNS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PREGNANCY ESTROGENS, DIET, AND BREAST CANCER RISK Principal Investigator & Institution: Hilakivi-Clarke, Leena A.; Professor; V T Lombardi Cancer Res Center; Georgetown University Washington, Dc 20057 Timing: Fiscal Year 2002; Project Start 15-AUG-2001; Project End 31-JUL-2006 Summary: Estrogen levels are elevated by 50-100 -fold during pregnancy, and interindividual variability in pregnancy estrogen levels is 4-6 -fold. Women exhibiting highest pregnancy estrogen levels are suggested to be at a significantly increased risk to develop breast cancer, perhaps due to an estrogen-induced promotion of existing transformed cells. Diet, particularly dietary fats, may affect pregnancy estrogen levels and later breast cancer risk. In our animal study, a high fat intake significantly increased pregnancy estrogen levels and increased pregnancy-promoted mammary tumor incidence. Polymorphism in genes that metabolize estrogens and have been linked to

Studies 65

increased breast cancer risk, may also affect pregnancy estrogen levels. Our proposed study has two general aims: (1) to study whether dietary fat intake affects pregnancy estrogen levels in women, perhaps by interacting with polymorphism in CYP17 and COMT, and (2) to study whether highest pregnancy estrogen levels might increase breast cancer risk by increasing growth factor levels. These growth factors could originate from mutated or already transformed mammary cells, which during pregnancy are stimulated by high estrogen levels. Growth factor levels will be measured in nipple aspirate fluid (NAF) that can be obtained using a breast pump from non-lactating breast. Consequently, the following hypotheses will be tested: Hypothesis1. We hypothesize that high dietary fat intake and weight gain increase pregnancy estrogen levels. We further hypothesize that polymorphism in CYP17 or COMT influences these interactions. Hypothesis-2. We hypothesize that higher circulating estradiol levels during pregnancy are associated with increased growth factor levels in nipple aspirate fluid, including EGF, TGFalpha and IGF-1/IGF binding protein 3. These aims will be studied in 200 pregnant women attending the Maternity Clinic at Solna in NAF will be obtained 12 months after giving birth. Our results may lead to modifications of pregnancy diet to reduce the risk to develop breast cancer. In particular, women who already are at high risk, for example, due to family history of breast cancer, age at first pregnancy (greater than 30 years), or other reproductive risk factors, may significantly benefit from pregnancy dietary modifications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RECEPTORS

PREGNANCY

HORMONES

AND

MEMBRANE

ESTROGEN

Principal Investigator & Institution: Htun, Han; Obstetrics and Gynecology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 09-AUG-2002; Project End 31-JUL-2004 Summary: (provided by applicant): Uterotropic effects of pregnancy-related estrogens, such as 17beta-estradiol (E2) and estriol (E3), occur by two different mechanisms, involving intracellular and membrane estrogen receptors. Traditionally, steroid hormone activation of intracellular steroid receptors, ligand-dependent transcription factors, leads to changes in transcription occurring over hours to days, described as "genomic actions" of steroid hormones. In contrast, activation of plasma membranebound steroid receptors on the cell surface initiates changes in ioR fluxes, second messenger signals, and protein kinase activities in millisecond-to-minute time scale, collectively described as "rapid responses" or "nongenomic actions" of steroid hormones. Whether "rapid responses" ultimately lead to changes in transcription remains an open question. The underlying hypothesis of this proposal is that activation of plasma membrane-bound estrogen receptors by the two pregnancy-related hormones, 17betaestradiol (E2) and estriol (E3), leads to "rapid responses" which indirectly activate transcriptional regulation and cell proliferation. The research will use new chemically defined reagents constructed with E2 and E3 to isolate cells with membrane-bearing estrogen receptor. Preliminary studies have demonstrated that the reagent with E2 can bind to a subpopulation of MCF-7 cells. The following specific aims will be addressed: (1) Isolation can and characterization of plasma membrane estrogen receptor. Using the new chemically defined reagents of E2 and E3, as "bait," cells with membrane-bearing estrogen receptor will be isolated. Analysis of cell-surface-protein expression pattern of membrane estrogen receptor and non-receptor-bearing cells will identify candidate membrane estrogen-receptors. (2) Examination of biological effects of membrane estrogen receptor signaling. Using the same chemically defined reagents, the effect of

66

Estrogen

membrane estrogen signaling on transcription will be determined, and genes regulated by membrane signaling will be identified using a genome-wide based approach. Finally, the effects of membrane estrogen signally on cell proliferation will be examined. The research will open a new avenue of investigation in which the genome integrates the actions of both membrane and intracellular estrogen receptors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROGESTERONE TRANSMISSION

AND

ESTROGEN

ON

SIV

VAGINAL

Principal Investigator & Institution: Marx, Preston A.; Professor; Aaron Diamond Aids Research Center 455 1St Ave, 6Th Fl New York, Ny 100169102 Timing: Fiscal Year 2002; Project Start 01-SEP-1997; Project End 31-OCT-2002 Summary: Progesterone and estrogen have opposing effects on vaginal physiology. Estrogen promotes vaginal epithelial maturation and decreases pH, while progesterone is an estrogen antagonist. Previously, we showed that systemic progesterone enhanced simian immunodeficiency virus (SIV) vaginal transmission in ovary-intact females. During this grant period we showed that systemic estrogen completely blocked SIV vaginal transmission in ovariectomized (ovx) macaques. Wealso found that SIV vaginal transmission was enhanced in untreated ovx macaques, providing a new model for HIV transmission in post-menopausal women. New results show that the effects of estrogen were confined to the vaginal microenvironment. To capitalize on these findings, we propose to test topical estrogen for prevention of SIV vaginal transmission. The application was extensively revised in response to the critique. The studies on humans have been deleted. In the revision, topical estrogen will be tested in both ovx and in cycling macaques. These experiments will model the post-menopausal and premenopausal states. The new toxicity studies on topical estrogen will use sensitive assays for leutenizing hormone (an indictor of systemic estrogen leakage) and for endometrial hyperplasia. The aims are; Modified Specific Aim 1. To test the safety and efficacy of topical estrogen on SIV-vaginal transmission in ovx macaques. New Aim 2. To test the safety and efficacy of low dose, vaginal estrogen in protecting cycling macaques against SIV vaginal transmission. Using the macaque model, the aims focus on a practical and safe application of our findings to sexually active women,. Sexually active postmenopausal women are a growing risk group. Our studies could provide a method to reduce the risk to this population. The need for protecting pre-menopausal women is self-evident. This multi-disciplinary approach seeks to show prophylactixis in the SIV model that can be directly applied to HIV vaginal transmission. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROMOTER REGULATION OF AN ESTROGEN RECEPTOR VARIANT Principal Investigator & Institution: Bryant, Winnifred M.; Internal Medicine; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2002; Project Start 30-APR-2003; Project End 31-JUL-2003 Summary: (provided by applicant): The steroid hormone estrogen (E) acting via the estrogen receptor (ER) has many physiological actions, including mediating regulatory events in the neuroendocrine system that govern pituitary cell function and hormone secretion. Estrogen acts on the pituitary to regulate hormone secretion and gene expression. Our lab has identified and characterized a pituitary-specific truncated form of estrogen receptor-alpha (TERP). TERP is dramatically regulated by E, and has

Studies 67

stimulatory or suppressive effects on ER activity, dependent on its levels of expression relative to full-length ER. We have cloned the intronic TERP promoter, and propose to characterize its basal activity and E responsiveness in transient transfection assays with TERP-luciferase deletion/mutation constructs. We will also determine if TERP regulates its own promoter by modulating its response to E. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROTECTIVE EFFECT OF PREGNANCY DOSES OF ESTROGENS IN EAE Principal Investigator & Institution: Voskuhl, Rhonda R.; Associate Professor; Neurology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-JUL-2006 Summary: (provided by applicant): Putative T helper (Th)l-mediated autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA) improve during late pregnancy when estrogen levels are high. In animal models of MS and RA, pregnancy doses of estrogens (estriol and estradiol) have been shown to ameliorate disease. In murine experimental autoimmune encephalomyelitis (EAE), estrogen treatment has been shown to cause a favorable shift in cytokine profile with an increase in production of the anti-inflammatory cytokine interleukin (IL)-10 during autoantigenspecific responses. The purpose of this application is to investigate further the mechanisms which underlie the protective effect of treatment of female EAE mice with pregnancy doses of estrogens (estriol and estradiol). In Specific Aim 1, it will be determined whether estrogens ameliorate disease by acting through estrogen receptor alpha or beta. This will be achieved by inducing EAE in ER beta knockout mice and assessing whether treatment with estrogens are still protective. The role of ER alpha will be determined by using a potent ER blocking agent (ICI 182,780) in ER beta knockout mice to ascertain whether the protective effects of estrogens are blocked when ER alpha is blocked. Treatment of EAE mice with selective ER alpha or beta agonists will confirm data above regarding whether estrogens act on ER alpha or beta when mediating disease protection. In Specific Aim 2, the immune cells that express each ER and the cells that are producing increased amounts of IL-10 during estrogen treatment will be identified. These studies will reveal whether estrogens increase IL-10 production by acting directly on a given immune cell versus acting indirectly via other immune cells. While an estrogen-mediated increase in IL-10 production by immune cells would be expected to be protective in EAE, this does not preclude additional protective mechanisms through which estrogens may act. Therefore, in Specific Aim 3, the possibility that estrogens may act through mechanisms other than increasing IL-10 production in immune cells will be examined. EAE will be induced in estrogen treated, IL-10 knockout mice to determine whether estrogen treatment is still protective in the absence of the IL-10 gene. Finally, the site of action of estrogens during EAE may be in the peripheral immune system and/or within the central nervous system (CNS). Systemic estrogen treatment used in combination with an ER blocking agent that acts only in the periphery will demonstrate whether estrogens act in the peripheral immune system or within the CNS. Administration of estrogens intra-ventricularly, within the CNS, will be used as a complementary approach. A detailed understanding of how each estrogen abrogates EAE pathogenesis may lead to treatment of MS and possibly other Th1-mediated autoimmune diseases with Selective Estrogen Receptor Modulators (SERMS) targeted to the pathogenic site of action. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

68

•

Estrogen

Project Title: SOY PHYTOESTROGEN NEUROPROTECTION IN CEREBRAL ISCHEMIA Principal Investigator & Institution: Schreihofer, Derek A.; Physiology Endocrinology; Medical College of Georgia 1120 15Th St Augusta, Ga 30912

and

Timing: Fiscal Year 2004; Project Start 15-FEB-2004; Project End 31-JAN-2008 Summary: (provided by applicant): Estrogen is a powerful neuroprotective hormone that is particularly effective in reducing cerebral ischemic damage in stroke. Endogenous and exogenous estrogen is also associated with protection from neurodegenerative disease in humans. However, the benefits of estrogen are mitigated by recent clinical results suggesting that hormone replacement therapy (HRT) has health consequences. Concerns about hormone dependent cancer will continue to deter women from taking replacement therapy. Pharmacological selective estrogen receptor modulators (SERMs) show promise in preserving the beneficial effects of estrogen without increasing cancer risk. However, many women are already opting for "natural" SERMs such as plant derivatives containing soy and other phytoestrogens with the presumption that such therapies are both effective and safer than HRT. Epidemiological and experimental data suggest that diets high in soy phytoestrogens provide many of the same benefits as estrogen with the potential for decreased negative side effects seen with traditional HRT. Nevertheless, very little is known about the effects of dietary soy phytoestrogens in the brain. In vitro, soy phytoestrogens can mimic some of estrogen's neuroprotective actions, but these same compounds have also been shown to inhibit some estrogen actions in the brain. The present proposal seeks to determine the whether of soy phytoestrogens protect neurons from ischemic damage in vitro and in vivo. We hypothesize that physiologically relevant doses of soy phytoestrogens are neuroprotective by mimicking both genomic and non-genomic actions of estrogen. Aim 1 will test the hypothesis that the soy phytoestrogens genestein, daidzein, and equol inhibit apoptotic cell death in neuronal cell line models of cerebral ischemia in an estrogen receptor-dependent manner. Aim 2 will test the hypothesis that in the absence of endogenous estrogen a high soy diet will decrease infarct size and cell death associated with middle cerebral artery occlusion in rats. Aim 3 will test the hypothesis that in the absence of endogenous estrogen, ingestion of a high soy diet will induce the expression of the neuroprotective genes BDNF, NGF, Bcl-2, BCl-xL, and TrkB and reduce expression of the pro-apoptotic p75 NTR in brain regions damaged by middle cerebral artery occlusion. This proposal seeks to provide critical new information about the ability of phytoestrogens to protect the brain from focal cerebral ischemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PRODUCTION

STEROIDS

/VASCULAR

REACTIVITY

/NITRIC

Principal Investigator & Institution: Keller-Wood, Maureen Pharmacodynamics; University of Florida Gainesville, Fl 32611

E.;

OXIDE Professor;

Timing: Fiscal Year 2002; Project Start 06-APR-2001; Project End 31-MAR-2004 Summary: (Adapted from applicant's description): The overall goal of these studies is to test the hypothesis that there is an interaction between increased secretion of adrenal corticosteroids and increased secretion of estrogen during pregnancy which is necessary for normal blood pressure control in the peripartal period. Studies in pregnant, hypocorticoid ewes and clinical experience in pregnant women with hypoadrenocorticism suggest that normal blood pressure control in late pregnancy requires increased adrenal secretion. Insufficient supply of cortisol results in rapid and

Studies 69

profound hypotension, with increased morbidity and mortality in both mother and fetus. The experiments in this proposal will directly test the hypothesis that a decrease in cortisol at a time of increased estrogen results in a greater decrease in vascular reactivity to phenylephrine and that this correlates with increased production of nitric oxide production in one or more sites in the body. Four groups of ewes will be studied: adrenalectomized, ovariectomized ewes, adrenalectomized ovariectomized ewes treated with estradiol, adrenal- intact ovariectomized ewes, and adrenal-intact ovariectomized ewes treated with estradiol. All adrenalectomized ewes will be treated with aldosterone and cortisol for one week following surgery, and then the adrenal steroid infusions will be stopped to produce the hypoadrenal state. Animals will be studied at a time point (8 hours) in which the adrenalectomized estrogen treated animals are hypotensive, but the adrenalectomized ewes without estradiol treatment are not overtly hypotensive. Experiments will test vascular reactivity in response to phenylephrine in all 4 groups of ewes to test the hypothesis that estrogen administration decreases vascular reactivity in adrenalectomized ewes. Experiments will also determine plasma levels of nitrates and nitrites and the ability of infusion of L-NAME, an inhibitor of nitric oxide synthase (NOS), to increase vascular reactivity in adrenalectomized ewes with estradiol treatment. Experiments will also test the concentrations of cGMP, and levels of iNOS, eNOS, and nNOS protein measured by Western analysis and mRNA by RT-PCR in aorta, uterine artery, mesenteric artery, renal artery, renal interlobular artery, renal medulla and cortex, and skeletal muscle, taken from animals in the same 4 experimental groups. These experiments will determine if absence of cortisol results in increased NOS in one or more of these sites. Samples of tissue will also be examined by immunohistochemistry to more precisely identify the cell populations containing iNOS, eNOS or nNOS in these ewes. These experiments will therefore describe which isoform(s), and in which cells, NOS is altered by cortisol withdrawal, either alone or in combination with increased estrogen. This information will form the basis of future experiments to determine the mechanism of the interaction of estrogen and cortisol in control of NO and regulation of blood pressure during pregnancy. These studies will therefore add to our understanding of normal blood pressure control during pregnancy, and of the pathophysiology of hypoadrenocorticism at term. These studies will also to our understanding of the counterbalancing effects of increased cortisol and increased estrogens in control of normal blood pressure in normal pregnancy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STUDIES OF ESTROGEN RECEPTORS IN AUTOIMMUNITY Principal Investigator & Institution: Jarjour, Wael N.; Internal Medicine; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: This is an amended application for a mentored patient-oriented development award to enable Dr.Wael N. Jarjour to devote 75% of his time for five years to a program that includes didactic coursework and laboratory investigatiion to enable him to obtain training in biostatistics, human investigation, research design and experimental investigation. This program will facilitate his career development to be an independent clinical investigator. This program consists of didactic coursework involving basic statistics, advanced statistical modeling, fundamental methodologies in clinical investigation, and a intense course in ethical conduct of clinical investigation. It is proposed that he will be trained in molecular endocrinology by Dr.Margaret Shupnik who will serve as primary mentor, and in cellular immunology by Dr. Shu Man Fu as his co-mentor. A committee has been set up to monitor his progress and the

70

Estrogen

commitment from the Chair of the Department of Internal Medicine to have 75% protected time to achieve the goals as outlined for this award. A research program has been devised which addresses an important issue regarding gender bias in systemic lupus erythematosus (SLE) which affects females predominately and the kidney as one of the major target organs. The research plan has been revised taking the Reviewers' concerns in to consideration. It deals with the role of estrogen receptors (ER) in the pathogenesis of SLE. This disease affects predominately females in their reproductive life. It has also been demonstrated that female hormones such as estrogen have profound effects on the immune system. Thus, it is logical to study the role of estrogen receptors in SLE, a protyppic disease of systematic autoimmunity. Preliminary data have suggested marked differences between alpha nd beta estrogen receptor expression by lymphocytes from normals and SLE patients. Four specific aims are proposes: 1) to examine the protein and mRNA expression of ERalpha and Erbeta in circulating T cells of patients with SLE in comparison with healthy controls; 2) to determine if ER activation differs in T lymphocytes from SLE patients and controls; and 3) to determine whether altered sensitivity of T cells from SLE patients and certain normal control populations is due to the effects odf protein which regulate ER activty. This research plan will provide Dr. Jarjour the needed training in experimental design and techniques, data analyses, and manuscript preparation as well as to complement the didactic coursework. Through both didactic coursework and laboratory investigation, Dr. Jarjour will attain his goals to develop into an independent clinical investigator with ability to study mechanisms of human diseases of immunological basis and to devise novel therapeutic approaches based on the understanding of these mechanisms. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SYNAPTIC AROMATASE; A NOVEL FORM OF ESTROGEN DELIVERY Principal Investigator & Institution: Saldanha, Colin J.; Biological Sciences; Lehigh University Bethlehem, Pa 18015 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2006 Summary: (Provided by applicant): Steroid provision to neural pathways is achieved via endocrine pathways, but also paracrine and autocrine mechanisms within the brain itself. These modes of delivery underlie the considerable influence of steroids like estrogen on vertebrate brain and behavior, including that of songbirds. Using a novel antibody, we have discovered that estrogen can be provided to specific telencephalic neurons via synaptic innervation in the zebra finch (Taeniopygia guttata). This "synaptocrine" mechanism involves the transport of aromatase to synaptic terminals far from their source. This action combines the long-range characteristic of endocrine events with the targeted specificity of axonal innervation. Presynaptic aromatization could dramatically alter the steroidal milieu in the synaptic cleft, thus altering synaptic function. Recent findings that show the rapid modulation of aromatase activity by ionophores and estrogen receptor at post-synaptic densities strongly suggest that presynaptic aromatization is functional. In zebra finches and canaries (Serinus canarius), we will confirm the expression of synaptic aromatase using radioenzymatic assays and immuno-electron microscopy. Second, we will test the differential regulation of synaptosomal and microsomal aromatase, and the association of synaptic aromatization with singing behavior. Finally, we will establish the interaction of synaptic aromatase with estrogen- and androgen receptors using double-label confocal and electron microscopy. Presently, although synaptic aromatase has been documented in several species, including humans, nothing is known about its regulation and function. These

Studies 71

studies will describe a mechanism that couples electrical and hormonal signaling, possibly revealing a fundamental and novel characteristic of neuroendocrine function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SYNERGY BETWEEN SSRIS AND OVARIAN HORMONES Principal Investigator & Institution: Van De Kar, Louis D.; Professor; Pharmacol & Exper Therapeutics; Loyola University Medical Center Lewis Towers, 13Th Fl Chicago, Il 60611 Timing: Fiscal Year 2002; Project Start 05-AUG-1999; Project End 31-JUL-2004 Summary: Women suffer from disorders associated with serotonin (5-HT) deficiency, such as premenstrual syndrome (PMS) post-partum and post-menopausal depression, anxiety and bulimia. These mood and impulse control disorders are also associated with fluctuations in ovarian hormone levels. Estrogen can be used to treat some of these disorders, but serotonin reuptake inhibitors (SSRIs), such as fluoxetine (Prozac ) are the most effective drugs currently available. A major problem with SSRIs is the delay (2-3 weeks) in onset of clinical improvement of depression, a time which is associated with increased danger of suicide. Treatment with either fluoxetine or estrogen decreases the sensitivity of hypothalamic 5-HT1A receptor systems. These observations suggest that desensitization of 5-HT1A receptor signalling may underlie the therapeutic effectiveness of estrogen and SSRI treatments. Ovarian hormones act predominantly via genomic mechanisms, while fluoxetine induces adaptive responses via membrane proteins. Therefore, our central hypothesis is that estrogen will act synergistically with fluoxetine via complementary mechanisms to desensitize hypothalamic 5-HT1A receptor systems. Based on this hypothesis, we predict that estrogen or estrogen + progesterone will shorten the delay in the effects of SSRIs. The proposed studies will examine the mechanisms by which estrogen: 1) inhibits 5-HT1A signal transduction systems, and 2) reduces the delay in fluoxetine-induced desensitization of hypothalamic 5-HT1A receptor signalling. The proposed studies will use neuroendocrine, biochemical and molecular approaches to study the following specific aims: Specific Aim 1 will determine the doses of estrogen and progesterone that reduce hypothalamic 5-HT1A receptor function in ovariectomized rats. Specific Aim 2 will identify the estrogen receptor subtype(s) which mediate the effect of estrogen on 5-HT1A receptor systems in the hypothalamus. Specific Aim 3 will determine if estrogen shortens the delay in fluoxetine's effects on 5-HT1A receptor signalling. Specific Aim 4 will determine if progesterone increases estrogen's effectiveness in shortening the delay in fluoxetineinduced 5-HT1A receptor sub-sensitivity. The proposed studies will provide the scientific basis for the development of improved therapeutic regimens and novel drugs that provide faster clinical improvement in women suffering from PMS, depression, bulimia and anxiety disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: THE ROLE OF ESTROGEN IN BONE METABOLISM Principal Investigator & Institution: Oz, Orhan K.; Radiology; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 01-JUN-2000; Project End 31-MAY-2005 Summary: The candidate, Dr. Orhan K. Oz, is a diagnostic radiologist with previous scientific training in biophysics and tumor biology who seeks to become an independent investigator in the field of bone biology. To make this transition additional training will be necessary under the auspices of a career development award. His long-term career

72

Estrogen

goals are to improve understanding of the pathophysiology of osteoporosis and to use this understanding as the basis for new therapeutic and diagnostic modalities for this disease. A development plan has been developed in which the candidate will conduct research on the role of estrogen in bone metabolism under the guidance of Drs. Zerwekh and Sakhaee experienced investigators in the field of bone biology. They will direct the basic science and clinical activities necessary for this project. Dr. Oz will become an active participant in data conferences and the local Bone Research Society activities and an environment designed to enhance the candidate's transition to the field of bone science. The broad, long-term objective of the research is to elucidate the mechanisms of estrogen's effect on bone growth and metabolism and to use that information to develop new therapeutic and diagnostic modalities for osteoporosis. The enzyme aromatase synthesizes estrogen from its androgen precursors. Estrogen withdrawal in post-menopausal women is associated with an increase of bone turnover and acceleration of bone loss, that leads to an increased susceptibility to bone fractures and clinically relevant osteoporosis in one third of all women. The recent observation of a phenotype in men with aromatase deficiency or estrogen receptor deficiency comprising failure of epiphyseal fusion closure leading to excessive height together with osteopenia, is indicative of an important role of estrogen in bone growth and metabolism of males, as well as females. This leads to the issue of the origin of the estrogen involved in the bone metabolism and points to the possibility that local formation of estrogen within bone tissues may play an important role in bone mineral metabolism in both sexes. The central hypothesis is that estrogen is an important regulator of growth and metabolism which effects its regulatory function by influencing bone cell differentiation and the differentiated function of bone cells. A model of estrogen deficiency has recently been created, namely the aromatase-deficient (ArKO) mouse. Specific aims designed to test this hypothesis are: 1) To study the cellular distribution of aromatase in sections of bone tissue from mice of various ages; 2) To study bone metabolism in the ArKO knock-out mouse; 3) To determine whether aromatase deficiency affects bone cell differentiation and proliferation and; 4) To study expression of cytokines, critical to bone growth and metabolism, in bone marrow cells from aromtase deficient mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE YUCATAN MICROPIG CARDIOVASCULAR MODEL OF MENOPAUSE Principal Investigator & Institution: Goodrich, James A.; Comparative Medicine; Medical University of South Carolina 171 Ashley Ave Charleston, Sc 29425 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2007 Summary: (provided by applicant): Menopause in women is an understudied normal aspect of the aging process that is associated with a loss of estrogen production and increased risk of cardiovascular disease and other health problems. Estrogen is generally considered to be cardioprotective. There are currently unprecedented numbers of women, about 50 million, in the United States reaching menopause; cardiovascular disease is the number one killer of postmenopausal women. Animal models provide a means of performing critical studies of the biological mechanisms and responses to existing and emerging therapies for this condition (i.e. soy protein/isoflavones). A nonprimate animal model of menopause is needed to provide a research tool that is: 1) readily available to many researchers; 2) low in risk for zoonotic disease; 3) domesticated; 4) a low cost rapidly renewable resource; 5) possess a similar coronary artery anatomy; and 6) atherosclerotic lesion to that of women. The

Studies 73

ovariectomized Yucatan Micropig has the potential to fill this void, and will serve the interests of both the NIA and NHLBI. The overall objective of this application is to develop, characterize, and improve the Yucatan Micropig Model of Menopause for use in cardiovascular studies. This will be approached by Aim 1 clarifying the cardioprotective effects of soy protein in this model by measuring the extent of the reduction in coronary artery atherosclerosis, serum lipids, inflammatory risk factors (Creactive Protein, Interleukin-6) and blood pressure among soy, control, and conjugated equine estrogen treated groups. Establishing that soy protein can reduce coronary artery atherosclerosis in Micropigs, like it does in monkeys, would provide foundation data helpful to future soy isoflavone mechanistic studies in the Micropig model. Studies to determine how soy isoflavones and soy protein interact to reduce serum cholesterol and subsequently coronary artery atherosclerosis are needed. The next step is Aim 2, to examine the effects of these treatments on reproductive tissue. The investigators approach this aim by comparing uterine weights, and mammary and uterine immunohistology among these groups. The third step Aim 3, is to determine if and to what extent there is a natural female cardioprotection in the Yucatan Micropig. The investigators will approach this by comparing groups of male, ovariectomized female, and intact female Micropigs fed an atherogenic diet. The end points will be identical to those of the first aim. Finally, Aim 4, is to determine if and to what extent ovariectomized female Yucatan Micropigs experience vasomotor symptoms or hot flashes related to estrogen deficiency. This will be approached through continuous telemetric monitoring of skin temperature spikes before and after ovariectomy and then with and without estrogen replacement therapy. The future plans for this model are to use it to study the cardiovascular benefits/risks of new progestins, selective estrogen receptor modulators, tissue selective estrogens, and isoflavone products, as well as the mechanism by which soy protein lowers serum cholesterol and coronary artery atherosclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TISSUE INTERACTIONS AND HORMONAL RESPONSES IN THE UTERUS Principal Investigator & Institution: Bigsby, Robert M.; Associate Professor; Obstetrics and Gynecology; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2002; Project Start 15-APR-2000; Project End 31-MAR-2005 Summary: (Adapted from the applicant's abstract) Knowing how tissue interactions affect physiology is important for understanding pathologies of hormonally regulated organs. In the uterus, tissue interactions mediate steroid hormone effects, playing key roles in events of early pregnancy. Although estrogen regulates cell signaling in a stroma-to-epithelium direction in the uterus, a paracrine factor mediating this effect has not been identified. Also, hormonal regulation of a pathway in the reciprocal direction has not been studied. In both human and rodent, estrogen stimulation of a progesterone dominated uterus causes proliferation of the endometrial stroma. Proposed studies will test the hypothesis: 1) Progesterone priming for and estrogen induction of cellular proliferation in the uterine stroma occurs indirectly through activation of progesterone receptor (PR) and estrogen receptor-alpha (ER alpha) in the overlying epithelium. 2) IGF-I is a paracrine mediator of steroid action in the uterus. The hypothesis will be tested using tissue recombinations grown in xenograft. Uterine epithelium (epi) and mesenchyme (mes) will be derived from neonatal wild-type mice, ER alpha knockout (ER alpha KO) mice, PR knockout (PRKO) mice, or IGF-I knockout mice. These

74

Estrogen

knockout models were chosen because: ER alpha KO mouse uterus shows no growth response to estradiol stimulation, indicating that it is devoid of any growth-promoting ER; PRKO mouse uterus exhibits no stromal response to progesterone/estrogen treatment or to a decidualizing stimulus; in the IGF-I knockout mouse uterus estrogen stimulated cells are arrested in G2. The specific aims are: 1. Determine the tissue specificity of the steroid receptor-mediated events regulating cell proliferation. 2. Determine the role of tissue specific expression of IGF-I in mediation of steroid induced proliferation in the uterus. For each type of knockout animal, tissue will be separated and recombined in all 4 possible combinations: epi+/mes+, epi-/mes-, epi+/mes-, epi/mes+ (+, target gene status). Tissue recombinants will be grown in athymic mice. Effects of hormone treatments will be tested using tritiated thymidine incorporation or mitotic index as the endpoint. If hypothesis 1 proves correct, this will be a novel demonstration of hormonal regulation via an epithelium-to-stroma interaction, thereby leading to a new concept of hormone action in steroid-responsive organs. If IGF-I proves critical for tissue interactions it will be the first paracrine factor to be definitively identified as a mediator of steroid action in the uterus. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VITAMIN A AND REPRODUCTION Principal Investigator & Institution: Ong, David E.; Professor; Biochemistry; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 30-SEP-1989; Project End 31-MAR-2005 Summary: Vitamin A, retinol, is an essential nutrient that serves as precursor to the important hormone, retinoic acid (RA). Relatively little is known of the control of synthesis of RA from retinol in the normal, fully-developed animal and sites of action of RA are inferred, rather than demonstrated. Previous work has identified estrogen as a physiological signal which induces the synthesis of RA in the rat uterus and that coordinately directs cell-specific expression of the three cellular retinoid-binding proteins present in the uterus during the estrous cycle. Proposed studies will: l) Identify uterine genes that are under estrogen control indirectly, via RA stimulation. The techniques of differential display or subtractive hybridization followed by library screening or will be used to identify these genes. Candidate genes will be followed during the estrous cycle to confirm their physiological significance. 2) Demonstrate the site(s) of expression of the estrogen-stimulated RA responsive genes by in situ hybridization and immunolocalization during the estrous cycle. Demonstration of expression/non-expression of candidate genes in cells expressing cellular retinoic acidbinding protein will test the competing hypotheses that this protein either blocks or enhances the RA responsiveness of cells. 3) Establish the mechanism by which estrogen directly regulates cellular retinoic-acid binding protein (II) expression in the uterus. The promoter region of the rat gene will be cloned, dissected and tested using CAT reporter constructs in an estrogen responsive cell line. 4) Demonstrate the mechanism by which estrogen induces RA synthesis in the uterus. Specifically, is this induction a direct effect of estrogen on pre-existing enzymes, does it require transcription, or is it indirect? A novel radioreceptor assay capable of detecting small amounts of RA has been developed for this aim. In summary, the work to be accomplished here will allow dissection of the effects of the demonstrated estrogen-stimulated synthesis of RA signal that is part of a normal physiological process. This will provide important information on retinoic acid action in the unmanipulated, intact animal. Regulation of retinoic acid production by estrogen has direct importance for understanding/treating conditions such as endometriosis, breast cancer, and cancers of the female reproductive system.

Studies 75

Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS

XENOESTROGENS:

GENOMIC

AND

NON-GENOMIC

Principal Investigator & Institution: Ben-Jonathan, Nira; Professor; Cell Biol, Neurobiol/Anatomy; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2003; Project Start 02-MAY-2003; Project End 31-MAR-2007 Summary: (provided by applicant): Bisphenol A (BPA) and octylphenol (OP) are abundant in the environment, bind to the estrogen receptor (ER) and act as partial estrogen agonists. In spite of accumulating evidence on their multiple effects on the reproductive tract, little is known about their spectrum of actions within the neuroendocrine axis, especially on the estrogen-sensitive pituitary lactotroph. We previously reported that these compounds induced lactotroph proliferation, increased prolactin (PRL) gene expression and release, altered pituitary ERalpha and ERbeta expression and affected the growth and morphology of the female reproductive tract. Whereas these effects take hours to days to occur and involve gene transcription and protein synthesis, we recently found that low nanomolar concentrations of estrogens/xenoestrogens induced very rapid (within 10 min) activation of the MAP kinase (MAPK) system and stimulated PRL release from cultured anterior pituitary cells. Our main objective is to compare genomic vs. non-genomic actions of estrogens/ xenoestrogens in the pituitary and determine interactions between intracellular calcium, nitric oxide (NO) release, MAPK activation and nuclear ER transactivation which result in increased hormone release, gene activation and lactotroph cell proliferation. Specific aim 1 will test the hypothesis that estrogens rapidly stimulate PRL release via a membrane ER that is linked to calcium-dependent exocytosis and may also involve nitric oxide (NO) release. Free and conjugated estrogens/xenoestrogens will be used to determine: a) rapid stimulation of PRL release from dispersed anterior pituitary cells or GH3 lactotrophs in the absence and presence of ER antagonists, b) reversal of this effect by blockers of calcium, NO or MAPK, c) changes in intracellular calcium concentrations or NO release in response to estrogens, d) the ability of estrogens to increase PRL release in the presence of dopamine, and e) whether the PRL secretory response to estrogens is subjected to receptor desensitization. Specific aim 2 will test the hypothesis that a short exposure to estrogens/xenoestrogens is sufficient to initiate sequential activation of the MAPK and ER signaling pathways, resulting in the induction of selected target genes and altered cell proliferation/apoptosis. Lactotrophs will be pulsechased with free and conjugated estrogens in the presence or absence of MAPK and ER inhibitors. At various times thereafter we will determine: a) induction PRL and vascular endothelial growth factor (VEGF) gene expression, b) expression of ER isoforms that alter cellular sensitivity to estrogens, and c) increased lactotroph proliferation. Specific aim 3 will use a gene array approach to test the hypothesis that the profile of pituitary genes that are upregulated/downregulated in response to estradiol and BPA differs between the estrogensensitive Fischer 344 (F344) and the estrogen-insensitive Sprague Dawley (SD) rat. The results of these studies should provide much needed experimental foundation for assessing the vulnerability of the pituitary gland to insults by endocrine disruptors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

76

•

Estrogen

Project Title: ZEB/DELTAEF1 AND ESTROGEN SIGNALING CASCADES Principal Investigator & Institution: Sanders, Michel M.; Professor; Biochem/Mole Biol/Biophysics; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2003; Project Start 14-MAR-2003; Project End 31-JAN-2007 Summary: (provided by applicant): In addition to its normal physiological functions, estrogen directs events that lead to both the protection from and promotion of many pathological conditions. However, the molecular details linking the binding of the receptor to its target genes with the ultimate biological consequence often remain unclear. In an attempt to define signaling cascades triggered by estrogen, the novel observation was made that the ZEB/dEF1 gene is induced at the transcriptional level by estrogen. Other data show that ZEB/dEF1 is one of the links in estrogen signal transduction pathways in reproductive tissues. For example, ZEB/dEF1 expression is high in rapidly proliferating endometrial and ovarian cancers but is no longer regulated by estrogen. In contrast, the gene is deleted in slowly growing endometrial cancers. These data suggest that ZEB/deltaEF1 plays a pivotal role in reproductive tissues. ZEB/deltaEF1 is a transcription factor that contains several functional domains including two zinc finger clusters at each terminus. Most data suggest that ZEB/deltaEF1 is a transcriptional repressor but in some circumstances it functions as a transcriptional activator. The overall goals of this proposal are to define the mechanism of gene activation by ZEB/deltaEF1 and to identify its target genes. The specific aims of this proposal are to 1). Investigate the mechanism of gene activation by ZEB/deltaEF1, 2). Identify the proteins in reproductive tissues that act as co-activators with ZEBdeltaEF1, and 3). Identify the downstream targets of ZEB/deltaEF1 in a breast cancer cell line. The first aim will be approached primarily by truncating ZEB/dEF1 and determining the effects on reporter gene activation. The second specific aim will be addressed by two complementary approaches, tandem mass spectrometry and a yeast two-hybrid Ras recruitment system. For the last specific aim, target genes for ZEB/deltaEF1 will be identified using gene profiling with DNA microarrays. These experiments will provide important information about the mechanism of gene activation by ZEB/deltaEF1 and about estrogen signal transduction pathways. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

E-Journals: PubMed Central3 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).4 Access to this growing archive of e-journals is free and unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “estrogen” (or synonyms) into the search box. This search gives you access to fulltext articles. The following is a sample of items found for estrogen in the PubMed Central database: 3 4

Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.

With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print.

Studies 77

•

17[beta]-Estradiol Inhibits Apoptosis in MCF-7 Cells, Inducing bcl-2 Expression via Two Estrogen-Responsive Elements Present in the Coding Sequence. by Perillo B, Sasso A, Abbondanza C, Palumbo G.; 2000 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85519

•

4-Hydroxylation of Estrogens as Marker of Human Mammary Tumors. by Liehr JG, Ricci MJ.; 1996 Apr 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39600

•

4-Hydroxytamoxifen binds to and deactivates the estrogen-related receptor [gamma]. by Coward P, Lee D, Hull MV, Lehmann JM.; 2001 Jul 17; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=37529

•

A 13 bp palindrome is a functional estrogen responsive element and interacts specifically with estrogen receptor. by Klein-Hitpass L, Ryffel GU, Heitlinger E, Cato AC.; 1988 Jan 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=334683

•

A chimera of EBNA1 and the estrogen receptor activates transcription but not replication. by Middleton T, Sugden B.; 1992 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=240942

•

A critical period for estrogen action on neurons of the song control system in the zebra finch. by Konishi M, Akutagawa E.; 1988 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=282108

•

A crucial role for thiol antioxidants in estrogen-deficiency bone loss. by Lean JM, Davies JT, Fuller K, Jagger CJ, Kirstein B, Partington GA, Urry ZL, Chambers TJ.; 2003 Sep 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=193670

•

A Low-Affinity Estrogen-Binding Site in Pregnant Rat Uteri: Analysis and Partial Purification. by Gray WG, Biswas EE, Bashirelahi N, Biswas SB.; 1994 Nov 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=45259

•

A novel 80 kDa human estrogen receptor containing a duplication of exons 6 and 7. by Pink JJ, Wu SQ, Wolf DM, Bilimoria MM, Jordan VC.; 1996 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=145723

•

A peptide derived from [alpha]-fetoprotein prevents the growth of estrogendependent human breast cancers sensitive and resistant to tamoxifen. by Bennett JA, Mesfin FB, Andersen TT, Gierthy JF, Jacobson HI.; 2002 Feb 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122344

•

A retinoic acid response element that overlaps an estrogen response element mediates multihormonal sensitivity in transcriptional activation of the lactoferrin gene. by Lee MO, Liu Y, Zhang XK.; 1995 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=230658

78

Estrogen

•

A role for coactivators and histone acetylation in estrogen receptor [alpha]-mediated transcription initiation. by Kim MY, Hsiao SJ, Kraus WL.; 2001 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=125694

•

A role for estrogen receptor [beta] in the regulation of growth of the ventral prostate. by Weihua Z, Makela S, Andersson LC, Salmi S, Saji S, Webster JI, Jensen EV, Nilsson S, Warner M, Gustafsson JA.; 2001 May 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33468

•

A Selective Transcriptional Induction System for Mammalian Cells Based on Gal4Estrogen Receptor Fusion Proteins. by Braselmann S, Graninger P, Busslinger M.; 1993 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=45938

•

A Sensitive and Inexpensive Yeast Bioassay for the Mycotoxin Zearalenone and Other Compounds with Estrogenic Activity. by Mitterbauer R, Weindorfer H, Safaie N, Krska R, Lemmens M, Ruckenbauer P, Kuchler K, Adam G.; 2003 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=143629

•

A subfamily of RNA-binding DEAD-box proteins acts as an estrogen receptor [alpha] coactivator through the N-terminal activation domain (AF-1) with an RNA coactivator, SRA. by Watanabe M, Yanagisawa J, Kitagawa H, Takeyama KI, Ogawa S, Arao Y, Suzawa M, Kobayashi Y, Yano T, Yoshikawa H, Masuhiro Y, Kato S.; 2001 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=145523

•

A yeast-based bioassay for the determination of functional and non-functional estrogen receptors. by Balmelli-Gallacchi P, Schoumacher F, Liu JW, Eppenberger U, Mueller H, Picard D.; 1999 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=148396

•

Abolition of male sexual behaviors in mice lacking estrogen receptors [alpha] and [beta] ([alpha][beta]ERKO). by Ogawa S, Chester AE, Hewitt SC, Walker VR, Gustafsson JA, Smithies O, Korach KS, Pfaff DW.; 2000 Dec 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18988

•

Activated Estrogen Receptor Mediates Growth Arrest and Differentiation of a Neuroblastoma Cell Line. by Ma ZQ, Spreafico E, Pollio G, Santagati S, Conti E, Cattaneo E, Maggi A.; 1993 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46377

•

Activation of Estrogen Receptor Transfected into a Receptor-Negative Brest Cancer Cell Line Decreases the Metastatic and Invasive Potential of the Cells. by Garcia M, Derocq D, Freiss G, Rochefort H.; 1992 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=50587

•

Activation of the human estrogen receptor by the antiestrogens ICI 182,780 and tamoxifen in yeast genetic systems: Implications for their mechanism of action. by Dudley MW, Sheeler CQ, Wang H, Khan S.; 2000 Mar 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16302

Studies 79

•

Activation of vitellogenin gene transcription is a direct response to estrogen in Xenopus laevis liver. by Hayward MA, Brock ML, Shapiro DJ.; 1982 Dec 20; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=327084

•

ADA3-containing complexes associate with estrogen receptor alpha. by Benecke A, Gaudon C, Garnier JM, vom Baur E, Chambon P, Losson R.; 2002 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=117179

•

Age and stage dependency of estrogen receptor expression by lymphocyte precursors. by Igarashi H, Kouro T, Yokota T, Comp PC, Kincade PW.; 2001 Dec 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=64995

•

AIB1 Is a Conduit for Kinase-Mediated Growth Factor Signaling to the Estrogen Receptor. by Font de Mora J, Brown M.; 2000 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85954

•

Alteration of Large-Scale Chromatin Structure by Estrogen Receptor. by Nye AC, Rajendran RR, Stenoien DL, Mancini MA, Katzenellenbogen BS, Belmont AS.; 2002 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=133805

•

Alteration of Reproductive Function but Not Prenatal Sexual Development After Insertional Disruption of the Mouse Estrogen Receptor Gene. by Lubahn DB, Moyer JS, Golding TS, Couse JF, Korach KS, Smithies O.; 1993 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47942

•

Altered expression of estrogen receptor-[alpha] variant messenger RNAs between adjacent normal breast and breast tumor tissues. by Leygue E, Dotzlaw H, Watson PH, Murphy LC.; 2000; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=13912

•

An Antiestrogen: A Phosphotyrosyl Peptide that Blocks Dimerization of the Human Estrogen Receptor. by Arnold SF, Notides AC.; 1995 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41362

•

An Estrogen Receptor Pathway Regulates the Telogen-Anagen Hair Follicle Transition and Influences Epidermal Cell Proliferation. by Oh H, Smart RC.; 1996 Oct 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38025

•

An estrogen receptor repressor induces cataract formation in transgenic mice. by Davis VL, Chan CC, Schoen TJ, Couse JF, Chader GJ, Korach KS.; 2002 Jul 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=123157

•

An estrogen receptor-selective coregulator that potentiates the effectiveness of antiestrogens and represses the activity of estrogens. by Montano MM, Ekena K, Delage-Mourroux R, Chang W, Martini P, Katzenellenbogen BS.; 1999 Jun 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22022

•

An estrogen-dependent demethylation at the 5' end of the chicken vitellogenin gene is independent of DNA synthesis. by Wilks A, Seldran M, Jost JP.; 1984 Jan 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=318563

80

Estrogen

•

An estrogen-dependent four-gene micronet regulating social recognition: A study with oxytocin and estrogen receptor-[alpha] and -[beta] knockout mice. by Choleris E, Gustafsson JA, Korach KS, Muglia LJ, Pfaff DW, Ogawa S.; 2003 May 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=156348

•

An estrogen-dependent polysomal protein binds to the 5' untranslated region of the chicken vitellogenin mRNA. by Liang HM, Jost JP.; 1991 May 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=329432

•

Androgen receptor expression in the rat prostate is down-regulated by dietary phytoestrogens. by Lund TD, Munson DJ, Adlercreutz H, Handa RJ, Lephart ED.; 2004; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=340387

•

Another role highlighted for estrogens in the male: Sexual behavior. by Simpson ER, Davis SR.; 2000 Dec 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=34093

•

Antiestrogen ICI 164,384 Reduces Cellular Estrogen Receptor Content by Increasing Its Turnover. by Dauvois S, Danielian PS, White R, Parker MG.; 1992 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=49008

•

Aromatase expression and role of estrogens in male gonad : a review. by Carreau S, Lambard S, Delalande C, Denis-Galeraud I, Bilinska B, Bourguiba S.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155680

•

Assessment of xenoestrogenic exposure by a biomarker approach: application of the E-Screen bioassay to determine estrogenic response of serum extracts. by Rasmussen TH, Nielsen F, Andersen HR, Nielsen JB, Weihe P, Grandjean P.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=270076

•

Avian Osteoclasts as Estrogen Target Cells. by Oursler MJ, Osdoby P, Pyfferoen J, Riggs BL, Spelsberg TC.; 1991 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52137

•

Behavioral effects of estrogen receptor gene disruption in male mice. by Ogawa S, Lubahn DB, Korach KS, Pfaff DW.; 1997 Feb 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19816

•

Binding of type II nuclear receptors and estrogen receptor to full and half-site estrogen response elements in vitro. by Klinge CM, Bodenner DL, Desai D, Niles RM, Traish AM.; 1997 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=146682

•

Biotransformation and Bioconcentration of Steroid Estrogens by Chlorella vulgaris. by Lai KM, Scrimshaw MD, Lester JN.; 2002 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=126709

•

Bombesin antagonists inhibit growth of MDA-MB-435 estrogen-independent breast cancers and decrease the expression of the ErbB-2 /HER-2 oncoprotein and c-jun and c-fos oncogenes. by Bajo AM, Schally AV, Krupa M, Hebert F, Groot K, Szepeshazi K.; 2002 Mar 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122610

Studies 81

•

Brain is the Major Site of Estrogen Synthesis in a Male Songbird. by Schlinger BA, Arnold AP.; 1991 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=51624

•

BRCA1 mediates ligand-independent transcriptional repression of the estrogen receptor. by Zheng L, Annab LA, Afshari CA, Lee WH, Boyer TG.; 2001 Aug 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=55496

•

BRG-1 Is Recruited to Estrogen-Responsive Promoters and Cooperates with Factors Involved in Histone Acetylation. by DiRenzo J, Shang Y, Phelan M, Sif S, Myers M, Kingston R, Brown M.; 2000 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86306

•

Bringing estrogen receptors under control. by Horwitz KB.; 1999; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=138501

•

Candida albicans Estrogen-Binding Protein Gene Encodes an Oxidoreductase that is Inhibited by Estradiol. by Madani ND, Malloy PJ, Rodriguez-Pombo P, Krishnan AV, Feldman D.; 1994 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43065

•

Cells transformed by a v-Myb-estrogen receptor fusion differentiate into multinucleated giant cells. by Engelke U, Wang DM, Lipsick JS.; 1997 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=191526

•

Chromatin exposes intrinsic differences in the transcriptional activities of estrogen receptors [alpha] and [beta]. by Cheung E, Schwabish MA, Kraus WL.; 2003 Feb 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=140722

•

CIA, a Novel Estrogen Receptor Coactivator with a Bifunctional Nuclear Receptor Interacting Determinant. by Sauve F, McBroom LD, Gallant J, Moraitis AN, Labrie F, Giguere V.; 2001 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88807

•

Circulating Estrogens in a Male Songbird Originat in the Brain. by Schlinger BA, Arnold AP.; 1992 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=49768

•

Cleavage properties of an estrogen-regulated polysomal ribonuclease involved in the destabilization of albumin mRNA. by Chernokalskaya E, Dompenciel R, Schoenberg DR.; 1997 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=146505

•

c-Myc or Cyclin D1 Mimics Estrogen Effects on Cyclin E-Cdk2 Activation and Cell Cycle Reentry. by Prall OW, Rogan EM, Musgrove EA, Watts CK, Sutherland RL.; 1998 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109035

•

Conversion of a 3-desoxysteroid to 3-desoxyestrogen by human placental aromatase. by Cole PA, Bean JM, Robinson CH.; 1990 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=53821

82

Estrogen

•

Correlation of expression of BP1, a homeobox gene, with estrogen receptor status in breast cancer. by Fu SW, Schwartz A, Stevenson H, Pinzone JJ, Davenport GJ, Orenstein JM, Gutierrez P, Simmens SJ, Abraham J, Poola I, Stephan DA, Berg PE.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=165014

•

Coupling of Dual Signaling Pathways: Epidermal Growth Factor Action Involves the Estrogen Receptor. by Ignar-Trowbridge DM, Nelson KG, Bidwell MC, Curtis SW, Washburn TF, McLachlan JA, Korach KS.; 1992 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=49142

•

Covalent binding of the endogenous estrogen 16 alpha-hydroxyestrone to estradiol receptor in human breast cancer cells: characterization and intranuclear localization. by Swaneck GE, Fishman J.; 1988 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=282290

•

Critical role of oxidative stress in estrogen-induced carcinogenesis. by Bhat HK, Calaf G, Hei TK, Loya T, Vadgama JV.; 2003 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153022

•

Crystallographic comparison of the estrogen and progesterone receptor's ligand binding domains. by Tanenbaum DM, Wang Y, Williams SP, Sigler PB.; 1998 May 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=27574

•

Cyclin D1 stimulation of estrogen receptor transcriptional activity independent of cdk4. by Neuman E, Ladha MH, Lin N, Upton TM, Miller SJ, DiRenzo J, Pestell RG, Hinds PW, Dowdy SF, Brown M, Ewen ME.; 1997 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=232384

•

Debate: The potential role of estrogen in the prevention of heart disease in women after menopause. by Rossouw JE.; 2000; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59619

•

Debate: The potential role of estrogen in the prevention of heart disease in women after menopause. by Johnson RR, Sweeney ME.; 2000; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59620

•

Defining a minimal estrogen receptor DNA binding domain. by Mader S, Chambon P, White JH.; 1993 Mar 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=309272

•

Developmental changes in estrogen-sensitive neurons in the forebrain of the zebra finch. by Gahr M, Konishi M.; 1988 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=282190

•

Developmental regulation of the estrogen receptor and the estrogen responsiveness of five yolk protein genes in the avian liver. by Evans MI, O'Malley PJ, Krust A, Burch JB.; 1987 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=299570

•

Different modes of hippocampal plasticity in response to estrogen in young and aged female rats. by Adams MM, Shah RA, Janssen WG, Morrison JH.; 2001 Jul 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=35469

Studies 83

•

Differential colocalization of estrogen receptor [beta] (ER[beta]) with oxytocin and vasopressin in the paraventricular and supraoptic nuclei of the female rat brain: An immunocytochemical study. by Alves SE, Lopez V, McEwen BS, Weiland NG.; 1998 Mar 17; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19733

•

Differential DNA-binding abilities of estrogen receptor occupied with two classes of antiestrogens: studies using human estrogen receptor overexpressed in mammalian cells. by Reese JC, Katzenellenbogen BS.; 1991 Dec 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=329226

•

Differential regulation by estrogens of growth and prolactin synthesis in pituitary cells suggests that only a small pool of estrogen receptors is required for growth. by Chun TY, Gregg D, Sarkar DK, Gorski J.; 1998 Mar 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19333

•

Differential screening and suppression subtractive hybridization identified genes differentially expressed in an estrogen receptor-positive breast carcinoma cell line. by Kuang WW, Thompson DA, Hoch RV, Weigel RJ.; 1998 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=147366

•

Differentiation between vasculoprotective and uterotrophic effects of ligands with different binding affinities to estrogen receptors [alpha] and [beta]. by Makela S, Savolainen H, Aavik E, Myllarniemi M, Strauss L, Taskinen E, Gustafsson JA, Hayry P.; 1999 Jun 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22061

•

Direct Visualization of the Human Estrogen Receptor [alpha] Reveals a Role for Ligand in the Nuclear Distribution of the Receptor. by Htun H, Holth LT, Walker D, Davie JR, Hager GL.; 1999 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25181

•

Discovery of estrogen-responsive genes using an improved method which combines subtractive hybridization and PCR. by Liu W, Su W, Roberts TM.; 1998 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=147722

•

Disruption of estrogen receptor [beta] gene impairs spatial learning in female mice. by Rissman EF, Heck AL, Leonard JE, Shupnik MA, Gustafsson JA.; 2002 Mar 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122637

•

Disruption of estrogen signaling does not prevent progesterone action in the estrogen receptor [alpha] knockout mouse uterus. by Curtis SW, Clark J, Myers P, Korach KS.; 1999 Mar 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22348

•

Disruption of the estrogen receptor [beta] gene in mice causes myeloproliferative disease resembling chronic myeloid leukemia with lymphoid blast crisis. by Shim GJ, Wang L, Andersson S, Nagy N, Kis LL, Zhang Q, Makela S, Warner M, Gustafsson JA.; 2003 May 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=164509

•

Dissection of the LXXLL Nuclear Receptor-Coactivator Interaction Motif Using Combinatorial Peptide Libraries: Discovery of Peptide Antagonists of Estrogen

84

Estrogen

Receptors [alpha] and [beta]. by Chang CY, Norris JD, Gron H, Paige LA, Hamilton PT, Kenan DJ, Fowlkes D, McDonnell DP.; 1999 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84907 •

Distinct Signaling Pathways Mediate Stimulation of Cell Cycle Progression and Prevention of Apoptotic Cell Death by Estrogen in Rat Pituitary Tumor PR1 Cells. by Caporali S, Imai M, Altucci L, Cancemi M, Caristi S, Cicatiello L, Matarese F, Penta R, Sarkar DK, Bresciani F, Weisz A.; 2003 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=284806

•

Dominant Activity of Activation Function 1 (AF-1) and Differential Stoichiometric Requirements for AF-1 and -2 in the Estrogen Receptor [alpha]-[beta] Heterodimeric Complex. by Tremblay GB, Tremblay A, Labrie F, Giguere V.; 1999 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=83985

•

Down-regulation of p21WAF1 /CIP1 or p27Kip1 abrogates antiestrogen-mediated cell cycle arrest in human breast cancer cells. by Cariou S, Donovan JC, Flanagan WM, Milic A, Bhattacharya N, Slingerland JM.; 2000 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16818

•

Dragon ERE Finder version 2: a tool for accurate detection and analysis of estrogen response elements in vertebrate genomes. by Bajic VB, Tan SL, Chong A, Tang S, Strom A, Gustafsson JA, Lin CY, Liu ET.; 2003 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=168924

•

Early estrogen-induced metabolic changes and their inhibition by actinomycin D and cycloheximide in human breast cancer cells: 31P and 13C NMR studies. by Neeman M, Degani H.; 1989 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=297667

•

Early membrane estrogenic effects required for full expression of slower genomic actions in a nerve cell line. by Vasudevan N, Kow LM, Pfaff DW.; 2001 Oct 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59803

•

Effect of prenatal exposure to oestrogen on quality of semen: comparison of twins and singleton brothers. by Storgaard L, Bonde JP, Ernst E, Andersen CY, Kyvik KO, Olsen J.; 2002 Aug 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=117639

•

Effect of soybean phytoestrogen intake on low density lipoprotein oxidation resistance. by Tikkanen MJ, Wahala K, Ojala S, Vihma V, Adlercreutz H.; 1998 Mar 17; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19702

•

Effect of Surgical Menopause and Estrogen Replacement on Cytokine Release from Human Blood Mononuclear Cells. by Pacifici R, Brown C, Puscheck E, Friedrich E, Slatopolsky E, Maggio D, McCracken R, Avioli LV.; 1991 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=51826

•

Effects of estrogen on growth plate senescence and epiphyseal fusion. by Weise M, De-Levi S, Barnes KM, Gafni RI, Abad V, Baron J.; 2001 Jun 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=34445

Studies 85

•

Effects of natural and synthetic polyamines on the conformation of an oligodeoxyribonucleotide with the estrogen response element. by Thomas T, Kulkarni GD, Gallo MA, Greenfield N, Lewis JS, Shirahata A, Thomas TJ.; 1997 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=146762

•

Effects of SERM (selective estrogen receptor modulator) treatment on growth and proliferation in the rat uterus. by Stygar D, Muravitskaya N, Eriksson B, Eriksson H, Sahlin L.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=156658

•

Endogenously expressed estrogen receptor and coactivator AIB1 interact in MCF-7 human breast cancer cells. by Tikkanen MK, Carter DJ, Harris AM, Le HM, Azorsa DO, Meltzer PS, Murdoch FE.; 2000 Nov 7; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18799

•

Enhancement of adherence and growth of Chlamydia trachomatis by estrogen treatment of HeLa cells. by Bose SK, Goswami PC.; 1986 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=260842

•

Enhancement of Escherichia coli adherence to epithelial cells derived from estrogenstimulated rats. by Sobel JD, Kaye D.; 1986 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=260074

•

Enhancement of Splenic-Macrophage Fc[gamma] Receptor Expression by Treatment with Estrogens. by Gomez F, Ruiz P, Bernal JA, Escobar M, Garcia-Egido A, Lopez-Saez JJ.; 2001 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=96147

•

Epidermal Growth Factor Replaces Estrogen in the Stimulation of Female GenitalTract Growth and Differentiation. by Nelson KG, Takahashi T, Bossert NL, Walmer DK, McLachlan JA.; 1991 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=50739

•

Epidermal growth factor-induced nuclear factor [kappa]B activation: A major pathway of cell-cycle progression in estrogen-receptor negative breast cancer cells. by Biswas DK, Cruz AP, Gansberger E, Pardee AB.; 2000 Jul 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26984

•

Equine estrogens differentially inhibit DNA fragmentation induced by glutamate in neuronal cells by modulation of regulatory proteins involved in programmed cell death. by Zhang Y, Lu X, Bhavnani BR.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=340384

•

ER[beta] Binds N-CoR in the Presence of Estrogens via an LXXLL-like Motif in the NCoR C-terminus. by Webb P, Valentine C, Nguyen P, Price RH Jr, Marimuthu A, West BL, Baxter JD, Kushner PJ.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=179877

•

ERGDB: Estrogen Responsive Genes Database. by Tang S, Han H, Bajic VB.; 2004 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=308817

86

Estrogen

•

Essential Role for Estrogen in Protection against Vibrio vulnificus-Induced Endotoxic Shock. by Merkel SM, Alexander S, Zufall E, Oliver JD, Huet-Hudson YM.; 2001 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98741

•

Estradiol repression of tumor necrosis factor-[alpha] transcription requires estrogen receptor activation function-2 and is enhanced by coactivators. by An J, Ribeiro RC, Webb P, Gustafsson JA, Kushner PJ, Baxter JD, Leitman DC.; 1999 Dec 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24790

•

Estrogen action and male fertility: Roles of the sodium /hydrogen exchanger-3 and fluid reabsorption in reproductive tract function. by Zhou Q, Clarke L, Nie R, Carnes K, Lai LW, Lien YH, Verkman A, Lubahn D, Fisher JS, Katzenellenbogen BS, Hess RA.; 2001 Nov 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=61180

•

Estrogen alters behavior and forebrain c-fos expression in ovariectomized rats subjected to the forced swim test. by Rachman IM, Unnerstall JR, Pfaff DW, Cohen RS.; 1998 Nov 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24977

•

Estrogen alters thresholds for B cell apoptosis and activation. by Grimaldi CM, Cleary J, Dagtas AS, Moussai D, Diamond B.; 2002 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151010

•

Estrogen and Thyroid Hormone Interaction on Regulation of Gene Expression. by Zhu Y, Yen PM, Chin WW, Pfaff DW.; 1996 Oct 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38036

•

Estrogen differentially regulates neuropeptide gene expression in a sexually dimorphic olfactory pathway. by Simerly RB, Young BJ, Capozza MA, Swanson LW.; 1989 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=287354

•

Estrogen in the adult male reproductive tract: A review. by Hess RA.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=179885

•

Estrogen increases synaptic connectivity between single presynaptic inputs and multiple postsynaptic CA1 pyramidal cells: A serial electron-microscopic study. by Yankova M, Hart SA, Woolley CS.; 2001 Mar 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=30686

•

Estrogen induces tissue specific changes in the chromatin conformation of the vitellogenin genes in Xenopus. by Gerber-Huber S, Felber BK, Weber R, Ryffel GU.; 1981 Jun 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=326865

•

Estrogen induction of the cyclin D1 promoter: Involvement of a cAMP response-like element. by Sabbah M, Courilleau D, Mester J, Redeuilh G.; 1999 Sep 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18014

•

Estrogen inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation, an effect mediated by SOCS-2. by Leung KC, Doyle N, Ballesteros M, Sjogren K, Watts CK, Low TH, Leong GM, Ross RJ, Ho KK.; 2003 Feb 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=298718

Studies 87

•

Estrogen inhibits the vascular injury response in estrogen receptor [beta]-deficient female mice. by Karas RH, Hodgin JB, Kwoun M, Krege JH, Aronovitz M, Mackey W, Gustafsson JA, Korach KS, Smithies O, Mendelsohn ME.; 1999 Dec 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24785

•

Estrogen is a critical determinant that specifies the duration of the window of uterine receptivity for implantation. by Ma WG, Song H, Das SK, Paria BC, Dey SK.; 2003 Mar 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151449

•

Estrogen modulates cutaneous wound healing by downregulating macrophage migration inhibitory factor. by Ashcroft GS, Mills SJ, Lei K, Gibbons L, Jeong MJ, Taniguchi M, Burow M, Horan MA, Wahl SM, Nakayama T.; 2003 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154440

•

Estrogen Modulates Expression of the Glycosyltransferases that Synthesize Sulfated Oligosaccharides on Lutropin. by Dharmesh SM, Baenziger JU.; 1993 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47935

•

Estrogen Opposes the Apoptotic Effects of Bone Morphogenetic Protein 7 on Tissue Remodeling. by Monroe DG, Jin DF, Sanders MM.; 2000 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85866

•

Estrogen protects against the synergistic toxicity by HIV proteins, methamphetamine and cocaine. by Turchan J, Anderson C, Hauser KF, Sun Q, Zhang J, Liu Y, Wise PM, Kruman I, Maragos W, Mattson MP, Booze R, Nath A.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=29103

•

Estrogen receptor (ER) [beta], a modulator of ER[alpha] in the uterus. by Weihua Z, Saji S, Makinen S, Cheng G, Jensen EV, Warner M, Gustafsson JA.; 2000 May 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18537

•

Estrogen receptor (ER) modulators each induce distinct conformational changes in ER [alpha] and ER [beta]. by Paige LA, Christensen DJ, Gron H, Norris JD, Gottlin EB, Padilla KM, Chang CY, Ballas LM, Hamilton PT, McDonnell DP, Fowlkes DM.; 1999 Mar 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22409

•

Estrogen receptor (ER)[beta] knockout mice reveal a role for ER[beta] in migration of cortical neurons in the developing brain. by Wang L, Andersson S, Warner M, Gustafsson JA.; 2003 Jan 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=141060

•

Estrogen receptor [alpha], not [beta], is a critical link in estradiol-mediated protection against brain injury. by Dubal DB, Zhu H, Yu J, Rau SW, Shughrue PJ, Merchenthaler I, Kindy MS, Wise PM.; 2001 Feb 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=29363

•

Estrogen receptor alpha dinucleotide repeat polymorphism in Japanese patients with autoimmune thyroid diseases. by Ban Y, Taniyama M, Tozaki T, Tomita M, Ban Y.; 2000; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=29093

•

Estrogen receptor interaction with estrogen response elements. by Klinge CM.; 2001 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=55815

88

Estrogen

•

Estrogen receptor of primary breast cancers: evidence for intracellular proteolysis. by Maaroufi Y, Lacroix M, Lespagnard L, Journe F, Larsimont D, Leclercq G.; 2000; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=13922

•

Estrogen receptor selectively binds the "coding strand" of an estrogen responsive element. by Lannigan DA, Notides AC.; 1989 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=286578

•

Estrogen receptor specificity in the regulation of skeletal growth and maturation in male mice. by Vidal O, Lindberg MK, Hollberg K, Baylink DJ, Andersson G, Lubahn DB, Mohan S, Gustafsson JA, Ohlsson C.; 2000 May 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25853

•

Estrogen receptor transcription and transactivation: Basic aspects of estrogen action. by Nilsson S, Gustafsson JA.; 2000; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=138658

•

Estrogen receptor transcription and transactivation: Estrogen receptor alpha and estrogen receptor beta - regulation by selective estrogen receptor modulators and importance in breast cancer. by S Katzenellenbogen B, A Katzenellenbogen J.; 2000; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=138655

•

Estrogen receptor transcription and transactivation: Estrogen receptor knockout mice what their phenotypes reveal about mechanisms of estrogen action. by Curtis Hewitt S, F Couse J, S Korach K.; 2000; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=138656

•

Estrogen receptor transcription and transactivation: Structure-function relationship in DNA- and ligand-binding domains of estrogen receptors. by Ruff M, Gangloff M, Marie Wurtz J, Moras D.; 2000; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=138657

•

Estrogen receptor-[alpha] mediates the brain antiinflammatory activity of estradiol. by Vegeto E, Belcredito S, Etteri S, Ghisletti S, Brusadelli A, Meda C, Krust A, Dupont S, Ciana P, Chambon P, Maggi A.; 2003 Aug 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=170966

•

Estrogen Receptor-Dependent Proteasomal Degradation of the Glucocorticoid Receptor Is Coupled to an Increase in Mdm2 Protein Expression. by Kinyamu HK, Archer TK.; 2003 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=166332

•

Estrogen receptor-dependent regulation of sensory neuron survival in developing dorsal root ganglion. by Patrone C, Andersson S, Korhonen L, Lindholm D.; 1999 Sep 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17981

•

Estrogen receptor-dependent sexual differentiation of dopaminergic neurons in the preoptic region of the mouse. by Simerly RB, Zee MC, Pendleton JW, Lubahn DB, Korach KS.; 1997 Dec 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28435

•

Estrogen receptor-interacting protein that modulates its nongenomic activity-crosstalk with Src /Erk phosphorylation cascade. by Wong CW, McNally C, Nickbarg E, Komm BS, Cheskis BJ.; 2002 Nov 12; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=137496

Studies 89

•

Estrogen receptors [alpha] and [beta] in the rodent mammary gland. by Saji S, Jensen EV, Nilsson S, Rylander T, Warner M, Gustafsson JA.; 2000 Jan 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26664

•

Estrogen receptors activate atrial natriuretic peptide in the rat heart. by Jankowski M, Rachelska G, Donghao W, McCann SM, Gutkowska J.; 2001 Sep 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=58804

•

Estrogen receptors and proliferation markers in primary and recurrent breast cancer. by Jensen EV, Cheng G, Palmieri C, Saji S, Makela S, Van Noorden S, Wahlstrom T, Warner M, Coombes RC, Gustafsson JA.; 2001 Dec 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=65006

•

Estrogen Receptors Colocalize with Low-Affinity Nerve Growth Factor Receptors in Cholinergic Neurons of the Basal Forebrain. by Toran-Allerand CD, Miranda RC, Bentham WD, Sohrabji F, Brown TJ, Hochberg RB, MacLusky nJ.; 1992 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=49144

•

Estrogen Regulates the Expression of Several Different Estrogen Receptor mRNA Isoforms in Rat Pituitary. by Friend KE, Ang LW, Shupnik MA.; 1995 May 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41945

•

Estrogen regulates the rate of bone turnover but bone balance in ovariectomized rats is modulated by prevailing mechanical strain. by Westerlind KC, Wronski TJ, Ritman EL, Luo ZP, An KN, Bell NH, Turner RT.; 1997 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20601

•

Estrogen Response Elements Function as Allosteric Modulators of Estrogen Receptor Conformation. by Wood JR, Greene GL, Nardulli AM.; 1998 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=121422

•

Estrogen stimulates microglia and brain recovery from hypoxia-ischemia in normoglycemic but not diabetic female mice. by Zhang L, Nair A, Krady K, Corpe C, Bonneau RH, Simpson IA, Vannucci SJ.; 2004 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=300764

•

Estrogen up-regulates Bcl-2 and blocks tolerance induction of naive B cells. by Bynoe MS, Grimaldi CM, Diamond B.; 2000 Mar 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15993

•

Estrogen, Progesterone and Epithelial Ovarian Cancer. by Ho SM.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=239900

•

Estrogen-Astrocyte interactions: Implications for neuroprotection. by Dhandapani KM, Brann DW.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=116596

•

Estrogenic modulation of brain activity:implications for schizophreniaand Parkinson's disease. by Cyr M, Calon F, Morissette M, Di Paolo T.; 2002 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149792

•

Estrogenic responses in estrogen receptor-[alpha] deficient mice reveal a distinct estrogen signaling pathway. by Das SK, Taylor JA, Korach KS, Paria BC, Dey SK, Lubahn DB.; 1997 Nov 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24216

90

Estrogen

•

Estrogen-induced activation of mitogen-activated protein kinase requires mobilization of intracellular calcium. by Improta-Brears T, Whorton AR, Codazzi F, York JD, Meyer T, McDonnell DP.; 1999 Apr 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16393

•

Estrogen-induced apoptosis by inhibition of the erythroid transcription factor GATA1. by Blobel GA, Orkin SH.; 1996 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=231155

•

Estrogen-induced transcription of the progesterone receptor gene does not parallel estrogen receptor occupancy. by Lee Y, Gorski J.; 1996 Dec 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26377

•

Estrogen-inducible and liver-specific expression of the chicken Very Low Density Apolipoprotein II gene locus in transgenic mice. by Wijnholds J, Philipsen S, Pruzina S, Fraser P, Grosveld F, Ab G.; 1993 Apr 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=309373

•

Estrogen-inducible, sex-specific expression of brain-derived neurotrophic factor mRNA in a forebrain song control nucleus of the juvenile zebra finch. by Dittrich F, Feng Y, Metzdorf R, Gahr M.; 1999 Jul 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22219

•

Estrogen-responsive element of the human pS2 gene is an imperfectly palindromic sequence. by Berry M, Nunez AM, Chambon P.; 1989 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=286657

•

Estrogens inhibit mycelium-to-yeast transformation in the fungus Paracoccidioides brasiliensis: implications for resistance of females to paracoccidioidomycosis. by Restrepo A, Salazar ME, Cano LE, Stover EP, Feldman D, Stevens DA.; 1984 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=261537

•

Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun repression. by Shevde NK, Bendixen AC, Dienger KM, Pike JW.; 2000 Jul 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16630

•

Evidence of high expression of peptidylglycine [alpha]-amidating monooxygenase in the rat uterus: Estrogen regulation. by Meskini RE, Delfino C, Boudouresque F, Oliver C, Martin PM, Ouafik L'.; 1998 Jun 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22780

•

Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions. by Thornton JW.; 2001 May 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33271

•

Expression and localization of estrogen receptor-[beta] in annulus cells of the human intervertebral disc and the mitogenic effect of 17-[beta]-estradiol in vitro. by Gruber HE, Yamaguchi D, Ingram J, Leslie K, Huang W, Miller TA, Hanley EN Jr.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=65546

•

Expression and localization of estrogen receptor-alpha protein in normal and abnormal term placentae and stimulation of trophoblast differentiation by estradiol.

Studies 91

by Bukovsky A, Cekanova M, Caudle MR, Wimalasena J, Foster JS, Henley DC, Elder RF.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151787 •

Expression of human estrogen receptor-[alpha] and -[beta], progesterone receptor, and androgen receptor mRNA in normal and malignant ovarian epithelial cells. by Lau KM, Mok SC, Ho SM.; 1999 May 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21927

•

Expression of the gene for the POU domain transcription factor Tst-1/Oct6 is regulated by an estrogen-dependent enhancer. by Renner K, Sock E, Bermingham JR Jr, Wegner M.; 1996 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=146271

•

Formation of nuclear bodies in hepatocytes of estrogen-treated roosters. by Ochs RL, Stein TW Jr, Andrade LE, Gallo D, Chan EK, Tan EM, Brasch K.; 1995 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=301192

•

Functional Estrogen Receptors in a Human Preosteoclastic Cell Line. by Fiorelli G, Gori F, Petilli M, Tanini A, Benvenuti S, Serio M, Bernabei P, Brandi ML.; 1995 Mar 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42280

•

Functional role of estrogen in pituitary tumor pathogenesis. by Heaney AP, Fernando M, Melmed S.; 2002 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150842

•

Galanin is an estrogen-inducible, secretory product of the rat anterior pituitary. by Kaplan LM, Gabriel SM, Koenig JI, Sunday ME, Spindel ER, Martin JB, Chin WW.; 1988 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=282196

•

Generation and reproductive phenotypes of mice lacking estrogen receptor [beta]. by Krege JH, Hodgin JB, Couse JF, Enmark E, Warner M, Mahler JF, Sar M, Korach KS, Gustafsson JA, Smithies O.; 1998 Dec 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28103

•

Glucocorticoid and estrogen regulation of a rat T-kininogen gene. by Anderson KP, Lingrel JB.; 1989 Apr 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=317660

•

Histone H1 Represses Estrogen Receptor [alpha] Transcriptional Activity by Selectively Inhibiting Receptor-Mediated Transcription Initiation. by Cheung E, Zarifyan AS, Kraus WL.; 2002 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=133703

•

Hormone-regulatable neoplastic transformation induced by a Jun-estrogen receptor chimera. by Kruse U, Iacovoni JS, Goller ME, Vogt PK.; 1997 Nov 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24963

•

How does the estrogen receptor work? by Gross JM, Yee D.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=138721

92

Estrogen

•

Human Giant Cell Tumors of the Bone (Osteoclastomas) are Estrogen Target Cells. by Oursler MJ, Pederson L, Fitzpatrick L, Riggs BL, Spelsberg T.; 1994 Jun 7; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43967

•

ICI 164,384: a control for investigating estrogen responsive genes. by Bondy KL, Zacharewski TR.; 1993 Nov 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=310650

•

Identification of a Putative Estrogen Response Element in the Gene Encoding BrainDerived Neurotrophic Factor. by Sohrabji F, Miranda RC, Toran-Allerand CD.; 1995 Nov 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40581

•

Identification of a Structural Determinant Necessary for the Localization and Function of Estrogen Receptor [alpha] at the Plasma Membrane. by Razandi M, Alton G, Pedram A, Ghonshani S, Webb P, Levin ER.; 2003 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151696

•

Identification of a third distinct estrogen receptor and reclassification of estrogen receptors in teleosts. by Hawkins MB, Thornton JW, Crews D, Skipper JK, Dotte A, Thomas P.; 2000 Sep 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=27095

•

Identification of an estrogen response element upstream of the human c-fos gene that binds the estrogen receptor and the AP-1 transcription factor. by Weisz A, Rosales R.; 1990 Sep 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=332129

•

Identification of the Novel Player [delta]EF1 in Estrogen Transcriptional Cascades. by Chamberlain EM, Sanders MM.; 1999 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84156

•

Immunodetection of estrogen receptor in epithelial and stromal tissues of neonatal mouse uterus. by Korach KS, Horigome T, Tomooka Y, Yamashita S, Newbold RR, McLachlan JA.; 1988 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=280203

•

In vivo footprinting of the estrogen-inducible vitellogenin II gene from chicken. by Philipsen JN, Hennis BC, Ab G.; 1988 Oct 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=338771

•

Increased adipose tissue in male and female estrogen receptor-[alpha] knockout mice. by Heine PA, Taylor JA, Iwamoto GA, Lubahn DB, Cooke PS.; 2000 Nov 7; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18832

•

Increased anxiety and synaptic plasticity in estrogen receptor [beta]-deficient mice. by Krezel W, Dupont S, Krust A, Chambon P, Chapman PF.; 2001 Oct 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59805

Studies 93

•

Increased B-lymphopoiesis by interleukin 7 induces bone loss in mice with intact ovarian function: Similarity to estrogen deficiency. by Miyaura C, Onoe Y, Inada M, Maki K, Ikuta K, Ito M, Suda T.; 1997 Aug 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23193

•

Increased cell survival by inhibition of BRCA1 using an antisense approach in an estrogen responsive ovarian carcinoma cell line. by Annab LA, Hawkins RE, Solomon G, Barrett JC, Afshari CA.; 2000; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=13916

•

Increased production of IL-7 uncouples bone formation from bone resorption during estrogen deficiency. by Weitzmann MN, Roggia C, Toraldo G, Weitzmann L, Pacifici R.; 2002 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151629

•

Induction of hTERT Expression and Telomerase Activity by Estrogens in Human Ovary Epithelium Cells. by Misiti S, Nanni S, Fontemaggi G, Cong YS, Wen J, Hirte HW, Piaggio G, Sacchi A, Pontecorvi A, Bacchetti S, Farsetti A.; 2000 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85692

•

Influence of estrogen on host resistance: increased susceptibility of mice to Listeria monocytogenes correlates with depressed production of interleukin 2. by Pung OJ, Tucker AN, Vore SJ, Luster MI.; 1985 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=262140

•

Influence of steroidal and nonsteroidal sex hormones on host resistance in mice: increased susceptibility to Listeria monocytogenes after exposure to estrogenic hormones. by Pung OJ, Luster MI, Hayes HT, Rader J.; 1984 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=261530

•

Inhibition by estrogens of conidium-to-yeast conversion in the fungus Paracoccidioides brasiliensis. by Salazar ME, Restrepo A, Stevens DA.; 1988 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=259352

•

Inhibition of Estrogen Receptor-DNA Binding by the "Pure" Antiestrogen ICI 164,384 Appears to be Mediated by Impaired Receptor Dimerization. by Fawell SE, White R, Hoare S, Sydenham M, Page M, Parker MG.; 1990 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=54642

•

Interaction of Proteins with Transcriptionally Active Estrogen Receptors. by Cavailles V, Dauvois S, Danielian PS, Parker MG.; 1994 Oct 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=44947

•

Introduction of estrogen-responsiveness into mammalian cell lines. by Druege PM, Klein-Hitpass L, Green S, Stack G, Chambon P, Ryffel GU.; 1986 Dec 9; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=311961

94

Estrogen

•

Involvement of bone morphogenetic protein 4 (BMP-4) in pituitary prolactinoma pathogenesis through a Smad /estrogen receptor crosstalk. by Paez-Pereda M, Giacomini D, Refojo D, Nagashima AC, Hopfner U, Grubler Y, Chervin A, Goldberg V, Goya R, Hentges ST, Low MJ, Holsboer F, Stalla GK, Arzt E.; 2003 Feb 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=298721

•

Involvement of estrogen receptor [beta] in terminal differentiation of mammary gland epithelium. by Forster C, Makela S, Warri A, Kietz S, Becker D, Hultenby K, Warner M, Gustafsson JA.; 2002 Nov 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=137759

•

Isolation of estrogen receptor-binding sites in human genomic DNA. by Inoue S, Kondo S, Hashimoto M, Kondo T, Muramatsu M.; 1991 Aug 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=328545

•

Isolation of Estrogen-Responsive Genes with a CpG Island Library. by Watanabe T, Inoue S, Hiroi H, Orimo A, Kawashima H, Muramatsu M.; 1998 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=121513

•

Kinetic analysis of estrogen receptorligand interactions. by Rich RL, Hoth LR, Geoghegan KF, Brown TA, LeMotte PK, Simons SP, Hensley P, Myszka DG.; 2002 Jun 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124311

•

Lack of association between estrogen receptor [beta] dinucleotide repeat polymorphism and autoimmune thyroid diseases in Japanese patients. by Ban Y, Tozaki T, Taniyama M, Tomita M, Ban Y.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=29094

•

Ligand dependence of estrogen receptor induced changes in chromatin structure. by Gilbert DM, Losson R, Chambon P.; 1992 Sep 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=334180

•

Ligand-dependent repression of the erythroid transcription factor GATA-1 by the estrogen receptor. by Blobel GA, Sieff CA, Orkin SH.; 1995 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=230546

•

Ligand-Mediated Assembly and Real-Time Cellular Dynamics of Estrogen Receptor [alpha]-Coactivator Complexes in Living Cells. by Stenoien DL, Nye AC, Mancini MG, Patel K, Dutertre M, O'Malley BW, Smith CL, Belmont AS, Mancini MA.; 2001 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87100

•

Manipulation of prenatal hormones and dietary phytoestrogens during adulthood alter the sexually dimorphic expression of visual spatial memory. by Lund TD, Lephart ED.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=64559

•

Mechanism for Biotransformation of Nonylphenol Polyethoxylates to Xenoestrogens in Pseudomonas putida. by John DM, White GF.; 1998 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=107438

•

Mechanism of estrogen-mediated neuroprotection: Regulation of mitochondrial calcium and Bcl-2 expression. by Nilsen J, Brinton RD.; 2003 Mar 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151428

Studies 95

•

Mediation of estrogen mitogenic effect in human breast cancer MCF-7 cells by PCcell-derived growth factor (PCDGF /granulin precursor). by Lu R, Serrero G.; 2001 Jan 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=14558

•

Mediator and p300/CBP-Steroid Receptor Coactivator Complexes Have Distinct Roles, but Function Synergistically, during Estrogen Receptor [alpha]-Dependent Transcription with Chromatin Templates. by Acevedo ML, Kraus WL.; 2003 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=140681

•

Modulation of Cell Proliferation and Gene Expression by a p53-Estrogen Receptor Hybrid Protein. by Roemer K, Friedmann T.; 1993 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47545

•

Modulation of the Ligand-Independent Activation of the Human Estrogen Receptor by Hormone and Antihormone. by Smith CL, Conneely OM, O'Malley BW.; 1993 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46879

•

Molecular cloning and characterization of human estrogen receptor betacx: a potential inhibitor ofestrogen action in human. by Ogawa S, Inoue S, Watanabe T, Orimo A, Hosoi T, Ouchi Y, Muramatsu M.; 1998 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=147730

•

Molecular Determinants of the Estrogen Receptor-Coactivator Interface. by Mak HY, Hoare S, Henttu PM, Parker MG.; 1999 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84247

•

Molecular determinants of tissue selectivity in estrogen receptor modulators. by Grese TA, Sluka JP, Bryant HU, Cullinan GJ, Glasebrook AL, Jones CD, Matsumoto K, Palkowitz AD, Sato M, Termine JD, Winter MA, Yang NN, Dodge JA.; 1997 Dec 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28440

•

Molecular mechanism of inhibition of estrogen-induced cathepsin D gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in MCF-7 cells. by Krishnan V, Porter W, Santostefano M, Wang X, Safe S.; 1995 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=230924

•

Molecular origin of cancer: Catechol estrogen-3,4-quinones as endogenous tumor initiators. by Cavalieri EL, Stack DE, Devanesan PD, Todorovic R, Dwivedy I, Higginbotham S, Johansson SL, Patil KD, Gross ML, Gooden JK, Ramanathan R, Cerny RL, Rogan EG.; 1997 Sep 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23537

•

Morphological abnormalities in the brains of estrogen receptor [beta] knockout mice. by Wang L, Andersson S, Warner M, Gustafsson JA.; 2001 Feb 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=30218

•

Multifaceted Regulation of Cell Cycle Progression by Estrogen: Regulation of Cdk Inhibitors and Cdc25A Independent of Cyclin D1-Cdk4 Function. by Foster JS, Henley DC, Bukovsky A, Seth P, Wimalasena J.; 2001 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86671

96

Estrogen

•

Naturally occurring variations in maternal behavior in the rat are associated with differences in estrogen-inducible central oxytocin receptors. by Champagne F, Diorio J, Sharma S, Meaney MJ.; 2001 Oct 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=60123

•

NF-[kappa]B activation and interleukin 6 production in fibroblasts by estrogen receptor-negative breast cancer cell-derived interleukin 1[alpha]. by Bhat-Nakshatri P, Newton TR, Goulet R Jr, Nakshatri H.; 1998 Jun 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22705

•

Nitric oxide in the contractile action of bradykinin, oxytocin, and prostaglandin F2 [alpha] in the estrogenized rat uterus. by Chaud M, Franchi AM, Rettori V, McCann SM, Gimeno MF.; 1997 Sep 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23588

•

Nongenomic actions of estrogens and xenoestrogens by binding at a plasma membrane receptor unrelated to estrogen receptor [alpha] and estrogen receptor [beta]. by Nadal A, Ropero AB, Laribi O, Maillet M, Fuentes E, Soria B.; 2000 Oct 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17247

•

Nuclear estrogen receptor molecular heterogeneity in the mouse uterus. by Golding TS, Korach KS.; 1988 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=279483

•

Nuclease-hypersensitive sites in chromatin of the estrogen-inducible apoVLDL II gene of chicken. by Kok K, Snippe L, Ab G, Gruber M.; 1985 Jul 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=321858

•

Oestrogen facilitates the binding of ubiquitous and liver-enriched nuclear proteins to the apoVLDL II promoter in vivo. by Wijnholds J, Muller E, Ab G.; 1991 Jan 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=333531

•

Organochlorine exposures influence on breast cancer risk and survival according to estrogen receptor status: a Danish cohort-nested case-control study. by Hoyer AP, Jorgensen T, Rank F, Grandjean P.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=37543

•

P /CAF associates with cyclin D1 and potentiates its activation of the estrogen receptor. by McMahon C, Suthiphongchai T, DiRenzo J, Ewen ME.; 1999 May 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21868

•

P21-activated kinase-1 phosphorylates and transactivates estrogen receptor-[alpha] and promotes hyperplasia in mammary epithelium. by Wang RA, Mazumdar A, Vadlamudi RK, Kumar R.; 2002 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=129075

•

Phosphorylation of Human Estrogen Receptor [alpha] by Protein Kinase A Regulates Dimerization. by Chen D, Pace PE, Coombes RC, Ali S.; 1999 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=116031

Studies 97

•

Physiological Coupling of Growth Factor and Steroid Receptor Signaling Pathways: Estrogen Receptor Knockout Mice Lack Estrogen-Like Response to Epidermal Growth Factor. by Curtis SW, Washburn T, Sewall C, DiAugustine R, Lindzey J, Couse JF, Korach KS.; 1996 Oct 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38043

•

Placental expression of estrogen receptor beta and its hormone binding variant -comparison with estrogen receptor alpha and a role for estrogen receptors in asymmetric division and differentiation of estrogen-dependent cells. by Bukovsky A, Caudle MR, Cekanova M, Fernando RI, Wimalasena J, Foster JS, Henley DC, Elder RF.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155643

•

Plasma membrane localization and function of the estrogen receptor [alpha] variant (ER46) in human endothelial cells. by Li L, Haynes MP, Bender JR.; 2003 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153637

•

Polysomal ribonuclease 1 exists in a latent form on polysomes prior to estrogen activation of mRNA decay. by Cunningham KS, Hanson MN, Schoenberg DR.; 2001 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=29717

•

Potential role of the interaction between equine estrogens, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) in the prevention of coronary heart and neurodegenerative diseases in postmenopausal women. by Perrella J, Berco M, Cecutti A, Gerulath A, Bhavnani BR.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=194865

•

POU Transcription Factors Brn-3a and Brn-3b Interact with the Estrogen Receptor and Differentially Regulate Transcriptional Activity via an Estrogen Response Element. by Budhram-Mahadeo V, Parker M, Latchman DS.; 1998 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=108815

•

pp90rsk1 Regulates Estrogen Receptor-Mediated Transcription through Phosphorylation of Ser-167. by Joel PB, Smith J, Sturgill TW, Fisher TL, Blenis J, Lannigan DA.; 1998 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=121427

•

Prebending the estrogen response element destabilizes binding of the estrogen receptor DNA binding domain. by Kim J, de Haan G, Nardulli AM, Shapiro DJ.; 1997 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=232170

•

Prevention of mammary carcinogenesis by short-term estrogen and progestin treatments. by Rajkumar L, Guzman RC, Yang J, Thordarson G, Talamantes F, Nandi S.; 2004; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=314450

•

Probing protein conformational changes in living cells by using designer binding proteins: Application to the estrogen receptor. by Koide A, Abbatiello S, Rothgery L, Koide S.; 2002 Feb 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122176

98

Estrogen

•

Probing the structure and function of the estrogen receptor ligand binding domain by analysis of mutants with altered transactivation characteristics. by Eng FC, Lee HS, Ferrara J, Willson TM, White JH.; 1997 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=232317

•

Progesterone Inhibits Estrogen-Induced Cyclin D1 and cdk4 Nuclear Translocation, Cyclin E- and Cyclin A-cdk2 Kinase Activation, and Cell Proliferation in Uterine Epithelial Cells in Mice. by Tong W, Pollard JW.; 1999 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84018

•

Promoter specificity of the two transcriptional activation functions of the human oestrogen receptor in yeast. by Metzger D, Losson R, Bornert JM, Lemoine Y, Chambon P.; 1992 Jun 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=336926

•

Properties of a high-affinity DNA binding site for estrogen receptor. by Peale FV Jr, Ludwig LB, Zain S, Hilf R, Bambara RA.; 1988 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=279696

•

Proteasome-dependent degradation of the human estrogen receptor. by Nawaz Z, Lonard DM, Dennis AP, Smith CL, O'Malley BW.; 1999 Mar 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26701

•

Protective effects of estrogen in a rat model of age-related cataracts. by Bigsby RM, Cardenas H, Caperell --Grant A, Grubbs CJ.; 1999 Aug 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17782

•

Protein Disulfide Isomerase, a Component of the Estrogen Receptor Complex, Is Associated with Chlamydia trachomatis Serovar E Attached to Human Endometrial Epithelial Cells. by Davis CH, Raulston JE, Wyrick PB.; 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128041

•

Prothymosin Alpha Selectively Enhances Estrogen Receptor Transcriptional Activity by Interacting with a Repressor of Estrogen Receptor Activity. by Martini PG, DelageMourroux R, Kraichely DM, Katzenellenbogen BS.; 2000 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86097

•

Purification and Identification of p68 RNA Helicase Acting as a Transcriptional Coactivator Specific for the Activation Function 1 of Human Estrogen Receptor [alpha]. by Endoh H, Maruyama K, Masuhiro Y, Kobayashi Y, Goto M, Tai H, Yanagisawa J, Metzger D, Hashimoto S, Kato S.; 1999 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84379

•

Quantitative characterization of the interaction between purified human estrogen receptor [alpha] and DNA using fluorescence anisotropy. by Boyer M, Poujol N, Margeat E, Royer CA.; 2000 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=102715

•

Reduction of post injury neointima formation due to 17[beta]-estradiol and phytoestrogen treatment is not influenced by the pure synthetic estrogen receptor antagonist ICI 182,780 in vitro. by Finking G, Lenz C, Schochat T, Hanke H.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=119852

Studies 99

•

Regulation of Estrogen Receptor Nuclear Export by Ligand-Induced and p38Mediated Receptor Phosphorylation. by Lee H, Bai W.; 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=133965

•

Regulation of the chicken ovalbumin gene by estrogen and corticosterone requires a novel DNA element that binds a labile protein, Chirp-1. by Dean DM, Jones PS, Sanders MM.; 1996 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=231188

•

Regulation of the Functional Interaction between Cyclin D1 and the Estrogen Receptor. by Lamb J, Ladha MH, McMahon C, Sutherland RL, Ewen ME.; 2000 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86475

•

Regulation of vascular endothelial growth factor (VEGF) gene transcription by estrogen receptors [alpha] and [beta]. by Mueller MD, Vigne JL, Minchenko A, Lebovic DI, Leitman DC, Taylor RN.; 2000 Sep 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=27133

•

Repression of the interleukin-6 promoter by estrogen receptor is mediated by NFkappa B and C/EBP beta. by Stein B, Yang MX.; 1995 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=230744

•

Responses in the brain of estrogen receptor [alpha]-disrupted mice. by Shughrue PJ, Lubahn DB, Negro-Vilar A, Korach KS, Merchenthaler I.; 1997 Sep 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23564

•

Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. by Gehm BD, McAndrews JM, Chien PY, Jameson JL.; 1997 Dec 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28446

•

Ribosome loading, but not protein synthesis, is required for estrogen stabilization of Xenopus laevis vitellogenin mRNA. by Blume JE, Shapiro DJ.; 1989 Nov 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=335109

•

Role for Hsp90-Associated Cochaperone p23 in Estrogen Receptor Signal Transduction. by Knoblauch R, Garabedian MJ.; 1999 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=84199

•

Role of endogenous oestrogen in aetiology of coronary heart disease: analysis of age related trends in coronary heart disease and breast cancer in England and Wales and Japan. by Lawlor DA, Ebrahim S, Davey Smith G.; 2002 Aug 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=117771

•

Rsk2 allosterically activates estrogen receptor[alpha] by docking to the hormonebinding domain. by Clark DE, Poteet-Smith CE, Smith JA, Lannigan DA.; 2001 Jul 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=125527

•

Selective binding of the estrogen receptor to one strand of the estrogen responsive element. by Mukherjee R.; 1993 Jun 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=309595

•

Semiquinone radical intermediate in catecholic estrogen-mediated cytotoxicity and mutagenesis: Chemoprevention strategies with antioxidants. by Samuni AM, Chuang EY, Krishna MC, Stein W, DeGraff W, Russo A, Mitchell JB.; 2003 Apr 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154355

100

Estrogen

•

Sequence homologies in the region preceding the transcription initiation site of the liver estrogen-responsive vitellogenin and apo-VLDLII genes. by Walker P, Germond JE, Brown-Luedi M, Givel F, Wahli W.; 1984 Nov 26; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=320402

•

Sequence of the pS2 mRNA induced by estrogen in the human breast cancer cell line MCF-7. by Jakowlew SB, Breathnach R, Jeltsch JM, Masiakowski P, Chambon P.; 1984 Mar 26; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=318711

•

Sexually dimorphic expression of estrogen receptor [beta] in the anteroventral periventricular nucleus of the rat preoptic area: Implication in luteinizing hormone surge. by Orikasa C, Kondo Y, Hayashi S, McEwen BS, Sakuma Y.; 2002 Mar 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122514

•

Short-term exposure to pregnancy levels of estrogen prevents mammary carcinogenesis. by Rajkumar L, Guzman RC, Yang J, Thordarson G, Talamantes F, Nandi S.; 2001 Sep 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=58802

•

Signaling through estrogen receptors modulates telomerase activity in human prostate cancer. by Nanni S, Narducci M, Della Pietra L, Moretti F, Grasselli A, De Carli P, Sacchi A, Pontecorvi A, Farsetti A.; 2002 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151062

•

Specific estrogen-induced cell proliferation of cultured Syrian hamster renal proximal tubular cells in serum-free chemically defined media. by Oberley TD, Lauchner LJ, Pugh TD, Gonzalez A, Goldfarb S, Li SA, Li JJ.; 1989 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=286857

•

Specific expression of the pS2 gene in subclasses of breast cancers in comparison with expression of the estrogen and progesterone receptors and the oncogene ERBB2. by Rio MC, Bellocq JP, Gairard B, Rasmussen UB, Krust A, Koehl C, Calderoli H, Schiff V, Renaud R, Chambon P.; 1987 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=299729

•

Specific Mutations in the Estrogen Receptor Change the Properties of Antiestrogens to Full Agonists. by Mahfoudi A, Roulet E, Dauvois S, Parker MG, Wahli W.; 1995 May 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41912

•

Stromal estrogen receptors mediate mitogenic effects of estradiol on uterine epithelium. by Cooke PS, Buchanan DL, Young P, Setiawan T, Brody J, Korach KS, Taylor J, Lubahn DB, Cunha GR.; 1997 Jun 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21085

•

Structural Differences Between the Hormone and Antihormone Estrogen Receptor Complexes Bound to the Hormone Response Element. by Sabbah M, Goulilleux F, Sola B, Reheuilh G, Baulieu E.; 1991 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=50816

Studies 101

•

Structure of the human oestrogen-responsive gene pS2. by Jeltsch JM, Roberts M, Schatz C, Garnier JM, Brown AM, Chambon P.; 1987 Feb 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=340557

•

Subunit Structure of the Nonactivated Human Estrogen Receptor. by Segnitz B, Gehring U.; 1995 Mar 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42447

•

Survival of reproductive behaviors in estrogen receptor [beta] gene-deficient ([beta]ERKO) male and female mice. by Ogawa S, Chan J, Chester AE, Gustafsson JA, Korach KS, Pfaff DW.; 1999 Oct 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23148

•

Tamoxifen inhibits acidification in cells independent of the estrogen receptor. by Altan N, Chen Y, Schindler M, Simon SM.; 1999 Apr 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16349

•

Tamoxifen Prevents Induction of Hepatic Neoplasia by Zeranol, an Estrogenic Food Contaminant. by Coe JE, Ishak KG, Ward JM, Ross MJ.; 1992 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=48390

•

Tamoxifen stimulates arachidonic acid release from rat liver cells by an estrogen receptor-independent, non-genomic mechanism. by Levine L.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=212317

•

Targeting of SWI /SNF chromatin remodelling complexes to estrogen-responsive genes. by Belandia B, Orford RL, Hurst HC, Parker MG.; 2002 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=126156

•

The 29-kDa Proteins Phosphorylated in Thrombin-Activated Human Platelets are Forms of the Estrogen Receptor-Related 27-kDa Heat Shock Protein. by Medelsohn ME, Zhu Y, O'Neill S.; 1991 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=53104

•

The analysis of chimeric human /rainbow trout estrogen receptors reveals amino acid residues outside of P- and D-boxes important for the transactivation function. by Petit FG, Valotaire Y, Pakdel F.; 2000 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=102667

•

The antiestrogen ICI 182,780 decreases the expression of estrogen receptor-alpha but has no effect on estrogen receptor-beta and androgen receptor in rat efferent ductules. by Oliveira CA, Nie R, Carnes K, Franca LR, Prins GS, Saunders PT, Hess RA.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=270006

•

The antiestrogen ICI 182,780 induces early effects on the adult male mouse reproductive tract and long-term decreased fertility without testicular atrophy. by Cho HW, Nie R, Carnes K, Zhou Q, Sharief NA, Hess RA.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=194658

•

The antioxidant neuroprotective effects of estrogens and phenolic compounds are independent from their estrogenic properties. by Moosmann B, Behl C.; 1999 Aug 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17699

102

Estrogen

•

The Aryl Hydrocarbon Receptor Mediates Degradation of Estrogen Receptor [alpha] through Activation of Proteasomes. by Wormke M, Stoner M, Saville B, Walker K, Abdelrahim M, Burghardt R, Safe S.; 2003 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149455

•

The basic helix --loop --helix --PAS protein ARNT functions as a potent coactivator of estrogen receptor-dependent transcription. by Brunnberg S, Pettersson K, Rydin E, Matthews J, Hanberg A, Pongratz I.; 2003 May 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=164478

•

The effect of anandamide on prolactin secretion is modulated by estrogen. by Scorticati C, Mohn C, De Laurentiis A, Vissio P, Fernandez Solari J, Seilicovich A, McCann SM, Rettori V.; 2003 Feb 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149971

•

The effects of estrogen, its antagonist ICI 182, 780, and interferon-tau on the expression of estrogen receptors and integrin alphaV beta 3 on cycle day 16 in bovine endometrium. by Kimmins S, Russell GL, Lim HC, Hall BK, MacLaren LA.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155788

•

The heat shock-induced hyperphosphorylation of [tau] is estrogen-independent and prevented by androgens: Implications for Alzheimer disease. by Papasozomenos SC.; 1997 Jun 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21206

•

The Modified Human DNA Repair Enzyme O6-Methylguanine-DNA Methyltransferase Is a Negative Regulator of Estrogen Receptor-Mediated Transcription upon Alkylation DNA Damage. by Teo AK, Oh HK, Ali RB, Li BF.; 2001 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=99886

•

The nuclear factor kappa B (NF-[kappa]B): A potential therapeutic target for estrogen receptor negative breast cancers. by Biswas DK, Dai SC, Cruz A, Weiser B, Graner E, Pardee AB.; 2001 Aug 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=56970

•

The nuclear orphan receptors COUP-TF and ARP-1 positively regulate the trout estrogen receptor gene through enhancing autoregulation. by Lazennec G, Kern L, Valotaire Y, Salbert G.; 1997 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=232356

•

The orphan nuclear receptor estrogen-related receptor alpha is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene. by Sladek R, Bader JA, Giguere V.; 1997 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=232390

•

The Orphan Nuclear Receptor SHP Utilizes Conserved LXXLL-Related Motifs for Interactions with Ligand-Activated Estrogen Receptors. by Johansson L, Bavner A, Thomsen JS, Farnegardh M, Gustafsson JA, Treuter E.; 2000 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85230

•

The phytoestrogen genistein induces thymic and immune changes: A human health concern? by Yellayi S, Naaz A, Szewczykowski MA, Sato T, Woods JA, Chang J, Segre M, Allred CD, Helferich WG, Cooke PS.; 2002 May 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124301

Studies 103

•

The quinone reductase gene: A unique estrogen receptor-regulated gene that is activated by antiestrogens. by Montano MM, Katzenellenbogen BS.; 1997 Mar 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20131

•

The retinoblastoma-interacting zinc-finger protein RIZ is a downstream effector of estrogen action. by Abbondanza C, Medici N, Nigro V, Rossi V, Gallo L, Piluso G, Belsito A, Roscigno A, Bontempo P, Puca AA, Molinari AM, Moncharmont B, Puca GA.; 2000 Mar 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16204

•

The role of cytokines in regulating estrogen synthesis: implications for the etiology of breast cancer. by Purohit A, Newman SP, Reed MJ.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=138722

•

The TRAP /Mediator coactivator complex interacts directly with estrogen receptors [alpha] and [beta] through the TRAP220 subunit and directly enhances estrogen receptor function in vitro. by Kang YK, Guermah M, Yuan CX, Roeder RG.; 2002 Mar 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122401

•

The tyrosine kinase and mitogen-activated protein kinase pathways mediate multiple effects of estrogen in hippocampus. by Bi R, Broutman G, Foy MR, Thompson RF, Baudry M.; 2000 Mar 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16286

•

Thyroid Hormone and Estrogen Interact to Regulate Behavior. by Dellovade TL, Zhu Y, Krey L, Pfaff DW.; 1996 Oct 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38035

•

Tracking the estrogen receptor in neurons: Implications for estrogen-induced synapse formation. by McEwen B, Akama K, Alves S, Brake WG, Bulloch K, Lee S, Li C, Yuen G, Milner TA.; 2001 Jun 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=34628

•

Transient administration of estradiol-17 beta establishes an autoregulatory loop permanently inducing estrogen receptor mRNA. by Barton MC, Shapiro DJ.; 1988 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=282135

•

Two Domains of the Progesterone Receptor Interact with the Estrogen Receptor and Are Required for Progesterone Activation of the c-Src/Erk Pathway in Mammalian Cells. by Ballare C, Uhrig M, Bechtold T, Sancho E, Di Domenico M, Migliaccio A, Auricchio F, Beato M.; 2003 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149459

•

Underdeveloped uterus and reduced estrogen responsiveness in mice with disruption of the estrogen-responsive finger protein gene, which is a direct target of estrogen receptor [alpha]. by Orimo A, Inoue S, Minowa O, Tominaga N, Tomioka Y, Sato M, Kuno J, Hiroi H, Shimizu Y, Suzuki M, Noda T, Muramatsu M.; 1999 Oct 12; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18406

•

Up-regulation of TNF-producing T cells in the bone marrow: A key mechanism by which estrogen deficiency induces bone loss in vivo. by Roggia C, Gao Y, Cenci S, Weitzmann MN, Toraldo G, Isaia G, Pacifici R.; 2001 Nov 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=61149

104

Estrogen

•

Use of postmenopausal estrogen replacement therapy from 1981 to 1997. by Csizmadi I, Benedetti A, Boivin JF, Hanley JA, Collet JP.; 2002 Jan 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=99271

•

Use of Suppressor Mutants To Probe the Function of Estrogen Receptor-p160 Coactivator Interactions. by Mak HY, Parker MG.; 2001 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87097

•

Visual spatial memory is enhanced in female rats (but inhibited in males) by dietary soy phytoestrogens. by Lund TD, West TW, Tian LY, Bu LH, Simmons DL, Setchell KD, Adlercreutz H, Lephart ED.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=64558

•

Widespread expression and estrogen regulation of PPEIA-3[prime prime or minute] nuclear RNA in the rat brain. by Brooks PJ, Kleopoulos SP, Funabashi T, Mobbs CV, Pfaff DW.; 1997 Dec 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28428

The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine.6 The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to use. If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with estrogen, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “estrogen” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for estrogen (hyperlinks lead to article summaries): •

A comparison of two different dosages of conjugated equine estrogen in continuous combined hormone replacement therapy with progestin. Author(s): Xing S, Wu Y, Liu J, Xu R, Zhang Z, Wang Y. Source: Chinese Medical Journal. 2003 April; 116(4): 584-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12875727&dopt=Abstract

•

A fractal analysis of analyte-estrogen receptor binding and dissociation kinetics using biosensors: environmental effects. Author(s): Butala HD, Sadana A. Source: Journal of Colloid and Interface Science. 2003 July 15; 263(2): 420-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12909031&dopt=Abstract

6

PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.

Studies 105

•

A new indole-3-carbinol tetrameric derivative inhibits cyclin-dependent kinase 6 expression, and induces G1 cell cycle arrest in both estrogen-dependent and estrogenindependent breast cancer cell lines. Author(s): Brandi G, Paiardini M, Cervasi B, Fiorucci C, Filippone P, De Marco C, Zaffaroni N, Magnani M. Source: Cancer Research. 2003 July 15; 63(14): 4028-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12874002&dopt=Abstract

•

A review of selective estrogen receptor modulators and national surgical adjuvant breast and bowel project clinical trials. Author(s): Smith RE. Source: Seminars in Oncology. 2003 October; 30(5 Suppl 16): 4-13. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14613021&dopt=Abstract

•

Activator protein-2gamma (AP-2gamma) expression is specifically induced by oestrogens through binding of the oestrogen receptor to a canonical element within the 5'-untranslated region. Author(s): Orso F, Cottone E, Hasleton MD, Ibbitt JC, Sismondi P, Hurst HC, De Bortoli M. Source: The Biochemical Journal. 2004 January 15; 377(Pt 2): 429-38. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14565844&dopt=Abstract

•

Adaptive hypersensitivity following long-term estrogen deprivation: involvement of multiple signal pathways. Author(s): Yue W, Wang JP, Conaway MR, Li Y, Santen RJ. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 September; 86(3-5): 265-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14623520&dopt=Abstract

•

Adaptive hypersensitivity to estrogen: mechanism for sequential responses to hormonal therapy in breast cancer. Author(s): Santen RJ, Song RX, Zhang Z, Yue W, Kumar R. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2004 January 1; 10(1 Pt 2): 337S-45S. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14734489&dopt=Abstract

•

Addition of adjuvant tamoxifen to cyclophosphamide, methotrexate and 5fluorouracil for premenopausal women with oestrogen receptor-positive breast cancer. Author(s): Li HC, Wen XF, Hou YF, Shen KW, Wu J, Lu JS, Shen ZZ, Shao ZM. Source: Asian J Surg. 2003 July; 26(3): 163-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12925292&dopt=Abstract

106

Estrogen

•

Additive antitumour effect of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (Iressa, ZD1839) and the antioestrogen fulvestrant (Faslodex, ICI 182,780) in breast cancer cells. Author(s): Okubo S, Kurebayashi J, Otsuki T, Yamamoto Y, Tanaka K, Sonoo H. Source: British Journal of Cancer. 2004 January 12; 90(1): 236-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14710235&dopt=Abstract

•

Additive estrogenic activities of the binary mixtures of four estrogenic chemicals in recombinant yeast expressing human estrogen receptor. Author(s): Kang KS, Cho SD, Lee YS. Source: Journal of Veterinary Science (Suwon-Si, Korea). 2002 March; 3(1): 1-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14614265&dopt=Abstract

•

Adjunctive estrogen treatment in women with chronic schizophrenia: a double-blind, randomized, and placebo-controlled trial. Author(s): Akhondzadeh S, Nejatisafa AA, Amini H, Mohammadi MR, Larijani B, Kashani L, Raisi F, Kamalipour A. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2003 September; 27(6): 1007-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14499318&dopt=Abstract

•

Advances in breast cancer treatment and prevention: preclinical studies on aromatase inhibitors and new selective estrogen receptor modulators (SERMs). Author(s): Schiff R, Chamness GC, Brown PH. Source: Breast Cancer Research : Bcr. 2003; 5(5): 228-31. Epub 2003 July 28. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12927029&dopt=Abstract

•

Advances in estrogen receptor biology: prospects for improvements in targeted breast cancer therapy. Author(s): Shao W, Brown M. Source: Breast Cancer Research : Bcr. 2004; 6(1): 39-52. Epub 2003 November 07. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14680484&dopt=Abstract

•

Alternatives to estrogen. Author(s): Fitzpatrick LA. Source: The Medical Clinics of North America. 2003 September; 87(5): 1091-113, X. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14621333&dopt=Abstract

Studies 107

•

An adenosine analogue, IB-MECA, down-regulates estrogen receptor alpha and suppresses human breast cancer cell proliferation. Author(s): Lu J, Pierron A, Ravid K. Source: Cancer Research. 2003 October 1; 63(19): 6413-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14559831&dopt=Abstract

•

An overview of nomegestrol acetate selective receptor binding and lack of estrogenic action on hormone-dependent cancer cells. Author(s): Shields-Botella J, Duc I, Duranti E, Puccio F, Bonnet P, Delansorne R, Paris J. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 November; 87(2-3): 111-22. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14672731&dopt=Abstract

•

Analysis of polymorphisms of the vitamin D receptor, estrogen receptor, and collagen Ialpha1 genes and their relationship with height in children with bone cancer. Author(s): Ruza E, Sotillo E, Sierrasesumaga L, Azcona C, Patino-Garcia A. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2003 October; 25(10): 780-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14528100&dopt=Abstract

•

AND-34/BCAR3, a GDP exchange factor whose overexpression confers antiestrogen resistance, activates Rac, PAK1, and the cyclin D1 promoter. Author(s): Cai D, Iyer A, Felekkis KN, Near RI, Luo Z, Chernoff J, Albanese C, Pestell RG, Lerner A. Source: Cancer Research. 2003 October 15; 63(20): 6802-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14583477&dopt=Abstract

•

Androgen receptor expression in estrogen receptor-negative breast cancer. Immunohistochemical, clinical, and prognostic associations. Author(s): Agoff SN, Swanson PE, Linden H, Hawes SE, Lawton TJ. Source: American Journal of Clinical Pathology. 2003 November; 120(5): 725-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14608899&dopt=Abstract

•

Antiandrogenic activity of the phytoestrogens naringenin, 6-(1,1dimethylallyl)naringenin and 8-prenylnaringenin. Author(s): Zierau O, Morrissey C, Watson RW, Schwab P, Kolba S, Metz P, Vollmer G. Source: Planta Medica. 2003 September; 69(9): 856-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14598215&dopt=Abstract

108

Estrogen

•

Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling. Author(s): Clarke R, Liu MC, Bouker KB, Gu Z, Lee RY, Zhu Y, Skaar TC, Gomez B, O'Brien K, Wang Y, Hilakivi-Clarke LA. Source: Oncogene. 2003 October 20; 22(47): 7316-39. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14576841&dopt=Abstract

•

Anti-estrogens in the treatment of breast cancer: current status and future directions. Author(s): Barker S. Source: Curr Opin Investig Drugs. 2003 June; 4(6): 652-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12901222&dopt=Abstract

•

Are “facts” in medicine fads and fashions? The changing landscape of the estrogen story and its heroes. Author(s): Legato MJ. Source: J Gend Specif Med. 2003; 6(3): 4-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14513569&dopt=Abstract

•

Associated response in bone mineral density and atherogenic lipid profile during treatment with two different selective estrogen receptor modulators: levormeloxifene and raloxifene. Author(s): Bloch-Thomsen A, Silvestri S, Christiansen C, Bjarnason NH. Source: Climacteric : the Journal of the International Menopause Society. 2003 June; 6(2): 159-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12841887&dopt=Abstract

•

Association between estrogen receptor alpha gene variation and cardiovascular disease. Author(s): Shearman AM, Cupples LA, Demissie S, Peter I, Schmid CH, Karas RH, Mendelsohn ME, Housman DE, Levy D. Source: Jama : the Journal of the American Medical Association. 2003 November 5; 290(17): 2263-70. Erratum In: Jama. 2004 January 14; 291(2): 186. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14600184&dopt=Abstract

•

Association of breast cancer risk with a GT dinucleotide repeat polymorphism upstream of the estrogen receptor-alpha gene. Author(s): Cai Q, Gao YT, Wen W, Shu XO, Jin F, Smith JR, Zheng W. Source: Cancer Research. 2003 September 15; 63(18): 5727-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14522892&dopt=Abstract

Studies 109

•

Association of estrogen receptor alpha and beta3-adrenergic receptor polymorphisms with endometrial cancer. Author(s): Iwamoto I, Fujino T, Douchi T, Nagata Y. Source: Obstetrics and Gynecology. 2003 September; 102(3): 506-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12962933&dopt=Abstract

•

Association of genetic polymorphisms in CYP19 and CYP1A1 with the oestrogen receptor-positive breast cancer risk. Author(s): Miyoshi Y, Ando A, Hasegawa S, Ishitobi M, Yamamura J, Irahara N, Tanji Y, Taguchi T, Tamaki Y, Noguchi S. Source: European Journal of Cancer (Oxford, England : 1990). 2003 November; 39(17): 2531-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14602139&dopt=Abstract

•

Association of polymorphisms in the estrogen receptor alpha gene with body fat distribution. Author(s): Okura T, Koda M, Ando F, Niino N, Ohta S, Shimokata H. Source: International Journal of Obesity and Related Metabolic Disorders : Journal of the International Association for the Study of Obesity. 2003 September; 27(9): 1020-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12917706&dopt=Abstract

•

Association study of polymorphisms in the human estrogen receptor alpha gene and prostate cancer risk. Author(s): Cancel-Tassin G, Latil A, Rousseau F, Mangin P, Bottius E, Escary JL, Berthon P, Cussenot O. Source: European Urology. 2003 October; 44(4): 487-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14499686&dopt=Abstract

•

Baseline health-related quality of life in postmenopausal women with coronary heart disease: the Estrogen Replacement and Atherosclerosis (ERA) trial. Author(s): Sherman AM, Shumaker SA, Kancler C, Zheng B, Reboussin DM, Legault C, Herrington DM; ERA Trial Investigators. Source: Journal of Women's Health (2002). 2003 May; 12(4): 351-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12804342&dopt=Abstract

•

Benefit of Paclitaxel in estrogen receptor-negative versus estrogen receptor-positive early breast cancer. Author(s): Bryce C, Kennecke H, Chia S, Ragaz J. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 December 1; 21(23): 4465; Author Reply 4465-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14645445&dopt=Abstract

110

Estrogen

•

Better oral reading and short-term memory in midlife, postmenopausal women taking estrogen. Author(s): Shaywitz SE, Naftolin F, Zelterman D, Marchione KE, Holahan JM, Palter SF, Shaywitz BA. Source: Menopause (New York, N.Y.). 2003 September-October; 10(5): 420-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14501603&dopt=Abstract

•

Biological response to hormonal manipulation in oestrogen receptor positive ductal carcinoma in situ of the breast. Author(s): Boland GP, McKeown A, Chan KC, Prasad R, Knox WF, Bundred NJ. Source: British Journal of Cancer. 2003 July 21; 89(2): 277-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12865917&dopt=Abstract

•

Body composition, visceral fat distribution and fat oxidation in postmenopausal women using oral or transdermal oestrogen. Author(s): dos Reis CM, de Melo NR, Meirelles ES, Vezozzo DP, Halpern A. Source: Maturitas. 2003 September 25; 46(1): 59-68. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12963170&dopt=Abstract

•

Bone mass, bone turnover, vitamin D, and estrogen receptor gene polymorphisms in male to female transsexuals: effects of estrogenic treatment on bone metabolism of the male. Author(s): Sosa M, Jodar E, Arbelo E, Dominguez C, Saavedra P, Torres A, Salido E, de Tejada MJ, Hernandez D. Source: Journal of Clinical Densitometry : the Official Journal of the International Society for Clinical Densitometry. 2003 Fall; 6(3): 297-304. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14515001&dopt=Abstract

•

Both estrogen and raloxifene cause G1 arrest of vascular smooth muscle cells. Author(s): Takahashi K, Ohmichi M, Yoshida M, Hisamoto K, Mabuchi S, ArimotoIshida E, Mori A, Tsutsumi S, Tasaka K, Murata Y, Kurachi H. Source: The Journal of Endocrinology. 2003 August; 178(2): 319-29. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12904179&dopt=Abstract

•

Breast cancer chemoprevention: risk-benefit effects of the antioestrogen tamoxifen. Author(s): Brown K. Source: Expert Opinion on Drug Safety. 2002 September; 1(3): 253-67. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12904141&dopt=Abstract

Studies 111

•

Breast cancer tissue estrogens and their manipulation with aromatase inhibitors and inactivators. Author(s): Geisler J. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 September; 86(3-5): 245-53. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14623518&dopt=Abstract

•

Breathing during sleep in menopause: a randomized, controlled, crossover trial with estrogen therapy. Author(s): Polo-Kantola P, Rauhala E, Helenius H, Erkkola R, Irjala K, Polo O. Source: Obstetrics and Gynecology. 2003 July; 102(1): 68-75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12850609&dopt=Abstract

•

Bullous autoimmune estrogen dermatitis. Author(s): Mutasim DF, Baumbach JL. Source: Journal of the American Academy of Dermatology. 2003 July; 49(1): 130-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12833026&dopt=Abstract

•

Cadmium mimics the in vivo effects of estrogen in the uterus and mammary gland. Author(s): Johnson MD, Kenney N, Stoica A, Hilakivi-Clarke L, Singh B, Chepko G, Clarke R, Sholler PF, Lirio AA, Foss C, Reiter R, Trock B, Paik S, Martin MB. Source: Nature Medicine. 2003 August; 9(8): 1081-4. Epub 2003 July 13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12858169&dopt=Abstract

•

Cadmium's disguise dupes the estrogen receptor. Author(s): Safe S. Source: Nature Medicine. 2003 August; 9(8): 1000-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12894163&dopt=Abstract

•

Causation and prevention of solely estrogen-induced oncogenesis: similarities to human ductal breast cancer. Author(s): Li JJ, Li SA. Source: Advances in Experimental Medicine and Biology. 2003; 532: 195-207. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12908558&dopt=Abstract

•

Changes in metabolic activity and estrogen receptors in the human medial mamillary nucleus: relation to sex, aging and Alzheimer's disease. Author(s): Ishunina TA, Kamphorst W, Swaab DF. Source: Neurobiology of Aging. 2003 October; 24(6): 817-28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12927764&dopt=Abstract

112

Estrogen

•

Characterization of new estrogen receptor destabilizing compounds: effects on estrogen-sensitive and tamoxifen-resistant breast cancer. Author(s): Hoffmann J, Bohlmann R, Heinrich N, Hofmeister H, Kroll J, Kunzer H, Lichtner RB, Nishino Y, Parczyk K, Sauer G, Gieschen H, Ulbrich HF, Schneider MR. Source: Journal of the National Cancer Institute. 2004 February 4; 96(3): 210-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14759988&dopt=Abstract

•

Characterization of reproductive steroid receptors and response to estrogen in a rat serotonergic cell line. Author(s): Bethea CL, Lu NZ, Reddy A, Shlaes T, Streicher JM, Whittemore SR. Source: Journal of Neuroscience Methods. 2003 July 15; 127(1): 31-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12865146&dopt=Abstract

•

Clinical practice. Combination estrogen-progestin oral contraceptives. Author(s): Petitti DB. Source: The New England Journal of Medicine. 2003 October 9; 349(15): 1443-50. Review. Erratum In: N Engl J Med. 2004 January 1; 350(1): 92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14534338&dopt=Abstract

•

Clinical significance of the expression of estrogen receptors alpha and beta for endocrine therapy of breast cancer. Author(s): Iwase H, Zhang Z, Omoto Y, Sugiura H, Yamashita H, Toyama T, Iwata H, Kobayashi S. Source: Cancer Chemotherapy and Pharmacology. 2003 July; 52 Suppl 1: S34-8. Epub 2003 June 19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12819932&dopt=Abstract

•

Combined estrogen-progestin oral contraceptives. Author(s): Sutherland SE, Munarriz RM, Goldstein I. Source: The New England Journal of Medicine. 2004 January 15; 350(3): 307-8; Author Reply 307-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14732939&dopt=Abstract

•

Combined estrogen-progestin oral contraceptives. Author(s): Martinelli I, Battaglioli T, Mannucci PM. Source: The New England Journal of Medicine. 2004 January 15; 350(3): 307-8; Author Reply 307-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14724315&dopt=Abstract

Studies 113

•

Combined inhibition of estrogen-dependent human breast carcinoma by soy and tea bioactive components in mice. Author(s): Zhou JR, Yu L, Mai Z, Blackburn GL. Source: International Journal of Cancer. Journal International Du Cancer. 2004 January 1; 108(1): 8-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14618609&dopt=Abstract

•

Comment on: “The minimum effective dose of estrogen for prevention of postmenopausal bone loss”. Author(s): Piktin RM. Source: Obstetrics and Gynecology. 2003 November; 102(5 Pt 1): 896. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14672459&dopt=Abstract

•

Comparison of the selective estrogen receptor modulator arzoxifene (LY353381) with tamoxifen on tumor growth and biomarker expression in an MCF-7 human breast cancer xenograft model. Author(s): Detre S, Riddler S, Salter J, A'Hern R, Dowsett M, Johnston SR. Source: Cancer Research. 2003 October 1; 63(19): 6516-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14559845&dopt=Abstract

•

Constrained phytoestrogens and analogues as ERbeta selective ligands. Author(s): Miller CP, Collini MD, Harris HA. Source: Bioorganic & Medicinal Chemistry Letters. 2003 July 21; 13(14): 2399-403. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12824043&dopt=Abstract

•

Correlation of expression of BP1, a homeobox gene, with estrogen receptor status in breast cancer. Author(s): Fu SW, Schwartz A, Stevenson H, Pinzone JJ, Davenport GJ, Orenstein JM, Gutierrez P, Simmens SJ, Abraham J, Poola I, Stephan DA, Berg PE. Source: Breast Cancer Research : Bcr. 2003; 5(4): R82-7. Epub 2003 April 22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12817998&dopt=Abstract

•

Cross-talk between estrogen receptor and growth factor pathways as a molecular target for overcoming endocrine resistance. Author(s): Schiff R, Massarweh SA, Shou J, Bharwani L, Mohsin SK, Osborne CK. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2004 January 1; 10(1 Pt 2): 331S-6S. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14734488&dopt=Abstract

114

Estrogen

•

CYP1B1 gene polymorphisms have higher risk for endometrial cancer, and positive correlations with estrogen receptor alpha and estrogen receptor beta expressions. Author(s): Sasaki M, Tanaka Y, Kaneuchi M, Sakuragi N, Dahiya R. Source: Cancer Research. 2003 July 15; 63(14): 3913-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12873984&dopt=Abstract

•

Cytotoxic and xenoestrogenic effects via biotransformation of trans-anethole on isolated rat hepatocytes and cultured MCF-7 human breast cancer cells. Author(s): Nakagawa Y, Suzuki T. Source: Biochemical Pharmacology. 2003 July 1; 66(1): 63-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12818366&dopt=Abstract

•

Declining estrogen receptor-beta expression defines malignant progression of human breast neoplasia. Author(s): Shaaban AM, O'Neill PA, Davies MP, Sibson R, West CR, Smith PH, Foster CS. Source: The American Journal of Surgical Pathology. 2003 December; 27(12): 1502-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14657709&dopt=Abstract

•

Decreased estrogen receptor-alpha expression in hippocampal neurons in relation to hyperphosphorylated tau in Alzheimer patients. Author(s): Hu XY, Qin S, Lu YP, Ravid R, Swaab DF, Zhou JN. Source: Acta Neuropathologica. 2003 September; 106(3): 213-20. Epub 2003 June 19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12819990&dopt=Abstract

•

Dehydroepiandrosterone sulfate causes proliferation of estrogen receptor-positive breast cancer cells despite treatment with fulvestrant. Author(s): Calhoun KE, Pommier RF, Muller P, Fletcher WS, Toth-Fejel S. Source: Archives of Surgery (Chicago, Ill. : 1960). 2003 August; 138(8): 879-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12912747&dopt=Abstract

•

Detection of breast cancer cells in the peripheral blood is positively correlated with estrogen-receptor status and predicts for poor prognosis. Author(s): Gaforio JJ, Serrano MJ, Sanchez-Rovira P, Sirvent A, Delgado-Rodriguez M, Campos M, de la Torre N, Algarra I, Duenas R, Lozano A. Source: International Journal of Cancer. Journal International Du Cancer. 2003 December 20; 107(6): 984-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14601059&dopt=Abstract

Studies 115

•

Development of autoimmune exocrinopathy resembling Sjogren's syndrome in estrogen-deficient mice of healthy background. Author(s): Ishimaru N, Arakaki R, Watanabe M, Kobayashi M, Miyazaki K, Hayashi Y. Source: American Journal of Pathology. 2003 October; 163(4): 1481-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14507655&dopt=Abstract

•

Dietary phytoestrogens and bone health. Author(s): Cassidy A. Source: The Journal of the British Menopause Society. 2003 March; 9(1): 17-21. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12804308&dopt=Abstract

•

Dietary phytoestrogens and their effect on bone: evidence from in vitro and in vivo, human observational, and dietary intervention studies. Author(s): Setchell KD, Lydeking-Olsen E. Source: The American Journal of Clinical Nutrition. 2003 September; 78(3 Suppl): 593S609S. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12936954&dopt=Abstract

•

Differences in estrogen modulation of tissue inhibitor of matrix metalloproteinase-1 and matrix metalloproteinase-1 expression in cultured fibroblasts from continent and incontinent women. Author(s): Chen B, Wen Y, Wang H, Polan ML. Source: American Journal of Obstetrics and Gynecology. 2003 July; 189(1): 59-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12861139&dopt=Abstract

•

Different effects of oral and transdermal estrogen replacement therapy on matrix metalloproteinase and their inhibitor in postmenopausal women. Author(s): Wakatsuki A, Ikenoue N, Shinohara K, Watanabe K, Fukaya T. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2003 October 1; 23(10): 19489. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14555643&dopt=Abstract

•

Differential amplification and overexpression of HER-2/neu, p53, MIB1, and estrogen receptor/progesterone receptor among medullary carcinoma, atypical medullary carcinoma, and high-grade invasive ductal carcinoma of breast. Author(s): Xu R, Feiner H, Li P, Yee H, Inghirami G, Delgado Y, Perle MA. Source: Archives of Pathology & Laboratory Medicine. 2003 November; 127(11): 1458-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14567723&dopt=Abstract

116

Estrogen

•

Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Author(s): Scarabin PY, Oger E, Plu-Bureau G; EStrogen and THromboEmbolism Risk Study Group. Source: Lancet. 2003 August 9; 362(9382): 428-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12927428&dopt=Abstract

•

Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: a randomized trial. Author(s): Oger E, Alhenc-Gelas M, Lacut K, Blouch MT, Roudaut N, Kerlan V, Collet M, Abgrall JF, Aiach M, Scarabin PY, Mottier D; SARAH Investigators. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2003 September 1; 23(9): 1671-6. Epub 2003 July 17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12869355&dopt=Abstract

•

Differential recruitment of coregulator proteins steroid receptor coactivator-1 and silencing mediator for retinoid and thyroid receptors to the estrogen receptorestrogen response element by beta-estradiol and 4-hydroxytamoxifen in human breast cancer. Author(s): Fleming FJ, Hill AD, McDermott EW, O'Higgins NJ, Young LS. Source: The Journal of Clinical Endocrinology and Metabolism. 2004 January; 89(1): 37583. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14715875&dopt=Abstract

•

Distinct molecular conformations of the estrogen receptor alpha complex exploited by environmental estrogens. Author(s): Bentrem D, Fox JE, Pearce ST, Liu H, Pappas S, Kupfer D, Zapf JW, Jordan VC. Source: Cancer Research. 2003 November 1; 63(21): 7490-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14612550&dopt=Abstract

•

Dragon ERE Finder version 2: A tool for accurate detection and analysis of estrogen response elements in vertebrate genomes. Author(s): Bajic VB, Tan SL, Chong A, Tang S, Strom A, Gustafsson JA, Lin CY, Liu ET. Source: Nucleic Acids Research. 2003 July 1; 31(13): 3605-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12824376&dopt=Abstract

•

Drops in estrogen levels affect brain, body and behavior: reported relationship between attitudes and menopausal symptoms. Author(s): DeSoto MC. Source: Maturitas. 2003 August 20; 45(4): 299-301. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12927317&dopt=Abstract

Studies 117

•

Dual action of oestrogens on the mouse constitutive androstane receptor. Author(s): Makinen J, Reinisalo M, Niemi K, Viitala P, Jyrkkarinne J, Chung H, Pelkonen O, Honkakoski P. Source: The Biochemical Journal. 2003 December 1; 376(Pt 2): 465-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12948398&dopt=Abstract

•

Effect of epidermal growth factor receptor inhibitor on development of estrogen receptor-negative mammary tumors. Author(s): Lu C, Speers C, Zhang Y, Xu X, Hill J, Steinbis E, Celestino J, Shen Q, Kim H, Hilsenbeck S, Mohsin SK, Wakeling A, Osborne CK, Brown PH. Source: Journal of the National Cancer Institute. 2003 December 17; 95(24): 1825-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14679152&dopt=Abstract

•

Effect of oestrogen replacement therapy on serum lipid profile. Author(s): Nanda S, Gupta N, Mehta HC, Sangwan K. Source: The Australian & New Zealand Journal of Obstetrics & Gynaecology. 2003 June; 43(3): 213-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14712987&dopt=Abstract

•

Effects of estrogen plus progestin on health-related quality of life. Author(s): Watts NB. Source: The New England Journal of Medicine. 2004 February 5; 350(6): 622. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14768071&dopt=Abstract

•

Effects of estrogen plus progestin on health-related quality of life. Author(s): Lopes AA, Latado A, Lopes GB. Source: The New England Journal of Medicine. 2004 February 5; 350(6): 622. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14762196&dopt=Abstract

•

Effects of estrogen therapy on hearing in postmenopausal women. Author(s): Kilicdag EB, Yavuz H, Bagis T, Tarim E, Erkan AN, Kazanci F. Source: American Journal of Obstetrics and Gynecology. 2004 January; 190(1): 77-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14749639&dopt=Abstract

•

Effects of low-dose oral and transdermal estrogen replacement therapy on hemostatic factors in healthy postmenopausal women: a randomized placebo-controlled study. Author(s): Post MS, van der Mooren MJ, van Baal WM, Blankenstein MA, Merkus HM, Kroeks MV, Franke HR, Kenemans P, Stehouwer CD. Source: American Journal of Obstetrics and Gynecology. 2003 November; 189(5): 1221-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14634544&dopt=Abstract

118

Estrogen

•

Effects of the phytoestrogen genistein on the circulating soluble receptor activator of nuclear factor kappaB ligand-osteoprotegerin system in early postmenopausal women. Author(s): Crisafulli A, Altavilla D, Squadrito G, Romeo A, Adamo EB, Marini R, Inferrera MA, Marini H, Bitto A, D'Anna R, Corrado F, Bartolone S, Frisina N, Squadrito F. Source: The Journal of Clinical Endocrinology and Metabolism. 2004 January; 89(1): 18892. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14715848&dopt=Abstract

•

Efficacy, safety and acceptability of a seven-day, transdermal estradiol patch for estrogen replacement therapy. Author(s): Jarupanich T, Lamlertkittikul S, Chandeying V. Source: J Med Assoc Thai. 2003 September; 86(9): 836-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14649968&dopt=Abstract

•

Elevated serum CA15-3 levels correlate with positive estrogen receptor and initial favorable outcome in patients who died from recurrent breast cancer. Author(s): Nishimura R, Nagao K, Miyayama H, Matsuda M, Baba K, Matsuoka Y, Yamashita H. Source: Breast Cancer. 2003; 10(3): 220-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12955034&dopt=Abstract

•

Endometrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate: two-year substudy results. Author(s): Pickar JH, Yeh IT, Wheeler JE, Cunnane MF, Speroff L. Source: Fertility and Sterility. 2003 November; 80(5): 1234-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14607581&dopt=Abstract

•

ERGDB: Estrogen Responsive Genes Database. Author(s): Tang S, Han H, Bajic VB. Source: Nucleic Acids Research. 2004 January 1; 32 Database Issue: D533-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14681475&dopt=Abstract

•

Estradiol supplementation in postmenopausal women doubles rebound-like release of growth hormone (GH) triggered by sequential infusion and withdrawal of somatostatin: evidence that estrogen facilitates endogenous GH-releasing hormone drive. Author(s): Veldhuis JD, Anderson SM, Patrie JT, Bowers CY. Source: The Journal of Clinical Endocrinology and Metabolism. 2004 January; 89(1): 1217. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14715838&dopt=Abstract

Studies 119

•

Estrogen and androgen receptors as comediators of breast cancer cell proliferation: providing a new therapeutic tool. Author(s): Toth-Fejel S, Cheek J, Calhoun K, Muller P, Pommier RF. Source: Archives of Surgery (Chicago, Ill. : 1960). 2004 January; 139(1): 50-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14718276&dopt=Abstract

•

Estrogen and cognition: applying preclinical findings to clinical perspectives. Author(s): Gibbs RB, Gabor R. Source: Journal of Neuroscience Research. 2003 December 1; 74(5): 637-43. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14635215&dopt=Abstract

•

Estrogen and growth factor signaling pathway: basic approaches for clinical application. Author(s): Hayashi S, Sakamoto T, Inoue A, Yoshida N, Omoto Y, Yamaguchi Y. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 September; 86(3-5): 433-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14623541&dopt=Abstract

•

Estrogen and its metabolites are carcinogenic agents in human breast epithelial cells. Author(s): Russo J, Hasan Lareef M, Balogh G, Guo S, Russo IH. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 October; 87(1): 1-25. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14630087&dopt=Abstract

•

Estrogen and the aging hippocampal synapse. Author(s): Adams MM, Morrison JH. Source: Cerebral Cortex (New York, N.Y. : 1991). 2003 December; 13(12): 1271-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14615293&dopt=Abstract

•

Estrogen deficiency symptom management in breast cancer survivors in the changing context of menopausal hormone therapy. Author(s): Chlebowski RT, Kim JA, Col NF. Source: Seminars in Oncology. 2003 December; 30(6): 776-88. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14663778&dopt=Abstract

•

Estrogen dermatitis that appeared twice in each menstrual period. Author(s): Murano K, Koyano T. Source: The Journal of Dermatology. 2003 October; 30(10): 719-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14684953&dopt=Abstract

120

Estrogen

•

Estrogen plus progestin therapy: the cardiovascular risks exceed the benefits. Author(s): Penckofer SM, Hackbarth D, Schwertz DW. Source: The Journal of Cardiovascular Nursing. 2003 November-December; 18(5): 34755. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14680337&dopt=Abstract

•

Estrogen receptor modulators: relationships of ligand structure, receptor affinity and functional activity. Author(s): Wallace OB, Richardson TI, Dodge JA. Source: Current Topics in Medicinal Chemistry. 2003; 3(14): 1663-82. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14683521&dopt=Abstract

•

Estrogen receptor-alpha directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter. Author(s): Metivier R, Penot G, Hubner MR, Reid G, Brand H, Kos M, Gannon F. Source: Cell. 2003 December 12; 115(6): 751-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14675539&dopt=Abstract

•

Estrogen receptors in the spinal cord, sensory ganglia, and pelvic autonomic ganglia. Author(s): Papka RE, Mowa CN. Source: Int Rev Cytol. 2003; 231: 91-127. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14713004&dopt=Abstract

•

Estrogen research. Brain researchers try to salvage estrogen treatments. Author(s): Wickelgren I. Source: Science. 2003 November 14; 302(5648): 1138-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14615509&dopt=Abstract

•

Estrogen research. The great estrogen conundrum. Author(s): Couzin J. Source: Science. 2003 November 14; 302(5648): 1136-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14615508&dopt=Abstract

•

Estrogen-containing oral contraceptives are allowable in young women with factor V Leiden heterozygosity without a history of thrombosis. Author(s): Budev MM, Abu-Hajir M, Deitcher SR, Gomes MP. Source: The Medical Clinics of North America. 2003 November; 87(6): 1225-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14680303&dopt=Abstract

Studies 121

•

Estrogenic activities of Ginkgo biloba extracts. Author(s): Oh SM, Chung KH. Source: Life Sciences. 2004 January 30; 74(11): 1325-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14706564&dopt=Abstract

•

Estrogen-related receptor alpha 1 up-regulates endothelial nitric oxide synthase expression. Author(s): Sumi D, Ignarro LJ. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 November 25; 100(24): 14451-6. Epub 2003 Nov 10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14610283&dopt=Abstract

•

Evidence of a lack of effect of a phytoestrogen regimen on the levels of C-reactive protein, E-selectin, and nitrate in postmenopausal women. Author(s): Nikander E, Metsa-Heikkila M, Tiitinen A, Ylikorkala O. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 November; 88(11): 5180-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14602747&dopt=Abstract

•

Expression and mitogenic effect of fibroblast growth factor-9 in human endometriotic implant is regulated by aberrant production of estrogen. Author(s): Wing LY, Chuang PC, Wu MH, Chen HM, Tsai SJ. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 November; 88(11): 5547-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14602803&dopt=Abstract

•

Familial hyperestrogenism in both sexes: clinical, hormonal, and molecular studies of two siblings. Author(s): Martin RM, Lin CJ, Nishi MY, Billerbeck AE, Latronico AC, Russell DW, Mendonca BB. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 July; 88(7): 3027-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12843139&dopt=Abstract

•

First-line endocrine treatment of breast cancer: aromatase inhibitor or antioestrogen? Author(s): Wong ZW, Ellis MJ. Source: British Journal of Cancer. 2004 January 12; 90(1): 20-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14710200&dopt=Abstract

122

Estrogen

•

Fruits and vegetables intake differentially affects estrogen receptor negative and positive breast cancer incidence rates. Author(s): Olsen A, Tjonneland A, Thomsen BL, Loft S, Stripp C, Overvad K, Moller S, Olsen JH. Source: The Journal of Nutrition. 2003 July; 133(7): 2342-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12840204&dopt=Abstract

•

Full-length estrogen receptor alpha and its ligand-binding domain adopt different conformations upon binding ligand. Author(s): Bapat AR, Frail DE. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 August; 86(2): 143-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14568565&dopt=Abstract

•

Fulvestrant: an estrogen receptor antagonist that downregulates the estrogen receptor. Author(s): Jones SE. Source: Seminars in Oncology. 2003 October; 30(5 Suppl 16): 14-20. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14613022&dopt=Abstract

•

Genetic effects of estrogen receptor alpha and collagen IA1 genes on the relationships of parathyroid hormone and 25 hydroxyvitamin D with bone mineral density in Caucasian women. Author(s): Sapir-Koren R, Livshits G, Kobyliansky E. Source: Metabolism: Clinical and Experimental. 2003 September; 52(9): 1129-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14506618&dopt=Abstract

•

Genetic polymorphisms in the estrogen receptor alpha gene and risk of breast cancer: results from the Shanghai Breast Cancer Study. Author(s): Cai Q, Shu XO, Jin F, Dai Q, Wen W, Cheng JR, Gao YT, Zheng W. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2003 September; 12(9): 853-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14504194&dopt=Abstract

•

Genetic polymorphisms of estrogen receptor alpha, CYP19, catechol-Omethyltransferase are associated with familial prostate carcinoma risk in a Japanese population. Author(s): Suzuki K, Nakazato H, Matsui H, Koike H, Okugi H, Kashiwagi B, Nishii M, Ohtake N, Nakata S, Ito K, Yamanaka H. Source: Cancer. 2003 October 1; 98(7): 1411-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14508827&dopt=Abstract

Studies 123

•

Global analysis of ligand sensitivity of estrogen inducible and suppressible genes in MCF7/BUS breast cancer cells by DNA microarray. Author(s): Coser KR, Chesnes J, Hur J, Ray S, Isselbacher KJ, Shioda T. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 November 25; 100(24): 13994-9. Epub 2003 Nov 10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14610279&dopt=Abstract

•

Growth response of colon cancer cell lines to selective estrogen receptor modulators. Author(s): Picariello L, Fiorelli G, Martineti V, Tognarini I, Pampaloni B, Tonelli F, Brandi ML. Source: Anticancer Res. 2003 May-June; 23(3B): 2419-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12894523&dopt=Abstract

•

Height in pre- and postmenopausal women is influenced by estrogen receptor alpha gene polymorphisms. Author(s): Schuit SC, van Meurs JB, Bergink AP, van der Klift M, Fang Y, Leusink G, Hofman A, van Leeuwen JP, Uitterlinden AG, Pols HA. Source: The Journal of Clinical Endocrinology and Metabolism. 2004 January; 89(1): 3039. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14715865&dopt=Abstract

•

High intraepithelial expression of estrogen and progesterone receptors in the transformation zone of the uterine cervix. Author(s): Remoue F, Jacobs N, Miot V, Boniver J, Delvenne P. Source: American Journal of Obstetrics and Gynecology. 2003 December; 189(6): 1660-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14710094&dopt=Abstract

•

High isoflavone content and estrogenic activity of 25 year-old Glycine max tissue cultures. Author(s): Federici E, Touche A, Choquart S, Avanti O, Fay L, Offord E, Courtois D. Source: Phytochemistry. 2003 October; 64(3): 717-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13679094&dopt=Abstract

•

H-ras dependent estrogenic effects of epidermal growth factor in the estrogenindependent breast cancer cell line MDA-MB-231. Author(s): Treeck O, Weber A, Boester M, Porz S, Frey N, Diedrich K, Ortmann O. Source: Breast Cancer Research and Treatment. 2003 July; 80(2): 155-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12908818&dopt=Abstract

124

Estrogen

•

Human estrogen receptor beta 548 is not a common variant in three distinct populations. Author(s): Xu L, Pan-Hammarstrom Q, Forsti A, Hemminki K, Hammarstrom L, Labuda D, Gustafsson JA, Dahlman-Wright K. Source: Endocrinology. 2003 August; 144(8): 3541-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12865336&dopt=Abstract

•

Hypoxia and estrogen receptor profile influence the responsiveness of human breast cancer cells to estradiol and antiestrogens. Author(s): Coradini D, Pellizzaro C, Speranza A, Daidone MG. Source: Cellular and Molecular Life Sciences : Cmls. 2004 January; 61(1): 76-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14704855&dopt=Abstract

•

Identification and characterization of a phytoestrogen-specific gene from the MCF-7 human breast cancer cell. Author(s): Ramanathan L, Gray WG. Source: Toxicology and Applied Pharmacology. 2003 September 1; 191(2): 107-17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12946647&dopt=Abstract

•

Identification of a novel inhibitor of breast cell growth that is down-regulated by estrogens and decreased in breast tumors. Author(s): Wittmann BM, Wang N, Montano MM. Source: Cancer Research. 2003 August 15; 63(16): 5151-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12941847&dopt=Abstract

•

Identification of genes involved in growth inhibition of breast cancer cells transduced with estrogen receptor. Author(s): Licznar A, Caporali S, Lucas A, Weisz A, Vignon F, Lazennec G. Source: Febs Letters. 2003 October 23; 553(3): 445-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14572667&dopt=Abstract

•

Immunohistochemical double staining with estrogen receptor and HER2 on primary breast cancer. Author(s): Horiguchi J, Koibuchi Y, Iijima K, Yoshida T, Yoshida M, Takata D, Oyama T, Iino Y, Morishita Y. Source: International Journal of Molecular Medicine. 2003 December; 12(6): 855-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14612957&dopt=Abstract

Studies 125

•

Immunohistochemical expression of heat shock protein 27, in normal hyperplastic and neoplastic endometrium: correlation with estrogen and progesterone receptor status, p53, pRb and proliferation associated indices (PCNA, MIB1). Author(s): Zagorianakou N, Ioachim E, Mitselou A, Kitsou E, Zagorianakou P, Makrydimas G, Salmas M, Agnantis NJ. Source: Eur J Gynaecol Oncol. 2003; 24(3-4): 299-304. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12807244&dopt=Abstract

•

Immunohistochemical expression of steroid receptors and glycodelin A in isolated proliferative human endometrial glandular cells after stimulation with tamoxifen and phytoestrogens (genistein and daidzein). Author(s): Mylonas I, Jeschke U, Makovitzky J, Winkler L, Richter DU, Friese K, Briese V. Source: Anticancer Res. 2003 March-April; 23(2A): 1119-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12820358&dopt=Abstract

•

Impact of the nuclear receptor coactivator AIB1 isoform AIB1-Delta3 on estrogenic ligands with different intrinsic activity. Author(s): Reiter R, Oh AS, Wellstein A, Riegel AT. Source: Oncogene. 2004 January 15; 23(2): 403-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14691461&dopt=Abstract

•

Importance of estrogen on bone health in Turner syndrome: a cross-sectional and longitudinal study using dual-energy X-ray absorptiometry. Author(s): Hogler W, Briody J, Moore B, Garnett S, Lu PW, Cowell CT. Source: The Journal of Clinical Endocrinology and Metabolism. 2004 January; 89(1): 1939. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14715849&dopt=Abstract

•

In lymph node-negative invasive breast carcinomas, specific chromosomal aberrations are strongly associated with high mitotic activity and predict outcome more accurately than grade, tumour diameter, and oestrogen receptor. Author(s): Janssen EA, Baak JP, Guervos MA, van Diest PJ, Jiwa M, Hermsen MA. Source: The Journal of Pathology. 2003 December; 201(4): 555-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14648658&dopt=Abstract

•

In vitro and in vivo biologic evaluation of long-circulating biodegradable drug carriers loaded with the pure antiestrogen RU 58668. Author(s): Ameller T, Marsaud V, Legrand P, Gref R, Renoir JM. Source: International Journal of Cancer. Journal International Du Cancer. 2003 September 1; 106(3): 446-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12845687&dopt=Abstract

126

Estrogen

•

In vitro and in vivo regulation of antioxidant response element-dependent gene expression by estrogens. Author(s): Ansell PJ, Espinosa-Nicholas C, Curran EM, Judy BM, Philips BJ, Hannink M, Lubahn DB. Source: Endocrinology. 2004 January; 145(1): 311-7. Epub 2003 October 09. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14551226&dopt=Abstract

•

Increase in prefrontal cortex serotonin 2A receptors following estrogen treatment in postmenopausal women. Author(s): Kugaya A, Epperson CN, Zoghbi S, van Dyck CH, Hou Y, Fujita M, Staley JK, Garg PK, Seibyl JP, Innis RB. Source: The American Journal of Psychiatry. 2003 August; 160(8): 1522-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12900319&dopt=Abstract

•

Increased estrogen-dependent expression of calcineurin in female SLE T cells is regulated by multiple mechanisms. Author(s): Rider V, Keltner S, Abdou NI. Source: J Gend Specif Med. 2003; 6(2): 14-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12813997&dopt=Abstract

•

Increased neuronal metabolic activity and estrogen receptors in the vertical limb of the diagonal band of Broca in Alzheimer's disease: relation to sex and aging. Author(s): Ishunina TA, Swaab DF. Source: Experimental Neurology. 2003 September; 183(1): 159-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12957499&dopt=Abstract

•

Increases in estrogen receptor-alpha concentration in breast cancer cells promote serine 118/104/106-independent AF-1 transactivation and growth in the absence of estrogen. Author(s): Fowler AM, Solodin N, Preisler-Mashek MT, Zhang P, Lee AV, Alarid ET. Source: The Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology. 2004 January; 18(1): 81-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14718389&dopt=Abstract

•

Indole-3-carbinol is a negative regulator of estrogen. Author(s): Auborn KJ, Fan S, Rosen EM, Goodwin L, Chandraskaren A, Williams DE, Chen D, Carter TH. Source: The Journal of Nutrition. 2003 July; 133(7 Suppl): 2470S-2475S. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12840226&dopt=Abstract

Studies 127

•

Induction of aromatase (CYP19) expression in breast cancer cells through a nongenomic action of estrogen receptor alpha. Author(s): Kinoshita Y, Chen S. Source: Cancer Research. 2003 July 1; 63(13): 3546-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12839940&dopt=Abstract

•

Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. Author(s): Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D, Rodabough RJ, Gilligan MA, Cyr MG, Thomson CA, Khandekar J, Petrovitch H, McTiernan A; WHI Investigators. Source: Jama : the Journal of the American Medical Association. 2003 June 25; 289(24): 3243-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12824205&dopt=Abstract

•

Influence of estrogens on neurodegenerative processes. Author(s): Czlonkowska A, Ciesielska A, Joniec I. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2003 October; 9(10): Ra247-56. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14523340&dopt=Abstract

•

Inhibition of estrogen receptor alpha expression and function in MCF-7 cells by kaempferol. Author(s): Hung H. Source: Journal of Cellular Physiology. 2004 February; 198(2): 197-208. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14603522&dopt=Abstract

•

Inhibition of estrone sulfate-induced uterine growth by potent nonestrogenic steroidal inhibitors of steroid sulfatase. Author(s): Ciobanu LC, Luu-The V, Martel C, Labrie F, Poirier D. Source: Cancer Research. 2003 October 1; 63(19): 6442-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14559834&dopt=Abstract

•

Inhibitory action of ICI-182,780, an estrogen receptor antagonist, on BK(Ca) channel activity in cultured endothelial cells of human coronary artery. Author(s): Liu YC, Lo YC, Huang CW, Wu SN. Source: Biochemical Pharmacology. 2003 November 15; 66(10): 2053-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14599564&dopt=Abstract

128

Estrogen

•

Ini, a small nuclear protein that enhances the response of the connexin43 gene to estrogen. Author(s): Oltra E, Pfeifer I, Werner R. Source: Endocrinology. 2003 July; 144(7): 3148-58. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12810571&dopt=Abstract

•

Insomnia related to postmenopausal syndrome and hormone replacement therapy: sleep laboratory studies on baseline differences between patients and controls and double-blind, placebo-controlled investigations on the effects of a novel estrogenprogestogen combination (Climodien, Lafamme) versus estrogen alone. Author(s): Saletu-Zyhlarz G, Anderer P, Gruber G, Mandl M, Gruber D, Metka M, Huber J, Oettel M, Graser T, Abu-Bakr MH, Gratzhofer E, Saletu B. Source: Journal of Sleep Research. 2003 September; 12(3): 239-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12941063&dopt=Abstract

•

Interaction between vitamin D receptor genotype and estrogen receptor alpha genotype influences vertebral fracture risk. Author(s): Colin EM, Uitterlinden AG, Meurs JB, Bergink AP, van de Klift M, Fang Y, Arp PP, Hofman A, van Leeuwen JP, Pols HA. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 August; 88(8): 3777-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12915669&dopt=Abstract

•

Interaction effects between estrogen receptor alpha gene, vitamin D receptor gene, age, and sex on bone mineral density in Chinese. Author(s): Long J, Liu P, Zhang Y, Shen H, Liu Y, Dvornyk V, Deng HW. Source: Journal of Human Genetics. 2003; 48(10): 514-9. Epub 2003 September 19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14505233&dopt=Abstract

•

Interactions between estrogen and growth factor receptors in human breast cancers and the tumor-associated vasculature. Author(s): Pietras RJ. Source: The Breast Journal. 2003 September-October; 9(5): 361-73. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12968955&dopt=Abstract

•

Investigations on the influence of terminal groups at the C2-propyl side chain of 1,1bis(4-hydroxyphenyl)-2-phenylpent-1-ene and 1,1,2-tris(4-hydroxyphenyl)pent-1-ene on the estrogen receptor binding and the estrogenic/anti-estrogenic properties. Author(s): Gust R, Lubczyk V. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 July; 86(1): 5770. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12943745&dopt=Abstract

Studies 129

•

Is black cohosh estrogenic? Author(s): Mahady GB. Source: Nutrition Reviews. 2003 May; 61(5 Pt 1): 183-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12822708&dopt=Abstract

•

Joint effect of estrogen receptor beta sequence variants and endogenous estrogen exposure on breast cancer risk in Chinese women. Author(s): Zheng SL, Zheng W, Chang BL, Shu XO, Cai Q, Yu H, Dai Q, Xu J, Gao YT. Source: Cancer Research. 2003 November 15; 63(22): 7624-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14633679&dopt=Abstract

•

Lack of dose-responsive effect of dietary phyto-oestrogens on transepithelial calcium transport in human intestinal-like Caco-2 cells. Author(s): Cotter AA, Cashman KD. Source: The British Journal of Nutrition. 2004 January; 91(1): 5-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14748934&dopt=Abstract

•

Large effects from small exposures. I. Mechanisms for endocrine-disrupting chemicals with estrogenic activity. Author(s): Welshons WV, Thayer KA, Judy BM, Taylor JA, Curran EM, vom Saal FS. Source: Environmental Health Perspectives. 2003 June; 111(8): 994-1006. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12826473&dopt=Abstract

•

Ligand-independent activation of estrogen receptor alpha by XBP-1. Author(s): Ding L, Yan J, Zhu J, Zhong H, Lu Q, Wang Z, Huang C, Ye Q. Source: Nucleic Acids Research. 2003 September 15; 31(18): 5266-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12954762&dopt=Abstract

•

Lipid changes on hormone therapy and coronary heart disease events in the Heart and Estrogen/progestin Replacement Study (HERS). Author(s): Shlipak MG, Chaput LA, Vittinghoff E, Lin F, Bittner V, Knopp RH, Hulley SB; Heart and Estrogen/progestin Replacement Study Investigators. Source: American Heart Journal. 2003 November; 146(5): 870-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14597937&dopt=Abstract

•

Local estrogen formation by nontumoral, cirrhotic, and malignant human liver tissues and cells. Author(s): Castagnetta LA, Agostara B, Montalto G, Polito L, Campisi I, Saetta A, Itoh T, Yu B, Chen S, Carruba G. Source: Cancer Research. 2003 August 15; 63(16): 5041-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12941832&dopt=Abstract

130

Estrogen

•

Local estrogen treatment in patients with urogenital symptoms. Author(s): Simunic V, Banovic I, Ciglar S, Jeren L, Pavicic Baldani D, Sprem M. Source: International Journal of Gynaecology and Obstetrics: the Official Organ of the International Federation of Gynaecology and Obstetrics. 2003 August; 82(2): 187-97. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12873780&dopt=Abstract

•

Localisation of oestrogen receptors (ERalpha and ERbeta) in the human and rat epididymides. Author(s): Kolasa A, Wiszniewska B, Marchlewicz M, Wenda-Rozewicka L. Source: Folia Morphol (Warsz). 2003 November; 62(4): 467-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14655143&dopt=Abstract

•

Long-term toxicities of selective estrogen-receptor modulators and antiaromatase agents. Author(s): Mortimer JE, Urban JH. Source: Oncology (Huntingt). 2003 May; 17(5): 652-9; Discussion 659, 662, 666 Passim. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12800793&dopt=Abstract

•

Low-dose estrogen therapy for menopausal women: a review of efficacy and safety. Author(s): Crandall C. Source: Journal of Women's Health (2002). 2003 October; 12(8): 723-47. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14588124&dopt=Abstract

•

Making decisions about hormone replacement therapy: preparations containing oestrogen should not be given during treatment for breast cancer. Author(s): Hinton CP, Coventry C, Borrowclough B. Source: Bmj (Clinical Research Ed.). 2003 June 21; 326(7403): 1398; Author Reply 1398-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12816848&dopt=Abstract

•

Measurement of endogenous estrogens: analytical challenges and recent advances. Author(s): Giese RW. Source: J Chromatogr A. 2003 June 6; 1000(1-2): 401-12. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12877181&dopt=Abstract

•

Mechanisms governing the accumulation of estrogen receptor alpha in MCF-7 breast cancer cells treated with hydroxytamoxifen and related antiestrogens. Author(s): Laios I, Journe F, Laurent G, Nonclercq D, Toillon RA, Seo HS, Leclercq G. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 November; 87(2-3): 207-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14672741&dopt=Abstract

Studies 131

•

MeCP2 and MBD2 expression in human neoplastic and non-neoplastic breast tissue and its association with oestrogen receptor status. Author(s): Muller HM, Fiegl H, Goebel G, Hubalek MM, Widschwendter A, MullerHolzner E, Marth C, Widschwendter M. Source: British Journal of Cancer. 2003 November 17; 89(10): 1934-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14612906&dopt=Abstract

•

Membrane receptors for oestrogen in the brain. Author(s): Beyer C, Pawlak J, Karolczak M. Source: Journal of Neurochemistry. 2003 November; 87(3): 545-50. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14535938&dopt=Abstract

•

Memories of estrogen. Author(s): Healy B. Source: U.S. News & World Report. 2003 December 29-2004 January 5; 135(23): 68, 70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14723185&dopt=Abstract

•

Metabolic syndrome and coronary angiographic disease progression: the Women's Angiographic Vitamin & Estrogen trial. Author(s): Hsia J, Bittner V, Tripputi M, Howard BV. Source: American Heart Journal. 2003 September; 146(3): 439-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12947360&dopt=Abstract

•

Methoxyestrogens exert feedback inhibition on cytochrome P450 1A1 and 1B1. Author(s): Dawling S, Roodi N, Parl FF. Source: Cancer Research. 2003 June 15; 63(12): 3127-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12810639&dopt=Abstract

•

Minimum formalin fixation time for consistent estrogen receptor immunohistochemical staining of invasive breast carcinoma. Author(s): Goldstein NS, Ferkowicz M, Odish E, Mani A, Hastah F. Source: American Journal of Clinical Pathology. 2003 July; 120(1): 86-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12866377&dopt=Abstract

•

Mining the complexities of the estrogen signaling pathways for novel therapeutics. Author(s): McDonnell DP. Source: Endocrinology. 2003 October; 144(10): 4237-40. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14500558&dopt=Abstract

132

Estrogen

•

Mitoxantrone mediates demethylation and reexpression of cyclin d2, estrogen receptor and 14.3.3sigma in breast cancer cells. Author(s): Parker BS, Cutts SM, Nudelman A, Rephaeli A, Phillips DR, Sukumar S. Source: Cancer Biology & Therapy. 2003 May-June; 2(3): 259-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12878861&dopt=Abstract

•

Modeling the annual costs of postmenopausal prevention therapy: raloxifene, alendronate, or estrogen-progestin therapy. Author(s): Mullins CD, Ohsfeldt RL. Source: J Manag Care Pharm. 2003 March-April; 9(2): 150-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14613344&dopt=Abstract

•

Modulation of antioxidant enzyme expression and function by estrogen. Author(s): Strehlow K, Rotter S, Wassmann S, Adam O, Grohe C, Laufs K, Bohm M, Nickenig G. Source: Circulation Research. 2003 July 25; 93(2): 170-7. Epub 2003 June 19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12816884&dopt=Abstract

•

Modulation of estrogen receptor activity by selective coregulators. Author(s): Martini PG, Katzenellenbogen BS. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 June; 85(2-5): 117-22. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12943695&dopt=Abstract

•

Molecular and clinical evidence for the unique nature of individual selective estrogen receptor modulators. Author(s): Draper MW, Chin WW. Source: Clinical Obstetrics and Gynecology. 2003 June; 46(2): 265-97. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12808380&dopt=Abstract

•

Molecular epidemiology of sporadic breast cancer. The role of polymorphic genes involved in oestrogen biosynthesis and metabolism. Author(s): Mitrunen K, Hirvonen A. Source: Mutation Research. 2003 September; 544(1): 9-41. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12888106&dopt=Abstract

•

Molecular quantum similarity analysis of estrogenic activity. Author(s): Gallegos Saliner A, Amat L, Carbo-Dorca R, Schultz TW, Cronin MT. Source: Journal of Chemical Information and Computer Sciences. 2003 July-August; 43(4): 1166-76. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12870908&dopt=Abstract

Studies 133

•

Mutual repression of transcriptional activation between the ETS-related factor ERG and estrogen receptor. Author(s): Vlaeminck-Guillem V, Vanacker JM, Verger A, Tomavo N, Stehelin D, Laudet V, Duterque-Coquillaud M. Source: Oncogene. 2003 November 6; 22(50): 8072-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14603248&dopt=Abstract

•

Neurite-localized estrogen receptor-alpha mediates rapid signaling by estrogen. Author(s): Xu Y, Traystman RJ, Hurn PD, Wang MM. Source: Journal of Neuroscience Research. 2003 October 1; 74(1): 1-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13130501&dopt=Abstract

•

New biology of the oestrogen receptor. Author(s): Dowsett M, Ashworth A. Source: Lancet. 2003 July 26; 362(9380): 260-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12892953&dopt=Abstract

•

No increased risk of non-Hodgkin's lymphoma with steroids, estrogens and psychotropics (Netherlands). Author(s): Beiderbeck AB, Holly EA, Sturkenboom MC, Coebergh JW, Stricker BH, Leufkens HG. Source: Cancer Causes & Control : Ccc. 2003 September; 14(7): 639-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14575361&dopt=Abstract

•

Nonendocrine pathways and endocrine resistance: observations with antiestrogens and signal transduction inhibitors in combination. Author(s): Nicholson RI, Hutcheson IR, Knowlden JM, Jones HE, Harper ME, Jordan N, Hiscox SE, Barrow D, Gee JM. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2004 January 1; 10(1 Pt 2): 346S-54S. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14734490&dopt=Abstract

•

Novel estrogen receptor ligands based on an anthranylaldoxime structure: role of the phenol-type pseudocycle in the binding process. Author(s): Minutolo F, Antonello M, Bertini S, Ortore G, Placanica G, Rapposelli S, Sheng S, Carlson KE, Katzenellenbogen BS, Katzenellenbogen JA, Macchia M. Source: Journal of Medicinal Chemistry. 2003 September 11; 46(19): 4032-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12954056&dopt=Abstract

134

Estrogen

•

Nrf2, not the estrogen receptor, mediates catechol estrogen-induced activation of the antioxidant responsive element. Author(s): Lee JM, Anderson PC, Padgitt JK, Hanson JM, Waters CM, Johnson JA. Source: Biochimica Et Biophysica Acta. 2003 October 1; 1629(1-3): 92-101. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14522084&dopt=Abstract

•

Obesity and estrogen as risk factors for gastroesophageal reflux symptoms. Author(s): Nilsson M, Johnsen R, Ye W, Hveem K, Lagergren J. Source: Jama : the Journal of the American Medical Association. 2003 July 2; 290(1): 6672. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12837713&dopt=Abstract

•

Obesity, tamoxifen use, and outcomes in women with estrogen receptor-positive early-stage breast cancer. Author(s): Dignam JJ, Wieand K, Johnson KA, Fisher B, Xu L, Mamounas EP. Source: Journal of the National Cancer Institute. 2003 October 1; 95(19): 1467-76. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14519753&dopt=Abstract

•

Observations on the extragenital effects of oestrogen in females: a report. Author(s): Das AK, Majumdar A, Das AK, Sinha NK, Singh MA. Source: J Indian Med Assoc. 2003 February; 101(2): 98, 100-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12841493&dopt=Abstract

•

Oestrogen and progesterone receptor expression influences DNA ploidy and the proliferation potential of breast cancer cells. Author(s): Andronas M, Dlay SS, Sherbet GV. Source: Anticancer Res. 2003 May-June; 23(3C): 3029-39. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12926157&dopt=Abstract

•

Oestrogen exposure and breast cancer risk. Author(s): Travis RC, Key TJ. Source: Breast Cancer Research : Bcr. 2003; 5(5): 239-47. Epub 2003 July 28. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12927032&dopt=Abstract

•

Oestrogen receptor alpha gene polymorphism is related to aortic valve sclerosis in postmenopausal women. Author(s): Nordstrom P, Glader CA, Dahlen G, Birgander LS, Lorentzon R, Waldenstrom A, Lorentzon M. Source: Journal of Internal Medicine. 2003 August; 254(2): 140-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12859695&dopt=Abstract

Studies 135

•

Oestrogen receptor alpha increases p21(WAF1/CIP1) gene expression and the antiproliferative activity of histone deacetylase inhibitors in human breast cancer cells. Author(s): Margueron R, Licznar A, Lazennec G, Vignon F, Cavailles V. Source: The Journal of Endocrinology. 2003 October; 179(1): 41-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14529564&dopt=Abstract

•

Oestrogen receptor downregulation: an opportunity for extending the window of endocrine therapy in advanced breast cancer. Author(s): Piccart M, Parker LM, Pritchard KI. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 2003 July; 14(7): 1017-25. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12853342&dopt=Abstract

•

Oestrogen receptor-mediated modulation of the EGFR/MAPK pathway in tamoxifenresistant MCF-7 cells. Author(s): Hutcheson IR, Knowlden JM, Madden TA, Barrow D, Gee JM, Wakeling AE, Nicholson RI. Source: Breast Cancer Research and Treatment. 2003 September; 81(1): 81-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14531500&dopt=Abstract

•

Oestrogen receptors in cultured epithelial cells from salivary glands of Sjogren's syndrome patients. Author(s): Kassi E, Moutsatsou P, Sekeris CE, Moutsopoulos HM, Manoussakis MN. Source: Rheumatology (Oxford, England). 2003 September; 42(9): 1120-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12923274&dopt=Abstract

•

Oestrogen supplementation, mainly diethylstilbestrol, for preventing miscarriages and other adverse pregnancy outcomes. Author(s): Bamigboye AA, Morris J. Source: Cochrane Database Syst Rev. 2003; (3): Cd004271. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12918007&dopt=Abstract

•

Oestrogen therapy for multiple sclerosis: not the way forward. Author(s): Hutchinson M. Source: Int Ms J. 2003 August; 10(3): 98; Author Reply 99-100. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14561377&dopt=Abstract

•

Oestrogen, brain function, and neuropsychiatric disorders. Author(s): Cutter WJ, Norbury R, Murphy DG. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2003 July; 74(7): 837-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12810759&dopt=Abstract

136

Estrogen

•

Oestrogenic compounds and oxidative stress (in human sperm and lymphocytes in the Comet assay). Author(s): Anderson D, Schmid TE, Baumgartner A, Cemeli-Carratala E, Brinkworth MH, Wood JM. Source: Mutation Research. 2003 November; 544(2-3): 173-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14644319&dopt=Abstract

•

Oestrogens and selective oestrogen receptor (ER) modulators regulate EGF receptor gene expression through human ER alpha and beta subtypes via an Sp1 site. Author(s): Salvatori L, Pallante P, Ravenna L, Chinzari P, Frati L, Russo MA, Petrangeli E. Source: Oncogene. 2003 July 31; 22(31): 4875-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12894229&dopt=Abstract

•

Oestrogens for urinary incontinence in women. Author(s): Moehrer B, Hextall A, Jackson S. Source: Cochrane Database Syst Rev. 2003; (2): Cd001405. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12804406&dopt=Abstract

•

Overexpression of histone deacetylase HDAC1 modulates breast cancer progression by negative regulation of estrogen receptor alpha. Author(s): Kawai H, Li H, Avraham S, Jiang S, Avraham HK. Source: International Journal of Cancer. Journal International Du Cancer. 2003 November 10; 107(3): 353-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14506733&dopt=Abstract

•

Overexpression of superoxide dismutase 1 protects against beta-amyloid peptide toxicity: effect of estrogen and copper chelators. Author(s): Celsi F, Ferri A, Casciati A, D'Ambrosi N, Rotilio G, Costa A, Volonte C, Carri MT. Source: Neurochemistry International. 2004 January; 44(1): 25-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12963085&dopt=Abstract

•

Overexpression of vascular endothelial growth factor by MCF-7 breast cancer cells promotes estrogen-independent tumor growth in vivo. Author(s): Guo P, Fang Q, Tao HQ, Schafer CA, Fenton BM, Ding I, Hu B, Cheng SY. Source: Cancer Research. 2003 August 1; 63(15): 4684-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12907650&dopt=Abstract

Studies 137

•

Ovulation induction is not the same as superovulation: the effect of selective estrogen receptor modulators and aromatase inhibitors. Author(s): Tourgeman DE. Source: Fertility and Sterility. 2003 December; 80(6): 1333-4; Discussion 1339. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14667862&dopt=Abstract

•

p33(ING1b) stimulates the transcriptional activity of the estrogen receptor alpha via its activation function (AF) 2 domain. Author(s): Toyama T, Iwase H, Yamashita H, Hara Y, Sugiura H, Zhang Z, Fukai I, Miura Y, Riabowol K, Fujii Y. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 October; 87(1): 57-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14630091&dopt=Abstract

•

p53, estrogen and progesterone receptors in diagnostic curettage for endometrial adenocarcinoma and their correlation with morphological data and disease stage at hysterectomy. Author(s): Bonfitto VL, de Angelo Andrade LA. Source: Sao Paulo Medical Journal = Revista Paulista De Medicina. 2003 July 1; 121(4): 163-6. Epub 2003 October 29. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14595509&dopt=Abstract

•

Pharmacodynamics of follicle stimulating hormone (FSH) in postmenopausal women during pulsed estrogen therapy: Evidence that FSH release and synthesis are controlled by distinct pathways. Author(s): Christin-Maitre S, Laveille C, Collette J, Brion N, Reginster JY. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 November; 88(11): 5405-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14602781&dopt=Abstract

•

Pharmacogenetics of estrogen metabolism and transport in relation to cancer. Author(s): Lakhani NJ, Venitz J, Figg WD, Sparreboom A. Source: Current Drug Metabolism. 2003 December; 4(6): 505-13. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14683478&dopt=Abstract

•

Phytoestrogen intake and endometrial cancer risk. Author(s): Horn-Ross PL, John EM, Canchola AJ, Stewart SL, Lee MM. Source: Journal of the National Cancer Institute. 2003 August 6; 95(15): 1158-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12902445&dopt=Abstract

138

Estrogen

•

Phytoestrogen supplements for the treatment of hot flashes: the Isoflavone Clover Extract (ICE) Study: a randomized controlled trial. Author(s): Tice JA, Ettinger B, Ensrud K, Wallace R, Blackwell T, Cummings SR. Source: Jama : the Journal of the American Medical Association. 2003 July 9; 290(2): 20714. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12851275&dopt=Abstract

•

Phytoestrogens and 17beta-estradiol influence vitamin D metabolism and receptor expression-relevance for colon cancer prevention. Author(s): Lechner D, Cross HS. Source: Recent Results Cancer Res. 2003; 164: 379-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12899537&dopt=Abstract

•

Phytoestrogens and breast cancer. Author(s): Ziegler RG. Source: The American Journal of Clinical Nutrition. 2004 February; 79(2): 183-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14749221&dopt=Abstract

•

Phytoestrogens increase the capacity of serum to stimulate prostacyclin release in human endothelial cells. Author(s): Garcia-Martinez MC, Hermenegildo C, Tarin JJ, Cano A. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2003 August; 82(8): 705-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12848640&dopt=Abstract

•

Phytoestrogens. Author(s): Cabot W. Source: J Am Acad Orthop Surg. 2003 May-June; 11(3): 153-6. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12828444&dopt=Abstract

•

Phytoestrogens: a review of the present state of research. Author(s): Ososki AL, Kennelly EJ. Source: Phytotherapy Research : Ptr. 2003 September; 17(8): 845-69. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13680814&dopt=Abstract

•

Phytoestrogens: potential benefits and implications for breast cancer survivors. Author(s): Duffy C, Cyr M. Source: Journal of Women's Health (2002). 2003 September; 12(7): 617-31. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14583103&dopt=Abstract

Studies 139

•

Phytoestrogens: recent developments. Author(s): Cos P, De Bruyne T, Apers S, Vanden Berghe D, Pieters L, Vlietinck AJ. Source: Planta Medica. 2003 July; 69(7): 589-99. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12898412&dopt=Abstract

•

Polymorphisms in the estrogen receptor beta gene and risk of breast cancer: no association. Author(s): Forsti A, Zhao C, Israelsson E, Dahlman-Wright K, Gustafsson JA, Hemminki K. Source: Breast Cancer Research and Treatment. 2003 June; 79(3): 409-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12846425&dopt=Abstract

•

Polymorphisms of estrogen receptor alpha in prostate cancer. Author(s): Tanaka Y, Sasaki M, Kaneuchi M, Shiina H, Igawa M, Dahiya R. Source: Molecular Carcinogenesis. 2003 August; 37(4): 202-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12891629&dopt=Abstract

•

Postmenopausal levels of oestrogen, androgen, and SHBG and breast cancer: longterm results of a prospective study. Author(s): Zeleniuch-Jacquotte A, Shore RE, Koenig KL, Akhmedkhanov A, Afanasyeva Y, Kato I, Kim MY, Rinaldi S, Kaaks R, Toniolo P. Source: British Journal of Cancer. 2004 January 12; 90(1): 153-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14710223&dopt=Abstract

•

Postmenopausal osteoporosis and estrogen. Author(s): Nelson HD. Source: American Family Physician. 2003 August 15; 68(4): 606, 610, 612. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12952379&dopt=Abstract

•

Potential use of estrogen-like drugs for the prevention of Alzheimer's disease. Author(s): Smith JD, Levin-Allerhand JA. Source: Journal of Molecular Neuroscience : Mn. 2003; 20(3): 277-81. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14501008&dopt=Abstract

•

Potentiation of human estrogen receptor alpha-mediated gene expression by steroid receptor coactivator-1 (SRC-1) in Saccharomyces cerevisiae. Author(s): Ellison AR, Lofing J, Bitter GA. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 July; 86(1): 1526. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12943741&dopt=Abstract

140

Estrogen

•

Predicting the effects of estrogen replacement therapy on lumbar bone mineral density in oophorectomized women: analysis of a 10-year longitudinal study. Author(s): Nagata H, Nozaki M, Nakano H. Source: Osteoporosis International : a Journal Established As Result of Cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the Usa. 2003 November; 14(11): 905-12. Epub 2003 October 08. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14534773&dopt=Abstract

•

Preliminary evidence that estrogen protects against age-related hippocampal atrophy. Author(s): Eberling JL, Wu C, Haan MN, Mungas D, Buonocore M, Jagust WJ. Source: Neurobiology of Aging. 2003 September; 24(5): 725-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12885580&dopt=Abstract

•

Prescriptions for estrogen replacement therapy in Ontario before and after publication of the Women's Health Initiative Study. Author(s): Austin PC, Mamdani MM, Tu K, Jaakkimainen L. Source: Jama : the Journal of the American Medical Association. 2003 June 25; 289(24): 3241-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12824204&dopt=Abstract

•

Prevalence of estrogen or estrogen-progestin hormone therapy use. Author(s): Brett KM, Reuben CA. Source: Obstetrics and Gynecology. 2003 December; 102(6): 1240-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14662210&dopt=Abstract

•

Primary vaginal endometrioid carcinoma following unopposed estrogen administration. Author(s): Adjetey V, Ganesan R, Downey GP. Source: Journal of Obstetrics and Gynaecology : the Journal of the Institute of Obstetrics and Gynaecology. 2003 May; 23(3): 316-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12918477&dopt=Abstract

•

Profiling of estrogen up- and down-regulated gene expression in human breast cancer cells: insights into gene networks and pathways underlying estrogenic control of proliferation and cell phenotype. Author(s): Frasor J, Danes JM, Komm B, Chang KC, Lyttle CR, Katzenellenbogen BS. Source: Endocrinology. 2003 October; 144(10): 4562-74. Epub 2003 July 10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12959972&dopt=Abstract

Studies 141

•

Progesterone receptors A and B differentially affect the growth of estrogendependent human breast tumor xenografts. Author(s): Sartorius CA, Shen T, Horwitz KB. Source: Breast Cancer Research and Treatment. 2003 June; 79(3): 287-99. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12846413&dopt=Abstract

•

Protective effects of estrogens on polyglutamine-expanded androgen receptor aggregation in mice. Author(s): Darrington RS, Leigh PN, Gallo JM. Source: Neuroscience Letters. 2003 October 16; 350(1): 37-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12962912&dopt=Abstract

•

Quantitative fluorescence cytometric measurement of estrogen and progesterone receptors: correlation with the hormone binding assay. Author(s): Gritzapis AD, Baxevanis CN, Missitzis I, Katsanou ES, Alexis MN, Yotis J, Papamichail M. Source: Breast Cancer Research and Treatment. 2003 July; 80(1): 1-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12889594&dopt=Abstract

•

Quantitative real-time RT-PCR analysis of eight novel estrogen-regulated genes in breast cancer. Author(s): Sorbello V, Fuso L, Sfiligoi C, Scafoglio C, Ponzone R, Biglia N, Weisz A, Sismondi P, De Bortoli M. Source: Int J Biol Markers. 2003 April-June; 18(2): 123-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12841681&dopt=Abstract

•

Quantitative structure-activity relationship models for prediction of estrogen receptor binding affinity of structurally diverse chemicals. Author(s): Schmieder PK, Ankley G, Mekenyan O, Walker JD, Bradbury S. Source: Environmental Toxicology and Chemistry / Setac. 2003 August; 22(8): 1844-54. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12924583&dopt=Abstract

•

Raloxifene inhibits estrogen-induced up-regulation of telomerase activity in a human breast cancer cell line. Author(s): Kawagoe J, Ohmichi M, Takahashi T, Ohshima C, Mabuchi S, Takahashi K, Igarashi H, Mori-Abe A, Saitoh M, Du B, Ohta T, Kimura A, Kyo S, Inoue M, Kurachi H. Source: The Journal of Biological Chemistry. 2003 October 31; 278(44): 43363-72. Epub 2003 August 13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12917431&dopt=Abstract

142

Estrogen

•

Raloxifene, conjugated oestrogen and endothelial function in postmenopausal women. Author(s): Duschek EJ, Stehouwer CD, de Valk-de Roo GW, Schalkwijk CG, Lambert J, Netelenbos C. Source: Journal of Internal Medicine. 2003 July; 254(1): 85-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12823645&dopt=Abstract

•

Randomized controlled trial evidence that estrogen replacement therapy reduces the progression of subclinical atherosclerosis in healthy postmenopausal women without preexisting cardiovascular disease. Author(s): Hodis HN, Mack WJ, Lobo RA. Source: Circulation. 2003 July 8; 108(1): E5; Author Reply E5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12847059&dopt=Abstract

•

Reduced expression of oestrogen receptor beta in invasive breast cancer and its reexpression using DNA methyl transferase inhibitors in a cell line model. Author(s): Skliris GP, Munot K, Bell SM, Carder PJ, Lane S, Horgan K, Lansdown MR, Parkes AT, Hanby AM, Markham AF, Speirs V. Source: The Journal of Pathology. 2003 October; 201(2): 213-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14517838&dopt=Abstract

•

Regional cyclin D1 overexpression or hypoxia correlate inversely with heterogeneous oestrogen receptor-alpha expression in human breast cancer. Author(s): Kronblad A, Helczynska K, Nielsen NH, Pahlman E, Emdin S, Pahlman S, Landberg G. Source: In Vivo. 2003 July-August; 17(4): 311-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12929585&dopt=Abstract

•

Regulation of intestinal NaPi-IIb cotransporter gene expression by estrogen. Author(s): Xu H, Uno JK, Inouye M, Xu L, Drees JB, Collins JF, Ghishan FK. Source: American Journal of Physiology. Gastrointestinal and Liver Physiology. 2003 December; 285(6): G1317-24. Epub 2003 July 31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12893629&dopt=Abstract

•

Removal of estrogenic activity from municipal waste landfill leachate assessed with a bioassay based on reporter gene expression. Author(s): Coors A, Jones PD, Giesy JP, Ratte HT. Source: Environmental Science & Technology. 2003 August 1; 37(15): 3430-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12966991&dopt=Abstract

Studies 143

•

Reporter gene assay demonstrates functional differences in estrogen receptor activity in purified breast cancer cells: a pilot study. Author(s): Singh A, Ali S, Kothari MS, De Bella MT, Smith C, Timms E, Slade MJ, Foxwell BM, Coombes RC. Source: International Journal of Cancer. Journal International Du Cancer. 2003 December 10; 107(5): 700-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14566818&dopt=Abstract

•

Reproducibility over time of measurements of androgens, estrogens and hydroxy estrogens in urine samples from post-menopausal women. Author(s): Rinaldi S, Moret CN, Kaaks R, Biessy C, Kurzer MS, Dechaud H, Peeters PH, van Noord PA. Source: European Journal of Epidemiology. 2003; 18(5): 417-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12889688&dopt=Abstract

•

Requirement of metabolic activation for estrogenic activity of Pueraria mirifica. Author(s): Lee YS, Park JS, Cho SD, Son JK, Cherdshewasart W, Kang KS. Source: Journal of Veterinary Science (Suwon-Si, Korea). 2002 December; 3(4): 273-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12819377&dopt=Abstract

•

Residual urine in an elderly female population: novel implications for oral estrogen replacement and impact on recurrent urinary tract infection. Author(s): Stern JA, Hsieh YC, Schaeffer AJ. Source: The Journal of Urology. 2004 February; 171(2 Pt 1): 768-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14713807&dopt=Abstract

•

Response of estrogen receptor-positive intraabdominal fibromatosis to aromatase inhibitor therapy. Author(s): Klemi P, Alanen K, Hietanen S, Grenman S, Varpula M, Salmi T. Source: Obstetrics and Gynecology. 2003 November; 102(5 Pt 2): 1155-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14607040&dopt=Abstract

•

Resurrecting the ancestral steroid receptor: ancient origin of estrogen signaling. Author(s): Thornton JW, Need E, Crews D. Source: Science. 2003 September 19; 301(5640): 1714-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14500980&dopt=Abstract

•

Review on raloxifene: profile of a selective estrogen receptor modulator. Author(s): Heringa M. Source: Int J Clin Pharmacol Ther. 2003 August; 41(8): 331-45. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12940590&dopt=Abstract

144

Estrogen

•

Risk factors for breast cancer according to estrogen and progesterone receptor status. Author(s): Colditz GA, Rosner BA, Chen WY, Holmes MD, Hankinson SE. Source: Journal of the National Cancer Institute. 2004 February 4; 96(3): 218-28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14759989&dopt=Abstract

•

Risk factors for breast cancer in young women by oestrogen receptor and progesterone receptor status. Author(s): McCredie MR, Dite GS, Southey MC, Venter DJ, Giles GG, Hopper JL. Source: British Journal of Cancer. 2003 November 3; 89(9): 1661-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14583766&dopt=Abstract

•

Risk of invasive cancer of the cervix in relation to the use of injectable progestogen contraceptives and combined estrogen/progestogen oral contraceptives (South Africa). Author(s): Shapiro S, Rosenberg L, Hoffman M, Kelly JP, Cooper DD, Carrara H, Denny LE, du Toit G, Allan BR, Stander IA, Williamson AL. Source: Cancer Causes & Control : Ccc. 2003 June; 14(5): 485-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12946044&dopt=Abstract

•

Role of estrogen and androgen in pubertal skeletal physiology. Author(s): Frank GR. Source: Medical and Pediatric Oncology. 2003 September; 41(3): 217-21. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12868122&dopt=Abstract

•

Role of steroid sulfatase in local formation of estrogen in post-menopausal breast cancer patients. Author(s): Nakata T, Takashima S, Shiotsu Y, Murakata C, Ishida H, Akinaga S, Li PK, Sasano H, Suzuki T, Saeki T. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 September; 86(3-5): 455-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14623544&dopt=Abstract

•

Roles of estrogen receptor alpha (ER alpha) in the regulation of the human Mullerian inhibitory substance (MIS) promoter. Author(s): Chen G, Shinka T, Kinoshita K, Yan HT, Iwamoto T, Nakahori Y. Source: J Med Invest. 2003 August; 50(3-4): 192-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13678390&dopt=Abstract

•

Selective estrogen receptor modulators 4-hydroxytamoxifen and raloxifene impact the stability and function of SRC-1 and SRC-3 coactivator proteins. Author(s): Lonard DM, Tsai SY, O'Malley BW. Source: Molecular and Cellular Biology. 2004 January; 24(1): 14-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14673139&dopt=Abstract

Studies 145

•

Selective estrogen-receptor modulators. Author(s): Cosman F. Source: Clinics in Geriatric Medicine. 2003 May; 19(2): 371-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12916292&dopt=Abstract

•

Sequential action of phase I and II enzymes cytochrome p450 1B1 and glutathione Stransferase P1 in mammary estrogen metabolism. Author(s): Hachey DL, Dawling S, Roodi N, Parl FF. Source: Cancer Research. 2003 December 1; 63(23): 8492-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14679015&dopt=Abstract

•

Serum lipids and apolipoproteins in Greek postmenopausal women: association with estrogen, estrogen-progestin, tibolone and raloxifene therapy. Author(s): Creatsas G, Christodoulakos G, Lambrinoudaki I, Panoulis C, Chondros C, Patramanis P. Source: J Endocrinol Invest. 2003 June; 26(6): 545-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12952369&dopt=Abstract

•

Seventy-five microgram desogestrel minipill, a new perspective in estrogen-free contraception. Author(s): Benagiano G, Primiero FM. Source: Annals of the New York Academy of Sciences. 2003 November; 997: 163-73. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14644823&dopt=Abstract

•

Sexual psychophysiology and effects of sildenafil citrate in oestrogenised women with acquired genital arousal disorder and impaired orgasm: a randomised controlled trial. Author(s): Basson R, Brotto LA. Source: Bjog : an International Journal of Obstetrics and Gynaecology. 2003 November; 110(11): 1014-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14592587&dopt=Abstract

•

Signaling pathways of apoptosis activated by aromatase inhibitors and antiestrogens. Author(s): Thiantanawat A, Long BJ, Brodie AM. Source: Cancer Research. 2003 November 15; 63(22): 8037-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14633737&dopt=Abstract

146

Estrogen

•

Six polymorphisms on estrogen receptor 1 gene in Japanese, American and German populations. Author(s): Sasaki M, Tanaka Y, Sakuragi N, Dahiya R. Source: European Journal of Clinical Pharmacology. 2003 September; 59(5-6): 389-93. Epub 2003 August 16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12923601&dopt=Abstract

•

Ski-related novel protein N (SnoN), a negative controller of transforming growth factor-beta signaling, is a prognostic marker in estrogen receptor-positive breast carcinomas. Author(s): Zhang F, Lundin M, Ristimaki A, Heikkila P, Lundin J, Isola J, Joensuu H, Laiho M. Source: Cancer Research. 2003 August 15; 63(16): 5005-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12941827&dopt=Abstract

•

Sources of estrogen and their importance. Author(s): Simpson ER. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 September; 86(3-5): 225-30. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14623515&dopt=Abstract

•

Soy phytoestrogens do not prevent bone loss in postmenopausal monkeys. Author(s): Register TC, Jayo MJ, Anthony MS. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 September; 88(9): 4362-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12970311&dopt=Abstract

•

Stable transfection of an estrogen receptor beta cDNA isoform into MDA-MB-231 breast cancer cells. Author(s): Tonetti DA, Rubenstein R, DeLeon M, Zhao H, Pappas SG, Bentrem DJ, Chen B, Constantinou A, Craig Jordan V. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 October; 87(1): 47-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14630090&dopt=Abstract

•

Statin therapy in the heart and estrogen/progestin replacement study. Author(s): Daniel KR, Herrington DM. Source: Minerva Ginecol. 2003 June; 55(3): 209-15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14581866&dopt=Abstract

Studies 147

•

Steroid sulfatase and estrogen sulfotransferase in normal human tissue and breast carcinoma. Author(s): Suzuki T, Miki Y, Nakata T, Shiotsu Y, Akinaga S, Inoue K, Ishida T, Kimura M, Moriya T, Sasano H. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 September; 86(3-5): 449-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14623543&dopt=Abstract

•

Steroid sulfatase and estrogen sulfotransferase in the atherosclerotic human aorta. Author(s): Nakamura Y, Miki Y, Suzuki T, Nakata T, Darnel AD, Moriya T, Tazawa C, Saito H, Ishibashi T, Takahashi S, Yamada S, Sasano H. Source: American Journal of Pathology. 2003 October; 163(4): 1329-39. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14507642&dopt=Abstract

•

Steroids and adrenomedullin growth patterns in human ovarian cancer cells: estrogenic-regulation assay. Author(s): Giacalone PL, Daures JP, Ouafik L, Martin PM, Laffargue F, Maudelonde T. Source: Gynecologic Oncology. 2003 December; 91(3): 651-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14675694&dopt=Abstract

•

Study on interactions of endocrine disruptors with estrogen receptor using fluorescence polarization. Author(s): Ohno K, Suzuki S, Fukushima T, Maeda M, Santa T, Imai K. Source: The Analyst. 2003 August; 128(8): 1091-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12964612&dopt=Abstract

•

Supplementation with flaxseed alters estrogen metabolism in postmenopausal women to a greater extent than does supplementation with an equal amount of soy. Author(s): Brooks JD, Ward WE, Lewis JE, Hilditch J, Nickell L, Wong E, Thompson LU. Source: The American Journal of Clinical Nutrition. 2004 February; 79(2): 318-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14749240&dopt=Abstract

•

Synthesis and estrogenic activity of bisphenol a mono- and di-beta-Dglucopyranosides, plant metabolites of bisphenol A. Author(s): Morohoshi K, Shiraishi F, Oshima Y, Koda T, Nakajima N, Edmonds JS, Morita M. Source: Environmental Toxicology and Chemistry / Setac. 2003 October; 22(10): 2275-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14551989&dopt=Abstract

148

Estrogen

•

Synthetic estrogen-mediated activation of ERK 2 intracellular signaling molecule. Author(s): Prifti S, Mall P, Rabe T. Source: Gynecological Endocrinology : the Official Journal of the International Society of Gynecological Endocrinology. 2003 October; 17(5): 423-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14710592&dopt=Abstract

•

The allelic modulation of apolipoprotein E expression by oestrogen: potential relevance for Alzheimer's disease. Author(s): Lambert JC, Coyle N, Lendon C. Source: Journal of Medical Genetics. 2004 February; 41(2): 104-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14757857&dopt=Abstract

•

The benefit of oestrogens and progestogens in postnatal depression. Author(s): Karuppaswamy J, Vlies R. Source: Journal of Obstetrics and Gynaecology : the Journal of the Institute of Obstetrics and Gynaecology. 2003 July; 23(4): 341-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12881067&dopt=Abstract

•

The clinical and pathogenetic significance of estrogen receptor-beta expression in chronic liver diseases and liver carcinoma. Author(s): Iavarone M, Lampertico P, Seletti C, Francesca Donato M, Ronchi G, del Ninno E, Colombo M. Source: Cancer. 2003 August 1; 98(3): 529-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12879470&dopt=Abstract

•

The effect of neoadjuvant chemotherapy on estrogen and progesterone receptor expression and hormone receptor status in breast cancer. Author(s): Lee SH, Chung MA, Quddus MR, Steinhoff MM, Cady B. Source: American Journal of Surgery. 2003 October; 186(4): 348-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14553848&dopt=Abstract

•

The effects of 2-methoxy oestrogens and their sulphamoylated derivatives in conjunction with TNF-alpha on endothelial and fibroblast cell growth, morphology and apoptosis. Author(s): Ho YT, Newman SP, Purohit A, Leese MP, Potter BV, Reed MJ. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 August; 86(2): 189-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14568571&dopt=Abstract

Studies 149

•

The effects of transdermal and oral oestrogen replacement therapy on colorectal cancer risk in postmenopausal women. Author(s): Csizmadi I, Collet JP, Benedetti A, Boivin JF, Hanley JA. Source: British Journal of Cancer. 2004 January 12; 90(1): 76-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14710210&dopt=Abstract

•

The effects of transdermal estrogen therapy on bone mass and turnover in early postmenopausal smokers: a prospective, controlled study. Author(s): Valimaki MJ, Laitinen KA, Tahtela RK, Hirvonen EJ, Risteli JP. Source: American Journal of Obstetrics and Gynecology. 2003 November; 189(5): 121320. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14634543&dopt=Abstract

•

The homeopathic approach to the treatment of symptoms of oestrogen withdrawal in breast cancer patients. A prospective observational study. Author(s): Thompson EA, Reilly D. Source: Homeopathy. 2003 July; 92(3): 131-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12884894&dopt=Abstract

•

The impact of dose and route of estrogen administration on the somatotropic axis in normal women. Author(s): Lissett CA, Shalet SM. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 October; 88(10): 4668-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14557438&dopt=Abstract

•

The inhibitory effects of flavonoids and antiestrogens on the Glut1 glucose transporter in human erythrocytes. Author(s): Martin HJ, Kornmann F, Fuhrmann GF. Source: Chemico-Biological Interactions. 2003 December 15; 146(3): 225-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14642735&dopt=Abstract

•

The intratumoral aromatase model: studies with aromatase inhibitors and antiestrogens. Author(s): Brodie AH, Jelovac D, Long B. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 September; 86(3-5): 283-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14623522&dopt=Abstract

150

Estrogen

•

The nuclear BAG-1 isoform, BAG-1L, enhances oestrogen-dependent transcription. Author(s): Cutress RI, Townsend PA, Sharp A, Maison A, Wood L, Lee R, Brimmell M, Mullee MA, Johnson PW, Royle GT, Bateman AC, Packham G. Source: Oncogene. 2003 August 7; 22(32): 4973-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12902980&dopt=Abstract

•

The phytoestrogen genistein enhances osteogenesis and represses adipogenic differentiation of human primary bone marrow stromal cells. Author(s): Heim M, Frank O, Kampmann G, Sochocky N, Pennimpede T, Fuchs P, Hunziker W, Weber P, Martin I, Bendik I. Source: Endocrinology. 2004 February; 145(2): 848-59. Epub 2003 November 06. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14605006&dopt=Abstract

•

The role of estrogen and estrogen-related drugs in cardiovascular diseases. Author(s): Ogita H, Node K, Kitakaze M. Source: Current Drug Metabolism. 2003 December; 4(6): 497-504. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14683477&dopt=Abstract

•

The role of estrogen in cardiovascular disease. Author(s): Baker L, Meldrum KK, Wang M, Sankula R, Vanam R, Raiesdana A, Tsai B, Hile K, Brown JW, Meldrum DR. Source: The Journal of Surgical Research. 2003 December; 115(2): 325-44. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14697301&dopt=Abstract

•

The role of estrogens in female lower urinary tract dysfunction. Author(s): Robinson D, Cardozo LD. Source: Urology. 2003 October; 62(4 Suppl 1): 45-51. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14550837&dopt=Abstract

•

The role of selective estrogen receptor modulators (SERMs) in postmenopausal health. Author(s): Draper MW. Source: Annals of the New York Academy of Sciences. 2003 November; 997: 373-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14644844&dopt=Abstract

•

The use of estrogen in older women. Author(s): Birge SJ. Source: Clinics in Geriatric Medicine. 2003 August; 19(3): 617-27, Viii. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14567012&dopt=Abstract

Studies 151

•

The utility of estrogen receptor and progesterone receptor immunohistochemistry in the distinction of metastatic breast carcinoma from other tumors in the liver. Author(s): Nash JW, Morrison C, Frankel WL. Source: Archives of Pathology & Laboratory Medicine. 2003 December; 127(12): 1591-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14632573&dopt=Abstract

•

Transdermal versus oral estrogen therapy in postmenopausal smokers: hemodynamic and endothelial effects. Author(s): Girdler SS, Hinderliter AL, Wells EC, Sherwood A, Grewen KM, Light KC. Source: Obstetrics and Gynecology. 2004 January; 103(1): 169-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14704262&dopt=Abstract

•

Update on estrogen signaling. Author(s): Weihua Z, Andersson S, Cheng G, Simpson ER, Warner M, Gustafsson JA. Source: Febs Letters. 2003 July 3; 546(1): 17-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12829231&dopt=Abstract

•

Urinary and serum concentrations of seven phytoestrogens in a human reference population subset. Author(s): Valentin-Blasini L, Blount BC, Caudill SP, Needham LL. Source: Journal of Exposure Analysis and Environmental Epidemiology. 2003 July; 13(4): 276-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12923554&dopt=Abstract

•

Urinary phytoestrogen excretion and breast cancer risk: evaluating potential effect modifiers endogenous estrogens and anthropometrics. Author(s): Dai Q, Franke AA, Yu H, Shu XO, Jin F, Hebert JR, Custer LJ, Gao YT, Zheng W. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2003 June; 12(6): 497-502. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12814993&dopt=Abstract

•

Use of estrogen antagonists and aromatase inhibitors in endometriosis. Author(s): Vigano P, Mangioni S, Odorizzi MP, Chiodini A, Rocca S, Chiodo I. Source: Curr Opin Investig Drugs. 2003 October; 4(10): 1209-12. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14649213&dopt=Abstract

•

Valproic acid increases the stimulatory effect of estrogens on proliferation of human endometrial adenocarcinoma cells. Author(s): Graziani G, Tentori L, Portarena I, Vergati M, Navarra P. Source: Endocrinology. 2003 July; 144(7): 2822-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12810536&dopt=Abstract

152

Estrogen

Academic Periodicals covering Estrogen Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to estrogen. To find the latest studies published, go to http://www.ncbi.nlm.nih.gov/pubmed, type the name of the periodical into the search box, and click “Go.” If you want complete details about the historical contents of a journal, visit the following Web site: http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi. Here, type in the name of the journal or its abbreviation, and you will receive an index of published articles. At http://locatorplus.gov/, you can retrieve more indexing information on medical periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.”

Dissertations on Estrogen ProQuest Digital Dissertations, the largest archive of academic dissertations available, is located at the following Web address: http://wwwlib.umi.com/dissertations. From this archive, we have compiled the following list covering dissertations devoted to estrogen. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “estrogen” (or a synonym) in their titles. The following covers recent dissertations found when using this search procedure: •

Effect of Estrogen and Dietary Phosphate on Renal Cyclic AMP Production by Reichert, Helen Beverley Rush; PhD from University of Guelph (Canada), 1981 http://wwwlib.umi.com/dissertations/fullcit/NK48812

•

Estrogen Receptor Beta: Influence on Urokinase-Type Plasminogen Activator in Vascular Smooth Muscle Cells by Paradis, Madeleine Aimee, MSC from University of Ottawa (Canada), 2003, 97 pages http://wwwlib.umi.com/dissertations/fullcit/MQ76539

•

Genotoxic Effects Induced by Equine Estrogen Metabolites in Breast Cancer Cells by Liu, Xuemei, PhD from University of Illinois at Chicago, Health Sciences Center, 2003, 125 pages http://wwwlib.umi.com/dissertations/fullcit/3083949

•

Prognosis of Breast Cancer a Survival Analysis of 1184 Patients with 4-10 Years Follow-Up, Illustrating the Relative Importance of Estrogen Receptors, Axillary Nodes, Clinical Stage and Tumor Necrosis by Shek, Lydia L. M; PhD from The University of British Columbia (Canada), 1988 http://wwwlib.umi.com/dissertations/fullcit/NL44652

•

Steroid Estrogen, Progesterone and Androgen Concentrations in the Plasma of the Domestic Fowl in Relation to the Ovulation Cycle by Peterson, Andrew James; PhD from McGill University (Canada), 1973 http://wwwlib.umi.com/dissertations/fullcit/NK15965

153

CHAPTER 2. NUTRITION AND ESTROGEN Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and estrogen.

Finding Nutrition Studies on Estrogen The National Institutes of Health’s Office of Dietary Supplements (ODS) offers a searchable bibliographic database called the IBIDS (International Bibliographic Information on Dietary Supplements; National Institutes of Health, Building 31, Room 1B29, 31 Center Drive, MSC 2086, Bethesda, Maryland 20892-2086, Tel: 301-435-2920, Fax: 301-480-1845, E-mail: [email protected]). The IBIDS contains over 460,000 scientific citations and summaries about dietary supplements and nutrition as well as references to published international, scientific literature on dietary supplements such as vitamins, minerals, and botanicals.7 The IBIDS includes references and citations to both human and animal research studies. As a service of the ODS, access to the IBIDS database is available free of charge at the following Web address: http://ods.od.nih.gov/databases/ibids.html. Once you have entered the search area, you have three choices: (1) IBIDS Consumer Database, (2) Full IBIDS Database, or (3) Peer Reviewed Citations Only. Now that you have selected a database, click on the “Advanced” tab. An advanced search allows you to retrieve up to 100 fully explained references in a comprehensive format. Type “estrogen” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.

7

Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.

154

Estrogen

The following is a typical result when searching for recently indexed consumer information on estrogen: •

Another chapter in the heart and estrogen story. Source: Anonymous Harv-Womens-Health-Watch. 2001 April; 8(8): 1-2 1070-910X

•

Atrophic vaginitis. Estrogen can help. Source: Anonymous Mayo-Clin-Health-Lett. 2001 January; 19(1): 6 0741-6245

•

Because I had a lumpectomy, chemotherapy, and radiation for breast cancer in 1990, I am not a candidate for estrogen replacement therapy. One of my friends suggested that I should also avoid soy products because there is natural estrogen in them. This was news to me. Will the type and amount of estrogen in soy foods be detrimental to my future health? Source: Robb Nicholson, C Harv-Womens-Health-Watch. 1998 February; 5(6): 8 1070910X

•

By the way, doctor. I am 70 years old and have taken estrogen (Premarin 1.25 mg) for 14 years. Recently, my bone density test showed osteopenia, which my doctor says is the beginning of osteoporosis. Why would I still get osteoporosis after taking large doses of estrogen for so long? Source: Robb Nicholson, C Harv-Womens-Health-Watch. 1999 July; 6(11): 8 1070-910X

•

By the way, doctor. I'm 70. I took hormone therapy for a while after menopause, but stopped taking it long ago. My memory definitely isn't as good as it used to be. If I started taking estrogen again, would my memory improve? Source: Lee, T H Harv-Health-Lett. 2000 December; 26(2): 8 1052-1577

•

Can estrogen be taken without progesterone? Source: Anonymous Johns-Hopkins-Med-Lett-Health-After-50. 2000 October; 12(8): 8 1042-1882

•

Do estrogens reduce glycemic levels? Source: Wilson, P W Diabetes-Care. 1998 October; 21(10): 1585-6 0149-5992

•

Effect of postmenopausal hormone therapy on glucose and insulin concentrations. PEPI Investigators. Postmenopausal Estrogen/Progestin Interventions. Author(s): Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1063, USA. [email protected] Source: Espeland, M A Hogan, P E Fineberg, S E Howard, G Schrott, H Waclawiw, M A Bush, T L Diabetes-Care. 1998 October; 21(10): 1589-95 0149-5992

•

Estrogen and heart attack. Source: Anonymous Harv-Womens-Health-Watch. 1998 October; 6(2): 1 1070-910X

•

Estrogen and heart health: more data, more confusion. Source: Anonymous Harv-Heart-Lett. 1998 November; 9(3): 4-5 1051-5313

•

Estrogen and perimenopausal depression. Source: Anonymous Harv-Womens-Health-Watch. 2000 December; 8(4): 7 1070-910X

•

Estrogen for heart disease: risk or benefit? Source: Anonymous Harv-Womens-Health-Watch. 2000 June; 7(10): 1-2 1070-910X

•

Fine-tuning the estrogen decision. Source: Anonymous Johns-Hopkins-Med-Lett-Health-After-50. 1998 December; 10(10): 1-2 1042-1882

•

Getting estrogen through the skin. Source: Anonymous Harv-Womens-Health-Watch. 1998 December; 6(4): 2-3 1070-910X

Nutrition

155

•

High-density lipoproteins: effects of alcohol, estrogen, and phytoestrogens. Author(s): Lipid Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA. Source: Lamon Fava, Stefania Nutr-Revolume 2002 January; 60(1): 1-7 0029-6643

•

How estrogen works. Source: Anonymous Harv-Womens-Health-Watch. 1998 April; 5(8): 6 1070-910X

•

I am 51 years old, perimenopausal, have irritable bowel syndrome and a family history of breast cancer, and am told my bones are thinning. These conditions would seem to rule out my use of estrogen or Fosamax. I weight train and take 1,500 mg of calcium a day to stave off osteoporosis. What's left? Source: Robb Nicholson, C Harv-Womens-Health-Watch. 1998 November; 6(3): 8 1070910X

•

I am 59 years old and recently had a complete hysterectomy for endometrial cancer. The pathology report showed no migration of cancer cells outside the endometrium. Is it safe for me to take estrogen as hormone replacement therapy? Source: Robb Nicholson, C Harv-Womens-Health-Watch. 1998 September; 6(1): 8 1070910X

•

I am a 54-year-old woman who has gone through menopause. Six months after starting HRT, I discovered I had gallstones, after suffering four attacks. I am not interested in having my gallbladder out, and I have drastically reduced the amount of fat in my diet, which has eliminated further attacks. However, I have also read that there is a link between estrogen and gallstone formation. Should I stop taking the estrogen? Source: Robb Nicholson, C Harv-Womens-Health-Watch. 1998 October; 6(2): 8 1070910X

•

I had a hysterectomy and my ovaries were also removed in 1986, when I was 46. After combinations of estrogen in tablets and patches failed to relieve my hot flashes, my doctor tried monthly estrogen injections. They controlled my symptoms beautifully, and I have been taking them ever since. I have not been able to find much information about estrogen injections. is there any harm in taking the hormone this way? Source: Robb Nicholson, C Harv-Womens-Health-Watch. 1999 March; 6(7): 8 1070-910X

•

I have found vaginal estrogen cream to be very effective for vaginal dryness but am concerned about the long-term effects of using it. Are there any other treatments that work well for this? Source: Robb Nicholson, C Harv-Womens-Health-Watch. 1998 March; 5(7): 7 1070-910X

•

I have recently started taking Prempro (0.625 mg conjugated estrogens/2.5 mg medroxyprogesterone acetate). There is so much written about the benefits of taking estrogen, but I am wondering about the effects of the progesterone component. Will it counteract the benefits of estrogen? Source: Robb Nicholson, C Harv-Womens-Health-Watch. 1999 January; 6(5): 8 1070910X

•

I recently had a hysterectomy in which my cervix was not removed. What is the correct hormone replacement therapy for me? Do I have to take progesterone? Will the estrogen increase my risk of cervical cancer? Source: Robb Nicholson, C Harv-Womens-Health-Watch. 1998 September; 6(1): 8 1070910X

156

Estrogen

•

In an article last summer, you mentioned that a 0.3 milligram daily dose of estrogen is effective in preventing osteoporosis. Is a dose that low also effective for preventing heart disease? Author(s): Indiana University School of Medicine, USA. Source: Walsh, M N Health-News. 2000 March; 6(3): 10 1081-5880

•

Look to 3 E's of bone health: extra calcium, exercise, estrogen. Source: Forman, A. Environmental-nutrition (USA). (April 1993). volume 16(4) page 1, 6. bones strength calcium physical activity oestrogens adults 0893-4452

•

Low-dose estrogen for bone loss. Source: Anonymous Harv-Womens-Health-Watch. 1998 May; 5(9): 7 1070-910X

•

Menopause management. Estrogen update. Source: Anonymous Harv-Womens-Health-Watch. 1999 June; 6(10): 6 1070-910X

•

Postmenopausal estrogens and risk of myocardial infarction in diabetic women. Author(s): Cardiovascular Health Research Unit, University of Washington, Seattle 98101, USA. [email protected] Source: Kaplan, R C Heckbert, S R Weiss, N S Wahl, P W Smith, N L Newton, K M Psaty, B M Diabetes-Care. 1998 July; 21(7): 1117-21 0149-5992

•

Will statins unseat estrogen? Source: Anonymous Harv-Heart-Lett. 2000 November; 11(3): 1-4 1051-5313

The following information is typical of that found when using the “Full IBIDS Database” to search for “estrogen” (or a synonym): •

A randomized, open-label study of conjugated equine estrogens plus medroxyprogesterone acetate versus tibolone: effects on symptom control, bleeding pattern, lipid profile and tolerability. Author(s): Federal University of Sao Paulo, Sao Paulo. Source: Baracat, E C Barbosa, I C Giordano, M G Haidar, M A Marinho, R M Menegocci, J C Morais, K M Tomaz, G Wehba, S Climacteric. 2002 Mar; 5(1): 60-9 1369-7137

•

Acute toxicity, mutagenicity, and estrogenicity of biodegradation products of bisphenol-A. Author(s): Department of Environmental Engineering, Graduate School of Engineering, Osaka University, 2-1, Yamada-Oka, Suita, Osaka 565-0871 Japan. [email protected] Source: Ike, M Chen, M Y Jin, C S Fujita, M Environ-Toxicol. 2002 October; 17(5): 457-61 1520-4081

•

Anastrozole ('Arimidex') blocks oestrogen synthesis both peripherally and within the breast in postmenopausal women with large operable breast cancer. Author(s): Breast Unit, Western General Hospital, Edinburgh EH4 2XU, Scotland, UK. [email protected] Source: Miller, W R Stuart, M Sahmoud, T Dixon, J M Br-J-Cancer. 2002 October 21; 87(9): 950-5 0007-0920

•

Anti-oestrogenic prevention of breast cancer--the make or break point. Author(s): Breast Cancer Unit at the Royal Marsden Hospital, London SW2 5PT, UK. [email protected] Source: Powles, T J Nat-Rev-Cancer. 2002 October; 2(10): 787-94 1474-175X

Nutrition

157

•

Assessing estrogenic activity of phytochemicals using transcriptional activation and immature mouse uterotrophic responses. Author(s): Developmental Endocrinology Section, Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, PO Box 12233, Research Triangle Park, NC 27709, USA. Source: Jefferson, W N Padilla Banks, E Clark, G Newbold, R R J-Chromatogr-B-AnalytTechnol-Biomed-Life-Sci. 2002 September 25; 777(1-2): 179-89 1570-0232

•

Cognitive decline among female estrogen users in nursing homes. Author(s): Department of Clinical Neurosciences, Brown University, Providence, Rhode Island, USA. [email protected] Source: Ott, B R Belazi, D Lapane, K L J-Gerontol-A-Biol-Sci-Med-Sci. 2002 September; 57(9): M594-8 1079-5006

•

Comparison of tibolone and conjugated equine estrogens effects on carotid artery atherosclerosis of postmenopausal monkeys. Author(s): Comparative Medicine Clinical Research Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1040, USA. [email protected] Source: Clarkson, T B Anthony, M S Mikkola, T S St Clair, R W Stroke. 2002 November; 33(11): 2700-3 1524-4628

•

Effect of a single treatment (imprinting) with genistein or combined treatment with genistein+benzpyrene on the binding capacity of glucocorticoid and estrogen receptors of adult rats. Source:

•

Effect of estrogen and progesterone on the expression of 1, 25-dihydroxyvitamin D receptors mRNA in the liver of ovariectomized rats. Author(s): Department of Endocrionology, Zhujiang Hospital, First Military Medical University, Guangzhou 510282, China. Source: Zhou, Y Ye, R Q Cai, D H Zhang, H Di-Yi-Jun-Yi-Da-Xue-Xue-Bao. 2002 Jun; 22(6): 521-3 1000-2588

•

Effectiveness of estrogen replacement in restoration of cognitive function after longterm estrogen withdrawal in aging rats. Author(s): Neuromnemonics Laboratory, Department of Psychology, Johns Hopkins University, Baltimore, Maryland 21218, USA. [email protected] Source: Markowska, A L Savonenko, A V J-Neurosci. 2002 December 15; 22(24): 10985-95 1529-2401

•

Effects of a new clinically relevant antiestrogen (GW5638) related to tamoxifen on breast and endometrial cancer growth in vivo. Author(s): Department of Gynecology, Federal University of Sao Paulo, SP, Brazil 04023900. Source: Dardes, R C O'Regan, R M Gajdos, C Robinson, S P Bentrem, D De Los Reyes, A Jordan, V C Clin-Cancer-Res. 2002 June; 8(6): 1995-2001 1078-0432

•

Effects of estrogens and selective estrogen receptor modulators on indicators of cardiovascular health in postmenopausal women. Author(s): Department of Internal Medicine/Cardiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina, USA. Source: Klein, K P Herrington, D M Medscape-Womens-Health. 2002 Sep-October; 7(5): 2 1521-2076

158

Estrogen

•

Estradiol enhances the neurotoxicity of glutamate in GT1-7 cells through an estrogen receptor-dependent mechanism. Author(s): Department of Physiology, Kaohsiung Medical University, No. 100, ShihChuan 1st Road, Kaohsiung 807, Taiwan, ROC. Source: Yang, R C Shih, H C Hsu, H K Chang, H C Hsu, C Neurotoxicology. 2003 January; 24(1): 65-73 0161-813X

•

Estrogen and Alzheimer's disease. Author(s): The Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B Davis Jewish General Hospital, Montreal, Quebec, Canada. [email protected] Source: LeBlanc, A Curr-Opin-Investig-Drugs. 2002 May; 3(5): 768-73 1472-4472

•

Estrogen and colon cancer: current issues. Author(s): Gynaecology Research Unit, Department of Obstetrics and Gynaecology, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, LE2 7LX, UK. Source: al Azzawi, F Wahab, M Climacteric. 2002 March; 5(1): 3-14 1369-7137

•

Estrogen receptor expression in the prostate of rats treated with dietary genistein. Author(s): Division of Biochemical Toxicology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA. Source: Dalu, A Blaydes, B S Bryant, C W Latendresse, J R Weis, C C Barry Delclos, K JChromatogr-B-Analyt-Technol-Biomed-Life-Sci. 2002 September 25; 777(1-2): 249-60 1570-0232

•

Estrogen reduces CCL4- induced liver fibrosis in rats. Author(s): Department of Gastroenterology, Second Hospital of Xi'an Jiaotong University, Xi'an 710031, Shaanxi Province, China. [email protected] Source: Xu, J W Gong, J Chang, X M Luo, J Y Dong, L Hao, Z M Jia, A Xu, G P World-JGastroenterol. 2002 October; 8(5): 883-7 1007-9327

•

Estrogen replacement therapy for Alzheimer disease in postmenopausal women. Author(s): College of Pharmacy, Idaho State University, Campus Box 8356, Pocatello, ID 83209-8356, USA, [email protected] Source: Owens, C T Ann-Pharmacother. 2002 Jul-August; 36(7-8): 1273-6 1060-0280

•

Estrogen supplementation for female schizophrenics treated with atypical antipsychotics. Author(s): Department of Psychiatry, Executive Yuan Department of Health, Pali Psychiatric Hospital, Taipei, Taiwan, Republic of China. Source: Liao, D L Chen, H Lee, S M Tsai, S J Gen-Hosp-Psychiatry. 2002 Sep-October; 24(5): 357-9 0163-8343

•

Estrogens and receptors: an evolving concept. Author(s): INSERM U540, Endocrinologie Moleculaire et Cellulaire des Cancers, Montpellier, France. Source: Cavailles, V Climacteric. 2002 June; 5 Suppl 2: 20-6 1369-7137

•

In vitro regulation of vascular endothelial growth factor by estrogens and antiestrogens in estrogen-receptor positive breast cancer. Author(s): Northwestern University Medical School, Robert H. Lurie Comprehensive Cancer Center, USA. [email protected] Source: Takei, H Lee, E S Jordan, V C Breast-Cancer. 2002; 9(1): 39-42 1340-6868

Nutrition

159

•

Induction of the estrogen effect-switching phenomenon by ethanol and its correction. Author(s): Professor N. N. Petrov Science Research Institute of Oncology, Ministry of Health of the Russian Federation, 68 Leningradskaya Street, Pesochnyi-2, 189646 St. Petersburg, Russia. Source: Bershtein, L M Tsyrlina, E V Poroshina, T E Bychkova, N V Kalinina, N M Gamayunova, V B Kryukova, O G Kovalenko, I G Vasil'ev, D A Neurosci-BehavPhysiol. 2002 Nov-December; 32(6): 603-7 0097-0549

•

Inhibition of low-density lipoprotein oxidation by the pure antiestrogens ICI 182780 and EM-652 (SCH 57068). Author(s): Research Unit, Hospital Clinico Universitario de Valencia, Valencia, Spain. Source: Hermenegildo, C Garcia Martinez, M C Tarin, J J Cano, A Menopause. 2002 Nov-December; 9(6): 430-5 1072-3714

•

Morphine down regulates human vascular tissue estrogen receptor expression determined by real-time RT-PCR. Author(s): Neuroscience Research Institute, State University of New York at Old Westbury, NY 11568, USA. Source: Cadet, P Mantione, K Bilfinger, T V Stefano, G B Neuroendocrinol-Lett. 2002 April; 23(2): 95-100 0172-780X

•

NHLBI stops estrogen plus progestin trial. Source: Cockey, C D AWHONN-Lifelines. 2002 Aug-September; 6(4): 299-307 1091-5923

•

Overview of in vitro tools to assess the estrogenic and antiestrogenic activity of phytoestrogens. Author(s): Merck KGaA, Molecular Toxicology, Frankfurter Strasse 250, 64293, Darmstadt, Germany. [email protected] Source: Mueller, S O J-Chromatogr-B-Analyt-Technol-Biomed-Life-Sci. 2002 September 25; 777(1-2): 155-65 1570-0232

•

Phytoestrogens in the management of the menopause: up-to-date. Author(s): Clinical Research Fellow in Gynecology, Leicester University, Leicestershire, UK. [email protected] Source: Ewies, A A Obstet-Gynecol-Survolume 2002 May; 57(5): 306-13 0029-7828

•

Placebo-controlled trial of transdermal estrogen therapy alone in postmenopausal women: effects on arterial compliance and endothelial function. Author(s): Department of Medicine, Monash University, Dandenong Hospital, Dandenong, Australia. Source: Teede, H J Liang, Y L Kotsopoulos, D Zoungas, S Craven, R McGrath, B P Climacteric. 2002 June; 5(2): 160-9 1369-7137

•

Prevention and treatment of experimental breast cancer with the combination of a new selective estrogen receptor modulator, arzoxifene, and a new rexinoid, LG 100268. Author(s): Department of Pharmacology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA. Source: Suh, N Lamph, W W Glasebrook, A L Grese, T A Palkowitz, A D Williams, C R Risingsong, R Farris, M R Heyman, R A Sporn, M B Clin-Cancer-Res. 2002 October; 8(10): 3270-5 1078-0432

160

Estrogen

•

Prevention of bone loss and hypoestrogenic symptoms by estrogen and interrupted progestogen add-back in long-term GnRH-agonist down-regulated patients with endometriosis and premenstrual syndrome. Author(s): Division of Reproductive Sciences, Department of Obstetrics and Gynecology, Samuel Lunenfeld Research Institute and Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. Source: Mitwally, M F Gotlieb, L Casper, R F Menopause. 2002 Jul-August; 9(4): 236-41 1072-3714

•

Purified phytoestrogens in postmenopausal bone health: is there a role for genistein? Author(s): Centre for Metabolic Bone Disease, H. S. Brocklehurst Building, 220-236 Anlaby Road, Hull HU3 2RW, England. Source: Albertazzi, P Climacteric. 2002 June; 5(2): 190-6 1369-7137

•

Recognition of resveratrol by the human estrogen receptor-alpha: a molecular modeling approach to understand its biological actions. Author(s): Department of Applied Therapeutics, Faculty of Pharmacy, Kuwait University, PO Box 24923, 13110 Safat, Kuwait. [email protected] Source: el Mowafy, A M Abou Zeid, L A Edafiogho, I Med-Princ-Pract. 2002 Apr-June; 11(2): 86-92 1011-7571

•

Responsiveness of endometrial genes Connexin26, Connexin43, C3 and clusterin to primary estrogen, selective estrogen receptor modulators, phyto- and xenoestrogens. Author(s): Institute of Anatomy, University Hospital Essen, D-45122 Essen, Germany. Source: Heikaus, S Winterhager, E Traub, O Grummer, R J-Mol-Endocrinol. 2002 October; 29(2): 239-49 0952-5041

•

Sex hormones and the connective tissue diseases II: the pros and cons of estrogens and estrogen receptor modulators in patients with connective tissue diseases. Author(s): Lilly Research Laboratories, Department of Medicine, Indiana University School of Medicine, USA. [email protected] Source: Draper, M W Lupus. 2002; 11(10): 668-9 0961-2033

•

The effect of estrogen-progestin treatment on bone mineral density in anorexia nervosa. Author(s): Department of Pediatrics, Division of Adolescent Medicine, Schneider Children's Hospital of Long Island Jewish Medical Center, New Hyde Park, New York 11040, USA. [email protected] Source: Golden, N H Lanzkowsky, L Schebendach, J Palestro, C J Jacobson, M S Shenker, I R J-Pediatr-Adolesc-Gynecol. 2002 June; 15(3): 135-43 1083-3188

•

The effects of the phytoestrogen, coumestrol, on gonadotropin-releasing hormone (GnRH) mRNA expression in GT1-7 GnRH neurones. Author(s): Centre for Reproduction, Endocrinology and Diabetes, King's College London, UK. Source: Bowe, J Li, X F Sugden, D Katzenellenbogen, J A Katzenellenbogen, B S O'Byrne, K T J-Neuroendocrinol. 2003 February; 15(2): 105-8 0953-8194

•

Thyroid gland function in ovariectomized ewes exposed to phytoestrogens. Author(s): Department of Animal Physiology, Centre for Reproductive Biology in Uppsala, Swedish University of Agricultural Sciences (SLU), PO Box 7045, S-750 07, Uppsala, Sweden. [email protected] Source: Madej, A Persson, E Lundh, T Ridderstrale, Y J-Chromatogr-B-Analyt-TechnolBiomed-Life-Sci. 2002 September 25; 777(1-2): 281-7 1570-0232

Nutrition

161

•

Topical estrogens: their effects on connective tissue synthesis in hairless mouse skin. Author(s): Current address: Johnson & Johnson Pharmaceutical Research & Development, L.L.C., US Route 202, PO Box 300, Raritan, NJ 08869-0602, USA. [email protected] Source: Gendimenico, G J Mack, V J Siock, P A Mezick, J A Arch-Dermatol-Res. 2002 July; 294(5): 231-6 0340-3696

•

Urinary excretion pattern of catecholestrogens in preovulatory LH surge during the 4day estrous cycle of rats. Author(s): Department of Chemistry, Maharaja Manindra Chandra College, Calcutta, India. [email protected] Source: Panda, S K Chattoraj, S C J-Endocrinol-Invest. 2001 May; 24(5): 334-9 0391-4097

Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •

healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0

•

The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov

•

The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov

•

The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/

•

The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/

•

Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/

•

Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/

•

Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/

Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats

•

Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html

•

Google: http://directory.google.com/Top/Health/Nutrition/

162

Estrogen

•

Healthnotes: http://www.healthnotes.com/

•

Open Directory Project: http://dmoz.org/Health/Nutrition/

•

Yahoo.com: http://dir.yahoo.com/Health/Nutrition/

•

WebMD®Health: http://my.webmd.com/nutrition

•

WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

The following is a specific Web list relating to estrogen; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •

Vitamins Vitamin B Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10067,00.html Vitamin B6 Source: Healthnotes, Inc.; www.healthnotes.com Vitamin D Source: Healthnotes, Inc.; www.healthnotes.com Vitamin D Alternative names: Calciferol Source: Integrative Medicine Communications; www.drkoop.com Vitamin D Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin K Source: Prima Communications, Inc.www.personalhealthzone.com

•

Minerals Boron Source: Healthnotes, Inc.; www.healthnotes.com Boron Source: Prima Communications, Inc.www.personalhealthzone.com Calcium Source: Healthnotes, Inc.; www.healthnotes.com Calcium Source: Integrative Medicine Communications; www.drkoop.com

Nutrition

163

Calcium Source: Prima Communications, Inc.www.personalhealthzone.com Calcium D-glucarate Source: Healthnotes, Inc.; www.healthnotes.com Cisplatin Source: Healthnotes, Inc.; www.healthnotes.com Copper Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,886,00.html Folate Source: Prima Communications, Inc.www.personalhealthzone.com Magnesium Source: Healthnotes, Inc.; www.healthnotes.com Magnesium Source: Integrative Medicine Communications; www.drkoop.com Magnesium Source: Prima Communications, Inc.www.personalhealthzone.com Quercetin Source: Healthnotes, Inc.; www.healthnotes.com Zinc Source: Healthnotes, Inc.; www.healthnotes.com Zinc Source: Integrative Medicine Communications; www.drkoop.com Zinc Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10071,00.html •

Food and Diet Broccoli Source: Healthnotes, Inc.; www.healthnotes.com Brussels Sprouts Source: Healthnotes, Inc.; www.healthnotes.com Bulgur Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,305,00.html

164

Estrogen

Cabbage Source: Healthnotes, Inc.; www.healthnotes.com Cancer Prevention and Diet Source: Healthnotes, Inc.; www.healthnotes.com Cauliflower Source: Healthnotes, Inc.; www.healthnotes.com Flaxseeds Source: Healthnotes, Inc.; www.healthnotes.com High Cholesterol Source: Healthnotes, Inc.; www.healthnotes.com Soy Source: Healthnotes, Inc.; www.healthnotes.com Soy Source: Prima Communications, Inc.www.personalhealthzone.com Soy Flour Source: Healthnotes, Inc.; www.healthnotes.com Soy Milk Source: Healthnotes, Inc.; www.healthnotes.com Soy Milk Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,200,00.html Soy Products Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,135,00.html Soy Sauce Source: Healthnotes, Inc.; www.healthnotes.com Soybeans Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,105,00.html Textured Vegetable Protein Source: Healthnotes, Inc.; www.healthnotes.com

165

CHAPTER 3. ALTERNATIVE MEDICINE AND ESTROGEN Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to estrogen. At the conclusion of this chapter, we will provide additional sources.

The Combined Health Information Database The Combined Health Information Database (CHID) is a bibliographic database produced by health-related agencies of the U.S. federal government (mostly from the National Institutes of Health) that can offer concise information for a targeted search. The CHID database is updated four times a year at the end of January, April, July, and October. Check the titles, summaries, and availability of CAM-related information by using the “Simple Search” option at the following Web site: http://chid.nih.gov/simple/simple.html. In the drop box at the top, select “Complementary and Alternative Medicine.” Then type “estrogen” (or synonyms) in the second search box. We recommend that you select 100 “documents per page” and to check the “whole records” options. The following was extracted using this technique: •

Alternative Therapies for Managing Menopausal Symptoms Source: Gaithersburg, MD: National Center for Complementary and Alternative Medicine. 2002. 3 p. Contact: Available from National Center for Complementary and Alternative Medicine Clearinghouse. P.O. Box 7923, Gaithersburg, MD 20898. (888) 644-6226; INTERNATIONAL PHONE: (301) 519-3153; TTY: (866) 464-3615; FAX: (866) 464-3616; EMAIL: [email protected]. PRICE: Free. Publication Number: D169. Summary: This consumer advisory alerts consumers about recent research demonstrating that long-term use of estrogen in combination with progestin results in more risks than benefits. It discusses the use of alternative therapies for managing menopausal symptoms, provides information on the current scientific evidence of the effectiveness and safety of these therapies, and offers advice to consumers about using

166

Estrogen

hormone replacement therapy and alternative therapies for menopausal symptoms. The advisory also provides a list of sources for further information. •

Soy: Health Claims for Soy Protein, Questions About Other Components Source: FDA Consumer. 34(3): 13-15, 18-20. May-June 2000. Contact: Available from Food and Drug Administration. 5600 Fishers Lane, Rockville, MD 20857. (888) 463-6332. PRICE: Free. Summary: This Food and Drug Administration (FDA) Consumer magazine article discusses FDA permission to food manufacturers to put labels on products high in soy protein indicating that these foods may help lower heart disease risk. It includes information on concerns about certain components in soy products, particularly isoflavones, which have engulfed the health claim regulation in controversy. The article features quotes from Elizabeth A. Yetley, Ph.D., lead scientist for nutrition at FDA's Center for Food Safety and Applied Nutrition; Christine Lewis, acting Director of the Center for Food Safety and Applied Nutrition's Office of Nutritional Products, Labeling, and Dietary Supplements; Margo Woods, D.Sc., associate professor of medicine at Tufts University; and Daniel Sheehan, Ph.D., director of the Estrogen Knowledge Base Program at FDA's National Center for Toxicological Research. The article also includes sections on soy benefits, the different types of soy products, trends in soy consumption, adding soy to the diet, and soy health claims. Organizations where consumers can obtain additional information on soy are listed at the end of the article.

National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov/) has created a link to the National Library of Medicine’s databases to facilitate research for articles that specifically relate to estrogen and complementary medicine. To search the database, go to the following Web site: http://www.nlm.nih.gov/nccam/camonpubmed.html. Select “CAM on PubMed.” Enter “estrogen” (or synonyms) into the search box. Click “Go.” The following references provide information on particular aspects of complementary and alternative medicine that are related to estrogen: •

17beta-Estradiol and environmental estrogens significantly affect mammalian sperm function. Author(s): Adeoya-Osiguwa SA, Markoulaki S, Pocock V, Milligan SR, Fraser LR. Source: Human Reproduction (Oxford, England). 2003 January; 18(1): 100-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12525448&dopt=Abstract

•

17-epiestriol, an estrogen metabolite, is more potent than estradiol in inhibiting vascular cell adhesion molecule 1 (VCAM-1) mRNA expression. Author(s): Mukherjee TK, Nathan L, Dinh H, Reddy ST, Chaudhuri G. Source: The Journal of Biological Chemistry. 2003 April 4; 278(14): 11746-52. Epub 2003 January 23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12547825&dopt=Abstract

Alternative Medicine 167

•

4-ethoxymethylphenol: a novel phytoestrogen that acts as an agonist for human estrogen receptors. Author(s): Pearce V, Nawaz Z, Xiao W, Wiedenfeld D, Boyle N, Smith D. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 March; 84(4): 431-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12732288&dopt=Abstract

•

8-Prenyl naringenin is a potent ERalpha selective phytoestrogen present in hops and beer. Author(s): Schaefer O, Humpel M, Fritzemeier KH, Bohlmann R, Schleuning WD. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 February; 84(23): 359-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12711023&dopt=Abstract

•

A 2-year prospective study on the effects of depot medroxyprogesterone acetate on bone mass-response to estrogen and calcium therapy in individual users. Author(s): Merki-Feld GS, Neff M, Keller PJ. Source: Contraception. 2003 February; 67(2): 79-86. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12586317&dopt=Abstract

•

A binary screening assay for pro-oestrogens in food: metabolic activation using hepatic microsomes and detection with oestrogen sensitive recombinant yeast cells. Author(s): Coldham NG, Horton R, Byford MF, Sauer MJ. Source: Food Additives and Contaminants. 2002 December; 19(12): 1138-47. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12623674&dopt=Abstract

•

A case-control study of dietary phytoestrogens and testicular cancer risk. Author(s): Walcott FL, Hauptmann M, Duphorne CM, Pillow PC, Strom SS, Sigurdson AJ. Source: Nutrition and Cancer. 2002; 44(1): 44-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12672640&dopt=Abstract

•

A comparison of the anti-inflammatory activities of conjugated estrogens and 17-beta estradiol. Author(s): Thomas TN, Rhodin JA, Clark L, Garces A, Bryant M. Source: Inflammation Research : Official Journal of the European Histamine Research Society. [et Al.]. 2003 November; 52(11): 452-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14652679&dopt=Abstract

•

A ginsenoside-Rh1, a component of ginseng saponin, activates estrogen receptor in human breast carcinoma MCF-7 cells. Author(s): Lee Y, Jin Y, Lim W, Ji S, Choi S, Jang S, Lee S.

168

Estrogen

Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 March; 84(4): 463-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12732291&dopt=Abstract •

A homogeneous in vitro functional assay for estrogen receptors: coactivator recruitment. Author(s): Liu J, Knappenberger KS, Kack H, Andersson G, Nilsson E, Dartsch C, Scott CW. Source: Molecular Endocrinology (Baltimore, Md.). 2003 March; 17(3): 346-55. Epub 2002 December 05. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12554768&dopt=Abstract

•

A model to estimate the oestrogen receptor mediated effects from exposure to soy isoflavones in food. Author(s): Safford B, Dickens A, Halleron N, Briggs D, Carthew P, Baker V. Source: Regulatory Toxicology and Pharmacology : Rtp. 2003 October; 38(2): 196-209. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14550760&dopt=Abstract

•

A natural antioxidant mixture from spinach does not have estrogenic or antiestrogenic activity in immature CD-1 mice. Author(s): Lomnitski L, Padilla-Banks E, Jefferson WN, Nyska A, Grossman S, Newbold RR. Source: The Journal of Nutrition. 2003 November; 133(11): 3584-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14608077&dopt=Abstract

•

A randomized controlled trial of phytoestrogen supplementation, growth and bone turnover in adolescent males. Author(s): Jones G, Dwyer T, Hynes K, Dalais FS, Parameswaran V, Greenaway TM. Source: European Journal of Clinical Nutrition. 2003 February; 57(2): 324-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12571667&dopt=Abstract

•

A randomized placebo-controlled crossover trial with phytoestrogens in treatment of menopause in breast cancer patients. Author(s): Nikander E, Kilkkinen A, Metsa-Heikkila M, Adlercreutz H, Pietinen P, Tiitinen A, Ylikorkala O. Source: Obstetrics and Gynecology. 2003 June; 101(6): 1213-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12798527&dopt=Abstract

•

A toxicity identification evaluation approach to studying estrogenic substances in hog manure and agricultural runoff. Author(s): Burnison BK, Hartmann A, Lister A, Servos MR, Ternes T, Van der Kraak G.

Alternative Medicine 169

Source: Environmental Toxicology and Chemistry / Setac. 2003 October; 22(10): 2243-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14551985&dopt=Abstract •

Activation of estrogen receptor alpha and ERbeta by 4-methylbenzylidene-camphor in human and rat cells: comparison with phyto- and xenoestrogens. Author(s): Mueller SO, Kling M, Arifin Firzani P, Mecky A, Duranti E, Shields-Botella J, Delansorne R, Broschard T, Kramer PJ. Source: Toxicology Letters. 2003 April 30; 142(1-2): 89-101. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12765243&dopt=Abstract

•

Alternatives to estrogen. Author(s): Fitzpatrick LA. Source: The Medical Clinics of North America. 2003 September; 87(5): 1091-113, X. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14621333&dopt=Abstract

•

An estrogen replacement therapy containing nine synthetic plant-based conjugated estrogens promotes neuronal survival. Author(s): Zhao L, Chen S, Brinton RD. Source: Experimental Biology and Medicine (Maywood, N.J.). 2003 July; 228(7): 823-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12876302&dopt=Abstract

•

An observational study of severe hypertriglyceridemia, hypertriglyceridemic acute pancreatitis, and failure of triglyceride-lowering therapy when estrogens are given to women with and without familial hypertriglyceridemia. Author(s): Goldenberg NM, Wang P, Glueck CJ. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 2003 June; 332(1-2): 11-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12763274&dopt=Abstract

•

Analysis of estrogenic activity of foodstuffs and cigarette smoke condensates using a yeast estrogen screening method. Author(s): Takamura-Enya T, Ishihara J, Tahara S, Goto S, Totsuka Y, Sugimura T, Wakabayashi K. Source: Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association. 2003 April; 41(4): 543-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12615126&dopt=Abstract

•

Analysis of phyto-oestrogens in biological matrices. Author(s): Hoikkala AA, Schiavoni E, Wahala K. Source: The British Journal of Nutrition. 2003 June; 89 Suppl 1: S5-18. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12725650&dopt=Abstract

170

Estrogen

•

Androgen receptor expression in the rat prostate is down-regulated by dietary phytoestrogens. Author(s): Lund TD, Munson DJ, Adlercreutz H, Handa RJ, Lephart ED. Source: Reproductive Biology and Endocrinology [electronic Resource] : Rb&E. 2004 January 16; 2(1): 5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14728729&dopt=Abstract

•

Androgen receptor regulation by physiological concentrations of the isoflavonoid genistein in androgen-dependent LNCaP cells is mediated by estrogen receptor beta. Author(s): Bektic J, Berger AP, Pfeil K, Dobler G, Bartsch G, Klocker H. Source: European Urology. 2004 February; 45(2): 245-51; Discussion 251. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14734014&dopt=Abstract

•

Antiandrogenic activity of the phytoestrogens naringenin, 6-(1,1dimethylallyl)naringenin and 8-prenylnaringenin. Author(s): Zierau O, Morrissey C, Watson RW, Schwab P, Kolba S, Metz P, Vollmer G. Source: Planta Medica. 2003 September; 69(9): 856-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14598215&dopt=Abstract

•

Assessment of the estrogenicity of isoflavonoids, using MCF-7-ERE-Luc cells. Author(s): Joung KE, Kim YW, Sheen YY. Source: Arch Pharm Res. 2003 September; 26(9): 756-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14560926&dopt=Abstract

•

Benefit of Paclitaxel in estrogen receptor-negative versus estrogen receptor-positive early breast cancer. Author(s): Bryce C, Kennecke H, Chia S, Ragaz J. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 December 1; 21(23): 4465; Author Reply 4465-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14645445&dopt=Abstract

•

Bioavailability of phyto-oestrogens. Author(s): Rowland I, Faughnan M, Hoey L, Wahala K, Williamson G, Cassidy A. Source: The British Journal of Nutrition. 2003 June; 89 Suppl 1: S45-58. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12725656&dopt=Abstract

•

Black cohosh, a menopausal remedy, does not have estrogenic activity and does not promote breast cancer cell growth. Author(s): Lupu R, Mehmi I, Atlas E, Tsai MS, Pisha E, Oketch-Rabah HA, Nuntanakorn P, Kennelly EJ, Kronenberg F. Source: International Journal of Oncology. 2003 November; 23(5): 1407-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14532983&dopt=Abstract

Alternative Medicine 171

•

Cell-transforming activity and mutagenicity of 5 phytoestrogens in cultured mammalian cells. Author(s): Tsutsui T, Tamura Y, Yagi E, Someya H, Hori I, Metzler M, Barrett JC. Source: International Journal of Cancer. Journal International Du Cancer. 2003 June 20; 105(3): 312-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12704663&dopt=Abstract

•

Characterization of a membrane-associated estrogen receptor in a rat hypothalamic cell line (D12). Author(s): Deecher DC, Swiggard P, Frail DE, O'Connor LT. Source: Endocrine. 2003 December; 22(3): 211-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14709794&dopt=Abstract

•

Characterization of a zebrafish estrogen-sulfating cytosolic sulfotransferase: inhibitory effects and mechanism of action of phytoestrogens. Author(s): Ohkimoto K, Liu MY, Suiko M, Sakakibara Y, Liu MC. Source: Chemico-Biological Interactions. 2004 January 15; 147(1): 1-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14726148&dopt=Abstract

•

Combined in situ and in vitro assessment of the estrogenic activity of sewage and surface water samples. Author(s): Pawlowski S, Ternes T, Bonerz M, Kluczka T, van der Burg B, Nau H, Erdinger L, Braunbeck T. Source: Toxicological Sciences : an Official Journal of the Society of Toxicology. 2003 September; 75(1): 57-65. Epub 2003 June 12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12805642&dopt=Abstract

•

Combined inhibition of estrogen-dependent human breast carcinoma by soy and tea bioactive components in mice. Author(s): Zhou JR, Yu L, Mai Z, Blackburn GL. Source: International Journal of Cancer. Journal International Du Cancer. 2004 January 1; 108(1): 8-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14618609&dopt=Abstract

•

Comparative responses of three rat strains (DA/Han, Sprague-Dawley and Wistar) to treatment with environmental estrogens. Author(s): Diel P, Schmidt S, Vollmer G, Janning P, Upmeier A, Michna H, Bolt HM, Degen GH. Source: Archives of Toxicology. 2003 December 20 [epub Ahead of Print] http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14689164&dopt=Abstract

•

Comparison of hormonal activity (estrogen, androgen and progestin) of standardized plant extracts for large scale use in hormone replacement therapy. Author(s): Beck V, Unterrieder E, Krenn L, Kubelka W, Jungbauer A.

172

Estrogen

Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 February; 84(23): 259-68. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12711012&dopt=Abstract •

Composition, red blood cell uptake, and serum protein binding of phytoestrogens extracted from commercial kudzu-root and soy preparations. Author(s): Benlhabib E, Baker JI, Keyler DE, Singh AK. Source: Journal of Medicinal Food. 2002 Fall; 5(3): 109-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12495583&dopt=Abstract

•

Constrained phytoestrogens and analogues as ERbeta selective ligands. Author(s): Miller CP, Collini MD, Harris HA. Source: Bioorganic & Medicinal Chemistry Letters. 2003 July 21; 13(14): 2399-403. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12824043&dopt=Abstract

•

Convenient synthesis of 5,6,11,12,17,18- hexahydrocyclononal[1,2-b:4,5-b':7,8b'']triindole, a novel phytoestrogen. Author(s): Staub RE, Bjeldanes LF. Source: The Journal of Organic Chemistry. 2003 January 10; 68(1): 167-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12515475&dopt=Abstract

•

Determination of trace isoflavone phytoestrogens in biological materials by capillary electrochromatography. Author(s): Starkey JA, Mechref Y, Byun CK, Steinmetz R, Fuqua JS, Pescovitz OH, Novotny MV. Source: Analytical Chemistry. 2002 December 1; 74(23): 5998-6005. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12498195&dopt=Abstract

•

Dietary exposure to xenoestrogens in New Zealand. Author(s): Thomson BM, Cressey PJ, Shaw IC. Source: Journal of Environmental Monitoring : Jem. 2003 April; 5(2): 229-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12729260&dopt=Abstract

•

Dietary genistein results in larger MNU-induced, estrogen-dependent mammary tumors following ovariectomy of Sprague-Dawley rats. Author(s): Allred CD, Allred KF, Ju YH, Clausen LM, Doerge DR, Schantz SL, Korol DL, Wallig MA, Helferich WG. Source: Carcinogenesis. 2004 February; 25(2): 211-218. Epub 2003 October 24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14578162&dopt=Abstract

•

Dietary phytoestrogens and bone health. Author(s): Cassidy A.

Alternative Medicine 173

Source: The Journal of the British Menopause Society. 2003 March; 9(1): 17-21. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12804308&dopt=Abstract •

Dietary phytoestrogens and their effect on bone: evidence from in vitro and in vivo, human observational, and dietary intervention studies. Author(s): Setchell KD, Lydeking-Olsen E. Source: The American Journal of Clinical Nutrition. 2003 September; 78(3 Suppl): 593S609S. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12936954&dopt=Abstract

•

Dietary soy containing phytoestrogens does not have detectable estrogenic effects on hepatic protein synthesis in postmenopausal women. Author(s): Teede HJ, Dalais FS, McGrath BP. Source: The American Journal of Clinical Nutrition. 2004 March; 79(3): 396-401. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14985213&dopt=Abstract

•

Dietary soy oil content and soy-derived phytoestrogen genistein increase resistance to alopecia areata onset in C3H/HeJ mice. Author(s): McElwee KJ, Niiyama S, Freyschmidt-Paul P, Wenzel E, Kissling S, Sundberg JP, Hoffmann R. Source: Experimental Dermatology. 2003 February; 12(1): 30-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12631244&dopt=Abstract

•

Dietary soy phytoestrogens and ERalpha signalling modulate interferon gamma production in response to bacterial infection. Author(s): Curran EM, Judy BM, Newton LG, Lubahn DB, Rottinghaus GE, Macdonald RS, Franklin C, Estes DM. Source: Clinical and Experimental Immunology. 2004 February; 135(2): 219-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14738448&dopt=Abstract

•

Dietary soy phytoestrogens effects on retinal thickness in rats. Author(s): Lund TD, Fleming DE, Dayton JR, Lephart ED, Salyer DL. Source: Nutritional Neuroscience. 2003 February; 6(1): 47-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12608736&dopt=Abstract

•

Differential effects of natural and environmental estrogens on endothelin synthesis in bovine oviduct cells. Author(s): Reinhart KC, Dubey RK, Cometti B, Keller PJ, Rosselli M. Source: Biology of Reproduction. 2003 April; 68(4): 1430-6. Epub 2002 November 27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12606437&dopt=Abstract

174

Estrogen

•

Differential effects of oral versus transdermal estrogen replacement therapy on Creactive protein in postmenopausal women. Author(s): Vongpatanasin W, Tuncel M, Wang Z, Arbique D, Mehrad B, Jialal I. Source: Journal of the American College of Cardiology. 2003 April 16; 41(8): 1358-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12706932&dopt=Abstract

•

Differential recognition of resveratrol isomers by the human estrogen receptor-alpha: Molecular dynamics evidence for stereoselective ligand binding. Author(s): Abou-Zeid LA, El-Mowafy AM. Source: Chirality. 2004 March; 16(3): 190-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14770416&dopt=Abstract

•

Distinct molecular conformations of the estrogen receptor alpha complex exploited by environmental estrogens. Author(s): Bentrem D, Fox JE, Pearce ST, Liu H, Pappas S, Kupfer D, Zapf JW, Jordan VC. Source: Cancer Research. 2003 November 1; 63(21): 7490-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14612550&dopt=Abstract

•

Easing menopausal symptoms with dietary phytoestrogens. Author(s): Brewer S. Source: Community Nurse. 2000 July; 6(6): 13-5. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12778644&dopt=Abstract

•

Editorial: The search for alternative therapies for menopausal women: estrogenic effects of herbs. Author(s): Prestwood KM. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 September; 88(9): 4075-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12970264&dopt=Abstract

•

Effect of estrogen replacement therapy on parathyroid hormone secretion in elderly postmenopausal women. Author(s): Vincent A, Riggs BL, Atkinson EJ, Oberg AL, Khosla S. Source: Menopause (New York, N.Y.). 2003 March-April; 10(2): 165-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12627043&dopt=Abstract

•

Effect of ovariectomy on adipose tissue of mice in the absence of estrogen receptor alpha (ERalpha): a potential role for estrogen receptor beta (ERbeta). Author(s): Naaz A, Zakroczymski M, Heine P, Taylor J, Saunders P, Lubahn D, Cooke PS.

Alternative Medicine 175

Source: Hormone and Metabolic Research. Hormon- Und Stoffwechselforschung. Hormones Et Metabolisme. 2002 November-December; 34(11-12): 758-63. Erratum In: Horm Metab Res. 2003 April; 35(4): 271. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12660895&dopt=Abstract •

Effect of reproductive hormones and selective estrogen receptor modulators on mood during menopause. Author(s): Soares CN, Poitras JR, Prouty J. Source: Drugs & Aging. 2003; 20(2): 85-100. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12534310&dopt=Abstract

•

Effects of environmental estrogenic compounds on growth of a transplanted estrogen responsive pituitary tumor cell line in rats. Author(s): Fujimoto N, Honda H. Source: Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association. 2003 December; 41(12): 1711-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14563396&dopt=Abstract

•

Effects of estradiol, phytoestrogens, and Ginkgo biloba extracts against 1-methyl-4phenyl-pyridine-induced oxidative stress. Author(s): Gagne B, Gelinas S, Bureau G, Lagace B, Ramassamy C, Chiasson K, Valastro B, Martinoli MG. Source: Endocrine. 2003 June; 21(1): 89-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12777708&dopt=Abstract

•

Effects of extracts from Bangladeshi medicinal plants on in vitro proliferation of human breast cancer cell lines and expression of estrogen receptor alpha gene. Author(s): Lambertini E, Piva R, Khan MT, Lampronti I, Bianchi N, Borgatti M, Gambari R. Source: International Journal of Oncology. 2004 February; 24(2): 419-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14719119&dopt=Abstract

•

Effects of long-term administration of N-3 polyunsaturated fatty acids (PUFA) and selective estrogen receptor modulator (SERM) derivatives in ovariectomized (OVX) mice. Author(s): Zeitlin L, Segev E, Fried A, Wientroub S. Source: Journal of Cellular Biochemistry. 2003 October 1; 90(2): 347-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14505351&dopt=Abstract

•

Effects of long-term estrogen replacement therapy on articular cartilage IGFBP-2, IGFBP-3, collagen and proteoglycan levels in ovariectomized cynomolgus monkeys. Author(s): Ham KD, Oegema TR, Loeser RF, Carlson CS.

176

Estrogen

Source: Osteoarthritis and Cartilage / Oars, Osteoarthritis Research Society. 2004 February; 12(2): 160-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14723875&dopt=Abstract •

Effects of neonatal treatment with phytoestrogens, genistein and daidzein, on sex difference in female rat brain function: estrous cycle and lordosis. Author(s): Kouki T, Kishitake M, Okamoto M, Oosuka I, Takebe M, Yamanouchi K. Source: Hormones and Behavior. 2003 August; 44(2): 140-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13129486&dopt=Abstract

•

Effects of phytoestrogens on the trophoblast tumour cell lines BeWo and Jeg3. Author(s): Plessow D, Waldschlager J, Richter DU, Jeschke U, Bruer G, Briese V, Friese K. Source: Anticancer Res. 2003 March-April; 23(2A): 1081-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12820351&dopt=Abstract

•

Effects of the phytoestrogen genistein on the circulating soluble receptor activator of nuclear factor kappaB ligand-osteoprotegerin system in early postmenopausal women. Author(s): Crisafulli A, Altavilla D, Squadrito G, Romeo A, Adamo EB, Marini R, Inferrera MA, Marini H, Bitto A, D'Anna R, Corrado F, Bartolone S, Frisina N, Squadrito F. Source: The Journal of Clinical Endocrinology and Metabolism. 2004 January; 89(1): 18892. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14715848&dopt=Abstract

•

Effects of the phytoestrogens genistein and daidzein on BRCA2 tumor suppressor gene expression in breast cell lines. Author(s): Vissac-Sabatier C, Bignon YJ, Bernard-Gallon DJ. Source: Nutrition and Cancer. 2003; 45(2): 247-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12881020&dopt=Abstract

•

Estrogen agonists/antagonists may down-regulate growth hormone signaling in hepatocytes--an explanation for their impact on IGF-I, IGFBP-1, and lipoprotein(a). Author(s): McCarty MF. Source: Medical Hypotheses. 2003 September; 61(3): 335-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12944101&dopt=Abstract

•

Estrogen and insulin crosstalk: breast cancer risk implications. Author(s): McCance KL, Jones RE. Source: The Nurse Practitioner. 2003 May; 28(5): 12-23; Quiz 24-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12792265&dopt=Abstract

Alternative Medicine 177

•

Estrogen and phytoestrogen predispose to erectile dysfunction: do ER-alpha and ERbeta in the cavernosum play a role? Author(s): Srilatha B, Adaikan PG. Source: Urology. 2004 February; 63(2): 382-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14972507&dopt=Abstract

•

Estrogen bioactivity in fo-ti and other herbs used for their estrogen-like effects as determined by a recombinant cell bioassay. Author(s): Oerter Klein K, Janfaza M, Wong JA, Chang RJ. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 September; 88(9): 4077-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12970265&dopt=Abstract

•

Estrogen decreases biglycan mRNA expression in resistance blood vessels. Author(s): Rodrigo MC, Martin DS, Eyster KM. Source: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 2003 October; 285(4): R754-61. Epub 2003 June 26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12829444&dopt=Abstract

•

Estrogen deficiency symptom management in breast cancer survivors in the changing context of menopausal hormone therapy. Author(s): Chlebowski RT, Kim JA, Col NF. Source: Seminars in Oncology. 2003 December; 30(6): 776-88. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14663778&dopt=Abstract

•

Estrogen depletion increases blood pressure and hypothalamic norepinephrine in middle-aged spontaneously hypertensive rats. Author(s): Peng N, Clark JT, Wei CC, Wyss JM. Source: Hypertension. 2003 May; 41(5): 1164-7. Epub 2003 March 24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12654704&dopt=Abstract

•

Estrogen inhibits paclitaxel-induced apoptosis via the phosphorylation of apoptosis signal-regulating kinase 1 in human ovarian cancer cell lines. Author(s): Mabuchi S, Ohmichi M, Kimura A, Nishio Y, Arimoto-Ishida E, YadaHashimoto N, Tasaka K, Murata Y. Source: Endocrinology. 2004 January; 145(1): 49-58. Epub 2003 September 18. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14500571&dopt=Abstract

•

Estrogen receptor beta isoforms exhibit differences in ligand-activated transcriptional activity in an estrogen response element sequence-dependent manner. Author(s): Ramsey TL, Risinger KE, Jernigan SC, Mattingly KA, Klinge CM.

178

Estrogen

Source: Endocrinology. 2004 January; 145(1): 149-60. Epub 2003 September 18. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14500565&dopt=Abstract •

Estrogen receptor-dependent proteasomal degradation of the glucocorticoid receptor is coupled to an increase in mdm2 protein expression. Author(s): Kinyamu HK, Archer TK. Source: Molecular and Cellular Biology. 2003 August; 23(16): 5867-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12897156&dopt=Abstract

•

Estrogen receptor-mediated neuroprotection from oxidative stress requires activation of the mitogen-activated protein kinase pathway. Author(s): Mize AL, Shapiro RA, Dorsa DM. Source: Endocrinology. 2003 January; 144(1): 306-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12488359&dopt=Abstract

•

Estrogen response element-independent regulation of gene expression by genistein in intestinal cells. Author(s): Hua P, Tsai WJ, Kuo SM. Source: Biochimica Et Biophysica Acta. 2003 June 19; 1627(2-3): 63-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12818423&dopt=Abstract

•

Estrogenic activities of Ginkgo biloba extracts. Author(s): Oh SM, Chung KH. Source: Life Sciences. 2004 January 30; 74(11): 1325-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14706564&dopt=Abstract

•

Estrogenic activity in white and red wine extracts. Author(s): Klinge CM, Risinger KE, Watts MB, Beck V, Eder R, Jungbauer A. Source: Journal of Agricultural and Food Chemistry. 2003 March 26; 51(7): 1850-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12643641&dopt=Abstract

•

Estrogenic activity of phenylpropanoids from Sarcomelicope megistophylla and structure determination of a new norneolignan. Author(s): Fokialakis N, Magiatis P, Mitaku S, Pratsinis H, Tillequin F. Source: Planta Medica. 2003 June; 69(6): 566-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12865982&dopt=Abstract

•

Estrogenic and antiproliferative activities of isoliquiritigenin in MCF7 breast cancer cells. Author(s): Maggiolini M, Statti G, Vivacqua A, Gabriele S, Rago V, Loizzo M, Menichini F, Amdo S.

Alternative Medicine 179

Source: The Journal of Steroid Biochemistry and Molecular Biology. 2002 November; 82(4-5): 315-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12589938&dopt=Abstract •

Estrogenic compounds suppressed interferon-gamma production in mouse splenocytes through direct cell-cell interaction. Author(s): Nakaya M, Yamasaki M, Miyazaki Y, Tachibana H, Yamada K. Source: In Vitro Cellular & Developmental Biology. Animal. 2003 September [epub Ahead of Print] http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14602042&dopt=Abstract

•

Estrogenic effects of apigenin, kaempferol and bisphenol A in immature Wistar female rats and in MCF-7 cells. Author(s): Stroheker T, Pinnert MF, Picard K, Chagnon MC, Canivenc-Lavier MC. Source: Iarc Sci Publ. 2002; 156: 413-4. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12489529&dopt=Abstract

•

Estrogenic Effects of Cimicifuga racemosa (Black Cohosh) in Mice and on Estrogen Receptors in MCF-7 Cells. Author(s): Liu ZP, Yu B, Huo JS, Lu CQ, Chen JS. Source: Journal of Medicinal Food. 2001 Autumn; 4(3): 171-178. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12639411&dopt=Abstract

•

Estrogenic/antiestrogenic activity of homoisoflavonoids from bulbs of Muscari racemosum (L.) Miller. Author(s): Urbancikova M, Masterova I, Toth J. Source: Fitoterapia. 2002 December; 73(7-8): 724-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12490242&dopt=Abstract

•

Estrogenicity of solid phase-extracted water samples from two municipal sewage treatment plant effluents and river Rhine water using the yeast estrogen screen. Author(s): Pawlowski S, Ternes TA, Bonerz M, Rastall AC, Erdinger L, Braunbeck T. Source: Toxicology in Vitro : an International Journal Published in Association with Bibra. 2004 February; 18(1): 129-38. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14630071&dopt=Abstract

•

Estrogens activate bone morphogenetic protein-2 gene transcription in mouse mesenchymal stem cells. Author(s): Zhou S, Turgeman G, Harris SE, Leitman DC, Komm BS, Bodine PV, Gazit D. Source: Molecular Endocrinology (Baltimore, Md.). 2003 January; 17(1): 56-66. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12511606&dopt=Abstract

180

Estrogen

•

Estrogens and anti-estrogens: Key mediators of prostate carcinogenesis and new therapeutic candidates. Author(s): Ho SM. Source: Journal of Cellular Biochemistry. 2004 February 15; 91(3): 491-503. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14755680&dopt=Abstract

•

Estrogens and Parkinson disease: novel approach for neuroprotection. Author(s): Sawada H, Shimohama S. Source: Endocrine. 2003 June; 21(1): 77-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12777706&dopt=Abstract

•

Estrogens and phytoestrogens: brain plasticity of sexually dimorphic brain volumes. Author(s): Lephart ED, Rhees RW, Setchell KD, Bu LH, Lund TD. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 June; 85(2-5): 299-309. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12943716&dopt=Abstract

•

Estrogens inhibit l-glutamate uptake activity of astrocytes via membrane estrogen receptor alpha. Author(s): Sato K, Matsuki N, Ohno Y, Nakazawa K. Source: Journal of Neurochemistry. 2003 September; 86(6): 1498-505. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12950458&dopt=Abstract

•

Evaluation of the estrogenic effects of legume extracts containing phytoestrogens. Author(s): Boue SM, Wiese TE, Nehls S, Burow ME, Elliott S, Carter-Wientjes CH, Shih BY, McLachlan JA, Cleveland TE. Source: Journal of Agricultural and Food Chemistry. 2003 April 9; 51(8): 2193-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12670155&dopt=Abstract

•

Evidence for estrogen receptor beta-selective activity of Vitex agnus-castus and isolated flavones. Author(s): Jarry H, Spengler B, Porzel A, Schmidt J, Wuttke W, Christoffel V. Source: Planta Medica. 2003 October; 69(10): 945-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14648399&dopt=Abstract

•

Evidence for selective estrogen receptor modulator activity in a black cohosh (Cimicifuga racemosa) extract: comparison with estradiol-17beta. Author(s): Seidlova-Wuttke D, Hesse O, Jarry H, Christoffel V, Spengler B, Becker T, Wuttke W. Source: European Journal of Endocrinology / European Federation of Endocrine Societies. 2003 October; 149(4): 351-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14514351&dopt=Abstract

Alternative Medicine 181

•

Evidence of a lack of effect of a phytoestrogen regimen on the levels of C-reactive protein, E-selectin, and nitrate in postmenopausal women. Author(s): Nikander E, Metsa-Heikkila M, Tiitinen A, Ylikorkala O. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 November; 88(11): 5180-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14602747&dopt=Abstract

•

Evidence that estrogen receptor alpha, but not beta, mediates seasonal changes in the response of the ovine retrochiasmatic area to estradiol. Author(s): Hardy SL, Anderson GM, Valent M, Connors JM, Goodman RL. Source: Biology of Reproduction. 2003 March; 68(3): 846-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12604634&dopt=Abstract

•

Female gender, estrogen loss, and Sub-RPE deposit formation in aged mice. Author(s): Cousins SW, Marin-Castano ME, Espinosa-Heidmann DG, Alexandridou A, Striker L, Elliot S. Source: Investigative Ophthalmology & Visual Science. 2003 March; 44(3): 1221-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12601052&dopt=Abstract

•

Flavone and isoflavone phytoestrogens are agonists of estrogen-related receptors. Author(s): Suetsugi M, Su L, Karlsberg K, Yuan YC, Chen S. Source: Molecular Cancer Research : Mcr. 2003 November; 1(13): 981-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14638870&dopt=Abstract

•

Food sources of phyto-oestrogens and their precursors in Europe. Author(s): Fletcher RJ. Source: The British Journal of Nutrition. 2003 June; 89 Suppl 1: S39-43. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12725655&dopt=Abstract

•

Ginsenoside-Rb1 acts as a weak phytoestrogen in MCF-7 human breast cancer cells. Author(s): Lee YJ, Jin YR, Lim WC, Park WK, Cho JY, Jang S, Lee SK. Source: Arch Pharm Res. 2003 January; 26(1): 58-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12568360&dopt=Abstract

•

Guidelines for using in vitro methods to study the effects of phyto-oestrogens on bone. Author(s): Lieberherr M, Cournot G, Robins SP. Source: The British Journal of Nutrition. 2003 June; 89 Suppl 1: S59-73. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12725651&dopt=Abstract

•

Heregulin-beta1 regulates the estrogen receptor-alpha gene expression and activity via the ErbB2/PI 3-K/Akt pathway.

182

Estrogen

Author(s): Stoica GE, Franke TF, Wellstein A, Morgan E, Czubayko F, List HJ, Reiter R, Martin MB, Stoica A. Source: Oncogene. 2003 April 10; 22(14): 2073-87. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12687010&dopt=Abstract •

High isoflavone content and estrogenic activity of 25 year-old Glycine max tissue cultures. Author(s): Federici E, Touche A, Choquart S, Avanti O, Fay L, Offord E, Courtois D. Source: Phytochemistry. 2003 October; 64(3): 717-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13679094&dopt=Abstract

•

Identification and characterization of a phytoestrogen-specific gene from the MCF-7 human breast cancer cell. Author(s): Ramanathan L, Gray WG. Source: Toxicology and Applied Pharmacology. 2003 September 1; 191(2): 107-17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12946647&dopt=Abstract

•

Identification of phytoestrogens in bovine milk using liquid chromatography/electrospray tandem mass spectrometry. Author(s): Antignac JP, Cariou R, Le Bizec B, Cravedi JP, Andre F. Source: Rapid Communications in Mass Spectrometry : Rcm. 2003; 17(12): 1256-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12811748&dopt=Abstract

•

Immunohistochemical expression of steroid receptors and glycodelin A in isolated proliferative human endometrial glandular cells after stimulation with tamoxifen and phytoestrogens (genistein and daidzein). Author(s): Mylonas I, Jeschke U, Makovitzky J, Winkler L, Richter DU, Friese K, Briese V. Source: Anticancer Res. 2003 March-April; 23(2A): 1119-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12820358&dopt=Abstract

•

Impact of the nuclear receptor coactivator AIB1 isoform AIB1-Delta3 on estrogenic ligands with different intrinsic activity. Author(s): Reiter R, Oh AS, Wellstein A, Riegel AT. Source: Oncogene. 2004 January 15; 23(2): 403-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14691461&dopt=Abstract

•

In vitro and in vivo regulation of antioxidant response element-dependent gene expression by estrogens. Author(s): Ansell PJ, Espinosa-Nicholas C, Curran EM, Judy BM, Philips BJ, Hannink M, Lubahn DB.

Alternative Medicine 183

Source: Endocrinology. 2004 January; 145(1): 311-7. Epub 2003 October 09. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14551226&dopt=Abstract •

In vitro effects of genistein on the synthesis and distribution of glycosaminoglycans/proteoglycans by estrogen receptor-positive and -negative human breast cancer epithelial cells. Author(s): Mitropoulou TN, Tzanakakis GN, Nikitovic D, Tsatsakis A, Karamanos NK. Source: Anticancer Res. 2002 September-October; 22(5): 2841-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12530007&dopt=Abstract

•

Indole-3-carbinol is a negative regulator of estrogen. Author(s): Auborn KJ, Fan S, Rosen EM, Goodwin L, Chandraskaren A, Williams DE, Chen D, Carter TH. Source: The Journal of Nutrition. 2003 July; 133(7 Suppl): 2470S-2475S. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12840226&dopt=Abstract

•

Induction of apoptosis in estrogen dependent and independent breast cancer cells by the marine terpenoid dehydrothyrsiferol. Author(s): Pec MK, Aguirre A, Moser-Thier K, Fernandez JJ, Souto ML, Dorta J, DiazGonzalez F, Villar J. Source: Biochemical Pharmacology. 2003 May 1; 65(9): 1451-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12732357&dopt=Abstract

•

Induction of vitellogenin synthesis in an Atlantic salmon (Salmo salar) hepatocyte culture: a sensitive in vitro bioassay for the oestrogenic and anti-oestrogenic activity of chemicals. Author(s): Tollefsen KE, Mathisen R, Stenersen J. Source: Biomarkers : Biochemical Indicators of Exposure, Response, and Susceptibility to Chemicals. 2003 September-October; 8(5): 394-407. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14602523&dopt=Abstract

•

Inhibition of estrogen receptor alpha expression and function in MCF-7 cells by kaempferol. Author(s): Hung H. Source: Journal of Cellular Physiology. 2004 February; 198(2): 197-208. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14603522&dopt=Abstract

•

Inhibition of proliferation and estrogen receptor signaling by peroxisome proliferator-activated receptor gamma ligands in uterine leiomyoma. Author(s): Houston KD, Copland JA, Broaddus RR, Gottardis MM, Fischer SM, Walker CL.

184

Estrogen

Source: Cancer Research. 2003 March 15; 63(6): 1221-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12649180&dopt=Abstract •

Inhibitory action of ICI-182,780, an estrogen receptor antagonist, on BK(Ca) channel activity in cultured endothelial cells of human coronary artery. Author(s): Liu YC, Lo YC, Huang CW, Wu SN. Source: Biochemical Pharmacology. 2003 November 15; 66(10): 2053-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14599564&dopt=Abstract

•

Interaction of some traditional plant extracts with uterine oestrogen or progestin receptors. Author(s): Benie T, Thieulant ML. Source: Phytotherapy Research : Ptr. 2003 August; 17(7): 756-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12916073&dopt=Abstract

•

Interactions of phytoestrogens with estrogen receptors alpha and beta (III). Estrogenic activities of soy isoflavone aglycones and their metabolites isolated from human urine. Author(s): Kinjo J, Tsuchihashi R, Morito K, Hirose T, Aomori T, Nagao T, Okabe H, Nohara T, Masamune Y. Source: Biological & Pharmaceutical Bulletin. 2004 February; 27(2): 185-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14758030&dopt=Abstract

•

Investigating the role of natural phyto-oestrogens on bone health in postmenopausal women. Author(s): Valtuena S, Cashman K, Robins SP, Cassidy A, Kardinaal A, Branca F. Source: The British Journal of Nutrition. 2003 June; 89 Suppl 1: S87-99. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12725658&dopt=Abstract

•

Is black cohosh estrogenic? Author(s): Mahady GB. Source: Nutrition Reviews. 2003 May; 61(5 Pt 1): 183-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12822708&dopt=Abstract

•

Is there a role for estrogens in the maintenance of men's health? Author(s): Oettel M. Source: The Aging Male : the Official Journal of the International Society for the Study of the Aging Male. 2002 December; 5(4): 248-57. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12630073&dopt=Abstract

•

Isoflavonoid and lignan phytoestrogens as dietary biomarkers. Author(s): Lampe JW.

Alternative Medicine 185

Source: The Journal of Nutrition. 2003 March; 133 Suppl 3: 956S-964S. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12612182&dopt=Abstract •

Isolation of linoleic acid as an estrogenic compound from the fruits of Vitex agnuscastus L. (chaste-berry). Author(s): Liu J, Burdette JE, Sun Y, Deng S, Schlecht SM, Zheng W, Nikolic D, Mahady G, van Breemen RB, Fong HH, Pezzuto JM, Bolton JL, Farnsworth NR. Source: Phytomedicine : International Journal of Phytotherapy and Phytopharmacology. 2004 January; 11(1): 18-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14974442&dopt=Abstract

•

Lack of dose-responsive effect of dietary phyto-oestrogens on transepithelial calcium transport in human intestinal-like Caco-2 cells. Author(s): Cotter AA, Cashman KD. Source: The British Journal of Nutrition. 2004 January; 91(1): 5-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14748934&dopt=Abstract

•

Ligands differentially modulate the protein interactions of the human estrogen receptors alpha and beta. Author(s): Margeat E, Bourdoncle A, Margueron R, Poujol N, Cavailles V, Royer C. Source: Journal of Molecular Biology. 2003 February 7; 326(1): 77-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12547192&dopt=Abstract

•

Mechanism of estrogen-mediated neuroprotection: regulation of mitochondrial calcium and Bcl-2 expression. Author(s): Nilsen J, Diaz Brinton R. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 March 4; 100(5): 2842-7. Epub 2003 February 25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12604781&dopt=Abstract

•

Multifactorial activities of nonsteroidal antiestrogens against leukemia. Author(s): Hayon T, Atlas L, Levy E, Dvilansky A, Shpilberg O, Nathan I. Source: Cancer Detection and Prevention. 2003; 27(5): 389-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14585326&dopt=Abstract

•

Novel stimulatory actions of the phytoestrogen genistein: effects on the gain of cardiac excitation-contraction coupling. Author(s): Liew R, Macleod KT, Collins P. Source: The Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology. 2003 July; 17(10): 1307-9. Epub 2003 May 20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12759336&dopt=Abstract

186

Estrogen

•

Oestrogen receptor-beta and neurohypophysial hormones: functional interaction and neuroanatomical localisation. Author(s): Forsling ML, Kallo I, Hartley DE, Heinze L, Ladek R, Coen CW, File SE. Source: Pharmacology, Biochemistry, and Behavior. 2003 December; 76(3-4): 535-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14643853&dopt=Abstract

•

Oestrogen-androgen crosstalk in the pathophysiology of erectile dysfunction. Author(s): Srilatha B, Adaikan PG. Source: Asian Journal of Andrology. 2003 December; 5(4): 307-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14695981&dopt=Abstract

•

Oestrogenic compounds and oxidative stress (in human sperm and lymphocytes in the Comet assay). Author(s): Anderson D, Schmid TE, Baumgartner A, Cemeli-Carratala E, Brinkworth MH, Wood JM. Source: Mutation Research. 2003 November; 544(2-3): 173-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14644319&dopt=Abstract

•

Oestrogens and selective oestrogen receptor (ER) modulators regulate EGF receptor gene expression through human ER alpha and beta subtypes via an Sp1 site. Author(s): Salvatori L, Pallante P, Ravenna L, Chinzari P, Frati L, Russo MA, Petrangeli E. Source: Oncogene. 2003 July 31; 22(31): 4875-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12894229&dopt=Abstract

•

Phytoestrogen genistein acts as an estrogen agonist on human osteoblastic cells through estrogen receptors alpha and beta. Author(s): Rickard DJ, Monroe DG, Ruesink TJ, Khosla S, Riggs BL, Spelsberg TC. Source: Journal of Cellular Biochemistry. 2003 June 1; 89(3): 633-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12761896&dopt=Abstract

•

Phytoestrogen intake and endometrial cancer risk. Author(s): Horn-Ross PL, John EM, Canchola AJ, Stewart SL, Lee MM. Source: Journal of the National Cancer Institute. 2003 August 6; 95(15): 1158-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12902445&dopt=Abstract

•

Phytoestrogen regulation of a Vitamin D3 receptor promoter and 1,25dihydroxyvitamin D3 actions in human breast cancer cells. Author(s): Wietzke JA, Welsh J. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 February; 84(23): 149-57. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12710998&dopt=Abstract

Alternative Medicine 187

•

Phytoestrogen supplement use by women. Author(s): Kurzer MS. Source: The Journal of Nutrition. 2003 June; 133(6): 1983S-1986S. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12771350&dopt=Abstract

•

Phytoestrogen supplements for the treatment of hot flashes: the Isoflavone Clover Extract (ICE) Study: a randomized controlled trial. Author(s): Tice JA, Ettinger B, Ensrud K, Wallace R, Blackwell T, Cummings SR. Source: Jama : the Journal of the American Medical Association. 2003 July 9; 290(2): 20714. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12851275&dopt=Abstract

•

Phytoestrogens and 17beta-estradiol influence vitamin D metabolism and receptor expression-relevance for colon cancer prevention. Author(s): Lechner D, Cross HS. Source: Recent Results Cancer Res. 2003; 164: 379-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12899537&dopt=Abstract

•

Phytoestrogens and breast cancer prevention: what is the evidence? Author(s): Mishra SI, Dickerson V, Najm W. Source: American Journal of Obstetrics and Gynecology. 2003 May; 188(5 Suppl): S66-70. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12748453&dopt=Abstract

•

Phytoestrogens and breast cancer risk. Review of the epidemiological evidence. Author(s): Peeters PH, Keinan-Boker L, van der Schouw YT, Grobbee DE. Source: Breast Cancer Research and Treatment. 2003 January; 77(2): 171-83. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12602916&dopt=Abstract

•

Phytoestrogens and breast cancer risk: review of the epidemiological evidence. Author(s): Peeters PH, Keinan-Boker L, van der Schouw YT, Grobbee DE. Source: Iarc Sci Publ. 2002; 156: 331-6. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12484200&dopt=Abstract

•

Phytoestrogens and breast cancer. Author(s): Adlercreutz H. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2002 December; 83(1-5): 113-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12650707&dopt=Abstract

•

Phytoestrogens and breast cancer. Author(s): Ziegler RG.

188

Estrogen

Source: The American Journal of Clinical Nutrition. 2004 February; 79(2): 183-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14749221&dopt=Abstract •

Phytoestrogens and prostate cancer. Author(s): Morrissey C, Watson RW. Source: Current Drug Targets. 2003 April; 4(3): 231-41. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12643473&dopt=Abstract

•

Phytoestrogens for hormone replacement therapy? Author(s): Wuttke W, Jarry H, Westphalen S, Christoffel V, Seidlova-Wuttke D. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2002 December; 83(1-5): 133-47. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12650710&dopt=Abstract

•

Phytoestrogens increase the capacity of serum to stimulate prostacyclin release in human endothelial cells. Author(s): Garcia-Martinez MC, Hermenegildo C, Tarin JJ, Cano A. Source: Acta Obstetricia Et Gynecologica Scandinavica. 2003 August; 82(8): 705-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12848640&dopt=Abstract

•

Phytoestrogens inhibit aromatase but not 17beta-hydroxysteroid dehydrogenase (HSD) type 1 in human granulosa-luteal cells: evidence for FSH induction of 17betaHSD. Author(s): Whitehead SA, Lacey M. Source: Human Reproduction (Oxford, England). 2003 March; 18(3): 487-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12615812&dopt=Abstract

•

Phytoestrogens modulate binding response of estrogen receptors alpha and beta to the estrogen response element. Author(s): Kostelac D, Rechkemmer G, Briviba K. Source: Journal of Agricultural and Food Chemistry. 2003 December 17; 51(26): 7632-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14664520&dopt=Abstract

•

Phytoestrogens. Author(s): Cabot W. Source: J Am Acad Orthop Surg. 2003 May-June; 11(3): 153-6. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12828444&dopt=Abstract

•

Phytoestrogens: a review of the present state of research. Author(s): Ososki AL, Kennelly EJ.

Alternative Medicine 189

Source: Phytotherapy Research : Ptr. 2003 September; 17(8): 845-69. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13680814&dopt=Abstract •

Phytoestrogens: endocrine disrupters or replacement for hormone replacement therapy? Author(s): Wuttke W, Jarry H, Becker T, Schultens A, Christoffel V, Gorkow C, SeidlovaWuttke D. Source: Maturitas. 2003 March 14; 44 Suppl 1: S9-20. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12609555&dopt=Abstract

•

Phytoestrogens: pharmacological and therapeutic perspectives. Author(s): Bolego C, Poli A, Cignarella A, Paoletti R. Source: Current Drug Targets. 2003 January; 4(1): 77-87. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12528992&dopt=Abstract

•

Phytoestrogens: potential benefits and implications for breast cancer survivors. Author(s): Duffy C, Cyr M. Source: Journal of Women's Health (2002). 2003 September; 12(7): 617-31. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14583103&dopt=Abstract

•

Phytoestrogens: recent developments. Author(s): Cos P, De Bruyne T, Apers S, Vanden Berghe D, Pieters L, Vlietinck AJ. Source: Planta Medica. 2003 July; 69(7): 589-99. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12898412&dopt=Abstract

•

Phytoestrogens--mechanism of action and effect on bone markers and bone mineral density. Author(s): Fitzpatrick LA. Source: Endocrinology and Metabolism Clinics of North America. 2003 March; 32(1): 233-52, Viii. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12699301&dopt=Abstract

•

Phyto-oestrogen database of foods and average intake in Finland. Author(s): Valsta LM, Kilkkinen A, Mazur W, Nurmi T, Lampi AM, Ovaskainen ML, Korhonen T, Adlercreutz H, Pietinen P. Source: The British Journal of Nutrition. 2003 June; 89 Suppl 1: S31-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12725654&dopt=Abstract

•

Phyto-oestrogen levels in foods: the design and construction of the VENUS database. Author(s): Kiely M, Faughnan M, Wahala K, Brants H, Mulligan A.

190

Estrogen

Source: The British Journal of Nutrition. 2003 June; 89 Suppl 1: S19-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12725652&dopt=Abstract •

Phyto-oestrogens and osteoporosis: what is a safe dose? Author(s): Barnes S. Source: The British Journal of Nutrition. 2003 June; 89 Suppl 1: S101-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12725659&dopt=Abstract

•

Potential risks and benefits of phytoestrogen-rich diets. Author(s): Cassidy A. Source: Int J Vitam Nutr Res. 2003 March; 73(2): 120-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12747219&dopt=Abstract

•

Potential risks of phytoestrogens: experience from animal models. Author(s): Davies HL. Source: Climacteric : the Journal of the International Menopause Society. 2003 March; 6(1): 81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12725668&dopt=Abstract

•

Prediction of ligand binding affinity and orientation of xenoestrogens to the estrogen receptor by molecular dynamics simulations and the linear interaction energy method. Author(s): van Lipzig MM, ter Laak AM, Jongejan A, Vermeulen NP, Wamelink M, Geerke D, Meerman JH. Source: Journal of Medicinal Chemistry. 2004 February 12; 47(4): 1018-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14761204&dopt=Abstract

•

Prenatal exposure to estrogenic compounds alters the expression pattern of plateletderived growth factor receptors alpha and beta in neonatal rat testis: identification of gonocytes as targets of estrogen exposure. Author(s): Thuillier R, Wang Y, Culty M. Source: Biology of Reproduction. 2003 March; 68(3): 867-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12604637&dopt=Abstract

•

Prevention of osteopaenia by phyto-oestrogens: animal studies. Author(s): Coxam V. Source: The British Journal of Nutrition. 2003 June; 89 Suppl 1: S75-85. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12725657&dopt=Abstract

•

Problems for risk assessment of endocrine-active estrogenic compounds. Author(s): Safe SH, Pallaroni L, Yoon K, Gaido K, Ross S, McDonnell D.

Alternative Medicine 191

Source: Environmental Health Perspectives. 2002 December; 110 Suppl 6: 925-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12634121&dopt=Abstract •

Quantitation of soy-derived phytoestrogens in human breast tissue and biological fluids by high-performance liquid chromatography. Author(s): Maubach J, Bracke ME, Heyerick A, Depypere HT, Serreyn RF, Mareel MM, De Keukeleire D. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 January 25; 784(1): 137-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12504192&dopt=Abstract

•

Quantitative structure-activity relationships for estrogen receptor binding affinity of phenolic chemicals. Author(s): Hu JY, Aizawa T. Source: Water Research. 2003 March; 37(6): 1213-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12598185&dopt=Abstract

•

Quercetin, a phytoestrogen and dietary flavonoid, activates different membranebound guanylate cyclase isoforms in LLC-PK1 and PC12 cells. Author(s): Chen ZJ, Vetter M, Chang GD, Liu S, Chang CH. Source: The Journal of Pharmacy and Pharmacology. 2003 March; 55(3): 353-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12724041&dopt=Abstract

•

Rapid dereplication of estrogenic compounds in pomegranate (Punica granatum) using on-line biochemical detection coupled to mass spectrometry. Author(s): van Elswijk DA, Schobel UP, Lansky EP, Irth H, van der Greef J. Source: Phytochemistry. 2004 January; 65(2): 233-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14732284&dopt=Abstract

•

Recent advances in the development of phytoestrogens and derivatives: an update of the promising perspectives in the prevention of postmenopausal diseases. Author(s): Jacquot Y, Rojas C, Refouvelet B, Robert JF, Leclercq G, Xicluna A. Source: Mini Reviews in Medicinal Chemistry. 2003 August; 3(5): 387-400. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12769692&dopt=Abstract

•

Recombinant human estrogen, androgen and progesterone receptors for detection of potential endocrine disruptors. Author(s): Scippo ML, Argiris C, Van De Weerdt C, Muller M, Willemsen P, Martial J, Maghuin-Rogister G. Source: Analytical and Bioanalytical Chemistry. 2004 February; 378(3): 664-9. Epub 2003 October 25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14579009&dopt=Abstract

192

Estrogen

•

Regulation of apoA-I gene expression: mechanism of action of estrogen and genistein. Author(s): Lamon-Fava S, Micherone D. Source: Journal of Lipid Research. 2004 January; 45(1): 106-12. Epub 2003 October 16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14563824&dopt=Abstract

•

Requirement of metabolic activation for estrogenic activity of Pueraria mirifica. Author(s): Lee YS, Park JS, Cho SD, Son JK, Cherdshewasart W, Kang KS. Source: Journal of Veterinary Science (Suwon-Si, Korea). 2002 December; 3(4): 273-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12819377&dopt=Abstract

•

Resveratrol activates adenylyl-cyclase in human breast cancer cells: a novel, estrogen receptor-independent cytostatic mechanism. Author(s): El-Mowafy AM, Alkhalaf M. Source: Carcinogenesis. 2003 May; 24(5): 869-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12771030&dopt=Abstract

•

Resveratrol acts as an estrogen receptor (ER) agonist in breast cancer cells stably transfected with ER alpha. Author(s): Levenson AS, Gehm BD, Pearce ST, Horiguchi J, Simons LA, Ward JE 3rd, Jameson JL, Jordan VC. Source: International Journal of Cancer. Journal International Du Cancer. 2003 May 1; 104(5): 587-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12594813&dopt=Abstract

•

Significance of oestrogens in male (patho)physiology. Author(s): Gooren LJ, Toorians AW. Source: Annales D'endocrinologie. 2003 April; 64(2): 126-35. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12773948&dopt=Abstract

•

Silymarin is a selective estrogen receptor beta (ERbeta) agonist and has estrogenic effects in the metaphysis of the femur but no or antiestrogenic effects in the uterus of ovariectomized (ovx) rats. Author(s): Seidlova-Wuttke D, Becker T, Christoffel V, Jarry H, Wuttke W. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 August; 86(2): 179-88. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14568570&dopt=Abstract

•

Soy consumption and phytoestrogens: effect on serum prostate specific antigen when blood lipids and oxidized low-density lipoprotein are reduced in hyperlipidemic men. Author(s): Jenkins DJ, Kendall CW, D'Costa MA, Jackson CJ, Vidgen E, Singer W, Silverman JA, Koumbridis G, Honey J, Rao AV, Fleshner N, Klotz L.

Alternative Medicine 193

Source: The Journal of Urology. 2003 February; 169(2): 507-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12544298&dopt=Abstract •

Soy infant formula and phytoestrogens. Author(s): Tuohy PG. Source: Journal of Paediatrics and Child Health. 2003 August; 39(6): 401-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12919490&dopt=Abstract

•

Soy phytoestrogens do not prevent bone loss in postmenopausal monkeys. Author(s): Register TC, Jayo MJ, Anthony MS. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 September; 88(9): 4362-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12970311&dopt=Abstract

•

Soy protein and isoflavone effects on vasomotor symptoms in peri- and postmenopausal women: the Soy Estrogen Alternative Study. Author(s): Burke GL, Legault C, Anthony M, Bland DR, Morgan TM, Naughton MJ, Leggett K, Washburn SA, Vitolins MZ. Source: Menopause (New York, N.Y.). 2003 March-April; 10(2): 147-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12627040&dopt=Abstract

•

Soya phytoestrogens change cortical and hippocampal expression of BDNF mRNA in male rats. Author(s): File SE, Hartley DE, Alom N, Rattray M. Source: Neuroscience Letters. 2003 February 27; 338(2): 135-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12566171&dopt=Abstract

•

Soy-based formulas and phyto-oestrogens: a safety profile. Author(s): Miniello VL, Moro GE, Tarantino M, Natile M, Granieri L, Armenio L. Source: Acta Paediatrica (Oslo, Norway : 1992). Supplement. 2003 September; 91(441): 93-100. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14599051&dopt=Abstract

•

Stimulation of alkaline phosphatase activity in Ishikawa cells induced by various phytoestrogens and synthetic estrogens. Author(s): Wober J, Weisswange I, Vollmer G. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2002 December; 83(1-5): 227-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12650720&dopt=Abstract

•

Stress (hypothalamic-pituitary-adrenal axis) and pain response in male rats exposed lifelong to high vs. low phytoestrogen diets. Author(s): Lephart ED, Galindo E, Bu LH.

194

Estrogen

Source: Neuroscience Letters. 2003 May 15; 342(1-2): 65-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12727319&dopt=Abstract •

Study on interactions of endocrine disruptors with estrogen receptor using fluorescence polarization. Author(s): Ohno K, Suzuki S, Fukushima T, Maeda M, Santa T, Imai K. Source: The Analyst. 2003 August; 128(8): 1091-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12964612&dopt=Abstract

•

Study on interactions of endocrine disruptors with estrogen receptor-beta using fluorescence polarization. Author(s): Suzuki S, Ohno K, Santa T, Imai K. Source: Anal Sci. 2003 August; 19(8): 1103-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12945660&dopt=Abstract

•

Supplementation with flaxseed alters estrogen metabolism in postmenopausal women to a greater extent than does supplementation with an equal amount of soy. Author(s): Brooks JD, Ward WE, Lewis JE, Hilditch J, Nickell L, Wong E, Thompson LU. Source: The American Journal of Clinical Nutrition. 2004 February; 79(2): 318-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14749240&dopt=Abstract

•

Suppression of estrogen biosynthesis by procyanidin dimers in red wine and grape seeds. Author(s): Eng ET, Ye J, Williams D, Phung S, Moore RE, Young MK, Gruntmanis U, Braunstein G, Chen S. Source: Cancer Research. 2003 December 1; 63(23): 8516-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14679019&dopt=Abstract

•

Synthesis and estrogen receptor binding affinities of 7-hydroxy-3-(4-hydroxyphenyl)4H-1-benzopyran-4-ones containing a basic side chain. Author(s): Kim YW, Mobley JA, Brueggemeier RW. Source: Bioorganic & Medicinal Chemistry Letters. 2003 April 17; 13(8): 1475-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12668015&dopt=Abstract

•

The aryl hydrocarbon receptor mediates degradation of estrogen receptor alpha through activation of proteasomes. Author(s): Wormke M, Stoner M, Saville B, Walker K, Abdelrahim M, Burghardt R, Safe S. Source: Molecular and Cellular Biology. 2003 March; 23(6): 1843-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12612060&dopt=Abstract

Alternative Medicine 195

•

The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a double-blind placebo-controlled study: effects on menopause symptoms and bone markers. Author(s): Wuttke W, Seidlova-Wuttke D, Gorkow C. Source: Maturitas. 2003 March 14; 44 Suppl 1: S67-77. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12609561&dopt=Abstract

•

The effect of oestrogen and dietary phyto-oestrogens on transepithelial calcium transport in human intestinal-like Caco-2 cells. Author(s): Cotter AA, Jewell C, Cashman KD. Source: The British Journal of Nutrition. 2003 June; 89(6): 755-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12828792&dopt=Abstract

•

The effects of 2-substituted oestrogen sulphamates on the growth of prostate and ovarian cancer cells. Author(s): Day JM, Newman SP, Comninos A, Solomon C, Purohit A, Leese MP, Potter BV, Reed MJ. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 February; 84(23): 317-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12711018&dopt=Abstract

•

The effects of genistein on the synthesis and distribution of glycosaminoglycans/proteoglycans by two osteosarcoma cell lines depends on tyrosine kinase and the estrogen receptor density. Author(s): Nikitovic D, Tsatsakis AM, Karamanos NK, Tzanakakis GN. Source: Anticancer Res. 2003 January-February; 23(1A): 459-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12680249&dopt=Abstract

•

The effects of phytoestrogenic isoflavones on the formation and disposition of paracetamol sulfate in the isolated perfused rat liver. Author(s): Lucas AN, Nation RL, Milne RW, Reynolds GD, Evans AM. Source: The Journal of Pharmacy and Pharmacology. 2003 May; 55(5): 639-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12831506&dopt=Abstract

•

The effects of the phytoestrogen, coumestrol, on gonadotropin-releasing hormone (GnRH) mRNA expression in GT1-7 GnRH neurones. Author(s): Bowe J, Li XF, Sugden D, Katzenellenbogen JA, Katzenellenbogen BS, O'Byrne KT. Source: Journal of Neuroendocrinology. 2003 February; 15(2): 105-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12535152&dopt=Abstract

•

The homeopathic approach to the treatment of symptoms of oestrogen withdrawal in breast cancer patients. A prospective observational study. Author(s): Thompson EA, Reilly D.

196

Estrogen

Source: Homeopathy. 2003 July; 92(3): 131-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12884894&dopt=Abstract •

The immune system of geriatric mice is modulated by estrogenic endocrine disruptors (diethylstilbestrol, alpha-zearalanol, and genistein): effects on interferongamma. Author(s): Calemine J, Zalenka J, Karpuzoglu-Sahin E, Ward DL, Lengi A, Ahmed SA. Source: Toxicology. 2003 December 15; 194(1-2): 115-28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14636701&dopt=Abstract

•

The inhibitory effects of flavonoids and antiestrogens on the Glut1 glucose transporter in human erythrocytes. Author(s): Martin HJ, Kornmann F, Fuhrmann GF. Source: Chemico-Biological Interactions. 2003 December 15; 146(3): 225-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14642735&dopt=Abstract

•

The OECD program to validate the rat uterotrophic bioassay. Phase 2: dietary phytoestrogen analyses. Author(s): Owens W, Ashby J, Odum J, Onyon L. Source: Environmental Health Perspectives. 2003 September; 111(12): 1559-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12948898&dopt=Abstract

•

The phytoestrogen equol increases nitric oxide availability by inhibiting superoxide production: an antioxidant mechanism for cell-mediated LDL modification. Author(s): Hwang J, Wang J, Morazzoni P, Hodis HN, Sevanian A. Source: Free Radical Biology & Medicine. 2003 May 15; 34(10): 1271-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12726915&dopt=Abstract

•

The phytoestrogen genistein enhances osteogenesis and represses adipogenic differentiation of human primary bone marrow stromal cells. Author(s): Heim M, Frank O, Kampmann G, Sochocky N, Pennimpede T, Fuchs P, Hunziker W, Weber P, Martin I, Bendik I. Source: Endocrinology. 2004 February; 145(2): 848-59. Epub 2003 November 06. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14605006&dopt=Abstract

•

The phytoestrogen genistein suppresses cell-mediated immunity in mice. Author(s): Yellayi S, Zakroczymski MA, Selvaraj V, Valli VE, V Ghanta, Helferich WG, Cooke PS. Source: The Journal of Endocrinology. 2003 February; 176(2): 267-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12553875&dopt=Abstract

Alternative Medicine 197

•

Total calcium intake is associated with cortical bone mineral density in a cohort of postmenopausal women not taking estrogen. Author(s): Suzuki Y, Davison KS, Chilibeck PD. Source: J Nutr Health Aging. 2003; 7(5): 296-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12917743&dopt=Abstract

•

Urinary and serum concentrations of seven phytoestrogens in a human reference population subset. Author(s): Valentin-Blasini L, Blount BC, Caudill SP, Needham LL. Source: Journal of Exposure Analysis and Environmental Epidemiology. 2003 July; 13(4): 276-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12923554&dopt=Abstract

•

Urinary phytoestrogen excretion and breast cancer risk: evaluating potential effect modifiers endogenous estrogens and anthropometrics. Author(s): Dai Q, Franke AA, Yu H, Shu XO, Jin F, Hebert JR, Custer LJ, Gao YT, Zheng W. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2003 June; 12(6): 497-502. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12814993&dopt=Abstract

•

Vascular ECE-1 mRNA expression decreases in response to estrogens. Author(s): Rodrigo MC, Martin DS, Eyster KM. Source: Life Sciences. 2003 October 24; 73(23): 2973-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14519446&dopt=Abstract

Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •

Alternative Medicine Foundation, Inc.: http://www.herbmed.org/

•

AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats

•

Chinese Medicine: http://www.newcenturynutrition.com/

•

drkoop.com®: http://www.drkoop.com/InteractiveMedicine/IndexC.html

•

Family Village: http://www.familyvillage.wisc.edu/med_altn.htm

•

Google: http://directory.google.com/Top/Health/Alternative/

•

Healthnotes: http://www.healthnotes.com/

•

MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine

•

Open Directory Project: http://dmoz.org/Health/Alternative/

198

Estrogen

•

HealthGate: http://www.tnp.com/

•

WebMD®Health: http://my.webmd.com/drugs_and_herbs

•

WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

•

Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/

The following is a specific Web list relating to estrogen; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •

General Overview Acne Source: Integrative Medicine Communications; www.drkoop.com Amenorrhea Source: Healthnotes, Inc.; www.healthnotes.com Amenorrhea Source: Integrative Medicine Communications; www.drkoop.com Anorexia Nervosa Source: Integrative Medicine Communications; www.drkoop.com Athletic Performance Source: Healthnotes, Inc.; www.healthnotes.com Bone Loss Source: Integrative Medicine Communications; www.drkoop.com Breast Cancer Source: Healthnotes, Inc.; www.healthnotes.com Breast Cancer Source: Integrative Medicine Communications; www.drkoop.com Cancer Prevention (Reducing the Risk) Source: Prima Communications, Inc.www.personalhealthzone.com Canker Sores Source: Prima Communications, Inc.www.personalhealthzone.com Colorectal Cancer Source: Integrative Medicine Communications; www.drkoop.com Dementia Source: Integrative Medicine Communications; www.drkoop.com Depression Source: Healthnotes, Inc.; www.healthnotes.com

Alternative Medicine 199

Dysmenorrhea Source: Healthnotes, Inc.; www.healthnotes.com Dysmenorrhea Source: Integrative Medicine Communications; www.drkoop.com Eczema Source: Prima Communications, Inc.www.personalhealthzone.com Endometriosis Source: Healthnotes, Inc.; www.healthnotes.com Female Infertility Source: Healthnotes, Inc.; www.healthnotes.com Fibrocystic Breast Disease Source: Healthnotes, Inc.; www.healthnotes.com Heart Attack Source: Healthnotes, Inc.; www.healthnotes.com High Cholesterol Source: Integrative Medicine Communications; www.drkoop.com Hypercholesterolemia Source: Integrative Medicine Communications; www.drkoop.com Hyperparathyroidism Source: Integrative Medicine Communications; www.drkoop.com Insomnia Source: Prima Communications, Inc.www.personalhealthzone.com Lung Cancer Source: Healthnotes, Inc.; www.healthnotes.com Macular Degeneration Source: Integrative Medicine Communications; www.drkoop.com Menopausal Symptoms (Other Than Osteoporosis) Source: Prima Communications, Inc.www.personalhealthzone.com Menopause Source: Healthnotes, Inc.; www.healthnotes.com Menopause Source: Integrative Medicine Communications; www.drkoop.com Menstrual Pain Source: Integrative Medicine Communications; www.drkoop.com

200

Estrogen

Miscarriage Source: Integrative Medicine Communications; www.drkoop.com Osteoporosis Source: Healthnotes, Inc.; www.healthnotes.com Osteoporosis Source: Integrative Medicine Communications; www.drkoop.com Osteoporosis Source: Prima Communications, Inc.www.personalhealthzone.com PMS Source: Integrative Medicine Communications; www.drkoop.com PMS Alternative names: Premenstrual Stress Syndrome Source: Prima Communications, Inc.www.personalhealthzone.com Premenstrual Syndrome Source: Healthnotes, Inc.; www.healthnotes.com Premenstrual Syndrome Source: Integrative Medicine Communications; www.drkoop.com Prostate Cancer Source: Healthnotes, Inc.; www.healthnotes.com Prostate Cancer Source: Integrative Medicine Communications; www.drkoop.com Senile Dementia Source: Integrative Medicine Communications; www.drkoop.com Spontaneous Abortion Source: Integrative Medicine Communications; www.drkoop.com Systemic Lupus Erythematosus Source: Healthnotes, Inc.; www.healthnotes.com Ulcers Source: Prima Communications, Inc.www.personalhealthzone.com Urinary Incontinence Source: Integrative Medicine Communications; www.drkoop.com Vaginitis Source: Healthnotes, Inc.; www.healthnotes.com Viral Hepatitis Source: Prima Communications, Inc.www.personalhealthzone.com

Alternative Medicine 201

•

Alternative Therapy Herbal Medicine Source: Integrative Medicine Communications; www.drkoop.com

•

Herbs and Supplements 7-Keto Source: Healthnotes, Inc.; www.healthnotes.com ALA Source: Integrative Medicine Communications; www.drkoop.com Alfalfa Alternative names: Medicago sativa Source: Healthnotes, Inc.; www.healthnotes.com Alpha-Linolenic Acid (ALA) Source: Integrative Medicine Communications; www.drkoop.com Androstenedione Source: Healthnotes, Inc.; www.healthnotes.com Angelica sinensis Alternative names: Dong Quai Source: Integrative Medicine Communications; www.drkoop.com Anise Source: The Canadian Internet Directory for Holistic Help, WellNet, Health and Wellness Network; www.wellnet.ca Aristolochia Alternative names: Snakeroot, Guaco; Aristolochia sp Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Astragalus Sp Alternative names: Vetch, Rattlepod, Locoweed; Astragalus sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Beta-carotene Source: Prima Communications, Inc.www.personalhealthzone.com Betula Alternative names: Birch; Betula sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Black Cohosh Alternative names: Cimicifuga racemosa Source: Healthnotes, Inc.; www.healthnotes.com

202

Estrogen

Black Cohosh Alternative names: Black Snakeroot Source: Integrative Medicine Communications; www.drkoop.com Black Cohosh Source: Prima Communications, Inc.www.personalhealthzone.com Black Cohosh Source: The Canadian Internet Directory for Holistic Help, WellNet, Health and Wellness Network; www.wellnet.ca Black Cohosh Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10009,00.html Black Snakeroot Alternative names: Black Cohosh Source: Integrative Medicine Communications; www.drkoop.com Calciferol Alternative names: Vitamin D Source: Integrative Medicine Communications; www.drkoop.com Calcitonin Source: Healthnotes, Inc.; www.healthnotes.com Calcitrol Alternative names: Vitamin D Source: Integrative Medicine Communications; www.drkoop.com Carotenoids Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,763,00.html Chaste Tree Source: The Canadian Internet Directory for Holistic Help, WellNet, Health and Wellness Network; www.wellnet.ca Chasteberry Source: Prima Communications, Inc.www.personalhealthzone.com Chasteberry Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,767,00.html Chemotherapy Source: Healthnotes, Inc.; www.healthnotes.com

Alternative Medicine 203

Chinese Angelica Alternative names: Dong Quai Source: Integrative Medicine Communications; www.drkoop.com Cholecalciferol Alternative names: Vitamin D Source: Integrative Medicine Communications; www.drkoop.com Cimicifuga Alternative names: Black Cohosh; Cimicifuga racemosa (NUTT.) Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Cimicifuga racemosa (Actea) Alternative names: Black Cohosh Source: Integrative Medicine Communications; www.drkoop.com Curcuma Longa Source: Integrative Medicine Communications; www.drkoop.com Cyclophosphamide Source: Healthnotes, Inc.; www.healthnotes.com Damiana Alternative names: Turnera diffusa Source: Healthnotes, Inc.; www.healthnotes.com Danggui Alternative names: Dong Quai Source: Integrative Medicine Communications; www.drkoop.com Dehydroepiandrosterone (DHEA) Source: Healthnotes, Inc.; www.healthnotes.com Dehydroepiandrosterone (DHEA) Source: Integrative Medicine Communications; www.drkoop.com DHEA Source: Integrative Medicine Communications; www.drkoop.com DHEA Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10022,00.html DHEA (Dehydroepiandrosterone) Source: Prima Communications, Inc.www.personalhealthzone.com Docetaxel Source: Healthnotes, Inc.; www.healthnotes.com

204

Estrogen

Dong Quai Alternative names: Angelica sinensis Source: Healthnotes, Inc.; www.healthnotes.com Dong Quai Alternative names: Angelica sinensis Source: Integrative Medicine Communications; www.drkoop.com Dong Quai Source: Prima Communications, Inc.www.personalhealthzone.com Dong Quai (Angelica) Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,774,00.html Erocalciferol Alternative names: Vitamin D Source: Integrative Medicine Communications; www.drkoop.com Estradiol Source: Healthnotes, Inc.; www.healthnotes.com Estrogen Source: Prima Communications, Inc.www.personalhealthzone.com Estrogens Source: Healthnotes, Inc.; www.healthnotes.com Estrogens (Combined) Source: Healthnotes, Inc.; www.healthnotes.com Estropipate Source: Healthnotes, Inc.; www.healthnotes.com Fennel Alternative names: Foeniculum vulgare Source: Healthnotes, Inc.; www.healthnotes.com Fennel Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,849,00.html Fiber Source: Healthnotes, Inc.; www.healthnotes.com Flavonoids Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,782,00.html

Alternative Medicine 205

Flaxseed Alternative names: Linum usitatissimum, Linseed Source: Integrative Medicine Communications; www.drkoop.com Fluorouracil Source: Healthnotes, Inc.; www.healthnotes.com Glycyrrhiza glabra Source: Integrative Medicine Communications; www.drkoop.com Glycyrrhiza Alternative names: Licorice; Glycyrrhiza glabra L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Gymnema Alternative names: Gurmar; Gymnema sylvestre Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Hibiscus Alternative names: Hibiscus, Roselle; Hibiscus sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Hops Alternative names: Humulus lupulus Source: Healthnotes, Inc.; www.healthnotes.com Humulus Alternative names: Hops; Humulus lupulus L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Indole-3-carbinol Source: Healthnotes, Inc.; www.healthnotes.com Ipriflavone Source: Healthnotes, Inc.; www.healthnotes.com Ipriflavone Source: Prima Communications, Inc.www.personalhealthzone.com Ipriflavone Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10039,00.html Isoflavones Source: Prima Communications, Inc.www.personalhealthzone.com Licorice Alternative names: Glycyrrhiza glabra, Spanish Licorice Source: Integrative Medicine Communications; www.drkoop.com

206

Estrogen

Licorice Source: Prima Communications, Inc.www.personalhealthzone.com Licorice Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,801,00.html Linseed Source: Integrative Medicine Communications; www.drkoop.com Linum Usitatissimum Source: Integrative Medicine Communications; www.drkoop.com Medroxyprogesterone Source: Healthnotes, Inc.; www.healthnotes.com Melatonin Source: Prima Communications, Inc.www.personalhealthzone.com Methionine Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10084,00.html Methotrexate Source: Healthnotes, Inc.; www.healthnotes.com Methyltestosterone Source: Healthnotes, Inc.; www.healthnotes.com Musa Banana Alternative names: Plantain, Banana; Musa sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Naringin Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10089,00.html Natural Progesterone Cream Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10099,00.html Nettle Alternative names: Urtica dioica Source: Healthnotes, Inc.; www.healthnotes.com Oral Contraceptives Source: Healthnotes, Inc.; www.healthnotes.com

Alternative Medicine 207

Oral Contraceptives Source: Prima Communications, Inc.www.personalhealthzone.com Origanum Alternative names: Oregano; Origanum vulgare Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Paclitaxel Source: Healthnotes, Inc.; www.healthnotes.com Panax Alternative names: Ginseng; Panax ginseng Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Passiflora Alternative names: Passion Flower; Passiflora alata L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Pimpinella Alternative names: Anise; Pimpinella anisum (L) Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Piper Nigrum Alternative names: Black Pepper Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Pollen Source: Healthnotes, Inc.; www.healthnotes.com Pregnenolone Source: Prima Communications, Inc.www.personalhealthzone.com Prempro Source: Healthnotes, Inc.; www.healthnotes.com Progesterone Source: Healthnotes, Inc.; www.healthnotes.com Pueraria Alternative names: Kudzu; Pueraria lobata Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Pygeum Alternative names: African Prune; Pygeum africanum Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Raloxifene Source: Healthnotes, Inc.; www.healthnotes.com Red Clover Alternative names: Trifolium pratense Source: Healthnotes, Inc.; www.healthnotes.com

208

Estrogen

Red Clover Source: Integrative Medicine Communications; www.drkoop.com Red Clover Source: Prima Communications, Inc.www.personalhealthzone.com Resveratrol Source: Prima Communications, Inc.www.personalhealthzone.com Royal Jelly Source: Healthnotes, Inc.; www.healthnotes.com Sabal Serrulata Source: Integrative Medicine Communications; www.drkoop.com Saw Palmetto Alternative names: Serenoa serrulata, Serenoa repens, Sabal serrulata Source: Healthnotes, Inc.; www.healthnotes.com Saw Palmetto Alternative names: Serenoa repens, Sabal serrulata Source: Integrative Medicine Communications; www.drkoop.com Serenoa Repens Source: Integrative Medicine Communications; www.drkoop.com Silybum Alternative names: Milk Thistle; Silybum marianum (L.) Gaertn. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Soy Isoflavones Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10057,00.html Spanish Licorice Source: Integrative Medicine Communications; www.drkoop.com Tamoxifen Source: Healthnotes, Inc.; www.healthnotes.com Tang Kuei Source: Integrative Medicine Communications; www.drkoop.com Thymus Alternative names: Thyme; Thymus vulgaris Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Tocotrienols Source: Healthnotes, Inc.; www.healthnotes.com

Alternative Medicine 209

Turmeric Alternative names: Curcuma longa Source: Integrative Medicine Communications; www.drkoop.com Uncaria Catclaw Alternative names: Cat's Claw, Uno de Gato; Uncaria tomentosa (Willd.) D.C. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Vitex Alternative names: Vitex agnus-castus Source: Healthnotes, Inc.; www.healthnotes.com Wild Yam Alternative names: Dioscorea villosa Source: Healthnotes, Inc.; www.healthnotes.com Wild Yam Source: Prima Communications, Inc.www.personalhealthzone.com Yucca Source: Prima Communications, Inc.www.personalhealthzone.com

General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.

211

CHAPTER 4. CLINICAL TRIALS AND ESTROGEN Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning estrogen.

Recent Trials on Estrogen The following is a list of recent trials dedicated to estrogen.8 Further information on a trial is available at the Web site indicated. •

Alzheimer's Disease and Aging: Therapeutic potential of estrogen Condition(s): Alzheimer's Disease Study Status: This study is currently recruiting patients. Sponsor(s): Department of Veterans Affairs Medical Research Service Purpose - Excerpt: This study is designed to evaluate the potential beneficial effects of estrogen on cognitive function of women with Alzheimer's Disease. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00018343

•

Alzheimer's Disease: Therapeutic Potential of Estrogen Condition(s): Alzheimer Disease Study Status: This study is currently recruiting patients. Sponsor(s): National Institute on Aging (NIA) Purpose - Excerpt: This is a 15-month study to determine the effectiveness of hormone replacement therapy in improving memory and the ability to live independently in postmenopausal women with Alzheimer's disease.

8

These are listed at www.ClinicalTrials.gov.

212

Estrogen

Phase(s): Phase II; Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00066157 •

Calcium With or Without Estrogen and/or Risedronate in Preventing Osteoporosis in Patients with Prostate Cancer Condition(s): Osteoporosis; stage I prostate cancer; stage II prostate cancer; stage III prostate cancer Study Status: This study is currently recruiting patients. Sponsor(s): North Central Cancer Treatment Group; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Preventing bone loss in patients who are undergoing androgen ablation for prostate cancer may decrease the risk of fractures and may help patients live more comfortably. It is not yet known whether calcium is more effective with or without estrogen and/or risedronate in preventing osteoporosis. PURPOSE: Randomizedphase III trial to compare the effectiveness of two forms of calcium with or without estrogen and/or risedronate in preventing osteoporosis in patients with prostate cancer who are receiving androgen ablation therapy. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00043069

•

Clinical Trial of Estrogen for Postpartum Depression Condition(s): Postpartum Depression Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Mental Health (NIMH) Purpose - Excerpt: The purpose of this study is to evaluate the effectiveness of 17 betaestradiol, a form of estrogen, in treating women with postpartum depression (PPD). PPD causes significant distress to a large number of women; the demand for effective therapies to treat PPD is considerable. Estradiol therapy has a prophylactic effect in women at high risk for developing PPD. The prevention of a decline in estradiol levels may prevent the onset of PPD. Studies also suggest that estradiol has antidepressant effects in women and may provide a safe and effective alternative to traditional antidepressants in women with PPD. Participants will be screened with a medical history, physical examination, blood and urine tests, psychological tests, genetic studies, and self-rating scales and questionnaires. Upon study entry, women will be randomly assigned to wear skin patches containing either estradiol or placebo (a patch with no active ingredient) for 6 weeks. Women who receive estradiol and do not menstruate during the last week of the study will receive progesterone for 7 days to initiate menstruation. Women who receive placebo and do not menstruate during the last week of the study will continue to receive placebo at the end of the study. Every week, participants will have blood taken and will be asked to complete symptom self-rating scales. A urine sample and blood samples will be collected at different time points through out of the study. Participants who receive placebo and those whose symptoms

Clinical Trials 213

do not improve with estradiol therapy will be offered treatment with standard antidepressant medications for 8 weeks at the end of the study. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00059228 •

Comparison of Nolvadex 20 mg and placebo combination to Nolvadex 20 mg and ZD1839 (IRESSA(tm)) 250 mg combination in patients with metastatic breast cancer and estrogen receptor (ER) and/or progesterone (PR) positive tumours Condition(s): Breast Neoplasms Study Status: This study is currently recruiting patients. Sponsor(s): AstraZeneca Purpose - Excerpt: This study is being carried out to see if ZD1839 is effective in treating metastatic breast cancer in combination with Nolvadex, and if so, how it compares with Nolvadex alone. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00069290

•

Effects of Estrogen on Memory in Post-Menopausal Women and Patients With Alzheimer's Disease Condition(s): Alzheimer Disease Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Research Resources (NCRR); Alzheimer's Association; Pfizer; Eisai Medical Research Inc Purpose - Excerpt: The goal of this study is to examine whether the administration of estrogen to post-menopausal women and women with mild to moderate Alzheimer's disease will enhance their memory and their capacity for learning. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006399

•

Estrogen Modulation of Mood and Cognition Following Monoaminergic Depletion in Post-Menopausal Women Condition(s): Menopause Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Research Resources (NCRR) Purpose - Excerpt: This study will examine whether estrogen administration in postmenopausal women can alter the response to changes in brain chemistry brought

214

Estrogen

about by dietary manipulation. Women who are recently menopausal (50-60 yrs. of age) and over 20 years postmenopausal (>70 yrs. of age) will take estrogen or placebo for three months. At the end of that time they will participate in three challenges using dietary techniques to briefly change the relative amounts of neurotransmitters in the brain that are believed to be related to mood regulation (serotonin, dopamine, and norepinephrine). Previous research has shown that these dietary manipulations can briefly produce negative changes in mood. The investigator hypothesizes that estrogen administration will blunt or buffer these negative effects in a quantifiable way. The investigator believes that this will provide a direct test of the ability of estrogen to meaningfully change the brain chemistry of mood in a clinically measurable and positive way. The proposed procedure will also allow assessment of the effects of estrogen on brain neurotransmitter systems after many years of very low estrogen levels. Phase(s): Phase II; MedlinePlus consumer health information Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005768 •

Macrobiotic Diet and Flax Seed: Effects on Estrogens, Phytoestrogens, & Fibrinolytic Factors Condition(s): Cardiovascular Diseases; Osteoporosis; Breast Cancer; Endometrial Cancer Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Complementary and Alternative Medicine (NCCAM) Purpose - Excerpt: This study will assess whether alternative, high phytoestrogen dietary interventions result in favorable effects on biological parameters that have been associated with hormone-dependent cancers, cardiovascular disease, and osteoporosis. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00010829

•

The Effects of Estrogen on Cognition in Girls with Turner Syndrome Condition(s): Gonadal Dysgenesis; Turner's Syndrome Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Child Health and Human Development (NICHD) Purpose - Excerpt: The development of the brain in females is a result of a combination of factors. During puberty estrogen plays a role in influencing brain development. Cultural and environmental factors also play a role in the development of the brain. Female patients with Turner syndrome lack the ability to produce estrogen due to undeveloped ovaries. Therefore, Turner syndrome is the perfect condition to study how estrogen (or the lack of estrogen) influences a person's behavior and thinking. This study will compare cognitive differences (visual motor skills, visual-spatial, psychosocial behavior, and visual memory) of patients with Turner syndrome to normal patient controls. Researchers will use the Weschler Intelligence Scale for ChildrenRevised (WISC-R) along with other tests and scales to measure different aspects of the

Clinical Trials 215

patient's cognitive ability. In addition the study will review patients with Turner syndrome who previously received estrogen replacement as infants and children in a related research study. Researchers hope to demonstrate that estrogen replacement will improve cognition and behavior in girls with Turner syndrome. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001253 •

Trial Comparing Anastrozole-Placebo to the Combination Anastrozole-ZD1839 in Postmenopausal Patients with Estrogen Receptor (ER) and/or Progesterone Receptor (PgR) Metastatic Breast Cancer Condition(s): Breast Cancer Study Status: This study is currently recruiting patients. Sponsor(s): AstraZeneca Purpose - Excerpt: This study is being carried out to see if treatment with ZD1839 (Gefitinib) combined with Arimidex (Anastrozole) has improved efficacy over Arimidex alone in preventing progression of metastatic breast cancer. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00077025

•

Combined Use of Study Drug and a marketed SERM (Selective Estrogen Receptor Modulator) in Postmenopausal Women with Osteoporosis Condition(s): Osteoporosis, Postmenopausal Study Status: This study is no longer recruiting patients. Sponsor(s): Eli Lilly and Company Purpose - Excerpt: The purpose of this study is to compare treatment with both Study Drug and a SERM to treatment with Study Drug alone. The study will evaluate any side effects that may be associated with the two drugs and may help to determine whether Study Drug and a SERM together can help patients with osteoporosis more than Study Drug alone. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00046137

•

Estrogen Replacement Therapy in Treating Women With Early-Stage Endometrial Cancer Condition(s): stage I endometrial cancer; stage II endometrial cancer; endometrial adenocarcinoma Study Status: This study is no longer recruiting patients.

216

Estrogen

Sponsor(s): Gynecologic Oncology Group; National Cancer Institute (NCI); Eastern Cooperative Oncology Group; Southwest Oncology Group Purpose - Excerpt: RATIONALE: Estrogen replacement therapy may improve qualityof-life in postmenopausal women with endometrial cancer. It is not yet known whether estrogen replacement therapy will affect cancer recurrence. PURPOSE: Randomized double-blinded phase III trial to determine the effectiveness of estrogen replacement therapy in treating women who have stage I or stage II endometrial cancer. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00002976 •

Safety of Estrogens in Lupus: Birth Control Pills Condition(s): Systemic Lupus Erythematosus Study Status: This study is no longer recruiting patients. Sponsor(s): National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); Office of Research on Women's Health (ORWH) Purpose - Excerpt: Safety of Estrogens in Lupus Erythematosus - National Assessment (SELENA) is a study to test whether women with systemic lupus erythematosus (SLE or lupus) can safely use estrogen. We will determine this by looking at the effects of oral contraceptives (birth control pills, also known as "the pill") on disease activity and severity in women with SLE. The results of the study will show whether it is safe for women with SLE to use the pill. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000420

•

The Effect of Estrogen and Progesterone Levels on Knee and Ankle Joint Laxity Condition(s): Healthy; MedlinePlus consumer health information Study Status: This study is no longer recruiting patients. Sponsor(s): National Center for Research Resources (NCRR) Purpose - Excerpt: The proposed research is an observational study designed to compare estrogen and progesterone serum levels with knee and ankle joint laxity, and muscle reaction time as a measure of neuromuscular function. Three groups of women athletes with differing estrogen and progesterone profiles (normal menstrual cycles, amenorrheic, and exogenous estrogen supplementation) and one control group (male collegiate athletes) will be used to compare differences in joint laxity and neuromuscular function. Blood levels of estrogen and progesterone will be measured at four time points across the menstrual cycle. Joint laxity and muscle reaction time will also be measured at each of these points. The investigator hypothesizes that knee and ankle joint laxity and muscle reaction time will significantly increase with increasing estrogen and progesterone levels. Study Type: Observational

Clinical Trials 217

Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005923 •

Zometa - Femara Adjuvant Synergy Trial (ZFAST) - Cancer Treatment Related Bone Loss in Postmenopausal Women with Estrogen Receptor Positive and/or Progesterone Receptor Positive Breast Cancer Receiving Adjuvant Hormonal Therapy Condition(s): Breast Neoplasms; Osteoporosis Study Status: This study is no longer recruiting patients. Sponsor(s): Novartis Pharmaceuticals Purpose - Excerpt: This protocol is designed to compare the effect on bone of Zometa 4 mg every 6 months when given upfront versus delayed start ( based on a post-baseline BMD T- Score below -2.0 SD at either the lumbar spine or total hip, or any clinical fracture unrelated to trauma, or an asymptomatic fracture discovered at the month 36 scheduled visit) in stage I-IIIa postmenopausal women with hormone receptor positive breast cancer who will receive Femara 2.5 mg daily as an adjuvant therapy. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00050011

•

Adjuvant Radiation Therapy After Surgery Compared With Observation in Treating Women With Estrogen Receptor Positive or Progesterone Receptor Positive Ductal Carcinoma In Situ of the Breast Who Are Receiving Tamoxifen or Anastrozole Condition(s): intraductal breast carcinoma; breast cancer in situ Study Status: This study is not yet open for patient recruitment. Sponsor(s): National Cancer Research Institute (NCRI) Purpose - Excerpt: RATIONALE: Radiation therapy uses high-energy x-rays to damage tumor cells. It is not yet known whether radiation therapy after surgery is effective in preventing a recurrence of ductal carcinoma in situ. PURPOSE: Randomizedphase II trial to compare the effectiveness of adjuvant radiation therapy after surgery with that of observation in treating women with estrogen receptor positive or progesterone receptor positive ductal carcinoma in situ who are also receiving tamoxifen or anastrozole. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00077168

•

Bone Estrogen Strength Training Condition(s): Osteoporosis Study Status: This study is completed. Sponsor(s): National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

218

Estrogen

Purpose - Excerpt: We started the Bone, Estrogen, Strength Training (BEST) study in the fall of 1995 at the University of Arizona, Tucson, Arizona. The BEST study is the largest of its kind. It looks at the effects of hormone replacement therapy and strength training exercise on bone mineral density. (Bone mineral density affects bone strength and the risk of osteoporosis.) Six groups of about 300 women each participated in this osteoporosis prevention study. In 1998, the BEST study received additional funding to examine for another 2 years the long-term effects of strength training on bone mineral density. By 2001 we will have finished analyzing the results for all study groups on the 1-year effects of exercise on bone, as well as additional analyses on the effects of 2, 3, and 4 years of strength training and weight-bearing exercise on bone. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000399 •

Buccal estrogen in toothpaste study: Systemic absorption of estradiol when administered mixed with toothpaste in postmenopausal or surgically menopausal women Condition(s): Menopause; Postmenopause Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR) Purpose - Excerpt: Background: The use of estrogen in postmenopausal (or surgically menopausal) women is a common practice. Compliance is problematic in that estimates show only 1/3 of women use hormone replacement therapy (HRT) and only 30% are compliant. Estrogen has many documented benefits including symptomatic relief of hot flashes, improvement of the dry vagina and dysparunia. Estrogen has been found to improve bone mineral density and increase the high- density lipoprotein portion of a cholesterol panel. To improve compliance and to provide an alternate method of delivery, we propose the use of estrogen which is admixed in toothpaste and propose to study the absorption, rate of build-up and rate of decline. Hypothesis: Estrogen can potentially be absorbed systemically when toothpaste is admixed with estradiol and is applied in a timed, consistent fashion to postmenopausal or surgically postmenopausal women, not on HRT. Absorption takes place across the buccal mucosa. Specific Aims:1) To estimate the systemic absorption of estrogen from daily use of estrogen containing toothpaste. 2) To estimate the rate of build-up of serum estrogen levels based upon daily use of toothpaste containing estrogen for eight days. 3) To estimate the rate of decline in serum estrogen levels when the use of estrogen containing toothpaste is discontinued for a week. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00029757

•

Effect of Estrogen on Mental and Social Functioning in Girls with Turner's Syndrome Condition(s): Turner's Syndrome Study Status: This study is completed.

Clinical Trials 219

Sponsor(s): National Institute of Neurological Disorders and Stroke (NINDS); Jefferson Medical College of Thomas Jefferson University Purpose - Excerpt: RATIONALE: Turner's syndrome is a disease in which females are missing all or part of one X chromosome and do not produce estrogen. Giving estrogen is standard treatment for girls who have Turner's syndrome. Estrogen may be effective treatment for mental and social functioning problems experienced by girls with Turner's syndrome. PURPOSE: Clinical trial to study the effectiveness of long term estrogen therapy on mental and social functioning in girls who have Turner's syndrome. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004274 •

Endogenous Estrogen and Coronary Heart Disease in Women Condition(s): Cardiovascular Diseases; Coronary Disease; Heart Diseases; Myocardial Infarction; Postmenopause Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To investigate the relation between endogenous levels of estrogen in postmenopausal women and the subsequent development of coronary heart disease. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005446

•

Estrogen and Graft Atherosclerosis Research Trial (EAGER) Condition(s): Cardiovascular Diseases; Coronary Arteriosclerosis; Coronary Disease; Heart Diseases; Myocardial Ischemia; Postmenopause Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine if postmenopausal hormone replacement therapy in women following coronary bypass surgery will reduce the occurrence of graft occlusion and delay the development of graft atherosclerosis. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000605

•

Estrogen Protocol Condition(s): Alzheimer Disease Study Status: This study is completed. Sponsor(s): National Institute on Aging (NIA) Purpose - Excerpt: Estrogen is a hormone that is dominant in the female reproductive system. In women, most estrogen is produced by the ovaries. Men produce estrogen by

220

Estrogen

converting testosterone into estrogen. Because this hormone also has many beneficial effects on brain cells, it currently is being studied as a treatment for Alzheimer's disease. The enzyme that forms the neurotransmitter acetylcholine is promoted in the presence of estrogen. Several very small clinical studies have demonstrated improvement in cognitive function and mood measures in women with Alzheimer's disease who take estrogen. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000177 •

Estrogen Replacement and Atherosclerosis (ERA) in Older Women Condition(s): Cardiovascular Diseases; Coronary Arteriosclerosis; Coronary Disease; Heart Diseases; Myocardial Ischemia; Postmenopause Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine if estrogen replacement therapy, with or without low dose progesterone, slows progression or induces regression of coronary atherosclerosis in postmenopausal women. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000549

•

Estrogen, Cytokines and Heart Failure in Women Condition(s): Cardiovascular Diseases; Heart Failure, Congestive; Heart Diseases; Menopause Study Status: This study is not yet open for patient recruitment. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine the effects of estrogen therapy on postmenopausal women with congestive heart failure. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00041431

•

Myocardial Infarction and Non-contraceptive Estrogen Use Condition(s): Cardiovascular Menopause; Postmenopause

Diseases;

Heart

Diseases;

Myocardial

Infarction;

Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To evaluate whether the use of noncontraceptive estrogen influenced the incidence of first myocardial infarction in women.

Clinical Trials 221

Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005185 •

Phase III Randomized Study of the Effect of Postmenopausal Estrogen Replacement Therapy on Alveolar Bone Loss Condition(s): Osteoporosis Study Status: This study is completed. Sponsor(s): National Institute of Dental and Craniofacial Research (NIDCR); Washington University School of Medicine Purpose - Excerpt: Objectives: I. Quantify periodontal alveolar bone loss rates in postmenopausal women. II. Evaluate the effects of estrogen on alveolar bone loss rates in these patients. III. Determine whether changes in periodontal bone mass relate to bone mass changes in other skeletal sites in these patients. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004650

•

Postmenopausal Estrogen/Progestin Interventions (PEPI) Condition(s): Bone Diseases; Cardiovascular Diseases; Coronary Disease; Diabetes Mellitus; Heart Diseases; Hypercholesterolemia; Hypertension; Myocardial Ischemia; Osteoporosis; Thrombosis; Postmenopause Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI); National Institute on Aging (NIA); National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institute of Child Health and Human Development (NICHD) Purpose - Excerpt: To assess the effects of various postmenopausal estrogen replacement therapies on selected cardiovascular risk factors, including high density lipoprotein cholesterol, systolic blood pressure, fibrinogen, and insulin and on osteoporosis risk factors. Conducted in collaboration with the National Institute of Child Health and Human Development, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, The National Institute of Diabetes and Digestive and Kidney Diseases, and the National Institute on Aging. The extended follow-up is for 3 years focusing on endometrium and breast evaluation. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000466

•

Safety of Estrogens in Lupus: Hormone Replacement Therapy Condition(s): Systemic Lupus Erythematosus

222

Estrogen

Study Status: This study is terminated. Sponsor(s): National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); Office of Research on Women's Health (ORWH) Purpose - Excerpt: Safety of Estrogens in Lupus Erythematosus - National Assessment (SELENA) is a study to test whether postmenopausal women with systemic lupus erythematosus (SLE, or lupus) can safely use the hormone estrogen. In this part of the study, we will look at the effects of estrogen replacement therapy on the activity and severity of disease in women with SLE. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000419 •

Soy Estrogen Alternative Study (SEA) Condition(s): Cardiovascular Diseases; Endometrial Hyperplasia; Heart Diseases; Menopausal Complaints; Uterine Diseases; Menopause Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To conduct a three-armed trial assessing the effect of soy phytoestrogens on menopausal complaints, plasma lipids and lipoproteins, vaginal bleeding and endometrial proliferation, and health related quality of life. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000612

•

Stroke and MI in Users of Estrogen/Progestogen Condition(s): Cardiovascular Diseases; Heart Diseases; Coronary Cerebrovascular Accident; Myocardial Infarction; Postmenopause

Disease;

Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To estimate the relative risks of acute myocardial infarction (MI) and of stroke in postmenopausal users of estrogen/progestogen (E/P) combinations and to estimate the relative risks of MI and of stroke in users of estrogen alone. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005466 •

Using Soy Estrogens to Prevent Bone Loss and Other Menopausal Symptoms Condition(s): Menopause; Osteoporosis; Osteopenia Study Status: This study is not yet open for patient recruitment.

Clinical Trials 223

Sponsor(s): National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Purpose - Excerpt: The purpose of this study is to determine if soy-derived phytoestrogens (naturally occurring compounds similar to estrogen) can prevent bone loss and other menopausal symptoms in women who have recently gone through menopause. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00076050 •

Women's Angiographic Vitamin and Estrogen Trial (WAVE) Condition(s): Cardiovascular Diseases; Coronary Arteriosclerosis; Coronary Disease; Heart Diseases; Myocardial Ischemia; Postmenopause Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To assess whether hormonal replacement therapy and/or antioxidant treatment would stabilize or inhibit progression, and induce regression of coronary plaques. The mechanisms by which these treatments modified atherosclerosis in women were also explored. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000555

•

Women's Estrogen for Stroke Trial (WEST) Condition(s): Stroke Study Status: This study is completed. Sponsor(s): National Institute of Neurological Disorders and Stroke (NINDS) Purpose - Excerpt: To determine if estrogen hormone replacement therapy reduces the risk of stroke or death in postmenopausal women who have already had stroke or a transient ischemic attack (TIA). Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00026039

•

Women's Estrogen/Progestin Lipid Lowering Hormone Atherosclerosis Regression Trial (WELL-HART) Condition(s): Cardiovascular Diseases; Coronary Disease; Heart Diseases; Myocardial Ischemia; Postmenopause Study Status: This study is completed.

224

Estrogen

Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine the effects, in postmenopausal women, of hormone replacement therapy on progression/regression of coronary heart disease, as measured by quantitative angiography. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000559

Keeping Current on Clinical Trials The U.S. National Institutes of Health, through the National Library of Medicine, has developed ClinicalTrials.gov to provide current information about clinical research across the broadest number of diseases and conditions. The site was launched in February 2000 and currently contains approximately 5,700 clinical studies in over 59,000 locations worldwide, with most studies being conducted in the United States. ClinicalTrials.gov receives about 2 million hits per month and hosts approximately 5,400 visitors daily. To access this database, simply go to the Web site at http://www.clinicaltrials.gov/ and search by “estrogen” (or synonyms). While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: •

For clinical studies at the Warren Grant Magnuson Clinical Center located in Bethesda, Maryland, visit their Web site: http://clinicalstudies.info.nih.gov/

•

For clinical studies conducted at the Bayview Campus in Baltimore, Maryland, visit their Web site: http://www.jhbmc.jhu.edu/studies/index.html

•

For cancer trials, visit the National Cancer Institute: http://cancertrials.nci.nih.gov/

•

For eye-related trials, visit and search the Web page of the National Eye Institute: http://www.nei.nih.gov/neitrials/index.htm

•

For heart, lung and blood trials, visit the Web page of the National Heart, Lung and Blood Institute: http://www.nhlbi.nih.gov/studies/index.htm

•

For trials on aging, visit and search the Web site of the National Institute on Aging: http://www.grc.nia.nih.gov/studies/index.htm

•

For rare diseases, visit and search the Web site sponsored by the Office of Rare Diseases: http://ord.aspensys.com/asp/resources/rsch_trials.asp

•

For alcoholism, visit the National Institute on Alcohol Abuse and Alcoholism: http://www.niaaa.nih.gov/intramural/Web_dicbr_hp/particip.htm

•

For trials on infectious, immune, and allergic diseases, visit the site of the National Institute of Allergy and Infectious Diseases: http://www.niaid.nih.gov/clintrials/

Clinical Trials 225

•

For trials on arthritis, musculoskeletal and skin diseases, visit newly revised site of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health: http://www.niams.nih.gov/hi/studies/index.htm

•

For hearing-related trials, visit the National Institute on Deafness and Other Communication Disorders: http://www.nidcd.nih.gov/health/clinical/index.htm

•

For trials on diseases of the digestive system and kidneys, and diabetes, visit the National Institute of Diabetes and Digestive and Kidney Diseases: http://www.niddk.nih.gov/patient/patient.htm

•

For drug abuse trials, visit and search the Web site sponsored by the National Institute on Drug Abuse: http://www.nida.nih.gov/CTN/Index.htm

•

For trials on mental disorders, visit and search the Web site of the National Institute of Mental Health: http://www.nimh.nih.gov/studies/index.cfm

•

For trials on neurological disorders and stroke, visit and search the Web site sponsored by the National Institute of Neurological Disorders and Stroke of the NIH: http://www.ninds.nih.gov/funding/funding_opportunities.htm#Clinical_Trials

227

CHAPTER 5. PATENTS ON ESTROGEN Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.9 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “estrogen” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on estrogen, we have not necessarily excluded non-medical patents in this bibliography.

Patents on Estrogen By performing a patent search focusing on estrogen, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We

9Adapted from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.

228

Estrogen

will tell you how to obtain this information later in the chapter. The following is an example of the type of information that you can expect to obtain from a patent search on estrogen: •

3-benzyl-benzothiophenes Inventor(s): Muehl; Brian S. (Indianapolis, IN) Assignee(s): Eli Lilly and Company (indianapolis, In) Patent Number: 6,653,328 Date filed: March 10, 1995 Abstract: This invention relates to the fields of pharmaceutical and organic chemistry and provides novel 3-benzyl-benzothiophenes which are.alpha.-substituted with ether, thioether amino, cyano or halo that are useful for the treatment of the various medical indications associated with post-menopausal syndrome, as well as estrogen dependent diseases including cancer of the breast, uterus and cervix. The present invention further relates to intermediate compounds and processes useful for preparing the pharmaceutically active compounds of the present invention, and pharmaceutical compositions. Excerpt(s): This invention relates to the fields of pharmaceutical and organic chemistry and provides novel 3-benzyl-benzothiophenes which are.alpha.-substituted with ether, thioether, amine, cyano, or halo, which are useful for the treatment of the various medical indications associated with post-menopausal syndrome, as well as estrogen dependent diseases including cancer of the breast, uterus and cervix. The present invention further relates to intermediate compounds and processes useful for preparing the pharmaceutically active compounds of the present invention, and pharmaceutical compositions. Osteoporosis describes a group of diseases which arise from diverse etiologies, but which are characterized by the net loss of bone mass per unit volume. The consequence of this loss of bone mass and resulting bone fracture is the failure of the skeleton to provide adequate structural support for the body. One of the most common types of osteoporosis is that associated with menopause. Most women lose from about 20% to about 60% of the bone mass in the trabecular compartment of the bone within 3 to 6 years after the cessation of mensus. This rapid loss is generally associated with an increase of bone resorption and formation. However, the resorptive cycle is more dominant and the result is a net loss of bone mass. Osteoporosis is a common and serious disease among post-menopausal women. There are an estimated 25 million women in the United States, alone, who are afflicted with this disease. The results of osteoporosis are personally harmful and also account for a large economic loss due its chronicity and the need for extensive and long term support (hospitalization and nursing home care) from the disease sequelae. This is especially true in more elderly patients. Additionally, although osteoporosis is not generally thought of as a life threatening condition, a 20% to 30% mortality rate is related with hip fractures in elderly women. A large percentage of this mortality rate can be directly associated with postmenopausal osteoporosis. Web site: http://www.delphion.com/details?pn=US06653328__

Patents

•

229

Administration of non-oral androgenic steroids to women Inventor(s): Mazer; Norman A. (Salt Lake City, UT), Rosario-Jansen; Theresa (Loveland, OH) Assignee(s): Watson Pharmaceuticals, Inc. (corona, Ca) Patent Number: 6,583,129 Date filed: June 9, 2000 Abstract: The present invention provides compositions, methods, and kits for improving health in a woman having elevated SHBG levels, or who is receiving oral estrogen supplementation, by non-orally administering an effective amount of an androgenic steroid. Further, the present invention provides compositions, methods, and kits for coadministering an effective amount of an orally administered estrogen and an effective amount of a non-orally administered androgenic steroid for women in need of estrogen supplementation. Excerpt(s): This invention broadly relates to the administration of androgens to women. Accordingly, this invention covers the fields of pharmaceutical sciences and medicine. It is known that a functional level of androgenic hormones in females promotes sexual health and activity, feelings of well being, maximizes muscle mass and function, and inhibits bone loss. Further, a functional level of androgenic hormones may promote cardiovascular and coronary health, decrease breast tenderness, decrease vasomotor instability, modulate immune function, enhance certain cognitive abilities, improve urogential health, reduce estrogen supplementation related side effects, and provide direct neuroprotective effects. The attainment of functional levels of androgenic hormones in women, such as testosterone, may be influenced by the serum concentrations of sex hormone binding globulin (SHBG). SHBG is a protein produced by the liver that binds sex hormones such as testosterone and estradiol in the blood. The SHBG-bound sex hormones are generally "non-functional", i.e., unavailable to exert biological action at sex hormone receptors in target tissues and/or undergo clearance from the blood. Web site: http://www.delphion.com/details?pn=US06583129__

•

Compositions for conjugated estrogens and associated methods Inventor(s): Ho; Thomas (Irvine, CA) Assignee(s): Watson Pharmaceuticals, Inc. (corona, Ca) Patent Number: 6,630,166 Date filed: February 12, 2002 Abstract: Oral conjugated estrogen formulations are disclosed and described. In one aspect, the oral formulation may be a tablet having a core and one or more coatings thereon. In addition to conjugated estrogen ingredients, the core may include one or more organic excipients and one or more inorganic excipients. In one aspect, the organic excipients may include less than about 20% w/w of a cellulose ingredient, and less than about 50% w/w of a sugar ingredient. In another aspect, the inorganic excipients may include less than about 10% w/w of a calcium phosphate tribasic ingredient. In yet another aspect, the formulation does not crack when stored at about 40.degree. C. and about 75% relative humidity for about 2 months.

230

Estrogen

Excerpt(s): The present invention relates generally to conjugated estrogen formulations and methods of administering such compositions. Accordingly, this invention covers the fields of pharmaceutical sciences, medicine, cosmetics, and related sciences. Conjugated estrogens have been used for years as an estrogen supplement in order to treat or prevent a variety of conditions that are induced or exacerbated by estrogen hormone deficiency. Particularly, conditions experienced by peri-menopausal, menopausal, and post-menopausal women such as osteoporosis, hot flashes, vaginal atrophy, and loss of protection against heart attacks, can be ameliorated using conjugated estrogens as part of an estrogen replacement therapy routine. Although conjugated estrogens may be administered using various routes of administration, oral tablet administration has traditionally been the most common. Such formulations have not only contained conjugated estrogens, but have also included other hormones, such as progesterone in order to balance the physiological effects of estrogen supplementation. For example, oral estrogen replacement tablets containing either a conjugated estrogen, or combination of conjugated estrogen and medroxyprogesterone acetate are currently marketed under the trade names PREMARIN.RTM., PREMPRO.TM., and PREMPHASE.RTM., by Wyeth-Ayerst Laboratories, Inc. Web site: http://www.delphion.com/details?pn=US06630166__ •

Control of selective estrogen receptor modulators Inventor(s): Hodgen; Gary D. (Virginia Beach, VA) Assignee(s): Medical College of Hampton Roads (va) Patent Number: 6,653,297 Date filed: April 13, 1998 Abstract: The treatment of an estrogen sensitive condition by the administration of a selective estrogen receptor modulator is improved by additionally administering a progestationally active compound to the recipient. The additional agent can express both progestational and androgenic activity or an androgenically active material can be employed, if desired. Additionally, clomiphene in an array of isomeric ratios (EN:ZU) can be used alone for prevention of osteoporosis, maintenance of a healthful blood lipid profile, and prevention of breast tumors, or to sustain amenorrhea. Excerpt(s): The use of estrogens in the course of treatment of a variety of conditions is well known. For example, the most prevalent form of oral contraception is the so-called combined oral contraceptive preparation, a pill that combines both estrogen and a progestin. Apparently, the progestin acts foremostly to block gonadotropin release while the estrogen component primarily provides endometrial control to diminish breakthrough bleeding. Another well-known use is long term estrogen replacement therapy which is common for post-menopausal and other estrogen deficient women. Other estrogen dependent conditions include endometriosis, uterine fibroid tumors (leiomyomata), pre-menstrual syndrome, dysfunctional uterine bleeding, breast tumors (benign and malignant) and the like. Despite their value, estrogen treatments are also associated with undesirable side effects. For example, estrogen therapy has been associated with an increased incidence of endometrial cancer, especially due to the continual "unopposed" estrogen-induced proliferation of the endometrium. Other side effects include uterine bleeding and cyclotherapeutic withdrawal menstrual bleeding during a time in their lives when many women welcome cessation of menstrual bleeding as a normal occurrence in menopause. Estrogen therapy has also been implicated in the development of a variety of disorders including gallbladder disease,

Patents

231

hypertension, abnormal glucose tolerance, hypercoagulable states and breast cancer, although some of these observations are antidotal in nature and have not been confirmed. There have been numerous efforts to counteract the ill effects of estrogen therapy. For instance, attempts have been made to couple estrogen therapy with short periods of anti-estrogen supplementation. Another approach is to use anti-estrogens in place of the estrogen. Certain compounds are known as "anti-estrogens" because they can bind to the estrogen receptors and competitively block the binding of the more potent estrogens such as estradiol. Among the best known of these anti-estrogens are clomiphene and tamoxifen. However, all such anti-estrogens can be, in fact, active estrogens depending on the tissue, dose/regimen and hormonal milieu of the drug exposure. These are mixed function agonistic/antagonistic activities. The degree to which the anti-estrogen acts as an estrogen also depends on the particular material and the tissue site. Web site: http://www.delphion.com/details?pn=US06653297__ •

Crystalline form of 6-hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4methoxyphenyl)benzo [b]thiophene hydrochloride Inventor(s): Bush; Julie Kay (Fishers, IN), Conrad; Preston Charles (Indianapolis, IN), Flom; Merlyn Gerard (Noblesville, IN) Assignee(s): Eli Lilly and Company (indianapolis, In) Patent Number: 6,610,706 Date filed: January 10, 2002 Abstract: The present invention is directed to a novel crystalline hydrate of 6-hydroxy-3(4-[2-(piperidin-1-yl)ethoxy]-phenoxy)-2-(4-methoxyphenyl)benz o[b]thiophene hydrochloride and uses for same, including inhibition of disease states associated with estrogen deprivation including cardiovascular disease, hyperlipidemia, and osteoporosis; and inhibition of other pathological conditions such as endometriosis, uterine fibrosis, estrogen-dependent cancer (including breast and uterine cancer), prostate cancer, benign prostatic hyperplasia, CNS disorders including Alzheimer's disease, prevention of breast cancer, and up-regulating ChAT. Excerpt(s): 6-Hydroxy-3-(4-[2-(piperidin-1-yl)ethoxy]phenoxy)-2-(4methoxyphenyl)benzo[ b]thiophene hydrochloride (arzoxifene) was first described generically in U.S. Pat. No. 5,510,357 and was specifically disclosed in U.S. Pat. No. 5,723,474 ('474) and European Patent Application 0729956. Arzoxifene is a nonsteroidal mixed estrogen antagonist/agonist, useful for, inter alia, lowering serum cholesterol and for inhibiting hyperlipidemia, osteoporosis, estrogen dependent cancers including breast and uterine cancer, endometriosis, CNS disorders including Alzheimer's disease, aortal smooth muscle cell proliferation, and restenosis. Specifically, arzoxifene is useful for, and is being clinically evaluated for the treatment of receptor positive metastatic breast cancer; the adjuvent treatment of receptor positive patients following appropriate systemic or local therapy; the reduction of recurrence of invasive and noninvasive breast cancer; and the reduction of the incidence of invasive breast cancer and ductal carcinoma in situ (DCIS). Arzoxifene is also useful in combination with radiotherapy, aromatase inhibitors, LHRH analogues, and acetyl choline esterase (AChE) inhibitors. Xray powder diffraction (XRD), thermogravimetric (TGA), proton nuclear magnetic resonance (.sup.1 H NMR) and Karl Fischer (KF) analyses of bulk arzoxifene isolated by the procedures taught in '474 later indicated that said material was hydrated, poorly

232

Estrogen

crystalline, and contained variable amounts of an organic volatile (ethyl acetate) in its lattice. Web site: http://www.delphion.com/details?pn=US06610706__ •

Dosage forms and methods for oral delivery of progesterone Inventor(s): Ho; Thomas Chun (Irvine, CA), Hsia; David Chung (Irvine, CA), Tan; Domingo Yap (Irvine, CA), Weihmuller; Fredric B. (Huntington Beach, CA) Assignee(s): Watson Pharmaceuticals, Inc. (corona, Ca) Patent Number: 6,544,553 Date filed: December 28, 1999 Abstract: Provided is an oral dosage form suitable to deliver a combined dosage of progesterone and which upon delivery through the gastrointestinal tract provides a blood concentration of from about 0.1 ng/ml to about 400 ng/ml progesterone; said dosage form comprising a combination that includes (a) a first solid form comprising from about 25 mg to about 500 mg micronized progesterone in a solid polyethylene glycol carrier having an average molecular weight of from about 1000 to 10,000 and constituting at least about 30% of said first solid form; and (b) a second solid form comprising an estrogen. Excerpt(s): This invention relates to oral dosage forms of hormones and methods for their delivery to subjects needing hormone therapy. Agnus et al., U.S. Pat. No. 6,086,916, col. 1, line 56-col. 2, line 4, discusses Gram [Novo Nordisk ]WO 95/05807 as "describ[ing] tablets containing progesterone and a polyethylene glycol, as well as an excipient chosen from the group containing starches, starch-containing components, modified starches, celluloses, modified celluloses, pectins and tragacanth. [T]he presence of polyethylene glycol and of the excipient in the tablets results in a favourable effect on the bio-availability of orally administered progesterone. * * * [T]he tablets * * * contain high percentages of excipients." Gram's Abstract states that she provides an oral progeseterone that "may, conveniently, contain a PEG, and a further excipient selected from the group comprising a starch, a cellulose, pecting, and tragacanth." The polyethylene glycols are referred to as "liquid or solid polymers". Page 7, lines 20-22. Examples with progesterone and estradiol include maize starch, lactose, polyethylene glycol 6000, croscarmellose sodium, magnesium stearate and taclum powder. Agnus '916 itself has an an object progesterone dosage forms that also include "diluents, disintegrating agents, lubricants and binding agents." Col. 2, lines 36-37. "As examples of diluents, mention may be made of starches, polyols and celluloses * * * preferably pregelatinized maize starch, mannitol and microcrystalline cellulose." Id., lines 38-42. Polyvinylpyrrolidone is said to be the preferred binding agent. Web site: http://www.delphion.com/details?pn=US06544553__

Patents

•

233

Expression of human estrogen receptors in transgenic mice Inventor(s): Anderegg; Birgit (San Francisco, CA), Arbeit; Jeffrey M. (San Francisco, CA), Kushner; Peter J. (San Francisco, CA), Uht; Rosalie M. (San Francisco, CA) Assignee(s): The Regents of the University of California (oakland, Ca) Patent Number: 6,586,655 Date filed: August 2, 1999 Abstract: The present invention relates to improved compositions and methods for assaying the efficacy of novel drugs functioning either as agonists or antagonists at nuclear receptors. In particular, the invention provides transgenic non-human animals comprising a human steroid hormone receptor gene operably linked to a promoter which directs expression of the steroid hormone receptor gene in an epithelial cell of the non-human animals. Excerpt(s): This invention pertains to the field of transgenic non-human animals. In particular this invention pertains to transgenic animals that express human steroid hormone receptor genes in desired tissues, such as the epithelium, and to methods of screening potential therapeutics for activity at steroid hormone receptors. Steroid hormones are secreted by the adrenal cortex, testis, ovary and placenta and include the androgens (such as testosterone), estrogens (such as estradiol and estrone), glucocorticoids (cortisone, corticosterone, and cortisol), mineralocorticoids (primarily aldosterone), and progestogens (primarily progesterone). Steroid hormones regulate proliferation and differentiation in target cells within the reproductive tract, mammary gland, and peripheral tissues such as the bones, heart, blood vessels, and hair follicles (for a review, see Yamashita et al., Localization and functions of steroid hormone receptors, 1998, Histol. Histopathol. 13(1):255-70). Steroid hormones are highly lipophilic and act through nuclear receptors rather than through receptors on the plasma membrane. Steroid hormone receptors have been shown to support the development of cancer in the breast, prostate, uterus, cervix, and ovaries. In addition, steroid hormone receptors appear to prevent osteoporosis of the bones, to prevent atherosclerosis of the coronary arteries of the heart, and to mediate baldness in men. Therefore, steroid hormone nuclear receptors and other gene products that are involved in steroid hormone metabolism are attractive targets for the development of therapeutics that address the treatment of reproductive cancers and conditions such as osteoporosis, atherosclerosis, and baldness. Web site: http://www.delphion.com/details?pn=US06586655__

•

Hormone replacement therapy method Inventor(s): Elliesen; Jorg (Berlin, DE), Riedl; Jutta (Berlin, DE) Assignee(s): Schering Aktiengesellschaft (berlin, De) Patent Number: 6,551,611 Date filed: May 1, 2000 Abstract: Varying the daily dose of either or both of the estrogen and the progestogen administered for hormone replacement therapy (HRT) is readily and inexpensively accomplished, without the necessity of the physician prescribing a new product each time the daily dose of the estrogen or progestogen is changed, by administering preferably transdermally the estrogen and the progestogen contained in separate

234

Estrogen

extrudable pharmaceutical compositions from a dispenser which contains means, preferably adjustable only by the attending physician or dispensing pharmacist, for varying the volume of either or both of the respective compositions which is dispensed as a single dose from the dispenser in response to a defined digital dispensing manipulation of the dispenser thereby facilitating optimal compliance to a combination of HRT with individually adjusted dosages of the estrogen and progestogen. Excerpt(s): This invention relates to a method of conducting hormone replacement therapy (HRT) and to dispensers and kits adapted to practice the method. Thus, a fixed combination of an estrogen dosage and a progestogen dosage that is suitable for all menopausal women is impossible to design, for a variety of reasons. One reason is the wide variation from individual to individual in the resorption rate which exists with all modes of administration except intraveneous, which is not practiced in HRT. These differences in bioavailability can reach 100% or more. For example, the bioavailability of estradiol orally averages 5% of the oral dose, which means that in an individual it an be as low as 3% or as high as 6%. Another reason why a fixed combination is not suitable is because of variations in body weight and fat mass proportion, which has an endrocrine function because it contains enzymes to transform hormonal precursors into estrogens. A third reason is the interaction between estrogens and progestogens, i.e., progestogens may only become effective in the presence of estrogens because they stimulate the production of progestogen recepton. Consequently, estrogens and progestogen which are formulated commercially for HRT typically are sold as combined estrogen/progestogen tablets in more than one dosage strengths. However, the physician is still limited as to the size of the single dose of the estrogen and the progesterone which can be prescribed by those commercially available. Moreover, providing an estrogen/progestogen combination in tablets of multiple strengths adds to the manufacturing cost of producing a combination of a specific estrogen and a specific progestogen and increases significantly the inventory required of pharmacies to make any commercially available combination available to thepatients to whom it is prescribed. Therefore, some pharmacies do not stock their estrogen/progestogen products in tablet form in all of the dosage strengths which are commercially available, which can limit the flexibility desired by physicians in a dosage protocol for an individual patient, which ideally is customized in accordance with the symptoms of that patient which are currently manifested by is her. Web site: http://www.delphion.com/details?pn=US06551611__ •

Identifying, monitoring, and treating women for breast precancer or cancer Inventor(s): Cen; Hui (Oakland, CA), Hung; David (Belmont, CA), Love; Susan (Pacific Palisades, CA) Assignee(s): Cytyc Health Corporation (boxborough, Ma) Patent Number: 6,642,010 Date filed: February 10, 2000 Abstract: The invention is to methods for screening women for breast cancer and precancer by determining a level of an estrogen-related marker. The invention further provides methods of treating such patients identified as having one or more abnormal ductal epithelial cells and an estrogen-related marker. The invention provides methods for screening patient for hormone replacement therapy (HRT), and of monitoring such patients once they begin HRT. The invention provides methods of treating peri-, menopausal or postmenopausal women for both cancer risk reduction and menopausal

Patents

235

symptoms (or other conditions related to lowered systemic estrogen levels). The invention also provides kits for the screening, monitoring, and treating methods described. Excerpt(s): The field of this invention is identifying, treating and monitoring women at risk for or having breast precancer or cancer. Although the role of hormone replacement therapy (HRT) using estrogen or an estrogen/progestin combination in the etiology of breast cancer continues to be debated (Colditz, G A J. Women 's Health 8(3): 347-57 (1999), the magnitude of increase in breast cancer risk per year of hormone use is comparable to that associated with delaying menopause by a year (Colditz, G A J. Nat'l Cancer Inst 90(11): 814-23 (1998). Adding support to these conclusions is other research concluding that experimental and clinical evidence currently underway and recently completed suggests that breast neoplasia is a hormone-dependent process (Newman et al., J. Surg. Oncol. 71(4): 250-260 (1999)) and as such a postmenopausal patient may be placed at increased risk of breast neoplasia with prolonged HRT. Studies conducted by at least one group in Tavani and Vecchia, Drugs Aging 14(5): 347-57 (1999) indicate that there is a 2.3% risk of breast cancer for women on HRT for from 5 to 15 years if the women start the therapy at age 50. Estrogens and estrogen/progestin combination are most frequently prescribed to patients experiencing menopausal symptoms, and generally the duration of treatment is about a year but sometimes up to 5 years for these patients. Less frequently, estrogen is prescribed to postmenopausal women experiencing osteoporosis (bone density loss). The treatment duration for osteoporosis, a potentially serious and life threatening condition, can be prolonged. Osteoporosis is associated with increased mortality due to increased fractures, particularly hip fractures and affects millions of people worldwide. Women of postmenopausal age (i.e., approximately over 50 years of age) are one category prone to the development of low bone density associated with osteoporosis. See, Watts, Obstet Gynecol Surv 54(8): 532-8 (1999). Osteoporosis is reduced with estrogen administration. See, for example Shoupe D, Hosp Pract (OffEd) 34(8): 97-103, 107-8, 113-4 (1999). Estrogen administration has also positive effects to reduce the risk of cardiovascular risk in postmenopausal women. (See, for example Shoupe D, Hosp Pract (OffEd) 34(8): 97-103, 107-8, 113-4 (1999). There is evidence that estrogen therapy decreases risk for coronary heart disease (and for hip fracture), but long-term estrogen therapy increases risk for endometrial cancer and may be associated with a small increase risk for breast cancer (See, Grady, D et al., Ann Intern Med 117(12): 1016-37 (1992)). Web site: http://www.delphion.com/details?pn=US06642010__ •

Method for the treatment of urinary incontinence Inventor(s): Caruso; Frank S. (Colts Neck, NJ) Assignee(s): Endo Pharmaceuticals Inc. (chadds Ford, Pa) Patent Number: 6,562,835 Date filed: October 21, 1996 Abstract: Urinary incontinence is alleviated in a mammal by administering to the mammal a urinary incontinence alleviating amount of dextromethorphan, dextrorphan, their mixtures and/or pharmaceutically acceptable salts, alone or in combination with a pharmacologically active agent such as an anticholinergic, sympathomimetic, tricyclic antidepressant, antispasmodic, direct-acting smooth muscle relaxant, estrogen, compound having estrogen-like activity, or any combination of the foregoing.

236

Estrogen

Excerpt(s): The present invention relates to a method for treating urinary incontinence. Urinary incontinence is a fairly common medical problem in which urine is involuntarily lost. Urinary incontinence may be transient or persistent. Common causes of transient urinary incontinence include infection, atrophic urethritis, administration of diuretics and delirium. Persistent urinary incontinence is classified into four types: (1) stress incontinence which involves involuntary loss of urine during coughing, sneezing, laughing, or other physical activity; (2) urge incontinence which involves involuntary loss of urine associated with an abrupt or strong desire to void; (3) overflow incontinence which involves involuntary loss of urine associated with over-distension of the bladder; and (4) mixed incontinence which involves a combination of at least two of the above types. Persistent urinary incontinence can result from spastic or hyperactive bladder smooth muscle such as detrusor originating incontinence. In certain instances such incontinence is caused by loss of control resulting from spinal injury, parkinsonism, multiple sclerosis or recurrent bladder infection to name a few. Treatment of incontinence may involve surgery or administration of any of various pharmacological agents, e.g., a anticholinergic such as oxybutynin, atropine, propantheline, terodiline, dicyclomine and others, a sympathomimetic such as ephedrine, pseudoephedrine, phenylpropanolamine and others, a tricyclic antidepressant such as amitriptyline, imipramine, doxepin and others, an estrogen or a direct acting antispasmodic such as flavoxate. In addition to treating incontinence, such pharmacological agents may cause other powerful physiologic responses such as excitability (sympathomimetics), and dry mouth, drowsiness, dizziness or hallucinations (anticholinergics or tricyclic antidepressants). Web site: http://www.delphion.com/details?pn=US06562835__ •

Methods and kits for improving vascular health Inventor(s): Day; Wesley W. (San Diego, CA), Lee; Andrew G. (Old Lyme, CT), Thompson; David D. (Gales Ferry, CT) Assignee(s): Pfizer Inc. (new York, Ny) Patent Number: 6,620,806 Date filed: October 15, 2001 Abstract: The present invention provides methods and kits for improving or maintaining vascular health, including preventing myocardial infarction or stroke; maintaining or improving vascular reactivity; treating acute or chronic renal failure, peripheral arterial occlusive disease, coronary artery disease, or Raynaud's phenomenon; or lowering plasma levels of Lp(a) using an estrogen agonist/antagonist. Excerpt(s): This invention relates to methods and kits for improving vascular health, including preventing myocardial infarction or stroke; maintaining or improving vascular reactivity; treating acute or chronic renal failure, peripheral arterial occlusive disease, coronary artery disease, or Raynaud's phenomenon; or lowering plasma levels of Lp(a) using an estrogen agonist/antagonist. In premenopausal women, 17.beta.estradiol produced by the ovaries is the chief circulating estrogen. Serum estradiol concentrations are low in preadolescent girls and increase at menarche. In women, they range from about 100 pg per milliliter (367 pmol per liter) in the follicular phase to about 600 pg per milliliter (2200 pmol per liter) at the time of ovulation. They may rise to nearly 20,000 pg per milliliter (70,000 pmol per liter) during pregnancy. After menopause, serum estradiol concentrations fall to values similar to or lower than those in men of similar age (5 to 20 pg per milliliter [18 to 74 pmol per liter]) (Yen, S. S. C. and

Patents

237

Jaffe, R. B., eds. Reproductive Endocrinology: Physiology, Pathophysiology and Clinical Management, 3rd ed. Philadelphia: W. B. Saunders, (1991)). The ovaries are the principle source of estrogen in premenopausal women. The major secretory product is estradiol, synthesized by granulosa cells from androgenic precursors provided by thecal cells. Secreted estradiol is oxidized reversibly to estrone, and both of these estrogens can be converted to estriol. These transformations take place mainly in the liver, where interconversion between estrone and estradiol is catalyzed by 17-hydroxysteroid dehydrogenase. Web site: http://www.delphion.com/details?pn=US06620806__ •

Monoclonal antibody against estrogen stimulated leucine aminopeptidase Inventor(s): Pulido-Cejudo; Gabriel (Ottawa, CA) Assignee(s): Her Majesty the Queen in Right of Canada, AS Represented by the Minister of (ca) Patent Number: 6,649,743 Date filed: March 30, 2000 Abstract: The identification and characterization of risk factors and their molecular implications in the pathophysiology of human diseases such as cancer is essential for designing efficient diagnostic assays and therapeutic compounds. Estrogenic steroids, under normal physiological conditions, have been shown to play a critical function in several tissues. The response of such a variety of tissues to estrogen stimulation can explain in part its active role in the development and progression of different human diseases, particularly Breast Cancer. Searching for estrogen-responding cellular factors in parental cells of primary human breast carcinomas obtained from tumor biopsies an isoenzyme of putative Leucine Aminopeptidase (LAPase; EC 3.4.11.1) was idenditifed. Results have demonstrated that this marker is found to be elevated in the sera of women with invasive ductal and metastatic carcinomas. A monoclonal antibody against this cellular marker have been produced. This invention refers to the use of LAPase monoclonal antibodies for first line confimatory blood-based testing for Breast Cancer. Excerpt(s): This application claims benefit of foreign priority from Canada patent application 2,267,481, filed Mar. 30, 1999. The present invention relates to a monoclonal antibody which demonstrates specific binding to human estrogen-responsive isoenzyme of Leucine Aminopeptidase (es-LAPase). The present invention also relates to the hybridoma cell line, designated as 7B6, and the monoclonal antibody produced by the same. The present invention further relates to a diagnostic system using the monoclonal antibody from the hybridoma cell line 7B6, to detect blood, serum or plasma levels of the estrogen responsive isoenzyme of Leucine Aminopeptidase. The antibody is particularly useful for rapid diagnostic tests for breast cancer. The identification and characterization of risk factors and their molecular implications in the pathophysiology of human diseases such as breast cancer is essential for designing efficient diagnostic assays and therapeutic compounds. Amongst the various risk factors associated with the onset of early events leading to Breast Cancer, estrogen and estrogen-like compounds with estrogenic mimicking activity remain the most important determinants in the early events and progression of breast carcinogenesis. Under normal physiological conditions, there are several tissues whereby estrogenic steroids have been shown to play a critical function. These include the development of the reproductive tract, particularly secondary organs, such as the mammary glands. In addition, estrogens are also involved in the fine regulation of bone growth, liver and cardiovascular function and

238

Estrogen

the estrus cycle, most likely through the induction of cell proliferation in target tissues [Sutherland R. L. et al., pp. 197-215, Elsevier Science Publishing B. V., Amsterdam., Shekhar P. V. M., et al., J. NatL Cancer. Inst., 89: 1774-1782.]. The response of such a variety of tissues to estrogen stimulation can explain in part its active role in the development and progression of different human carcinomas and in particular of Breast Cancer. Although the precise molecular mechanisms by which estrogen stimulation regulates various physiological functions requires further elucidation, this steroid is involved in both "immediate-early" and "early" events of cell function. In this regard, it appears that immediate early events induced by estrogen lead to an increased cellular proliferation most likely through the reduction in the cell cycle by accelerating the rate at which cells progress from the G.sub.l phase towards the S phase. Recently, it has been proposed that estrogen promotes cellular proliferation by co-activating at similar estrogen concentrations, the expression of cyclin Dl-Cdk4 and cyclin E-Cdk2, two critical and potentially interrelated G.sub.l regulatory peptides [Prall, O. W. J., et al., J. Biol. Chem., 272: 10882-10894.]. Web site: http://www.delphion.com/details?pn=US06649743__ •

Non-steroidal estrogen receptor ligands Inventor(s): Kwiatkowski; Stefan (Lexington, KY), Lazarowych; Natalie (Richmond Hill, CA), Lowell; Jeffry Lawrence (Lexington, KY), Mercure; Julie (Guelph, CA), Pupek; Krzysztof (Woodrigh, IL), Schmidt; Jonathan Martin (Elora, CA), Whelan; John (Toronto, CA), Zhu; Shuguang (Seattle, WA) Assignee(s): Nanodesign, Inc. (montreal, Ca) Patent Number: 6,599,921 Date filed: August 21, 2001 Abstract: Novel non-steroidal estrogen receptor ligands and methods of synthesis are disclosed. The novel molecules are intended for use in therapeutic preparations for the treatment of estrogen receptor related disease states. The compounds specified are tetracyclic derivatives and have been shown to be antiproliferative against human estrogendependent cancer cells and to have good binding affinity for the estrogen receptor. Excerpt(s): The present invention relates to non-steroidal compounds that demonstrate high-binding affinity for the estrogen receptor, while being devoid of any agonistic effects on reproductive tissues and to non-steroidal compounds that have a high binding affinity for the estrogen receptor while also having some agonistic activity specific to the skeletal and cardiovascular systems. More particularly, the present invention relates to novel non-steroidal ligands for the estrogen receptor as well as methods of making the same and their applications in treating a variety of disease states. Interfering with the activity of endogenously produced estrogens can modulate the course of many estrogen-dependent diseases. One approach has been to prevent estrogen biosynthesis using inhibitors of aromatase enzymes, which are responsible for the conversion of androgens to estrogens. Alternatively, estrogen activity may be interrupted at the receptor level using estrogen antagonists. The involvement of estrogens in the development and progression of breast cancer has been known for over 100 years. In normal breast tissue, only 6% of the mammary epithelial cells express estrogen receptors (McDonnell et al., Ann. N. Y. Acad. Sci. 1996; 121-37), whereas over 60% of primary breast tumors are estrogen receptor positive and are dependent on estrogen for growth. However, it has been documented that other agents (e.g. growth factors) can activate estrogen receptors in the absence of estrogen (Pareczyk and Schneider, J.

Patents

239

Cancer Res. Clin. Oncol. 1996; 122:383-96). As a result, blocking activity at the estrogen receptor is potentially a more effective therapeutic strategy than inhibition of estrogen biosynthesis. Web site: http://www.delphion.com/details?pn=US06599921__ •

Steroid hormone receptor interacting protein kinase Inventor(s): Balk; Steven (Needham, MA) Assignee(s): Beth Israel Deaconess Medical Center (boston, Ma) Patent Number: 6,673,586 Date filed: January 19, 2001 Abstract: The present invention features a novel p21-activated kinase that interacts with steroid hormone receptors, the steroid hormone receptor interacting p21-activated kinase (PAK.sub.SI). In general, the invention provides methods of inhibiting hormone related cancers. More particularly, the present invention relates to inhibiting prostate cancer and breast cancer. The present invention further provides methods of activating the therapeutic effects of steroid hormone receptors, particularly the estrogen receptor. Alternatively, the present invention provides methods of diagnosing steroid hormone receptor-related diseases. Excerpt(s): Prostate cancer now ranks as the most prevalent cancer in men. Approximately 160,000 new cases are diagnosed each year; of these new cases, 35,000 will die of metastatic disease. In women, breast cancer kills 45,000 women per year. Steroid hormone receptors and the factors that bind steroid hormone receptors are key players in the maintenance of healthy tissue. Similarly, disregulation of steroid hormone receptors and steroid hormone receptor interacting proteins are important to the development of a wide variety of sex steroid hormone dependent cancers and diseases. Current therapies for such afflictions include surgery (e.g., castration) and chemical treatment (e.g., chemotherapy and hormone ablation therapy). Androgens in normal prostate epithelium appear to primarily drive differentiation. In contrast, prostate cancer growth is directly androgen stimulated. Thus, one common therapy for the treatment of prostate cancer is androgen ablation therapy, to which most patients respond. Unfortunately, virtually all prostate cancer relapse is clinically androgen independent. Significantly, most androgen independent tumors express high levels of androgen receptor as well as androgen receptor regulated genes, indicating that the androgen receptor is transcriptionally active (van der Kwastet et al., Int. J. Cancer 48, 189-193 (1991); Ruizeveld de Winter et al., Am. J. Pathol. 144, 735-746 (1994); Taplin et al., N. Engl. J. Med. 332, 1393-1398 (1995); Hobisch et al., Cancer Res. 55, 3068-3072 (1995); Visakorpi et al., Nat. Genet. 9, 401-406 (1995); and Koivisto et al., Cancer Res. 57, 314-319 (1997)). It has been demonstrated that structural changes in the androgen receptor contribute to altered androgen receptor function in primary or androgen independent prostate cancer. Most reports find that the androgen receptor is wild-type in primary androgen dependent prostate cancer, with a few exceptions (Tilley et al., Clin. Cancer Res. 2, 277-285 (1996)). In contrast, androgen receptor mutations have been identified in androgen independent prostate cancer (Taplin et al., supra; Culig et al., Mol. Endocrinol. 7, 1541-1550 (1993); Suzuki et al., J. Steroid Biochem. Mol. Biol. 46, 759-765 (1993); Suzuki et al., Prostate 29, 153-158 (1996); and Taplin et al., Cancer Res. 59, 2511-2515. (1999)). An analysis of androgen independent prostate cancer from a large number of bone marrow metastases recently showed that androgen receptor ligand binding domain mutations occur primarily in patients treated with the androgen receptor antagonist flutamide

240

Estrogen

(Taplin et al., supra). Importantly, these mutations result in androgen receptors that are strongly stimulated by hydroxyflutamide. Fortunately, patients with these mutations respond to subsequent treatment with bicalutamide, an androgen receptor antagonist that remains active against these mutant androgen receptors (Taplin et al., supra; and Joyce et al., J. Urol. 159, 149-153 (1998)). Web site: http://www.delphion.com/details?pn=US06673586__ •

Transdermal administration of steroid drugs using hydroxide-releasing agents as permeation enhancers Inventor(s): Hsu; Tsung-Min (San Diego, CA), Luo; Eric C. (Plano, TX) Assignee(s): Dermatrends, Inc. (san Diego, Ca) Patent Number: 6,562,370 Date filed: December 14, 2000 Abstract: A method is provided for increasing the permeability of skin or mucosal tissue to transdermally administered steroid drugs. The method involves use of a specified amount of a hydroxide-releasing agent, the amount optimized to increase the flux of the drug through a body surface while minimizing the likelihood of skin damage, irritation or sensitization. Formulations and drug delivery systems for co-administering a hydroxide-releasing agent with a steroid drug are provided as well. Optimally, the steroid drugs are a combination of an estrogen and progestin that may be administered in female hormone replacement therapy, to provide female contraception, and the like. Excerpt(s): This invention relates generally to transdermal administration of pharmacologically active agents, and more particularly relates to methods and compositions for transdermally administering steroid drugs, particularly progestins and estrogens. The delivery of drugs through the skin provides many advantages; primarily, such a means of delivery is a comfortable, convenient and noninvasive way of administering drugs. The variable rates of absorption and metabolism encountered in oral treatment are avoided, and other inherent inconveniences--e.g., gastrointestinal irritation and the like--are eliminated as well. Transdermal drug delivery also makes possible a high degree of control over blood concentrations of any particular drug. Skin is a structurally complex, relatively thick membrane. Molecules moving from the environment into and through intact skin must first penetrate the stratum corneum and any material on its surface. They must then penetrate the viable epidermis, the papillary dermis, and the capillary walls into the blood stream or lymph channels. To be so absorbed, molecules must overcome a different resistance to penetration in each type of tissue. Transport across the skin membrane is thus a complex phenomenon. However, it is the cells of the stratum corneum which present the primary barrier to absorption of topical compositions or transdermally administered drugs. The stratum corneum is a thin layer of dense, highly keratinized cells approximately 10-15 microns thick over most of the body. It is believed to be the high degree of keratinization within these cells as well as their dense packing which creates in most cases a substantially impermeable barrier to drug penetration. With many drugs, the rate of permeation through the skin is extremely low and is particularly problematic for high molecular weight drugs such as steroids. Consequently, a means for enhancing the permeability of the skin is desired to effect transport of a steroid drug into and through intact skin. Web site: http://www.delphion.com/details?pn=US06562370__

Patents

241

Patent Applications on Estrogen As of December 2000, U.S. patent applications are open to public viewing.10 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to estrogen: •

Diagnosis and prognosis of breast cancer patients Inventor(s): Bernards, Rene; (Abcoude, NL), Dai, HongYue; (Bothell, WA), Hart, A.A. M.; (Castricum, NL), He, Yudong; (Kirkland, WA), Linsley, Peter S.; (Seattle, WA), Mao, Mao; (Kirkland, WA), Roberts, Christopher J.; (Seattle, WA), Van de Vijver, Marc J.; (Amsterdam, NL), Van't Veer, Laura Johanna; (Amsterdam, NL) Correspondence: Pennie And Edmonds; 1155 Avenue OF The Americas; New York; NY; 100362711 Patent Application Number: 20030224374 Date filed: June 14, 2002 Abstract: The present invention relates to genetic markers whose expression is correlated with breast cancer. Specifically, the invention provides sets of markers whose expression patterns can be used to differentiate clinical conditions associated with breast cancer, such as the presence or absence of the estrogen receptor ESR1, and BRCA1 and sporadic tumors, and to provide information on the likelihood of tumor distant metastases within five years of initial diagnosis. The invention relates to methods of using these markers to distinguish these conditions. The invention also relates to kits containing ready-to-use microarrays and computer software for data analysis using the statistical methods disclosed herein. Excerpt(s): This application claims benefit of U.S. Provisional Application No. 60/298,918, filed Jun. 18, 2001, and U.S. Provisional Application No. 60/380,710, filed on May 14, 2002, each of which is incorporated by reference herein in its entirety. This application includes a Sequence Listing submitted on compact disc, recorded on two compact discs, including one duplicate, containing Filename 9301175999.txt, of size 6,766,592 bytes, created Jun. 13, 2002. The sequence listing on the compact discs is incorporated by reference herein in its entirety. The present invention relates to the identification of marker genes useful in the diagnosis and prognosis of breast cancer. More particularly, the invention relates to the identification of a set of marker genes associated with breast cancer, a set of marker genes differentially expressed in estrogen receptor (+) versus estrogen receptor (-) tumors, a set of marker genes differentially expressed in BRCA1 versus sporadic tumors, and a set of marker genes differentially expressed in sporadic tumors from patients with good clinical prognosis (i.e., metastasis- or disease-free >5 years) versus patients with poor clinical prognosis (i.e., metastasis- or disease-free <5 years). For each of the marker sets above, the invention further relates to methods of distinguishing the breast cancer-related conditions. The invention further provides methods for determining the course of treatment of a patient with breast cancer. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

10

This has been a common practice outside the United States prior to December 2000.

242

•

Estrogen

Dipeptide derivatives Inventor(s): Carpino, Philip Albert; (Groton, CT), Griffith, David Andrew; (Old Saybrook, CT), Lefker, Bruce Allen; (Gales Ferry, CT) Correspondence: Pfizer INC.; Patent Department, Ms8260-1611; Eastern Point Road; Groton; CT; 06340; US Patent Application Number: 20030216399 Date filed: February 21, 2003 Abstract: This invention is directed to compounds of the formula 1and the pharmaceutically-acceptable salts thereof, where the substituents are as defined in the Specification, which are growth hormone secretogogues and which increase the level of endogenous growth hormone. The compounds of this invention are useful for the treatment and prevention of osteoporosis and/or frailty, congestive heart failure, frailty associated with aging, obesity; accelerating bone fracture repair, attenuating protein catabolic response after a major operation, reducing cachexia and protein loss due to chronic illness, accelerating wound healing, or accelerating the recovery of burn patients or patients having undergone major surgery; improving muscle strength, mobility, maintenance of skin thickness, metabolic homeostasis or renal homeostasis. The compounds of the present invention are also useful in treating osteoporosis and/or frailty when used in combination with: a bisphosphonate compound such as alendronate; estrogen, premarin, and optionally progesterone; an estrogen agonist or antagonist; or calcitonin, and pharmaceutical compositions useful therefor. Further, the present invention is directed to pharmaceutical compositions useful for increasing the endogenous production or release of growth hormone in a human or other animal which comprises an effective amount of a compound of the present invention and a growth hormone secretagogue selected from GHRP-6, Hexarelin, GHRP-1, growth hormone releasing factor (GRF), IGF-1, IGF-2 or B-HT920. The invention is also directed to intermediates useful in the preparation of compounds of Formula I. Excerpt(s): This invention relates to dipeptide compounds which are growth hormone secretagogues and are useful for the treatment and prevention of osteoporosis and/or frailty. 3. Increased mobilization of free fatty acids and use of fatty acids for energy. Deficiency in growth hormone results in a variety of medical disorders. In children, it causes dwarfism. In adults, the consequences of acquired GH deficiency include profound reduction in lean body mass and concomitant increase in total body fat, particularly in the truncal region. Decreased skeletal and cardiac muscle mass and muscle strength lead to a significant reduction in exercise capacity. Bone density is also reduced. Administration of exogenous growth hormone has been shown to reverse many of the metabolic changes. Additional benefits of therapy have included reduction in LDL cholesterol and improved psychological well-being. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Estrogen receptor modulators Inventor(s): DiNinno, Frank P.; (Old Bridge, NJ), Hammond, Milton Lloyd; (Somerville, NJ) Correspondence: Merck And CO Inc; P O Box 2000; Rahway; NJ; 070650907 Patent Application Number: 20030225132 Date filed: March 11, 2003

Patents

243

Abstract: The present invention relates to compounds and derivatives thereof, their synthesis, and their use as estrogen receptor modulators. The compounds of the instant invention are ligands for estrogen receptors and as such may be useful for treatment or prevention of a variety of conditions related to estrogen functioning including: bone loss, bone fractures, osteoporosis, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased levels of LDL cholesterol, cardiovascular disease, impairment of cognitive functioning, cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity, incontinence, and cancer, in particular of the breast, uterus and prostate. Excerpt(s): Naturally occurring and synthetic estrogens have broad therapeutic utility, including: relief of menopausal symptoms, treatment of acne, treatment of dysmenorrhea and dysfunctional uterine bleeding, treatment of osteoporosis, treatment of hirsutism, treatment of prostatic cancer, treatment of hot flashes and prevention of cardiovascular disease. Because estrogen is very therapeutically valuable, there has been great interest in discovering compounds that mimic estrogen-like behavior in estrogen responsive tissues. For example, estrogen-like compounds would be beneficial in the treatment and prevention of bone loss. Bone loss occurs in a wide range of subjects, including women that are post-menopausal or have had a hysterectomy, patients who were or are currently being treated with corticosteroids, and patient's having gonadal dysgenesis. The current major bone diseases of public concern are osteoporosis, hypercalcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, immobilization-induced osteopenia, and glucocorticoid-induced osteoporosis. All of these conditions are characterized by bone loss, resulting from an imbalance between bone resorption, i.e. breakdown, and bone formation, which continues throughout life at the rate of about 14% per year on the average. However, the rate of bone turnover differs from site to site, for example, it is higher in the trabecular bone of the vertebrae and the alveolar bone in the jaws than in the cortices of the long bones. The potential for bone loss is directly related to turnover and can amount to over 5% per year in vertebrae immediately following menopause, a condition which leads to increased fracture risk. In the U.S., there are currently about 20 million people with detectable fractures of the vertebrae due to osteoporosis. In addition, there are about 250,000 hip fractures per year attributed to osteoporosis. This clinical situation is associated with a 12% mortality rate within the first two years, while 30% of the patients require nursing home care after the fracture. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Exemestane as chemopreventing agent Inventor(s): Di Salle, Enrico; (Milan, IT), Martini, Alessandro; (Milan, IT), Massimini, Giorgio; (Abbiategrasso Milan, IT), Muggetti, Lorena; (Meda, IT), Piscitelli, Gabriella; (Milan, IT), Purandare, Dinesh; (Branchburg, NJ) Correspondence: Stephen H Docter; Mcdonnell Boehnen Hulbert & Berghoff; Suite 3200; 300 South Wacker; Chicago; IL; 60606; US Patent Application Number: 20040024044 Date filed: August 4, 2003 Abstract: The present invention concerns the use of aromatase inhibitor exemestane, either alone or in combination with other therapeutic agents in the chemoprevention of

244

Estrogen

estrogen dependent cancer in mammals, including humans, at increased risk of the disease. Excerpt(s): The invention belongs to the fields of pharmaceutical chemistry and anticancer medicine, and provides a method of chemoprevention of estrogen dependent cancer. Cancers, including estrogen dependent cancers, are generally thought to result from a multistep process, in which a series of somatic mutations, and/or chromosomal changes occur. Each step results in a greater deviation from normal cellular behavior, until cells lose the normal ability to regulate their own growth and therefore proliferate. The altered cells first proliferate into a precanceruos neoplasm, which progresses in stages toward metastatic cancer. This process is known as tumor progression. On the other hand, for instance approximately 30% of breast cancers are hormone-sensitive and are treated with a variety of agents other than oophorectomy (surgical or radiological), including anti-estrogens, progestins and aromatase inhibitors. Despite the variety of treatments available, approximately on third of the early treated breast cancer (EBC) will relapse within 10 years from diagnosis, and as soon as the disease becomes metastatic (BMC), the medium life expectancy is of about 2,5-3 years. There is therefore a high and unmet medical need for therapeutic agents aimed at prevention of hormone dependent tumors and, in particular, of both primary and secondary breast cancer. Cancer chemoprevention is a new discipline whose foundation rests upon epidemiologic evidence suggesting that dietary components including vitamins and micronutrients such as beta-carotene, vitamin E, calcium and selenium may be inhibitors of carcinogenesis. However, although the precise biological mechanisms of cellular carcinogenesis are incomplete, a number of specific mechanisms seem to be procarcinogenic. Accordingly, estrogen modulators for instance may act as a chemopreventive agents in breast cancer by disrupting estrogen production, receptor binding or receptor activation. In this connection, the chemopreventive properties of tamoxifen were first demonstrated by the reduction of second primaries in a metaanalysis of breast cancer survivors who had taken the drug for 5 years. A major concern remains, however: the increased risk of endometrial cancer associated with tamoxifen administration. Since chemopreventive agents are intended for chronic (or long lasting) use in healthy or relative healthy subjects, toxicity, even if mild and reversible, is problematic. Accordingly, there is the need in this field of drugs endowed with low side effects and combinations of anticancer agents with non-overlapping toxicity while having enhanced therapeutic effect. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Identifying, Monitoring and treating women with breast precancer or cancer Inventor(s): Cen, Hui; (Oakland, CA), Hung, David; (Belmont, CA), Love, Susan; (Pacific Palisades, CA) Correspondence: Banner & Witcoff; 1001 G Street N W; Suite 1100; Washington; DC; 20001; US Patent Application Number: 20040029202 Date filed: August 11, 2003 Abstract: The invention is to methods for screening women for breast cancer and precancer by determining a level of an estrogen-related marker. The invention further provides methods of treating such patients identified as having one or more abnormal ductal epithelial cells and an estrogen-related marker. The invention provides methods for screening patient for hormone replacement therapy (HRT), and of monitoring such

Patents

245

patients once they begin HRT. The invention provides methods of treating peri-, menopausal or postmenopausal women for both cancer risk reduction and menopausal symptoms (or other conditions related to lowered systemic estrogen levels). The invention also provides kits for the screening, monitoring, and treating methods described. Excerpt(s): The present application is a continuation-in-part of U.S. application Ser. No. 09/313,463, filed on May 17, 1999, which claimed the benefit and priority of Provisional U.S. application Ser. No. 60/117,281 filed on Jan. 26, 1999, under 37 CFR.sctn.1.78, the full disclosures of which are incorporated herein by reference. The field of this invention is identifying, treating and monitoring women at risk for or having breast precancer or cancer. Although the role of hormone replacement therapy (HRT) using estrogen or an estrogen/progestin combination in the etiology of breast cancer continues to be debated (Colditz, G A J. Women's Health 8(3): 347-57 (1999), the magnitude of increase in breast cancer risk per year of hormone use is comparable to that associated with delaying menopause by a year (Colditz, G A J. Nat'l Cancer Inst 90(11): 814-23 (1998). Adding support to these conclusions is other research concluding that experimental and clinical evidence currently underway and recently completed suggests that breast neoplasia is a hormone-dependent process (Newman et al., J. Surg. Oncol. 71(4): 250-260 (1999)) and as such a postmenopausal patient may be placed at increased risk of breast neoplasia with prolonged HRT. Studies conducted by at least one group in Tavani and Vecchia, Drugs Aging 14(5): 347-57 (1999) indicate that there is a 2.3% risk of breast cancer for women on HRT for from 5 to 15 years if the women start the therapy at age 50. Estrogens and estrogen/progestin combination are most frequently prescribed to patients experiencing menopausal symptoms, and generally the duration of treatment is about a year but sometimes up to 5 years for these patients. Less frequently, estrogen is prescribed to postmenopausal women experiencing osteoporosis (bone density loss). The treatment duration for osteoporosis, a potentially serious and life threatening condition, can be prolonged. Osteoporosis is associated with increased mortality due to increased fractures, particularly hip fractures and affects millions of people worldwide. Women of postmenopausal age (i.e., approximately over 50 years of age) are one category prone to the development of low bone density associated with osteoporosis. See, Watts, Obstet Gynecol Surv 54(8): 532-8 (1999). Osteoporosis is reduced with estrogen administration. See, for example Shoupe D, Hosp Pract (OffEd) 34(8): 97-103, 107-8, 113-4 (1999). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Non-steroidal progesting Inventor(s): Fuhrmann, Ulrike; (Berlin, DE), Hegele-Hartung, Christa; (Muelheim/Ruhr, DE), Klotzbuecher, Michael; (Berlin, DE), Lehmann, Manfred; (Berlin, DE), Muhn, Peter; (Berlin, DE), Schmees, Norbert; (Berlin, DE) Correspondence: Millen, White, Zelano & Branigan, P.C.; 2200 Clarendon BLVD.; Suite 1400; Arlington; VA; 22201; US Patent Application Number: 20030232824 Date filed: March 11, 2003 Abstract: The present invention relates to non-steroidal progestins of the general formula (I) 1whereinR.sub.1 and R.sub.2 are independently of each other --H or -F,R.sub.3 is --CH.sub.3 or --CF.sub.3, andAr is 2or a pharmaceutically acceptable derivative or analogue thereof. These progestins are suitable for selectively modulating progesterone receptor mediated effects in different target tissues, particularly in uterine

246

Estrogen

tissue versus breast tissue. Therefore, the progestins of the present invention, optionally in combination with estrogens, may be used for contraception (in particular in estrogenfree oral contraceptives), hormone replacement therapy and the treatment of gynecological disorders. The present invention furthermore relates to methods for selectively modulating progesterone receptor mediated effects in different target tissues or organs. Excerpt(s): This application claims the benefit of the filing date of U.S. Provisional Application Serial No. 60/363,044 filed Mar. 11, 2002. The present invention relates to non-steroidal progestins of the general formula (I) as well as to uses of said compounds for selectively modulating progesterone receptor mediated effects in different target tissues, i.e., to progestins having a dissociated activity profile regarding different target tissues, preferably a uterus/breast dissociated profile. The present invention further relates to uses of said compounds as well as to methods for selectively enhancing progesterone receptor mediated effects in uterine tissue with respect to progesterone receptor mediated effects in breast tissue. Due to the unique dissociated activity and selectivity profile of the progestins according to the present invention, the invention in particular relates to the use of said compounds for fertility control, in particular for oral contraception, hormone replacement therapy and the treatment of gynecological disorders. The progestins according to the present invention are especially suitable for use in estrogen-free oral contraceptives. Progesterone is a unique reproductive hormone, and it plays a decisive role for tissues of female reproduction. Its principal target organs are uterus, ovary, breast and the hypothalamus-pituitary axis. In addition to the primary use as pregnancy control for women (e.g., oral contraception (OC)), progestins, optionally combined with estrogens, are widely used in hormone replacement therapy (HRT). Progestins are also used to treat several gynecological disorders, e.g., dysmenorrhea, endometriosis, and dysfunctional uterine bleeding caused by hormonal deficiency or imbalance. Due to certain effects of progestins, which may be undesirable for some applications, or cross-reactivities with receptors other than the progesterone receptor, the development of new generations of progestins to improve their activity profile has been a great challenge. Additionally, the exploration of therapeutic applications such as oncology demands progestins with new activity profiles. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Novel heteroatom containing tetracyclic derivatives as selective estrogen receptor modulators Inventor(s): Jain, Nareshkumar F.; (Raritan, NJ), Kanojia, Ramesh M.; (Raritan, NJ), Ng, Raymond; (Raritan, NJ), Sui, Zhihua; (Raritan, NJ), Xu, Jiayi; (Raritan, NJ) Correspondence: Audley A. Ciamporcero JR.; Johnson & Johnson; One Johnson & Johnson Plaza; New Brunswick; NJ; 08933-7003; US Patent Application Number: 20030216463 Date filed: December 2, 2002 Abstract: The present invention is directed to novel heteroatom containing tetracyclic derivatives, pharmaceutical compositions containing them, their use in the treatment and/or prevention of disorders mediated by one or more estrogen receptors and processes for their preparation. The compounds of the invention are useful in the treatment and/or prevention of disorders associated with the depletion of estrogen such as hot flashes, vaginal dryness, osteopenia and osteoporosis; hormone sensitive cancers

Patents

247

and hyperplasia of the breast, endometrium, cervix and prostate; endometriosis, uterine fibroids, osteoarthritis and as contraceptive agents, alone or in combination with a progestogen or progestogen antagonist. Excerpt(s): This application claims the benefit of U. S. Provisional Application 60/341,957, filed on Dec. 19, 2001, which is incorporated by reference herein in its entirety. The present invention is directed to novel heteroatom containing tetracyclic derivatives, pharmaceutical compositions containing them, their use in the treatment of disorders mediated by one or more estrogen receptors and processes for their preparation. The compounds of the invention are thus useful for the treatment and/or prevention of disorders associated with estrogen depletion (including, but not limited to hot flashes, vaginal dryness, osteopenia, osteoporosis, hyperlipidemia, loss of cognitive function, degenerative brain diseases, cardiovascular and cerebrovascular diseases); for the treatment of hormone sensitive cancers and hyperplasia (in tissues including breast, endometrium, and cervix in women and prostate in men); for the treatment and prevention of endometriosis, uterine fibroids, and osteoarthritis; and as contraceptive agents either alone or in combination with a progestogen or progestogen antagonist. Estrogens are a group of female hormones essential for the reproductive process and for the development of the uterus, breasts, and other physical changes associated with puberty. Estrogens have an effect on various tissues throughout a woman's body, not only those involved in the reproductive process, such as the uterus, breasts, and external genitalia, but also tissues in the central nervous system, bones, the liver, skin, and the urinary tract. The ovaries produce most of the estrogens in a woman's body. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Selective nuclear receptor-targeted systems for delivery of cytotoxins to cancer cells for targeted photodynamic therapy Inventor(s): Mohr, Scott C.; (Welesley, MA), Ray, Rahul; (Wayland, MA), Swamy, Narasimha; (Providence, RI) Correspondence: Weingarten, Schurgin, Gagnebin & Lebovici Llp; Ten Post Office Square; Boston; MA; 02109; US Patent Application Number: 20030220313 Date filed: November 7, 2002 Abstract: An estrogen/antiestrogen-porphyrin conjugate, their composition and methods for their use are claimed. The active compounds of the invention are conjugates consisting of an estrogen or anti estrogen portion, tether or linker portion and a porphyrin portion. The method of invention exploits an active process that involves strong and specific interactions between nuclear receptor and its cognate ligand. Excerpt(s): This application claims the priority of U.S. Provisional Application No. 60/196,637 filed Apr. 12, 2000 entitled, DEVELOPMENT OF SELECTIVE NUCLEAR RECEPTOR-TARGETED SYSTEMS TO DELIVER CYTOTOXINS, INCLUDING PHOTOSENSITIZERS, TO CANCER CELLS FOR TARGETED PHOTODYNAMIC THERAPY, the whole of which is hereby incorporated by reference herein. Photodynamic therapy (PDT), a recently developed method of intervention in the treatment of cancer, is based on the systemic administration of certain photosensitizing dyes, e.g. psoralens, pthalocyanins, acridine orange, and porphyrins in a manner that results in their selective accumulation into rapidly-proliferating cancer cells and the subsequent exposure of the tumor to light from a tunable laser, to kill the tumor (1,2).

248

Estrogen

The dyes, due to their photosensizing nature, capture photons from the light and transfer the energy to a neighboring oxygen molecule. This secondary reaction converts oxygen molecules to highly cytotoxic singlet oxygen, which leads to the death of the tumor cells. Since the irradiation is carried out at a wavelength of 600-800 nm, and singlet oxygen can travel only 0.1-0.2.mu.m from its site of generation, little damage occurs to the surrounding healthy tissues. The above description, however, is somewhat of an idealized situation because (a) selective accumulation of the PDT dyes solely by tumor cells is often difficult to achieve, (b) normal cells are also capable of accumulating porphyrins, and (c) the excretion of porphyrins from tissue is often slow. Clinically, these problems are often countered by the administration of a high dose of the dye, which can cause killing of the healthy cells surrounding the malignant tissues and prolonged toxicity of large body areas toward light-exposure. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Treatment of hypertension in women receiving hormone replacement therapy Inventor(s): Karara, Adel H; (Branchburg, NJ) Correspondence: Millen, White, Zelano & Branigan, P.C.; 2200 Clarendon BLVD.; Suite 1400; Arlington; VA; 22201; US Patent Application Number: 20040034001 Date filed: April 24, 2003 Abstract: A method is described to lower blood pressure and effect hormone replacement therapy (HRT) in a hypertensive woman receiving HRT, comprising administering to the woman effective amounts of drospirenone and an estrogen. In one embodiment, the woman is already taking hypertensive medicine when the method is carried out. Excerpt(s): This application claims the benefit of U.S. Provisional Application Serial No. 60/375,439, filed Apr. 26, 2002, which is incorporated herein in full by reference. The present invention is directed e.g., to a method to lower blood pressure and effect hormone replacement therapy (HRT) in a hypertensive human female (woman) receiving HRT, comprising administering to the woman an effective amount of drospirenone and an estrogen. In one embodiment, the woman simultaneously takes antihypertensive medicine. Drospirenone (DRSP) is a 17-.alpha.-spirolactone derivative progestin that, in combination with estrogens, is used for hormone replacement therapy (HRT), e.g., in postmenopausal women. The present inventor has found, unexpectedly, that when hypertensive women in need of HRT, e.g., women who are already taking antihypertensive medication, are administered a combination of DRSP and estrogen, their blood pressure is unexpectedly reduced compared to women taking the antihypertensive alone. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Patents

•

249

Use of 4-hydroxytestosterone to lower estrogen levels in humans Inventor(s): Llewellyn, William Charles; (Sound Beach, NY) Correspondence: William Llewellyn; PO Box 1162; Sound Beach; NY; 11789; US Patent Application Number: 20030229063 Date filed: June 5, 2002 Abstract: This invention discloses methods of administering 4-hydroxytestosterone in order to lower estrogen levels in humans. As men age, a decline in androgenic hormone levels is typically noted, possibly resulting in muscle mass, bone density and energy loss. This is often accompanied by elevated estrogen to androgen ratio. Various methods have therefore been developed to supplement androgens for men with declining levels and/or correct this ratio. Some such have focused on the use of direct aromatse inhibitors, as a means of lowering levels of estrogen in humans. This invention is an improvement over the use of the aromatase inhibitor 4-hydroxyandrostenedione, in that the subject of this invention is an aromatase inhibitor developed by modifying an active androgen instead of an inactive metabolite. This may be a very advantageous trait for aging men who require a safe and effective way to treat estrogen/androgen imbalance. Excerpt(s): There are numerous endocrine disorders in men characterized by a high ratio of estrogens to androgens. Androgens such as testosterone are responsible for the development and maintenance of male sexual characteristics, including external virilization, sexual maturity at puberty, spermatogenesis, sexual behavior/libido and erectile functioning. They also support bone and muscle tissue growth, and remain vital to ones health and well being throughout life. After physical maturity, men often notice a slow decline in the level of testosterone produced by the body. Dubbed andropause, subnormal androgen levels can lead to a decline in muscle mass, libido, sexual functioning and overall sense of well being later in life. Andropause is also commonly characterized by elevated estrogen to androgen to ratio, which is not surprising given that estrogen itself is suppressive of testosterone production in men. Elevated estrogen to androgen ratio is not only an important factor in andropause, but also in the development of a gynecomastia (female breast tissue development) condition. In many instances this indicates a need not only for some form of androgen replacement in later adulthood, but also some form of therapy to combat estrogenic activity. A number of methods have been developed to mitigate the effects of estrogen in humans. The estrogen receptor antagonist tamoxifen for example, can drastically reduce the biological activity of serum estrogens by blocking their ability to interact with the appropriate receptor. Although still present in the body, estrogens are left will little ability to exert their effects. Clomiphene citrate is a chemically related selective estrogenreceptor modifier with similar activity in many human tissues, and has also been used effectively in men to block the effects of endogenous estrogen. Although these both are useful medications, it is more desirable in many circumstances to actually lower the level of estrogen in the blood instead of competitively inhibiting their activity however. This is most efficiently accomplished by direct inhibition of the aromatase enzyme, which is responsible for the formation of estrogens from androgen precursors. Over the years numerous aromatase inhibitors have been developed. One such compound is 4hydroxyandrostenedione. This compound is a 4-hydroxylated derivative of the natural hormone androstenedione, and has been shown to be a suicide substrate for the aromatase enzyme complex. This means that it irrevocably attaches the enzyme, preventing its ability to further interact with other aromatizable substrates. Studies have clearly supported the effectiveness of this compound, allowing it to be successfully used in many countries today. 4-hydroxyandrostenedione is in many regards close to an ideal

250

Estrogen

method of dealing with estrogen in men suffering from andropause. It however could only be improved if a more active base steroid was used to create an aromatase inhibitor instead of the almost totally inactive androgen metabolite androstenedione. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Keeping Current In order to stay informed about patents and patent applications dealing with estrogen, you can access the U.S. Patent Office archive via the Internet at the following Web address: http://www.uspto.gov/patft/index.html. You will see two broad options: (1) Issued Patent, and (2) Published Applications. To see a list of issued patents, perform the following steps: Under “Issued Patents,” click “Quick Search.” Then, type “estrogen” (or synonyms) into the “Term 1” box. After clicking on the search button, scroll down to see the various patents which have been granted to date on estrogen. You can also use this procedure to view pending patent applications concerning estrogen. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.

251

CHAPTER 6. BOOKS ON ESTROGEN Overview This chapter provides bibliographic book references relating to estrogen. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on estrogen include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.

Book Summaries: Federal Agencies The Combined Health Information Database collects various book abstracts from a variety of healthcare institutions and federal agencies. To access these summaries, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. You will need to use the “Detailed Search” option. To find book summaries, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer. For the format option, select “Monograph/Book.” Now type “estrogen” (or synonyms) into the “For these words:” box. You should check back periodically with this database which is updated every three months. The following is a typical result when searching for books on estrogen: •

Health Tips for Living with Polycystic Kidney Disease Source: Kansas City, MO: PKD (Polycystic Kidney Disease) Foundation. 2001. 72 p. Contact: Available from PKD (Polycystic Kidney Disease) Foundation. 4901 Main Street, Suite 200, Kansas City, MO 64112-2634. (800) PKD-CURE. Fax: (816) 931-8655. Email: [email protected] Website: www.pkdcure.org. PRICE: $10.00 for PKD members; $15.00 for nonmembers. ISBN: 931365155. Summary: Polycystic kidney disease (PKD) has two hereditary forms: autosomal dominant (ADPKD), the most common of all life-threatening genetic diseases, or autosomal recessive (ARPKD), a relatively rare disease that often causes significant mortality in the first month of life. Cysts are sacs of fluid that cause the kidney to enlarge and that can hinder the kidney's filtering ability. Recent research has found certain dietary modifications, hypertension (high blood pressure) treatments, and lifestyle changes to have a favorable, progression-slowing impact on PKD. This book

252

Estrogen

offers strategies for healthy living for people with ADPKD. The book is divided into four sections: a comprehensive section regarding diet and ADPKD; a section reviewing issues of pregnancy and estrogen use for women with PKD; a section dealing with chronic pain and exercise; and a section on where to go in the renal community for support and information. The book concludes with a list of websites for additional information, a listing of National ESRD (End Stage Renal Disease) Network Organizations, and appendices that list sodium content of common foods, high quality protein vegetarian combinations, and special menus. 4 figures. •

Heart health for black women: A natural approach to healing and preventing heart disease Source: New York, NY: Marlowe. 2000. 244 pp. Contact: Available from Marlowe and Company, 841 Broadway, 4th Floor, New York, NY 10003. $15.95. Summary: This book for health and community service professionals and the general public, focuses on heart disease risks common among black women. Topics include high blood pressure, obesity, diabetes, nutrition, cholesterol, estrogen replacement therapy, and smoking. Alternative treatments such as herbs, vitamins, stress reduction techniques, and visualization techniques are discussed. Appendices include questions for healthcare providers, resources, a stay-on-track checklist, an exercise checklist, and a glossary. An index is provided.

•

Women's concise guide to a healthier heart Source: Cambridge, MA: Harvard University Press. 1997. 136 pp. Contact: Available from Harvard University Press, 79 Garden Street, Cambridge, MA 02138. Telephone: (800) 448-2242 or (617) 495-2600 / fax: (800) 962-4983. $12.95. Summary: This book for the general public focuses on recognizing and preventing heart diseases in women. It is divided into three parts. Part one defines the most common heart diseases such as angina pectoris, arrhythmia, coronary artery disease, heart failure, and heart valve disorders. The second part elaborates on other conditions that impact the heart's function. Topics include diabetes, high blood pressure, high cholesterol, obesity, and stroke. Part three discusses various ways of preventing or controlling heart disease, such as alcohol use, diet, estrogen replacement therapy, exercise, quitting smoking, stress reduction, and weight control. The book concludes with a resource listing and an index.

•

Taking our pulse: The health of America's women Source: Stanford, CA: Stanford University Press. 1997. 349 pp. Contact: Available from Stanford University Press, 521 Lomita Mall, Stanford, CA 94305-2235. Telephone: (650) 723-9434 or (800) 872-7423 / fax: (650) 725-3457 / Web site: http://www.sup.org. $19.95. Summary: This book presents women's health issue throughout the life cycle. Part one discusses lifespan differences in females from adolescence, early adulthood, perimenopausal years, to older years. Topics include physical and reproductive changes during puberty, psychosocial development, health consequences of entering the paid labor force, fertility and pregnancy, stress, urogenital problems, high blood pressure, menopause, estrogen replacement therapy, breast cancer, ovarian cancer, osteoporosis,

Books 253

stroke, and coronary heart disease. Part two discusses special health issues for women in each life stage, involving sexually transmitted diseases, pregnancy and its prevention, assisted reproductive technologies, mental health, substance abuse, violence against children and women, nutrition, and exercise. Part three addresses health policy issues for women including the standards and costs of care for women in the United States, women as doctors, choosing a physician, and the status of research in women health, particularly study of drug dosages and their interaction with female hormones. Appendices include ten leading causes of death in women at each life stage, comprehensive geriatric assessment, glossary of reproductive technology terms, DSMIV diagnostic criteria for anorexia nervosa and bulimia nervosa, and recommended daily allowances. The book concludes with references and an index. •

Boning Up on Osteoporosis: A Guide to Prevention and Treatment Source: Washington, DC: National Osteoporosis Foundation (NOF). 1998. 75 p. Contact: Available from National Osteoporosis Foundation. 1150 17th Street, NW, Suite 500, Washington, DC 20036-4603. (202) 223-2226. Fax (202) 223-2237. Website: www.nof.org. PRICE: $3.00; bulk orders available at cost. Summary: This book provides the general public and people who have osteoporosis with information on preventing and treating this disease. It is characterized by a loss of bone mass and by poor bone quality, leading to reduced bone strength and increased risk of fractures. The first section explains how bones grow and change through the process of bone remodeling. A description of risk factors for osteoporosis follows. Risk factors that people cannot change are gender, age, family history, body size, and ethnicity. Risk factors that people can change are hormone levels, diet, exercise, and lifestyle choices. A description of other factors that influence bone health and a discussion of osteoporosis and arthritis are included. The next section focuses on preventing bone loss at all ages. Building and maintaining strong bones involves attaining peak bone mass during childhood, adolescence, and young adulthood; maintaining peak bone mass; and preventing bone loss in later life. In addition, this section discusses the prevention of osteoporosis by consuming enough calcium and vitamin D, exercising, and taking medications such as estrogen and hormone replacement therapy and alendronate sodium. The occurrence of osteoporosis in children and men is also discussed. The third section uses a question and answer format to provide information on using bone mineral density tests to diagnose osteoporosis. In addition, this section discusses other methods of diagnosis such as detecting biochemical markers and using laboratory and other tests. The next section deals with treatment. Approved medications are estrogen, calcitonin, alendronate sodium, and etridronate. In addition, many experimental treatments may prevent bone breakdown or stimulate the formation of new bone. The section also presents strategies for recovering from fractures and managing pain, discusses osteoporosis support groups, provides tips on moving safely, and describes exercises designed to promote and maintain good posture. A final section presents suggestions on finding better fitting clothing, remaining sexually active, and preventing falls. Numerous figures, 7 tables, and 3 references.

•

Vascular Dementia Source: Armonk, NY: Futura Publishing Company, Inc. 2001. 310 p.

254

Estrogen

Contact: Available from Blackwell Publishing. P.O. Box 20, Williston, VT 05495-9957. (800) 216-2522; FAX: (802) 864-7626. E-mail: [email protected]. Website: www.blackwellpublishing.com. PRICE: $92.95. ISBN: 0879934255. Summary: This book summarizes information on the diagnosis and treatment of vascular dementia (VAD). Topics include: (1) the epidemiology of VAD; (2) cardiovascular risk factors contributing to degenerative changes, cognitive decline, and dementia; (3) risk factors for VAD; (4) neuropathological correlates of VAD; (5) microvascular pathology in VAD and related dementias; (6) recent advances in VAD research; (7) clinical features of VAD versus Alzheimer's disease (AD); (8) neuropsychological assessments for cognitive decline; (9) subcortical arteriosclerotic encephalopathy Binswanger type or chronic microvascular leukoencephalopathy syndrome; (10) criteria for diagnosis of VAD; (11) classification of subtypes of VAD including subcortical versus cortical dementias; (12) neuroimaging in VAD; (13) clinical observation during long-term follow-up in VAD; (14) prevention and treatment of VAD; (15) scientific basis for plasmapheresis in VAD; (16) estrogen therapy for prevention of dementia in postmenopausal women; and (17) factors influencing long-term survival among patients with VAD versus AD.

Book Summaries: Online Booksellers Commercial Internet-based booksellers, such as Amazon.com and Barnes&Noble.com, offer summaries which have been supplied by each title’s publisher. Some summaries also include customer reviews. Your local bookseller may have access to in-house and commercial databases that index all published books (e.g. Books in Print®). IMPORTANT NOTE: When following the link below, you may discover non-medical books that use the generic term “estrogen” (or a synonym) in their titles. •

Amazon.com: http://www.amazon.com/exec/obidos/externalsearch?tag=icongroupinterna&keyword=estrogen&mode=books

Chapters on Estrogen In order to find chapters that specifically relate to estrogen, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and estrogen using the “Detailed Search” option. Go to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find book chapters, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Book Chapter.” Type “estrogen” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on estrogen: •

Treatment of the Sphincter: Medical Therapy Source: in Corcos, J.; Schick, E., eds. Urinary Sphincter. New York, NY: Marcel Dekker, Inc. 2001. p. 483-496. Contact: Available from Marcel Dekker, Inc. Cimarron Road, P.O. Box 5005, Monticello, NY 12701. (800) 228-1160 or (845) 796-1919. Fax (845) 796-1772. E-mail: [email protected]. International E-mail: [email protected]. Website: www.dekker.com. PRICE: $225.00 plus shipping and handling. ISBN: 0824704770.

Books 255

Summary: Medical treatment for sphincteric (the controlling muscles of the bladder opening) pathology is often pursued as a first line approach for the patient with either incontinence (involuntary loss of urine) or obstructive voiding. The decision to pursue medical therapy may be patient or physician driven and based on the desire to avoid more aggressive invasive procedures. This chapter on medical therapy for treatment of the sphincter is from a textbook that presents a detailed and systematic account of the current knowledge on the anatomy, physiology, functional relationships, and range of dysfunctions that affect the urinary sphincter. The medical approach to the treatment of the dysfunctional sphincter may be divided practically into medications that are used to either enhance sphincteric function (as in stress incontinence) or weaken sphincteric function (as in dyssynergia or voiding dysfunction) and promote bladder emptying. The author reviews medical therapy for the hyperactive sphincter, including the use of alpha adrenergic blockers, benzodiazepines, beta adrenergic agents, dantrolene sodium, botulinum toxin, phenol block, and baclofen; and medical therapy for the incompetent sphincter, including the use of alpha adrenergic agonists, imipramine, and estrogen therapy. The author concludes that for the smooth sphincter, alpha adrenergic agonists and antagonists represent an effective way to modulate sphincteric function. Although many different drugs have been tried to target striated sphincteric dysfunction, few have been selective enough to warrant widespread clinical use. Too commonly, adverse systemic side effects limit their clinical effectiveness. For a select group of patients, however, these drugs allow them to overcome striated sphincteric dysfunction, without resorting to surgery. 2 tables. 107 references. •

Possible Causes Source: in Haybach, P.J. Meniere's Disease: What You Need to Know. Portland, OR: Vestibular Disorders Association. 1998. p. 53-60. Contact: Available from Vestibular Disorders Association. P.O. Box 4467, Portland, OR 97208-4467. (800) 837-8428. E-mail: [email protected]. Website: www.vestibular.org. PRICE: $24.95 plus shipping and handling. ISBN: 0963261118. Summary: The cause of Meniere's disease is unknown, however many theories have been proposed to explain the symptoms of Meniere's or the factors that may aggravate those symptoms. This chapter is from a book that provides information for people who have or suspect they have Meniere's disease want to know more about its diagnosis and treatment, as well as strategies for coping with its effects. Written in nontechnical language, this chapter discusses the possible causes of Meniere's disease. Listed in alphabetical order, they include: abnormal circulation, adrenal-pituitary insufficiency, allergy, autoimmune disease, autonomic nervous system malfunction, bacterial infection, blockage of endolymph, estrogen insufficiency, head injury, heredity, hormonal imbalance, malformed or small endolymphatic sac, malfunction in the use of foods by the body (high cholesterol, triglycerides, or lipids), meningitis, menstrual or premenstrual problems, noise pollution (noise trauma or acoustic trauma), otosclerosis, stress, and viral infection. The author discusses the most widely accepted theories of the causes of Meniere's disease and then briefly considers specific conditions that are known or thought to sometimes cause symptoms like those of Meniere's disease. 24 references.

•

Cognition and Alzheimer's Disease Source: in Cudkowicz, M.E.; Irizarry, M.C. Neurologic Disorders In Women. Boston, MA: Butterworth-Heinemann. 1997. p. 121-131.

256

Estrogen

Contact: Butterworth-Heinemann. 313 Washington Street, Newton, MA 02158-1626. (617) 928-2500; FAX (617) 928-2620; Internet access: http://www.bh.com/med. PRICE: $55.00. ISBN: 0-7506-9745-8. Summary: This book chapter examines gender differences in cognitive function in Alzheimer's disease (AD), the effects of estrogen on cognitive function and AD, and the gender differences in AD risk and clinical course. Mild gender differences in cognitive function have been observed, with males performing better on spatial tasks and females in verbal performance; however, in AD, females typically perform worse on neuropsychological tests and measures of language function. Epidemiologic studies suggest estrogen reduces the risk for AD, and in a subset of AD patients clinical studies suggest estrogen has a cognition-enhancing effect on memory, mood, and behavior. AD risk is higher in women, in part because they live longer than men; and the mean age of onset is older in women. There appear to be no gender influences on disease course, although cognitive deficits, as determined by neuropsychological tests, do appear to be affected by gender. More studies are attempting to determine the benefits of estrogen replacement therapy in the presence of AD. 2 figures, 51 references. •

Effect of Medications on Diabetes Source: in Carlisle, B.A.; Kroon, L.A.; Koda-Kimble, M.A. 101 Medication Tips for People with Diabetes. Alexandria, VA: American Diabetes Association. 1999. p. 76-83. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $14.95 plus shipping and handling. ISBN: 1580400329. Order number 483301. Summary: This chapter answers questions about the effects of common medications, alcohol, birth control pills, estrogen therapy, beta blockers, hydrochlorothiazide, and niacin on blood glucose levels. Common medications that can increase blood glucose include glucocorticoids, niacin, and protease inhibitors. Glucocorticoids taken as pills or by injection are likely to increase blood glucose levels if they are taken in large doses. If they are inhaled or applied to the skin, they are unlikely to increase blood glucose. The effect of alcohol on blood glucose depends on how much a person drinks during a particular timespan. Birth control pills will not generally make diabetes worse, and estrogen replacement therapy is safe for most women with diabetes. The benefits of beta blockers for people who have diabetes and who have had a heart attack far exceed the risks; currently prescribed doses of hydrochlorothiazide used to control blood pressure have minimal effects on blood glucose level. The amount of niacin in multivitamins is not high enough to increase blood glucose levels.

•

Narrowing Down the Causes Source: in King, B.D. and Harke, J. Coping with Bowel and Bladder Problems. San Diego, CA: Singular Publishing. 1994. p. 13-27. Contact: Available from Singular Publishing Group, Inc. 401 West A Street, Suite 325, San Diego, CA 92101-7904. (800) 521-8545 or (619) 238-6777. Fax (800) 774-8398 or (619) 238-6789. PRICE: $18.95. ISBN: 1565930681. Summary: This chapter is from a book in the Coping with Aging Series on managing bowel and bladder problems. The chapter provides a discussion of the causes of incontinence for patients, their families, and other caregivers. Topics include a definition of acute incontinence; medication-related urinary incontinence; the effect of alcohol

Books 257

consumption on bladder function; specific illnesses that can make a person more prone to urine loss; irritants in the urine; how constipation can affect urinary incontinence; the role of estrogen loss in incontinent women; persistent incontinence and its symptoms; overflow incontinence; stress incontinence; urge incontinence; functional incontinence; mixed incontinence; and evaluating symptoms and assessing a bladder control problem. 2 figures. 2 tables. •

Clinical Approach to Urinary Incontinence in the Elderly Source: in Andreucci, V.E., and Fine, L.G., eds. International Yearbook of Nephrology Dialysis Transplantation. 1995. p. 93-102. Contact: Available as a supplement to Nephrology Dialysis Transplantation, Volume 10. Oxford University Press, 2001 Evans Road, Cary, NC 27513-2009. (800) 334-4249. ISBN: 0192626493. Summary: This chapter of the International Yearbook of Nephrology, Dialysis, and Transplantation describes a clinial approach to urinary incontinence in the elderly. Topics include diagnosis and urodynamic assessment; urinalysis; the treatment of urinary incontinence; bladder retraining; stabilization of the bladder; correcting sphincter incompetence; treating voiding disorders; estrogen replacement therapy; and the science of urinary incontinence in the development of new pharmaceutical agents. 3 figures. 117 references.

•

Medication Use Source: in Dierich, M. and Froe, F. Overcoming Incontinence: A Straightforward Guide to Your Options. Somerset, NJ: John Wiley and Sons, Inc. 2000. p. 49-56. Contact: Available from John Wiley and Sons, Inc. Distribution Center, 1 Wiley Drive, Somerset, NJ 08875-1272. (800) 225-5945 or (732) 469-4400. Fax (732) 302-2300. E-mail: [email protected]. Website: www.wiley.com. PRICE: $14.95 plus shipping and handling. ISBN: 0471347957. Summary: This chapter on medication use is from a practical guide that dispels the many myths associated with urinary incontinence, offering readers information about the latest options for treatment, from simple lifestyle changes and exercises to devices, medications, and surgery. The authors emphasize that incontinence can be prevented, is almost always treatable, and is often curable. In this chapter, the authors review the numerous medications used to treat incontinence. In general, drug therapy is used to treat urge incontinence (UI), sometimes for stress urinary incontinence (SUI), and occasionally for overflow incontinence. Specific drugs covered are oxybutynin (Ditropan and Ditropan XL) which is an antispasmodic; tolterodine (Detrol), an antispasmodic with fewer side effects; hyoscyamine (Levsinex), an antispasmodic that can be taken on an as-needed basis; dicyclomine (Bentyl), traditionally used for intestinal spasms; imipramine (Tofranil), an antidepressant with side effects that can be beneficial to patients with incontinence; propantheline (Probanthine), similar to oxybutynin; flavoxate (Urispas), similar to oxybutynin; phenylpropanolamine, which increases the tone of the sphincter muscle that closes the urethra; pseudoephedrine (Sudafed), similar to phenylpropanolamine; terazoxin (Hytrin), for overflow incontinence caused by prostate or urethral blockage; doxazosin (Cardura), similar to terazoxin; tamsulosin (Flomax), similar to terazosin but with quick response rate; finasteride (Proscar) for treatment of bladder symptoms caused by enlarged prostate; and urecholine, for overflow incontinence due to poor bladder muscle function. The authors also include a section on estrogen, notably estrogen replacement therapy, and a section on herbal

258

Estrogen

treatments for incontinence. The authors caution that, with any medication, interactions and side effects are possible. 2 tables. •

Menopause and Hormone Replacement Therapy Source: in Carlin, B.I. and Leong, F.C., eds. Female Pelvic Health and Reconstructive Surgery. New York, NY: Marcel Dekker, Inc. 2003. p. 417-474. Contact: Available from Marcel Dekker, Inc. 270 Madison Avenue, New York, NY 10016. (212) 696-9000. Fax (212) 685-4540. Website: www.dekker.com. PRICE: $185.00 plus shipping and handling. ISBN: 0824708229. Summary: This chapter on menopause and hormone replacement therapy (HRT) is from a textbook that provides comprehensive, authoritative coverage of female pelvic health and reconstructive surgery. The authors introduce menopause and discuss the factors that influence the age of menopause onset. They also discuss the transition to menopause; symptoms of menopause, including those of the central nervous system, skin, and genitourinary tract, osteoporosis, and cardiovascular disease; the use of estrogen in menopausal women for both primary and secondary prevention of cardiovascular disease; the risks of HRT, including endometrial cancer, breast cancer, venous thromboembolic events, and alternative benefits of HRT; regimens for HRT, including the supplementation with calcium and vitamin D; and alternative therapies for symptoms of menopause. The authors conclude that the menopause is a normal life event that carries with it an increased risk of morbidity and mortality. The use of HRT can be beneficial in obtaining preventive health benefits. Whether a woman chooses HRT or an alternative, the decision should be based on factual information about the risks and benefits of a given treatment. 5 figures. 11 tables. 266 references.

•

Preventing Urinary Tract Infections in Women Source: in Savitz, G. and Leslie, S.W. Kidney Stones Handbook: A Patient's Guide to Hope, Cure and Prevention. 2nd ed. Roseville, CA: Four Geez Press. 1999. p. 125-130. Contact: Available from Four Geez Press. 1911 Douglas Blvd., Suite 85-131, Roseville, CA 95661. (800) 2-Kidneys. Website: www.readerndex.com/fourgeez. PRICE: $17.95 plus shipping and handling. ISBN: 0963706861. Summary: This chapter on preventing urinary tract infections (UTIs) in women is from a patient education handbook that describes how virtually every patient who follows treatment based on appropriate testing, proper interpretation, and sound medical principles can substantially reduce or eliminate all future kidney stone production. The authors emphasize the need for patients to educate themselves and to take a proactive approach to preventing new stones, in many cases to the point of educating their physicians and demanding appropriate diagnostic and treatment methods. This chapter emphasizes that UTIs can lead to kidney stones as well as to serious kidney infections and renal failure. Usual symptoms include urinary frequency, burning, urgency, and lower abdominal pain. The basis for preventing urinary infections is to keep the area around the bladder opening as clean as possible, with minimal exposure to any new germs or bacteria. Keeping the urinary volume up and using antibiotics selectively are essential to prevention efforts. The authors provide a list of practical suggestions for daily hygiene, dietary changes (increasing fluids and avoiding irritating foods including caffeine), the use of estrogen, the use of prophylactic antibiotics, and how to sterilize washcloths for home use (suggested only for very resistant or severe cases of recurrent UTIs).

Books 259

•

Effects of Age on the Voice Source: in Sataloff, R.T., ed. Professional Voice: The Science and Art of Clinical Care. 2nd ed. San Diego, CA: Singular Publishing Group, Inc. 1997. p. 259-267. Contact: Available from Singular Publishing Group, Inc. 401 West 'A' Street, Suite 325, San Diego, CA 92101-7904. (800) 521-8545 or (619) 238-6777. Fax (800) 774-8398 or (619) 238-6789. E-mail: [email protected]. Website: www.singpub.com. PRICE: $325.00 plus shipping and handling. ISBN: 1565937287. Summary: This chapter on the effects of age on the voice is from a book on the clinical care of the professional voice. The authors discuss anatomy and physiology; vocal training, health, and pathology of the young voice; the young adult voice; the adult voice; the aging process; and intervention strategies. The authors note that certain aspects of the aging process are relatively easy to control medically. For example, as female singers reach menopause, estrogen deprivation causes substantial changes in the mucous membranes that line the vocal tract, the muscles, and throughout the patient's body. These and other hormonal effects are frequently reflected in the voice but can be forestalled for many years through hormone replacement therapy. The authors present a strategy of conceptualizing the aging voice as part of a continuum of performance range; intervention efforts are then focused on helping the patient perform higher on that range, to compensate for aging-related changes. In treating age related dysphonia, the therapists combine traditional voice therapy, singing training, acting voice techniques, and aerobic conditioning to optimize neuromuscular performance. The authors conclude with a discussion of the impact of personality and aging on the performing voice. 34 references.

•

Women and Exercise Source: in Devlin, J.T. and Schneider, S.H., eds. Handbook of Exercise in Diabetes. Alexandria, VA: American Diabetes Association. 2002. p.511-531. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $69.95 plus shipping and handling. ISBN: 1580400191. Summary: This chapter on women and exercise is from a book that provides a practical, comprehensive guide to diabetes and exercise for health care professionals involved in patient care. The authors focus on three areas: exercise and pregnancy, amenorrhea (lack of a menstrual period) and exercise, and osteoporosis and exercise. Exercise may not be effective for the pregestational woman with type 1 diabetes who is planning a pregnancy or is currently pregnant. Exercise in the form of arm ergometry has been documented to be safe for a sedentary, unfit pregnant woman and may be a helpful adjunctive therapy to medical nutritional therapy for a woman with gestational diabetes (a type of diabetes that occurs during pregnancy). After childbirth, if glucose control is maintained, the woman with diabetes should be able to return to an exercise program similar to that of a woman without diabetes. The adolescent girl with diabetes who is amenorrheic needs intensive therapy to ensure that she does not develop accelerated retinopathy (eye disease) when glucose control is achieved. If amenorrhea persists beyond the age of 16, treatment with estrogen therapy to protect the bones is advised. Women with diabetes should be offered a weight bearing exercise program along with hormonal replacement therapy when they reach menopause. In addition, smoking cessation programs are recommended to improve bone mass status. Insulin dosing for the exercising menopausal woman who is taking hormonal replacement therapy is

260

Estrogen

complicated; thus, a team that is expert in insulin therapy is needed as part of the exercise program. 3 figures. 2 tables. 59 references. •

What You Need to Know About Lipids and Exercise Source: in Hirsch, I.B. 12 Things You Must Know About Diabetes Care Right Now!. Alexandria, VA: American Diabetes Association. 2000. p. 115-130. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $14.95 plus shipping and handling. ISBN: 1580400612. Summary: This chapter provides information on blood lipids and exercise to treat lipid problems. Lipids, which are body fats, include triglycerides and cholesterol. Neither triglycerides nor cholesterol can be dissolved in blood, so they travel in the blood by joining with proteins called lipoproteins. Low density lipoprotein (LDL) is the major carrier for cholesterol in the blood. An excess of LDL causes atherosclerosis. High density lipoprotein (HDL), however, takes cholesterol away from the blood vessel walls and into the liver. Problems occur when levels of triglycerides and LDL and HDL cholesterol are out of balance. The most common problems in people who have type 2 diabetes have to do with triglycerides and HDL cholesterol. People who have type 1 diabetes and poor glucose control will have high triglyceride and LDL cholesterol levels. Adults who have high or out of balance lipids should be tested each year for total cholesterol, fasting triglycerides, and HDL and LDL cholesterol. The first approach to balancing lipid levels should be to improve blood glucose control with weight loss, exercise, and better meal planning. When lipid levels do not improve with meal planning, exercise, and glucose control, treatment with lipid lowering drugs is recommended. Drugs used to treat lipid problems include bile acid binding resins, fibric acid derivatives, HMG-CoA reductase inhibitors, nicotinic acid, estrogen, and aspirin. The chapter discusses the effects of these drugs and presents guidelines on coronary disease screening. In addition, the chapter includes a list of questions a patient may ask a doctor and questions a doctor may ask a patient. 3 tables.

•

Sensitive Bladders: The Unspoken Complaints Source: in Hoffman, E. Our Health, Our Lives: A Revolutionary Approach to Total Health Care for Women. New York, NY: Pocket Books. 1995. p. 165-181. Contact: Available from Pocket Books. 1230 Sixth Avenue, New York, NY 10020. (800) 223-2336. PRICE: $24. ISBN: 0671880853. Summary: This chapter, from a book about health care for women, discusses a holistic approach to diagnosing and managing sensitive bladders. Topics covered include the normal environment of the bladder; bacterial cystitis, including its causes, symptoms, diagnosis, and management; the hypersensitive or painful bladder; interstitial cystitis, including the symptoms and diagnostic difficulties associated with the disorder; urinary incontinence, including the symptoms, the four basic types, its diagnosis, and the use of pelvic exercises, biofeedback, bladder training, estrogen replacement, or surgery for its treatment; and the effects of urinary and bladder problems on one's social life. The chapter concludes with common questions and answers about bladder problems, along with a brief list of resources.

Books 261

•

Benign Prostatic Hyperplasia Source: in Sant, G.R., ed. Pathophysiologic Principles of Urology. Malden, MA: Blackwell Science, Inc. 1994. p. 123-154. Contact: Available from Blackwell Science, Inc. 350 Main Street, Commerce Place, Malden, MA 02148. (800) 215-1000 or (617) 388-8250. Fax (617) 388-8270. E-mail: [email protected]. PRICE: $55.00. ISBN: 0865422214. Summary: This chapter, from a urology textbook on pathophysiology, discusses benign prostatic hyperplasia (BPH). The authors summarize current information pertaining to the pathophysiology, pathogenesis, and new treatment modalities of BPH. Topics include the anatomy and embryology of the prostate; prostate physiology; the histology and anatomy of BPH; etiologic theories, including the dihyrotestosterone hypothesis, the estrogen hypothesis, stromal/epithelial interactions, and the stem cell theory; the epidemiology and natural history of BPH; clinical manifestations; treatment options, including balloon dilatation, prostatic stents, hyperthermia/thermotherapy, lasers, and cryotherapy; and pharmacologic treatment options, including androgen deprivation, the use of 5-alpha-reductase inhibitors, alpha-adrenergic blockers, and aromatase inhibitors. 4 figures. 13 tables. 13 annotated references.

263

CHAPTER 7. RESEARCHING MEDICATIONS Overview While a number of hard copy or CD-ROM resources are available for researching medications, a more flexible method is to use Internet-based databases. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.

U.S. Pharmacopeia Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications recommended for estrogen. One such source is the United States Pharmacopeia. In 1820, eleven physicians met in Washington, D.C. to establish the first compendium of standard drugs for the United States. They called this compendium the U.S. Pharmacopeia (USP). Today, the USP is a nonprofit organization consisting of 800 volunteer scientists, eleven elected officials, and 400 representatives of state associations and colleges of medicine and pharmacy. The USP is located in Rockville, Maryland, and its home page is located at http://www.usp.org/. The USP currently provides standards for over 3,700 medications. The resulting USP DI® Advice for the Patient® can be accessed through the National Library of Medicine of the National Institutes of Health. The database is partially derived from lists of federally approved medications in the Food and Drug Administration’s (FDA) Drug Approvals database, located at http://www.fda.gov/cder/da/da.htm. While the FDA database is rather large and difficult to navigate, the Phamacopeia is both user-friendly and free to use. It covers more than 9,000 prescription and over-the-counter medications. To access this database, simply type the following hyperlink into your Web browser: http://www.nlm.nih.gov/medlineplus/druginformation.html. To view examples of a given medication (brand names, category, description, preparation, proper use, precautions, side effects, etc.), simply follow the hyperlinks indicated within the United States Pharmacopeia (USP). Below, we have compiled a list of medications associated with estrogen. If you would like more information on a particular medication, the provided hyperlinks will direct you to ample documentation (e.g. typical dosage, side effects, drug-interaction risks, etc.). The

264

Estrogen

following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to estrogen: Anastrozole •

Systemic - U.S. Brands: Arimidex http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203659.html

Androgens and Estrogens •

Systemic - U.S. Brands: Depo-Testadiol; Estratest; Estratest H.S.; Valertest No. 1 http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202037.html

Calcium Supplements •

Systemic - U.S. Brands: Alka-Mints; Amitone; Calcarb 600; Calci-Chew; Calciday 667; Calcilac; Calci-Mix; Calcionate; Calcium 600; Caltrate Jr; Chooz; Citracal; Citracal Liquitabs; Dicarbosil; Gencalc 600; Liquid-Cal; Liquid Cal-600; Maalox Antacid Caplets; Mallamint; Neo-Calglucon; Nephro-Calci; Os-Cal 500; Os-Cal 500 Chewable; Oysco; Oyst-Cal 500; Oystercal 500; Posture; Rolaids Calcium Rich; Titralac; Tums http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202108.html

Clomiphene •

Systemic - U.S. Brands: Clomid; Milophene; Serophene http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202151.html

Conjugated Estrogens and Medroxyprogesterone for Ovarian Hormone Therapy (OHT) •

Systemic - U.S. Brands: Premphase; Prempro http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/209441.html

Estrogens •

Systemic - U.S. Brands: Alora; Aquest; Climara; Clinagen LA 40; Delestrogen; depGynogen; Depo-Estradiol; Depogen; Dioval 40; Dioval XX; Dura-Estrin; Duragen-20; E-Cypionate; Estinyl; Estrace; Estraderm; Estragyn 5; Estragyn LA 5; Estra-L 40; Estratab; Estro-A; Estro-Cyp; Estrofem; Estro-L.A.; Estrone 5; FemPatch; Gynogen L.A. 20; Gynogen L.A. 40; Kestrone-5; Menaval-20; Menest; Ogen .625; Ogen 1.25; Ogen 2.5; Ortho-Est .625; Ortho-Est 1.25; Premarin; Premarin Intravenous; Stilphostrol; Valergen-10; Valergen-20; Valergen-40; Vivelle; Vivelle-Dot; Wehgen http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202226.html

•

Vaginal - U.S. Brands: Estrace; Estring; Ogen; Ortho Dienestrol; Premarin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202227.html

Estrogens and Progestins (Ovarian Hormone Therapy) •

Systemic - U.S. Brands: Activella; femhrt; Ortho-Prefest http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500070.html

Researching Medications

265

Estrogens and Progestins Oral Contraceptives •

Systemic - U.S. Brands: Alesse; Brevicon; Demulen 1/35; Demulen 1/50; Desogen; Estrostep; Estrostep Fe; Genora 0.5/35; Genora 1/35; Genora 1/50; Intercon 0.5/35; Intercon 1/35; Intercon 1/50; Jenest; Levlen; Levlite; Levora 0.15/30; Lo/Ovral; Loestrin 1.5/30; Loestrin 1/20; Lo/Ovral; Mircette; ModiCon; Necon 0.5/35; Necon 1/35; Necon 1/50; Necon 10/11; N.E.E. 1/35; N.E.E. 1/50; Nelova 0.5/35E; Nelova 1/35E; Nelova 1/50M; Nelova 10/11; Nordette; Norethin 1/35E; Norethin 1/50M; Norinyl 1+35; Norinyl 1+50; Ortho-Cept; Ortho-Cyclen; Ortho-Novum 1/35; Ortho-Novum 1/50; Ortho-Novum 7/7/7; Ortho-Novum 10/11; Ortho Tri-Cyclen; Ovcon-35; Ovcon-50; Ovral; Tri-Levlen; Tri-Norinyl; Triphasil; Trivora; Zovia 1/35E; Zovia 1/50E http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202228.html

Exemestane •

Systemic - U.S. Brands: Aromasin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500082.html

Goserelin •

Systemic - U.S. Brands: Zoladex http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202267.html

Histrelin •

Systemic - U.S. Brands: Supprelin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203510.html

Leuprolide •

Systemic - U.S. Brands: Lupron; Viadur http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202322.html

Menotropins •

Systemic - U.S. Brands: Humegon; Pergonal http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202347.html

Nafarelin •

Systemic - U.S. Brands: Synarel http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202646.html

Progestins for Contraceptive Use •

Systemic - U.S. Brands: Depo-Provera Contraceptive Injection; Micronor; NORPLANT System; Nor-QD; Ovrette; Plan B http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202757.html

Progestins for Noncontraceptive Use •

Systemic - U.S. Brands: Amen; Aygestin; Crinone; Curretab; Cycrin; DepoProvera; Gesterol 50; Gesterol LA 250; Hy/Gestrone; Hylutin; Megace; Prodrox; Prometrium; Pro-Span; Provera http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202758.html

266

Estrogen

Raloxifene •

Systemic - U.S. Brands: Evista http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203396.html

Tamoxifen •

Systemic - U.S. Brands: Nolvadex http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202545.html

Toremifene •

Systemic - U.S. Brands: Fareston http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203072.html

Urofollitropin •

Systemic - U.S. Brands: Fertinex; Metrodin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202586.html

Commercial Databases In addition to the medications listed in the USP above, a number of commercial sites are available by subscription to physicians and their institutions. Or, you may be able to access these sources from your local medical library.

Mosby’s Drug Consult™ Mosby’s Drug Consult™ database (also available on CD-ROM and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Subscription information is available at the following hyperlink: http://www.mosbysdrugconsult.com/. PDRhealth The PDRhealth database is a free-to-use, drug information search engine that has been written for the public in layman’s terms. It contains FDA-approved drug information adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html. Other Web Sites Drugs.com (www.drugs.com) reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. (http://www.medletter.com/) which allows users to download articles on various drugs and therapeutics for a nominal fee. If you have any questions about a medical treatment, the FDA may have an office near you. Look for their number in the blue pages of the phone book. You can also contact the FDA

Researching Medications

267

through its toll-free number, 1-888-INFO-FDA (1-888-463-6332), or on the World Wide Web at www.fda.gov.

269

APPENDICES

271

APPENDIX A. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.

NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute11: •

Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm

•

National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/

•

National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html

•

National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25

•

National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm

•

National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm

•

National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375

•

National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/

11

These publications are typically written by one or more of the various NIH Institutes.

272

Estrogen

•

National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/publications/publications.htm

•

National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/

•

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm

•

National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm

•

National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/

•

National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/

•

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm

•

National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html

•

National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm

•

National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm

•

National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm

•

National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html

•

National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm

•

Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp

•

National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/

•

National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp

•

Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html

•

Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm

Physician Resources

273

NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.12 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:13 •

Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html

•

HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html

•

NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html

•

Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/

•

Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html

•

Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html

•

Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/

•

Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html

•

Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html

•

Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html

•

MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html

12

Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 13 See http://www.nlm.nih.gov/databases/databases.html.

274

Estrogen

•

Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html

•

Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html The Combined Health Information Database

A comprehensive source of information on clinical guidelines written for professionals is the Combined Health Information Database. You will need to limit your search to one of the following: Brochure/Pamphlet, Fact Sheet, or Information Package, and “estrogen” using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For the publication date, select “All Years.” Select your preferred language and the format option “Fact Sheet.” Type “estrogen” (or synonyms) into the “For these words:” box. The following is a sample result: •

Progress Report on Alzheimer's Disease 2000: Taking the Next Steps Source: Bethesda, MD: National Institute on Aging. 2000. 62 p. Contact: Available from Alzheimer's Disease Education and Referral (ADEAR) Center. PO Box 8250, Silver Spring, MD 20907-8250. (800) 438-4380, (301) 495-3311; FAX: (301) 495-3334. Internet: http://www.alzheimers.org. PRICE: Free. Order number: Z-164. NIH Publication Number: 00-4859. Summary: This annual report highlights recent research into Alzheimer's disease (AD) supported by the National Institute on Aging and eight other branches of the National Institutes of Health. The report first reviews the characteristics, causes, diagnosis and treatment of AD. Research advances include: etiology involving amyloid, presenilins, apoptosis, apolipoproteins, and protein aggregation; early diagnosis; drug treatments such as estrogen, anti-inflammatories, antioxidants, and neurotrophic factors; caregiver support; and research infrastructure. The report also reviews areas for future research. Sidebars throughout the report cover issues such as brain structure, AD and Parkinson's disease, and the AD Clinical Trials Database. 114 references.

•

Osteoarthritis: New Insights: Part 1: The Disease and Its Risk Factors Source: Annals of Internal Medicine. 133(8): 635-646. October 17, 2000. Summary: This journal article, the first of a two part summary of a National Institutes of Health conference on osteoarthritis (OA), provides health professionals with information on what OA is and on risk factors that predispose to it. The conference brought together experts on OA from diverse backgrounds and provided a multidisciplinary and comprehensive summary of recent advances in the prevention of OA onset, progression, and disability. OA is the most common form of arthritis, affecting millions of people in the United States. It is a complex disease whose etiology bridges biomechanics and biochemistry. Evidence is growing for the role of systemic factors such as ethnicity, genetics, dietary intake, estrogen use, and bone density, as well as local biomechanical factors such as muscle weakness, obesity, and joint laxity, in the development of OA. These risk factors are particularly important in weight bearing joints, and modifying them may present opportunities for prevention of pain and

Physician Resources

275

disability. The article discusses these systemic and biomechanical risk factors and examines the impact of OA on disability. 3 figures, 3 tables, and 120 references. (AA-M). •

Pharmocotherapy of Urge Incontinence Reviewed Source: in InConText. Management of the Incontinent Patient. Philadelphia, PA: CoMed Communications. 1990. p. 1, 3. Contact: Available from CoMed Communications. 210 West Washington Square, Philadelphia, PA 19106. (215) 592-1363. PRICE: Free. Summary: This report developed from a presentation at the symposium, 'Pharmacotherapy for Urge Incontinence,' held March 17, 1990 in Miami, Florida, reviews the drugs used to treat storage failure secondary to either bladder hyperactivity or bladder hypersensitivity. The following classes of drugs are discussed: the anticholinergics; antispasmodics or musculotropic relaxants; calcium antagonists; and tricyclic antidepressants. In addition, specific drugs including oxybutynin, propantheline, dicyclomine, terodiline, and phenazopyridine, are mentioned. The article concludes that sphincter incontinence is best treated pharmacologically with alphaadrenergic agonists. Finally, estrogen is noted as a useful adjunct therapy for postmenopausal women.

•

Fatal and Severe Hepatitis Associated with Rifampin and Pyrazinamide for the Treatment of Latent Tuberculosis Infection--New York and Georgia, 2000 Source: Morbidity and Mortality Weekly Report Weekly Apr 20 2001;50(15):289-291. Summary: This report presents two case reports to illustrate that the two-month regimen of rifampin (RIF) and pyrazinamide (PZA) for the treatment of latent tuberculosis infection (LBTI) can cause severe hepatitis in some people. The first case is that of a 53-year-old incarcerated man who was treated with 600 mg RIF and 1750 mg PZA daily while receiving treatment for hypertension. The patient died of liver necrosis and failure as a result of hepatitis following LTBI treatment. The second case is that of a 59-year-old woman who received 600 mg RIF and 2000 mg PZA for LTBI. She was also receiving treatment for nasal allergies and asthma and had a history of anaphylactic reactions to penicillin and an estrogen sulfates blend. On the 49th and last day of treatment this patient was admitted to a hospital because of jaundice and altered mental states. After treatment with 40 mg prednisone daily, the patient recovered. In these cases biochemical monitoring did not help avoid liver injury. The report advises that patients with LTBI and risk factors for active TB should be offered treatment and should receive instruction and reminders about the symptoms of hepatitis and of stopping medication if symptoms develop. Cases of severe hepatitis that develop in patients being treated for LTBI should be reported to the CDC.

The NLM Gateway14 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.15 To 14 15

Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.

The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH).

276

Estrogen

use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “estrogen” (or synonyms) into the search box and click “Search.” The results will be presented in a tabular form, indicating the number of references in each database category. Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total

Items Found 95047 2739 252 86 351 98475

HSTAT16 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.17 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.18 Simply search by “estrogen” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

Coffee Break: Tutorials for Biologists19 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.20 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.21 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for

16

Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html.

17

The HSTAT URL is http://hstat.nlm.nih.gov/.

18 Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations. 19 Adapted from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html. 20

The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 21 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process.

Physician Resources

277

general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •

CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.

•

Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.

The Genome Project and Estrogen In the following section, we will discuss databases and references which relate to the Genome Project and estrogen. Online Mendelian Inheritance in Man (OMIM) The Online Mendelian Inheritance in Man (OMIM) database is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere. OMIM was developed for the World Wide Web by the National Center for Biotechnology Information (NCBI).22 The database contains textual information, pictures, and reference information. It also contains copious links to NCBI’s Entrez database of MEDLINE articles and sequence information. To search the database, go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html. Type “estrogen” (or synonyms) into the search box, and click “Submit Search.” If too many results appear, you can narrow the search by adding the word “clinical.” Each report will have additional links to related research and databases. In particular, the option “Database Links” will search across technical databases that offer an abundance of information. The following is an example of the results you can obtain from the OMIM for estrogen: •

Breast Cancer Antiestrogen Resistance 1 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602941

•

Breast Cancer Antiestrogen Resistance 3 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=604704

•

Estrogen Receptor 1 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=133430

•

Estrogen Receptor 2 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601663

22 Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.

278

Estrogen

•

Estrogen Receptor-binding Site-associated Antigen, 9 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=605772

•

Estrogen-related Receptor, Alpha Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601998

•

Estrogen-related Receptor, Beta Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602167

•

Estrogen-related Receptor, Gamma Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602969

•

Estrogen-related Receptor-beta-like 1 Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606621

•

Sulfotransferase, Estrogen-preferring Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600043 Genes and Disease (NCBI - Map)

The Genes and Disease database is produced by the National Center for Biotechnology Information of the National Library of Medicine at the National Institutes of Health. This Web site categorizes each disorder by system of the body. Go to http://www.ncbi.nlm.nih.gov/disease/, and browse the system pages to have a full view of important conditions linked to human genes. Since this site is regularly updated, you may wish to revisit it from time to time. The following systems and associated disorders are addressed: •

Cancer: Uncontrolled cell division. Examples: Breast and ovarian cancer, Burkitt lymphoma, chronic myeloid leukemia, colon cancer, lung cancer, malignant melanoma, multiple endocrine neoplasia, neurofibromatosis, p53 tumor suppressor, pancreatic cancer, prostate cancer, Ras oncogene, RB: retinoblastoma, von Hippel-Lindau syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Cancer.html

•

Immune System: Fights invaders. Examples: Asthma, autoimmune polyglandular syndrome, Crohn’s disease, DiGeorge syndrome, familial Mediterranean fever, immunodeficiency with Hyper-IgM, severe combined immunodeficiency. Web site: http://www.ncbi.nlm.nih.gov/disease/Immune.html

•

Metabolism: Food and energy. Examples: Adreno-leukodystrophy, atherosclerosis, Best disease, Gaucher disease, glucose galactose malabsorption, gyrate atrophy, juvenile-onset diabetes, obesity, paroxysmal nocturnal hemoglobinuria, phenylketonuria, Refsum disease, Tangier disease, Tay-Sachs disease. Web site: http://www.ncbi.nlm.nih.gov/disease/Metabolism.html

•

Muscle and Bone: Movement and growth. Examples: Duchenne muscular dystrophy, Ellis-van Creveld syndrome, Marfan syndrome, myotonic dystrophy, spinal muscular atrophy. Web site: http://www.ncbi.nlm.nih.gov/disease/Muscle.html

•

Nervous System: Mind and body. Examples: Alzheimer disease, amyotrophic lateral sclerosis, Angelman syndrome, Charcot-Marie-Tooth disease, epilepsy, essential tremor, fragile X syndrome,

Physician Resources

279

Friedreich’s ataxia, Huntington disease, Niemann-Pick disease, Parkinson disease, Prader-Willi syndrome, Rett syndrome, spinocerebellar atrophy, Williams syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Brain.html •

Signals: Cellular messages. Examples: Ataxia telangiectasia, Cockayne syndrome, glaucoma, male-patterned baldness, SRY: sex determination, tuberous sclerosis, Waardenburg syndrome, Werner syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Signals.html

•

Transporters: Pumps and channels. Examples: Cystic fibrosis, deafness, diastrophic dysplasia, Hemophilia A, long-QT syndrome, Menkes syndrome, Pendred syndrome, polycystic kidney disease, sickle cell anemia, Wilson’s disease, Zellweger syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Transporters.html Entrez

Entrez is a search and retrieval system that integrates several linked databases at the National Center for Biotechnology Information (NCBI). These databases include nucleotide sequences, protein sequences, macromolecular structures, whole genomes, and MEDLINE through PubMed. Entrez provides access to the following databases: •

3D Domains: Domains from Entrez Structure, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

•

Books: Online books, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=books

•

Genome: Complete genome assemblies, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Genome

•

NCBI’s Protein Sequence Information Survey Results: Web site: http://www.ncbi.nlm.nih.gov/About/proteinsurvey/

•

Nucleotide Sequence Database (Genbank): Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Nucleotide

•

OMIM: Online Mendelian Inheritance in Man, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

•

PopSet: Population study data sets, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Popset

•

ProbeSet: Gene Expression Omnibus (GEO), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

•

Protein Sequence Database: Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Protein

•

PubMed: Biomedical literature (PubMed), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed

•

Structure: Three-dimensional macromolecular structures, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Structure

280

•

Estrogen

Taxonomy: Organisms in GenBank, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Taxonomy

To access the Entrez system at the National Center for Biotechnology Information, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=genome, and then select the database that you would like to search. The databases available are listed in the drop box next to “Search.” Enter “estrogen” (or synonyms) into the search box and click “Go.” Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database23 This online resource has been developed to facilitate the identification and differentiation of syndromic entities. Special attention is given to the type of information that is usually limited or completely omitted in existing reference sources due to space limitations of the printed form. At http://www.nlm.nih.gov/mesh/jablonski/syndrome_toc/toc_a.html, you can search across syndromes using an alphabetical index. Search by keywords at http://www.nlm.nih.gov/mesh/jablonski/syndrome_db.html. The Genome Database24 Established at Johns Hopkins University in Baltimore, Maryland in 1990, the Genome Database (GDB) is the official central repository for genomic mapping data resulting from the Human Genome Initiative. In the spring of 1999, the Bioinformatics Supercomputing Centre (BiSC) at the Hospital for Sick Children in Toronto, Ontario assumed the management of GDB. The Human Genome Initiative is a worldwide research effort focusing on structural analysis of human DNA to determine the location and sequence of the estimated 100,000 human genes. In support of this project, GDB stores and curates data generated by researchers worldwide who are engaged in the mapping effort of the Human Genome Project (HGP). GDB’s mission is to provide scientists with an encyclopedia of the human genome which is continually revised and updated to reflect the current state of scientific knowledge. Although GDB has historically focused on gene mapping, its focus will broaden as the Genome Project moves from mapping to sequence, and finally, to functional analysis. To access the GDB, simply go to the following hyperlink: http://www.gdb.org/. Search “All Biological Data” by “Keyword.” Type “estrogen” (or synonyms) into the search box, and review the results. If more than one word is used in the search box, then separate each one with the word “and” or “or” (using “or” might be useful when using synonyms).

23

Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html. 24 Adapted from the Genome Database: http://gdbwww.gdb.org/gdb/aboutGDB.html - mission.

281

APPENDIX B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on estrogen can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.

Patient Guideline Sources The remainder of this chapter directs you to sources which either publish or can help you find additional guidelines on topics related to estrogen. Due to space limitations, these sources are listed in a concise manner. Do not hesitate to consult the following sources by either using the Internet hyperlink provided, or, in cases where the contact information is provided, contacting the publisher or author directly. The National Institutes of Health The NIH gateway to patients is located at http://health.nih.gov/. From this site, you can search across various sources and institutes, a number of which are summarized below. Topic Pages: MEDLINEplus The National Library of Medicine has created a vast and patient-oriented healthcare information portal called MEDLINEplus. Within this Internet-based system are “health topic pages” which list links to available materials relevant to estrogen. To access this system, log on to http://www.nlm.nih.gov/medlineplus/healthtopics.html. From there you can either search using the alphabetical index or browse by broad topic areas. Recently, MEDLINEplus listed the following when searched for “estrogen”:

282

•

Estrogen

Other guides Breast Cancer http://www.nlm.nih.gov/medlineplus/breastcancer.html Hormone Replacement Therapy http://www.nlm.nih.gov/medlineplus/hormonereplacementtherapy.html Hormones http://www.nlm.nih.gov/medlineplus/hormones.html Infertility http://www.nlm.nih.gov/medlineplus/infertility.html Menopause http://www.nlm.nih.gov/medlineplus/menopause.html

Within the health topic page dedicated to estrogen, the following was listed: •

General/Overviews Hormone Therapy Source: American College of Obstetricians and Gynecologists http://www.medem.com/medlb/article_detaillb.cfm?article_ID=ZZZMIM8U5FD &sub_cat=2002 Hormones After Menopause Source: National Institute on Aging http://www.niapublications.org/engagepages/hormonesafter.asp Latest on Hormone Replacement Therapy Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=WO00037 Menopause and Hormones Source: Food and Drug Administration http://www.fda.gov/womens/menopause/mht-FS.html

•

Treatment FDA Approves Estrasorb for Treatment of Menopausal Hot Flashes Source: Food and Drug Administration http://www.fda.gov/bbs/topics/ANSWERS/2003/ANS01255.html

•

Alternative Therapy Hormone Replacement Therapy: Who Should Take It and What Are the Alternatives? Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=WO00046

Patient Resources 283

•

Specific Conditions/Aspects American Heart Association President Responds to New Findings From Women's Health Initiative Trial Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3003700 FDA Approves Lower Dose of Prempro, a Combination Estrogen and Progestin Drug for Postmenopausal Women Source: Food and Drug Administration http://www.fda.gov/bbs/topics/NEWS/2003/NEW00878.html FDA Approves New Labeling and Provides New Advice to Postmenopausal Women Who Use or Who Are Considering Using Estrogen and Estrogen With Progestin Source: Food and Drug Administration http://www.fda.gov/oc/factsheets/WHI.html Phytoestrogens and Bone Health Source: Osteoporosis and Related Bone Diseases-National Resource Center http://www.osteo.org/newfile.asp?doc=r618i&doctitle=Phytoestrogens%2Band%2 BBone%2BHealth&doctype=HTML%2BFact%2BSheet Pill Revisited: Benefits Beyond Birth Control Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=HQ01522 Questions and Answers for Estrogen and Estrogen with Progestin Therapies for Postmenopausal Women Source: Center for Drug Evaluation and Research http://www.fda.gov/cder/drug/infopage/estrogens_progestins/Q&A.htm

•

From the National Institutes of Health Facts About Postmenopausal Hormone Therapy Source: National Heart, Lung, and Blood Institute http://www.nhlbi.nih.gov/health/women/pht_facts.htm Menopausal Hormone Use: Questions and Answers Source: National Cancer Institute http://www.cancer.gov/newscenter/estrogenplus

•

Latest News Early Data Could Have Shown HRT Risks Source: 02/27/2004, Reuters Health http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/news/fullstory_16308 .html FDA Updates Hormone Therapy Information for Post Menopausal Women Source: 02/10/2004, Food and Drug Administration http://www.fda.gov/bbs/topics/NEWS/2004/NEW01022.html Hormone Therapy May Affect Hearing Source: 02/25/2004, Reuters Health http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/news/fullstory_16270 .html

284

Estrogen

Hormone Use Linked to Asthma in Women Source: 02/23/2004, Reuters Health http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/news/fullstory_16202 .html More News on Hormone Replacement Therapy http://www.nlm.nih.gov//www.nlm.nih.gov/medlineplus/alphanews_h.html#H ormoneReplacementTherapy •

Law and Policy Task Force Issues Caution on Combined Hormone Therapy Source: Agency for Healthcare Research and Quality http://www.ahrq.gov/news/press/pr2002/hrtrecpr.htm

•

Organizations American Society for Reproductive Medicine http://www.asrm.org/ Hormone Foundation http://www.hormone.org/ National Institute on Aging http://www.nia.nih.gov/ National Women's Health Information Center Source: Dept. of Health and Human Services http://www.4woman.gov/ North American Menopause Society http://www.menopause.org/

•

Prevention/Screening Postmenopausal Hormone Replacement Therapy to Prevent Chronic Conditions: Recommendations from the U.S. Preventive Services Task Force Source: American College of Physicians http://www.annals.org/cgi/content/full/137/10/I-48

•

Research Bone Loss after Stopping Estrogen or Alendronate Therapy Source: American College of Physicians http://www.annals.org/cgi/content/full/137/11/I-31 Cancer Risk May Vary by Hormone Regimen and How Recently Used Source: American College of Obstetricians and Gynecologists http://www.medem.com/medlb/article_detaillb.cfm?article_ID=ZZZWP40L19D& sub_cat=2 Changes in the Use of Postmenopausal Hormone Replacement Therapy after the Publication of Study Results Source: American College of Physicians http://www.annals.org/cgi/content/full/140/3/I-50

Patient Resources 285

Combination Hormone Therapy Raises Women's Stroke Risk Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3008846 Effects of Age, Breast Density, and Hormone Therapy on the Accuracy of Screening Mammograms Source: American College of Physicians http://www.annals.org/cgi/content/full/138/3/I-28 Ending Hormone Therapy Leads to Rapid Bone Loss in Elderly Women Source: Endocrine Society http://www.medem.com/medlb/article_detaillb.cfm?article_ID=ZZZW7Z7LL9D& sub_cat=2 Hormone Replacement Therapy Does Not Appear to Influence Breast Cancer Detection Source: American Medical Association http://www.medem.com/medlb/article_detaillb.cfm?article_ID=ZZZVXZAO66D &sub_cat=2 Hormone Therapy Can Relieve Menopause-Type Symptoms Common in Elderly Women: HERS Study Report Source: American College of Obstetricians and Gynecologists http://www.medem.com/medlb/article_detaillb.cfm?article_ID=ZZZRMBOL19D &sub_cat=2 Hormone Therapy Raises Risk of Breast Cancer Recurrence Source: American Cancer Society http://www.cancer.org/docroot/NWS/content/NWS_1_1x_Hormone_Therapy_R aises_Risk_of_Breast_Cancer_Recurrence.asp Increased Risk of Ovarian Cancer Is Linked to Estrogen Replacement Therapy Source: National Cancer Institute http://www.cancer.gov/newscenter/Laceyovarian Long-Term Use of Estrogen Replacement Therapy (ERT) Associated With Increased Risk of Ovarian Cancer Death Among Postmenopausal Women Source: American Medical Association http://www.medem.com/MedLB/article_detaillb.cfm?article_ID=ZZZ8VKGSIKC &sub_cat=638 NHLBI Stops Trial of Estrogen Plus Progestin Due to Increased Breast Cancer Risk, Lack of Overall Benefit Source: National Heart, Lung, and Blood Institute http://www.nih.gov/news/pr/jul2002/nhlbi-09.htm Postmenopausal Hormone Therapy and Blood Sugar Source: American College of Physicians http://www.annals.org/cgi/content/full/138/1/I-10 Rates of Dementia Increase among Older Women on Combination Hormone Therapy Source: National Institute on Aging http://www.nih.gov/news/pr/may2003/nia-27.htm

286

Estrogen

Reduced Risk of Alzheimer Disease Associated With Prior Use of Hormone Therapy in Older Women Source: American Medical Association http://www.medem.com/medlb/article_detaillb.cfm?article_ID=ZZZ68RHO78D& sub_cat=2 Risedronate and Hormone Replacement Therapy Improve Bone Mineral Density in Postmenopausal Women Source: Endocrine Society http://www.medem.com/MedLB/article_detaillb.cfm?article_ID=ZZZVDIQNQM C&sub_cat=638 Statement on Hormone Therapy for the Prevention and Treatment of Postmenopausal Osteoporosis Source: American College of Obstetricians and Gynecologists http://medem.com/medlb/article_detaillb.cfm?article_ID=ZZZJLS9PJLD&sub_cat =2009 Study Confirms Breast Cancer Risk in Continuous Combined Hormone Therapy Risk Begins to Return to Normal After Women Stop Taking Hormones Source: National Institute of Child Health and Human Development http://www.nih.gov/news/pr/nov2002/nichd-29.htm Study of Menopausal Women with Heart Disease Finds No Benefit, Potential for Harm from Hormone Therapy and Antioxidant Vitamins Source: National Heart, Lung, and Blood Institute http://www.nih.gov/news/pr/nov2002/nhlbi-19.htm WHIMS Study on Estrogen/Progestin Source: Food and Drug Administration http://www.fda.gov/bbs/topics/ANSWERS/2003/ANS01226.html You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. The Combined Health Information Database (CHID) CHID Online is a reference tool that maintains a database directory of thousands of journal articles and patient education guidelines on estrogen. CHID offers summaries that describe the guidelines available, including contact information and pricing. CHID’s general Web site is http://chid.nih.gov/. To search this database, go to http://chid.nih.gov/detail/detail.html. In particular, you can use the advanced search options to look up pamphlets, reports, brochures, and information kits. The following was recently posted in this archive: •

Estrogen and Alzheimer's Disease Source: Silver Spring, MD: ADEAR Center. 1998. 8 p.

Patient Resources 287

Contact: ADEAR Center. PO Box 8250, Silver Spring, MD 20907-8250. (800) 438-4380; (301) 495-3311; FAX (301) 495-3334. Internet access: http://www.alzheimers.org/adear. PRICE: Free. NIH Publication Number: 98-4011. Item number: Z-150. Summary: This fact sheet highlights current research on the relationship between estrogen use and a lowered risk for Alzheimer's disease (AD). Findings from some studies suggest that estrogen may delay or prevent the onset of AD or slow its progression. However, controlled clinical trials are needed to confirm these findings and determine safety, dose, and duration of estrogen treatment needed to produce these effects. The fact sheet reviews existing evidence regarding the relationship between estrogen and AD, describes some of the studies currently under way, discusses factors to consider in the decision to use estrogen, and suggests resources for additional information. Healthfinder™ Healthfinder™ is sponsored by the U.S. Department of Health and Human Services and offers links to hundreds of other sites that contain healthcare information. This Web site is located at http://www.healthfinder.gov. Again, keyword searches can be used to find guidelines. The following was recently found in this database: •

DES: Questions and Answers Summary: This fact sheet provides basic information about DES (a synthetic form of estrogen) and the health problems of children who were exposed to DES while in the womb. Source: Cancer Information Service, National Cancer Institute http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=7188

•

Estrogen and Estrogen with Progestin Therapies for Postmenopausal Women Summary: Information from the Women’s Health Initiative (WHI) trial about estrogens and progestins continues to have significant public health implications for postmenopausal women. Source: Center for Drug Evaluation and Research, U.S. Food and Drug Administration http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=7949

•

Estrogen and Progestin Dilemma: New Advice, Labeling Guidelines Summary: The Food and Drug Administration is giving important new safety advice to postmenopausal women and their health-care providers concerning drug products that contain estrogen. Source: U.S. Food and Drug Administration http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=7425

288

•

Estrogen

Evolution of Estrogen Summary: This timeline is a compilation of events that traces the evolution of estrogen in women's health and its role in hormone replacement therapy. Source: Hormone Foundation http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=7163

•

Hormone Replacement Therapy for Primary Prevention of Chronic Conditions: Recommendations and Rationale Summary: The U.S. Preventive Services Task Force (USPSTF) recommends against the routine use of estrogen and progestin for the prevention of chronic conditions in postmenopausal women. Source: Agency for Healthcare Research and Quality http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=6952

•

Questions and Answers: Use of Hormones After Menopause Summary: Postmenopausal hormone use usually involves hormone replacement therapy (HRT) with either estrogen alone or in combination with progestin to compensate for the decrease in natural hormones that occurs Source: National Cancer Institute, National Institutes of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=6794 The NIH Search Utility

The NIH search utility allows you to search for documents on over 100 selected Web sites that comprise the NIH-WEB-SPACE. Each of these servers is “crawled” and indexed on an ongoing basis. Your search will produce a list of various documents, all of which will relate in some way to estrogen. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats

•

Family Village: http://www.familyvillage.wisc.edu/specific.htm

•

Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/

•

Med Help International: http://www.medhelp.org/HealthTopics/A.html

Patient Resources 289

•

Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/

•

Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/

•

WebMD®Health: http://my.webmd.com/health_topics

News Services and Press Releases One of the simplest ways of tracking press releases on estrogen is to search the news wires. In the following sample of sources, we will briefly describe how to access each service. These services only post recent news intended for public viewing. PR Newswire To access the PR Newswire archive, simply go to http://www.prnewswire.com/. Select your country. Type “estrogen” (or synonyms) into the search box. You will automatically receive information on relevant news releases posted within the last 30 days. Reuters Health The Reuters’ Medical News and Health eLine databases can be very useful in exploring news archives relating to estrogen. While some of the listed articles are free to view, others are available for purchase for a nominal fee. To access this archive, go to http://www.reutershealth.com/en/index.html and search by “estrogen” (or synonyms). The NIH Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine. Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name. Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to

290

Estrogen

Market Wire’s home page at http://www.marketwire.com/mw/home, type “estrogen” (or synonyms) into the search box, and click on “Search News.” As this service is technology oriented, you may wish to use it when searching for press releases covering diagnostic procedures or tests. Search Engines Medical news is also available in the news sections of commercial Internet search engines. See the health news page at Yahoo (http://dir.yahoo.com/Health/News_and_Media/), or you can use this Web site’s general news search page at http://news.yahoo.com/. Type in “estrogen” (or synonyms). If you know the name of a company that is relevant to estrogen, you can go to any stock trading Web site (such as http://www.etrade.com/) and search for the company name there. News items across various news sources are reported on indicated hyperlinks. Google offers a similar service at http://news.google.com/. BBC Covering news from a more European perspective, the British Broadcasting Corporation (BBC) allows the public free access to their news archive located at http://www.bbc.co.uk/. Search by “estrogen” (or synonyms).

Newsletter Articles Use the Combined Health Information Database, and limit your search criteria to “newsletter articles.” Again, you will need to use the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. Go to the bottom of the search page where “You may refine your search by.” Select the dates and language that you prefer. For the format option, select “Newsletter Article.” Type “estrogen” (or synonyms) into the “For these words:” box. You should check back periodically with this database as it is updated every three months. The following is a typical result when searching for newsletter articles on estrogen: •

Why Fat Migrates to Your Middle Source: Tufts University Health and Nutrition Letter. 18(7):6. September 2000. Contact: 10 High St., Suite 706, Boston, MA 02110. [email protected] www.healthletter.tufts.edu. Summary: A book by Dr. Pamela Peeke, Fight Fat After Forty, proposes that middle- age women gain weight around their waists because of emotional stress which causes the steady release of the stress hormone cortisol. According to Dr. Peeke, cortisol not only causes chronic overeating but also causes excess calories to be stored as fat deep in the abdomen. Although it is true that weight gain around the middle is a health problem because it contributes to high blood pressure and increased blood levels of cholesterol, there is still too little research to determine whether a hectic lifestyle has anything to do with abdominal weight gain. Human studies have found a rough link between fat stores in the abdomen and higher cortisol levels, but it is not clear whether the cortisol levels induce the laying down of abdominal fat or whether the greater levels of abdominal fat cause the rise in cortisol levels. Most researchers believe obesity is a complicated

Patient Resources 291

problem that involves not only an individual's stress level, but many other factors as well. The article notes that difficulties in coping with life's problems could never be singled out as the defining factor in a woman's eating style and body shape. Other theories on why many women gain weight around the middle as they enter midlife include having a sedentary lifestyle, a loss of muscle tissue due to aging, and a decline in estrogen levels. •

Weight and Cancer: More Links Uncovered Source: Tufts University Health and Diet Letter. 20(7): 1,8. September 2002. Contact: P.O. Box 420235, Palm Coast, FL 32142-0235. 800/274-7581. www.healthletter.tufts.edu. Summary: Excess body fat seems to produce changes in the body that may contribute to the development of certain cancers. Research indicates that fat cells secrete growthproducing substances, including hormones, into the bloodstream. These substances send signals that prompt cells elsewhere in the body to grow and divide faster than they would otherwise. This in turn increases the risk that a random mutation could lead to the runaway cell growth of cancer. The cancers most affected by excess weight seem to be those related to the sex hormones estrogen and testosterone. They include cancers of the breast, endometrium, and prostate. Excess body fat may also contribute to cancer through insulin. People who are overweight may produce extra insulin, which can increase cell division and therefore cancer risk. Risk increases as weight increases, but even a 5 percent reduction in body weight translates into a significant safeguard against future illness.

•

Boning Up on Bone Health Source: University of California, Berkeley, Wellness Letter. 16(12):5. September 2000. Contact: Health Letter Associates. P.O. Box 412, Prince Street Station, New York, NY 10012-0007. Summary: Strong bones are dependent on more than just the mineral calcium. Depending on many factors, including testosterone in men and estrogen in women, calcium is laid down in bone and released from it. Weight-bearing exercise such as walking synergizes with nutrients and hormones to build up bone tissue. Lack of activity robs the body of bone mass. The article reviews the other nutrients besides calcium that are necessary for bone health: vitamin C, vitamin K, vitamin D, magnesium, potassium, zinc, copper, manganese, and boron. These nutrients can be found in diets rich in fruits, whole grains, vegetables, low-fat and non-fat dairy products, and fortified cereals. The author also recommends a daily multivitamin and mineral supplement for most people.

•

Menopausal Weight Gain Source: Mayo Clinic Women's HealthSource. December 1998. Contact: Mayo Clinic Women's HealthSource, P.O. Box 56931, Boulder, CO 80322-6931. Summary: This article discusses the changes a woman can expect to go through during perimenopause and menopause. The author points out the changes of puberty and pregnancy as models for the change of menopause. According to the author, lowered estrogen production contributes to the mood swings, sleep disturbances, and hot flashes of menopause. For most women, their metabolism also slows down, and their lean

292

Estrogen

muscle mass diminishes. This can lead to weight gain. A starvation diet is not the answer, according to the author, who says that exercise is a better choice. Exercise boosts the metabolism, burns fat, and can strengthen bones. All forms of exercise are potentially beneficial, including aerobic exercise to burn fat, stretching to increase flexibility, and strength training to improve muscle mass and strengthen bones. Other topics discussed include hormone replacement therapy and a healthy diet. •

The Obesity Factor: Excessive Weight Has Strong Cancer Links Source: AICR Newsletter. Issue 62, p.11. Winter 1999. Contact: AICR, 1759 R Street NW, Washington, DC. (202) 328-7744. Summary: This article discusses the link between obesity and cancer risk. According to two recent studies, obese individuals are at increased risk for certain kinds of cancer, especially if they have excess abdominal fat. The author suggests that this may be caused by increased levels of estrogen in the blood, or by an increased gut transit time (the time it takes for substances to pass through the large intestine). The article recommends weight control and exercise. A formula for calculating body mass index is provided.

•

Soy: Food, not Pills Source: University of California, Berkeley, Wellness Letter. 17(4):2-3. January 2001. Contact: Health Letter Associates. P.O. Box 412, Prince Street Station, New York, NY 10012-0007. www.wellnessletter.com. Summary: This article recommends eating soy foods for good health rather than taking soy supplements in the form of capsules and pills. Soy supplements contain phytoestrogens or plant estrogens that supposedly replenish declining estrogen levels and relieve menopausal symptoms as well as decrease the risk of heart disease and osteoporosis without promoting breast cancer. Notable among the phytoestrogens is a group of compounds called isoflavones. Genistein and daidzein are two primary isoflavones commonly found in many soy supplements. Research results indicate conflicting effects on the risk of cancer, and some isoflavones can be either estrogenboosting or estrogen-blocking. No one knows what the long-term effects of isoflavones are. Another issue is the variable amounts of isoflavones in soy supplements and how these differ from the levels in soy foods. In contrast, people have been eating soy foods for centuries, and there is good evidence that these are healthful.

•

Solving the Breast Cancer Puzzle Source: American Institute for Cancer Research Newsletter. p. 1, 3. Issue 77. Fall 2002. Contact: American Institute for Cancer Research. 1759 R Street, NW, Washington, DC 20009. 202/328-7744. Summary: This article reviews current research on reducing the risk of developing breast cancer. Research shows that obesity and overweight, particularly weight gained in adulthood, increase the risk of breast cancer later in life. Excess weight gained during pregnancy also raises breast cancer risk after menopause. Physical activity is important in breast cancer prevention. Exercise regulates levels of the hormones estrogen and insulin, and lower levels of these hormones means less risk of cancer. Reducing portion sizes and eating a predominately plant-based diet also reduces breast cancer risk and aids in weight management. To maintain a healthy body weight and lower breast cancer

Patient Resources 293

risk, the article recommends that women eat vegetables and fruits and limit animal fat and alcohol. Until further research shows otherwise, the article recommends moderate amounts of soy foods and flaxseed, which may offer breast cancer protection. •

Top Ten Tips to Help Celiacs Maintain Sturdy Bones Source: Gluten-Free Living. 1(5): 5. September-October 1996. Contact: Available from Gluten-Free Living. P.O. Box 105, Hastings-on-Hudson, NY 10706. Summary: This brief newsletter article lists ten tips to help people with celiac disease maintain sturdy bones. The tips include: have a bone densitometry test to diagnose bone disease; include foods that are naturally high in calcium in the daily diet; take calcium and Vitamin D supplements as necessary; consider estrogen replacement therapy, if appropriate; do weight-bearing exercises; restrict intake of coffee, alcohol, and salt; and don't smoke.

•

Nocturia: When Nature Calls at Night Source: Harvard Health Letter. 24(10): 6. August 1999. Contact: Available from Harvard Medical School Health Publications Group. Harvard Health Letter, P.O. Box 420300, Palm Coast, FL 32142-0300. (800) 829-9045. E-mail: [email protected]. Summary: This health newsletter article describes nocturia, the condition of frequent urination at night. Nocturia is often more of a bother than a major burden, but readers are cautioned that it can be a sign of early kidney, bladder, or prostate disease. Nocturia can also be a byproduct of heart failure and other conditions that cause edema (retention of fluid). Physicians usually treat nocturia by addressing the conditions that cause it. More men in their 40s and 50s are bothered by nocturia than women the same age, but the numbers start to even out with age. For men, nocturia is often associated with prostate problems. In this situation, the bladder can't completely empty because benign prostatic hyperplasia (BPH), the noncancerous enlargement of the prostate gland, compresses the urethra and slows or impedes the flow of urine. For women, childbirth and lower estrogen levels cause the muscles of the pelvic floor to weaken. Weaker pelvic floor muscles can mean less control and more interruptions at night to urinate. The article concludes by encouraging readers to seek treatment for nocturia, particularly that which interferes with adequate sleep, as there are a variety of approaches to the problem. 1 figure.

•

Gallbladder Disease: What to Do About Troublesome Stones Source: Mayo Clinic Women's Healthsource. 3(9): 6. September 1999. Contact: Available from Mayo Foundation for Medical Education and Research. 200 First Street SW, Rochester, MN 55905. Summary: This health newsletter article offers guidelines to identifying and managing a gallstone attack. The author notes the risk factors for gallstones, including female gender, family history, being moderately overweight, losing weight rapidly, and taking estrogen pills. The author then briefly reviews the placement and function of the gallbladder, notably as the storage facility for liver bile (which helps the small intestine digest fat). Gallstones can be tiny or big and about 80 percent of the time, stones cause no problems. However, gallstones can block the exit from the gallbladder which is when

294

Estrogen

the pain (biliary colic) begins. Gallbladder attacks are infrequent, occurring weeks, months, even years apart, and last from 30 minutes to several hours. Pain is the main symptom of gallstone disease. If the pain is severe and continuous in the upper abdomen and lasts for at least half an hour, the health care provider may recommend an ultrasound to confirm the presence of stones or other signs of gallbladder disease. The treatment for gallstones is usually cholecystectomy (gallbladder removal). Most often, the surgery is performed laparoscopically, which requires only three small incisions. Readers are reassured that gallstone attacks are usually infrequent, but if surgery is required, the cholecystectomy is a safe, common procedure. 2 figures. •

Use of Nerve Growth Factor Is Focus of Several Studies Source: Alzheimer's Research Review. [Newsletter] p. 1-2. Winter 1989-1990. Contact: Available from Alzheimer's Disease Research, American Health Assistance Foundation. 15825 Shady Grove Road, Suite 140, Rockville, MD 20850. (301) 948-3244 or (800) 437-2423. PRICE: Single copy free. Summary: This newsletter article describes three separate research efforts which are examining the potential impact and use of nerve growth factor (NGF) in Alzheimer's disease. The first study involves the Institute for Biogerontology Research in Arizona. These researchers are exploring theory that the degenerative events occurring in the basal forebrain are due to the loss of NGF receptors, and further, that such cell loss results in deficits in the central neural systems which underlie mental function. The second study, at the Columbia University College of Physicians and Surgeons, focuses not only on the role of NGF but also on the sex hormone estrogen. Researchers have found that some basal forebrain nerve cell contain receptors for both NGF and estrogen, while others contain one or the other, or neither. The last study, at the University of Washington, explores new and more efficient drug delivery systems for substances such as NGF. Researchers are studying the advantages and disadvantages of a polymeric drug delivery system which relies on the slow release of a drug in a specific brain region to counteract the Alzheimer's-related chemical loss.

•

Osteoporosis Revolution Source: Lupus News. 17(3):4-5; Autumn 1997. Contact: Lupus Foundation of America, Inc., 1300 Piccard Drive, Suite 200, Rockville, MD 20850-4303. (301) 670-9292. (301) 670-9486 (fax). Summary: This newsletter article for individuals with lupus reports on the revolution in the approach to the prevention and treatment of osteoporosis in postmenopausal women. The most important aspects of this revolution include the development of bone densitometry to measure the mineral content of the bones of the lower lumbar spine and of the upper end of the femur to help determine the risk of fracture and the use of bone markers to predict bone loss and assess the response to therapy. Another aspect of this revolution is the development of new agent drugs to inhibit bone breakdown, including bisphosphonates such as alendronate, estrogen analogs, and nasal calcitonin. Studies are also being conducted on the effectiveness of parathyroid hormone and fluoride in increasing bone formation.

•

Injury Prevention: Keeping Old Bones Whole Source: Harvard Health Letter. 21(11):1-2; September 1996.

Patient Resources 295

Contact: Harvard Medical School Health Publications Group, 164 Longwood Avenue, Boston, MA 02115. Summary: This newsletter article for the general public discusses ways to prevent latelife fractures. Basic approaches to preventing fractures include averting a fall, decreasing the severity if a fall occurs, and keeping bone strong. Falls can be avoided by removing households obstacles or objects likely to cause falls and exercising to improve balance, flexibility, muscle strength, and reaction time. Various padding systems can be used to reduce the severity of a fall. Pads are built into a tight-fitting undergarment, and they protect the hip by absorbing energy from a fall or transferring the energy away from the bone and into surrounding tissues. In addition, maintaining bone density throughout life by performing regular weight-bearing exercise and consuming adequate amounts of calcium and vitamin D is essential. Estrogen replacement therapy can prevent postmenopausal bone loss, and various medications can help both men and women preserve bone. 1 figure. •

Drugs in Development Source: Research and Practice. 5(3): 2-3. Fall 1997. Contact: Alzheimer's Association. 919 North Michigan Avenue, Suite 1000, Chicago, IL 60611-1676. (800) 272-3900. (312) 335-8700. FAX: (312) 335-1110. Internet: www.alz.org. PRICE: Free. Summary: This newsletter article highlights the status of new treatments under investigation for the treatment of Alzheimer's disease (AD). It discusses the types of drugs that currently are being studied and summarizes some of the initial findings about the effects of antioxidants such as vitamin E or selegiline, non-steroidal antiinflammatory drugs, and estrogen. It includes a chart summarizing current research into drugs that may improve the cognitive symptoms of AD. The chart includes the names of 22 drugs being studied and brief descriptions of the mechanisms of action, trial sponsors, and phase of development.

•

Systemic Lupus Erythematosus: Women's Health Issues Source: Bulletin on the Rheumatic Diseases. 49(8): 1-3. 2001. Contact: Available from Arthritis Foundation. 1330 West Peachtree Street, Atlanta, GA 30309. (404) 872-7100. Fax (404) 872-9559. Summary: This newsletter article provides health professionals with information on systemic lupus erythematosus (SLE) in relation to issues specific to women's health, including pregnancy, contraception, fertility, sexuality, management of menopause, osteoporosis, coronary artery disease, and chronic fatigue. Pregnancy is high risk for both the woman with SLE and her fetus. Pregnant women with SLE are at higher risk for both preeclampsia and premature membrane rupture. Fetal problems associated with SLE include preterm birth, intrauterine growth retardation, placental insufficiency, pregnancy loss, and congenital heart block. Although barrier contraception is the safest method in SLE, other options include oral contraceptives, the intrauterine device, and tubal ligation. Fertility is usually not a problem in women with SLE, but some SLE treatment regimens, such as monthly pulse intravenous cyclophosphamide, put fertility at risk. Women with SLE may face sexuality issues because their body image is affected both by the disease and by its treatment. More women with SLE are reaching menopause, and studies have suggested that estrogen replacement therapy does not increase SLE flares. Both premenopausal and postmenopausal women with SLE are at

296

Estrogen

risk for osteoporosis because of the use of prednisone. The major cause of death in women with SLE is cardiovascular disease, so they should be considered as candidates for screening for early atherosclerosis. Chronic fatigue is a major complaint of women with SLE. 4 tables and 18 references. •

Anatomy of an Itch Source: Quarterly: The Journal of the National Pemphigus Foundation. 27: 10. Winter 2001. Contact: Available from National Pemphigus Foundation. P.O. Box 9606, Berkeley, CA 94709-0606. (510) 527-4970. Fax: (510) 527-8497. Email: [email protected]. Website: www.pemphigus.org. Summary: This newsletter article provides tips for alleviating itching for patients with pemphigus. Antihistamines may help control itching, as well as wearing cotton clothing, staying indoors when it is hot outside, reducing stress, and using moisturizers and soap substitutes. A number of drugs such as anabolic steroids, B complex vitamins, estrogen, and testosterone should be avoided. Alcohol can also cause itching by changing the amount of blood flowing to the skin. For many people itching precedes the appearance of skin lesions.

•

Gallstones Source: Harvard Women's Health Watch. 3(8): 4-5. April 1996. Contact: Available from Harvard Women's Health Watch. P.O. Box 420234, Palm Coast, FL 32142-0234. (800) 829-5921. Summary: This newsletter article reminds health care providers and other medically astute readers of the risks of gallstone formation. Topics include the physiology of the bile ducts and how gallstones form; symptoms; diagnostic considerations; treatment; and managing risk factors, including estrogen levels, hypertriglyeridemia, drugs that lower cholesterol, obesity, and rapid weight loss. The authors note that women are about twice as likely to develop gallstones as men, and cholecystectomy is one of the most frequently performed operations on women. 1 figure.

Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to estrogen. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with estrogen. The National Health Information Center (NHIC) The National Health Information Center (NHIC) offers a free referral service to help people find organizations that provide information about estrogen. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797.

Patient Resources 297

Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://www.sis.nlm.nih.gov/Dir/DirMain.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. To access DIRLINE directly, go to the following Web site: http://dirline.nlm.nih.gov/. Simply type in “estrogen” (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://www.sis.nlm.nih.gov/hotlines/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information. The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “estrogen”. Type the following hyperlink into your Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” Type “estrogen” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months. The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type “estrogen” (or a synonym) into the search box, and click “Submit Query.”

299

APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.

Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.25

Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.

Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of

25

Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.

300

Estrogen

libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)26: •

Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/

•

Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)

•

Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm

•

California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html

•

California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html

•

California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html

•

California: Gateway Health Library (Sutter Gould Medical Foundation)

•

California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/

•

California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp

•

California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html

•

California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/

•

California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/

•

California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/

•

California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html

•

California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/

•

Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/

•

Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/

•

Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/

26

Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.

Finding Medical Libraries

301

•

Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml

•

Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute, Wilmington), http://www.christianacare.org/health_guide/health_guide_pmri_health_info.cfm

•

Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html

•

Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm

•

Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp

•

Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/

•

Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm

•

Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html

•

Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/

•

Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm

•

Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/

•

Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/

•

Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/

•

Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm

•

Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html

•

Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm

•

Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/

•

Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/

•

Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10

•

Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/

302

Estrogen

•

Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html

•

Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp

•

Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp

•

Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/

•

Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html

•

Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm

•

Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp

•

Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/

•

Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html

•

Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/

•

Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm

•

Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/

•

Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html

•

Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm

•

Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330

•

Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)

•

National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html

•

National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/

•

National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/

Finding Medical Libraries

303

•

Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm

•

New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/

•

New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm

•

New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm

•

New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/

•

New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html

•

New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/

•

New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html

•

New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/

•

Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm

•

Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp

•

Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/

•

Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/

•

Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml

•

Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html

•

Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html

•

Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml

•

Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp

•

Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm

•

Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/

304

Estrogen

•

South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp

•

Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/

•

Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/

•

Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72

305

ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •

ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html

•

MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp

•

Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/

•

Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html

•

On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/

•

Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp

•

Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm

Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a). The NIH suggests the following Web sites in the ADAM Medical Encyclopedia when searching for information on estrogen: •

Basic Guidelines for Estrogen Estrogen overdose Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002584.htm

•

Signs & Symptoms for Estrogen Breast tenderness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003152.htm Discoloration of urine Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003139.htm Drowsiness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003208.htm Emesis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003117.htm

306

Estrogen

Headache Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003024.htm Mental changes Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003205.htm Nausea and/or vomiting Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003117.htm Rash Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003220.htm Vaginal bleeding Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003156.htm

Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •

Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical

•

MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html

•

Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/

•

Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine

307

ESTROGEN DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 5-alpha: Enzyme converting testosterone to dihydrotestosterone. [NIH] Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal fat: Fat (adipose tissue) that is centrally distributed between the thorax and pelvis and that induces greater health risk. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Ablate: In surgery, is to remove. [NIH] Ablation: The removal of an organ by surgery. [NIH] Abortion: 1. The premature expulsion from the uterus of the products of conception - of the embryo, or of a nonviable fetus. The four classic symptoms, usually present in each type of abortion, are uterine contractions, uterine haemorrhage, softening and dilatation of the cervix, and presentation or expulsion of all or part of the products of conception. 2. Premature stoppage of a natural or a pathological process. [EU] Acantholysis: Separation of the prickle cells of the stratum spinosum of the epidermis, resulting in atrophy of the prickle cell layer. It is seen in diseases such as pemphigus vulgaris (see pemphigus) and keratosis follicularis. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acetylgalactosamine: The N-acetyl derivative of galactosamine. [NIH] Acetylglucosamine: The N-acetyl derivative of glucosamine. [NIH] Acne: A disorder of the skin marked by inflammation of oil glands and hair glands. [NIH] Acoustic: Having to do with sound or hearing. [NIH] Acridine Orange: Cationic cytochemical stain specific for cell nuclei, especially DNA. It is used as a supravital stain and in fluorescence cytochemistry. It may cause mutations in microorganisms. [NIH] Actin: Essential component of the cell skeleton. [NIH] Activities of Daily Living: The performance of the basic activities of self care, such as dressing, ambulation, eating, etc., in rehabilitation. [NIH] Acyl: Chemical signal used by bacteria to communicate. [NIH]

308

Estrogen

Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adduct: Complex formed when a carcinogen combines with DNA or a protein. [NIH] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adenovirus: A group of viruses that cause respiratory tract and eye infections. Adenoviruses used in gene therapy are altered to carry a specific tumor-fighting gene. [NIH] Adipose Tissue: Connective tissue composed of fat cells lodged in the meshes of areolar tissue. [NIH] Adjunctive Therapy: Another treatment used together with the primary treatment. Its purpose is to assist the primary treatment. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adjuvant: A substance which aids another, such as an auxiliary remedy; in immunology, nonspecific stimulator (e.g., BCG vaccine) of the immune response. [EU] Adjuvant Therapy: Treatment given after the primary treatment to increase the chances of a cure. Adjuvant therapy may include chemotherapy, radiation therapy, or hormone therapy. [NIH]

Administration, Oral: The giving of drugs, chemicals, or other substances by mouth. [NIH] Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Glands: Paired glands situated in the retroperitoneal tissues at the superior pole of each kidney. [NIH] Adrenal Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases catecholamines. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adrenergic Agents: Drugs that act on adrenergic receptors or affect the life cycle of adrenergic transmitters. Included here are adrenergic agonists and antagonists and agents that affect the synthesis, storage, uptake, metabolism, or release of adrenergic transmitters. [NIH]

Dictionary 309

Adrenergic Agonists: Drugs that bind to and activate adrenergic receptors. [NIH] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Aerobic Exercise: A type of physical activity that includes walking, jogging, running, and dancing. Aerobic training improves the efficiency of the aerobic energy-producing systems that can improve cardiorespiratory endurance. [NIH] Aetiology: Study of the causes of disease. [EU] Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Affinity Chromatography: In affinity chromatography, a ligand attached to a column binds specifically to the molecule to be purified. [NIH] Age of Onset: The age or period of life at which a disease or the initial symptoms or manifestations of a disease appear in an individual. [NIH] Age-Adjusted: Summary measures of rates of morbidity or mortality in a population using statistical procedures to remove the effect of age differences in populations that are being compared. Age is probably the most important and the most common variable in determining the risk of morbidity and mortality. [NIH] Agenesis: Lack of complete or normal development; congenital absence of an organ or part. [NIH]

Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] Agoraphobia: Obsessive, persistent, intense fear of open places. [NIH] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60 per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] Aldosterone: (11 beta)-11,21-Dihydroxy-3,20-dioxopregn-4-en-18-al. A hormone secreted by the adrenal cortex that functions in the regulation of electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. [NIH] Alendronate: A nonhormonal medication for the treatment of postmenopausal osteoporosis

310

Estrogen

in women. This drug builds healthy bone, restoring some of the bone loss as a result of osteoporosis. [NIH] Alendronate Sodium: A drug that affects bone metabolism. It is used in treating osteoporosis and Paget's disease, and is being studied in the treatment of hypercalcemia (abnormally high levels of calcium in the blood) and in treating and reducing the risk of bone pain caused by cancer. Alendronate sodium belongs to the family of drugs called bisphosphonates. [NIH] Alertness: A state of readiness to detect and respond to certain specified small changes occurring at random intervals in the environment. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alkaline: Having the reactions of an alkali. [EU] Alkaline Phosphatase: An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. EC 3.1.3.1. [NIH] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Alkylate: To treat with an alkylating agent. [EU] Alkylation: The covalent bonding of an alkyl group to an organic compound. It can occur by a simple addition reaction or by substitution of another functional group. [NIH] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Allylamine: Possesses an unusual and selective cytotoxicity for vascular smooth muscle cells in dogs and rats. Useful for experiments dealing with arterial injury, myocardial fibrosis or cardiac decompensation. [NIH] Alopecia: Absence of hair from areas where it is normally present. [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [NIH] Alpha-fetoprotein: AFP. A protein normally produced by a developing fetus. AFP levels are usually undetectable in the blood of healthy nonpregnant adults. An elevated level of AFP suggests the presence of either a primary liver cancer or germ cell tumor. [NIH] Alpha-helix: One of the secondary element of protein. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Alveolar Bone Loss: The resorption of bone in the supporting structures of the maxilla or mandible as a result of periodontal disease. [NIH] Alveolar Process: The thickest and spongiest part of the maxilla and mandible hollowed out into deep cavities for the teeth. [NIH]

Dictionary 311

Ameliorated: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Amenorrhea: Absence of menstruation. [NIH] Amine: An organic compound containing nitrogen; any member of a group of chemical compounds formed from ammonia by replacement of one or more of the hydrogen atoms by organic (hydrocarbon) radicals. The amines are distinguished as primary, secondary, and tertiary, according to whether one, two, or three hydrogen atoms are replaced. The amines include allylamine, amylamine, ethylamine, methylamine, phenylamine, propylamine, and many other compounds. [EU] Amino acid: Any organic compound containing an amino (-NH2 and a carboxyl (- COOH) group. The 20 a-amino acids listed in the accompanying table are the amino acids from which proteins are synthesized by formation of peptide bonds during ribosomal translation of messenger RNA; all except glycine, which is not optically active, have the L configuration. Other amino acids occurring in proteins, such as hydroxyproline in collagen, are formed by posttranslational enzymatic modification of amino acids residues in polypeptide chains. There are also several important amino acids, such as the neurotransmitter y-aminobutyric acid, that have no relation to proteins. Abbreviated AA. [EU] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amitriptyline: Tricyclic antidepressant with anticholinergic and sedative properties. It appears to prevent the re-uptake of norepinephrine and serotonin at nerve terminals, thus potentiating the action of these neurotransmitters. Amitriptyline also appears to antaganize cholinergic and alpha-1 adrenergic responses to bioactive amines. [NIH] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Amphetamines: Analogs or derivatives of amphetamine. Many are sympathomimetics and central nervous system stimulators causing excitation, vasopression, bronchodilation, and to varying degrees, anorexia, analepsis, nasal decongestion, and some smooth muscle relaxation. [NIH] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Amyloid: A general term for a variety of different proteins that accumulate as extracellular fibrils of 7-10 nm and have common structural features, including a beta-pleated sheet conformation and the ability to bind such dyes as Congo red and thioflavine (Kandel, Schwartz, and Jessel, Principles of Neural Science, 3rd ed). [NIH] Anabolic: Relating to, characterized by, or promoting anabolism. [EU] Anabolic Steroids: Chemical derivatives of testosterone that are used for anabolic promotion of growth and repair of body tissues and the development of male sexual characteristics. [NIH] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU]

312

Estrogen

Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anastrozole: An anticancer drug that belongs to the family of drugs called nonsteroidal aromatase inhibitors. Anastrozole is used to decrease estrogen production and suppress the growth of tumors that need estrogen to grow. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgen-Binding Protein: Carrier proteins produced in the Sertoli cells of the testis, secreted into the seminiferous tubules, and transported via the efferent ducts to the epididymis. They participate in the transport of androgens. Androgen-binding protein has the same amino acid sequence as sex hormone binding-globulin. They differ by their sites of synthesis and post-translational oligosacaccharide modifications. [NIH] Androgenic: Producing masculine characteristics. [EU] Androgens: A class of sex hormones associated with the development and maintenance of the secondary male sex characteristics, sperm induction, and sexual differentiation. In addition to increasing virility and libido, they also increase nitrogen and water retention and stimulate skeletal growth. [NIH] Androstenedione: A steroid with androgenic properties that is produced in the testis, ovary, and adrenal cortex. It is a precursor to testosterone and other androgenic hormones. [NIH] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Aneurysm: A sac formed by the dilatation of the wall of an artery, a vein, or the heart. [NIH] Angina: Chest pain that originates in the heart. [NIH] Angina Pectoris: The symptom of paroxysmal pain consequent to myocardial ischemia usually of distinctive character, location and radiation, and provoked by a transient stressful situation during which the oxygen requirements of the myocardium exceed the capacity of the coronary circulation to supply it. [NIH] Angiogenesis: Blood vessel formation. Tumor angiogenesis is the growth of blood vessels from surrounding tissue to a solid tumor. This is caused by the release of chemicals by the tumor. [NIH] Angiogenesis Factor: Substance causing proliferation of new blood vessels. It is found in tissues with high metabolic requirements, such as the retina, and in certain cancers. The factor is also released by hypoxic macrophages at the edges or outer surfaces of wounds and initiates revascularization in wound healing. [NIH] Angiography: Radiography of blood vessels after injection of a contrast medium. [NIH] Angiotensinogen: An alpha-globulin of which a fragment of 14 amino acids is converted by renin to angiotensin I, the inactive precursor of angiotensin II. It is a member of the serpin superfamily. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test

Dictionary 313

new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] Anisotropy: A physical property showing different values in relation to the direction in or along which the measurement is made. The physical property may be with regard to thermal or electric conductivity or light refraction. In crystallography, it describes crystals whose index of refraction varies with the direction of the incident light. It is also called acolotropy and colotropy. The opposite of anisotropy is isotropy wherein the same values characterize the object when measured along axes in all directions. [NIH] Ankle: That part of the lower limb directly above the foot. [NIH] Ankle Joint: The joint that is formed by the inferior articular and malleolar articular surfaces of the tibia, the malleolar articular surface of the fibula, and the medial malleolar, lateral malleolar, and superior surfaces of the talus. [NIH] Anomalies: Birth defects; abnormalities. [NIH] Anorexia: Lack or loss of appetite for food. Appetite is psychologic, dependent on memory and associations. Anorexia can be brought about by unattractive food, surroundings, or company. [NIH] Anorexia Nervosa: The chief symptoms are inability to eat, weight loss, and amenorrhea. [NIH]

Antagonism: Interference with, or inhibition of, the growth of a living organism by another living organism, due either to creation of unfavorable conditions (e. g. exhaustion of food supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Anthropometric measurements: Measurements of human body height, weight, and size of component parts, including skinfold measurement. Used to study and compare the relative proportions under normal and abnormal conditions. [NIH] Antiandrogens: Drugs used to block the production or interfere with the action of male sex hormones. [NIH] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticholinergic: An agent that blocks the parasympathetic nerves. Called also parasympatholytic. [EU] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Antidepressant: A drug used to treat depression. [NIH] Antigen: Any substance which is capable, under appropriate conditions, of inducing a

314

Estrogen

specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Antigen-presenting cell: APC. A cell that shows antigen on its surface to other cells of the immune system. This is an important part of an immune response. [NIH] Antihypertensive: An agent that reduces high blood pressure. [EU] Anti-infective: An agent that so acts. [EU] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antiproliferative: Counteracting a process of proliferation. [EU] Antipruritic: Relieving or preventing itching. [EU] Antiseptic: A substance that inhibits the growth and development of microorganisms without necessarily killing them. [EU] Antispasmodic: An agent that relieves spasm. [EU] Antitumour: Counteracting tumour formation. [EU] Antitussive: An agent that relieves or prevents cough. [EU] Antiviral: Destroying viruses or suppressing their replication. [EU] Anus: The opening of the rectum to the outside of the body. [NIH] Anxiety: Persistent feeling of dread, apprehension, and impending disaster. [NIH] Anxiety Disorders: Disorders in which anxiety (persistent feelings of apprehension, tension, or uneasiness) is the predominant disturbance. [NIH] Aorta: The main trunk of the systemic arteries. [NIH] Aortic Valve: The valve between the left ventricle and the ascending aorta which prevents backflow into the left ventricle. [NIH] Apolipoproteins: The protein components of lipoproteins which remain after the lipids to which the proteins are bound have been removed. They play an important role in lipid transport and metabolism. [NIH] Aponeurosis: Tendinous expansion consisting of a fibrous or membranous sheath which serves as a fascia to enclose or bind a group of muscles. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the

Dictionary 315

physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Applicability: A list of the commodities to which the candidate method can be applied as presented or with minor modifications. [NIH] Aptitude: The ability to acquire general or special types of knowledge or skill. [NIH] Aqueous: Having to do with water. [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Aromatase: An enzyme which converts androgens to estrogens by desaturating ring A of the steroid. This enzyme complex is located in the endoplasmic reticulum of estrogenproducing cells including ovaries, placenta, testicular Sertoli and Leydig cells, adipose, and brain tissues. The enzyme complex has two components, one of which is the CYP19 gene product, the aromatase cytochrome P-450. The other component is NADPH-cytochrome P450 reductase which transfers reducing equivalents to P-450(arom). EC 1.14.13.-. [NIH] Arrhythmia: Any variation from the normal rhythm or rate of the heart beat. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arteriolar: Pertaining to or resembling arterioles. [EU] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteriosclerosis: Thickening and loss of elasticity of arterial walls. Atherosclerosis is the most common form of arteriosclerosis and involves lipid deposition and thickening of the intimal cell layers within arteries. Additional forms of arteriosclerosis involve calcification of the media of muscular arteries (Monkeberg medial calcific sclerosis) and thickening of the walls of small arteries or arterioles due to cell proliferation or hyaline deposition (arteriolosclerosis). [NIH] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Articular: Of or pertaining to a joint. [EU] Aspartate: A synthetic amino acid. [NIH] Aspirate: Fluid withdrawn from a lump, often a cyst, or a nipple. [NIH] Aspiration: The act of inhaling. [NIH] Aspirin: A drug that reduces pain, fever, inflammation, and blood clotting. Aspirin belongs to the family of drugs called nonsteroidal anti-inflammatory agents. It is also being studied in cancer prevention. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astringent: Causing contraction, usually locally after topical application. [EU] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord.

316

Estrogen

Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [NIH] Asymptomatic: Having no signs or symptoms of disease. [NIH] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] ATP: ATP an abbreviation for adenosine triphosphate, a compound which serves as a carrier of energy for cells. [NIH] Atrial: Pertaining to an atrium. [EU] Atrium: A chamber; used in anatomical nomenclature to designate a chamber affording entrance to another structure or organ. Usually used alone to designate an atrium of the heart. [EU] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Atropine: A toxic alkaloid, originally from Atropa belladonna, but found in other plants, mainly Solanaceae. [NIH] Attenuation: Reduction of transmitted sound energy or its electrical equivalent. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Auditory: Pertaining to the sense of hearing. [EU] Autodigestion: Autolysis; a condition found in disease of the stomach: the stomach wall is digested by the gastric juice. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autoimmunity: Process whereby the immune system reacts against the body's own tissues. Autoimmunity may produce or be caused by autoimmune diseases. [NIH] Autonomic: Self-controlling; functionally independent. [EU] Autonomic Nervous System: The enteric, parasympathetic, and sympathetic nervous systems taken together. Generally speaking, the autonomic nervous system regulates the internal environment during both peaceful activity and physical or emotional stress. Autonomic activity is controlled and integrated by the central nervous system, especially the hypothalamus and the solitary nucleus, which receive information relayed from visceral afferents; these and related central and sensory structures are sometimes (but not here) considered to be part of the autonomic nervous system itself. [NIH] Avian: A plasmodial infection in birds. [NIH] Axonal: Condition associated with metabolic derangement of the entire neuron and is manifest by degeneration of the distal portion of the nerve fiber. [NIH]

Dictionary 317

Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH] Baclofen: A GABA derivative that is a specific agonist at GABA-B receptors. It is used in the treatment of spasticity, especially that due to spinal cord damage. Its therapeutic effects result from actions at spinal and supraspinal sites, generally the reduction of excitatory transmission. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Physiology: Physiological processes and activities of bacteria. [NIH] Bactericidal: Substance lethal to bacteria; substance capable of killing bacteria. [NIH] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [NIH] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Bacteriuria: The presence of bacteria in the urine with or without consequent urinary tract infection. Since bacteriuria is a clinical entity, the term does not preclude the use of urine/microbiology for technical discussions on the isolation and segregation of bacteria in the urine. [NIH] Balloon Dilatation: Nonoperative repair of occluded vessels, ducts, or valves by insertion of a balloon catheter. It is used, amoung other things, to treat varices, torn retinas, renal and biliary calculi, gastric, bronchial and rectal stenoses, and heart valves, and includes catheterization with Fogarty and Foley catheters. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its subdivisions is the basal (basement) lamina. [NIH] Beer: An alcoholic beverage usually made from malted cereal grain (as barley), flavored with hops, and brewed by slow fermentation. [NIH] Belladonna: A species of very poisonous Solanaceous plants yielding atropine (hyoscyamine), scopolamine, and other belladonna alkaloids, used to block the muscarinic autonomic nervous system. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

318

Estrogen

Benign prostatic hyperplasia: A benign (noncancerous) condition in which an overgrowth of prostate tissue pushes against the urethra and the bladder, blocking the flow of urine. Also called benign prostatic hypertrophy or BPH. [NIH] Benzene: Toxic, volatile, flammable liquid hydrocarbon biproduct of coal distillation. It is used as an industrial solvent in paints, varnishes, lacquer thinners, gasoline, etc. Benzene causes central nervous system damage acutely and bone marrow damage chronically and is carcinogenic. It was formerly used as parasiticide. [NIH] Benzodiazepines: A two-ring heterocyclic compound consisting of a benzene ring fused to a diazepine ring. Permitted is any degree of hydrogenation, any substituents and any Hisomer. [NIH] Beta blocker: A drug used to slow the heart rate and reduce pressure inside blood vessels. It also can regulate heart rhythm. [NIH] Beta-pleated: Particular three-dimensional pattern of amyloidoses. [NIH] Bicalutamide: An anticancer drug that belongs to the family of drugs called antiandrogens. [NIH]

Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile Acids and Salts: Steroid acids and salts. The primary bile acids are derived from cholesterol in the liver and usually conjugated with glycine or taurine. The secondary bile acids are further modified by bacteria in the intestine. They play an important role in the digestion and absorption of fat. They have also been used pharmacologically, especially in the treatment of gallstones. [NIH] Bile duct: A tube through which bile passes in and out of the liver. [NIH] Bile Pigments: Pigments that give a characteristic color to bile including: bilirubin, biliverdine, and bilicyanin. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Biliary Tract: The gallbladder and its ducts. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Binding agent: A substance that makes a loose mixture stick together. For example, binding agents can be used to make solid pills from loose powders. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioassay: Determination of the relative effective strength of a substance (as a vitamin, hormone, or drug) by comparing its effect on a test organism with that of a standard preparation. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Bioavailable: The ability of a drug or other substance to be absorbed and used by the body. Orally bioavailable means that a drug or other substance that is taken by mouth can be absorbed and used by the body. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU]

Dictionary 319

Biodegradation: The series of processes by which living organisms degrade pollutant chemicals, organic wastes, pesticides, and implantable materials. [NIH] Biological response modifier: BRM. A substance that stimulates the body's response to infection and disease. [NIH] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biomarkers: Substances sometimes found in an increased amount in the blood, other body fluids, or tissues and that may suggest the presence of some types of cancer. Biomarkers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and GI tract cancers), and PSA (prostate cancer). Also called tumor markers. [NIH] Biomechanics: The study of the application of mechanical laws and the action of forces to living structures. [NIH] Biophysics: The science of physical phenomena and processes in living organisms. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Biotin: Hexahydro-2-oxo-1H-thieno(3,4-d)imidazole-4-pentanoic acid. Growth factor present in minute amounts in every living cell. It occurs mainly bound to proteins or polypeptides and is abundant in liver, kidney, pancreas, yeast, and milk.The biotin content of cancerous tissue is higher than that of normal tissue. [NIH] Biotransformation: The chemical alteration of an exogenous substance by or in a biological system. The alteration may inactivate the compound or it may result in the production of an active metabolite of an inactive parent compound. The alteration may be either nonsynthetic (oxidation-reduction, hydrolysis) or synthetic (glucuronide formation, sulfate conjugation, acetylation, methylation). This also includes metabolic detoxication and clearance. [NIH] Bladder: The organ that stores urine. [NIH] Blast Crisis: Rapid increase in the proportion of blast cells in the blood and bone marrow. [NIH]

Blastocyst: The mammalian embryo in the post-morula stage in which a fluid-filled cavity, enclosed primarily by trophoblast, contains an inner cell mass which becomes the embryonic disc. [NIH] Blastomeres: The undifferentiated cells formed by cleavage of the fertilized ovum. This includes cells in the cleavage, morula, and blastula stages of the embryo. [NIH] Blastomyces: A genus of onygenacetous mitosporic fungi whose perfect state is Ajellomyces. The species Blastomyces dermatitidis (perfect state Ajellomyces dermatitidis) causes blastomycosis. [NIH] Blister: Visible accumulations of fluid within or beneath the epidermis. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH]

320

Estrogen

Blood Glucose: Glucose in blood. [NIH] Blood Platelets: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blood-Brain Barrier: Specialized non-fenestrated tightly-joined endothelial cells (tight junctions) that form a transport barrier for certain substances between the cerebral capillaries and the brain tissue. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]

Body Fluids: Liquid components of living organisms. [NIH] Body Image: Individuals' personal concept of their bodies as objects in and bound by space, independently and apart from all other objects. [NIH] Body Mass Index: One of the anthropometric measures of body mass; it has the highest correlation with skinfold thickness or body density. [NIH] Body Regions: Anatomical areas of the body. [NIH] Bone Density: The amount of mineral per square centimeter of bone. This is the definition used in clinical practice. Actual bone density would be expressed in grams per milliliter. It is most frequently measured by photon absorptiometry or x-ray computed tomography. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone Marrow Cells: Cells contained in the bone marrow including fat cells, stromal cells, megakaryocytes, and the immediate precursors of most blood cells. [NIH] Bone marrow metastases: Cancer that has spread from the original (primary) tumor to the bone marrow. [NIH] Bone metastases: Cancer that has spread from the original (primary) tumor to the bone. [NIH]

Bone Remodeling: The continuous turnover of bone matrix and mineral that involves first, an increase in resorption (osteoclastic activity) and later, reactive bone formation (osteoblastic activity). The process of bone remodeling takes place in the adult skeleton at discrete foci. The process ensures the mechanical integrity of the skeleton throughout life and plays an important role in calcium homeostasis. An imbalance in the regulation of bone remodeling's two contrasting events, bone resorption and bone formation, results in many of the metabolic bone diseases, such as osteoporosis. [NIH] Bone Resorption: Bone loss due to osteoclastic activity. [NIH] Bone scan: A technique to create images of bones on a computer screen or on film. A small amount of radioactive material is injected into a blood vessel and travels through the bloodstream; it collects in the bones and is detected by a scanner. [NIH]

Dictionary 321

Boron: A trace element with the atomic symbol B, atomic number 5, and atomic weight 10.81. Boron-10, an isotope of boron, is used as a neutron absorber in boron neutron capture therapy. [NIH] Boron Neutron Capture Therapy: A technique for the treatment of neoplasms, especially gliomas and melanomas in which boron-10, an isotope, is introduced into the target cells followed by irradiation with thermal neutrons. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Bowel Movement: Body wastes passed through the rectum and anus. [NIH] Brachytherapy: A collective term for interstitial, intracavity, and surface radiotherapy. It uses small sealed or partly-sealed sources that may be placed on or near the body surface or within a natural body cavity or implanted directly into the tissues. [NIH] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Brain Diseases: Pathologic conditions affecting the brain, which is composed of the intracranial components of the central nervous system. This includes (but is not limited to) the cerebral cortex; intracranial white matter; basal ganglia; thalamus; hypothalamus; brain stem; and cerebellum. [NIH] Brain Stem: The part of the brain that connects the cerebral hemispheres with the spinal cord. It consists of the mesencephalon, pons, and medulla oblongata. [NIH] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]

Breakdown: A physical, metal, or nervous collapse. [NIH] Bronchial: Pertaining to one or more bronchi. [EU] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Buccal mucosa: The inner lining of the cheeks and lips. [NIH] Bulimia: Episodic binge eating. The episodes may be associated with the fear of not being able to stop eating, depressed mood, or self-deprecating thoughts (binge-eating disorder) and may frequently be terminated by self-induced vomiting (bulimia nervosa). [NIH] Burns: Injuries to tissues caused by contact with heat, steam, chemicals (burns, chemical), electricity (burns, electric), or the like. [NIH] Burns, Electric: Burns produced by contact with electric current or from a sudden discharge of electricity. [NIH] Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH] Cachexia: General ill health, malnutrition, and weight loss, usually associated with chronic disease. [NIH] Caffeine: A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine's most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. It also relaxes smooth muscle, stimulates cardiac muscle, stimulates diuresis, and appears to be useful in the treatment of some types of headache. Several cellular actions of caffeine have been

322

Estrogen

observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide phosphodiesterases, antagonism of adenosine receptors, and modulation of intracellular calcium handling. [NIH] Calcineurin: A calcium- and calmodulin-binding protein present in highest concentrations in the central nervous system. Calcineurin is composed of two subunits. A catalytic subunit, calcineurin A, and a regulatory subunit, calcineurin B, with molecular weights of about 60 kD and 19 kD, respectively. Calcineurin has been shown to dephosphorylate a number of phosphoproteins including histones, myosin light chain, and the regulatory subunit of cAMP-dependent protein kinase. It is involved in the regulation of signal transduction and is the target of an important class of immunophilin-immunosuppressive drug complexes in T-lymphocytes that act by inhibiting T-cell activation. EC 3.1.3.-. [NIH] Calcitonin: A peptide hormone that lowers calcium concentration in the blood. In humans, it is released by thyroid cells and acts to decrease the formation and absorptive activity of osteoclasts. Its role in regulating plasma calcium is much greater in children and in certain diseases than in normal adults. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Calcium Channels: Voltage-dependent cell membrane glycoproteins selectively permeable to calcium ions. They are categorized as L-, T-, N-, P-, Q-, and R-types based on the activation and inactivation kinetics, ion specificity, and sensitivity to drugs and toxins. The L- and T-types are present throughout the cardiovascular and central nervous systems and the N-, P-, Q-, & R-types are located in neuronal tissue. [NIH] Calcium Oxalate: The calcium salt of oxalic acid, occurring in the urine as crystals and in certain calculi. [NIH] Calculi: An abnormal concretion occurring mostly in the urinary and biliary tracts, usually composed of mineral salts. Also called stones. [NIH] Calmodulin: A heat-stable, low-molecular-weight activator protein found mainly in the brain and heart. The binding of calcium ions to this protein allows this protein to bind to cyclic nucleotide phosphodiesterases and to adenyl cyclase with subsequent activation. Thereby this protein modulates cyclic AMP and cyclic GMP levels. [NIH] Camphor: A bicyclic monoterpene ketone found widely in plant (primarily the camphor tree, Cinnamomum camphora). Natural camphor is used topically as a skin antipruritic and as an anti-infective agent. [NIH] Canonical: A particular nucleotide sequence in which each position represents the base more often found when many actual sequences of a given class of genetic elements are compared. [NIH] Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Capillary Permeability: Property of blood capillary walls that allows for the selective exchange of substances. Small lipid-soluble molecules such as carbon dioxide and oxygen move freely by diffusion. Water and water-soluble molecules cannot pass through the endothelial walls and are dependent on microscopic pores. These pores show narrow areas

Dictionary 323

(tight junctions) which may limit large molecule movement. [NIH] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenesis: The process by which normal cells are transformed into cancer cells. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinogenicity: The ability to cause cancer. [NIH] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]

Carcinoma in Situ: A malignant tumor that has not yet invaded the basement membrane of the epithelial cell of origin and has not spread to other tissues. [NIH] Cardiac: Having to do with the heart. [NIH] Cardiac Output: The volume of blood passing through the heart per unit of time. It is usually expressed as liters (volume) per minute so as not to be confused with stroke volume (volume per beat). [NIH] Cardiorespiratory: Relating to the heart and lungs and their function. [EU] Cardiotonic: 1. Having a tonic effect on the heart. 2. An agent that has a tonic effect on the heart. [EU] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Cardiovascular System: The heart and the blood vessels by which blood is pumped and circulated through the body. [NIH] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH] Carotenoids: Substance found in yellow and orange fruits and vegetables and in dark green, leafy vegetables. May reduce the risk of developing cancer. [NIH] Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes. [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Castration: Surgical removal or artificial destruction of gonads. [NIH] Cataract: An opacity, partial or complete, of one or both eyes, on or in the lens or capsule, especially an opacity impairing vision or causing blindness. The many kinds of cataract are

324

Estrogen

classified by their morphology (size, shape, location) or etiology (cause and time of occurrence). [EU] Catechol: A chemical originally isolated from a type of mimosa tree. Catechol is used as an astringent, an antiseptic, and in photography, electroplating, and making other chemicals. It can also be man-made. [NIH] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Catheter: A flexible tube used to deliver fluids into or withdraw fluids from the body. [NIH] Catheterization: Use or insertion of a tubular device into a duct, blood vessel, hollow organ, or body cavity for injecting or withdrawing fluids for diagnostic or therapeutic purposes. It differs from intubation in that the tube here is used to restore or maintain patency in obstructions. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Caudate Nucleus: Elongated gray mass of the neostriatum located adjacent to the lateral ventricle of the brain. [NIH] Causal: Pertaining to a cause; directed against a cause. [EU] Causality: The relating of causes to the effects they produce. Causes are termed necessary when they must always precede an effect and sufficient when they initiate or produce an effect. Any of several factors may be associated with the potential disease causation or outcome, including predisposing factors, enabling factors, precipitating factors, reinforcing factors, and risk factors. [NIH] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Cecum: The beginning of the large intestine. The cecum is connected to the lower part of the small intestine, called the ileum. [NIH] Celiac Disease: A disease characterized by intestinal malabsorption and precipitated by gluten-containing foods. The intestinal mucosa shows loss of villous structure. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Adhesion: Adherence of cells to surfaces or to other cells. [NIH] Cell Communication: Any of several ways in which living cells of an organism communicate with one another, whether by direct contact between cells or by means of chemical signals carried by neurotransmitter substances, hormones, and cyclic AMP. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH]

Dictionary 325

Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Cellobiose: A disaccharide consisting of two glucose units in beta (1-4) glycosidic linkage. Obtained from the partial hydrolysis of cellulose. [NIH] Cellulose: A polysaccharide with glucose units linked as in cellobiose. It is the chief constituent of plant fibers, cotton being the purest natural form of the substance. As a raw material, it forms the basis for many derivatives used in chromatography, ion exchange materials, explosives manufacturing, and pharmaceutical preparations. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Centrifugation: A method of separating organelles or large molecules that relies upon differential sedimentation through a preformed density gradient under the influence of a gravitational field generated in a centrifuge. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebellum: Part of the metencephalon that lies in the posterior cranial fossa behind the brain stem. It is concerned with the coordination of movement. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Arteries: The arteries supplying the cerebral cortex. [NIH] Cerebral Cortex: The thin layer of gray matter on the surface of the cerebral hemisphere that develops from the telencephalon and folds into gyri. It reaches its highest development in man and is responsible for intellectual faculties and higher mental functions. [NIH] Cerebral Palsy: Refers to a motor disability caused by a brain dysfunction. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the "neck") of the uterus. [NIH] Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Chemoprevention: The use of drugs, vitamins, or other agents to try to reduce the risk of, or delay the development or recurrence of, cancer. [NIH] Chemopreventive: Natural or synthetic compound used to intervene in the early precancerous stages of carcinogenesis. [NIH] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH]

326

Estrogen

Chimera: An individual that contains cell populations derived from different zygotes. [NIH] Chin: The anatomical frontal portion of the mandible, also known as the mentum, that contains the line of fusion of the two separate halves of the mandible (symphysis menti). This line of fusion divides inferiorly to enclose a triangular area called the mental protuberance. On each side, inferior to the second premolar tooth, is the mental foramen for the passage of blood vessels and a nerve. [NIH] Chlorophyll: Porphyrin derivatives containing magnesium that act to convert light energy in photosynthetic organisms. [NIH] Cholecystectomy: Surgical removal of the gallbladder. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Cholesterol Esters: Fatty acid esters of cholesterol which constitute about two-thirds of the cholesterol in the plasma. The accumulation of cholesterol esters in the arterial intima is a characteristic feature of atherosclerosis. [NIH] Choline: A basic constituent of lecithin that is found in many plants and animal organs. It is important as a precursor of acetylcholine, as a methyl donor in various metabolic processes, and in lipid metabolism. [NIH] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Chondrocytes: Polymorphic cells that form cartilage. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Chylomicrons: A class of lipoproteins that carry dietary cholesterol and triglycerides from the small intestines to the tissues. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Clamp: A u-shaped steel rod used with a pin or wire for skeletal traction in the treatment of certain fractures. [NIH] Clear cell carcinoma: A rare type of tumor of the female genital tract in which the inside of the cells looks clear when viewed under a microscope. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]

Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH]

Dictionary 327

Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Clomiphene: A stilbene derivative that functions both as a partial estrogen agonist and complete estrogen antagonist depending on the target tissue. It antagonizes the estrogen receptor thereby initiating or augmenting ovulation in anovulatory women. [NIH] Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] Coca: Any of several South American shrubs of the Erythroxylon genus (and family) that yield cocaine; the leaves are chewed with alum for CNS stimulation. [NIH] Cocaine: An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake. [NIH] Codeine: An opioid analgesic related to morphine but with less potent analgesic properties and mild sedative effects. It also acts centrally to suppress cough. [NIH] Coenzyme: An organic nonprotein molecule, frequently a phosphorylated derivative of a water-soluble vitamin, that binds with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Cognition: Intellectual or mental process whereby an organism becomes aware of or obtains knowledge. [NIH] Coitus: Sexual intercourse. [NIH] Colic: Paroxysms of pain. This condition usually occurs in the abdominal region but may occur in other body regions as well. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU] Colloidal: Of the nature of a colloid. [EU] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and

328

Estrogen

leaves the body through the anus. [NIH] Colorectal: Having to do with the colon or the rectum. [NIH] Colorectal Cancer: Cancer that occurs in the colon (large intestine) or the rectum (the end of the large intestine). A number of digestive diseases may increase a person's risk of colorectal cancer, including polyposis and Zollinger-Ellison Syndrome. [NIH] Combination Therapy: Association of 3 drugs to treat AIDS (AZT + DDC or DDI + protease inhibitor). [NIH] Combinatorial: A cut-and-paste process that churns out thousands of potentially valuable compounds at once. [NIH] Comet Assay: A genotoxicological technique for measuring DNA damage in an individual cell using single-cell gel electrophoresis. Cell DNA fragments assume a "comet with tail" formation on electrophoresis and are detected with an image analysis system. Alkaline assay conditions facilitate sensitive detection of single-strand damage. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Compliance: Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. [NIH] Computational Biology: A field of biology concerned with the development of techniques

Dictionary 329

for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Concomitant: Accompanying; accessory; joined with another. [EU] Cones: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Confounding: Extraneous variables resulting in outcome effects that obscure or exaggerate the "true" effect of an intervention. [NIH] Congestive heart failure: Weakness of the heart muscle that leads to a buildup of fluid in body tissues. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Conjugation: 1. The act of joining together or the state of being conjugated. 2. A sexual process seen in bacteria, ciliate protozoa, and certain fungi in which nuclear material is exchanged during the temporary fusion of two cells (conjugants). In bacterial genetics a form of sexual reproduction in which a donor bacterium (male) contributes some, or all, of its DNA (in the form of a replicated set) to a recipient (female) which then incorporates differing genetic information into its own chromosome by recombination and passes the recombined set on to its progeny by replication. In ciliate protozoa, two conjugants of separate mating types exchange micronuclear material and then separate, each now being a fertilized cell. In certain fungi, the process involves fusion of two gametes, resulting in union of their nuclei and formation of a zygote. 3. In chemistry, the joining together of two compounds to produce another compound, such as the combination of a toxic product with some substance in the body to form a detoxified product, which is then eliminated. [EU] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue Cells: A group of cells that includes fibroblasts, cartilage cells, adipocytes, smooth muscle cells, and bone cells. [NIH] Connective Tissue Diseases: A heterogeneous group of disorders, some hereditary, others acquired, characterized by abnormal structure or function of one or more of the elements of connective tissue, i.e., collagen, elastin, or the mucopolysaccharides. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constipation: Infrequent or difficult evacuation of feces. [NIH] Constriction: The act of constricting. [NIH] Consumption: Pulmonary tuberculosis. [NIH] Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU] Continuum: An area over which the vegetation or animal population is of constantly

330

Estrogen

changing composition so that homogeneous, separate communities cannot be distinguished. [NIH]

Contraception: Use of agents, devices, methods, or procedures which diminish the likelihood of or prevent conception. [NIH] Contraceptive Agents: Chemical substances that prevent or reduce the probability of conception. [NIH] Contractility: Capacity for becoming short in response to a suitable stimulus. [EU] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Contralateral: Having to do with the opposite side of the body. [NIH] Contrast medium: A substance that is introduced into or around a structure and, because of the difference in absorption of x-rays by the contrast medium and the surrounding tissues, allows radiographic visualization of the structure. [EU] Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Controlled clinical trial: A clinical study that includes a comparison (control) group. The comparison group receives a placebo, another treatment, or no treatment at all. [NIH] Controlled study: An experiment or clinical trial that includes a comparison (control) group. [NIH]

Convulsions: A general term referring to sudden and often violent motor activity of cerebral or brainstem origin. Convulsions may also occur in the absence of an electrical cerebral discharge (e.g., in response to hypotension). [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Copulation: Sexual contact of a male with a receptive female usually followed by emission of sperm. Limited to non-human species. For humans use coitus. [NIH] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Corneum: The superficial layer of the epidermis containing keratinized cells. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary Circulation: The circulation of blood through the coronary vessels of the heart. [NIH]

Coronary Disease: Disorder of cardiac function due to an imbalance between myocardial function and the capacity of the coronary vessels to supply sufficient flow for normal function. It is a form of myocardial ischemia (insufficient blood supply to the heart muscle) caused by a decreased capacity of the coronary vessels. [NIH] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH]

Dictionary 331

Coronary Vessels: The veins and arteries of the heart. [NIH] Corpus: The body of the uterus. [NIH] Corpus Luteum: The yellow glandular mass formed in the ovary by an ovarian follicle that has ruptured and discharged its ovum. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Cortices: The outer layer of an organ; used especially of the cerebrum and cerebellum. [NIH] Corticosteroids: Hormones that have antitumor activity in lymphomas and lymphoid leukemias; in addition, corticosteroids (steroids) may be used for hormone replacement and for the management of some of the complications of cancer and its treatment. [NIH] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Cortisone: A natural steroid hormone produced in the adrenal gland. It can also be made in the laboratory. Cortisone reduces swelling and can suppress immune responses. [NIH] Coumarin: A fluorescent dye. [NIH] Coumestrol: A coumarin derivative occurring naturally in forage crops which has estrogenic activity. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH] Criterion: A standard by which something may be judged. [EU] Cruciferous vegetables: A family of vegetables that includes kale, collard greens, broccoli, cauliflower, cabbage, brussels sprouts, and turnip. These vegetables contain substances that may protect against cancer. [NIH] Cryotherapy: Any method that uses cold temperature to treat disease. [NIH] Cues: Signals for an action; that specific portion of a perceptual field or pattern of stimuli to which a subject has learned to respond. [NIH] Cultured cells: Animal or human cells that are grown in the laboratory. [NIH] Cuprizone: Copper chelator that inhibits monoamine oxidase and causes liver and brain damage. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Curettage: Removal of tissue with a curette, a spoon-shaped instrument with a sharp edge. [NIH]

Curette: A spoon-shaped instrument with a sharp edge. [NIH] Cutaneous: Having to do with the skin. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclin: Molecule that regulates the cell cycle. [NIH] Cycloheximide: Antibiotic substance isolated from streptomycin-producing strains of Streptomyces griseus. It acts by inhibiting elongation during protein synthesis. [NIH] Cyclophosphamide: Precursor of an alkylating nitrogen mustard antineoplastic and

332

Estrogen

immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It is used in the treatment of lymphomas, leukemias, etc. Its side effect, alopecia, has been made use of in defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. [NIH] Cyproterone: An anti-androgen that, in the form of its acetate, also has progestational properties. It is used in the treatment of hypersexuality in males, as a palliative in prostatic carcinoma, and, in combination with estrogen, for the therapy of severe acne and hirsutism in females. [NIH] Cyst: A sac or capsule filled with fluid. [NIH] Cystitis: Inflammation of the urinary bladder. [EU] Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytostatic: An agent that suppresses cell growth and multiplication. [EU] Cytotoxic: Cell-killing. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] Cytotoxins: Substances elaborated by microorganisms, plants or animals that are specifically toxic to individual cells; they may be involved in immunity or may be contained in venoms. [NIH]

Dairy Products: Raw and processed or manufactured milk and milk-derived products. These are usually from cows (bovine) but are also from goats, sheep, reindeer, and water buffalo. [NIH] Dantrolene: Skeletal muscle relaxant that acts by interfering with excitation-contraction coupling in the muscle fiber. It is used in spasticity and other neuromuscular abnormalities. Although the mechanism of action is probably not central, dantrolene is usually grouped with the central muscle relaxants. [NIH] Data Collection: Systematic gathering of data for a particular purpose from various sources, including questionnaires, interviews, observation, existing records, and electronic devices. The process is usually preliminary to statistical analysis of the data. [NIH] Deamination: The removal of an amino group (NH2) from a chemical compound. [NIH] Decidua: The epithelial lining of the endometrium that is formed before the fertilized ovum

Dictionary 333

reaches the uterus. The fertilized ovum embeds in the decidua. If the ovum is not fertilized, the decidua is shed during menstruation. [NIH] Decongestant: An agent that reduces congestion or swelling. [EU] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Dehydroepiandrosterone: DHEA. A substance that is being studied as a cancer prevention drug. It belongs to the family of drugs called steroids. [NIH] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Delirium: (DSM III-R) an acute, reversible organic mental disorder characterized by reduced ability to maintain attention to external stimuli and disorganized thinking as manifested by rambling, irrelevant, or incoherent speech; there are also a reduced level of consciousness, sensory misperceptions, disturbance of the sleep-wakefulness cycle and level of psychomotor activity, disorientation to time, place, or person, and memory impairment. Delirium may be caused by a large number of conditions resulting in derangement of cerebral metabolism, including systemic infection, poisoning, drug intoxication or withdrawal, seizures or head trauma, and metabolic disturbances such as hypoxia, hypoglycaemia, fluid, electrolyte, or acid-base imbalances, or hepatic or renal failure. Called also acute confusional state and acute brain syndrome. [EU] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Demethylation: Process that releases substantial amounts of carbon dioxide in the liver. [NIH]

Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Dendritic cell: A special type of antigen-presenting cell (APC) that activates T lymphocytes. [NIH]

Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Dentate Gyrus: Gray matter situated above the gyrus hippocampi. It is composed of three layers. The molecular layer is continuous with the hippocampus in the hippocampal fissure. The granular layer consists of closely arranged spherical or oval neurons, called granule cells, whose axons pass through the polymorphic layer ending on the dendrites of pyramidal cells in the hippocampus. [NIH] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Deprivation: Loss or absence of parts, organs, powers, or things that are needed. [EU] Dermatitis: Any inflammation of the skin. [NIH] Dermis: A layer of vascular connective tissue underneath the epidermis. The surface of the dermis contains sensitive papillae. Embedded in or beneath the dermis are sweat glands, hair follicles, and sebaceous glands. [NIH] DES: Diethylstilbestrol. A synthetic hormone that was prescribed from the early 1940s until 1971 to help women with complications of pregnancy. DES has been linked to an increased

334

Estrogen

risk of clear cell carcinoma of the vagina in daughters of women who used DES. DES may also increase the risk of breast cancer in women who used DES. [NIH] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Desogestrel: A synthetic progestational hormone used often as the progestogenic component of combined oral contraceptive agents. [NIH] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Developing Countries: Countries in the process of change directed toward economic growth, that is, an increase in production, per capita consumption, and income. The process of economic growth involves better utilization of natural and human resources, which results in a change in the social, political, and economic structures. [NIH] Dextroamphetamine: The d-form of amphetamine. It is a central nervous system stimulant and a sympathomimetic. It has also been used in the treatment of narcolepsy and of attention deficit disorders and hyperactivity in children. Dextroamphetamine has multiple mechanisms of action including blocking uptake of adrenergics and dopamine, stimulating release of monamines, and inhibiting monoamine oxidase. It is also a drug of abuse and a psychotomimetic. [NIH] Dextromethorphan: The d-isomer of the codeine analog of levorphanol. Dextromethorphan shows high affinity binding to several regions of the brain, including the medullary cough center. This compound is a NMDA receptor antagonist (receptors, N-methyl-D-aspartate) and acts as a non-competitive channel blocker. It is used widely as an antitussive agent, and is also used to study the involvement of glutamate receptors in neurotoxicity. [NIH] Dextrorphan: Dextro form of levorphanol. It acts as a noncompetitive NMDA receptor antagonist, among other effects, and has been proposed as a neuroprotective agent. It is also a metabolite of dextromethorphan. [NIH] Diabetes Insipidus: A metabolic disorder due to disorders in the production or release of vasopressin. It is characterized by the chronic excretion of large amounts of low specific gravity urine and great thirst. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diabetic Retinopathy: Retinopathy associated with diabetes mellitus, which may be of the background type, progressively characterized by microaneurysms, interretinal punctuate macular edema, or of the proliferative type, characterized by neovascularization of the retina and optic disk, which may project into the vitreous, proliferation of fibrous tissue, vitreous hemorrhage, and retinal detachment. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Dialysate: A cleansing liquid used in the two major forms of dialysis--hemodialysis and peritoneal dialysis. [NIH] Diastolic: Of or pertaining to the diastole. [EU] Dicyclomine: A muscarinic antagonist used as an antispasmodic and in urinary incontinence. It has little effect on glandular secretion or the cardiovascular system. It does have some local anesthetic properties and is used in gastrointestinal, biliary, and urinary tract spasms. [NIH] Diencephalon: The paired caudal parts of the prosencephalon from which the thalamus, hypothalamus, epithalamus, and subthalamus are derived. [NIH]

Dictionary 335

Dietary Fats: Fats present in food, especially in animal products such as meat, meat products, butter, ghee. They are present in lower amounts in nuts, seeds, and avocados. [NIH]

Diethylstilbestrol: DES. A synthetic hormone that was prescribed from the early 1940s until 1971 to help women with complications of pregnancy. DES has been linked to an increased risk of clear cell carcinoma of the vagina in daughters of women who used DES. DES may also increase the risk of breast cancer in women who used DES. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive system: The organs that take in food and turn it into products that the body can use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [NIH] Digestive tract: The organs through which food passes when food is eaten. These organs are the mouth, esophagus, stomach, small and large intestines, and rectum. [NIH] Dihydrotestosterone: Anabolic agent. [NIH] Dilatation: The act of dilating. [NIH] Dilatation, Pathologic: The condition of an anatomical structure's being dilated beyond normal dimensions. [NIH] Dilation: A process by which the pupil is temporarily enlarged with special eye drops (mydriatic); allows the eye care specialist to better view the inside of the eye. [NIH] Dimerization: The process by which two molecules of the same chemical composition form a condensation product or polymer. [NIH] Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Discrete: Made up of separate parts or characterized by lesions which do not become blended; not running together; separate. [NIH] Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis. [NIH] Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [EU] Disorientation: The loss of proper bearings, or a state of mental confusion as to time, place, or identity. [EU] Dispenser: Glass, metal or plastic shell fitted with valve from which a pressurized formulation is dispensed; an instrument for atomizing. [NIH] Disposition: A tendency either physical or mental toward certain diseases. [EU] Dissection: Cutting up of an organism for study. [NIH] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal

336

Estrogen

consciousness and, thus separated, function as a unitary whole. [EU] Dissociative Disorders: Sudden temporary alterations in the normally integrative functions of consciousness. [NIH] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Distention: The state of being distended or enlarged; the act of distending. [EU] Diuresis: Increased excretion of urine. [EU] Dizziness: An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. [NIH] DNA Topoisomerase: An enzyme catalyzing ATP-independent breakage of single-stranded DNA, followed by passage and rejoining of another single-stranded DNA. This enzyme class brings about the conversion of one topological isomer of DNA into another, e.g., the relaxation of superhelical turns in DNA, the interconversion of simple and knotted rings of single-stranded DNA, and the intertwisting of single-stranded rings of complementary sequences. (From Enzyme Nomenclature, 1992) EC 5.99.1.2. [NIH] Domesticated: Species in which the evolutionary process has been influenced by humans to meet their needs. [NIH] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Dosage Forms: Completed forms of the pharmaceutical preparation in which prescribed doses of medication are included. They are designed to resist action by gastric fluids, prevent vomiting and nausea, reduce or alleviate the undesirable taste and smells associated with oral administration, achieve a high concentration of drug at target site, or produce a delayed or long-acting drug effect. They include capsules, liniments, ointments, pharmaceutical solutions, powders, tablets, etc. [NIH] Dose-dependent: Refers to the effects of treatment with a drug. If the effects change when the dose of the drug is changed, the effects are said to be dose dependent. [NIH] Double-blind: Pertaining to a clinical trial or other experiment in which neither the subject nor the person administering treatment knows which treatment any particular subject is receiving. [EU] Double-blinded: A clinical trial in which neither the medical staff nor the person knows which of several possible therapies the person is receiving. [NIH] Doxazosin: A selective alpha-1-adrenergic blocker that lowers serum cholesterol. It is also effective in the treatment of hypertension. [NIH] Doxepin: A dibenzoxepin tricyclic compound. It displays a range of pharmacological actions including maintaining adrenergic innervation. Its mechanism of action is not fully understood, but it appears to block reuptake of monoaminergic neurotransmitters into presynaptic terminals. It also possesses anticholinergic activity and modulates antagonism of histamine H(1)- and H(2)-receptors. [NIH]

Dictionary 337

Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Carriers: Substances that facilitate time-controlled delivery, organ-specific targeting, protection, prolonged in vivo function, and decrease of toxicity of drugs. Liposomes, albumin microspheres, soluble synthetic polymers, DNA complexes, protein-drug conjugates, and carrier erythrocytes among others have been employed as biodegradable drug carriers. [NIH] Drug Delivery Systems: Systems of administering drugs through controlled delivery so that an optimum amount reaches the target site. Drug delivery systems encompass the carrier, route, and target. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Duct: A tube through which body fluids pass. [NIH] Ductal carcinoma in situ: DCIS. Abnormal cells that involve only the lining of a duct. The cells have not spread outside the duct to other tissues in the breast. Also called intraductal carcinoma. [NIH] Duodenum: The first part of the small intestine. [NIH] Dura mater: The outermost, toughest, and most fibrous of the three membranes (meninges) covering the brain and spinal cord; called also pachymeninx. [EU] Dwarfism: The condition of being undersized as a result of premature arrest of skeletal growth. It may be caused by insufficient secretion of growth hormone (pituitary dwarfism). [NIH]

Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] Dysmenorrhea: Painful menstruation. [NIH] Dyspareunia: Painful sexual intercourse. [NIH] Dysphonia: Difficulty or pain in speaking; impairment of the voice. [NIH] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Eclampsia: Onset of convulsions or coma in a previously diagnosed pre-eclamptic patient. [NIH]

Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Effector cell: A cell that performs a specific function in response to a stimulus; usually used to describe cells in the immune system. [NIH] Efferent: Nerve fibers which conduct impulses from the central nervous system to muscles

338

Estrogen

and glands. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Ejaculation: The release of semen through the penis during orgasm. [NIH] Elastic: Susceptible of resisting and recovering from stretching, compression or distortion applied by a force. [EU] Elastin: The protein that gives flexibility to tissues. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electric Conductivity: The ability of a substrate to allow the passage of electrons. [NIH] Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding ulcers) and to ablate tumors, mucosal lesions, and refractory arrhythmias. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH]

Electrophysiological: Pertaining to electrophysiology, that is a branch of physiology that is concerned with the electric phenomena associated with living bodies and involved in their functional activity. [EU] Electroplating: Coating with a metal or alloy by electrolysis. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Embryo Transfer: Removal of a mammalian embryo from one environment and replacement in the same or a new environment. The embryo is usually in the pre-nidation phase, i.e., a blastocyst. The process includes embryo or blastocyst transplantation or transfer after in vitro fertilization and transfer of the inner cell mass of the blastocyst. It is not used for transfer of differentiated embryonic tissue, e.g., germ layer cells. [NIH] Embryology: The study of the development of an organism during the embryonic and fetal stages of life. [NIH] Emulsion: A preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. Pharmaceutical emulsions for which official standards have been promulgated include cod liver oil emulsion, cod liver oil emulsion with malt, liquid petrolatum emulsion, and phenolphthalein in liquid petrolatum emulsion. [EU] Enamel: A very hard whitish substance which covers the dentine of the anatomical crown of a tooth. [NIH] Encephalitis: Inflammation of the brain due to infection, autoimmune processes, toxins, and other conditions. Viral infections (see encephalitis, viral) are a relatively frequent cause of this condition. [NIH] Encephalomyelitis: A general term indicating inflammation of the brain and spinal cord, often used to indicate an infectious process, but also applicable to a variety of autoimmune

Dictionary 339

and toxic-metabolic conditions. There is significant overlap regarding the usage of this term and encephalitis in the literature. [NIH] Encephalopathy: A disorder of the brain that can be caused by disease, injury, drugs, or chemicals. [NIH] Endemic: Present or usually prevalent in a population or geographical area at all times; said of a disease or agent. Called also endemial. [EU] Endocrine System: The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH] Endocrinology: A subspecialty of internal medicine concerned with the metabolism, physiology, and disorders of the endocrine system. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endolymph: The fluid contained in the membranous labyrinth of the ear. [NIH] Endolymphatic Duct: Duct connecting the endolymphatic sac with the membranous labyrinth. [NIH] Endolymphatic Sac: The blind pouch at the end of the endolymphatic duct. [NIH] Endometrial: Having to do with the endometrium (the layer of tissue that lines the uterus). [NIH]

Endometriosis: A condition in which tissue more or less perfectly resembling the uterine mucous membrane (the endometrium) and containing typical endometrial granular and stromal elements occurs aberrantly in various locations in the pelvic cavity. [NIH] Endometrium: The layer of tissue that lines the uterus. [NIH] Endopeptidases: A subclass of peptide hydrolases. They are classified primarily by their catalytic mechanism. Specificity is used only for identification of individual enzymes. They comprise the serine endopeptidases, EC 3.4.21; cysteine endopeptidases, EC 3.4.22; aspartic endopeptidases, EC 3.4.23, metalloendopeptidases, EC 3.4.24; and a group of enzymes yet to be assigned to any of the above sub-classes, EC 3.4.99. EC 3.4.-. [NIH] Endorphins: One of the three major groups of endogenous opioid peptides. They are large peptides derived from the pro-opiomelanocortin precursor. The known members of this group are alpha-, beta-, and gamma-endorphin. The term endorphin is also sometimes used to refer to all opioid peptides, but the narrower sense is used here; opioid peptides is used for the broader group. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have filtered through the capillaries into the tissue spaces. [NIH] Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood capillaries. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes

340

Estrogen

it. [NIH] Endotoxic: Of, relating to, or acting as an endotoxin (= a heat-stable toxin, associated with the outer membranes of certain gram-negative bacteria. Endotoxins are not secreted and are released only when the cells are disrupted). [EU] Endotoxin: Toxin from cell walls of bacteria. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Enkephalins: One of the three major families of endogenous opioid peptides. The enkephalins are pentapeptides that are widespread in the central and peripheral nervous systems and in the adrenal medulla. [NIH] Enteropeptidase: A specialized proteolytic enzyme secreted by intestinal cells. It converts trypsinogen into its active form trypsin by removing the N-terminal peptide. EC 3.4.21.9. [NIH]

Entorhinal Cortex: Cortex where the signals are combined with those from other sensory systems. [NIH] Environment Design: The structuring of the environment to permit or promote specific patterns of behavior. [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme Activation: Conversion of an inactive form of an enzyme to one possessing metabolic activity. It includes 1) activation by ions (activators); 2) activation by cofactors (coenzymes); and 3) conversion of an enzyme precursor (proenzyme or zymogen) to an active enzyme. [NIH] Ephedrine: An alpha- and beta-adrenergic agonist that may also enhance release of norepinephrine. It has been used in the treatment of several disorders including asthma, heart failure, rhinitis, and urinary incontinence, and for its central nervous system stimulatory effects in the treatment of narcolepsy and depression. It has become less extensively used with the advent of more selective agonists. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidemiological: Relating to, or involving epidemiology. [EU] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] Epidermal Growth Factor: A 6 kD polypeptide growth factor initially discovered in mouse submaxillary glands. Human epidermal growth factor was originally isolated from urine based on its ability to inhibit gastric secretion and called urogastrone. epidermal growth factor exerts a wide variety of biological effects including the promotion of proliferation and differentiation of mesenchymal and epithelial cells. [NIH]

Dictionary 341

Epidermal growth factor receptor: EGFR. The protein found on the surface of some cells and to which epidermal growth factor binds, causing the cells to divide. It is found at abnormally high levels on the surface of many types of cancer cells, so these cells may divide excessively in the presence of epidermal growth factor. Also known as ErbB1 or HER1. [NIH] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epidermoid carcinoma: A type of cancer in which the cells are flat and look like fish scales. Also called squamous cell carcinoma. [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epiphyseal: Pertaining to or of the nature of an epiphysis. [EU] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Erectile: The inability to get or maintain an erection for satisfactory sexual intercourse. Also called impotence. [NIH] Erection: The condition of being made rigid and elevated; as erectile tissue when filled with blood. [EU] Ergometer: An instrument for measuring the force of muscular contraction. [NIH] Ergometry: Any method of measuring the amount of work done by an organism, usually during exertion. Ergometry also includes measures of power. Some instruments used in these determinations include the hand crank and the bicycle ergometer. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]

Essential Tremor: A rhythmic, involuntary, purposeless, oscillating movement resulting from the alternate contraction and relaxation of opposing groups of muscles. [NIH] Estradiol: The most potent mammalian estrogenic hormone. It is produced in the ovary, placenta, testis, and possibly the adrenal cortex. [NIH] Estriol: (16 alpha,17 beta)-Estra-1,3,5(10)-triene-3,16,17-triol. A metabolite of estradiol and usually the predominant estrogenic metabolite in urine. During pregnancy, large amounts of estriol are produced by the placenta. It has also been obtained from plant sources. The 16 beta-isomer has also been isolated from the urine of pregnant women. [NIH] Estrogen: One of the two female sex hormones. [NIH] Estrogen Antagonists: Compounds which inhibit or antagonize the action or biosynthesis of estrogen. [NIH] Estrogen receptor: ER. Protein found on some cancer cells to which estrogen will attach. [NIH]

Estrogen Receptor Modulators: Substances that possess antiestrogenic actions but can also

342

Estrogen

produce estrogenic effects as well. They act as complete or partial agonist or as antagonist. They can be either steroidal or nonsteroidal in structure. [NIH] Estrogen receptor negative: ER-. Breast cancer cells that do not have a protein (receptor molecule) to which estrogen will attach. Breast cancer cells that are ER- do not need the hormone estrogen to grow and usually do not respond to hormone (antiestrogen) therapy that blocks these receptor sites. [NIH] Estrogen receptor positive: ER+. Breast cancer cells that have a protein (receptor molecule) to which estrogen will attach. Breast cancer cells that are ER+ need the hormone estrogen to grow and will usually respond to hormone (antiestrogen) therapy that blocks these receptor sites. [NIH] Estrogen Replacement Therapy: The use of hormonal agents with estrogen-like activity in postmenopausal or other estrogen-deficient women to alleviate effects of hormone deficiency, such as vasomotor symptoms, dyspareunia, and progressive development of osteoporosis. This may also include the use of progestational agents in combination therapy. [NIH]

Estrone: 3-Hydroxyestra-1,3,5(10)-trien-17-one. A metabolite of estradiol but possessing less biological activity. It is found in the urine of pregnant women and mares, in the human placenta, and in the urine of bulls and stallions. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985), estrone may reasonably be anticipated to be a carcinogen (Merck, 11th ed). [NIH] Ethanol: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. [NIH] Ether: One of a class of organic compounds in which any two organic radicals are attached directly to a single oxygen atom. [NIH] Ethnic Groups: A group of people with a common cultural heritage that sets them apart from others in a variety of social relationships. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Evacuation: An emptying, as of the bowels. [EU] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH] Excipient: Any more or less inert substance added to a prescription in order to confer a suitable consistency or form to the drug; a vehicle. [EU] Excitability: Property of a cardiac cell whereby, when the cell is depolarized to a critical level (called threshold), the membrane becomes permeable and a regenerative inward current causes an action potential. [NIH] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of energy, as the excitation of a molecule by absorption of photons. [EU] Excitatory: When cortical neurons are excited, their output increases and each new input they receive while they are still excited raises their output markedly. [NIH] Excitotoxicity: Excessive exposure to glutamate or related compounds can kill brain neurons, presumably by overstimulating them. [NIH] Exemestane: An anticancer drug used to decrease estrogen production and suppress the growth of estrogen-dependent tumors. [NIH]

Dictionary 343

Exhaustion: The feeling of weariness of mind and body. [NIH] Exocytosis: Cellular release of material within membrane-limited vesicles by fusion of the vesicles with the cell membrane. [NIH] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exons: Coding regions of messenger RNA included in the genetic transcript which survive the processing of RNA in cell nuclei to become part of a spliced messenger of structural RNA in the cytoplasm. They include joining and diversity exons of immunoglobulin genes. [NIH]

External-beam radiation: Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called external radiation. [NIH] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Matrix Proteins: Macromolecular organic compounds that contain carbon, hydrogen, oxygen, nitrogen, and usually, sulfur. These macromolecules (proteins) form an intricate meshwork in which cells are embedded to construct tissues. Variations in the relative types of macromolecules and their organization determine the type of extracellular matrix, each adapted to the functional requirements of the tissue. The two main classes of macromolecules that form the extracellular matrix are: glycosaminoglycans, usually linked to proteins (proteoglycans), and fibrous proteins (e.g., collagen, elastin, fibronectins and laminin). [NIH] Extrapyramidal: Outside of the pyramidal tracts. [EU] Exudate: Material, such as fluid, cells, or cellular debris, which has escaped from blood vessels and has been deposited in tissues or on tissue surfaces, usually as a result of inflammation. An exudate, in contrast to a transudate, is characterized by a high content of protein, cells, or solid materials derived from cells. [EU] Eye Infections: Infection, moderate to severe, caused by bacteria, fungi, or viruses, which occurs either on the external surface of the eye or intraocularly with probable inflammation, visual impairment, or blindness. [NIH] Facial: Of or pertaining to the face. [EU] Fallopian tube: The oviduct, a muscular tube about 10 cm long, lying in the upper border of the broad ligament. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]

Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Feces: The excrement discharged from the intestines, consisting of bacteria, cells exfoliated from the intestines, secretions, chiefly of the liver, and a small amount of food residue. [EU] Femoral: Pertaining to the femur, or to the thigh. [EU] Femoral Neck Fractures: Fractures of the short, constricted portion of the thigh bone

344

Estrogen

between the femur head and the trochanters. It excludes intertrochanteric fractures which are hip fractures. [NIH] Femur: The longest and largest bone of the skeleton, it is situated between the hip and the knee. [NIH] Fermentation: An enzyme-induced chemical change in organic compounds that takes place in the absence of oxygen. The change usually results in the production of ethanol or lactic acid, and the production of energy. [NIH] Fertilization in Vitro: Fertilization of an egg outside the body when the egg is normally fertilized in the body. [NIH] Fetoprotein: Transabdominal aspiration of fluid from the amniotic sac with a view to detecting increases of alpha-fetoprotein in maternal blood during pregnancy, as this is an important indicator of open neural tube defects in the fetus. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products. [NIH] Fibroblast Growth Factor: Peptide isolated from the pituitary gland and from the brain. It is a potent mitogen which stimulates growth of a variety of mesodermal cells including chondrocytes, granulosa, and endothelial cells. The peptide may be active in wound healing and animal limb regeneration. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibroid: A benign smooth muscle tumor, usually in the uterus or gastrointestinal tract. Also called leiomyoma. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Fibula: The bone of the lower leg lateral to and smaller than the tibia. In proportion to its length, it is the most slender of the long bones. [NIH] Finasteride: An orally active testosterone 5-alpha-reductase inhibitor. It is used as a surgical alternative for treatment of benign prostatic hyperplasia. [NIH] Fissure: Any cleft or groove, normal or otherwise; especially a deep fold in the cerebral cortex which involves the entire thickness of the brain wall. [EU] Fixation: 1. The act or operation of holding, suturing, or fastening in a fixed position. 2. The condition of being held in a fixed position. 3. In psychiatry, a term with two related but distinct meanings : (1) arrest of development at a particular stage, which like regression (return to an earlier stage), if temporary is a normal reaction to setbacks and difficulties but if protracted or frequent is a cause of developmental failures and emotional problems, and (2) a close and suffocating attachment to another person, especially a childhood figure, such as one's mother or father. Both meanings are derived from psychoanalytic theory and refer to 'fixation' of libidinal energy either in a specific erogenous zone, hence fixation at the oral, anal, or phallic stage, or in a specific object, hence mother or father fixation. 4. The use of a fixative (q.v.) to preserve histological or cytological specimens. 5. In chemistry, the process whereby a substance is removed from the gaseous or solution phase and localized, as in carbon dioxide fixation or nitrogen fixation. 6. In ophthalmology, direction of the gaze so that the visual image of the object falls on the fovea centralis. 7. In film processing, the

Dictionary 345

chemical removal of all undeveloped salts of the film emulsion, leaving only the developed silver to form a permanent image. [EU] Flavoxate: A drug that has been used in various urinary syndromes and as an antispasmodic. Its therapeutic usefulness and its mechanism of action are not clear. It may have local anesthetic activity and direct relaxing effects on smooth muscle as well as some activity as a muscarinic antagonist. [NIH] Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Fluorescence Polarization: Measurement of the polarization of fluorescent light from solutions or microscopic specimens. It is used to provide information concerning molecular size, shape, and conformation, molecular anisotropy, electronic energy transfer, molecular interaction, including dye and coenzyme binding, and the antigen-antibody reaction. [NIH] Fluorouracil: A pyrimidine analog that acts as an antineoplastic antimetabolite and also has immunosuppressant. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. [NIH] Fluoxetine: The first highly specific serotonin uptake inhibitor. It is used as an antidepressant and often has a more acceptable side-effects profile than traditional antidepressants. [NIH] Flutamide: An antiandrogen with about the same potency as cyproterone in rodent and canine species. [NIH] Foetoplacental: Pertaining to the fetus and placenta. [EU] Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Folic Acid: N-(4-(((2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-Lglutamic acid. A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses. Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia. [NIH] Follicles: Shafts through which hair grows. [NIH] Follicular Phase: The period of the menstrual cycle that begins with menstruation and ends with ovulation. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fossa: A cavity, depression, or pit. [NIH] Fovea: The central part of the macula that provides the sharpest vision. [NIH] Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. [NIH] Frontal Lobe: The anterior part of the cerebral hemisphere. [NIH] Functional magnetic resonance imaging: A noninvasive tool used to observe functioning in the brain or other organs by detecting changes in chemical composition, blood flow, or both. [NIH]

346

Estrogen

Fungi: A kingdom of eukaryotic, heterotrophic organisms that live as saprobes or parasites, including mushrooms, yeasts, smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi refer to those that grow as multicelluar colonies (mushrooms and molds). [NIH] Fungus: A general term used to denote a group of eukaryotic protists, including mushrooms, yeasts, rusts, moulds, smuts, etc., which are characterized by the absence of chlorophyll and by the presence of a rigid cell wall composed of chitin, mannans, and sometimes cellulose. They are usually of simple morphological form or show some reversible cellular specialization, such as the formation of pseudoparenchymatous tissue in the fruiting body of a mushroom. The dimorphic fungi grow, according to environmental conditions, as moulds or yeasts. [EU] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gallstones: The solid masses or stones made of cholesterol or bilirubin that form in the gallbladder or bile ducts. [NIH] Gamma Rays: Very powerful and penetrating, high-energy electromagnetic radiation of shorter wavelength than that of x-rays. They are emitted by a decaying nucleus, usually between 0.01 and 10 MeV. They are also called nuclear x-rays. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Ganglion: 1. A knot, or knotlike mass. 2. A general term for a group of nerve cell bodies located outside the central nervous system; occasionally applied to certain nuclear groups within the brain or spinal cord, e.g. basal ganglia. 3. A benign cystic tumour occurring on a aponeurosis or tendon, as in the wrist or dorsum of the foot; it consists of a thin fibrous capsule enclosing a clear mucinous fluid. [EU] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gastric: Having to do with the stomach. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gastroesophageal Reflux: Reflux of gastric juice and/or duodenal contents (bile acids, pancreatic juice) into the distal esophagus, commonly due to incompetence of the lower esophageal sphincter. Gastric regurgitation is an extension of this process with entry of fluid into the pharynx or mouth. [NIH] Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]

Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Therapy: The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors, transfection, homologous recombination, and injection of new genes into the nuclei of single cell embryos. The entire gene therapy process may consist of multiple steps. The new genes may be introduced into proliferating cells in vivo (e.g., bone marrow) or in vitro (e.g., fibroblast cultures) and the modified cells transferred to the site where the gene expression

Dictionary 347

is required. Gene therapy may be particularly useful for treating enzyme deficiency diseases, hemoglobinopathies, and leukemias and may also prove useful in restoring drug sensitivity, particularly for leukemia. [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic Markers: A phenotypically recognizable genetic trait which can be used to identify a genetic locus, a linkage group, or a recombination event. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genistein: An isoflavonoid derived from soy products. It inhibits protein-tyrosine kinase and topoisomerase-ii (dna topoisomerase (atp-hydrolysing)) activity and is used as an antineoplastic and antitumor agent. Experimentally, it has been shown to induce G2 phase arrest in human and murine cell lines. [NIH] Genital: Pertaining to the genitalia. [EU] Genitourinary: Pertaining to the genital and urinary organs; urogenital; urinosexual. [EU] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Geriatric Assessment: Evaluation of the level of physical, physiological, or mental functioning in the older population group. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] Gestational: Psychosis attributable to or occurring during pregnancy. [NIH] Giant Cells: Multinucleated masses produced by the fusion of many cells; often associated with viral infections. In AIDS, they are induced when the envelope glycoprotein of the HIV virus binds to the CD4 antigen of uninfected neighboring T4 cells. The resulting syncytium leads to cell death and thus may account for the cytopathic effect of the virus. [NIH] Ginseng: An araliaceous genus of plants that contains a number of pharmacologically active agents used as stimulants, sedatives, and tonics, especially in traditional medicine. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]

Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose Clamp Technique: Maintenance of a constant blood glucose level by perfusion or infusion with glucose or insulin. It is used for the study of metabolic rates (e.g., in glucose, lipid, amino acid metabolism) at constant glucose concentration. [NIH] Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration

348

Estrogen

following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glucose tolerance: The power of the normal liver to absorb and store large quantities of glucose and the effectiveness of intestinal absorption of glucose. The glucose tolerance test is a metabolic test of carbohydrate tolerance that measures active insulin, a hepatic function based on the ability of the liver to absorb glucose. The test consists of ingesting 100 grams of glucose into a fasting stomach; blood sugar should return to normal in 2 to 21 hours after ingestion. [NIH] Glucose Tolerance Test: Determination of whole blood or plasma sugar in a fasting state before and at prescribed intervals (usually 1/2 hr, 1 hr, 3 hr, 4 hr) after taking a specified amount (usually 100 gm orally) of glucose. [NIH] Glucuronic Acid: Derivatives of uronic acid found throughout the plant and animal kingdoms. They detoxify drugs and toxins by conjugating with them to form glucuronides in the liver which are more water-soluble metabolites that can be easily eliminated from the body. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]

Glutathione Peroxidase: An enzyme catalyzing the oxidation of 2 moles of glutathione in the presence of hydrogen peroxide to yield oxidized glutathione and water. EC 1.11.1.9. [NIH]

Gluten: The protein of wheat and other grains which gives to the dough its tough elastic character. [EU] Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosaminoglycans: Heteropolysaccharides which contain an N-acetylated hexosamine in a characteristic repeating disaccharide unit. The repeating structure of each disaccharide involves alternate 1,4- and 1,3-linkages consisting of either N-acetylglucosamine or Nacetylgalactosamine. [NIH] Goats: Any of numerous agile, hollow-horned ruminants of the genus Capra, closely related to the sheep. [NIH] Gonad: A sex organ, such as an ovary or a testicle, which produces the gametes in most multicellular animals. [NIH] Gonadal: Pertaining to a gonad. [EU] Gonadal Dysgenesis: Any of several developmental anomalies involving the total or partial failure of the indifferent embryonic gonad to differentiate into ovary or testis. This concept includes gonadal agenesis. [NIH] Gonadotropin: The water-soluble follicle stimulating substance, by some believed to originate in chorionic tissue, obtained from the serum of pregnant mares. It is used to supplement the action of estrogens. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Gp120: 120-kD HIV envelope glycoprotein which is involved in the binding of the virus to its membrane receptor, the CD4 molecule, found on the surface of certain cells in the body. [NIH]

Dictionary 349

Grade: The grade of a tumor depends on how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and spread. Grading systems are different for each type of cancer. [NIH] Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Grafting: The operation of transfer of tissue from one site to another. [NIH] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Granuloma: A relatively small nodular inflammatory lesion containing grouped mononuclear phagocytes, caused by infectious and noninfectious agents. [NIH] Granulosa Cells: Cells of the membrana granulosa lining the vesicular ovarian follicle which become luteal cells after ovulation. [NIH] Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Growth Plate: The area between the epiphysis and the diaphysis within which bone growth occurs. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Hair follicles: Shafts or openings on the surface of the skin through which hair grows. [NIH] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Health Policy: Decisions, usually developed by government policymakers, for determining present and future objectives pertaining to the health care system. [NIH] Health Status: The level of health of the individual, group, or population as subjectively assessed by the individual or by more objective measures. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH]

350

Estrogen

Hemodynamics: The movements of the blood and the forces involved in systemic or regional blood circulation. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobin A: Normal adult human hemoglobin. The globin moiety consists of two alpha and two beta chains. [NIH] Hemoglobinuria: The presence of free hemoglobin in the urine. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]

Heparin: Heparinic acid. A highly acidic mucopolysaccharide formed of equal parts of sulfated D-glucosamine and D-glucuronic acid with sulfaminic bridges. The molecular weight ranges from six to twenty thousand. Heparin occurs in and is obtained from liver, lung, mast cells, etc., of vertebrates. Its function is unknown, but it is used to prevent blood clotting in vivo and vitro, in the form of many different salts. [NIH] Hepatic: Refers to the liver. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatitis A: Hepatitis caused by hepatovirus. It can be transmitted through fecal contamination of food or water. [NIH] Hepatocyte: A liver cell. [NIH] Hepatovirus: A genus of Picornaviridae causing infectious hepatitis naturally in humans and experimentally in other primates. It is transmitted through fecal contamination of food or water. [NIH] Herbicide: A chemical that kills plants. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]

Hip Fractures: Fractures of the femur head, the femur neck, the trochanters, or the inter- or subtrochanteric region. Excludes fractures of the acetabulum and fractures of the femoral shaft below the subtrochanteric region. For the fractures of the femur neck the specific term femoral neck fractures is available. [NIH] Hippocampus: A curved elevation of gray matter extending the entire length of the floor of the temporal horn of the lateral ventricle (Dorland, 28th ed). The hippocampus, subiculum,

Dictionary 351

and dentate gyrus constitute the hippocampal formation. Sometimes authors include the entorhinal cortex in the hippocampal formation. [NIH] Hirsutism: Excess hair in females and children with an adult male pattern of distribution. The concept does not include hypertrichosis, which is localized or generalized excess hair. [NIH]

Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Histology: The study of tissues and cells under a microscope. [NIH] Histone Deacetylase: Hydrolyzes N-acetyl groups on histones. [NIH] Homeobox: Distinctive sequence of DNA bases. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormonal therapy: Treatment of cancer by removing, blocking, or adding hormones. Also called hormone therapy or endocrine therapy. [NIH] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Hormone Replacement Therapy: Therapeutic use of hormones to alleviate the effects of hormone deficiency. [NIH] Hormone therapy: Treatment of cancer by removing, blocking, or adding hormones. Also called endocrine therapy. [NIH] Horny layer: The superficial layer of the epidermis containing keratinized cells. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic acids can be formed by nucleic acid hybridization of DNA and RNA molecules. Protein hybridization allows for hybrid proteins to be formed from polypeptide chains. [NIH] Hybridoma: A hybrid cell resulting from the fusion of a specific antibody-producing spleen cell with a myeloma cell. [NIH] Hydrochlorothiazide: A thiazide diuretic often considered the prototypical member of this class. It reduces the reabsorption of electrolytes from the renal tubules. This results in increased excretion of water and electrolytes, including sodium, potassium, chloride, and magnesium. It has been used in the treatment of several disorders including edema, hypertension, diabetes insipidus, and hypoparathyroidism. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive

352

Estrogen

isotope tritium. [NIH] Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] Hydrogenation: Specific method of reduction in which hydrogen is added to a substance by the direct use of gaseous hydrogen. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hydroxylation: Hydroxylate, to introduce hydroxyl into (a compound or radical) usually by replacement of hydrogen. [EU] Hydroxylysine: A hydroxylated derivative of the amino acid lysine that is present in certain collagens. [NIH] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hyperalgesia: Excessive sensitiveness or sensibility to pain. [EU] Hyperbilirubinemia: Pathologic process consisting of an abnormal increase in the amount of bilirubin in the circulating blood, which may result in jaundice. [NIH] Hypercalcemia: Abnormally high level of calcium in the blood. [NIH] Hypercholesterolemia: Abnormally high levels of cholesterol in the blood. [NIH] Hyperlipidemia: An excess of lipids in the blood. [NIH] Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [NIH] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hyperthermia: A type of treatment in which body tissue is exposed to high temperatures to damage and kill cancer cells or to make cancer cells more sensitive to the effects of radiation and certain anticancer drugs. [NIH] Hypertrichosis: Localized or generalized excess hair. The concept does not include hirsutism, which is excess hair in females and children with an adult male pattern of distribution. [NIH] Hypertriglyceridemia: Condition of elevated triglyceride concentration in the blood; an inherited form occurs in familial hyperlipoproteinemia IIb and hyperlipoproteinemia type IV. It has been linked to higher risk of heart disease and arteriosclerosis. [NIH] Hypertrophy: General increase in bulk of a part or organ, not due to tumor formation, nor to an increase in the number of cells. [NIH] Hypoglycaemia: An abnormally diminished concentration of glucose in the blood, which may lead to tremulousness, cold sweat, piloerection, hypothermia, and headache, accompanied by irritability, confusion, hallucinations, bizarre behaviour, and ultimately, convulsions and coma. [EU] Hypokinesia: Slow or diminished movement of body musculature. It may be associated

Dictionary 353

with basal ganglia diseases; mental disorders; prolonged inactivity due to illness; experimental protocols used to evaluate the physiologic effects of immobility; and other conditions. [NIH] Hypotension: Abnormally low blood pressure. [NIH] Hypotensive: Characterized by or causing diminished tension or pressure, as abnormally low blood pressure. [EU] Hypothalamic: Of or involving the hypothalamus. [EU] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Hypoxic: Having too little oxygen. [NIH] Hysterectomy: Excision of the uterus. [NIH] Id: The part of the personality structure which harbors the unconscious instinctive desires and strivings of the individual. [NIH] Idiopathic: Describes a disease of unknown cause. [NIH] Imipramine: The prototypical tricyclic antidepressant. It has been used in major depression, dysthymia, bipolar depression, attention-deficit disorders, agoraphobia, and panic disorders. It has less sedative effect than some other members of this therapeutic group. [NIH]

Immune function: Production and action of cells that fight disease or infection. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]

effects

of

foreign

Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunofluorescence: A technique for identifying molecules present on the surfaces of cells or in tissues using a highly fluorescent substance coupled to a specific antibody. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulin: A protein that acts as an antibody. [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunophilin: A drug for the treatment of Parkinson's disease. [NIH]

354

Estrogen

Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implant radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] Impotence: The inability to perform sexual intercourse. [NIH] Impulse Control Disorders: Disorders whose essential features are the failure to resist an impulse, drive, or temptation to perform an act that is harmful to the individual or to others. Individuals experience an increased sense of tension prior to the act and pleasure, gratification, or release of tension at the time of committing the act. [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incompetence: Physical or mental inadequacy or insufficiency. [EU] Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Indole-3-carbinol: A substance that is being studied as a cancer prevention drug. It is found in cruciferous vegetables. [NIH] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]

Dictionary 355

Infertility: The diminished or absent ability to conceive or produce an offspring while sterility is the complete inability to conceive or produce an offspring. [NIH] Infiltrating cancer: Cancer that has spread beyond the layer of tissue in which it developed and is growing into surrounding, healthy tissues. Also called invasive cancer. [NIH] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Inlay: In dentistry, a filling first made to correspond with the form of a dental cavity and then cemented into the cavity. [NIH] Innervation: 1. The distribution or supply of nerves to a part. 2. The supply of nervous energy or of nerve stimulus sent to a part. [EU] Inorganic: Pertaining to substances not of organic origin. [EU] Inotropic: Affecting the force or energy of muscular contractions. [EU] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insomnia: Difficulty in going to sleep or getting enough sleep. [NIH] Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH] Interindividual: Occurring between two or more individuals. [EU] Interleukin-6: Factor that stimulates the growth and differentiation of human B-cells and is also a growth factor for hybridomas and plasmacytomas. It is produced by many different cells including T-cells, monocytes, and fibroblasts. [NIH] Interleukins: Soluble factors which stimulate growth-related activities of leukocytes as well as other cell types. They enhance cell proliferation and differentiation, DNA synthesis, secretion of other biologically active molecules and responses to immune and inflammatory

356

Estrogen

stimuli. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] Internal radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called brachytherapy, implant radiation, or interstitial radiation therapy. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intervention Studies: Epidemiologic investigations designed to test a hypothesized causeeffect relation by modifying the supposed causal factor(s) in the study population. [NIH] Intervertebral: Situated between two contiguous vertebrae. [EU] Intestinal: Having to do with the intestines. [NIH] Intestinal Mucosa: The surface lining of the intestines where the cells absorb nutrients. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intracellular Membranes: Membranes of subcellular structures. [NIH] Intraductal carcinoma: Abnormal cells that involve only the lining of a duct. The cells have not spread outside the duct to other tissues in the breast. Also called ductal carcinoma in situ. [NIH] Intraepithelial: Within the layer of cells that form the surface or lining of an organ. [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

Invasive cancer: Cancer that has spread beyond the layer of tissue in which it developed and is growing into surrounding, healthy tissues. Also called infiltrating cancer. [NIH] Involuntary: Reaction occurring without intention or volition. [NIH] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Ion Transport: The movement of ions across energy-transducing cell membranes. Transport can be active or passive. Passive ion transport (facilitated diffusion) derives its energy from the concentration gradient of the ion itself and allows the transport of a single solute in one direction (uniport). Active ion transport is usually coupled to an energy-yielding chemical or photochemical reaction such as ATP hydrolysis. This form of primary active transport is called an ion pump. Secondary active transport utilizes the voltage and ion gradients produced by the primary transport to drive the cotransport of other ions or molecules. These may be transported in the same (symport) or opposite (antiport) direction. [NIH] Ionizing: Radiation comprising charged particles, e. g. electrons, protons, alpha-particles, etc., having sufficient kinetic energy to produce ionization by collision. [NIH]

Dictionary 357

Ionophores: Chemical agents that increase the permeability of biological or artificial lipid membranes to specific ions. Most ionophores are relatively small organic molecules that act as mobile carriers within membranes or coalesce to form ion permeable channels across membranes. Many are antibiotics, and many act as uncoupling agents by short-circuiting the proton gradient across mitochondrial membranes. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Irradiation: The use of high-energy radiation from x-rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] Irritants: Drugs that act locally on cutaneous or mucosal surfaces to produce inflammation; those that cause redness due to hyperemia are rubefacients; those that raise blisters are vesicants and those that penetrate sebaceous glands and cause abscesses are pustulants; tear gases and mustard gases are also irritants. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Isoenzyme: Different forms of an enzyme, usually occurring in different tissues. The isoenzymes of a particular enzyme catalyze the same reaction but they differ in some of their properties. [NIH] Isoflavones: 3-Phenylchromones. Isomeric form of flavones in which the benzene group is attached to the 3 position of the benzopyran ring instead of the 2 position. [NIH] Jaundice: A clinical manifestation of hyperbilirubinemia, consisting of deposition of bile pigments in the skin, resulting in a yellowish staining of the skin and mucous membranes. [NIH]

Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [NIH] Kallidin: A decapeptide bradykinin homolog produced by the action of tissue and glandular kallikreins on low-molecular-weight kininogen. It is a smooth-muscle stimulant and hypotensive agent that functions through vasodilatation. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Keratin: A class of fibrous proteins or scleroproteins important both as structural proteins and as keys to the study of protein conformation. The family represents the principal constituent of epidermis, hair, nails, horny tissues, and the organic matrix of tooth enamel. Two major conformational groups have been characterized, alpha-keratin, whose peptide backbone forms an alpha-helix, and beta-keratin, whose backbone forms a zigzag or pleated sheet structure. [NIH] Keto: It consists of 8 carbon atoms and within the endotoxins, it connects poysaccharide and lipid A. [NIH] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH]

358

Estrogen

Kidney stone: A stone that develops from crystals that form in urine and build up on the inner surfaces of the kidney, in the renal pelvis, or in the ureters. [NIH] Kinetics: The study of rate dynamics in chemical or physical systems. [NIH] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Labyrinth: The internal ear; the essential part of the organ of hearing. It consists of an osseous and a membranous portion. [NIH] Lactation: The period of the secretion of milk. [EU] Laminin: Large, noncollagenous glycoprotein with antigenic properties. It is localized in the basement membrane lamina lucida and functions to bind epithelial cells to the basement membrane. Evidence suggests that the protein plays a role in tumor invasion. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Laxative: An agent that acts to promote evacuation of the bowel; a cathartic or purgative. [EU]

Lectin: A complex molecule that has both protein and sugars. Lectins are able to bind to the outside of a cell and cause biochemical changes in it. Lectins are made by both animals and plants. [NIH] Leiomyoma: A benign tumor derived from smooth muscle tissue, also known as a fibroid tumor. They rarely occur outside of the uterus and the gastrointestinal tract but can occur in the skin and subcutaneous tissues, probably arising from the smooth muscle of small blood vessels in these tissues. [NIH] Lens: The transparent, double convex (outward curve on both sides) structure suspended between the aqueous and vitreous; helps to focus light on the retina. [NIH] Leucine: An essential branched-chain amino acid important for hemoglobin formation. [NIH] Leukemia: Cancer of blood-forming tissue. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Leukoencephalopathy: A condition with spongy holes in the brain's white matter. [NIH] Leukoplakia: A white patch that may develop on mucous membranes such as the cheek, gums, or tongue and may become cancerous. [NIH] Leukotrienes: A family of biologically active compounds derived from arachidonic acid by oxidative metabolism through the 5-lipoxygenase pathway. They participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. They have potent actions on many essential organs and systems, including the cardiovascular, pulmonary, and central nervous system as well as the gastrointestinal tract and the immune system. [NIH] Levodopa: The naturally occurring form of dopa and the immediate precursor of dopamine. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to dopamine. It is used for the treatment of parkinsonism and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system. [NIH]

Dictionary 359

Levorphanol: A narcotic analgesic that may be habit-forming. It is nearly as effective orally as by injection. [NIH] Libido: The psychic drive or energy associated with sexual instinct in the broad sense (pleasure and love-object seeking). It may also connote the psychic energy associated with instincts in general that motivate behavior. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [NIH]

Life cycle: The successive stages through which an organism passes from fertilized ovum or spore to the fertilized ovum or spore of the next generation. [NIH] Life Expectancy: A figure representing the number of years, based on known statistics, to which any person of a given age may reasonably expect to live. [NIH] Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Ligands: A RNA simulation method developed by the MIT. [NIH] Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] Limbic: Pertaining to a limbus, or margin; forming a border around. [EU] Limbic System: A set of forebrain structures common to all mammals that is defined functionally and anatomically. It is implicated in the higher integration of visceral, olfactory, and somatic information as well as homeostatic responses including fundamental survival behaviors (feeding, mating, emotion). For most authors, it includes the amygdala, epithalamus, gyrus cinguli, hippocampal formation (see hippocampus), hypothalamus, parahippocampal gyrus, septal nuclei, anterior nuclear group of thalamus, and portions of the basal ganglia. (Parent, Carpenter's Human Neuroanatomy, 9th ed, p744; NeuroNames, http://rprcsgi.rprc.washington.edu/neuronames/index.html (September 2, 1998)). [NIH] Linear Models: Statistical models in which the value of a parameter for a given value of a factor is assumed to be equal to a + bx, where a and b are constants. The models predict a linear regression. [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipid: Fat. [NIH] Lipid A: Lipid A is the biologically active component of lipopolysaccharides. It shows strong endotoxic activity and exhibits immunogenic properties. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipolysis: The hydrolysis of lipids. [NIH] Lipophilic: Having an affinity for fat; pertaining to or characterized by lipophilia. [EU] Lipopolysaccharides: Substance consisting of polysaccaride and lipid. [NIH] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Lipoprotein(a): A family of lipoprotein particles varying in density and size depending on the protein-lipid ratio and the protein composition. These particles consist of apolipoprotein B-100 covalently linked to apolipoprotein-a by one or two disulfide bonds. There is a

360

Estrogen

correlation between high plasma levels of this lipoprotein and increased risk for atherosclerotic cardiovascular disease. [NIH] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver cancer: A disease in which malignant (cancer) cells are found in the tissues of the liver. [NIH]

Liver scan: An image of the liver created on a computer screen or on film. A radioactive substance is injected into a blood vessel and travels through the bloodstream. It collects in the liver, especially in abnormal areas, and can be detected by the scanner. [NIH] Lobe: A portion of an organ such as the liver, lung, breast, or brain. [NIH] Lobule: A small lobe or subdivision of a lobe. [NIH] Local therapy: Treatment that affects cells in the tumor and the area close to it. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [NIH] Locomotor: Of or pertaining to locomotion; pertaining to or affecting the locomotive apparatus of the body. [EU] Longitudinal study: Also referred to as a "cohort study" or "prospective study"; the analytic method of epidemiologic study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the probability of occurrence of a given disease or other outcome. The main feature of this type of study is to observe large numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [NIH] Long-Term Care: Care over an extended period, usually for a chronic condition or disability, requiring periodic, intermittent, or continuous care. [NIH] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside diameter) and used in transferring microorganisms. [NIH] Lordosis: The anterior concavity in the curvature of the lumbar and cervical spine as viewed from the side. The term usually refers to abnormally increased curvature (hollow back, saddle back, swayback). It does not include lordosis as normal mating posture in certain animals ( = posture + sex behavior, animal). [NIH] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] Lower Esophageal Sphincter: The muscle between the esophagus and stomach. When a person swallows, this muscle relaxes to let food pass from the esophagus to the stomach. It stays closed at other times to keep stomach contents from flowing back into the esophagus. [NIH]

Lubricants: Oily or slippery substances. [NIH] Lucida: An instrument, invented by Wollaton, consisting essentially of a prism or a mirror through which an object can be viewed so as to appear on a plane surface seen in direct view

Dictionary 361

and on which the outline of the object may be traced. [NIH] Luciferase: Any one of several enzymes that catalyze the bioluminescent reaction in certain marine crustaceans, fish, bacteria, and insects. The enzyme is a flavoprotein; it oxidizes luciferins to an electronically excited compound that emits energy in the form of light. The color of light emitted varies with the organism. The firefly enzyme is a valuable reagent for measurement of ATP concentration. (Dorland, 27th ed) EC 1.13.12.-. [NIH] Lumbar: Pertaining to the loins, the part of the back between the thorax and the pelvis. [EU] Lumpectomy: Surgery to remove the tumor and a small amount of normal tissue around it. [NIH]

Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH] Luteal Phase: The period of the menstrual cycle that begins with ovulation and ends with menstruation. [NIH] Lutein Cells: The cells of the corpus luteum which are derived from the granulosa cells and the theca cells of the Graafian follicle. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]

Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [NIH] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Macroglia: A type of neuroglia composed of astrocytes. [NIH] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Malabsorption: Impaired intestinal absorption of nutrients. [EU] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH]

362

Estrogen

Malignant tumor: A tumor capable of metastasizing. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

Malondialdehyde: The dialdehyde of malonic acid. [NIH] Mammary: Pertaining to the mamma, or breast. [EU] Mammography: Radiographic examination of the breast. [NIH] Mandible: The largest and strongest bone of the face constituting the lower jaw. It supports the lower teeth. [NIH] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Man-made: Ionizing radiation emitted by artificial or concentrated natural, radioactive material or resulting from the operation of high voltage apparatus, such as X-ray apparatus or particle accelerators, of nuclear reactors, or from nuclear explosions. [NIH] Mannans: Polysaccharides consisting of mannose units. [NIH] Maternal Behavior: The behavior patterns associated with or characteristic of a mother. [NIH]

Matrix metalloproteinase: A member of a group of enzymes that can break down proteins, such as collagen, that are normally found in the spaces between cells in tissues (i.e., extracellular matrix proteins). Because these enzymes need zinc or calcium atoms to work properly, they are called metalloproteinases. Matrix metalloproteinases are involved in wound healing, angiogenesis, and tumor cell metastasis. [NIH] Meat: The edible portions of any animal used for food including domestic mammals (the major ones being cattle, swine, and sheep) along with poultry, fish, shellfish, and game. [NIH] Meat Products: Articles of food which are derived by a process of manufacture from any portion of carcasses of any animal used for food (e.g., head cheese, sausage, scrapple). [NIH] Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] Medical Staff: Professional medical personnel who provide care to patients in an organized facility, institution or agency. [NIH] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Medroxyprogesterone: (6 alpha)-17-Hydroxy-6-methylpregn-4-ene-3,20-dione. A synthetic progestational hormone used in veterinary practice as an estrus regulator. [NIH] Medroxyprogesterone Acetate: An injectable contraceptive, generally marketed under the name Depo-Provera. [NIH] Medullary: Pertaining to the marrow or to any medulla; resembling marrow. [EU] Megakaryocytes: Very large bone marrow cells which release mature blood platelets. [NIH] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH]

Dictionary 363

Melanin: The substance that gives the skin its color. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Glycoproteins: Glycoproteins found on the membrane or surface of cells. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Menarche: The establishment or beginning of the menstrual function. [EU] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Meningitis: Inflammation of the meninges. When it affects the dura mater, the disease is termed pachymeningitis; when the arachnoid and pia mater are involved, it is called leptomeningitis, or meningitis proper. [EU] Menopause: Permanent cessation of menstruation. [NIH] Menorrhagia: Excessive menstrual flow. [NIH] Menstrual Cycle: The period of the regularly recurring physiologic changes in the endometrium occurring during the reproductive period in human females and some primates and culminating in partial sloughing of the endometrium (menstruation). [NIH] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Health: The state wherein the person is well adjusted. [NIH] Mental Processes: Conceptual functions or thinking in all its forms. [NIH] Mesencephalic: Ipsilateral oculomotor paralysis and contralateral tremor, spasm. or choreic movements of the face and limbs. [NIH] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Mesenteric: Pertaining to the mesentery : a membranous fold attaching various organs to the body wall. [EU] Mesenteric Veins: Veins which return blood from the intestines; the inferior mesenteric vein empties into the splenic vein, the superior mesenteric vein joins the splenic vein to form the portal vein. [NIH] Mesentery: A layer of the peritoneum which attaches the abdominal viscera to the abdominal wall and conveys their blood vessels and nerves. [NIH]

364

Estrogen

Mesoderm: The middle germ layer of the embryo. [NIH] Meta-Analysis: A quantitative method of combining the results of independent studies (usually drawn from the published literature) and synthesizing summaries and conclusions which may be used to evaluate therapeutic effectiveness, plan new studies, etc., with application chiefly in the areas of research and medicine. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH] Metastatic: Having to do with metastasis, which is the spread of cancer from one part of the body to another. [NIH] Metastatic cancer: Cancer that has spread from the place in which it started to other parts of the body. [NIH] Methamphetamine: A central nervous system stimulant and sympathomimetic with actions and uses similar to dextroamphetamine. The smokable form is a drug of abuse and is referred to as crank, crystal, crystal meth, ice, and speed. [NIH] Methotrexate: An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of dihydrofolate reductase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. [NIH] Methyltransferase: A drug-metabolizing enzyme. [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microglia: The third type of glial cell, along with astrocytes and oligodendrocytes (which together form the macroglia). Microglia vary in appearance depending on developmental stage, functional state, and anatomical location; subtype terms include ramified, perivascular, ameboid, resting, and activated. Microglia clearly are capable of phagocytosis and play an important role in a wide spectrum of neuropathologies. They have also been suggested to act in several other roles including in secretion (e.g., of cytokines and neural growth factors), in immunological processing (e.g., antigen presentation), and in central nervous system development and remodeling. [NIH] Microgram: A unit of mass (weight) of the metric system, being one-millionth of a gram (106 gm.) or one one-thousandth of a milligram (10-3 mg.). [EU] Micronutrients: Essential dietary elements or organic compounds that are required in only small quantities for normal physiologic processes to occur. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Microsomal: Of or pertaining to microsomes : vesicular fragments of endoplasmic reticulum formed after disruption and centrifugation of cells. [EU]

Dictionary 365

Microspheres: Small uniformly-sized spherical particles frequently radioisotopes or various reagents acting as tags or markers. [NIH]

labeled

with

Microtubules: Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin. [NIH] Middle Cerebral Artery: The largest and most complex of the cerebral arteries. Branches of the middle cerebral artery supply the insular region, motor and premotor areas, and large regions of the association cortex. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Milligram: A measure of weight. A milligram is approximately 450,000-times smaller than a pound and 28,000-times smaller than an ounce. [NIH] Milliliter: A measure of volume for a liquid. A milliliter is approximately 950-times smaller than a quart and 30-times smaller than a fluid ounce. A milliliter of liquid and a cubic centimeter (cc) of liquid are the same. [NIH] Mineralocorticoids: A group of corticosteroids primarily associated with the regulation of water and electrolyte balance. This is accomplished through the effect on ion transport in renal tubules, resulting in retention of sodium and loss of potassium. Mineralocorticoid secretion is itself regulated by plasma volume, serum potassium, and angiotensin II. [NIH] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mitotic: Cell resulting from mitosis. [NIH] Mitotic Index: An expression of the number of mitoses found in a stated number of cells. [NIH]

Mobility: Capability of movement, of being moved, or of flowing freely. [EU] Mobilization: The process of making a fixed part or stored substance mobile, as by separating a part from surrounding structures to make it accessible for an operative procedure or by causing release into the circulation for body use of a substance stored in the body. [EU] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU]

Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecular Conformation: The characteristic three-dimensional shape of a molecule. [NIH] Molecular Probes: A group of atoms or molecules attached to other molecules or cellular structures and used in studying the properties of these molecules and structures. Radioactive DNA or RNA sequences are used in molecular genetics to detect the presence of a complementary sequence by molecular hybridization. [NIH] Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. [NIH] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the

366

Estrogen

same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoamine: Enzyme that breaks down dopamine in the astrocytes and microglia. [NIH] Monoamine Oxidase: An enzyme that catalyzes the oxidative deamination of naturally occurring monoamines. It is a flavin-containing enzyme that is localized in mitochondrial membranes, whether in nerve terminals, the liver, or other organs. Monoamine oxidase is important in regulating the metabolic degradation of catecholamines and serotonin in neural or target tissues. Hepatic monoamine oxidase has a crucial defensive role in inactivating circulating monoamines or those, such as tyramine, that originate in the gut and are absorbed into the portal circulation. (From Goodman and Gilman's, The Pharmacological Basis of Therapeutics, 8th ed, p415) EC 1.4.3.4. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monoclonal antibodies: Laboratory-produced substances that can locate and bind to cancer cells wherever they are in the body. Many monoclonal antibodies are used in cancer detection or therapy; each one recognizes a different protein on certain cancer cells. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to a tumor. [NIH] Monocytes: Large, phagocytic mononuclear leukocytes produced in the vertebrate bone marrow and released into the blood; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. [NIH] Mononuclear: A cell with one nucleus. [NIH] Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Morula: The early embryo at the developmental stage in which the blastomeres, resulting from repeated mitotic divisions of the fertilized ovum, form a compact mass. [NIH] Motility: The ability to move spontaneously. [EU] Motor Skills: Performance of complex motor acts. [NIH] Mucinous: Containing or resembling mucin, the main compound in mucus. [NIH] Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucositis: A complication of some cancer therapies in which the lining of the digestive system becomes inflamed. Often seen as sores in the mouth. [NIH] Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [NIH] Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Muscle relaxant: An agent that specifically aids in reducing muscle tension, as those acting

Dictionary 367

at the polysynaptic neurons of motor nerves (e.g. meprobamate) or at the myoneural junction (curare and related compounds). [EU] Muscular Atrophy: Derangement in size and number of muscle fibers occurring with aging, reduction in blood supply, or following immobilization, prolonged weightlessness, malnutrition, and particularly in denervation. [NIH] Muscular Dystrophies: A general term for a group of inherited disorders which are characterized by progressive degeneration of skeletal muscles. [NIH] Mustard Gas: Severe irritant and vesicant of skin, eyes, and lungs. It may cause blindness and lethal lung edema and was formerly used as a war gas. The substance has been proposed as a cytostatic and for treatment of psoriasis. It has been listed as a known carcinogen in the Fourth Annual Report on Carcinogens (NTP-85-002, 1985) (Merck, 11th ed). [NIH] Mutagenic: Inducing genetic mutation. [EU] Mutagenicity: Ability to damage DNA, the genetic material; the power to cause mutations. [NIH]

Mycosis: Any disease caused by a fungus. [EU] Mydriatic: 1. Dilating the pupil. 2. Any drug that dilates the pupil. [EU] Myelin: The fatty substance that covers and protects nerves. [NIH] Myeloma: Cancer that arises in plasma cells, a type of white blood cell. [NIH] Myocardial infarction: Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Myocardial Ischemia: A disorder of cardiac function caused by insufficient blood flow to the muscle tissue of the heart. The decreased blood flow may be due to narrowing of the coronary arteries (coronary arteriosclerosis), to obstruction by a thrombus (coronary thrombosis), or less commonly, to diffuse narrowing of arterioles and other small vessels within the heart. Severe interruption of the blood supply to the myocardial tissue may result in necrosis of cardiac muscle (myocardial infarction). [NIH] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myoglobin: A conjugated protein which is the oxygen-transporting pigment of muscle. It is made up of one globin polypeptide chain and one heme group. [NIH] Myometrium: The smooth muscle coat of the uterus, which forms the main mass of the organ. [NIH] Myosin: Chief protein in muscle and the main constituent of the thick filaments of muscle fibers. In conjunction with actin, it is responsible for the contraction and relaxation of muscles. [NIH] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] Naive: Used to describe an individual who has never taken a certain drug or class of drugs (e. g., AZT-naive, antiretroviral-naive), or to refer to an undifferentiated immune system cell. [NIH]

Narcolepsy: A condition of unknown cause characterized by a periodic uncontrollable tendency to fall asleep. [NIH] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense

368

Estrogen

pain, food poisoning, and various enteroviruses. [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Need: A state of tension or dissatisfaction felt by an individual that impels him to action toward a goal he believes will satisfy the impulse. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Nephrolithiasis: Kidney stones. [NIH] Nephropathy: Disease of the kidneys. [EU] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Nerve Growth Factor: Nerve growth factor is the first of a series of neurotrophic factors that were found to influence the growth and differentiation of sympathetic and sensory neurons. It is comprised of alpha, beta, and gamma subunits. The beta subunit is responsible for its growth stimulating activity. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers or strands. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neural Pathways: Neural tracts connecting one part of the nervous system with another. [NIH]

Neural tube defects: These defects include problems stemming from fetal development of the spinal cord, spine, brain, and skull, and include birth defects such as spina bifida, anencephaly, and encephalocele. Neural tube defects occur early in pregnancy at about 4 to 6 weeks, usually before a woman knows she is pregnant. Many babies with neural tube defects have difficulty walking and with bladder and bowel control. [NIH] Neurodegenerative Diseases: Hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral nervous system structures. [NIH] Neuroendocrine: Having to do with the interactions between the nervous system and the endocrine system. Describes certain cells that release hormones into the blood in response to stimulation of the nervous system. [NIH] Neuroendocrinology: The study of the anatomical and functional relationships between the nervous system and the endocrine system. [NIH] Neuromuscular: Pertaining to muscles and nerves. [EU] Neuromuscular Junction: The synapse between a neuron and a muscle. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU]

Dictionary 369

Neuronal Plasticity: The capacity of the nervous system to change its reactivity as the result of successive activations. [NIH] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropeptide: A member of a class of protein-like molecules made in the brain. Neuropeptides consist of short chains of amino acids, with some functioning as neurotransmitters and some functioning as hormones. [NIH] Neuropsychological Tests: Tests designed to assess neurological function associated with certain behaviors. They are used in diagnosing brain dysfunction or damage and central nervous system disorders or injury. [NIH] Neurotoxic: Poisonous or destructive to nerve tissue. [EU] Neurotoxicity: The tendency of some treatments to cause damage to the nervous system. [NIH]

Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Neurotrophins: A nerve growth factor. [NIH] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Niacin: Water-soluble vitamin of the B complex occurring in various animal and plant tissues. Required by the body for the formation of coenzymes NAD and NADP. Has pellagra-curative, vasodilating, and antilipemic properties. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH] Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Nocturia: Excessive urination at night. [EU] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through

370

Estrogen

the kidneys. [NIH] Nuclear Matrix: The fibrogranular network of residual structural elements within which are immersed both chromatin and ribonucleoproteins. It extends throughout the nuclear interior from the nucleolus to the nuclear pore complexes along the nuclear periphery. [NIH] Nuclear Pore: An opening through the nuclear envelope formed by the nuclear pore complex which transports nuclear proteins or RNA into or out of the cell nucleus and which, under some conditions, acts as an ion channel. [NIH] Nuclear Proteins: Proteins found in the nucleus of a cell. Do not confuse with nucleoproteins which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleic Acid Hybridization: The process whereby two single-stranded polynucleotides form a double-stranded molecule, with hydrogen bonding between the complementary bases in the two strains. [NIH] Nucleolus: A small dense body (sub organelle) within the nucleus of eukaryotic cells, visible by phase contrast and interference microscopy in live cells throughout interphase. Contains RNA and protein and is the site of synthesis of ribosomal RNA. [NIH] Nucleoproteins: Proteins conjugated with nucleic acids. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleus Accumbens: Collection of pleomorphic cells in the caudal part of the anterior horn of the lateral ventricle, in the region of the olfactory tubercle, lying between the head of the caudate nucleus and the anterior perforated substance. It is part of the so-called ventral striatum, a composite structure considered part of the basal ganglia. [NIH] Observational study: An epidemiologic study that does not involve any intervention, experimental or otherwise. Such a study may be one in which nature is allowed to take its course, with changes in one characteristic being studied in relation to changes in other characteristics. Analytical epidemiologic methods, such as case-control and cohort study designs, are properly called observational epidemiology because the investigator is observing without intervention other than to record, classify, count, and statistically analyze results. [NIH] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Oculomotor: Cranial nerve III. It originate from the lower ventral surface of the midbrain and is classified as a motor nerve. [NIH] Odds Ratio: The ratio of two odds. The exposure-odds ratio for case control data is the ratio of the odds in favor of exposure among cases to the odds in favor of exposure among noncases. The disease-odds ratio for a cohort or cross section is the ratio of the odds in favor of disease among the exposed to the odds in favor of disease among the unexposed. The prevalence-odds ratio refers to an odds ratio derived cross-sectionally from studies of prevalent cases. [NIH] Oestrogen: A generic term for oestrus-producing steroid compounds; the female sex hormones. In humans, oestrogen is formed in the ovary, possibly the adrenal cortex, the

Dictionary 371

testis, and the foetoplacental unit; it has various functions in both sexes. It is responsible for the development of the female secondary sex characteristics, and during the menstrual cycle it acts on the female genitalia to produce an environment suitable for the fertilization, implantation, and nutrition of the early embryo. Oestrogen is used in oral contraceptives and as a palliative in cancer of the breast after menopause and cancer of the prostate; other uses include the relief of the discomforts of menopause, inhibition of lactation, and treatment of osteoporosis, threatened abortion, and various functional ovarian disorders. [EU]

Office Visits: Visits made by patients to health service providers' offices for diagnosis, treatment, and follow-up. [NIH] Ointments: Semisolid preparations used topically for protective emollient effects or as a vehicle for local administration of medications. Ointment bases are various mixtures of fats, waxes, animal and plant oils and solid and liquid hydrocarbons. [NIH] Oligonucleotide Probes: Synthetic or natural oligonucleotides used in hybridization studies in order to identify and study specific nucleic acid fragments, e.g., DNA segments near or within a specific gene locus or gene. The probe hybridizes with a specific mRNA, if present. Conventional techniques used for testing for the hybridization product include dot blot assays, Southern blot assays, and DNA:RNA hybrid-specific antibody tests. Conventional labels for the probe include the radioisotope labels 32P and 125I and the chemical label biotin. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Oncology: The study of cancer. [NIH] On-line: A sexually-reproducing population derived from a common parentage. [NIH] Oophorectomy: Surgery to remove one or both ovaries. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Operon: The genetic unit consisting of a feedback system under the control of an operator gene, in which a structural gene transcribes its message in the form of mRNA upon blockade of a repressor produced by a regulator gene. Included here is the attenuator site of bacterial operons where transcription termination is regulated. [NIH] Ophthalmology: A surgical specialty concerned with the structure and function of the eye and the medical and surgical treatment of its defects and diseases. [NIH] Opsin: A protein formed, together with retinene, by the chemical breakdown of metarhodopsin. [NIH] Optic Chiasm: The X-shaped structure formed by the meeting of the two optic nerves. At the optic chiasm the fibers from the medial part of each retina cross to project to the other side of the brain while the lateral retinal fibers continue on the same side. As a result each half of the brain receives information about the contralateral visual field from both eyes. [NIH]

Optic Disk: The portion of the optic nerve seen in the fundus with the ophthalmoscope. It is formed by the meeting of all the retinal ganglion cell axons as they enter the optic nerve. [NIH]

Oral Health: The optimal state of the mouth and normal functioning of the organs of the mouth without evidence of disease. [NIH] Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the

372

Estrogen

organ. [NIH] Orgasm: The crisis of sexual excitement in either humans or animals. [NIH] Osmotic: Pertaining to or of the nature of osmosis (= the passage of pure solvent from a solution of lesser to one of greater solute concentration when the two solutions are separated by a membrane which selectively prevents the passage of solute molecules, but is permeable to the solvent). [EU] Ossicles: The hammer, anvil and stirrup, the small bones of the middle ear, which transmit the vibrations from the tympanic membrane to the oval window. [NIH] Ossification: The formation of bone or of a bony substance; the conversion of fibrous tissue or of cartilage into bone or a bony substance. [EU] Osteoarthritis: A progressive, degenerative joint disease, the most common form of arthritis, especially in older persons. The disease is thought to result not from the aging process but from biochemical changes and biomechanical stresses affecting articular cartilage. In the foreign literature it is often called osteoarthrosis deformans. [NIH] Osteoclasts: A large multinuclear cell associated with the absorption and removal of bone. An odontoclast, also called cementoclast, is cytomorphologically the same as an osteoclast and is involved in cementum resorption. [NIH] Osteogenesis: The histogenesis of bone including ossification. It occurs continuously but particularly in the embryo and child and during fracture repair. [NIH] Osteogenic sarcoma: A malignant tumor of the bone. Also called osteosarcoma. [NIH] Osteoporosis: Reduction of bone mass without alteration in the composition of bone, leading to fractures. Primary osteoporosis can be of two major types: postmenopausal osteoporosis and age-related (or senile) osteoporosis. [NIH] Osteosarcoma: A cancer of the bone that affects primarily children and adolescents. Also called osteogenic sarcoma. [NIH] Otosclerosis: The formation of spongy bone in the labyrinth capsule. The ossicles can become fixed and unable to transmit sound vibrations, thereby causing deafness. [NIH] Outpatient: A patient who is not an inmate of a hospital but receives diagnosis or treatment in a clinic or dispensary connected with the hospital. [NIH] Ovalbumin: An albumin obtained from the white of eggs. It is a member of the serpin superfamily. [NIH] Ovarian Follicle: Spheroidal cell aggregation in the ovary containing an ovum. It consists of an external fibro-vascular coat, an internal coat of nucleated cells, and a transparent, albuminous fluid in which the ovum is suspended. [NIH] Ovariectomy: The surgical removal of one or both ovaries. [NIH] Ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. [NIH] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overdose: An accidental or deliberate dose of a medication or street drug that is in excess of what is normally used. [NIH] Overweight: An excess of body weight but not necessarily body fat; a body mass index of 25 to 29.9 kg/m2. [NIH] Ovulation: The discharge of a secondary oocyte from a ruptured graafian follicle. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH]

Dictionary 373

Ovum Implantation: Endometrial implantation of the blastocyst. [NIH] Oxalate: A chemical that combines with calcium in urine to form the most common type of kidney stone (calcium oxalate stone). [NIH] Oxalic Acid: A strong dicarboxylic acid occurring in many plants and vegetables. It is produced in the body by metabolism of glyoxylic acid or ascorbic acid. It is not metabolized but excreted in the urine. It is used as an analytical reagent and general reducing agent. [NIH] Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

Oxidation-Reduction: A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). [NIH] Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). [NIH] Oxytocin: A nonapeptide posterior pituitary hormone that causes uterine contractions and stimulates lactation. [NIH] Pachymeningitis: Inflammation of the dura mater of the brain, the spinal cord or the optic nerve. [NIH] Paclitaxel: Antineoplastic agent isolated from the bark of the Pacific yew tree, Taxus brevifolia. Paclitaxel stabilizes microtubules in their polymerized form and thus mimics the action of the proto-oncogene proteins c-mos. [NIH] Palindrome: In genetic terms a DNA sequence which is the same (or very similar) when complementary strands are read in opposite directions. It has the property of rotational (dyad) symmetry. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] Pancreatic Juice: The fluid containing digestive enzymes secreted by the pancreas in response to food in the duodenum. [NIH] Pancreatitis: Acute or chronic inflammation of the pancreas, which may be asymptomatic or symptomatic, and which is due to autodigestion of a pancreatic tissue by its own enzymes. It is caused most often by alcoholism or biliary tract disease; less commonly it may be associated with hyperlipaemia, hyperparathyroidism, abdominal trauma (accidental or operative injury), vasculitis, or uraemia. [EU] Panic: A state of extreme acute, intense anxiety and unreasoning fear accompanied by disorganization of personality function. [NIH]

374

Estrogen

Panic Disorder: A type of anxiety disorder characterized by unexpected panic attacks that last minutes or, rarely, hours. Panic attacks begin with intense apprehension, fear or terror and, often, a feeling of impending doom. Symptoms experienced during a panic attack include dyspnea or sensations of being smothered; dizziness, loss of balance or faintness; choking sensations; palpitations or accelerated heart rate; shakiness; sweating; nausea or other form of abdominal distress; depersonalization or derealization; paresthesias; hot flashes or chills; chest discomfort or pain; fear of dying and fear of not being in control of oneself or going crazy. Agoraphobia may also develop. Similar to other anxiety disorders, it may be inherited as an autosomal dominant trait. [NIH] Papilla: A small nipple-shaped elevation. [NIH] Papillary: Pertaining to or resembling papilla, or nipple. [EU] Papillomavirus: A genus of Papovaviridae causing proliferation of the epithelium, which may lead to malignancy. A wide range of animals are infected including humans, chimpanzees, cattle, rabbits, dogs, and horses. [NIH] Paracoccidioidomycosis: A mycosis affecting the skin, mucous membranes, lymph nodes, and internal organs. It is caused by Paracoccidioides brasiliensis. It is also called paracoccidioidal granuloma. Superficial resemblance of P. brasiliensis to Blastomyces brasiliensis (blastomyces) may cause misdiagnosis. [NIH] Paralysis: Loss of ability to move all or part of the body. [NIH] Parathyroid: 1. Situated beside the thyroid gland. 2. One of the parathyroid glands. 3. A sterile preparation of the water-soluble principle(s) of the parathyroid glands, ad-ministered parenterally as an antihypocalcaemic, especially in the treatment of acute hypoparathyroidism with tetany. [EU] Parathyroid Glands: Two small paired endocrine glands in the region of the thyroid gland. They secrete parathyroid hormone and are concerned with the metabolism of calcium and phosphorus. [NIH] Parathyroid hormone: A substance made by the parathyroid gland that helps the body store and use calcium. Also called parathormone, parathyrin, or PTH. [NIH] Parietal: 1. Of or pertaining to the walls of a cavity. 2. Pertaining to or located near the parietal bone, as the parietal lobe. [EU] Parietal Lobe: Upper central part of the cerebral hemisphere. [NIH] Parkinsonism: A group of neurological disorders characterized by hypokinesia, tremor, and muscular rigidity. [EU] Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Parturition: The act or process of given birth to a child. [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]

Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathologies: The study of abnormality, especially the study of diseases. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH]

Dictionary 375

Patient Education: The teaching or training of patients concerning their own health needs. [NIH]

Pectins: High molecular weight polysaccharides present in the cell walls of all plants. Pectins cement cell walls together. They are used as emulsifiers and stabilizers in the food industry. They have been tried for a variety of therpeutic uses including as antidiarreals, where they are now generally considered ineffective, and in the treatment of hypercholesterolemia. [NIH] Pelvic: Pertaining to the pelvis. [EU] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] Pemphigus: Group of chronic blistering diseases characterized histologically by acantholysis and blister formation within the epidermis. [NIH] Penicillin: An antibiotic drug used to treat infection. [NIH] Penis: The external reproductive organ of males. It is composed of a mass of erectile tissue enclosed in three cylindrical fibrous compartments. Two of the three compartments, the corpus cavernosa, are placed side-by-side along the upper part of the organ. The third compartment below, the corpus spongiosum, houses the urethra. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide T: N-(N-(N(2)-(N-(N-(N-(N-D-Alanyl L-seryl)-L-threonyl)-L-threonyl) L-threonyl)L-asparaginyl)-L-tyrosyl) L-threonine. Octapeptide sharing sequence homology with HIV envelope protein gp120. It is potentially useful as antiviral agent in AIDS therapy. The core pentapeptide sequence, TTNYT, consisting of amino acids 4-8 in peptide T, is the HIV envelope sequence required for attachment to the CD4 receptor. [NIH] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Pericardium: The fibroserous sac surrounding the heart and the roots of the great vessels. [NIH]

Perimenopausal: The time of a woman's life when menstrual periods become irregular. Refers to the time near menopause. [NIH] Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously defined as beginning with completion of the twentieth to twenty-eighth week of gestation and ending 7 to 28 days after birth. [EU] Periodontal disease: Disease involving the supporting structures of the teeth (as the gums and periodontal membranes). [NIH] Periodontal disease: Disease involving the supporting structures of the teeth (as the gums and periodontal membranes). [NIH] Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Peritoneal: Having to do with the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Peritoneal Dialysis: Dialysis fluid being introduced into and removed from the peritoneal

376

Estrogen

cavity as either a continuous or an intermittent procedure. [NIH] Perivascular: Situated around a vessel. [EU] Pesticides: Chemicals used to destroy pests of any sort. The concept includes fungicides (industrial fungicides), insecticides, rodenticides, etc. [NIH] PH: The symbol relating the hydrogen ion (H+) concentration or activity of a solution to that of a given standard solution. Numerically the pH is approximately equal to the negative logarithm of H+ concentration expressed in molarity. pH 7 is neutral; above it alkalinity increases and below it acidity increases. [EU] Phagocytosis: The engulfing of microorganisms, other cells, and foreign particles by phagocytic cells. [NIH] Phallic: Pertaining to the phallus, or penis. [EU] Pharmaceutical Preparations: Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form. [NIH] Pharmaceutical Solutions: Homogeneous liquid preparations that contain one or more chemical substances dissolved, i.e., molecularly dispersed, in a suitable solvent or mixture of mutually miscible solvents. For reasons of their ingredients, method of preparation, or use, they do not fall into another group of products. [NIH] Pharmacist: A person trained to prepare and distribute medicines and to give information about them. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharynx: The hollow tube about 5 inches long that starts behind the nose and ends at the top of the trachea (windpipe) and esophagus (the tube that goes to the stomach). [NIH] Phenazopyridine: A local anesthetic that has been used in urinary tract disorders. Its use is limited by problems with toxicity (primarily blood disorders) and potential carcinogenicity. [NIH]

Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenyl: Ingredient used in cold and flu remedies. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phenylephrine: An alpha-adrenergic agonist used as a mydriatic, nasal decongestant, and cardiotonic agent. [NIH] Phenylpropanolamine: A sympathomimetic that acts mainly by causing release of norepinephrine but also has direct agonist activity at some adrenergic receptors. It is most commonly used as a nasal vasoconstrictor and an appetite depressant. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for

Dictionary 377

the body's cells.) [NIH] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylates: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Photocoagulation: Using a special strong beam of light (laser) to seal off bleeding blood vessels such as in the eye. The laser can also burn away blood vessels that should not have grown in the eye. This is the main treatment for diabetic retinopathy. [NIH] Photodynamic therapy: Treatment with drugs that become active when exposed to light. These drugs kill cancer cells. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]

Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Pigments: Any normal or abnormal coloring matter in plants, animals, or micro-organisms. [NIH]

Pilot study: The initial study examining a new method or treatment. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH] Placenta: A highly vascular fetal organ through which the fetus absorbs oxygen and other nutrients and excretes carbon dioxide and other wastes. It begins to form about the eighth day of gestation when the blastocyst adheres to the decidua. [NIH] Placental Insufficiency: Failure of the placenta to deliver an adequate supply of nutrients and oxygen to the fetus. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma protein: One of the hundreds of different proteins present in blood plasma, including carrier proteins ( such albumin, transferrin, and haptoglobin), fibrinogen and other coagulation factors, complement components, immunoglobulins, enzyme inhibitors, precursors of substances such as angiotension and bradykinin, and many other types of proteins. [EU] Plasmapheresis: Procedure whereby plasma is separated and extracted from anticoagulated whole blood and the red cells retransfused to the donor. Plasmapheresis is also employed for therapeutic use. [NIH] Plasticity: In an individual or a population, the capacity for adaptation: a) through gene changes (genetic plasticity) or b) through internal physiological modifications in response to changes of environment (physiological plasticity). [NIH]

378

Estrogen

Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelet-Derived Growth Factor: Mitogenic peptide growth hormone carried in the alphagranules of platelets. It is released when platelets adhere to traumatized tissues. Connective tissue cells near the traumatized region respond by initiating the process of replication. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Platinum: Platinum. A heavy, soft, whitish metal, resembling tin, atomic number 78, atomic weight 195.09, symbol Pt. (From Dorland, 28th ed) It is used in manufacturing equipment for laboratory and industrial use. It occurs as a black powder (platinum black) and as a spongy substance (spongy platinum) and may have been known in Pliny's time as "alutiae". [NIH] Pleated: Particular three-dimensional pattern of amyloidoses. [NIH] Pleomorphic: Occurring in various distinct forms. In terms of cells, having variation in the size and shape of cells or their nuclei. [NIH] Pneumonia: Inflammation of the lungs. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Polycystic: An inherited disorder characterized by many grape-like clusters of fluid-filled cysts that make both kidneys larger over time. These cysts take over and destroy working kidney tissue. PKD may cause chronic renal failure and end-stage renal disease. [NIH] Polyethylene: A vinyl polymer made from ethylene. It can be branched or linear. Branched or low-density polyethylene is tough and pliable but not to the same degree as linear polyethylene. Linear or high-density polyethylene has a greater hardness and tensile strength. Polyethylene is used in a variety of products, including implants and prostheses. [NIH]

Polyethylene Glycols: Alpha-Hydro-omega-hydroxypoly(oxy-1,2-ethanediyls). Additional polymers of ethylene oxide and water and their ethers. They vary in consistency from liquid to solid, depending on the molecular weight, indicated by a number following the name. Used as surfactants in industry, including foods, cosmetics and pharmaceutics; in biomedicine, as dispersing agents, solvents, ointment and suppository bases, vehicles, tablet excipients. Some specific groups are lauromagrogols, nonoxynols, octoxynols and poloxamers. [NIH] Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymers: Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., polypeptides, proteins, plastics). [NIH] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH]

Dictionary 379

Polyposis: The development of numerous polyps (growths that protrude from a mucous membrane). [NIH] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Polyunsaturated fat: An unsaturated fat found in greatest amounts in foods derived from plants, including safflower, sunflower, corn, and soybean oils. [NIH] Porphyrins: A group of compounds containing the porphin structure, four pyrrole rings connected by methine bridges in a cyclic configuration to which a variety of side chains are attached. The nature of the side chain is indicated by a prefix, as uroporphyrin, hematoporphyrin, etc. The porphyrins, in combination with iron, form the heme component in biologically significant compounds such as hemoglobin and myoglobin. [NIH] Portal Vein: A short thick vein formed by union of the superior mesenteric vein and the splenic vein. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-synaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potassium Channels: Cell membrane glycoproteins selective for potassium ions. [NIH] Potentiate: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiating: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Precancerous: A term used to describe a condition that may (or is likely to) become cancer. Also called premalignant. [NIH] Precipitating Factors: Factors associated with the definitive onset of a disease, illness, accident, behavioral response, or course of action. Usually one factor is more important or more obviously recognizable than others, if several are involved, and one may often be regarded as "necessary". Examples include exposure to specific disease; amount or level of an infectious organism, drug, or noxious agent, etc. [NIH]

380

Estrogen

Preclinical: Before a disease becomes clinically recognizable. [EU] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Prednisolone: A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states. [NIH] Prednisone: A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. [NIH] Preeclampsia: A toxaemia of late pregnancy characterized by hypertension, edema, and proteinuria, when convulsions and coma are associated, it is called eclampsia. [EU] Prefrontal Cortex: The rostral part of the frontal lobe, bounded by the inferior precentral fissure in humans, which receives projection fibers from the mediodorsal nucleus of the thalamus. The prefrontal cortex receives afferent fibers from numerous structures of the diencephalon, mesencephalon, and limbic system as well as cortical afferents of visual, auditory, and somatic origin. [NIH] Pregnancy Outcome: Results of conception and ensuing pregnancy, including live birth, stillbirth, spontaneous abortion, induced abortion. The outcome may follow natural or artificial insemination or any of the various reproduction techniques, such as embryo transfer or fertilization in vitro. [NIH] Pregnenolone: Steroid hormone. [NIH] Premalignant: A term used to describe a condition that may (or is likely to) become cancer. Also called precancerous. [NIH] Premarin: A hormone replacement therapy drug developed by AHP (USA). [NIH] Premenopausal: Refers to the time before menopause. Menopause is the time of life when a women's menstrual periods stop permanently; also called "change of life." [NIH] Premenstrual: Occurring before menstruation. [EU] Premenstrual Syndrome: A syndrome occurring most often during the last week of the menstrual cycle and ending soon after the onset of menses. Some of the symptoms are emotional instability, insomnia, headache, nausea, vomiting, abdominal distension, and painful breasts. [NIH] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Preoptic Area: Region of hypothalamus between the anterior commissure and optic chiasm. [NIH]

Presynaptic: Situated proximal to a synapse, or occurring before the synapse is crossed. [EU] Presynaptic Terminals: The distal terminations of axons which are specialized for the release of neurotransmitters. Also included are varicosities along the course of axons which have similar specializations and also release transmitters. Presynaptic terminals in both the central and peripheral nervous systems are included. [NIH] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Primary tumor: The original tumor. [NIH] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH]

Dictionary 381

Proenzyme: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH] Progeny: The offspring produced in any generation. [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] Progesterone receptor positive: Breast cancer cells that have a protein (receptor molecule) to which progesterone will attach. Breast cancer cells that are PR+ need the hormone progesterone to grow and will usually respond to hormonal therapy. [NIH] Progestogen: A term applied to any substance possessing progestational activity. [EU] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Prolactin: Pituitary lactogenic hormone. A polypeptide hormone with a molecular weight of about 23,000. It is essential in the induction of lactation in mammals at parturition and is synergistic with estrogen. The hormone also brings about the release of progesterone from lutein cells, which renders the uterine mucosa suited for the embedding of the ovum should fertilization occur. [NIH] Proliferative Retinopathy: A disease of the small blood vessels of the retina of the eye. [NIH] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Promotor: In an operon, a nucleotide sequence located at the operator end which contains all the signals for the correct initiation of genetic transcription by the RNA polymerase holoenzyme and determines the maximal rate of RNA synthesis. [NIH] Prone: Having the front portion of the body downwards. [NIH] Propantheline: A muscarinic antagonist used as an antispasmodic, in rhinitis, in urinary incontinence, and in the treatment of ulcers. At high doses it has nicotinic effects resulting in neuromuscular blocking. [NIH] Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward opposite poles. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostaglandin: Any of a group of components derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway that are extremely potent mediators of a diverse group of physiologic processes. The abbreviation for prostaglandin is PG; specific compounds are designated by adding one of the letters A through I to indicate the type of substituents found on the hydrocarbon skeleton and a subscript (1, 2 or 3) to indicate the number of double bonds in the hydrocarbon skeleton e.g., PGE2. The

382

Estrogen

predominant naturally occurring prostaglandins all have two double bonds and are synthesized from arachidonic acid (5,8,11,14-eicosatetraenoic acid) by the pathway shown in the illustration. The 1 series and 3 series are produced by the same pathway with fatty acids having one fewer double bond (8,11,14-eicosatrienoic acid or one more double bond (5,8,11,14,17-eicosapentaenoic acid) than arachidonic acid. The subscript a or ß indicates the configuration at C-9 (a denotes a substituent below the plane of the ring, ß, above the plane). The naturally occurring PGF's have the a configuration, e.g., PGF2a. All of the prostaglandins act by binding to specific cell-surface receptors causing an increase in the level of the intracellular second messenger cyclic AMP (and in some cases cyclic GMP also). The effect produced by the cyclic AMP increase depends on the specific cell type. In some cases there is also a positive feedback effect. Increased cyclic AMP increases prostaglandin synthesis leading to further increases in cyclic AMP. [EU] Prostaglandins A: (13E,15S)-15-Hydroxy-9-oxoprosta-10,13-dien-1-oic acid (PGA(1)); (5Z,13E,15S)-15-hydroxy-9-oxoprosta-5,10,13-trien-1-oic acid (PGA(2)); (5Z,13E,15S,17Z)-15hydroxy-9-oxoprosta-5,10,13,17-tetraen-1-oic acid (PGA(3)). A group of naturally occurring secondary prostaglandins derived from PGE. PGA(1) and PGA(2) as well as their 19hydroxy derivatives are found in many organs and tissues. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Prostate gland: A gland in the male reproductive system just below the bladder. It surrounds part of the urethra, the canal that empties the bladder, and produces a fluid that forms part of semen. [NIH] Prostatic Hyperplasia: Enlargement or overgrowth of the prostate gland as a result of an increase in the number of its constituent cells. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protease Inhibitors: Compounds which inhibit or antagonize biosynthesis or actions of proteases (endopeptidases). [NIH] Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific proteinbinding measures are often used as assays in diagnostic assessments. [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [NIH] Protein Folding: A rapid biochemical reaction involved in the formation of proteins. It begins even before a protein has been completely synthesized and proceeds through discrete intermediates (primary, secondary, and tertiary structures) before the final structure (quaternary structure) is developed. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino

Dictionary 383

acids determines the shape and function of the protein. [NIH] Protein-Tyrosine Kinase: An enzyme that catalyzes the phosphorylation of tyrosine residues in proteins with ATP or other nucleotides as phosphate donors. EC 2.7.1.112. [NIH] Proteinuria: The presence of protein in the urine, indicating that the kidneys are not working properly. [NIH] Proteoglycan: A molecule that contains both protein and glycosaminoglycans, which are a type of polysaccharide. Proteoglycans are found in cartilage and other connective tissues. [NIH]

Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Proto-Oncogene Proteins: Products of proto-oncogenes. Normally they do not have oncogenic or transforming properties, but are involved in the regulation or differentiation of cell growth. They often have protein kinase activity. [NIH] Proto-Oncogene Proteins c-mos: Cellular proteins encoded by the c-mos genes. They function in the cell cycle to maintain maturation promoting factor in the active state and have protein-serine/threonine kinase activity. Oncogenic transformation can take place when c-mos proteins are expressed at the wrong time. [NIH] Protozoa: A subkingdom consisting of unicellular organisms that are the simplest in the animal kingdom. Most are free living. They range in size from submicroscopic to macroscopic. Protozoa are divided into seven phyla: Sarcomastigophora, Labyrinthomorpha, Apicomplexa, Microspora, Ascetospora, Myxozoa, and Ciliophora. [NIH] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Psoralens: Substances found in many different plants, especially Psoralea corylifolia (Legume). They are used for skin diseases, especially vitiligo and as sunscreens. They interact with nucleic acids and are also used as research tools. Psoralens have a coumarin molecule with a furan ring. [NIH] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychoactive: Those drugs which alter sensation, mood, consciousness or other psychological or behavioral functions. [NIH] Psychological Tests: Standardized tests designed to measure abilities, as in intelligence, aptitude, and achievement tests, or to evaluate personality traits. [NIH] Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Psychomotor: Pertaining to motor effects of cerebral or psychic activity. [EU] Psychophysiology: The study of the physiological basis of human and animal behavior. [NIH]

Puberty: The period during which the secondary sex characteristics begin to develop and

384

Estrogen

the capability of sexual reproduction is attained. [EU] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary Edema: An accumulation of an excessive amount of watery fluid in the lungs, may be caused by acute exposure to dangerous concentrations of irritant gasses. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]

Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Purulent: Consisting of or containing pus; associated with the formation of or caused by pus. [EU] Pyramidal Cells: Projection neurons in the cerebral cortex and the hippocampus. Pyramidal cells have a pyramid-shaped soma with the apex and an apical dendrite pointed toward the pial surface and other dendrites and an axon emerging from the base. The axons may have local collaterals but also project outside their cortical region. [NIH] Pyrazinamide: A pyrazine that is used therapeutically as an antitubercular agent. [NIH] Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [NIH] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Quaternary: 1. Fourth in order. 2. Containing four elements or groups. [EU] Quinones: Hydrocarbon rings which contain two ketone moieties in any position. They can be substituted in any position except at the ketone groups. [NIH] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH]

Dictionary 385

Radioactive: Giving off radiation. [NIH] Radioimmunoassay: Classic quantitative assay for detection of antigen-antibody reactions using a radioactively labeled substance (radioligand) either directly or indirectly to measure the binding of the unlabeled substance to a specific antibody or other receptor system. Nonimmunogenic substances (e.g., haptens) can be measured if coupled to larger carrier proteins (e.g., bovine gamma-globulin or human serum albumin) capable of inducing antibody formation. [NIH] Radioimmunotherapy: Radiotherapy where cytotoxic radionuclides are linked to antibodies in order to deliver toxins directly to tumor targets. Therapy with targeted radiation rather than antibody-targeted toxins (immunotoxins) has the advantage that adjacent tumor cells, which lack the appropriate antigenic determinants, can be destroyed by radiation cross-fire. Radioimmunotherapy is sometimes called targeted radiotherapy, but this latter term can also refer to radionuclides linked to non-immune molecules (radiotherapy). [NIH] Radioisotope: An unstable element that releases radiation as it breaks down. Radioisotopes can be used in imaging tests or as a treatment for cancer. [NIH] Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Radiologist: A doctor who specializes in creating and interpreting pictures of areas inside the body. The pictures are produced with x-rays, sound waves, or other types of energy. [NIH]

Radiology: A specialty concerned with the use of x-ray and other forms of radiant energy in the diagnosis and treatment of disease. [NIH] Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays, gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an antibody or other immunologic molecule, the technique is called radioimmunotherapy. [NIH] Raloxifene: A second generation selective estrogen receptor modulator (SERM) used to prevent osteoporosis in postmenopausal women. It has estrogen agonist effects on bone and cholesterol metabolism but behaves as a complete estrogen antagonist on mammary gland and uterine tissue. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial. [NIH] Randomized Controlled Trials: Clinical trials that involve at least one test treatment and one control treatment, concurrent enrollment and follow-up of the test- and control-treated groups, and in which the treatments to be administered are selected by a random process, such as the use of a random-numbers table. Treatment allocations using coin flips, odd-even numbers, patient social security numbers, days of the week, medical record numbers, or other such pseudo- or quasi-random processes, are not truly randomized and trials employing any of these techniques for patient assignment are designated simply controlled clinical trials. [NIH]

386

Estrogen

Reaction Time: The time from the onset of a stimulus until the organism responds. [NIH] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Receptivity: The condition of the reproductive organs of a female flower that permits effective pollination. [NIH] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Receptor Aggregation: Chemically stimulated aggregation of cell surface receptors, which potentiates the action of the effector cell. [NIH] Receptors, Serotonin: Cell-surface proteins that bind serotonin and trigger intracellular changes which influence the behavior of cells. Several types of serotonin receptors have been recognized which differ in their pharmacology, molecular biology, and mode of action. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Rectal: By or having to do with the rectum. The rectum is the last 8 to 10 inches of the large intestine and ends at the anus. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Reflex: An involuntary movement or exercise of function in a part, excited in response to a stimulus applied to the periphery and transmitted to the brain or spinal cord. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Regurgitation: A backward flowing, as the casting up of undigested food, or the backward flowing of blood into the heart, or between the chambers of the heart when a valve is incompetent. [EU] Relapse: The return of signs and symptoms of cancer after a period of improvement. [NIH] Relative risk: The ratio of the incidence rate of a disease among individuals exposed to a specific risk factor to the incidence rate among unexposed individuals; synonymous with

Dictionary 387

risk ratio. Alternatively, the ratio of the cumulative incidence rate in the exposed to the cumulative incidence rate in the unexposed (cumulative incidence ratio). The term relative risk has also been used synonymously with odds ratio. This is because the odds ratio and relative risk approach each other if the disease is rare ( 5 percent of population) and the number of subjects is large. [NIH] Relaxant: 1. Lessening or reducing tension. 2. An agent that lessens tension. [EU] Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Renal Artery: A branch of the abdominal aorta which supplies the kidneys, adrenal glands and ureters. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Renal pelvis: The area at the center of the kidney. Urine collects here and is funneled into the ureter, the tube that connects the kidney to the bladder. [NIH] Renin: An enzyme which is secreted by the kidney and is formed from prorenin in plasma and kidney. The enzyme cleaves the Leu-Leu bond in angiotensinogen to generate angiotensin I. EC 3.4.23.15. (Formerly EC 3.4.99.19). [NIH] Renin-Angiotensin System: A system consisting of renin, angiotensin-converting enzyme, and angiotensin II. Renin, an enzyme produced in the kidney, acts on angiotensinogen, an alpha-2 globulin produced by the liver, forming angiotensin I. The converting enzyme contained in the lung acts on angiotensin I in the plasma converting it to angiotensin II, the most powerful directly pressor substance known. It causes contraction of the arteriolar smooth muscle and has other indirect actions mediated through the adrenal cortex. [NIH] Repressor: Any of the specific allosteric protein molecules, products of regulator genes, which bind to the operator of operons and prevent RNA polymerase from proceeding into the operon to transcribe messenger RNA. [NIH] Reproduction Techniques: Methods pertaining to the generation of new individuals. [NIH] Reproductive History: An important aggregate factor in epidemiological studies of women's health. The concept usually includes the number and timing of pregnancies and their outcomes, the incidence of breast feeding, and may include age of menarche and menopause, regularity of menstruation, fertility, gynecological or obstetric problems, or contraceptive usage. [NIH] Reproductive system: In women, this system includes the ovaries, the fallopian tubes, the uterus (womb), the cervix, and the vagina (birth canal). The reproductive system in men includes the prostate, the testes, and the penis. [NIH] Research Design: A plan for collecting and utilizing data so that desired information can be obtained with sufficient precision or so that an hypothesis can be tested properly. [NIH] Resorption: The loss of substance through physiologic or pathologic means, such as loss of dentin and cementum of a tooth, or of the alveolar process of the mandible or maxilla. [EU] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Response Elements: Nucleotide sequences, usually upstream, which are recognized by

388

Estrogen

specific regulatory transcription factors, thereby causing gene response to various regulatory agents. These elements may be found in both promotor and enhancer regions. [NIH] Response rate: The percentage of patients whose cancer shrinks or disappears after treatment. [NIH] Restoration: Broad term applied to any inlay, crown, bridge or complete denture which restores or replaces loss of teeth or oral tissues. [NIH] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retinoid: Vitamin A or a vitamin A-like compound. [NIH] Retinol: Vitamin A. It is essential for proper vision and healthy skin and mucous membranes. Retinol is being studied for cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Retinopathy: 1. Retinitis (= inflammation of the retina). 2. Retinosis (= degenerative, noninflammatory condition of the retina). [EU] Retrograde: 1. Moving backward or against the usual direction of flow. 2. Degenerating, deteriorating, or catabolic. [EU] Rheumatism: A group of disorders marked by inflammation or pain in the connective tissue structures of the body. These structures include bone, cartilage, and fat. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] Rhinitis: Inflammation of the mucous membrane of the nose. [NIH] Rhodopsin: A photoreceptor protein found in retinal rods. It is a complex formed by the binding of retinal, the oxidized form of retinol, to the protein opsin and undergoes a series of complex reactions in response to visible light resulting in the transmission of nerve impulses to the brain. [NIH] Ribonuclease: RNA-digesting enzyme. [NIH] Ribonucleoproteins: Proteins conjugated with ribonucleic acids (RNA) or specific RNA. Many viruses are ribonucleoproteins. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [NIH] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH]

Dictionary 389

Rigidity: Stiffness or inflexibility, chiefly that which is abnormal or morbid; rigor. [EU] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Rod: A reception for vision, located in the retina. [NIH] Ryanodine: Insecticidal alkaloid isolated from Ryania speciosa; proposed as a myocardial depressant. [NIH] Saliva: The clear, viscous fluid secreted by the salivary glands and mucous glands of the mouth. It contains mucins, water, organic salts, and ptylin. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Saponin: A substance found in soybeans and many other plants. Saponins may help lower cholesterol and may have anticancer effects. [NIH] Saturated fat: A type of fat found in greatest amounts in foods from animals, such as fatty cuts of meat, poultry with the skin, whole-milk dairy products, lard, and in some vegetable oils, including coconut, palm kernel, and palm oils. Saturated fat raises blood cholesterol more than anything else eaten. On a Step I Diet, no more than 8 to 10 percent of total calories should come from saturated fat, and in the Step II Diet, less than 7 percent of the day's total calories should come from saturated fat. [NIH] Scans: Pictures of structures inside the body. Scans often used in diagnosing, staging, and monitoring disease include liver scans, bone scans, and computed tomography (CT) or computerized axial tomography (CAT) scans and magnetic resonance imaging (MRI) scans. In liver scanning and bone scanning, radioactive substances that are injected into the bloodstream collect in these organs. A scanner that detects the radiation is used to create pictures. In CT scanning, an x-ray machine linked to a computer is used to produce detailed pictures of organs inside the body. MRI scans use a large magnet connected to a computer to create pictures of areas inside the body. [NIH] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Scleroproteins: Simple proteins characterized by their insolubility and fibrous structure. Within the body, they perform a supportive or protective function. [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Sebaceous: Gland that secretes sebum. [NIH] Sebaceous gland: Gland that secretes sebum. [NIH] Secondary tumor: Cancer that has spread from the organ in which it first appeared to another organ. For example, breast cancer cells may spread (metastasize) to the lungs and cause the growth of a new tumor. When this happens, the disease is called metastatic breast cancer, and the tumor in the lungs is called a secondary tumor. Also called secondary

390

Estrogen

cancer. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Sedative: 1. Allaying activity and excitement. 2. An agent that allays excitement. [EU] Sedentary: 1. Sitting habitually; of inactive habits. 2. Pertaining to a sitting posture. [EU] Sediment: A precipitate, especially one that is formed spontaneously. [EU] Segmental: Describing or pertaining to a structure which is repeated in similar form in successive segments of an organism, or which is undergoing segmentation. [NIH] Segmentation: The process by which muscles in the intestines move food and wastes through the body. [NIH] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Selective estrogen receptor modulator: SERM. A drug that acts like estrogen on some tissues, but blocks the effect of estrogen on other tissues. Tamoxifen and raloxifene are SERMs. [NIH] Selegiline: A selective, irreversible inhibitor of Type B monoamine oxidase. It is used in newly diagnosed patients with Parkinson's disease. It may slow progression of the clinical disease and delay the requirement for levodopa therapy. It also may be given with levodopa upon onset of disability. (From AMA Drug Evaluations Annual, 1994, p385) The compound without isomeric designation is Deprenyl. [NIH] Selenium: An element with the atomic symbol Se, atomic number 34, and atomic weight 78.96. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of glutathione peroxidase. [NIH] Self Care: Performance of activities or tasks traditionally performed by professional health care providers. The concept includes care of oneself or one's family and friends. [NIH] Sella: A deep depression in the shape of a Turkish saddle in the upper surface of the body of the sphenoid bone in the deepest part of which is lodged the hypophysis cerebri. [NIH] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Senescence: The bodily and mental state associated with advancing age. [NIH] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Senility: Old age; the physical and mental deterioration associated with old age. [EU] Sensibility: The ability to receive, feel and appreciate sensations and impressions; the quality of being sensitive; the extend to which a method gives results that are free from false negatives. [NIH] Sensitization: 1. Administration of antigen to induce a primary immune response; priming; immunization. 2. Exposure to allergen that results in the development of hypersensitivity. 3. The coating of erythrocytes with antibody so that they are subject to lysis by complement in the presence of homologous antigen, the first stage of a complement fixation test. [EU]

Dictionary 391

Sequence Homology: The degree of similarity between sequences. Studies of amino acid and nucleotide sequences provide useful information about the genetic relatedness of certain species. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Serum Albumin: A major plasma protein that serves in maintaining the plasma colloidal osmotic pressure and transporting large organic anions. [NIH] Sex Behavior: Sexual activities of humans. [NIH] Sex Behavior, Animal: Sexual activities of animals. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Sex Determination: The biological characteristics which distinguish human beings as female or male. [NIH] Sex Hormone-Binding Globulin: A glycoprotein migrating as a beta-globulin. Its molecular weight, 52,000 or 95,000-115,000, indicates that it exists as a dimer. The protein binds testosterone, dihydrotestosterone, and estradiol in the plasma. Sex hormone-binding protein has the same amino acid sequence as androgen-binding protein. They differ by their sites of synthesis and post-translational oligosacaccharide modifications. [NIH] Sexually Transmitted Diseases: Diseases due to or propagated by sexual contact. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled

392

Estrogen

to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skin graft: Skin that is moved from one part of the body to another. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smoking Cessation: Discontinuation of the habit of smoking, the inhaling and exhaling of tobacco smoke. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Smooth Muscle Tumor: A tumor composed of smooth muscle tissue, as opposed to leiomyoma, a tumor derived from smooth muscle. [NIH] Sneezing: Sudden, forceful, involuntary expulsion of air from the nose and mouth caused by irritation to the mucous membranes of the upper respiratory tract. [NIH] Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Social Security: Government sponsored social insurance programs. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] Solitary Nucleus: Gray matter located in the dorsomedial part of the medulla oblongata associated with the solitary tract. The solitary nucleus receives inputs from most organ systems including the terminations of the facial, glossopharyngeal, and vagus nerves. It is a major coordinator of autonomic nervous system regulation of cardiovascular, respiratory, gustatory, gastrointestinal, and chemoreceptive aspects of homeostasis. The solitary nucleus is also notable for the large number of neurotransmitters which are found therein. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the

Dictionary 393

axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Somatic mutations: Alterations in DNA that occur after conception. Somatic mutations can occur in any of the cells of the body except the germ cells (sperm and egg) and therefore are not passed on to children. These alterations can (but do not always) cause cancer or other diseases. [NIH] Somatostatin: A polypeptide hormone produced in the hypothalamus, and other tissues and organs. It inhibits the release of human growth hormone, and also modulates important physiological functions of the kidney, pancreas, and gastrointestinal tract. Somatostatin receptors are widely expressed throughout the body. Somatostatin also acts as a neurotransmitter in the central and peripheral nervous systems. [NIH] Sound wave: An alteration of properties of an elastic medium, such as pressure, particle displacement, or density, that propagates through the medium, or a superposition of such alterations. [NIH] Soy Proteins: Proteins which are present in or isolated from soybeans. [NIH] Soybean Oil: Oil from soybean or soybean plant. [NIH] Spasm: An involuntary contraction of a muscle or group of muscles. Spasms may involve skeletal muscle or smooth muscle. [NIH] Spastic: 1. Of the nature of or characterized by spasms. 2. Hypertonic, so that the muscles are stiff and the movements awkward. 3. A person exhibiting spasticity, such as occurs in spastic paralysis or in cerebral palsy. [EU] Spasticity: A state of hypertonicity, or increase over the normal tone of a muscle, with heightened deep tendon reflexes. [EU] Spatial disorientation: Loss of orientation in space where person does not know which way is up. [NIH] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Spermatogenesis: Process of formation and development of spermatozoa, including spermatocytogenesis and spermiogenesis. [NIH] Sphincter: A ringlike band of muscle fibres that constricts a passage or closes a natural orifice; called also musculus sphincter. [EU] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH]

394

Estrogen

Spinous: Like a spine or thorn in shape; having spines. [NIH] Spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. It is located on the left side of the abdomen near the stomach. [NIH] Splenic Vein: Vein formed by the union (at the hilus of the spleen) of several small veins from the stomach, pancreas, spleen and mesentery. [NIH] Spontaneous Abortion: The non-induced birth of an embryo or of fetus prior to the stage of viability at about 20 weeks of gestation. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Squamous: Scaly, or platelike. [EU] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Squamous cells: Flat cells that look like fish scales under a microscope. These cells cover internal and external surfaces of the body. [NIH] Stabilization: The creation of a stable state. [EU] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]

Steel: A tough, malleable, iron-based alloy containing up to, but no more than, two percent carbon and often other metals. It is used in medicine and dentistry in implants and instrumentation. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Stents: Devices that provide support for tubular structures that are being anastomosed or for body cavities during skin grafting. [NIH] Sterile: Unable to produce children. [NIH] Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stillbirth: The birth of a dead fetus or baby. [NIH] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]

Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other

Dictionary 395

excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Streptomycin: O-2-Deoxy-2-(methylamino)-alpha-L-glucopyranosyl-(1-2)-O-5- deoxy-3-Cformyl-alpha-L-lyxofuranosyl-(1-4)-N,N'-bis- (aminoiminomethyl)-D-streptamine. Antibiotic substance produced by the soil actinomycete Streptomyces griseus. It acts by inhibiting the initiation and elongation processes during protein synthesis. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stress incontinence: An involuntary loss of urine that occurs at the same time that internal abdominal pressure is increased, such as with laughing, sneezing, coughing, or physical activity. [NIH] Stress urinary: Leakage of urine caused by actions--such as coughing, laughing, sneezing, running, or lifting--that place pressure on the bladder from inside the body. Stress urinary incontinence can result from either a fallen bladder or weak sphincter muscles. [NIH] Stria: 1. A streak, or line. 2. A narrow bandlike structure; a general term for such longitudinal collections of nerve fibres in the brain. [EU] Striatum: A higher brain's domain thus called because of its stripes. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Stroma: The middle, thickest layer of tissue in the cornea. [NIH] Stromal: Large, veil-like cell in the bone marrow. [NIH] Stromal Cells: Connective tissue cells of an organ found in the loose connective tissue. These are most often associated with the uterine mucosa and the ovary as well as the hematopoietic system and elsewhere. [NIH] Structure-Activity Relationship: The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Other factors contributing to structure-activity relationship include chemical reactivity, electronic effects, resonance, and inductive effects. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Subiculum: A region of the hippocampus that projects to other areas of the brain. [NIH] Submaxillary: Four to six lymph glands, located between the lower jaw and the submandibular salivary gland. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally

396

Estrogen

conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]

Substrate: A substance upon which an enzyme acts. [EU] Subtrochanteric: Below a trochanter. [NIH] Sulfates: Inorganic salts of sulfuric acid. [NIH] Sulfuric acid: A strong acid that, when concentrated is extemely corrosive to the skin and mucous membranes. It is used in making fertilizers, dyes, electroplating, and industrial explosives. [NIH] Superovulation: Occurrence or induction of release of more ova than are normally released at the same time in a given species. The term applies to both animals and humans. [NIH] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Superoxide Dismutase: An oxidoreductase that catalyzes the reaction between superoxide anions and hydrogen to yield molecular oxygen and hydrogen peroxide. The enzyme protects the cell against dangerous levels of superoxide. EC 1.15.1.1. [NIH] Supplementation: Adding nutrients to the diet. [NIH] Support group: A group of people with similar disease who meet to discuss how better to cope with their cancer and treatment. [NIH] Suppository: A medicated mass adapted for introduction into the rectal, vaginal, or urethral orifice of the body, suppository bases are solid at room temperature but melt or dissolve at body temperature. Commonly used bases are cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol. [EU] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Suppressive: Tending to suppress : effecting suppression; specifically : serving to suppress activity, function, symptoms. [EU] Supraspinal: Above the spinal column or any spine. [NIH] Sweat: The fluid excreted by the sweat glands. It consists of water containing sodium chloride, phosphate, urea, ammonia, and other waste products. [NIH] Sweat Glands: Sweat-producing structures that are embedded in the dermis. Each gland consists of a single tube, a coiled body, and a superficial duct. [NIH] Sympathetic Nervous System: The thoracolumbar division of the autonomic nervous system. Sympathetic preganglionic fibers originate in neurons of the intermediolateral column of the spinal cord and project to the paravertebral and prevertebral ganglia, which in turn project to target organs. The sympathetic nervous system mediates the body's response to stressful situations, i.e., the fight or flight reactions. It often acts reciprocally to the parasympathetic system. [NIH] Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Symphysis: A secondary cartilaginous joint. [NIH]

Dictionary 397

Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Synapse: The region where the processes of two neurons come into close contiguity, and the nervous impulse passes from one to the other; the fibers of the two are intermeshed, but, according to the general view, there is no direct contiguity. [NIH] Synapsis: The pairing between homologous chromosomes of maternal and paternal origin during the prophase of meiosis, leading to the formation of gametes. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Syncytium: A living nucleated tissue without apparent cellular structure; a tissue composed of a mass of nucleated protoplasm without cell boundaries. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Systemic: Affecting the entire body. [NIH] Systemic lupus erythematosus: SLE. A chronic inflammatory connective tissue disease marked by skin rashes, joint pain and swelling, inflammation of the kidneys, inflammation of the fibrous tissue surrounding the heart (i.e., the pericardium), as well as other problems. Not all affected individuals display all of these problems. May be referred to as lupus. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Systolic blood pressure: The maximum pressure in the artery produced as the heart contracts and blood begins to flow. [NIH] Talus: The second largest of the tarsal bones and occupies the middle and upper part of the tarsus. [NIH] Tamoxifen: A first generation selective estrogen receptor modulator (SERM). It acts as an agonist for bone tissue and cholesterol metabolism but is an estrogen antagonist in mammary and uterine. [NIH] Tear Gases: Gases that irritate the eyes, throat, or skin. Severe lacrimation develops upon irritation of the eyes. [NIH] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [NIH] Telomerase: Essential ribonucleoprotein reverse transcriptase that adds telomeric DNA to the ends of eukaryotic chromosomes. Telomerase appears to be repressed in normal human somatic tissues but reactivated in cancer, and thus may be necessary for malignant transformation. EC 2.7.7.-. [NIH] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Tendon: A discrete band of connective tissue mainly composed of parallel bundles of collagenous fibers by which muscles are attached, or two muscles bellies joined. [NIH] Testicle: The male gonad where, in adult life, spermatozoa develop; the testis. [NIH] Testicular: Pertaining to a testis. [EU] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Testosterone: A hormone that promotes the development and maintenance of male sex

398

Estrogen

characteristics. [NIH] Tetany: 1. Hyperexcitability of nerves and muscles due to decrease in concentration of extracellular ionized calcium, which may be associated with such conditions as parathyroid hypofunction, vitamin D deficiency, and alkalosis or result from ingestion of alkaline salts; it is characterized by carpopedal spasm, muscular twitching and cramps, laryngospasm with inspiratory stridor, hyperreflexia and choreiform movements. 2. Tetanus. [EU] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [NIH] Thalamus: Paired bodies containing mostly gray substance and forming part of the lateral wall of the third ventricle of the brain. The thalamus represents the major portion of the diencephalon and is commonly divided into cellular aggregates known as nuclear groups. [NIH]

Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Third Ventricle: A narrow cleft inferior to the corpus callosum, within the diencephalon, between the paired thalami. Its floor is formed by the hypothalamus, its anterior wall by the lamina terminalis, and its roof by ependyma. It communicates with the fourth ventricle by the cerebral aqueduct, and with the lateral ventricles by the interventricular foramina. [NIH] Thorax: A part of the trunk between the neck and the abdomen; the chest. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thromboembolism: Obstruction of a vessel by a blood clot that has been transported from a distant site by the blood stream. [NIH] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]

Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thromboxanes: Physiologically active compounds found in many organs of the body. They are formed in vivo from the prostaglandin endoperoxides and cause platelet aggregation, contraction of arteries, and other biological effects. Thromboxanes are important mediators of the actions of polyunsaturated fatty acids transformed by cyclooxygenase. [NIH] Thymidine: A chemical compound found in DNA. Also used as treatment for mucositis. [NIH]

Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH]

Dictionary 399

Thyroid Gland: A highly vascular endocrine gland consisting of two lobes, one on either side of the trachea, joined by a narrow isthmus; it produces the thyroid hormones which are concerned in regulating the metabolic rate of the body. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Tibia: The second longest bone of the skeleton. It is located on the medial side of the lower leg, articulating with the fibula laterally, the talus distally, and the femur proximally. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Culture: Maintaining or growing of tissue, organ primordia, or the whole or part of an organ in vitro so as to preserve its architecture and/or function (Dorland, 28th ed). Tissue culture includes both organ culture and cell culture. [NIH] Tissue Distribution: Accumulation of a drug or chemical substance in various organs (including those not relevant to its pharmacologic or therapeutic action). This distribution depends on the blood flow or perfusion rate of the organ, the ability of the drug to penetrate organ membranes, tissue specificity, protein binding. The distribution is usually expressed as tissue to plasma ratios. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tome: A zone produced by a number of irregular spaces contained in the outermost layer of denture of the root of a tooth. [NIH] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Tone: 1. The normal degree of vigour and tension; in muscle, the resistance to passive elongation or stretch; tonus. 2. A particular quality of sound or of voice. 3. To make permanent, or to change, the colour of silver stain by chemical treatment, usually with a heavy metal. [EU] Tonus: A state of slight tension usually present in muscles even when they are not undergoing active contraction. [NIH] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures preparatory to specified dental therapeutic and surgical measures. [NIH] Topical: On the surface of the body. [NIH] Toremifene: A first generation selective estrogen receptor modulator (SERM). Like tamoxifen, it is an estrogen agonist for bone tissue and cholesterol metabolism but is antagonistic on mammary and uterine tissue. [NIH] Toxaemia: 1. The condition resulting from the spread of bacterial products (toxins) by the bloodstream. 2. A condition resulting from metabolic disturbances, e.g. toxaemia of pregnancy. [EU] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH]

400

Estrogen

Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Traction: The act of pulling. [NIH] Tragacanth: Powdered exudate from Astragalus gummifer and related plants. It forms gelatinous mass in water. Tragacanth is used as suspending agent, excipient or emulsifier in foods, cosmetics and pharmaceuticals. It has also been used as a bulk-forming laxative. [NIH] Transcriptase: An enzyme which catalyses the synthesis of a complementary mRNA molecule from a DNA template in the presence of a mixture of the four ribonucleotides (ATP, UTP, GTP and CTP). [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transdermal: Entering through the dermis, or skin, as in administration of a drug applied to the skin in ointment or patch form. [EU] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transferases: Transferases are enzymes transferring a group, for example, the methyl group or a glycosyl group, from one compound (generally regarded as donor) to another compound (generally regarded as acceptor). The classification is based on the scheme "donor:acceptor group transferase". (Enzyme Nomenclature, 1992) EC 2. [NIH] Transgenes: Genes that are introduced into an organism using gene transfer techniques. [NIH]

Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Tremor: Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of Parkinson disease. [NIH] Tricyclic: Containing three fused rings or closed chains in the molecular structure. [EU]

Dictionary 401

Triglyceride: A lipid carried through the blood stream to tissues. Most of the body's fat tissue is in the form of triglycerides, stored for use as energy. Triglycerides are obtained primarily from fat in foods. [NIH] Trophoblast: The outer layer of cells of the blastocyst which works its way into the endometrium during ovum implantation and grows rapidly, later combining with mesoderm. [NIH] Truncal: The bilateral dissection of the abdominal branches of the vagus nerve. [NIH] Trypsin: A serine endopeptidase that is formed from trypsinogen in the pancreas. It is converted into its active form by enteropeptidase in the small intestine. It catalyzes hydrolysis of the carboxyl group of either arginine or lysine. EC 3.4.21.4. [NIH] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tubal ligation: An operation to tie the fallopian tubes closed. This procedure prevents pregnancy by blocking the passage of eggs from the ovaries to the uterus. [NIH] Tubercle: A rounded elevation on a bone or other structure. [NIH] Tuberous Sclerosis: A rare congenital disease in which the essential pathology is the appearance of multiple tumors in the cerebrum and in other organs, such as the heart or kidneys. [NIH] Tumor marker: A substance sometimes found in an increased amount in the blood, other body fluids, or tissues and which may mean that a certain type of cancer is in the body. Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. [NIH] Tumor model: A type of animal model which can be used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Tumor Necrosis Factor: Serum glycoprotein produced by activated macrophages and other mammalian mononuclear leukocytes which has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. It mimics the action of endotoxin but differs from it. It has a molecular weight of less than 70,000 kDa. [NIH] Tumor suppressor gene: Genes in the body that can suppress or block the development of cancer. [NIH] Tumorigenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH]

Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] Type 2 diabetes: Usually characterized by a gradual onset with minimal or no symptoms of metabolic disturbance and no requirement for exogenous insulin. The peak age of onset is 50 to 60 years. Obesity and possibly a genetic factor are usually present. [NIH] Tyramine: An indirect sympathomimetic. Tyramine does not directly activate adrenergic receptors, but it can serve as a substrate for adrenergic uptake systems and monoamine oxidase so it prolongs the actions of adrenergic transmitters. It also provokes transmitter release from adrenergic terminals. Tyramine may be a neurotransmitter in some invertebrate nervous systems. [NIH] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH]

402

Estrogen

Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Uncoupling Agents: Chemical agents that uncouple oxidation from phosphorylation in the metabolic cycle so that ATP synthesis does not occur. Included here are those ionophores that disrupt electron transfer by short-circuiting the proton gradient across mitochondrial membranes. [NIH] Uraemia: 1. An excess in the blood of urea, creatinine, and other nitrogenous end products of protein and amino acids metabolism; more correctly referred to as azotemia. 2. In current usage the entire constellation of signs and symptoms of chronic renal failure, including nausea, vomiting anorexia, a metallic taste in the mouth, a uraemic odour of the breath, pruritus, uraemic frost on the skin, neuromuscular disorders, pain and twitching in the muscles, hypertension, edema, mental confusion, and acid-base and electrolyte imbalances. [EU]

Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Ureters: Tubes that carry urine from the kidneys to the bladder. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

Urethritis: Inflammation of the urethra. [EU] Uric: A kidney stone that may result from a diet high in animal protein. When the body breaks down this protein, uric acid levels rise and can form stones. [NIH] Urinalysis: Examination of urine by chemical, physical, or microscopic means. Routine urinalysis usually includes performing chemical screening tests, determining specific gravity, observing any unusual color or odor, screening for bacteriuria, and examining the sediment microscopically. [NIH] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [NIH] Urinary tract infection: An illness caused by harmful bacteria growing in the urinary tract. [NIH]

Urinate: To release urine from the bladder to the outside. [NIH] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Urodynamic: Measures of the bladder's ability to hold and release urine. [NIH] Urogenital: Pertaining to the urinary and genital apparatus; genitourinary. [EU] Urology: A surgical specialty concerned with the study, diagnosis, and treatment of diseases of the urinary tract in both sexes and the genital tract in the male. It includes the specialty of andrology which addresses both male genital diseases and male infertility. [NIH] Uterine Contraction: Contraction of the uterine muscle. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also

Dictionary 403

called the birth canal. [NIH] Vaginal: Of or having to do with the vagina, the birth canal. [NIH] Vaginitis: Inflammation of the vagina characterized by pain and a purulent discharge. [NIH] Vagus Nerve: The 10th cranial nerve. The vagus is a mixed nerve which contains somatic afferents (from skin in back of the ear and the external auditory meatus), visceral afferents (from the pharynx, larynx, thorax, and abdomen), parasympathetic efferents (to the thorax and abdomen), and efferents to striated muscle (of the larynx and pharynx). [NIH] Valves: Flap-like structures that control the direction of blood flow through the heart. [NIH] Varices: Stretched veins such as those that form in the esophagus from cirrhosis. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vascular endothelial growth factor: VEGF. A substance made by cells that stimulates new blood vessel formation. [NIH] Vascular Resistance: An expression of the resistance offered by the systemic arterioles, and to a lesser extent by the capillaries, to the flow of blood. [NIH] Vasculitis: Inflammation of a blood vessel. [NIH] Vasoactive: Exerting an effect upon the calibre of blood vessels. [EU] Vasodilation: Physiological dilation of the blood vessels without anatomic change. For dilation with anatomic change, dilatation, pathologic or aneurysm (or specific aneurysm) is used. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] Vasomotor: 1. Affecting the calibre of a vessel, especially of a blood vessel. 2. Any element or agent that effects the calibre of a blood vessel. [EU] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venoms: Poisonous animal secretions forming fluid mixtures of many different enzymes, toxins, and other substances. These substances are produced in specialized glands and secreted through specialized delivery systems (nematocysts, spines, fangs, etc.) for disabling prey or predator. [NIH] Venous: Of or pertaining to the veins. [EU] Venter: Belly. [NIH] Ventral: 1. Pertaining to the belly or to any venter. 2. Denoting a position more toward the belly surface than some other object of reference; same as anterior in human anatomy. [EU] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vertebrae: A bony unit of the segmented spinal column. [NIH] Vertebral: Of or pertaining to a vertebra. [EU] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Vestibular: Pertaining to or toward a vestibule. In dental anatomy, used to refer to the tooth

404

Estrogen

surface directed toward the vestibule of the mouth. [EU] Vestibule: A small, oval, bony chamber of the labyrinth. The vestibule contains the utricle and saccule, organs which are part of the balancing apparatus of the ear. [NIH] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Villous: Of a surface, covered with villi. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Virilization: The induction or development of male secondary sec characters, especially the induction of such changes in the female, including enlargement of the clitoris, growth of facial and body hair, development of a hairline typical of the male forehead, stimulation of secretion and proliferation of the sebaceous glands (often with acne), and deepening of the voice. Called also masculinization) [EU] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Visceral Afferents: The sensory fibers innervating the viscera. [NIH] Visceral fat: One of the three compartments of abdominal fat. Retroperitoneal and subcutaneous are the other two compartments. [NIH] Vitellogenin: A serum and yolk protein which has been characterized as a calcium-binding glycolipophosphoprotein. It is induced by estrogen or juvenile hormone and is essential for yolk formation in various insect species. [NIH] Vitiligo: A disorder consisting of areas of macular depigmentation, commonly on extensor aspects of extremities, on the face or neck, and in skin folds. Age of onset is often in young adulthood and the condition tends to progress gradually with lesions enlarging and extending until a quiescent state is reached. [NIH] Vitreous: Glasslike or hyaline; often used alone to designate the vitreous body of the eye (corpus vitreum). [EU] Vitreous Hemorrhage: Hemorrhage into the vitreous body. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Void: To urinate, empty the bladder. [NIH] Volition: Voluntary activity without external compulsion. [NIH] Vulgaris: An affection of the skin, especially of the face, the back and the chest, due to chronic inflammation of the sebaceous glands and the hair follicles. [NIH] Wakefulness: A state in which there is an enhanced potential for sensitivity and an efficient responsiveness to external stimuli. [NIH] Weight Gain: Increase in body weight over existing weight. [NIH] Weight-Bearing: The physical state of supporting an applied load. This often refers to the weight-bearing bones or joints that support the body's weight, especially those in the spine,

Dictionary 405

hip, knee, and foot. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]

Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Womb: A hollow, thick-walled, muscular organ in which the impregnated ovum is developed into a child. [NIH] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] X-ray therapy: The use of high-energy radiation from x-rays to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. X-ray therapy is also called radiation therapy, radiotherapy, and irradiation. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Zebrafish: A species of North American fishes of the family Cyprinidae. They are used in embryological studies and to study the effects of certain chemicals on development. [NIH] Zygote: The fertilized ovum. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]

407

INDEX 5 5-alpha, 261, 307, 344 A Abdomen, 290, 294, 307, 321, 356, 360, 373, 375, 394, 395, 398, 403 Abdominal, 60, 63, 258, 290, 292, 307, 327, 363, 373, 374, 375, 380, 387, 395, 401, 404 Abdominal fat, 290, 292, 307, 404 Abdominal Pain, 63, 258, 307 Aberrant, 60, 121, 307 Ablate, 35, 307, 338 Ablation, 212, 239, 307 Abortion, 307, 371, 380 Acantholysis, 307, 375 Acceptor, 307, 359, 373, 400 Acetylcholine, 220, 307, 326, 369 Acetylgalactosamine, 307, 348 Acetylglucosamine, 307, 348 Acne, 198, 243, 307, 332, 404 Acoustic, 255, 307 Acridine Orange, 247, 307 Actin, 32, 307, 367 Activities of Daily Living, 11, 307 Acyl, 102, 307 Adaptability, 308, 324, 325 Adaptation, 26, 46, 308, 377 Adduct, 54, 308 Adenine, 308, 384 Adenocarcinoma, 18, 137, 151, 215, 308 Adenosine, 107, 308, 316, 322, 376 Adenovirus, 34, 308 Adipose Tissue, 92, 174, 307, 308 Adjunctive Therapy, 259, 308 Adjustment, 9, 12, 15, 308 Adjuvant, 105, 217, 308 Adjuvant Therapy, 217, 308 Administration, Oral, 230, 308 Adolescence, 252, 253, 308 Adrenal Cortex, 233, 308, 309, 312, 331, 341, 370, 381, 387 Adrenal Glands, 308, 387 Adrenal Medulla, 308, 324, 340, 341, 369 Adrenergic, 11, 109, 255, 261, 275, 308, 309, 311, 336, 340, 341, 376, 396, 401 Adrenergic Agents, 255, 308 Adrenergic Agonists, 255, 275, 308, 309 Adverse Effect, 8, 309, 391 Aerobic, 259, 292, 309, 365

Aerobic Exercise, 292, 309 Aetiology, 99, 309 Afferent, 63, 309, 380 Affinity, 22, 23, 28, 31, 37, 43, 49, 57, 77, 89, 98, 120, 141, 190, 191, 238, 309, 316, 334, 359, 392 Affinity Chromatography, 23, 309 Age of Onset, 15, 256, 309, 401 Age-Adjusted, 7, 309 Agenesis, 309, 348 Agoraphobia, 309, 353, 374 Albumin, 81, 309, 337, 372, 377 Aldosterone, 69, 233, 309 Alendronate, 132, 242, 253, 284, 294, 309, 310 Alendronate Sodium, 253, 310 Alertness, 310, 321 Algorithms, 310, 319 Alkaline, 193, 310, 311, 322, 328, 398 Alkaline Phosphatase, 193, 310 Alkaloid, 310, 316, 327, 389 Alkylate, 22, 310 Alkylation, 22, 102, 310 Alleles, 13, 21, 30, 63, 310 Allergen, 310, 334, 390 Allylamine, 310, 311 Alopecia, 173, 310, 332 Alpha Particles, 310, 384 Alpha-1, 310, 311, 336 Alpha-fetoprotein, 310, 344 Alpha-helix, 310, 357 Alternative medicine, 289, 310 Alveolar Bone Loss, 221, 310 Alveolar Process, 310, 387 Ameliorated, 230, 311 Amenorrhea, 198, 230, 259, 311, 313 Amine, 228, 311, 351 Amino Acid Sequence, 23, 311, 312, 313, 391 Amitriptyline, 236, 311 Ammonia, 311, 396 Amphetamines, 311, 327 Amplification, 115, 311 Amyloid, 16, 136, 274, 311 Anabolic, 296, 311, 335 Anabolic Steroids, 296, 311 Anaesthesia, 311, 354 Anal, 194, 311, 344, 360

408

Estrogen

Analog, 311, 334, 345 Analogous, 311, 400 Anaphylatoxins, 312, 328 Anastrozole, 156, 215, 217, 264, 312 Anatomical, 5, 312, 316, 320, 326, 335, 338, 354, 364, 368, 389 Androgen-Binding Protein, 312, 391 Androgenic, 229, 230, 237, 249, 312 Androgens, 39, 48, 53, 102, 143, 229, 233, 238, 239, 249, 264, 308, 312, 315 Androstenedione, 201, 249, 312 Anemia, 279, 312, 345 Anesthesia, 36, 312 Aneurysm, 312, 403 Angina, 252, 312 Angina Pectoris, 252, 312 Angiogenesis, 35, 58, 312, 362 Angiogenesis Factor, 58, 312 Angiography, 224, 312 Angiotensinogen, 312, 387 Animal model, 12, 19, 33, 34, 43, 67, 72, 190, 312, 401 Anions, 309, 313, 357, 391, 396 Anisotropy, 98, 313, 345 Ankle, 216, 313 Ankle Joint, 216, 313 Anomalies, 313, 348 Anorexia, 160, 198, 253, 311, 313, 402 Anorexia Nervosa, 160, 198, 253, 313 Antagonism, 62, 313, 322, 336 Anthropometric measurements, 30, 313 Antiandrogens, 313, 318 Antibacterial, 313, 393 Antibiotic, 313, 331, 375, 393, 395 Antibodies, 23, 313, 349, 353, 361, 366, 377, 385 Anticholinergic, 235, 236, 311, 313, 336 Anticoagulant, 313, 382 Antidepressant, 13, 212, 235, 236, 257, 311, 313, 345, 353 Antigen, 192, 278, 309, 313, 314, 328, 333, 345, 347, 351, 352, 353, 354, 362, 364, 385, 390 Antigen-Antibody Complex, 314, 328 Antigen-presenting cell, 314, 333 Antihypertensive, 248, 314 Anti-infective, 314, 322, 352 Anti-inflammatory, 40, 45, 67, 167, 314, 315, 347, 380 Anti-Inflammatory Agents, 314, 315 Antimetabolite, 314, 345, 364 Antineoplastic, 314, 331, 345, 347, 364, 373

Antioxidant, 101, 126, 132, 134, 168, 182, 196, 223, 286, 314, 373 Antiproliferative, 135, 178, 238, 314 Antipruritic, 314, 322 Antiseptic, 314, 324 Antispasmodic, 235, 236, 257, 314, 334, 345, 381 Antitumour, 106, 314 Antitussive, 314, 334 Antiviral, 314, 355, 375 Anus, 311, 314, 321, 328, 386 Anxiety, 36, 64, 71, 92, 314, 373, 374 Anxiety Disorders, 36, 71, 314, 374 Aorta, 31, 69, 147, 314, 387, 403 Aortic Valve, 134, 314 Apolipoproteins, 145, 274, 314, 359 Aponeurosis, 314, 346 Apoptosis, 25, 30, 34, 75, 77, 86, 90, 145, 148, 177, 183, 274, 314 Applicability, 21, 315 Aptitude, 315, 383 Aqueous, 315, 317, 332, 338, 352, 358 Arachidonic Acid, 101, 315, 358, 381 Arginine, 312, 315, 369, 401 Arrhythmia, 252, 315 Arterial, 31, 33, 36, 37, 159, 236, 310, 315, 326, 352, 382, 397 Arteries, 24, 37, 233, 314, 315, 320, 325, 330, 331, 360, 364, 367, 398 Arteriolar, 315, 321, 387 Arterioles, 315, 320, 322, 367, 403 Arteriosclerosis, 115, 116, 219, 220, 223, 315, 352, 367 Artery, 24, 53, 59, 60, 68, 69, 72, 127, 157, 184, 236, 252, 295, 312, 315, 330, 365, 384, 397 Articular, 175, 313, 315, 372 Aspartate, 315, 334 Aspirate, 65, 315 Aspiration, 315, 344 Aspirin, 260, 315 Assay, 22, 45, 58, 62, 74, 136, 141, 143, 147, 167, 168, 186, 315, 328, 385 Astringent, 315, 324 Astrocytes, 10, 20, 46, 64, 180, 315, 361, 364, 366 Asymptomatic, 15, 217, 316, 373 Ataxia, 279, 316, 398 ATP, 316, 336, 347, 356, 361, 376, 383, 400, 402 Atrial, 89, 316 Atrium, 316, 403

Index 409

Atrophy, 6, 101, 140, 230, 278, 279, 307, 316, 368 Atropine, 236, 316, 317 Attenuation, 37, 316 Atypical, 115, 158, 316 Auditory, 316, 380, 403 Autodigestion, 316, 373 Autoimmune disease, 51, 67, 255, 316, 366 Autoimmunity, 70, 316 Autonomic, 36, 120, 255, 307, 316, 317, 369, 375, 392, 396 Autonomic Nervous System, 255, 316, 317, 375, 392, 396 Avian, 80, 82, 316 Axonal, 12, 70, 316 Axons, 317, 333, 371, 380, 384 B Baclofen, 255, 317 Bacteria, 258, 307, 313, 314, 317, 318, 329, 340, 343, 361, 364, 386, 393, 400, 402 Bacterial Physiology, 308, 317 Bactericidal, 317, 342 Bacteriophage, 317, 400 Bacterium, 317, 329 Bacteriuria, 317, 402 Balloon Dilatation, 261, 317 Basal Ganglia, 316, 317, 321, 346, 353, 359, 370 Basal Ganglia Diseases, 316, 317, 353 Base, 4, 7, 55, 166, 250, 308, 317, 322, 333, 357, 384, 397, 402 Basement Membrane, 317, 323, 343, 358 Beer, 167, 317 Belladonna, 316, 317 Benign, 53, 230, 231, 261, 293, 317, 318, 344, 346, 349, 358, 368, 385 Benign prostatic hyperplasia, 53, 231, 261, 293, 318, 344 Benzene, 318, 357 Benzodiazepines, 255, 318 Beta blocker, 256, 318 Beta-pleated, 311, 318 Bicalutamide, 240, 318 Bilateral, 318, 401 Bile, 260, 293, 296, 318, 346, 357, 360, 394 Bile Acids, 318, 346, 394 Bile Acids and Salts, 318 Bile duct, 296, 318, 346 Bile Pigments, 318, 357 Biliary, 294, 317, 318, 322, 334, 373 Biliary Tract, 318, 322, 373 Bilirubin, 309, 318, 346, 352

Binding agent, 232, 318 Binding Sites, 23, 40, 57, 318 Bioassay, 78, 80, 142, 177, 183, 196, 318 Bioavailability, 48, 170, 234, 318 Bioavailable, 49, 318 Biodegradation, 156, 319 Biological response modifier, 319, 355 Biological therapy, 319, 349 Biomarkers, 20, 54, 58, 122, 151, 183, 184, 197, 319 Biomechanics, 274, 319 Biophysics, 17, 71, 76, 319 Biopsy, 47, 319 Biotechnology, 76, 104, 273, 277, 278, 279, 280, 289, 319 Biotin, 319, 371 Biotransformation, 80, 94, 114, 319 Bladder, 7, 236, 255, 256, 257, 258, 260, 275, 293, 318, 319, 328, 332, 354, 366, 368, 382, 387, 395, 402, 404 Blast Crisis, 83, 319 Blastocyst, 54, 319, 329, 338, 373, 377, 401 Blastomeres, 319, 366 Blastomyces, 319, 374 Blister, 319, 375 Blood Coagulation, 319, 320, 322, 398 Blood Glucose, 7, 256, 260, 320, 347, 350, 355 Blood Platelets, 320, 362, 391 Blood pressure, 7, 33, 36, 37, 42, 68, 73, 177, 248, 251, 252, 256, 290, 314, 320, 323, 352, 353, 366, 392 Blood-Brain Barrier, 46, 320, 358 Blot, 43, 46, 320, 371 Body Fluids, 319, 320, 321, 337, 392, 401 Body Image, 295, 320 Body Mass Index, 292, 320, 372 Body Regions, 320, 327 Bone Density, 154, 235, 245, 249, 274, 295, 320 Bone Marrow, 72, 103, 150, 196, 239, 318, 319, 320, 346, 353, 361, 362, 366, 392, 395 Bone Marrow Cells, 72, 320, 362 Bone marrow metastases, 239, 320 Bone metastases, 243, 320 Bone Remodeling, 253, 320 Bone Resorption, 29, 93, 228, 243, 320 Bone scan, 320, 389 Boron, 162, 291, 321 Boron Neutron Capture Therapy, 321 Bowel, 55, 63, 105, 155, 256, 311, 321, 335, 356, 358, 368, 395

410

Estrogen

Bowel Movement, 321, 335, 395 Brachytherapy, 321, 356, 357, 384, 405 Bradykinin, 96, 321, 357, 369, 377 Brain Diseases, 247, 321 Brain Stem, 321, 325 Branch, 303, 321, 338, 361, 374, 384, 387, 393, 398 Breakdown, 29, 243, 253, 294, 321, 335, 346, 371 Bronchial, 317, 321, 351 Buccal, 218, 321, 361 Buccal mucosa, 218, 321 Bulimia, 71, 253, 321 Burns, 292, 321 Burns, Electric, 321 Bypass, 219, 321 C Cachexia, 242, 321 Caffeine, 258, 321, 384 Calcineurin, 126, 322 Calcitonin, 202, 242, 253, 294, 322 Calcium Channels, 42, 322 Calcium Oxalate, 4, 322, 373 Calculi, 317, 322 Calmodulin, 28, 322 Camphor, 169, 322 Canonical, 105, 322 Capillary, 172, 240, 321, 322, 403 Capillary Permeability, 321, 322 Capsules, 292, 323, 336 Carbohydrate, 323, 348, 379 Carbon Dioxide, 322, 323, 333, 344, 377, 387 Carcinogen, 50, 308, 323, 342, 367 Carcinogenesis, 22, 82, 97, 100, 139, 172, 180, 192, 237, 244, 323, 325 Carcinogenic, 23, 119, 318, 323, 355, 381, 394, 401 Carcinogenicity, 54, 57, 323, 376 Carcinoma, 83, 93, 113, 115, 122, 131, 140, 147, 148, 151, 167, 171, 217, 323, 332 Carcinoma in Situ, 217, 323 Cardiac, 42, 185, 242, 310, 321, 323, 330, 341, 342, 367, 394 Cardiac Output, 42, 323 Cardiorespiratory, 309, 323 Cardiotonic, 323, 376 Cardiovascular disease, 8, 9, 32, 35, 37, 72, 108, 142, 150, 214, 231, 243, 258, 296, 323, 360 Cardiovascular System, 40, 238, 323, 334 Carotene, 201, 244, 323, 388

Carotenoids, 40, 202, 323 Carrier Proteins, 323, 377, 385 Case report, 14, 275, 323, 326 Castration, 239, 323 Cataract, 41, 79, 323 Catechol, 22, 53, 95, 122, 134, 324 Catecholamine, 324, 336 Catheter, 317, 324 Catheterization, 317, 324 Caudal, 324, 334, 353, 370, 379 Caudate Nucleus, 317, 324, 370 Causal, 324, 356 Causality, 11, 324 Cause of Death, 29, 296, 324 Cecum, 324, 358 Celiac Disease, 293, 324 Cell Adhesion, 166, 324 Cell Communication, 19, 324 Cell Death, 26, 40, 58, 68, 84, 85, 314, 324, 347 Cell Differentiation, 72, 324, 391 Cell Division, 278, 291, 317, 324, 349, 362, 365, 377, 381 Cell membrane, 322, 323, 324, 333, 343, 356, 376, 379 Cell Respiration, 325, 365, 387 Cell Survival, 58, 93, 325, 349 Cellobiose, 325 Cellulose, 229, 232, 325, 346, 377 Centrifugation, 325, 364 Cerebellar, 18, 48, 316, 325, 386, 400 Cerebellum, 18, 321, 325, 331, 386 Cerebral Arteries, 325, 365 Cerebral Cortex, 119, 316, 321, 325, 342, 344, 384 Cerebral Palsy, 325, 393 Cerebrovascular, 222, 247, 317, 323, 325, 398 Cerebrum, 325, 331, 401 Cervical, 20, 155, 325, 360 Cervix, 25, 123, 144, 155, 228, 233, 247, 307, 325, 387 Character, 312, 325, 333, 348 Chemoprevention, 54, 99, 110, 243, 244, 325 Chemopreventive, 244, 325 Chemotactic Factors, 325, 328 Chemotherapy, 112, 148, 154, 202, 239, 308, 325 Chimera, 77, 91, 326 Chin, 86, 91, 132, 326, 363 Chlorophyll, 326, 346

Index 411

Cholecystectomy, 294, 296, 326 Cholesterol Esters, 326, 359 Choline, 231, 326 Cholinergic, 11, 15, 34, 89, 311, 326 Chondrocytes, 326, 344 Chromatin, 79, 81, 86, 94, 95, 96, 101, 315, 326, 370 Chromosomal, 125, 244, 311, 326 Chromosome, 219, 326, 329, 349, 359 Chronic Disease, 321, 326 Chronic renal, 236, 326, 378, 402 Chylomicrons, 326, 359 CIS, 231, 326, 388 Clamp, 47, 61, 326 Clear cell carcinoma, 326, 334, 335 Clinical Medicine, 326, 380 Clinical study, 326, 330 Clomiphene, 230, 231, 249, 264, 327 Cloning, 95, 319, 327 Coagulation, 59, 319, 327, 350, 377 Coca, 327 Cocaine, 50, 87, 327 Codeine, 327, 334 Coenzyme, 102, 327, 345 Cofactor, 62, 327, 382, 398 Cognition, 9, 10, 12, 13, 15, 33, 35, 38, 64, 119, 213, 214, 215, 255, 256, 327 Coitus, 327, 330 Colic, 294, 327 Collagen, 37, 107, 122, 175, 311, 317, 327, 329, 343, 344, 362, 378, 381 Collapse, 321, 327 Colloidal, 309, 327, 338, 391 Colon, 55, 123, 138, 158, 187, 278, 327, 328, 358 Colorectal, 40, 55, 63, 149, 198, 328 Colorectal Cancer, 55, 149, 198, 328 Combination Therapy, 328, 342 Combinatorial, 83, 120, 328 Comet Assay, 22, 328 Complement, 29, 70, 312, 328, 347, 377, 390 Complementary and alternative medicine, 165, 166, 209, 328 Complementary medicine, 166, 328 Compliance, 11, 159, 218, 234, 328 Computational Biology, 273, 277, 328 Computed tomography, 320, 329, 389 Conception, 307, 329, 330, 344, 380, 393, 394 Concomitant, 60, 242, 329 Cones, 329, 388

Confounding, 5, 11, 329 Congestive heart failure, 220, 242, 329 Conjugation, 39, 57, 319, 329 Connective Tissue, 160, 161, 320, 327, 329, 333, 344, 346, 361, 363, 383, 388, 395, 397 Connective Tissue Cells, 329 Connective Tissue Diseases, 160, 329 Consciousness, 329, 333, 336, 383 Constipation, 257, 329 Constriction, 329, 357 Consumption, 26, 27, 30, 166, 192, 257, 329, 334, 387 Contamination, 329, 350 Continuum, 259, 329 Contraception, 145, 167, 230, 240, 246, 295, 330 Contraceptive Agents, 247, 330, 334 Contractility, 36, 330 Contraindications, ii, 330 Contralateral, 330, 363, 371, 386 Contrast medium, 312, 330 Control group, 216, 330 Controlled clinical trial, 287, 330, 385 Controlled study, 5, 117, 149, 195, 330 Convulsions, 330, 337, 352, 380 Coordination, 325, 330, 366 Copulation, 64, 330 Cornea, 330, 395 Corneum, 240, 330, 341 Coronary Circulation, 312, 330 Coronary Disease, 59, 219, 220, 221, 222, 223, 260, 330 Coronary heart disease, 29, 41, 44, 99, 109, 129, 219, 224, 235, 253, 323, 330 Coronary Thrombosis, 330, 364, 367 Coronary Vessels, 330, 331 Corpus, 331, 361, 375, 381, 398, 404 Corpus Luteum, 331, 361, 381 Cortex, 10, 21, 69, 331, 340, 365, 380, 386 Cortical, 28, 32, 38, 41, 87, 193, 197, 254, 331, 342, 380, 384, 390, 398 Cortices, 243, 331 Corticosteroids, 68, 243, 331, 347, 365, 380 Cortisol, 24, 68, 233, 290, 309, 331 Cortisone, 233, 331, 380 Coumarin, 331, 383 Coumestrol, 160, 195, 331 Cranial, 325, 331, 349, 370, 375, 403 Creatinine, 28, 331, 402 Criterion, 37, 331 Cruciferous vegetables, 331, 354 Cryotherapy, 261, 331

412

Estrogen

Cues, 50, 331 Cultured cells, 51, 331 Cuprizone, 51, 331 Curative, 331, 369, 398 Curettage, 137, 331 Curette, 331 Cutaneous, 87, 331, 357, 361 Cyclic, 152, 238, 322, 324, 331, 349, 369, 379, 382 Cyclin, 51, 81, 82, 86, 95, 96, 98, 99, 105, 107, 132, 142, 238, 331 Cycloheximide, 84, 331 Cyclophosphamide, 105, 203, 295, 331 Cyproterone, 332, 345 Cyst, 315, 332 Cystitis, 260, 332 Cytochrome, 54, 131, 145, 315, 332 Cytokine, 56, 67, 84, 332 Cytoplasm, 315, 324, 332, 343, 349, 366, 388 Cytoskeleton, 32, 332, 365 Cytostatic, 192, 332, 367 Cytotoxic, 114, 248, 332, 385, 392 Cytotoxicity, 99, 310, 332 Cytotoxins, 247, 332 D Dairy Products, 291, 332, 389 Dantrolene, 255, 332 Data Collection, 45, 332 Deamination, 332, 366 Decidua, 332, 377 Decongestant, 333, 376 Degenerative, 59, 243, 247, 254, 294, 333, 350, 372, 388 Dehydroepiandrosterone, 114, 203, 333 Deletion, 47, 53, 67, 315, 333 Delirium, 236, 333 Dementia, 4, 5, 10, 11, 12, 14, 15, 16, 17, 198, 200, 253, 254, 285, 333 Demethylation, 79, 132, 333 Dendrites, 333, 369, 384 Dendritic, 28, 56, 333, 363 Dendritic cell, 56, 333 Dentate Gyrus, 333, 351 Depolarization, 333, 392 Deprivation, 25, 105, 231, 259, 261, 333 Dermatitis, 111, 119, 333 Dermis, 240, 333, 396, 400 DES, 158, 287, 312, 333, 335 Desensitization, 71, 75, 334 Desogestrel, 145, 334 Deuterium, 334, 351

Developing Countries, 57, 334 Dextroamphetamine, 334, 364 Dextromethorphan, 235, 334 Dextrorphan, 235, 334 Diabetes Insipidus, 334, 351 Diabetes Mellitus, 9, 221, 334, 348, 350 Diabetic Retinopathy, 6, 334, 377 Diagnostic procedure, 227, 290, 334 Dialysate, 50, 334 Diastolic, 334, 352 Dicyclomine, 236, 257, 275, 334 Diencephalon, 334, 353, 380, 398 Dietary Fats, 64, 335 Diethylstilbestrol, 14, 135, 196, 333, 335 Digestion, 28, 318, 321, 335, 356, 360, 395 Digestive system, 225, 335, 366 Digestive tract, 335, 392, 394 Dihydrotestosterone, 49, 307, 335, 386, 391 Dilatation, 307, 312, 335, 380, 403 Dilatation, Pathologic, 335, 403 Dilation, 321, 335, 403 Dimerization, 32, 79, 93, 96, 335 Diploid, 335, 377 Discrete, 18, 320, 335, 382, 397 Disease Progression, 51, 131, 335 Disinfectant, 335, 342 Disorientation, 333, 335 Dispenser, 234, 335 Disposition, 195, 335 Dissection, 74, 83, 335, 401 Dissociation, 104, 309, 335 Dissociative Disorders, 335, 336 Distal, 316, 336, 346, 380, 383 Distention, 63, 336 Diuresis, 321, 336 Dizziness, 236, 336, 374 DNA Topoisomerase, 336, 347 Domesticated, 72, 336 Dopamine, 50, 75, 214, 327, 334, 336, 358, 366, 369, 376 Dorsal, 50, 63, 88, 336, 379 Dosage Forms, 232, 336 Dose-dependent, 13, 336 Double-blind, 9, 13, 14, 30, 106, 128, 195, 216, 336 Double-blinded, 216, 336 Doxazosin, 257, 336 Doxepin, 236, 336 Drive, ii, vi, 49, 73, 118, 153, 239, 257, 294, 337, 354, 356, 359 Drug Carriers, 125, 337 Drug Delivery Systems, 240, 294, 337

Index 413

Drug Interactions, 266, 337 Drug Tolerance, 337, 399 Duct, 324, 337, 339, 356, 389, 396 Ductal carcinoma in situ, 110, 217, 231, 337, 356 Duodenum, 318, 337, 373, 395 Dura mater, 337, 363, 373 Dwarfism, 242, 337 Dyes, 247, 311, 337, 396 Dysmenorrhea, 199, 243, 246, 337 Dyspareunia, 337, 342 Dysphonia, 259, 337 Dysplasia, 279, 337 Dystrophy, 278, 337 E Eclampsia, 337, 380 Edema, 6, 293, 334, 337, 351, 367, 380, 402 Effector, 28, 103, 307, 328, 337, 386 Effector cell, 337, 386 Efferent, 101, 312, 337 Efficacy, 8, 10, 16, 29, 34, 48, 58, 59, 66, 118, 130, 215, 233, 338 Ejaculation, 338, 390 Elastic, 37, 338, 348, 393 Elastin, 37, 327, 329, 338, 343 Elective, 99, 144, 145, 338 Electric Conductivity, 313, 338 Electrocoagulation, 327, 338 Electrolyte, 309, 333, 338, 365, 379, 392, 402 Electrophoresis, 328, 338 Electrophysiological, 63, 338 Electroplating, 324, 338, 396 Embryo, 55, 307, 319, 324, 338, 354, 364, 366, 371, 372, 380, 394 Embryo Transfer, 338, 380 Embryology, 261, 338 Emulsion, 338, 345 Enamel, 338, 357 Encephalitis, 338, 339 Encephalomyelitis, 67, 338 Encephalopathy, 254, 339 Endemic, 339, 394 Endocrine System, 339, 368 Endolymph, 255, 339 Endolymphatic Duct, 339 Endolymphatic Sac, 255, 339 Endometriosis, 74, 151, 160, 199, 230, 231, 243, 246, 247, 339 Endometrium, 22, 25, 62, 102, 125, 155, 221, 230, 247, 291, 332, 339, 363, 401 Endopeptidases, 339, 382

Endorphins, 339, 369 Endothelial cell, 46, 52, 62, 97, 127, 138, 184, 188, 320, 339, 344, 398 Endothelium, 24, 339, 369 Endothelium, Lymphatic, 339 Endothelium, Vascular, 339 Endothelium-derived, 339, 369 Endotoxic, 86, 340, 359 Endotoxin, 40, 340, 401 End-stage renal, 326, 340, 378 Enhancer, 91, 340, 388 Enkephalins, 340, 369 Enteropeptidase, 340, 401 Entorhinal Cortex, 340, 351 Environment Design, 72, 340 Environmental Exposure, 340, 371 Environmental Health, 129, 157, 191, 196, 272, 274, 340 Enzymatic, 311, 322, 323, 328, 340, 351, 388 Enzyme Activation, 46, 340 Ephedrine, 236, 340 Epidemic, 340, 394 Epidemiological, 26, 41, 45, 54, 59, 63, 68, 187, 340, 387 Epidermal, 79, 82, 85, 97, 106, 117, 123, 340, 341, 363 Epidermal Growth Factor, 82, 85, 97, 106, 117, 123, 340, 341 Epidermal growth factor receptor, 106, 117, 341 Epidermis, 240, 307, 319, 330, 333, 340, 341, 351, 357, 375 Epidermoid carcinoma, 341, 394 Epinephrine, 308, 336, 341, 369, 401 Epiphyseal, 72, 84, 341 Epithelial Cells, 32, 49, 85, 91, 98, 119, 135, 183, 234, 238, 244, 340, 341, 358 Epithelium, 20, 26, 49, 54, 73, 93, 94, 96, 100, 233, 239, 317, 339, 341, 374 Erectile, 177, 186, 249, 341, 375 Erection, 341 Ergometer, 341 Ergometry, 259, 341 Erythrocytes, 149, 196, 312, 320, 337, 341, 390 Esophagus, 335, 341, 346, 360, 376, 395, 403 Essential Tremor, 278, 341 Estriol, 65, 67, 237, 341 Estrogen Antagonists, 36, 151, 238, 341 Estrogen receptor, 17, 18, 19, 22, 25, 26, 27, 28, 29, 31, 34, 38, 41, 42, 46, 47, 48, 49,

414

Estrogen

51, 52, 53, 55, 56, 57, 58, 59, 60, 61, 62, 65, 66, 67, 68, 70, 71, 72, 73, 75, 77, 78, 79, 80, 81, 82, 83, 85, 86, 87, 88, 89, 90, 91, 92, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 120, 122, 123, 124, 126, 127, 128, 129, 130, 131, 132, 133, 134, 136, 137, 139, 141, 143, 144, 146, 147, 148, 150, 151, 157, 158, 159, 160, 167, 168, 169, 170, 171, 174, 175, 177, 178, 180, 181, 183, 184, 185, 186, 188, 190, 191, 192, 194, 195, 213, 217, 230, 231, 233, 238, 239, 241, 242, 243, 246, 247, 249, 327, 341, 342, 385, 390, 397, 399 Estrogen Receptor Modulators, 28, 62, 67, 68, 73, 88, 95, 105, 106, 108, 123, 132, 137, 144, 150, 157, 160, 175, 230, 243, 246, 341 Estrogen receptor negative, 102, 122, 342 Estrogen receptor positive, 217, 238, 342 Estrone, 7, 11, 14, 38, 127, 233, 237, 342 Ethanol, 19, 48, 159, 342, 344 Ether, 228, 342 Ethnic Groups, 45, 342 Eukaryotic Cells, 342, 354, 370 Evacuation, 329, 342, 358 Evoke, 342, 394 Excipient, 232, 342, 400 Excitability, 236, 342 Excitation, 185, 311, 332, 342, 369 Excitatory, 317, 342, 348 Excitotoxicity, 40, 342 Exemestane, 243, 265, 342 Exhaustion, 313, 343 Exocytosis, 75, 343 Exogenous, 6, 26, 44, 47, 61, 68, 216, 242, 319, 339, 343, 382, 401 Exons, 77, 343 External-beam radiation, 343, 357, 384, 405 Extracellular, 10, 311, 316, 329, 343, 344, 362, 392, 398 Extracellular Matrix, 329, 343, 344, 362 Extracellular Matrix Proteins, 343, 362 Extrapyramidal, 336, 343 Exudate, 343, 400 Eye Infections, 308, 343 F Facial, 343, 392, 404 Fallopian tube, 343, 387, 401 Family Planning, 273, 343

Fatigue, 295, 343, 349 Fatty acids, 242, 309, 343, 381 Feces, 329, 343, 395 Femoral, 343, 350 Femoral Neck Fractures, 343, 350 Femur, 192, 294, 343, 344, 350, 399 Fermentation, 317, 344 Fertilization in Vitro, 344, 380 Fetoprotein, 77, 344 Fetus, 25, 69, 295, 307, 310, 344, 345, 377, 380, 394, 402 Fibrinogen, 221, 344, 377, 398 Fibroblast Growth Factor, 58, 121, 344 Fibroblasts, 96, 115, 329, 344, 355 Fibroid, 230, 243, 344, 358 Fibrosis, 158, 231, 279, 310, 344, 389 Fibula, 313, 344, 399 Finasteride, 257, 344 Fissure, 333, 344, 380 Fixation, 131, 344, 390 Flavoxate, 236, 257, 345 Fluorescence, 98, 141, 147, 194, 307, 345 Fluorescence Polarization, 147, 194, 345 Fluorouracil, 105, 205, 345 Fluoxetine, 13, 71, 345 Flutamide, 48, 239, 345 Foetoplacental, 345, 371 Folate, 40, 163, 345 Fold, 18, 26, 64, 344, 345, 363 Folic Acid, 345 Follicles, 345 Follicular Phase, 236, 345 Forearm, 320, 345 Fossa, 325, 345 Fovea, 344, 345 Free Radicals, 314, 335, 345 Frontal Lobe, 345, 380 Functional magnetic resonance imaging, 13, 345 Fungi, 319, 329, 343, 346, 364, 405 Fungus, 90, 93, 346, 367 G Gallbladder, 3, 155, 230, 293, 307, 318, 326, 335, 346 Gallstones, 3, 155, 293, 296, 318, 346 Gamma Rays, 346, 384, 385 Ganglia, 120, 307, 317, 346, 368, 375, 396 Ganglion, 88, 346, 371 Gas, 311, 323, 346, 351, 367, 369 Gastric, 316, 317, 336, 340, 346, 351 Gastrin, 346, 351 Gastroesophageal Reflux, 134, 346

Index 415

Gastrointestinal, 142, 232, 240, 321, 334, 341, 342, 344, 346, 358, 391, 392, 393, 396, 401 Gastrointestinal tract, 232, 342, 344, 346, 358, 391, 393, 401 Gene Therapy, 308, 346 Genetic Engineering, 319, 327, 347 Genetic Markers, 241, 347 Genetics, 52, 128, 148, 274, 329, 347, 365 Genital, 5, 32, 51, 85, 145, 326, 347, 402 Genitourinary, 258, 347, 402 Genotype, 18, 41, 128, 347, 376 Geriatric Assessment, 253, 347 Germ Cells, 347, 362, 372, 392, 393, 397 Gestation, 25, 347, 375, 377, 394 Gestational, 259, 347 Giant Cells, 81, 347 Ginseng, 167, 207, 347 Gland, 30, 49, 51, 89, 94, 111, 160, 233, 308, 331, 347, 361, 373, 374, 377, 382, 385, 389, 390, 394, 395, 396, 398, 399 Glomerular, 347, 387 Glucocorticoid, 24, 36, 88, 91, 157, 178, 243, 347, 380 Glucose Clamp Technique, 47, 347 Glucose Intolerance, 334, 347 Glucose tolerance, 9, 61, 231, 348 Glucose Tolerance Test, 348 Glucuronic Acid, 348, 350 Glutamate, 10, 34, 85, 158, 180, 334, 342, 348 Glutamic Acid, 345, 348, 369, 381 Glutathione Peroxidase, 348, 390 Gluten, 293, 324, 348 Glycine, 123, 182, 311, 318, 348, 369, 391 Glycoprotein, 56, 344, 347, 348, 358, 391, 398, 401 Glycosaminoglycans, 183, 195, 343, 348, 383 Goats, 332, 348 Gonad, 80, 348, 397 Gonadal, 43, 50, 63, 214, 243, 348, 394 Gonadal Dysgenesis, 214, 243, 348 Gonadotropin, 160, 195, 230, 348 Governing Board, 348, 379 Gp120, 348, 375 Grade, 115, 125, 349 Graft, 219, 349, 351, 354 Grafting, 349, 354 Granulocytes, 349, 392, 405 Granuloma, 349, 374 Granulosa Cells, 237, 349, 361

Growth factors, 10, 38, 51, 65, 238, 349, 364 Growth Plate, 84, 349 Guanylate Cyclase, 191, 349, 369 H Hair follicles, 233, 333, 349, 404 Haploid, 349, 377 Haptens, 309, 349, 385 Headache, 306, 321, 349, 352, 380 Health Policy, 253, 349 Health Status, 45, 349 Heart attack, 154, 230, 256, 323, 349 Heart failure, 252, 293, 340, 349 Heme, 318, 332, 349, 367, 379 Hemodialysis, 334, 349 Hemodynamics, 62, 350 Hemoglobin, 312, 341, 349, 350, 358, 379 Hemoglobin A, 350, 379 Hemoglobinuria, 278, 350 Hemorrhage, 338, 349, 350, 395, 404 Hemostasis, 350, 391 Heparin, 47, 54, 350 Hepatic, 44, 101, 167, 173, 309, 333, 348, 350, 366 Hepatitis, 200, 275, 350 Hepatitis A, 275, 350 Hepatocyte, 183, 350 Hepatovirus, 350 Herbicide, 40, 350 Hereditary, 251, 329, 350, 368, 388 Heredity, 255, 346, 347, 350 Heterogeneity, 96, 309, 350 Hip Fractures, 228, 235, 243, 245, 344, 350 Hippocampus, 21, 103, 333, 350, 359, 384, 395 Hirsutism, 243, 332, 351, 352 Histamine, 167, 312, 336, 351 Histology, 29, 37, 52, 261, 351 Histone Deacetylase, 135, 136, 351 Homeobox, 82, 113, 351 Homeostasis, 242, 320, 351, 392 Homogeneous, 168, 330, 351, 376 Homologous, 310, 346, 351, 390, 397 Hormonal therapy, 105, 351, 381 Hormone Replacement Therapy, 4, 6, 7, 8, 13, 29, 30, 41, 59, 68, 104, 128, 130, 155, 166, 171, 188, 189, 211, 218, 219, 221, 223, 224, 233, 234, 235, 240, 244, 245, 246, 248, 253, 258, 259, 282, 284, 285, 286, 288, 292, 351, 380 Hormone therapy, 9, 59, 119, 129, 140, 154, 177, 232, 308, 351 Horny layer, 341, 351

416

Estrogen

Host, 93, 317, 351, 353, 354, 358, 404 Hybrid, 76, 95, 351, 371 Hybridization, 74, 83, 351, 365, 371 Hybridoma, 237, 351 Hydrochlorothiazide, 256, 351 Hydrogen, 86, 307, 311, 317, 323, 334, 343, 348, 351, 352, 359, 366, 369, 370, 373, 376, 383, 396 Hydrogen Peroxide, 348, 352, 359, 396 Hydrogenation, 318, 352 Hydrolysis, 319, 325, 352, 356, 359, 376, 383, 401 Hydrophobic, 352, 359 Hydroxylation, 39, 57, 77, 352 Hydroxylysine, 327, 352 Hydroxyproline, 311, 327, 352 Hyperalgesia, 63, 352 Hyperbilirubinemia, 352, 357 Hypercalcemia, 243, 310, 352 Hypercholesterolemia, 199, 221, 352, 375 Hyperlipidemia, 231, 247, 352 Hyperplasia, 66, 96, 222, 247, 352 Hypersensitivity, 25, 105, 275, 310, 334, 352, 358, 388, 390 Hypertension, 6, 31, 33, 37, 42, 60, 177, 221, 231, 248, 251, 275, 323, 336, 349, 351, 352, 380, 402 Hyperthermia, 261, 352 Hypertrichosis, 351, 352 Hypertriglyceridemia, 169, 352 Hypertrophy, 318, 352 Hypoglycaemia, 333, 352 Hypokinesia, 352, 374 Hypotension, 69, 330, 353 Hypotensive, 69, 353, 357 Hypothalamic, 21, 34, 37, 43, 64, 71, 171, 177, 193, 353 Hypothalamus, 13, 21, 43, 71, 246, 316, 321, 334, 353, 359, 377, 380, 393, 398 Hypoxia, 89, 124, 142, 333, 353, 398 Hypoxic, 312, 353 Hysterectomy, 11, 34, 137, 155, 243, 353 I Id, 161, 197, 232, 277, 278, 282, 283, 288, 302, 304, 353 Idiopathic, 38, 353 Imipramine, 236, 255, 257, 353 Immune function, 229, 353 Immune response, 35, 308, 314, 316, 331, 349, 353, 354, 390, 396, 404 Immune system, 67, 70, 196, 314, 316, 319, 337, 353, 354, 358, 361, 366, 367, 402, 405

Immunity, 196, 332, 353 Immunization, 353, 354, 390 Immunodeficiency, 66, 278, 353 Immunofluorescence, 55, 353 Immunogenic, 353, 359, 385 Immunoglobulin, 313, 343, 353, 366 Immunohistochemistry, 27, 55, 69, 151, 353 Immunologic, 325, 353, 385 Immunology, 51, 69, 173, 308, 309, 353 Immunophilin, 322, 353 Immunosuppressant, 345, 354, 364 Immunosuppressive, 322, 332, 347, 354 Immunotherapy, 319, 334, 354 Impairment, 12, 34, 243, 316, 333, 337, 343, 354, 363 Implant radiation, 354, 356, 357, 384, 405 Implantation, 54, 87, 329, 354, 371, 373 Impotence, 341, 354 Impulse Control Disorders, 71, 354 In situ, 50, 55, 74, 171, 217, 354 In Situ Hybridization, 55, 74, 354 In vitro, 19, 23, 25, 26, 28, 29, 34, 43, 46, 48, 52, 56, 58, 61, 63, 64, 68, 80, 90, 98, 103, 115, 125, 126, 158, 159, 168, 171, 173, 175, 181, 182, 183, 338, 346, 354, 399 Incision, 354, 356 Incompetence, 257, 346, 354 Incontinence, 5, 136, 200, 235, 236, 243, 255, 256, 257, 260, 275, 334, 340, 354, 381, 395 Indicative, 72, 354, 374, 403 Indole-3-carbinol, 105, 126, 183, 205, 354 Infarction, 219, 220, 222, 354 Infection, 20, 173, 236, 255, 275, 316, 319, 325, 333, 338, 343, 353, 354, 361, 375, 388, 395, 405 Infertility, 34, 55, 199, 282, 355, 402 Infiltrating cancer, 355, 356 Infusion, 47, 69, 118, 347, 355 Ingestion, 68, 348, 355, 378, 398 Initiation, 7, 28, 42, 48, 78, 91, 100, 355, 381, 395, 400 Inlay, 355, 388 Innervation, 70, 336, 355 Inorganic, 229, 355, 396 Inotropic, 336, 355 Insight, 19, 44, 58, 60, 355 Insomnia, 128, 199, 355, 380 Insulator, 355, 366 Insulin, 6, 9, 47, 60, 154, 176, 221, 259, 291, 292, 347, 348, 355, 401

Index 417

Insulin-dependent diabetes mellitus, 355 Interferon, 102, 173, 179, 196, 355 Interferon-alpha, 355 Interindividual, 21, 355 Interleukin-6, 73, 99, 355 Interleukins, 44, 355 Intermittent, 356, 360, 376 Internal Medicine, 18, 25, 36, 40, 52, 66, 69, 70, 134, 142, 157, 274, 339, 356 Internal radiation, 356, 357, 384, 405 Interstitial, 260, 321, 356, 357, 387, 405 Intervention Studies, 115, 173, 356 Intervertebral, 90, 356 Intestinal, 129, 142, 178, 185, 195, 257, 323, 324, 340, 348, 356, 361 Intestinal Mucosa, 324, 356 Intestine, 318, 321, 328, 356, 358 Intoxication, 333, 356, 405 Intracellular, 19, 46, 53, 56, 65, 75, 88, 90, 148, 322, 354, 356, 363, 369, 379, 382, 386, 390, 391 Intracellular Membranes, 356, 363 Intraductal carcinoma, 337, 356 Intraepithelial, 123, 356 Intravenous, 295, 355, 356 Intrinsic, 81, 125, 182, 309, 317, 356 Invasive, 59, 78, 115, 125, 131, 142, 144, 231, 237, 255, 353, 355, 356, 361 Invasive cancer, 144, 355, 356 Involuntary, 5, 236, 255, 317, 341, 356, 367, 386, 392, 393, 395 Ion Channels, 316, 356 Ion Transport, 356, 365 Ionizing, 310, 340, 356, 362, 385 Ionophores, 70, 357, 402 Ions, 317, 322, 335, 338, 340, 351, 356, 357, 365, 379 Irradiation, 248, 321, 357, 405 Irritants, 257, 357 Ischemia, 15, 68, 89, 316, 357 Isoenzyme, 237, 357 Isoflavones, 27, 29, 57, 72, 166, 168, 195, 205, 208, 292, 357 J Jaundice, 275, 352, 357 Joint, 129, 216, 274, 313, 315, 357, 372, 396, 397 K Kallidin, 321, 357 Kb, 272, 357 Keratin, 20, 357 Keto, 25, 201, 357

Kidney Disease, 221, 225, 251, 272, 279, 357 Kidney stone, 4, 258, 358, 368, 373, 402 Kinetics, 57, 104, 322, 358 L Labile, 99, 328, 358 Labyrinth, 339, 358, 372, 404 Lactation, 358, 371, 373, 381 Laminin, 37, 317, 343, 358 Large Intestine, 292, 324, 328, 335, 356, 358, 386, 392 Latent, 97, 275, 358 Laxative, 358, 400 Lectin, 358, 363 Leiomyoma, 34, 183, 344, 358, 392 Lens, 41, 323, 358 Leucine, 237, 358 Leukemia, 83, 185, 278, 347, 358 Leukocytes, 320, 325, 349, 355, 358, 366, 401 Leukoencephalopathy, 254, 358 Leukoplakia, 20, 358 Leukotrienes, 315, 358 Levodopa, 358, 390 Levorphanol, 334, 359 Libido, 249, 312, 359 Library Services, 302, 359 Life cycle, 252, 308, 346, 359 Life Expectancy, 244, 359 Ligament, 343, 359, 382 Ligands, 28, 58, 62, 83, 113, 125, 133, 172, 182, 183, 185, 238, 243, 359 Ligation, 359 Limbic, 359, 380 Limbic System, 359, 380 Linear Models, 27, 359 Linkage, 325, 347, 359 Lipid A, 8, 28, 359 Lipid Peroxidation, 48, 359, 373 Lipolysis, 60, 359 Lipophilic, 233, 359 Lipopolysaccharides, 359 Lipoprotein, 8, 15, 84, 97, 176, 218, 221, 260, 359, 360 Lipoprotein(a), 176, 359 Liver cancer, 54, 310, 360 Liver scan, 360, 389 Lobe, 360 Lobule, 13, 360 Local therapy, 231, 360 Localization, 49, 63, 82, 90, 92, 97, 233, 353, 360

418

Estrogen

Localized, 133, 344, 351, 352, 354, 358, 360, 366, 377 Locomotion, 37, 360, 377 Locomotor, 37, 360 Longitudinal study, 15, 125, 140, 360 Long-Term Care, 71, 360 Loop, 102, 103, 360 Lordosis, 64, 176, 360 Low-density lipoprotein, 97, 159, 192, 359, 360 Lower Esophageal Sphincter, 346, 360 Lubricants, 232, 360 Lucida, 358, 360 Luciferase, 22, 67, 361 Lumbar, 140, 217, 294, 360, 361 Lumpectomy, 154, 361 Lupus, 160, 200, 216, 221, 222, 294, 295, 361, 397 Luteal Phase, 45, 361 Lutein Cells, 361, 381 Lymph, 125, 240, 325, 339, 361, 374, 395 Lymph node, 125, 325, 361, 374 Lymphatic, 339, 354, 361, 363, 392, 394 Lymphatic system, 361, 392, 394 Lymphocyte, 79, 314, 361, 362 Lymphoid, 83, 313, 331, 361 Lymphoma, 133, 278, 361 Lysine, 352, 361, 401 M Macroglia, 361, 364 Macrophage, 85, 87, 361 Magnetic Resonance Imaging, 361, 389 Malabsorption, 278, 324, 361 Malignancy, 243, 361, 374 Malignant, 20, 23, 26, 91, 114, 129, 230, 248, 278, 308, 314, 323, 360, 361, 362, 368, 372, 385, 397 Malignant tumor, 323, 362, 372 Malnutrition, 309, 316, 321, 362, 367 Malondialdehyde, 48, 362 Mammography, 26, 127, 362 Mandible, 310, 326, 362, 387 Manifest, 316, 362 Man-made, 324, 362 Mannans, 346, 362 Maternal Behavior, 96, 362 Matrix metalloproteinase, 46, 115, 362 Meat, 335, 362, 389 Meat Products, 335, 362 Medial, 36, 111, 313, 315, 362, 371, 399 Mediate, 20, 25, 29, 34, 35, 53, 62, 64, 71, 73, 84, 100, 103, 178, 233, 336, 362

Mediator, 73, 95, 103, 116, 362, 391 Medical Staff, 336, 362 MEDLINE, 15, 273, 277, 279, 362 Medroxyprogesterone, 10, 118, 155, 156, 167, 206, 230, 264, 362 Medroxyprogesterone Acetate, 10, 118, 155, 156, 167, 230, 362 Medullary, 115, 334, 362 Megakaryocytes, 320, 362 Meiosis, 362, 397 Melanin, 363, 376, 401 Melanocytes, 363 Melanoma, 278, 321, 363 Membrane Glycoproteins, 363 Membrane Proteins, 71, 363 Memory, 4, 9, 11, 12, 13, 15, 33, 35, 46, 94, 104, 110, 154, 211, 213, 214, 256, 313, 333, 363 Menarche, 17, 236, 363, 387 Meninges, 325, 337, 363 Meningitis, 255, 363 Menorrhagia, 34, 363 Menstrual Cycle, 5, 11, 38, 45, 48, 216, 345, 361, 363, 371, 380, 381 Menstruation, 212, 311, 333, 337, 345, 361, 363, 380, 387 Mental, iv, 10, 11, 12, 13, 16, 17, 212, 218, 219, 225, 253, 272, 275, 276, 280, 294, 306, 325, 326, 327, 333, 335, 343, 347, 353, 354, 363, 383, 384, 389, 390, 402 Mental Disorders, 225, 353, 363, 383 Mental Health, iv, 17, 212, 225, 253, 272, 276, 363, 384 Mental Processes, 335, 363, 383 Mesencephalic, 37, 363, 386 Mesenchymal, 179, 340, 363 Mesenteric, 42, 69, 363, 379 Mesenteric Veins, 42, 363 Mesentery, 363, 394 Mesoderm, 364, 401 Meta-Analysis, 244, 364 Metabolite, 23, 27, 39, 166, 249, 250, 319, 334, 341, 342, 364 Metastasis, 57, 241, 362, 364 Metastatic, 78, 151, 213, 215, 231, 237, 239, 244, 364, 389 Metastatic cancer, 244, 364 Methamphetamine, 87, 364 Methotrexate, 105, 206, 364 Methyltransferase, 102, 122, 364 MI, 82, 93, 135, 222, 306, 364 Microbe, 364, 399

Index 419

Microbiology, 51, 308, 316, 317, 364 Microglia, 89, 316, 364, 366 Microgram, 145, 364 Micronutrients, 244, 364 Microorganism, 327, 364, 404 Microscopy, 70, 317, 364, 370 Microsomal, 70, 364 Microspheres, 337, 365 Microtubules, 365, 373 Middle Cerebral Artery, 68, 365 Migration, 87, 155, 365 Milligram, 156, 364, 365 Milliliter, 236, 320, 365 Mineralocorticoids, 233, 308, 365 Mitochondria, 46, 365 Mitosis, 315, 365 Mitotic, 74, 125, 365, 366 Mitotic Index, 74, 365 Mobility, 242, 365 Mobilization, 90, 242, 365 Modeling, 69, 132, 160, 365 Modification, 27, 196, 311, 347, 365, 384 Modulator, 52, 60, 62, 85, 87, 113, 143, 159, 175, 180, 215, 230, 365, 385, 390, 397, 399 Molecular Conformation, 116, 174, 365 Molecular Probes, 23, 365 Molecular Structure, 365, 400 Monitor, 33, 62, 69, 127, 331, 366, 369 Monoamine, 13, 331, 334, 366, 390, 401 Monoamine Oxidase, 13, 331, 334, 366, 390, 401 Monoclonal, 237, 357, 366, 384, 405 Monoclonal antibodies, 237, 366 Monocytes, 355, 358, 366 Mononuclear, 84, 349, 366, 401 Morphological, 95, 137, 338, 346, 363, 366 Morphology, 75, 148, 324, 366 Morula, 55, 319, 366 Motility, 366, 391 Motor Skills, 214, 366 Mucinous, 346, 366 Mucosa, 361, 366, 381, 395 Mucositis, 366, 398 Multiple sclerosis, 56, 67, 135, 236, 366 Muscle Fibers, 366, 367 Muscle relaxant, 235, 332, 366 Muscular Atrophy, 278, 367 Muscular Dystrophies, 337, 367 Mustard Gas, 357, 367 Mutagenic, 54, 367 Mutagenicity, 156, 171, 367 Mycosis, 367, 374

Mydriatic, 335, 367, 376 Myelin, 56, 366, 367 Myeloma, 351, 367 Myocardial infarction, 59, 156, 220, 222, 236, 330, 364, 367 Myocardial Ischemia, 219, 220, 221, 223, 312, 330, 367 Myocardium, 312, 364, 367 Myoglobin, 367, 379 Myometrium, 25, 34, 367 Myosin, 32, 322, 367 Myotonic Dystrophy, 278, 367 N Naive, 89, 367 Narcolepsy, 334, 340, 367 Nausea, 306, 336, 367, 374, 380, 402 NCI, 1, 212, 216, 224, 271, 326, 368 Neonatal, 18, 73, 92, 176, 190, 368 Neoplasia, 37, 101, 114, 235, 245, 278, 368 Neoplasm, 244, 368, 401 Neoplastic, 91, 125, 131, 361, 368 Nephrolithiasis, 4, 368 Nephropathy, 357, 368 Nerve Growth Factor, 89, 294, 368, 369 Nervous System, 11, 12, 17, 42, 51, 56, 67, 247, 258, 278, 307, 309, 311, 316, 318, 321, 322, 325, 327, 334, 337, 340, 346, 348, 349, 358, 362, 364, 366, 368, 369, 375, 391, 396, 401 Networks, 18, 140, 368 Neural, 12, 15, 33, 35, 36, 38, 42, 48, 58, 70, 294, 309, 311, 344, 364, 366, 368 Neural Pathways, 70, 368 Neural tube defects, 344, 368 Neurodegenerative Diseases, 97, 317, 368 Neuroendocrine, 35, 36, 43, 49, 66, 71, 75, 368 Neuroendocrinology, 36, 195, 368 Neuromuscular, 216, 259, 307, 332, 368, 381, 402 Neuromuscular Junction, 307, 368 Neuronal, 12, 16, 18, 20, 28, 36, 38, 40, 46, 48, 61, 62, 68, 85, 126, 169, 322, 368, 369 Neuronal Plasticity, 38, 369 Neuropeptide, 86, 369 Neuropsychological Tests, 256, 369 Neurotoxic, 16, 45, 369 Neurotoxicity, 158, 334, 369 Neurotrophins, 16, 38, 369 Neutrons, 310, 321, 357, 369, 384 Niacin, 256, 369, 401

420

Estrogen

Nitric Oxide, 24, 28, 33, 42, 61, 69, 75, 121, 196, 369 Nitrogen, 310, 311, 312, 331, 343, 344, 369, 401 Nocturia, 5, 293, 369 Norepinephrine, 177, 214, 308, 311, 336, 340, 369, 376 Nuclear Matrix, 23, 370 Nuclear Pore, 370 Nuclear Proteins, 96, 370 Nuclei, 83, 307, 310, 329, 343, 346, 347, 359, 361, 365, 369, 370, 378, 383 Nucleic acid, 351, 354, 369, 370, 371, 383, 384 Nucleic Acid Hybridization, 351, 370 Nucleolus, 370, 388 Nucleoproteins, 370 Nucleus Accumbens, 50, 370 O Observational study, 149, 169, 195, 216, 370 Ocular, 41, 370 Oculomotor, 363, 370 Odds Ratio, 7, 12, 370, 387 Oestrogen, 15, 84, 96, 98, 99, 101, 105, 109, 110, 116, 117, 125, 130, 131, 132, 133, 134, 135, 136, 139, 142, 144, 148, 149, 150, 156, 167, 168, 184, 186, 189, 195, 370 Office Visits, 53, 371 Ointments, 336, 371 Oligonucleotide Probes, 23, 371 Oncogene, 100, 108, 125, 133, 136, 150, 182, 186, 278, 371 On-line, 191, 305, 371 Oophorectomy, 244, 371 Opacity, 42, 323, 333, 371 Operon, 371, 381, 387 Ophthalmology, 181, 344, 371 Opsin, 371, 388 Optic Chiasm, 353, 371, 380 Optic Disk, 334, 371 Oral Health, 20, 371 Organ Culture, 371, 399 Orgasm, 145, 338, 372 Osmotic, 309, 372, 391 Ossicles, 372 Ossification, 372 Osteoarthritis, 176, 247, 274, 372 Osteoclasts, 80, 322, 372 Osteogenesis, 150, 196, 372 Osteogenic sarcoma, 372 Osteosarcoma, 195, 372

Otosclerosis, 255, 372 Outpatient, 4, 372 Ovalbumin, 99, 372 Ovarian Follicle, 331, 349, 372 Ovariectomy, 35, 61, 63, 73, 172, 174, 372 Ovaries, 49, 59, 64, 155, 214, 219, 233, 236, 247, 315, 371, 372, 387, 391, 401 Ovary, 39, 59, 66, 93, 233, 246, 312, 331, 341, 348, 370, 372, 395 Overdose, 305, 372 Overweight, 60, 161, 291, 292, 293, 372 Ovulation, 64, 137, 152, 236, 327, 345, 349, 361, 372 Ovum, 319, 331, 332, 347, 359, 366, 372, 373, 381, 401, 405 Ovum Implantation, 373, 401 Oxalate, 4, 373 Oxalic Acid, 322, 373 Oxidation, 8, 22, 84, 110, 159, 307, 314, 319, 332, 348, 359, 373, 402 Oxidation-Reduction, 319, 373 Oxidative Stress, 28, 40, 82, 136, 175, 178, 186, 373 Oxytocin, 80, 83, 96, 373 P Pachymeningitis, 363, 373 Paclitaxel, 109, 170, 177, 207, 373 Palindrome, 77, 373 Palliative, 332, 371, 373, 398 Pancreas, 307, 319, 335, 355, 373, 393, 394, 401 Pancreatic, 278, 346, 373 Pancreatic cancer, 278, 373 Pancreatic Juice, 346, 373 Pancreatitis, 169, 373 Panic, 353, 373, 374 Panic Disorder, 353, 374 Papilla, 374 Papillary, 240, 374 Papillomavirus, 20, 374 Paracoccidioidomycosis, 90, 374 Paralysis, 363, 374, 393 Parathyroid, 122, 174, 294, 374, 398 Parathyroid Glands, 374 Parathyroid hormone, 122, 174, 294, 374 Parietal, 13, 44, 374 Parietal Lobe, 374 Parkinsonism, 236, 358, 374 Paroxysmal, 278, 312, 374 Parturition, 25, 374, 381 Patch, 8, 118, 212, 358, 374, 400

Index 421

Pathogenesis, 20, 31, 41, 53, 67, 70, 91, 94, 261, 374 Pathologic, 315, 319, 321, 330, 352, 374, 387 Pathologic Processes, 315, 374 Pathologies, 73, 374 Pathophysiology, 32, 69, 72, 186, 237, 261, 374 Patient Education, 258, 286, 300, 302, 306, 375 Pectins, 232, 375 Pelvic, 34, 120, 258, 260, 293, 339, 375, 382 Pelvis, 307, 361, 372, 375, 402 Pemphigus, 296, 307, 375 Penicillin, 275, 313, 375 Penis, 338, 375, 376, 387 Peptide, 23, 24, 77, 79, 83, 89, 136, 311, 322, 339, 340, 344, 357, 375, 378, 382, 383 Peptide T, 136, 375 Perfusion, 347, 353, 375, 399 Pericardium, 375, 397 Perimenopausal, 154, 155, 252, 375 Perinatal, 25, 375 Periodontal disease, 243, 310, 375 Peripheral blood, 22, 44, 114, 355, 375 Peripheral Nervous System, 340, 368, 369, 375, 380, 393, 396 Peritoneal, 334, 375 Peritoneal Dialysis, 334, 375 Perivascular, 364, 376 Pesticides, 319, 376 PH, 53, 79, 106, 114, 117, 143, 187, 261, 293, 320, 376 Phagocytosis, 364, 376 Phallic, 344, 376 Pharmaceutical Preparations, 325, 342, 376 Pharmaceutical Solutions, 336, 376 Pharmacist, 234, 376 Pharmacologic, 261, 312, 376, 399 Pharynx, 346, 376, 403 Phenazopyridine, 275, 376 Phenotype, 20, 34, 72, 140, 376 Phenyl, 175, 376 Phenylalanine, 376, 401 Phenylephrine, 69, 376 Phenylpropanolamine, 6, 236, 257, 376 Phospholipases, 376, 391 Phospholipids, 343, 359, 376 Phosphorus, 322, 374, 376, 377 Phosphorylated, 101, 327, 377 Phosphorylates, 96, 377

Phosphorylation, 32, 48, 63, 86, 88, 96, 97, 99, 177, 377, 383, 402 Photocoagulation, 327, 377 Photodynamic therapy, 247, 377 Physical Examination, 212, 377 Physiologic, 47, 52, 62, 236, 309, 353, 363, 364, 377, 381, 386, 387, 400 Pigments, 318, 323, 377, 388 Pilot study, 143, 377 Pituitary Gland, 30, 75, 344, 377 Placenta, 25, 233, 315, 341, 342, 345, 377, 381 Placental Insufficiency, 295, 377 Plasma, 19, 29, 41, 65, 69, 92, 96, 97, 152, 222, 233, 236, 237, 309, 313, 322, 324, 326, 339, 344, 347, 348, 350, 360, 365, 367, 377, 387, 390, 391, 399 Plasma cells, 313, 367, 377 Plasma protein, 309, 339, 377, 391 Plasmapheresis, 254, 377 Plasticity, 10, 34, 38, 82, 92, 180, 377 Platelet Activation, 378, 392 Platelet Aggregation, 312, 369, 378, 398 Platelet-Derived Growth Factor, 190, 378 Platelets, 101, 369, 378 Platinum, 360, 378 Pleated, 357, 378 Pleomorphic, 370, 378 Pneumonia, 330, 378 Poisoning, 333, 356, 368, 378 Polycystic, 251, 279, 378 Polyethylene, 232, 378, 396 Polyethylene Glycols, 232, 378, 396 Polymerase, 378, 381, 387 Polymers, 232, 337, 378, 382 Polymorphic, 132, 326, 333, 378 Polymorphism, 64, 87, 94, 108, 134, 378 Polyposis, 328, 379 Polysaccharide, 314, 325, 379, 383 Polyunsaturated fat, 26, 175, 379, 398 Porphyrins, 247, 379 Portal Vein, 363, 379 Posterior, 44, 311, 316, 325, 336, 373, 379 Postnatal, 148, 379, 394 Postsynaptic, 86, 379, 391 Post-synaptic, 70, 379 Post-translational, 312, 379, 391 Potassium, 24, 42, 291, 309, 351, 365, 379 Potassium Channels, 42, 379 Potentiate, 49, 379 Potentiating, 50, 58, 311, 379 Potentiation, 139, 379, 392

422

Estrogen

Practice Guidelines, 276, 379 Precancerous, 325, 379, 380 Precipitating Factors, 324, 379 Preclinical, 12, 106, 119, 380 Precursor, 74, 95, 312, 315, 326, 331, 336, 337, 339, 340, 358, 369, 376, 380, 401 Prednisolone, 380 Prednisone, 275, 296, 380 Preeclampsia, 295, 380 Prefrontal Cortex, 36, 126, 380 Pregnancy Outcome, 135, 380 Pregnenolone, 64, 207, 380 Premalignant, 20, 379, 380 Premarin, 154, 242, 264, 380 Premenopausal, 34, 105, 236, 295, 380 Premenstrual, 71, 160, 200, 255, 380 Premenstrual Syndrome, 71, 160, 200, 380 Prenatal, 50, 79, 84, 94, 190, 338, 380 Preoptic Area, 100, 380 Presynaptic, 70, 86, 336, 369, 380 Presynaptic Terminals, 336, 380 Prevalence, 20, 140, 370, 380 Primary tumor, 57, 380 Probe, 104, 371, 380 Proenzyme, 340, 381 Progeny, 31, 329, 381 Progesterone receptor positive, 217, 381 Progestogen, 128, 144, 160, 222, 233, 234, 247, 381 Progressive, 16, 324, 326, 333, 337, 342, 349, 367, 368, 372, 378, 381, 387, 401 Projection, 63, 369, 380, 381, 384, 386 Prolactin, 19, 30, 75, 83, 102, 381 Proliferative Retinopathy, 6, 381 Proline, 327, 352, 381 Promoter, 20, 43, 67, 74, 86, 96, 98, 99, 107, 120, 144, 186, 233, 381 Promotor, 381, 388 Prone, 235, 245, 257, 381 Propantheline, 236, 257, 275, 381 Prophase, 381, 397 Prophylaxis, 6, 381 Prospective study, 139, 167, 360, 381 Prostaglandin, 24, 96, 381, 398 Prostaglandins A, 382 Prostate gland, 293, 382 Prostatic Hyperplasia, 261, 382 Protease, 256, 328, 382 Protease Inhibitors, 256, 382 Protein Binding, 172, 382, 399 Protein C, 63, 73, 97, 242, 309, 311, 314, 317, 357, 359, 382

Protein Conformation, 63, 97, 311, 357, 382 Protein Folding, 62, 382 Protein S, 75, 99, 173, 279, 319, 331, 382, 388, 395 Proteins, 19, 21, 22, 26, 40, 42, 43, 46, 62, 74, 76, 78, 85, 87, 93, 97, 101, 116, 144, 239, 260, 311, 312, 314, 319, 320, 323, 324, 326, 327, 328, 343, 351, 357, 362, 363, 366, 369, 370, 375, 377, 378, 382, 383, 386, 388, 389, 391, 393, 398, 400 Protein-Tyrosine Kinase, 347, 383 Proteinuria, 380, 383 Proteoglycan, 175, 383 Proteolytic, 310, 328, 340, 344, 383 Protocol, 217, 219, 234, 383 Protons, 310, 351, 356, 383, 384 Proto-Oncogene Proteins, 373, 383 Proto-Oncogene Proteins c-mos, 373, 383 Protozoa, 329, 364, 383 Proximal, 100, 336, 380, 383 Psoralens, 247, 383 Psychiatry, 11, 12, 36, 43, 106, 126, 135, 158, 344, 383 Psychic, 359, 363, 383, 390 Psychoactive, 383, 405 Psychological Tests, 212, 383 Psychology, 35, 48, 50, 157, 335, 383 Psychomotor, 333, 383 Psychophysiology, 145, 383 Puberty, 20, 214, 247, 249, 252, 291, 383 Public Health, 26, 36, 59, 276, 287, 384 Public Policy, 273, 384 Pulmonary, 40, 320, 329, 358, 384, 403 Pulmonary Artery, 320, 384, 403 Pulmonary Edema, 40, 384 Pulse, 75, 252, 295, 366, 384 Purines, 384, 391 Purulent, 384, 403 Pyramidal Cells, 86, 333, 384 Pyrazinamide, 275, 384 Pyrimidines, 384, 391 Q Quality of Life, 109, 117, 222, 384 Quaternary, 382, 384 Quinones, 22, 95, 384 R Race, 365, 384 Radiation, 154, 217, 308, 312, 340, 343, 345, 346, 352, 356, 357, 362, 384, 385, 389, 405 Radiation therapy, 217, 308, 343, 356, 357, 384, 405

Index 423

Radioactive, 320, 351, 354, 356, 357, 360, 362, 365, 366, 369, 384, 385, 389, 401, 405 Radioimmunoassay, 7, 385 Radioimmunotherapy, 385 Radioisotope, 371, 385 Radiolabeled, 357, 384, 385, 405 Radiological, 244, 385 Radiologist, 71, 385 Radiology, 71, 385 Radiotherapy, 231, 321, 357, 384, 385, 405 Raloxifene, 28, 34, 60, 108, 110, 132, 141, 142, 143, 144, 145, 207, 266, 385, 390 Randomized clinical trial, 44, 385 Randomized Controlled Trials, 14, 385 Reaction Time, 216, 295, 386 Reactive Oxygen Species, 40, 386 Reagent, 65, 361, 373, 386 Receptivity, 55, 87, 386 Receptor Aggregation, 141, 386 Receptors, Serotonin, 386, 391 Recombinant, 35, 106, 167, 177, 191, 386, 403 Recombination, 329, 346, 347, 386 Rectal, 317, 386, 396 Rectum, 55, 314, 321, 327, 328, 335, 346, 354, 358, 382, 386 Recurrence, 4, 27, 216, 217, 231, 285, 325, 386 Red Nucleus, 316, 386 Reductase, 25, 53, 103, 260, 261, 315, 344, 364, 386 Refer, 1, 321, 328, 336, 339, 344, 346, 360, 367, 369, 385, 386, 400, 403 Reflex, 36, 386 Refraction, 313, 386, 393 Regeneration, 12, 344, 386 Regimen, 8, 30, 121, 181, 231, 275, 284, 338, 386 Regurgitation, 346, 386 Relapse, 239, 244, 386 Relative risk, 9, 15, 222, 386 Relaxant, 387 Remission, 386, 387 Renal Artery, 69, 387 Renal failure, 258, 333, 387 Renal pelvis, 358, 387 Renin, 33, 312, 387 Renin-Angiotensin System, 33, 387 Repressor, 41, 76, 79, 98, 371, 387 Reproduction Techniques, 380, 387 Reproductive History, 18, 30, 387 Reproductive system, 74, 219, 382, 387

Research Design, 69, 387 Resorption, 29, 234, 310, 320, 372, 387 Respiration, 323, 366, 387 Response Elements, 27, 42, 51, 80, 84, 87, 89, 116, 387 Response rate, 257, 388 Restoration, 157, 388, 405 Retina, 312, 329, 334, 358, 371, 381, 388, 389 Retinal, 6, 173, 334, 371, 388 Retinoblastoma, 103, 278, 388 Retinoid, 74, 116, 388 Retinol, 74, 388 Retinopathy, 6, 259, 334, 388 Retrograde, 63, 388 Rheumatism, 388 Rheumatoid, 67, 243, 388 Rheumatoid arthritis, 67, 243, 388 Rhinitis, 340, 381, 388 Rhodopsin, 371, 388 Ribonuclease, 81, 97, 388 Ribonucleoproteins, 370, 388 Ribose, 308, 388 Ribosome, 99, 388, 400 Rigidity, 32, 374, 377, 389 Rod, 317, 326, 389 Ryanodine, 24, 389 S Saliva, 389 Salivary, 135, 335, 373, 389, 395 Salivary glands, 135, 335, 389 Saponin, 167, 389 Saturated fat, 26, 389 Scans, 12, 44, 389 Schizoid, 389, 405 Schizophrenia, 106, 389, 405 Schizotypal Personality Disorder, 389, 405 Scleroproteins, 357, 389 Sclerosis, 51, 134, 278, 315, 366, 389 Screening, 5, 26, 74, 83, 167, 169, 233, 234, 244, 260, 284, 285, 296, 327, 389, 402 Sebaceous, 333, 357, 389, 404 Sebaceous gland, 333, 357, 389, 404 Secondary tumor, 364, 389 Secretion, 19, 66, 68, 102, 174, 334, 337, 340, 351, 355, 358, 364, 365, 390, 404 Secretory, 75, 91, 237, 390 Sedative, 311, 327, 353, 390 Sedentary, 259, 291, 390 Sediment, 390, 402 Segmental, 63, 390 Segmentation, 390

424

Estrogen

Seizures, 51, 333, 374, 390 Selegiline, 295, 390 Selenium, 244, 390 Self Care, 307, 390 Sella, 377, 390 Semen, 84, 338, 382, 390 Senescence, 33, 84, 390 Senile, 17, 200, 372, 390 Senility, 17, 390 Sensibility, 311, 352, 390 Sensitization, 50, 63, 240, 390 Sequence Homology, 375, 391 Sequencing, 23, 391 Serine, 126, 339, 383, 391, 401 Serotonin, 71, 126, 214, 311, 345, 366, 369, 386, 391, 401 Serous, 339, 391 Serum Albumin, 385, 391 Sex Behavior, 360, 391 Sex Behavior, Animal, 360, 391 Sex Characteristics, 308, 312, 371, 383, 391, 398 Sex Determination, 279, 391 Sex Hormone-Binding Globulin, 44, 391 Sexually Transmitted Diseases, 253, 391 Shock, 40, 86, 101, 102, 125, 391, 400 Side effect, 14, 34, 68, 215, 229, 230, 244, 255, 257, 263, 309, 319, 332, 391, 399 Signal Transduction, 18, 19, 58, 71, 76, 99, 133, 322, 391 Signs and Symptoms, 386, 387, 392, 402 Skeletal, 39, 69, 88, 144, 221, 238, 242, 312, 326, 332, 337, 367, 392, 393 Skeleton, 39, 228, 307, 320, 344, 357, 381, 392, 399 Skin graft, 392, 394 Skull, 368, 392, 397 Small intestine, 293, 324, 326, 337, 351, 356, 392, 401 Smoking Cessation, 259, 392 Smooth Muscle Tumor, 344, 392 Sneezing, 236, 392, 395 Social Environment, 384, 392 Social Security, 385, 392 Sodium, 86, 232, 252, 253, 255, 309, 310, 351, 365, 392, 396 Soft tissue, 320, 392 Solid tumor, 312, 392 Solitary Nucleus, 316, 392 Solvent, 318, 342, 372, 376, 392 Soma, 384, 392, 393

Somatic, 244, 308, 359, 362, 365, 375, 380, 393, 397, 403 Somatic mutations, 244, 393 Somatostatin, 118, 393 Sound wave, 385, 393 Soy Proteins, 29, 393 Soybean Oil, 379, 393 Spasm, 314, 363, 393, 398 Spastic, 236, 393 Spasticity, 317, 332, 393 Spatial disorientation, 336, 393 Specialist, 296, 335, 393 Specificity, 40, 70, 74, 88, 98, 309, 322, 339, 393, 399 Spectrum, 8, 34, 75, 364, 393 Sperm, 136, 166, 186, 312, 326, 330, 393 Spermatogenesis, 249, 393 Sphincter, 254, 255, 257, 275, 393, 395 Spinal cord, 63, 120, 315, 317, 321, 325, 326, 337, 338, 346, 363, 368, 373, 375, 386, 393, 396 Spinous, 341, 394 Spleen, 351, 361, 394 Splenic Vein, 363, 379, 394 Spontaneous Abortion, 200, 380, 394 Sporadic, 132, 241, 368, 388, 394 Squamous, 20, 341, 394 Squamous cell carcinoma, 20, 341, 394 Squamous cells, 394 Stabilization, 37, 99, 257, 394 Staging, 389, 394 Steel, 326, 394 Stem Cells, 179, 394 Stents, 261, 394 Sterile, 374, 394 Sterility, 118, 137, 332, 355, 394 Stillbirth, 380, 394 Stimulant, 321, 334, 351, 357, 364, 394 Stimulus, 74, 330, 337, 342, 355, 356, 386, 394, 398 Stomach, 307, 316, 335, 341, 346, 348, 351, 360, 367, 376, 392, 394, 395 Stool, 327, 354, 358, 395 Strand, 22, 88, 99, 328, 378, 395 Streptomycin, 331, 395 Stress, 6, 36, 64, 193, 200, 236, 252, 255, 257, 290, 296, 316, 324, 331, 367, 373, 388, 395 Stress incontinence, 6, 236, 255, 257, 395 Stress urinary, 257, 395 Stria, 36, 395 Striatum, 50, 370, 395

Index 425

Stroke, 15, 16, 21, 41, 61, 68, 157, 219, 222, 223, 225, 236, 252, 253, 272, 285, 323, 395 Stroma, 73, 395 Stromal, 74, 90, 92, 100, 150, 196, 261, 320, 339, 395 Stromal Cells, 150, 196, 320, 395 Structure-Activity Relationship, 141, 191, 395 Subacute, 354, 395 Subclinical, 142, 354, 390, 395 Subcutaneous, 35, 337, 358, 395, 404 Subiculum, 350, 395 Submaxillary, 340, 395 Subspecies, 393, 395 Substance P, 364, 381, 390, 395, 396 Substrate, 249, 338, 396, 401 Subtrochanteric, 350, 396 Sulfates, 275, 396 Sulfuric acid, 396 Superovulation, 137, 396 Superoxide, 136, 196, 396 Superoxide Dismutase, 136, 396 Supplementation, 5, 27, 118, 135, 147, 158, 168, 194, 216, 229, 230, 231, 258, 396 Support group, 253, 396 Suppository, 378, 396 Suppression, 60, 83, 194, 396 Suppressive, 67, 249, 396 Supraspinal, 63, 317, 396 Sweat, 333, 352, 396 Sweat Glands, 333, 396 Sympathetic Nervous System, 33, 316, 396 Sympathomimetic, 235, 236, 334, 336, 341, 364, 369, 376, 396, 401 Symphysis, 326, 382, 396 Symptomatic, 218, 373, 397 Synapse, 38, 103, 119, 308, 368, 380, 397, 400 Synapsis, 397 Synaptic, 10, 12, 70, 86, 92, 369, 392, 397 Syncytium, 347, 397 Synergistic, 87, 381, 397 Systemic lupus erythematosus, 70, 216, 222, 295, 397 Systolic, 221, 352, 397 Systolic blood pressure, 221, 397 T Talus, 313, 397, 399 Tear Gases, 357, 397 Telangiectasia, 279, 397 Telomerase, 93, 100, 141, 397 Temporal, 44, 350, 397

Tendon, 346, 393, 397 Testicle, 348, 397 Testicular, 101, 167, 315, 397 Testis, 190, 233, 312, 341, 348, 371, 397 Testosterone, 49, 220, 229, 233, 249, 291, 296, 307, 311, 312, 344, 386, 391, 397 Tetany, 374, 398 Thalamic, 316, 398 Thalamic Diseases, 316, 398 Thalamus, 321, 334, 359, 380, 398 Therapeutics, 71, 131, 160, 233, 266, 366, 398 Thermal, 313, 321, 335, 369, 398 Third Ventricle, 353, 398 Thorax, 307, 361, 398, 403 Threonine, 375, 383, 391, 398 Threshold, 46, 342, 352, 398 Thrombin, 101, 344, 378, 382, 398 Thromboembolism, 116, 398 Thrombomodulin, 382, 398 Thrombosis, 45, 115, 116, 120, 221, 382, 395, 398 Thromboxanes, 315, 398 Thymidine, 74, 398 Thyroid, 86, 87, 94, 103, 116, 160, 322, 374, 398, 399, 401 Thyroid Gland, 374, 399 Thyroxine, 309, 376, 399 Tibia, 313, 344, 399 Tissue Culture, 37, 61, 123, 182, 399 Tissue Distribution, 43, 399 Tolerance, 89, 308, 348, 399 Tome, 209, 399 Tomography, 12, 43, 329, 389, 399 Tone, 4, 42, 52, 62, 257, 373, 393, 399 Tonus, 399 Tooth Preparation, 308, 399 Topical, 66, 161, 240, 315, 342, 352, 399 Toremifene, 54, 266, 399 Toxaemia, 380, 399 Toxic, iv, 316, 318, 329, 332, 339, 340, 353, 390, 399, 400 Toxicity, 22, 48, 66, 87, 156, 168, 244, 248, 337, 376, 399 Toxicology, 41, 46, 124, 141, 147, 157, 158, 159, 168, 169, 171, 175, 179, 182, 196, 274, 399 Toxin, 255, 340, 399, 400 Trace element, 321, 400 Trachea, 376, 398, 399, 400 Traction, 326, 400 Tragacanth, 232, 400

426

Estrogen

Transcriptase, 397, 400 Transcription Factors, 65, 97, 388, 400 Transdermal, 110, 115, 116, 117, 118, 149, 151, 159, 174, 240, 400 Transduction, 35, 40, 76, 391, 400 Transfection, 49, 67, 146, 319, 346, 400 Transferases, 53, 400 Transgenes, 43, 400 Translation, 63, 311, 400 Translocation, 48, 98, 400 Transmitter, 307, 316, 336, 356, 362, 369, 400, 401 Transplantation, 257, 326, 338, 353, 400 Trauma, 46, 217, 255, 317, 333, 349, 373, 398, 400 Tremor, 363, 374, 400 Tricyclic, 235, 236, 275, 311, 336, 353, 400 Triglyceride, 169, 260, 352, 401 Trophoblast, 90, 176, 319, 401 Truncal, 242, 401 Trypsin, 28, 340, 381, 401 Tryptophan, 327, 391, 401 Tubal ligation, 295, 401 Tubercle, 370, 401 Tuberous Sclerosis, 279, 401 Tumor marker, 319, 401 Tumor model, 57, 401 Tumor Necrosis Factor, 86, 401 Tumor suppressor gene, 176, 401 Tumorigenic, 22, 31, 401 Tumour, 125, 176, 314, 346, 401 Type 2 diabetes, 9, 60, 260, 401 Tyramine, 366, 401 Tyrosine, 23, 103, 106, 195, 336, 383, 401 U Unconscious, 353, 402 Uncoupling Agents, 357, 402 Uraemia, 373, 402 Uremia, 387, 402 Ureters, 358, 387, 402 Urethra, 257, 293, 318, 375, 382, 402 Urethritis, 236, 402 Uric, 4, 384, 402 Urinalysis, 257, 402 Urinary tract, 5, 8, 53, 143, 150, 247, 258, 317, 334, 376, 402 Urinary tract infection, 5, 143, 258, 317, 402 Urinate, 293, 402, 404 Urodynamic, 257, 402 Urogenital, 5, 130, 252, 347, 402

Urology, 4, 109, 143, 150, 170, 177, 193, 261, 402 Uterine Contraction, 307, 373, 402 V Vaccine, 308, 383, 402 Vagina, 7, 32, 218, 325, 334, 335, 363, 387, 402, 403 Vaginal, 5, 8, 32, 66, 140, 155, 222, 230, 246, 247, 264, 306, 396, 403 Vaginitis, 154, 200, 403 Vagus Nerve, 392, 401, 403 Valves, 317, 403 Varices, 317, 403 Vascular endothelial growth factor, 58, 75, 99, 136, 158, 403 Vascular Resistance, 31, 403 Vasculitis, 373, 403 Vasoactive, 52, 403 Vasodilation, 61, 403 Vasodilator, 31, 321, 336, 351, 403 Vasomotor, 45, 52, 73, 193, 229, 342, 403 Vector, 400, 403 Vein, 312, 356, 363, 369, 379, 394, 403 Venoms, 332, 403 Venous, 41, 42, 116, 258, 382, 403 Venter, 144, 403 Ventral, 78, 353, 370, 403 Ventricle, 314, 324, 350, 370, 384, 397, 398, 403 Venules, 320, 322, 339, 403 Vertebrae, 243, 356, 393, 403 Vertebral, 128, 403 Vesicular, 349, 364, 403 Vestibular, 255, 403 Vestibule, 403, 404 Veterinary Medicine, 273, 404 Villous, 324, 404 Viral, 20, 61, 200, 255, 338, 347, 400, 401, 404 Virilization, 249, 404 Virulence, 399, 404 Virus, 66, 317, 340, 347, 348, 355, 400, 404 Visceral, 60, 63, 110, 316, 359, 403, 404 Visceral Afferents, 316, 403, 404 Visceral fat, 60, 110, 404 Vitellogenin, 79, 80, 86, 92, 99, 100, 183, 404 Vitiligo, 383, 404 Vitreous, 334, 358, 388, 404 Vitreous Hemorrhage, 334, 404 Vivo, 19, 23, 25, 26, 28, 29, 43, 46, 48, 51, 56, 58, 61, 63, 64, 68, 92, 96, 103, 111,

Index 427

115, 125, 126, 136, 142, 157, 173, 182, 337, 346, 350, 354, 398, 404 Void, 73, 236, 404 Volition, 356, 404 Vulgaris, 80, 208, 307, 404 W Wakefulness, 333, 404 Weight Gain, 65, 290, 291, 292, 404 Weight-Bearing, 218, 293, 295, 404 White blood cell, 313, 358, 361, 367, 377, 405 Windpipe, 376, 398, 405 Withdrawal, 11, 35, 48, 69, 72, 118, 149, 157, 195, 230, 333, 405

Womb, 287, 387, 402, 405 Wound Healing, 87, 242, 312, 344, 362, 405 X Xenograft, 73, 113, 313, 401, 405 X-ray, 125, 217, 231, 320, 329, 330, 345, 346, 357, 362, 369, 384, 385, 389, 405 X-ray therapy, 357, 405 Y Yeasts, 346, 376, 405 Z Zebrafish, 171, 405 Zygote, 329, 405 Zymogen, 340, 381, 382, 405

428

Estrogen

Estrogen - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Estrogen Therapy - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Influenza A - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Hepatitis A Vaccine: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Foot and Mouth Disease - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Butternut Squash: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Facial Paralysis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Wine - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Breast Augmentation - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Premenstrual Dysphoric Disorder - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Anagrelide: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Peanut Allergy: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Cauda Equina Syndrome - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Magnesium Citrate: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Lipomas - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Barbiturates - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Cephalexin - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Body Dysmorphic Disorder: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Lymphedema - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Dermabrasion: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Septra: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Vaginitis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Feet - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Glioblastoma Multiforme - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Female Infertility - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Living Will - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Hip Pain: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Benzene - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Marburg Virus: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Erythema Multiforme - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Alopecia Areata - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Estrogen - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Estrogen Therapy - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Influenza A - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Hepatitis A Vaccine: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Foot and Mouth Disease - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Butternut Squash: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Facial Paralysis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Wine - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Breast Augmentation - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Premenstrual Dysphoric Disorder - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Anagrelide: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Peanut Allergy: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Cauda Equina Syndrome - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Magnesium Citrate: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Lipomas - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Barbiturates - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Cephalexin - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Body Dysmorphic Disorder: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Lymphedema - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Dermabrasion: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Septra: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Vaginitis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Feet - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Glioblastoma Multiforme - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Female Infertility - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Living Will - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Hip Pain: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Benzene - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Marburg Virus: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Erythema Multiforme - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Alopecia Areata - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Recommend Documents