1600 John F. Kennedy Blvd. Suite 1800 Philadelphia, PA 19103-2899 REPRODUCTIVE ENDOCRINOLOGY AND INFERTILITY Copyright © 2007 by Mosby, Inc., an affiliate of Elsevier Inc.
ISBN- 13: 978–0–323–04054–9 ISBN- 10: 0–323–04054–3
All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Health Sciences Rights Department in Philadelphia, PA, USA: phone: (+1) 215 239 3804, fax: (+1) 215 239 3805, e-mail:
[email protected]. You may also complete your request on-line via the Elsevier homepage (http://www.elsevier.com), by selecting “Customer Support” and then “Obtaining Permissions”.
Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment, and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on their own experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the Authors assume any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book. The Publisher
Library of Congress Cataloging-in-Publication Data Alvero, Ruben. Reproductive endocrinology and infertility : the requisites in obstetrics and gynecology/Ruben Alvero, William D. Schlaff.—1st ed. p. cm. ISBN 0–323–04054–3 1. Endocrine gynecology. 2. Obstetrical endocrinology. 3. Infertility. I. Schlaff, William D. II. Title RG159.A48 2007 618.1—dc22 2006048137
Acquisitions Editor: Rebecca Gaertner Publishing Services Manager: Frank Polizzano Senior Project Manager: Peter Faber Design Direction: Steven Stave
Printed in the United States of America. Last digit is the print number: 9 8 7 6 5 4 3 2 1
Dr. Alvero dedicates this book to
Karen, Erika, Alicia, and William. Dr. Schlaff dedicates this book to
Lorraine, Daniel, Maura, and Julia.
CONTRIBUTORS
Ruben Alvero, MD Associate Professor, Advanced Reproductive Medicine, Department of Obstetrics and Gynecology, University of Colorado Health Sciences Center, Aurora, Colorado
Alicia Armstrong, MD Combined Federal Fellowship in Reproductive Endocrinology, Walter Reed Army Medical Center; National Naval Medical Center; Uniformed Services University of the Health Sciences F. Edward Hébert School of Medicine; and National Institutes of Health, Bethesda, Maryland
Linda A. Barbour, MD, MSPH, FACP Associate Professor, Division of Endocrinology, Metabolism, and Diabetes, Departments of Medicine and Obstetrics and Gynecology, University of Colorado Health Sciences Center, Aurora, Colorado
Bruce R. Carr, MD Paul C. MacDonald, MD Distinguished Chair and Director, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, UT Southwestern Medical School, Dallas, Texas
William H. Catherino, MD, PhD Assistant Professor, Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences F. Edward Hébert School of Medicine; Combined Federal Fellowship in Reproductive Endocrinology and Infertility, National Institutes of Health, Bethesda, Maryland
Seth G. Derman, MD Clinical Assistant Professor of Obstetrics, Gynecology, and Reproductive Sciences, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, New Brunswick; Director, Reproductive Endocrinology and IVF Program, Princeton IVF, Delaware Valley OB/GYN and Infertility Group, Lawrenceville, New Jersey
Sheri M. Dey, MD Division of Urology, Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorado
Jani R. Jensen, MD, MS Fellow in Reproductive Endocrinology and Infertility, UT Health Sciences Center at San Antonio, San Antonio, Texas
Shahryar K. Kavoussi, MD, MPH Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Michigan Medical School, Ann Arbor, Michigan
vii
Contributors
Andrew J. Levi, MD Attending, Division of Reproductive Endocrinology and Infertility, Bridgeport Hospital, Bridgeport, Connecticut
Richard Scott Lucidi, MD Chief, Reproductive Endocrinology Infertility, Department of Obstetrics and Gynecology, Tripler Army Medical Center, Honolulu, Hawaii
Kirsten J. Lund, MD Associate Professor, Department of Obstetrics and Gynecology, University of Colorado Health Sciences Center, Aurora; Staff Physician, University of Colorado Hospital, Denver, Colorado
Deborah L. Manzi-Smith, MD viii
Director, Assisted Reproduction, Advanced Reproductive Medicine, Department of Obstetrics and Gynecology, University of Colorado Health Sciences Center, Aurora, Colorado
Randall B. Meacham, MD Associate Professor , Division of Urology, Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorado
Jesse N. Mills, MD Chief Resident, Division of Urology, Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorado
Randall Odem, MD Professor and Chief, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Washington University in St. Louis School of Medicine, St. Louis, Missouri
Mark Payson, MD Combined Federal Fellowship in Reproductive Endocrinology, Walter Reed Army Medical Center; National Naval Medical Center; Uniformed Services University of the Health Sciences F. Edward Hébert School of Medicine; and National Institutes of Health, Bethesda, Maryland
Rocio I. Pereira, MD Instructor in Medicine, Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Colorado School of Medicine at Denver and Health Sciences Center, Aurora; Associate Investigator, Denver VA Medical Center, Denver, Colorado
William D. Petok, PhD Clinical Assistant Professor, University of Colorado Health Sciences Center, Denver, Colorado
John M. Randolph, Jr., MD Professor and Director, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology; Associate Research Scientist, Reproductive Sciences Program, University of Michigan Medical School, Ann Arbor, Michigan
Contributors
Randal D. Robinson, MD Associate Professor of Obstetrics and Gynecology, Uniformed Services University of Health Sciences, Bethesda, Maryland; Chairman and Residency Program Director, Department of Obstetrics and Gynecology, San Antonio Uniformed Services Health Education Consortium, Wilford Hall Medical Center, Lackland AFB, and Brooke Army Medical Center, San Antonio, Texas
Stacey Leigh Rubin, MD Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Washington University in St. Louis School of Medicine, St. Louis, Missouri
William D. Schlaff, MD Professor and Chief, Section of Reproductive Endocrinology and Infertility, University of Colorado Health Sciences Center, Aurora, Colorado
Stephen M. Scott, MD Associate Professor, Department of Obstetrics and Gynecology, University of Colorado Health Sciences Center; Chairman, Department of Pediatrics and Adolescents, The Children’s Hospital, Denver, Colorado
David B. Seifer, MD Professor of Obstetrics, Gynecology and Reproductive Sciences, Mount Sinai School of Medicine, New York, New York; Co-Director, Genesis Fertility And Reproductive Medicine, Maimonides Medical Center, Brookyln, New York
Michael D. Wittenberger, MD Assistant Professor, Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences F. Edward Hébert School of Medicine; Combined Federal Fellowship in Reproductive Endocrinology and Infertility, National Institutes of Health, Walter Reed Medical Center, Bethesda, Maryland
Craig A. Witz, MD Associate Professor and Chief, Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio, Texas
Lynda J. Wolf, MD Assistant Professor and Director, Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Medical University of Ohio at Toledo; Director, Fertility Center, Department of Obstetrics and Gynecology, Richard D. Ruppert Health Center, Toledo, Ohio
ixix
The Requisites in Obstetrics and Gynecology
FOREWORD We are living in an era of rapidly changing technologies, in which technical and now many medical services can be performed remotely and often impersonally. At the same time, the cultures of medical practice and training have been radically transformed, as resident work rules, the use of new xi procedures and equipment, and changing perspectives on the practice of medicine have evolved quite significantly over the past two decades. As a consequence, the overall approach to medical education, the slower rate of increasing responsibilities given to residents during their training, and the tolerance for non-standardized approaches to patient care have likewise changed, with both positive and negative consequences. Thus, the basics, the “requisites,” needed to operate in the current environment likewise have evolved. In this series, the editors and chapter authors crystallize the foundations needed for independent practitioners to survive and, in fact, thrive in the current medical climate. We hope readers will view the materials as the basis for evolving sophistication in the practice of obstetrics and gynecology. Mark I. Evans, MD
PREFACE It has been a wonderful experience for us to complete the first edition of Reproductive Endocrinology and Infertility for the Requisites in Obstetrics and Gynecology series. We have brought together an outstanding set of practitioners and academicians to cover the various topics in this rapidly growing field, and we feel fortunate to have worked with them. The first half of the book broadly covers normal physiology and pathophysiology not related to infertility. Some basic science is necessary to understand this area, and the first chapter addresses steroids and prostaglandins, which play an important role in the normal menstrual cycle. The normal xiii menstrual cycle, as well as normal pubertal development, is then reviewed, along with some of the aberrations that occur during adolescence. Special focus is given to amenorrhea, which may be a primary disorder or can occur after normal female cyclicity has been established. Polycystic ovarian syndrome is the most common endocrinopathy in women of reproductive age, so, along with other hyperandrogenic disorders, it gets its own chapter. Abnormal uterine bleeding is one of the most common causes for visits to the gynecologist’s office, and this is ably addressed in its own chapter. As the population ages, the issues faced by menopausal women have moved to the forefront of society, and the climacteric and osteoporosis each are considered in their own chapters. Human sexuality is an important yet surprisingly little-recognized aspect of reproductive life, and it too gets ample treatment in this book. Infertility is a critical area for most reproductive endocrinologists. With one in eight couples suffering from this disorder, this probably is the most common reason to visit a reproductive endocrinologist. An entire chapter is devoted to evaluating the infertile female, and then another to male factor infertility. Ovulatory dysfunction is related to polycystic ovarian syndrome but is reemphasized in its own chapter. Anatomic infertility and endometriosis are similarly related, but each receives separate treatment, to ensure that the nuances are amply considered. With more women delaying childbearing to pursue careers, diminished ovarian reserve is an increasingly important infertility diagnosis, and it is incumbent on the practitioner to adequately counsel patients in this complicated and emotional area. Equally trying for the affected couple is recurrent pregnancy loss, and this topic also receives its own chapter. Finally, assisted reproductive technologies constitute a mainstay of treatment for the infertile couple regardless of their diagnosis. Indeed, greater than 1% of all babies born in the United States now come from in vitro fertilization, so this critical treatment modality gets its own chapter as well. We hope that all of these chapters will provide the reader with a comprehensive view of the field of reproductive endocrinology and infertility. Although a subspecialty of obstetrics and gynecology, this field surfaces
Preface
very commonly in many clinical practices, including family medicine, internal medicine, and of course obstetrics and gynecology. This book is the result of an impressive effort by the contributing chapter authors, and our jobs were greatly simplified by the high quality of the product that they submitted. We would like to thank them for their efforts. Finally, we would like to thank our families for their support throughout this process.
xiv
1 STEROIDS AND PROSTAGLANDINS Shahryar K. Kavoussi and John M. Randolph, Jr. DEFINITIONS Steroids Pregnanes Androstanes Estranes Prostaglandins
A family of chemical compounds with a structure consisting of three 6-carbon rings and an adjoined 5-carbon ring A group of steroids, including progestins, glucocorticoids, and mineralocorticoids, with a 21-carbon structure A group of steroids, consisting primarily of androgens, with a 19-carbon structure A group of steroids, consisting primarily of androgens, with an 18-carbon structure Fatty acid–derived compounds, containing 20 carbons in the basic structure, that have a multitude of tissue effects
STEROIDS The main classes of steroid hormones are progestins, androgens, estrogens, glucocorticoids, and mineralocorticoids. They are pervasive in nature, present in animal and plant systems, and integral to homeostasis and physiology in humans. Based on structure and receptor activity, steroid hormones are lipophilic compounds that affect various functions in different organ systems in an endocrine, autocrine, paracrine, or intracrine fashion. The basic structural unit of a steroid is termed perhydrocyclopentaphenanthrene. This steroid “nucleus” is composed of three 6-carbon rings (phenanthrene) and an adjoining 5-carbon ring (cyclopentane). The various natural steroid hormones are produced via a series of interrelated pathways. Acetate (2 carbons) molecules undergo a complex series of reactions to produce cholesterol (27 carbons), the essential structural foundation that is modified to yield steroid hormones. The synthesis of cholesterol from acetate is performed by all of the organs that produce steroids, with the exception of the placenta. Sex steroids, mineralocorticoids, and glucocorticoids are end products that are characterized by a specified number of carbons with side chain carbons added to the steroid nucleus. Pregnanes (progestins, glucocorticoids, and mineralocorticoids) have 21 carbons, androstanes (androgens) have 19 carbons, and estranes (estrogens) have
3
Reproductive Endocrinology and Infertility
18 carbons (Fig. 1-1). The enzymes that facilitate the reactions in the steroid pathways are members of the cytochrome P-450 family.
Physiology and Clinical Presentation
4
The ovaries, adrenals, and placenta function as the major organs that produce steroids in women. The ovaries produce estrogens, progestins, and androgens. Because of a lack of the enzymes 21α-hydroxylase, 11β-hydroxylase, and 18hydroxylase, ovaries do not produce glucocorticoids or mineralocorticoids. The adrenal glands have limited amounts of the enzyme aromatase to convert androgens to estrogens and produce lesser amounts of estrogen. The main androgens synthesized by the ovaries are testosterone and androstenedione, a portion of which is secreted as androgen and most of which is converted to estradiol and estrone. The theca-granulosa “two-cell system” accounts for the production of these steroids. The production of androgen occurs in the theca cell, where luteinizing hormone (LH) acts on its receptor at the cell surface, activating cyclic adenosine monophosphate (cAMP). cAMP acts on cholesterol to produce androstenedione, some of which is converted to testosterone. These two androgens diffuse out of the theca cell and cross the adjacent basement membrane into the granulosa cell, where aromatase catalyzes the conversion of androstenedione to estrone and testosterone to estradiol. The transport of lipophilic steroids through the bloodstream is predominantly through binding to hydrophilic proteins, such as steroid-binding globulins and albumin. Sex hormone–binding globulin (SHBG) is a β-globulin that binds most estradiol and testosterone molecules in the bloodstream.
Figure 1-1 Basic steroid structures.
C27 Cholesterol
C21 Progesterone
C19 Testosterone Androstenedione C18 Estrone Estradiol Estriol
Steroids and Prostaglandins Table 1-1 Fractions of Bound and Unbound Estrogen and Testosterone
Estrogen Testosterone
SHBG
Albumin
Free Hormone
69% 69%
30% 30%
1% 1%
SHBG, sex hormone–binding globulin.
Albumin binds with less affinity to most of the remaining circulating hormone. Corticosteroid-binding globulin (CBG) binds to progesterone and corticosteroids. Free, unbound hormone, which is the biologically active fraction, is present in the bloodstream in relatively small quantities (Table 1-1). Although the percentage of free, active hormone seems low, changes in the concentration of SHBG can produce a dramatic effect in the relative levels of unbound hormone, exerting a profound physiologic effect. As listed in Table 1-2, various physiologic and disease processes can affect the concentration of SHBG. Weight gain may modestly decrease SHBG levels, resulting in an increase in free androgen from 1% to 2%. This seemingly subtle increase may manifest as hirsutism as a result of a twofold increase in free androgen levels. In such a scenario, it may be important to measure the free androgen concentrations because total androgen levels may not reflect a clinically significant increase if hirsutism is due to decreased SHBG levels. Hormones that are transported in the bloodstream produce their biologic effects at target cells in various organ systems. Each class of steroid hormone has a corresponding steroid receptor (or receptors). In contrast to glycoprotein hormones, which bind to cell-surface receptors, steroid hormones traverse cell membranes via simple diffusion and interact with receptors located within the cell. It is believed that estrogens, androgens, and progesterone bind to steroid receptors within the nucleus. Glucocorticoids and mineralocorticoids bind to steroid receptors in the cytoplasm and subsequently are transported to the nucleus. When a steroid is transported to the cell nucleus as part of a hormonereceptor complex, it binds to DNA hormone response elements, and transcription of mRNA is initiated. This interaction leads to changes in the DNA that result in effects at many levels, including an increased affinity to bind the remaining available estrogen and an amplification of the responsiveness of the progesterone receptor gene. Antiestrogens, such as the triphenylethylene clomiphene citrate, have the opposite effect on estrogen activity. They bind to estrogen receptors and result in the interaction with hormone response elements, but minimal transcription occurs, and the affinity of Table 1-2 Physiologic and Disease Processes and Effects on Sex Hormone–Binding Globulin (SHBG)
Increase SHBG
Decrease SHBG
Estrogen use/hypersecretion Thyroid hormone use/hypersecretion Pregnancy Anorexia nervosa
Testosterone use/hypersecretion Hypothyroidism Obesity/polycystic ovary syndrome Corticosteroid use/hypersecretion
5
Reproductive Endocrinology and Infertility
DNA to available estrogen is decreased. Conformational changes may activate other hormone response elements or corepressors at the level of the hormone-receptor complex and DNA.
Estrogens and Estrogen Receptors
Estrone (E1) is produced in the ovary by the aromatization of androstenedione, after which estrone can be secreted or converted to estradiol in the granulosa layer. Estrone possesses one-tenth the potency of estradiol but is produced in much greater quantities. Estrone also is produced in skin, muscle, and adipose tissue by the peripheral conversion of circulating androstenedione. Estradiol (E2) is the most potent estrogen but is produced in much smaller amounts than estrone. Estradiol is secreted by the ovary and can be synthesized by the conversion of androstenedione to testosterone, which is quickly aromatized. In addition, androstenedione can be aromatized to estrone, which is secreted from the ovary and can be converted to estradiol peripherally. Estriol (E3) is one-one hundredth as potent as estradiol and is a metabolic by-product of estrone and estradiol inactivation. Estriol also is a product of the placenta during pregnancy, the only time when estriol is secreted and known to be clinically significant. Its synthesis and measured levels provide indirect evidence of an intact fetoplacental unit. Estriol also is measured in conjunction with other markers prenatally to assess risk for chromosomal abnormalities. Levels are decreased in conditions such as Down syndrome. Estrogens have various clinical effects on multiple organ systems. Some of these physiologic and pathologic processes depend on the stage of a woman’s life; the major processes are listed in Table 1-3. There are at least two estrogen receptors, ER-α and ER-β. Proportions of each receptor vary by tissue, and effects vary as a result. ER-α is predominant in the uterus, breast, liver, bone, and cardiovascular system, whereas ER-β is predominant in the brain, cardiovascular system, and ovarian granulosa cells. Both receptors are found in the breast. It has been shown that one estrogen receptor type may potentiate and the other may inhibit the effects of estrogen within the same site. The estrogen agonist or antagonist response depends on the estrogen (E1, E2, E3), the estrogen receptor type (ERα, ER-β), and the site at which the hormone/receptor interaction occurs and effects at the DNA level. The estrogen/receptor system has multiple layers of variability, providing significant plasticity.
Progestins and Progestin Receptors
Progesterone is primarily synthesized by the ovary. A small amount is made by the adrenal gland as an intermediate in the pathway of mineralocorticoid and glucocorticoid production. Progesterone has primary effects on the endometrium, which undergoes secretory changes after ovulation. Progesterone also facilitates the growth of the alveoli in breast lobules during development. An increased risk of breast cancer with exogenous progesterone use is postulated. Progesterone produces smooth muscle relaxation. During preg-
6
Steroids and Prostaglandins Table 1-3 Physiologic Effects of Estrogen
Organ System
Effect
Central nervous system
Suggested positive effects on mood, memory, sense of well-being, cognitive function, and adult sexual behavior Temperature regulation/preventing vasomotor symptoms Breast ductal development Reported increased risk in estrogen-positive breast cancer Increased risk for thrombosis/stroke Lipid profile effects: increased HDL, decreased LDL, increased triglycerides Possible effects on plaque formation in vascular endothelium Promotes urogenital development and maturation Prevention of vaginal atrophy Promotes müllerian growth Endometrial proliferation Increased risk of endometrial hyperplasia/cancer if unopposed Promotes bone growth and closure of epiphyses by inhibiting osteoclasts Minimizes bone mineral density loss
Breasts
Cardiovascular
Urogenital tract
Bone
HDL, high-density lipoprotein; LDL, low-density lipoprotein.
nancy, the effects of high levels of progesterone include relaxation of the smooth muscle of the ureters and the lower esophageal sphincter. Prolonged relaxation of the ureters and the lower esophageal sphincter is presumably responsible for the increased incidence of pyelonephritis and gastroesophageal reflux disease. The two receptors for progesterone are known as PR-A and PR-B. It has been shown that the transcription of progesterone receptors is increased by estrogens and decreased by progestins. These receptors are predominantly found in the breast and genital tract.
Androgens and Androgen Receptors
Androgens are produced by the ovaries and the adrenal glands. The ovaries synthesize and secrete androstenedione and, to a much lesser extent, testosterone. The adrenals synthesize dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), androstenedione, and testosterone. Androgens are integral to development of male sexual organs and are active in skin. Testosterone acts directly on structures derived from the wolffian ducts. In the skin, testosterone is reduced to dihydrotestosterone, which acts primarily on hair follicles. Dihydrotestosterone also acts on structures derived from the urogenital sinus. The effects of androgens on mood and behavior are reported, but are not well characterized. The potential for androgen supplementation to increase libido in postmenopausal women is under investigation.
7
Reproductive Endocrinology and Infertility
8
Diagnostic Testing
Methods for assaying steroidal hormones in the blood include enzyme-linked immunosorbent assay and radioimmunoassay. Normal ranges for assays vary depending on the assay and the laboratory (Box 1-1). Estrogen assays have been shown to allow for reliable comparisons for cycling, reproductiveage women within a given time frame in the menstrual cycle. Similarly, progesterone measurements are reliable for midfollicular and midluteal phases, with a lesser degree of reliability for women who are perimenopausal. Clinically available testosterone assays were designed for measuring male hormone levels. The lower limits of the assay values are less reliable for measuring low testosterone levels in women.
Therapeutic Interventions
Hormonal Contraception Hormonal contraception may consist of an estrogen and a progestin (E+P) or a progestin alone (P). It may be administered via different routes: oral (E+P, P), transdermal (E+P), intramuscular (P), vaginal ring (E+P), and intrauterine device (P). Contraceptives with E+P are the most effective in suppressing ovulation because the P component inhibits the LH surge and the E component inhibits follicle-stimulating hormone (FSH), suppressing follicular selection and growth. The mechanism of action of progestins is multipronged in that they induce an endometrium that is not conducive to implantation, alter tubal motility, and thicken cervical mucus, creating a barrier to sperm transport. Side effects are mostly due to estrogen. Headache, nausea, breast tenderness, weight gain, and hair loss have been reported. If a patient has side effects with oral contraceptive pills that contain E+P, it is reasonable to have the patient try a different pill, such as one with a lower dose of estrogen, or to use a different delivery system. Absolute contraindications include breast cancer, liver disease, clotting disorders, undiagnosed vaginal bleeding, and smoking after age 35. Relative contraindications include migraines, hypertension, diabetes, and seizure disorders. In addition, postpartum women who breastfeed their newborns may have decreased milk production as a result of systemic absorption of hormonal contraception with an estrogen component. Hormone Therapy During the perimenopausal and postmenopausal years, patients may elect hormone therapy for short-term or long-term benefit. Short-term (<5 years) benefits include prevention of hot flashes and urogenital atrophy and theorized mood and cognitive improvements. Long-term benefits include prevention of osteoporotic fractures and colon cancer. Cardioprotection previously was believed to be a long-term benefit of hormone therapy and was supported by observational studies. The Women’s Health Initiative (WHI), Box 1-1 ● ● ●
Units of Measurement for Sex Steroid Hormones
Estradiol—pg/mL Testosterone—ng/dL Progesterone—ng/dL
Steroids and Prostaglandins
a large randomized primary prevention trial, did not support that observation, however, and suggested an increased risk of cardiovascular events and stroke with E+P therapy. Although the subjects were patients with a history of cardiovascular events, the Heart and Estrogen/Progestin Replacement Study (HERS) did not show a decrease in the risk of coronary events with hormone therapy. Women with a history of hysterectomy may take estrogen alone for hormone therapy, whereas women with an intact uterus are advised to add a progestin to the regimen to minimize the risk of endometrial hyperplasia and cancer. In light of the WHI and the HERS trials, patient selection for hormone therapy should be considered by assessing potential risks and benefits, based on individual history and risk factors. Hormone therapy may be administered via the oral, transdermal, subcutaneous, or vaginal route. 9
SUMMARY OF KEY POINTS—STEROIDS 1. 2.
3. 4.
5. 6. 7.
Estrogen, progesterone, and testosterone share a common basic structure and are derived from cholesterol. The ovaries produce androstenedione and testosterone in theca cells, and these two androgens are aromatized to estrone and estradiol in granulosa cells. Changes in SHBG/CBG levels can have dramatic, inversely proportional effects on free hormone levels, which can have great clinical significance. Estrogens, produced by the ovaries and converted peripherally, have various effects on different tissues based on the type of estrogen (E1, E2, E3), the estrogen receptor, the tissue involved, and factors at the DNA level. Progesterone, produced almost exclusively by the ovaries, exerts most of its action on the female breast, urogenital tract, and smooth muscle. Androgens are produced by the ovaries and adrenal glands. They affect hair follicles, body composition, and possibly mood and cognition. Examples of steroids in clinical practice include hormonal contraception and menopausal hormone therapy, both of which have risks and benefits. Patients should be selected for such therapies based on history and risk factor profiles.
PROSTAGLANDINS Naturally occurring prostaglandins (PGs), 20-carbon fatty acid derivatives, are the products of arachidonic acid (AA), which is provided through the diet and synthesized from linoleic acid. AA is a compound that is found in vast quantities and is predominantly present as an esterified form in phospholipid membranes and esterified cholesterol. Sex steroids and other stimuli promote the action of phospholipase enzymes A2 and C, which release AA from membranes. AA can be catalyzed by the lipoxygenase pathway or by
Reproductive Endocrinology and Infertility
the cyclooxygenase pathway. The lipoxygenase pathway leads to the formation of leukotrienes and eicosanoids. The cyclooxygenase pathway leads to the formation of prostanoids via the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) (Fig. 1-2).
Physiology and Clinical Presentation
10
PGs, produced via the cyclooxygenase pathway, are clinically relevant in reproductive medicine in terms of pathophysiology and therapy. Clinically significant PGs include PGG2 and PGH2, both of which are short-lived intermediates. PGG2 and PGH2 are converted to PGs with longer half-lives, such as prostacyclin (PGI2), thromboxane (TX), PGE2, and PGF2α. After PG synthesis is completed, they are secreted from the cell. PGs primarily exert their actions locally (Box 1-2). PG receptors are cell surface, G protein–coupled members of a superfamily of rhodopsin-like proteins with seven domains that traverse the cell membrane. PGs can elicit responses in multiple organ systems simultaneously, such as the bronchoconstriction
Figure 1-2
O
Basic prostaglandin structures.
O OH OH
Arachidonic acid O PGI2
Leukotrienes Lipooxygenase pathway
Cyclooxygenase pathway
O
OH
O
PGE2 OH O
OH
OH TXA2 OH
O
O
O OH PGF2α
HO
OH HO
O
O Prostaglandins
Steroids and Prostaglandins
Box 1-2
Effects of Prostaglandins
PGI2 Vasodilation Inhibition of platelet aggregation TX Vasoconstriction Promotion of platelet aggregation PGF2α Vasoconstriction Bronchoconstriction Smooth muscle contraction in cervix and myometrium PGE2 Vasodilation Promotion of platelet aggregation Smooth muscle relaxation in cervix
that occurs in an obstetric patient who is undergoing cervical ripening with PGs. PGs are transported to distant sites via free fatty acids. PGI2 and TXs have several effects that counterbalance each other. TXs are predominantly produced by platelets, but also are made by the spleen and the placenta. They are vasoconstrictors and increase platelet aggregation to repair sites of damage (e.g., on vascular endothelium). PGI2 is synthesized mostly by blood vessel endothelium, but also is made by the heart, stomach, and lungs. It is a vasodilator and inhibits platelet aggregation to prevent clot formation on vascular endothelium. In pregnancy, disruption of the homeostasis between TX and PGI2 occurs, leading to an increased TX-to-PGI2 ratio, and suggesting an underlying mechanism of preeclampsia. During labor, measurements of PG levels in the blood and amniotic fluid have shown increased levels from baseline. The AA in fetal membranes is metabolized via the COX-2 pathway, which results in an increased level of PGE2. For the purposes of ripening the cervix and for inducing labor, the use of synthetic PGs, such as PGE1 (misoprostol) and PGE2 (dinoprostone), has become commonplace. Preterm labor is treated with PG inhibitors, such as indomethacin and sulindac. Because of concern for increased risk of intrauterine closure of the fetal ductus arteriosus and pulmonary hypertension after 32 weeks, however, these agents are not recommended for use after this gestational age. PGs such as PGE1 also have been effective when used as abortifacients. PGs have been found to play a role in ovarian physiology, specifically that of folliculogenesis and the corpus luteum. An increase in blood supply to selected follicles has been attributed to PGs. In addition, PGF2α, present in follicular fluid, may inhibit collagen production and facilitate the rupture of an ovulatory follicle.
Therapeutic Interventions
Primary Dysmenorrhea The diagnosis of primary dysmenorrhea, painful cramps with menstruation, is made when no anatomic or functional abnormality is identified. High levels of PGF2α have been detected in the secretory endometrium of
11
Reproductive Endocrinology and Infertility
patients with primary dysmenorrhea. These levels peak during the time of menstruation, resulting in myometrial exposure to PG and increased myometrial contractility with consequent cramping and pain. In addition, some patients experience gastrointestinal symptoms in association with high PG levels during menses. The pharmacologic inhibition of PG is an effective treatment, achieved by the administration of pharmacologic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors. Ibuprofen, naproxen, and mefenamic acid are examples of NSAIDs. Celecoxib is an example of a COX-2 inhibitor. Rofecoxib, another COX-2 inhibitor, was removed from the market because of an increased risk of cardiovascular events, such as heart attack and stroke, and now there are concerns about all agents in this class of medications. NSAIDs have been shown to decrease the levels of PG produced by the endometrium, shorten the duration of menses, and decrease the amount of menstrual flow. PG-mediated gastrointestinal symptoms also may be alleviated. The major side effect of NSAIDs is gastrointestinal with potential ulceration; excessive use may lead to renal toxicity. COX inhibitors have been synthesized to inhibit COX-1 and COX-2 selectively. The COX-1 enzyme, present in virtually all tissues, is instrumental in producing PG. As a result of the presence of COX-1 in gastric mucosa, inhibition of this enzyme leads to decreased levels of PGE2, increasing the risk of gastrointestinal side effects and ulcers. The COX-2 enzyme is considered the inducible form of COX and is produced in response to inflammation. The selective inhibition of COX-2 seems to reduce the incidence of gastrointestinal sequelae.
12
Postpartum Hemorrhage Synthetic PGs, such as PGF2α (carboprost tromethamine [Hemabate]) and PGE1 (misoprostol), are useful in treating postpartum hemorrhage that is secondary to uterine atony. PGs typically are administered if ergot alkaloids (e.g., methylergonovine maleate [Methergine]) do not diminish the bleeding or if the patient has a contraindication to ergots, such as hypertensive disease. Asthma is a contraindication to the use of PGF2α because of its bronchoconstrictive properties. The smooth muscle contraction elicited by these particular PGs is instrumental in achieving increased uterine tone postpartum. These agents have been found to be useful in the treatment of uterine atony.
SUMMARY OF KEY POINTS—PROSTAGLANDINS 1. 2. 3. 4.
PGs are derived from AA by the COX pathway via the enzymes COX-1 and COX-2. PGI2 and TX have counterbalancing effects on vessel caliber and platelet aggregation. PGE1 and PGE2 are useful for cervical ripening and induction of labor. PGE1 and PGF2α are useful in treating postpartum hemorrhage, but PGF2α is contraindicated in asthmatics.
Steroids and Prostaglandins
SUGGESTED READINGS Chu MC, Lobo RA: Formulations and use of androgens in women. Mayo Clin Proc 2004;79(suppl):S3-S7. Fears TR, Ziegler RG, Donaldson JL, et al: Reproducibility studies and interlaboratory concordance for androgen assays in female plasma. Cancer Epidemiol Biomarkers Prev 2000;9:403-412. Gail MH, Fears TR, Chandler DW, et al: Reproducibility studies and interlaboratory concordance for assays of serum hormone levels: estrone, estradiol, estone sulfate, and progesterone. Cancer Epidemiol Biomarkers Prev 1996;5:835-844. Gallo MF, Grimes DA, Schulz KF: Skin patch and vaginal ring versus combined oral contraceptives for contraception. Cochrane Database Syst Rev 2003;1: CD003552. Gulmezoglu AM, Forna F, Villar J, Hofmeyr GJ: Prostaglandins for prevention of postpartum
haemorrhage. Cochrane Database Syst Rev 2002;3: CD000494. Marjoribanks J, Proctor ML, Farquhar C: Nonsteroidal anti-inflammatory drugs for primary dysmenorrhea. Cochrane Database Syst Rev 2003;4:CD001751. Mendel CM: The free hormone hypothesis: a physiologically based mathematical model. Endocr Rev 1989;10:232-274. Narumiya S, Sugimoto Y, Ushikubi F: Prostanoid structures, properties, and functions. Physiol Rev 1999;79:1193-1226. Nelson HD: Assessing benefits and harms of hormone replacement therapy: clinical applications. JAMA 2002;288:882-884. 1313 Nelson HD, Humphrey LL, Nygren P, et al: Postmenopausal hormone replacement therapy: scientific review. JAMA 2002;288:872-881.
2 THE NORMAL MENSTRUAL CYCLE Randal D. Robinson* The normal menstrual cycle is simultaneously one of the simplest and most complex and elegant physiologic processes. To manage obstetrics and gynecology patients competently, one must understand the normal menstrual 15 cycle. One cannot deal with physiologic or anatomic abnormalities or pathologic processes without an adequate understanding of what constitutes normal. Disturbances in normal menstrual function are usually concerning to patients and frequently lead them to seek medical evaluation. This evaluation could reveal a temporary deviation from normal or might uncover one of numerous pathologic processes. Normal menstruation is defined as the periodic efflux of the sloughed endometrium and blood out of the uterine cavity into the vagina and ultimately outside of a woman’s body. There are many different cultural beliefs, myths, and taboos, even within educated countries, about the purpose and function of the menstrual cycle. For adolescent girls, it is an obvious sign of pubertal development and signifies the passage into womanhood and the capability and responsibility of reproducing. Monthly menses become for many women a reassuring sign that they are not pregnant, if conception was not desired, or a cause of frustration and disappointment if pregnancy was desired. Teleologically and functionally, the ultimate aim of the human menstrual cycle is the development of a mature oocyte that is ovulated and fertilized. Ultimately, if fertilization is successful, implantation of a dividing pre-embryo into the receptive endometrium of the uterus occurs. Primates are the only mammals known to menstruate. Menarche, the age at onset of menstruation, averages 12.8 years in the United States. There is significant ethnic variability in the age of menstrual onset, with AfricanAmerican adolescent girls experiencing menarche earlier than white girls. The normal age range for menarche is 10 to 16 years. The average age for menarche has steadily declined over the past 200 years. The decline in age at first menses is attributed to the improvement in nutrition and subsequent increased weight of adolescent girls today compared with their ancestors.
*The opinions and assertions contained herein are the expressed views of the author and are not to be construed as official or reflecting the opinions of the Department of the Army, Department of the Air Force, or Department of Defense.
Reproductive Endocrinology and Infertility Figure 2-1
16
16
14
12
Percentage of incidence
Length of menstrual cycles. (Modified from Munster K, Schmidt L, Hahm P: Length and variation in the menstrual cycle: a cross-sectional study from a Danish country. Br J Obstet Gynaecol 1992;99:422.)
10
8
6
4
2
0 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 40 Days
The idealized length of the normal human menstrual cycle is 28 days from the onset of bleeding until the next episode of bleeding (Fig. 2-1). The average length of the menstrual cycle found in large population studies is 28.1 days; 28 days is merely the most common or modal distribution, however. Only 14% of women experience a menstrual cycle of 28 days in length. There is great variability in menstrual cycle length; an interval of 24 to 35 days is considered normal. The amount of bleeding also varies widely in the number of days of bleeding and the amount of blood lost. The number of days of bleeding ranges from 2 to 8 days, but the usual length is 4 to 6 days. The average amount of blood lost with each menstrual cycle is 30 mL, and the normal range is 25 to 60 mL. Even this relatively small amount of blood loss can lead to iron deficiency anemia if adequate iron is not ingested or absorbed. Blood loss of greater than 80 mL is excessive and commonly leads to iron deficiency anemia. Ovulatory women individually have consistent menstrual cycle lengths and number of days of bleeding (Box 2-1). There is some cycle length variability for most women, however. Even in a woman with regular menstrual
Box 2-1 ● ● ● ●
Normal Menstrual Cycle
Modal interval—28 days Normal range—24-35 days Mean blood loss—30 mL (range 25-60 mL) Usual length of menstrual bleeding—4-6 days (normal range 2-8 days)
The Normal Menstrual Cycle
cycles, variation by 2 days in length can be seen in one third of their cycles. This variation in cycle length is attributed to the variability in the length of the follicular phase of the cycle. The luteal phase consistently is 13 to 15 days in length after menarche and remains consistent until the perimenopausal period. Great variability is seen at the extremes of reproductive life, with adolescents and perimenopausal women experiencing wide fluctuations in menstrual cycle length and the number of days of bleeding because of their tendency to experience anovulatory cycles (Fig. 2-2). Adolescent girls average menstrual cycle lengths of 34 days. There is a gradual decrease in cycle length until women reach their late 30s or early 40s, when cycle length averages 27 days. Anovulatory cycles frequently begin when a woman reaches her late 40s. Cycles lengthen again and average 33 days beginning 3 years before menopause. Significant variation in the menstrual cycle length or number of days of menses commonly leads reproductive-age women to seek 17 medical advice. Pregnancy-related reasons for alterations in menstrual cycle length are the most common reasons for disruption in normal menstrual cycles in reproductive-age women. Lactation and abnormal pregnancies always must be ruled out as reasons for a change in menstrual pattern in every woman who seeks evaluation. The normal menstrual cycle is best conceptualized by focusing on the physiologic effect on the two main organ systems involved in menstrual function—the uterus and the ovary. The menstrual cycle classically is divided into phases. These phases are a convenient way to examine what is happening at different times at the level of the two main organ systems. The first Figure 2-2 75
Mean interval in days between menstrual onset
Distribution of menstrual intervals throughout menstrual life. (Modified from Treloar AE, Boynton RE, Borghild BG, Brown BW: Variation of the human menstrual cycle through reproductive life. Int J Fertil 1967;12:77.)
70
60
50
40
95%
75% Mean
30
20
25% 5%
10 15
20
25
30
35
40
Chronological age
45
50
55
60
Reproductive Endocrinology and Infertility
phase of the menstrual cycle is called the follicular phase at the level of the ovary and the proliferative phase at the level of the uterus. The follicular phase ends with the onset of the luteinizing hormone (LH) surge. Ovulation occurs in response to the LH surge. The next phase of the menstrual cycle, which begins after the onset of the LH surge, is called the luteal phase at the level of the ovary and the secretory phase at the level of the uterus.
FOLLICULAR/PROLIFERATIVE PHASE Early Follicular/ Menstrual Phase 18
Endometrium It is convenient to divide the follicular/proliferative phase into early, mid-, and late phases. By convention, day 1 of the menstrual cycle is the start of vaginal bleeding and is characterized as menstrual bleeding at the level of the uterus/endometrium. The endometrium is often indistinct on ultrasound during menses and is seen as a thin echogenic line on completion of menses. The endometrium is composed of two main layers: the stratum basale adjacent to the myometrium and the stratum functionale above the basale and closer to the lumen of the uterus (Box 2-2). The basale layer does not slough with menses and changes minimally throughout the menstrual cycle. The functionale layer is subdivided further: A superficial layer closer to the lumen, the stratum compactum, is composed of gland necks and dense stromal cells. The deeper functionale layer is called the stratum spongiosum and is adjacent to the underlying basale layer. The spongiosum contains predominantly endometrial glands, increased interstitial tissue, and less dense stroma. The entire stratum compactum and a portion of the stratum spongiosum are sloughed with menses. After menses, the endometrium consists of the stratum basale and a portion of the stratum spongiosum. The stratum functionale begins rapid proliferation and growth in response to the increase in estrogen seen in the early follicular phase. Ovary The onset of menses also signals the beginning of the follicular phase in the ovary. The early follicular phase (days 1-5) is hormonally quiescent, from a sex steroid standpoint, because estradiol and progesterone serum levels are very low (Fig. 2-3). This physiologic quiescence also is observed on ultrasound evaluation of the female pelvis. The ovaries exhibit small preantral follicles that measure 3 to 8 mm in diameter, and an occasional residual or resolving corpus luteum sometimes can be visualized.
Box 2-2 ● ●
Endometrial Layers
Stratum basale: adjacent to myometrium Stratum functionale ● Stratum compactum: superficial layer adjacent to lumen; contains gland necks and dense stroma ● Stratum spongiosum: adjacent to basale; contains glands, interstitial tissue, and less dense stroma
The Normal Menstrual Cycle Figure 2-3
Follicular growth
Ovulation
Mature corpus luteum
Corpus luteum involution
Inhibin FSH Estradiol IU/L pg/mL 20
Progesterone 17-OHP Ng/mL Progesterone
500
16
10
LH
18
9
400
8
300
6
14 12
7
8
FSH
4
Inhibin-B
3
200
6 4
2
100 Estradiol
2 0
19
5
10
1
0
0
Inhibin-A 1
7
Ovulation 14
Period of Period First growth regression of rest period
28
21
Second growth period
Period of regression
Premenstural phase
Menstrual phase
Menstrual phase
Postmenstrual phase
1
5
Bleeding
14 Proliferative, follicular, or estrogenic phase
24 Secretory, luteal or progestational phase
28 1 Pre-menstrual involution Ischemia
Changes throughout the normal menstrual cycle in the ovary and the endometrium. (Modified from Shaw ST Jr, Roche PC: Menstruation. In Finn CA [ed]: Oxford Reviews of Reproduction and Endocrinology, vol 2. London: Oxford University Press; 1980; and Regulation of the menstrual cycle. In Speroff L, Fritz MA [eds]: Clinical Gynecologic Endocrinology and Infertility, 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2005: 195–198.)
5
Bleeding
The low serum levels of sex steroids found in the early follicular phase, combined with declining luteal phase inhibin A levels, effectively release the hypothalamus from the negative feedback exerted by these substances in the previous luteal phase. Inhibin A, estrogen, and progesterone levels begin to decline with the demise of the corpus luteum. The low levels of these substances allow for increases in gonadotropin-releasing hormone (GnRH) pulse frequency. This increase in GnRH pulsatility begins in the late luteal phase with the decline in serum progesterone, estrogen, and inhibin A that occurs if a pregnancy has not developed and the corpus luteum involutes.
Reproductive Endocrinology and Infertility
20
GnRH pulses increase from 3 per day to 14 per day. This increase in GnRH pulse frequency results in an increase in follicle-stimulating hormone (FSH) production from the anterior pituitary, which also begins to increase in the previous late luteal phase. The increased GnRH pulse frequency selectively favors FSH production over LH. Mean levels of FSH increase from 4 to 15 IU/L compared with a mean of 4.8 to 8 IU/L for LH. FSH levels begin increasing 2 days before menstrual bleeding. The late luteal phase increase in FSH is only 30% greater than the usual midluteal level, but this minimal increase is sufficient to recruit a cohort of follicles, one of which is destined to be the dominant follicle that eventually ovulates a mature oocyte. The late luteal phase increase in GnRH pulsatility increases LH pulse frequency from one LH pulse every 4 hours in the late luteal phase to one every 90 minutes in the early follicular phase. The primordial follicles that ultimately give rise to the single dominant follicle originate as primordial germ cells. Primordial germ cells are derived embryologically from the endoderm cell layer and migrate from the yolk sac, allantois, and hindgut to the gonadal ridge region at 5 to 6 weeks of gestation. When in the gonadal ridge area, the primordial germ cells undergo mitotic division with a maximum number of 6 million to 7 million achieved by 16 to 20 weeks of gestation. There is a large decline in the number of primordial germ cells to 2 million at birth. A continual decrease in germ cell number occurs until there are approximately 300,000 oocytes remaining at puberty. This tremendous atresia of germ cells occurs via programmed cell death known as apoptosis. Depending on a woman’s pregnancy and lactation history and use of hormonal contraceptives, it is estimated that only about 400 follicles are ovulated during a woman’s reproductive lifespan. When the primordial germ cells have reached the gonadal ridge region and are surrounded by a single layer of granulosa cells, they are called primordial follicles or germinal vesicles. Primordial follicles are composed of the oocyte at the diplotene stage of prophase of the first meiotic division and a single layer of granulosa cells. The primordial follicles individually undergo growth or atresia throughout the lifespan of the woman. It is unknown what triggers the growth of a specific cohort or what determines the number of primordial follicles to be recruited each cycle. It also is unclear how the dominant follicle is selected from this cohort of follicles. Ultimately, one follicle wins the race because of its greater ability to respond to the late luteal/early follicular increase in FSH and the local autocrine or paracrine environment that optimizes its response to this stimulation. Many autocrine/paracrine factors have been found to play a role in the regulation of this follicular development, including various peptides, growth factors, and cytokines (Table 2-1). The dominant follicle that ultimately ovulates is recruited and develops its competitive advantage over the rest of the recruited cohort of follicles during the transition from the luteal to follicular phase and during the first few days of the menstrual cycle. The remainder of the cohort of follicles that do not reach dominant follicle status undergo apoptosis. It takes 85 days for the follicle that is ultimately ovulated to mature. Most of this maturation is independent of hormonal stimulation. Hormonal stimulation becomes dominant
FGF
TGF-β
Follistatin (FSH induces)
Activin (FSH induces)
Inhibin B (FSH induces)
↓ FSH ↓ Activin ↑ Follistatin ↑ FSH ↑ Inhibin ↑ Aromatase ↓P ↑ E2 ↑ Follistatin ↓ Activin →↓ FSH ↑ Inhibin activity ↓ Cell growth ↑ FSH-induced FSH and LH receptors ↓ Angiogenesis ↑ E2 ↑ GC growth ↓ FSH-induced FSH and LH receptors ↑ Angiogenesis ↓ E2
Follicular
↑ FSH
↓ FSH
Luteal
Ovary: Granulosa Cell
↓ A, T
↑ A, T
↓ A, T production
↑ A, T
↓ LH-induced A, T production
↑ LH-induced A, T production
↑ LH-induced A, T production
Luteal
Ovary: Theca Cell Follicular
Role of Cytokines and Growth Factors in the Normal Menstrual Cycle
Inhibin A (LH induces)
Factor
Table 2-1
↑ VEGF
↑ VEGF
Proliferative
Inhibits MMP
Secretory
Endometrium
Continued
↓ Activin →↓ FSH
↑ FSH ↑ GnRH
↓ FSH
↓ FSH
Pituitary
The Normal Menstrual Cycle
21
↑ Angiogenesis
↑ Angiogenesis of GC
↑ Angiogenesis
↑ A, T ↑ Theca cell growth
↑ Theca cell growth
↑ Theca cell growth
↑ A, T ↑ Theca cell growth
↑ A, T
↑P
↑P
↑ Endometrial mitosis ↑ Angiogenesis
↑ VEGF
↑ A, T
↑ VEGF
Proliferative
Secretory
Endometrium Pituitary
↓ = decreases or inhibits; ↑ = increases or induces; → = leads to; A, androstenedione; AMH, antimüllerian hormone; E2, estradiol; EGF, epidermal growth factor; FGF, fibroblast growth factor; FSH, follicle-stimulating hormone; GC, granulosa cell; GH, growth hormone; GnRH, gonadotropin-releasing hormone; IGF-I, insulin-like growth factor I; IGF-II, insulin-like growth factor II; LH, luteinizing hormone; MMP, matrix metalloproteinase; P, progesterone; T, testosterone; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor.
VEGF (induced by LH)
↑ FSH-induced LH receptors ↑ Inhibin B ↑ Aromatase ↑ E2 ↑ GC growth ↑ GC growth ↑ Aromatase ↑ E2
Luteal
↓ E2 ↑ Cell growth ↑ A, T
Follicular
Ovary: Theca Cell
22
IGF-II (FSH, LH, GH induces)
IGF-I (FSH, LH, GH, E2, EGF induces)
TGF-α
EGF
↑ Apoptosis ↑ Luteolysis ↑P
↓ growth
↓ GC growth Inhibits oocyte meiosis ↓ EGF cell growth ↑ Apoptosis ↓ E2 ↓ FSH-induced inhibin, E2, and LH receptors ↓ Aromatase ↑ Cell growth
AMH
TNF-α
Luteal
Follicular
Ovary: Granulosa Cell
Role of Cytokines and Growth Factors in the Normal Menstrual Cycle—cont’d
Factor
Table 2-1
Reproductive Endocrinology and Infertility
The Normal Menstrual Cycle
only in the late stages of oocyte maturation. If FSH secretion and stimulation does not occur at the appropriate time, and if maintenance of this secretion does not occur, the cohort of follicles undergoes atresia. Even without FSH stimulation, some of the primordial follicles develop into primary or preantral follicles. Preantral follicles are composed of the oocyte surrounded by multiple layers of granulosa cells. Preantral follicles are unable to progress to the antral or secondary follicle stage of development without the presence of FSH.
Two-Cell Ovarian Physiology
With the FSH-induced increase in granulosa cell number, gap junctions develop between the granulosa cells and between the granulosa cells and the oocyte. Gap junctions increase communication between the cells surrounding the oocyte and with the oocyte itself. The stromal layer surrounding the 23 granulosa cells also undergoes differentiation into two cell layers, an inner theca interna and an outer theca externa. The theca layer is separated from the granulosa layer by a basal lamina. The oocyte also enlarges and is encased in the zona pellucida membrane layer. As the number of granulosa cells increases, an increase in estradiol level is noted, and FSH receptors are seen for the first time on the granulosa cells. FSH and estradiol play a role in increasing FSH receptor number and granulosa cell number. FSH also increases the secretion of aromatase, which further increases estrogen production. Aromatase is produced by granulosa cells and aromatizes the androgens produced by the theca cell layer to maximize an estrogenic follicular milieu. The granulosa cells are capable of producing androgens, estrogens, or progesterone, but FSH stimulation in concert with the aromatization of androgens pushes steroid production decidedly toward estradiol production. Estradiol stimulates preantral follicular growth, prevents follicular apoptosis, and increases the action of FSH on granulosa cells. Androgens have the opposing effect, and this balance between androgens and estrogens in the microfollicular environment ultimately determines if a follicle undergoes atresia or continues to develop. Preantral follicles have FSH receptors only on the granulosa cell layer and LH receptors only on the theca cell layer. Theca cells produce androgens in response to LH, and granulosa cells produce estrogens in response to FSH. An androgenic microenvironment is seen early on in follicular development and changes to an estrogenic microenvironment in response to the late luteal and early follicular increase in FSH secretion. If an androgenic microenvironment persists, programmed cell death and follicular atresia occur. The dominant follicle produces the greatest amount of estradiol and increases its own FSH receptor number. The increased estradiol level ultimately downregulates the surrounding cohort of the follicle’s FSH receptor number, however. The increasing serum level of estradiol also begins to exert a negative feedback effect on FSH production at the level of the pituitary. The granulosa cells also produce inhibin B with feedback inhibition effect on FSH production. The decrease in FSH has a negative effect on the nondominant follicles and contributes to their atresia. The dominant follicle continues to have a competitive advantage because of its
Reproductive Endocrinology and Infertility
much higher FSH receptor level and estrogenic environment. Additionally, the dominant follicle’s theca cell layer is more vascular, and FSH is better able to reach the dominant follicle’s FSH receptors. This results in a continued competitive advantage for the dominant follicle to aromatize androgens into estradiol within its own microenvironment.
Midfollicular/ Proliferative Phase
24
Ovary As the granulosa cells continue to proliferate, follicular fluid is produced. This follicular fluid eventually accumulates sufficiently to form a fluid-filled cavity within the substance of the granulosa cells. When the fluid-filled follicular cavity forms, the follicle is now designated an antral follicle. By cycle day 7, multiple antral follicles can be visualized on transvaginal ultrasound as 9- to 10-mm follicles. The granulosa cells that remain in close proximity and surround the oocyte differentiate and are now called the cumulus oophorus. The follicular fluid is an efficient system to maximize an estrogenic microenvironment around the oocyte and essentially functions as an “estradiol sink.” Estradiol concentrations are significantly higher within the follicular fluid compared with levels measured in the serum. LH acts on the theca cell layer to produce androgens that can be aromatized to estrogens by the granulosa cells, and FSH increases the number of theca LH receptors to enhance this effect. In late stages of follicular development, FSH also induces development of LH receptors on granulosa cells, which are necessary for the granulosa cells to be able to respond to the midcycle LH surge. Serum inhibin B, produced by granulosa cells from the entire cohort of follicles, is at its maximum during the early follicular phase. Inhibin B levels steadily increase to reach a peak by cycle day 7 to 8 (see Fig. 2-3) and, in combination with increasing estradiol levels, result in negative feedback at the hypothalamus and pituitary with resulting decreases in FSH. Inhibin also reduces the number of pituitary GnRH receptors and contributes to the degradation of the gonadotropins. Inhibin B and insulin-like growth factor I (IGF-I) increase LH production of theca cell androgens that increase the substrate available for aromatase action and further increase follicular estradiol. The FSH suppression induced by estradiol and inhibin gives the dominant follicle a further developmental advantage because the smaller follicles have fewer FSH receptors and undergo atresia. The dominant follicle is selected by cycle days 5 to 7. A slow, steady increase in estradiol accompanies the selection of the dominant follicle, and serum estradiol begins to increase substantially by cycle day 7. When the remainder of the cohort of follicles begins to undergo atresia, local cytokines and growth factors start to play an important role. A complete understanding of the role for each of these factors is still evolving and is complex. The role for these factors becomes even more confusing when their interaction with each other is included. These polypeptide growth factors act locally as autocrine and paracrine regulators of endocrine and cellular function. Because they may have stimulatory or inhibitory roles, depending on the phase of the menstrual cycle and the animal species studied, their precise role and understanding of their function are ever evolving. The following
The Normal Menstrual Cycle
description is a simplification of their role in ovarian physiology, as it is currently understood (see Table 2-1). Inhibin A and B have been described previously as important inhibitors of FSH. In general, inhibin B is the predominant peptide produced in the follicular phase, and inhibin A is the predominant product of the luteal phase. The inhibins are regulated further locally via epidermal growth factor (EGF) and GnRH. Both of these peptides decrease inhibin production. IGF-I increases inhibin production, however. IGF-II seems to be the dominant IGF in the human follicle and is involved in granulosa cell proliferation, increased ovarian steroidogenesis via enhanced aromatase activity, and gonadotropin stimulation. Both IGF factors stimulate proliferation and differentiation of cells. To complicate the IGF role in ovarian physiology further, there are also at least six IGF binding proteins. These binding proteins and the tissue expression of the IGF receptors regulate IGF function. FSH decreases IGF binding 25 protein synthesis, which results in increased IGF availability. The overall roles for the IGFs are to facilitate the action of FSH and LH at the appropriate phase of the cycle and to ensure an estrogen-dominant microenvironment for the dominant follicle. Activin also is produced by the granulosa cells in response to FSH stimulation and, as expected based on its name, “activates” or augments FSH action within the ovary. It also increases GnRH receptor formation in the pituitary, and its action is blocked by inhibin. Activin also plays a role in LHinduced androgen production by inhibiting theca cell androgen production. Follistatin binds activin to inhibit pituitary FSH secretion. Activin increases the production of follistatin, and inhibin blocks follistatin action. Tumor necrosis factor-␣ (TNF) inhibits estradiol production in the nondominant follicles. TNF-␣ levels are significantly decreased in the dominant follicle, augmenting estradiol production at this site. Antimüllerian hormone augments the success of the dominant follicle by inhibiting nondominant primordial follicle growth. EGF (granulosa) and its homologue transforming growth factor (TGF)-α (theca) suppress FSH receptor upregulation and increase granulosa cell proliferation. Vascular endothelial growth factor (VEGF) also is produced by the granulosa and is responsible for the increased vascularity of the theca cell layer, which is especially pronounced for the dominant follicle and improves its competitive advantage over the remaining cohort of follicles. Numerous other hormones and cytokines are found within the follicular fluid. The role for these additional substances is still being elucidated. The regulation of the menstrual cycle will continue to become more complex as their role is defined.
Endometrial Changes The increasing levels of estrogen stimulate endometrial gland and stroma proliferation and thickening of the stratum functionale. Stromal and glandular mitotic activity steadily increases, and pseudostratification of glandular nuclei is seen (Fig. 2-4). Growth factors also play a role in endometrial development, with VEGF promoting endometrial mitotic activity. VEGF is induced by TNF, TGF-β, and IGF-I. On ultrasound, a trilaminar appearance
Reproductive Endocrinology and Infertility Figure 2-4 Patterns of histologic change throughout the menstrual cycle. (Modified from Noyes RW, Hertig AT, Rock J: Dating the endometrial biopsy. Fertil Steril 1950;1:3.)
Early
Mid
Late
Early
Mid
Late
Menses Secretory
Proliferative
Gland mitosis
Pseudostratification of nuclei
Basal vacuolation
26 Secretion
Stomal edema
Pseudodecidual reacton
Stomal mitoses
Leukocytic infiltration
Early
Mid
Late
Early
Mid
Late
Menses Proliferative
Secretory
to the endometrium is noted, and the endometrial thickness increases from a mean of 1 to 2 mm after menstruation to an average of 6 mm by cycle day 7 (Fig. 2-5).
Late Follicular/ Proliferative Phase
Ovary The follicle grows 1 to 2 mm/day when it has reached the antral stage. On ultrasound, the dominant follicle reaches 20 to 26 mm before the onset of the LH surge, and the LH surge does not occur unless the dominant follicle reaches 15 mm mean diameter. Local factors prevent premature luteiniza-
The Normal Menstrual Cycle Figure 2-5 Early follicular phase ultrasound image of the endometrium. (Image courtesy of Martin KA: Randal Robinson, M.D.)
27
tion and ovulation, such as oocyte maturation inhibitor and luteinization inhibitor factor. The estradiol level in the late follicular phase increases steadily initially, but increases dramatically 24 to 36 hours before ovulation when estradiol is at its peak. As the levels of estrogen and inhibin B continue to increase from the midfollicular into the late follicular phase, further suppression of FSH occurs. With the further increase in estradiol, however, a change in LH feedback occurs. The initial suppression of LH seen with low levels of estradiol in the early follicular and midfollicular phases switches to positive feedback when estradiol reaches 200 pg/mL for approximately 50 hours. The high estrogen levels also increase production of a more bioactive form of FSH and LH. The 10-fold increased level of LH seen during the LH surge is from an increase in amplitude of the LH pulse. The exact mechanism that results in this switch from negative to positive feedback is not completely understood. The preovulatory granulosa cells continue to enlarge and acquire lipid inclusions. The oocyte resumes its march toward completion of the first meiotic reduction division. The increased number of FSH-induced LH receptors found on the granulosa cells allows the surge in LH to begin the process of luteinization of the granulosa cells. The surge in LH further androgenizes the remaining cohort of smaller follicles and ensures they undergo atresia, whereas the luteinization of the granulosa cells in the dominant follicle results in the production of progesterone. LH also induces progesterone receptor formation on the granulosa cells. Progesterone in an estrogenic environment contributes to the positive feedback of estrogen on LH. If progesterone is found in higher levels (>2 ng/mL) or without an estrogenic environment, it can block the LH surge. An appropriately timed and low level of progesterone production has a positive feedback effect on FSH and accounts
Reproductive Endocrinology and Infertility
for the midcycle surge of FSH. Preovulatory estrogen production and LH receptor formation on granulosa cells are maximized by this second surge of FSH. The LH surge leads to increased androgen production by the theca cell layer. This increase in androgens may serve to increase female libido and sexual activity around the time of ovulation. Inhibin B production begins to decrease by cycle day 7, and inhibin A production starts to increase slowly (see Fig. 2-3). Some theca cells are luteinized and contribute to progesterone production, whereas others continue to produce androgens. IGF-I also facilitates LH-stimulated progesterone production by luteinized granulosa cells and androgen production by the theca.
Endometrial Changes The trilaminar endometrium continues to thicken and frequently measures greater than 8 mm on ultrasound evaluation immediately before ovulation. The mean endometrial stripe thickness on ultrasound is 12 mm. Women usually notice an increase in cervical mucus production and an increased “stringiness” (spinnbarkheit) of the cervical mucus. This change in cervical mucus is the crucial factor monitored by women who use natural family planning methods of fertility regulation. Histologically, the endometrial glands increase in tortuosity, and the stromal and glandular mitotic figures are at a peak. Pseudostratification of the cells lining the glandular epithelium also is at a peak (see Fig. 2-4).
28
Ovulation
When the LH surge begins, ovulation is expected within 34 to 36 hours after LH surge onset and peak estradiol levels. Ovulation occurs approximately 12 hours after the LH peak. The LH surge lasts about 48 hours and must be maintained for a minimum of 14 to 27 hours for oocyte maturation to be complete. Progesterone production continues to increase after ovulation and is probably responsible for the termination of the LH surge. Completion of metaphase I and extrusion of the first polar body occur after the LH surge and simultaneously with ovulation. When LH levels reach their peak, there is a precipitous decrease in estradiol levels as steroid production shifts from estradiol to progesterone production. This dramatic decline in estrogen occasionally can result in midcycle spotting for some women secondary to estrogen withdrawal bleeding. The midcycle LH and FSH surge also stimulates production of plasminogen activator. Plasminogen is converted into plasmin by plasminogen activator. Plasmin aids in detachment of the cumulus oophorus from the surrounding granulosa cells. Hyaluronic acid also increases in response to FSH and facilitates release of the cumulus-oocyte complex from the surrounding granulosa cells and leads to a free-floating cumulus-oocyte cell mass within the follicular fluid. Immediately before ovulation, there is an increase in follicular fluid volume, and the follicular wall thins. FSH, LH, and progesterone stimulate production of proteolytic factors, such as collagenase, which digest the follicular wall. Plasmin also increases collagenase production to facilitate
The Normal Menstrual Cycle
follicular rupture and oocyte release. The midcycle gonadotropin surge also stimulates the production of prostaglandins (PGs), PGF2α and PGE2, and histamine. These products all seem to play a role in extrusion of the cumulusoocyte complex at the time of ovulation. Growth factors, such as EGF and interleukin-1β, also regulate synthesis of the proteolytic enzymes. Extrusion of the oocyte and cumulus oophorus is not an explosive event. Progesterone acts directly on the follicular wall to increase its distensibility, and the follicular wall becomes thin and stretched. The follicular levels of the PGs, proteolytic enzymes, and histamine are significantly elevated and result in erosion of the collagenous matrix in the region of the follicular wall that ruptures and extrudes the oocyte. PGs also assist in extrusion of the oocyte by inducing ovarian smooth muscle cell contraction. Histologically, the granulosa cell and theca cell layers take up lipids and lutein pigment and develop the characteristic, yellow appearance of the corpus luteum. 29
LUTEAL/SECRETORY PHASE Early Luteal/ Secretory Phase
Ovary The granulosa cell layer becomes vascularized only after ovulation. The vascularization of the luteinized granulosa cells is crucial for adequate corpus luteum function. Progesterone and estradiol production depends on adequate cholesterol delivery to the luteinized granulosa cells by low-density lipoprotein (LDL). LH regulates this process by increasing LDL receptors and LDL receptor binding and modulating postreceptor processing. Oxytocin also may play a role in the function of the corpus luteum by increasing intercellular, gap junction communication; this suggests a paracrine role for oxytocin to maximize corpus luteum steroidogenesis. Vascular development is mediated via the action of VEGF and other angiogenic growth factors. By day 8 to 9 after ovulation, peak vascularization is noted and correlates with peak luteal phase estrogen and progesterone blood levels. Just as estradiol is the predominant steroid produced in the follicular phase, progesterone is the dominant steroid in the luteal phase. Estrogen levels, although lower than their preovulatory peak, remain substantial after ovulation. Peak luteal estradiol levels measure 100 to 150 pg/mL (see Fig. 2-3). Endometrial Changes Steadily increasing progesterone levels result in profound changes within the endometrium. Glandular mitoses end, and glycogen-rich subnuclear vacuoles appear in the glandular cells at their base. Subnuclear vacuolization is the first histologic evidence of progesterone effect, but does not mean ovulation has occurred. When the progesterone levels increase in the early luteal phase, the glycogen-laden vacuoles migrate toward the glandular lumen (see Fig. 2-4). On ultrasound, shortly after ovulation, the late follicular, trilaminar pattern is lost, and an increased and uniform echogenicity of the endometrial stripe is visualized. Ultrasonographers describe this as hyperechoic. The mean endometrial thickness on ultrasound is 12 mm.
Reproductive Endocrinology and Infertility
Midluteal to Late Luteal/ Secretory Phase and Menstrual Phase
30
Ovary Progesterone levels continue to increase as long as LH is present. Progesterone plateaus about 1 week after ovulation if a pregnancy does not develop. Progesterone production is also pulsatile and occurs after each pulse of LH secretion; this can result in measurements of relatively low serum progesterone values in a normal midluteal phase. Progesterone measurements frequently are used incorrectly to determine the adequacy of the luteal phase and should be used clinically only to determine if ovulation has occurred. Loss of LH or failure of human chorionic gonadotropin (hCG) to be produced results in luteolysis. Luteolysis occurs approximately 14 days after the LH surge, with a normal luteal phase range of 11 to 17 days. In the absence of hCG, the lifespan of the corpus luteum cannot be extended even with LH supplementation; this suggests that an active luteolysis mechanism exists in primates. No definitive luteolytic factor has been identified in primates, however, in contrast to other mammals, in which PGF2α, endothelin-1, and TNF-α mediate luteolysis. Experiments suggest that estradiol might mediate its luteolytic action via nitric oxide, which has been shown in humans to induce PG production and decrease progesterone concentrations. The actual process of luteolysis involves the matrix metalloproteinases (MMPs), which are proteolytic enzymes. Throughout the luteal phase, tissue inhibitors of metalloproteinases (TIMPs) are produced by the corpus luteum and inhibit the MMPs. Toward the end of the luteal phase, MMPs increase without a concomitant increase in TIMPs resulting in luteal cell proteolysis. If a successful pregnancy occurs, hCG stimulates progesterone production by acting on hCG receptors on the corpus luteum. hCG also suppresses MMP formation and may increase TIMP expression to prevent luteolysis. The corpus luteum is a dynamic tissue and includes other cell lines besides luteal cells, including leukocytes, fibroblasts, and endothelial cells. These other cell lines produce substances such as interleukin-1β and TNF-α, which are important local regulators of corpus luteum activity. The progressive increase in luteal phase progesterone leads to gradual slowing of LH pulses to one every 4 hours by the late luteal phase. This progressive decline in LH secretion eventually leads to gradual decreases in estrogen and progesterone concentrations in the late luteal phase. Progesterone and estradiol levels begin to decrease 4 to 6 days before menses. This decline in luteal phase steroids and inhibin concentrations results in the luteal-tofollicular transition and allows for the initial increase in FSH immediately before the onset of the next menses. Endometrial Changes The mid to late secretory endometrial glands become increasingly tortuous, and the stroma becomes edematous and vascular. If implantation of the blastocyst into the endometrium does not occur, and hCG is not present, the glands begin to fragment and collapse in the late luteal phase. Neutrophils and monocytes begin to infiltrate the endometrial glands and stroma. Macrophages and neutrophils produce inflammatory proteases. Interleukin-8 seems to play a key role in recruitment of these endometrial immunologic cells. Neutrophils degranulate and release a wide variety of
The Normal Menstrual Cycle
cytokines and proteases that contribute to the degradation of the extracellular matrix. Progesterone seems to inhibit endometrial production of interleukin-8; declining progesterone levels permit its increase, which increases endometrial levels of macrophages and neutrophils. Matrix metallopeptidases, such as collagenase, also are inhibited by progesterone via progesterone’s action on TGF-β. Declining levels of progesterone decrease TGF-β, which increases matrix metallopeptidase production. The end result of the release of these enzymatic degradative substances is disruption of the vascular endometrium with PG release, vascular thrombosis, platelet deposition, extravasation of red blood cells, and ultimately tissue necrosis. The current theory of endometrial sloughing is different from the classic view that the onset of menstrual bleeding primarily resulted from hypoxia secondary to ischemic necrosis of the endometrium. This vascular theory proposed that withdrawal of estrogen and progesterone led to vasoconstriction of 31 the spiral arteries that supplied the upper two thirds of the endometrium with resulting necrosis and sloughing of the endometrium. It is now understood that estrogen/progesterone withdrawal results in an enzymatic degradation of the stratum compactum and some portions of the stratum spongiosum. Steroid withdrawal releases intracellular lysosomal enzymes, activates inflammatory proteases, and increases the activity of proteolytic MMPs. Each of these substances contributes to the enzymatic digestion of the stratum functionale and results in disruption of the underlying capillary and venous endometrial vessels. Late luteal phase progesterone withdrawal permits lysosomal membrane instability and the release of lysosomal intracellular products. These substances promote cytoplasmic digestion and degradation of the structural elements of the extracellular matrix and basement membrane; this results in interstitial hemorrhage and eventual sloughing of the functionale layer and bleeding. A cleavage plane is found between the stratum functionale and the basal layer. Menstruation begins in different areas of the endometrium at different times. Sloughing of the endometrium occurs predominantly in the fundus and minimally in the isthmus or cornual regions. Autolysis with subsequent desquamation of the stratum functionale layer begins. Cessation of menses occurs via local vasoconstriction of the denuded spiral arteries, clotting, and re-epithelialization of the sloughed endometrium. Vasoconstriction is mediated via endothelins and PGF2α. Regeneration of the endometrium begins 36 hours after menses onset and begins even as endometrial shedding continues in other areas of the uterus. Regeneration occurs from epithelial outgrowth from the mouths of the basal glands and ingrowth of endometrium from the cervical and cornual regions. Bleeding ceases after complete re-epithelialization of the endometrium is accomplished, which is usually by cycle day 5.
SUMMARY OF KEY POINTS 1.
Menarche occurs at an average age of 12.8 years in the United States. The mean length of the menstrual cycle is 28.1 days. Great variability exists in menstrual cycle length; 24 to 35 days is considered normal.
Reproductive Endocrinology and Infertility
2.
3.
4.
32 5.
The menstrual cycle is divided into two main phases: follicular/proliferative and luteal/secretory. The follicular/proliferative phase begins with the onset of menstrual bleeding and ends with the onset of the LH surge. The luteal/secretory phase begins with the onset of the LH surge and ends with the onset of the next menses. The endometrium consists of two main cell layers, the deeper stratum basale and the more superficial stratum functionale. The stratum basale does not slough with menses. The stratum functionale proliferates in response to estrogen and sloughs with progesterone withdrawal. The dominant follicle attains its competitive advantage from the cohort of primordial follicles during the luteal-to-follicular transition. The dominant follicle succeeds over the surrounding follicles by its ability to respond preferentially to FSH and local autocrine/paracrine factors to maximize its production of estradiol in the follicular phase. The two-cell theory of ovarian follicular development suggests that FSH acts on granulosa cells to maximize estrogen production, and LH acts on theca cells to produce the correct amount of androgens to maximize aromatization of androgens into estrogens and ultimately optimize microfollicular estrogen production by the dominant follicle.
SUGGESTED READINGS Auletta FJ, Flint APF: Mechanisms controlling corpus luteum function in sheep, cows, nonhuman primates, and women especially in relation to the time of luteolysis. Endocr Rev 1988;9:88. Brannian JD, Stouffer RL: Cellular approaches to understanding the function and regulation of the primate corpus luteum. Semin Reprod Endocrinol 1991;9:341. Erickson GF: An analysis of follicle development and ovum maturation. Semin Reprod Endocrinol 1986;4:233. Giudice LC: Insulin-like growth factors and ovarian follicular development. Endocr Rev 1992;13:641. Hedricks C, Piccinino LJ, Udry JR, Chimbira TH: Peak coital rate coincides with onset of luteinizing hormone surge. Fertil Steril 1987;48:234. Katt JA, Duncan JA, Herbon L, et al: The frequency of gonadotropin-releasing hormone stimulation determines the number of pituitary gonadotropinreleasing hormone receptors. Endocrinology 1985;116:2113. Liu JH, Yen SS: Induction of midcycle gonadotropin surge by ovarian steroids in women: a critical evaluation. J Clin Endocrinol Metab 1983;57:797.
Lockwood GM, Muttukrishna S, Ledger WL: Inhibins and activins in human ovulation, conception and pregnancy. Hum Reprod Update 1998;4:284. Munster K, Schmidt L, Hahm P: Length and variation in the menstrual cycle: a cross-sectional study from a Danish country. Br J Obstet Gynaecol 1992;99:422. Pall M, Friden BE, Brannstrom M: Induction of delayed follicular rupture in the human by the selective COX-2 inhibitor rofecoxib: a randomized double-blind study. Hum Reprod 2001;16:1323. Regulation of the menstrual cycle. In Speroff L, Fritz MA (eds): Clinical Gynecologic Endocrinology and Infertility, 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2005:195. Shaw ST Jr, Roche PC: Menstruation. In Finn CA (ed): Oxford Reviews of Reproduction and Endocrinology, vol 2. London: Oxford University Press; 1980. Welt CK, Pagan YI, Smith PC, et al: Control of follicle-stimulating hormone by estradiol and the inhibins: critical role of estradiol at the hypothalamus during the luteal-follicular transition. J Clin Endocrinol Metab 2003;88:1766.
3 NORMAL AND ABNORMAL PUBERTY Stephen M. Scott
DEFINITIONS Precocious puberty Central precocious puberty Peripheral precocious puberty Mixed precocious puberty Premature thelarche Premature adrenarche
Early pubertal initiation, traditionally defined as younger than 8 years of age; more recent modifications of this definition are controversial Early pubertal development as a result of premature development of the hypothalamic-pituitary-ovarian axis Early pubertal development resulting from stimulation independent of the hypothalamic-pituitary-ovarian axis Peripheral precocious puberty that triggers central precocious puberty owing to persistent exposure to elevated estrogen levels Isolated breast tissue development Pubic hair development without any other evidence of sexual development before age 8 in girls and 9 in boys
Puberty marks a time when young women experience some of the most intense physical, emotional, and social changes of their lives. Puberty reflects a complex mechanism of signaling between the brain, adrenal gland, and ovaries that is influenced by genetic, nutritional, and health factors. In contrast to other animal species, the initiation of pubertal changes in humans can vary over a span of 4 to 5 years. This individual variability is due to differences in genetic signaling and other environmental influences. Alterations in the timing of this signaling can have a profound impact on final adult height, sexual development, self-image, and psychosocial interactions with others.
HORMONAL RESPONSES IN CHILDHOOD AND PUBERTY The hormonal mechanisms that initiate and maintain the physical changes of puberty include gonadotropin-releasing hormone (GnRH) signaling from the hypothalamus that stimulates the pituitary gland to secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The pituitary hormones stimulate ovarian production of androgens, estrogens, and progesterone to bring about the end-organ changes seen in pubertal development and adult
33
Reproductive Endocrinology and Infertility
function. Hypothalamic and pituitary signals also stimulate androgen production from the adrenal glands during this time. The hypothalamic-pituitary-ovarian (HPO) axis signaling system develops in fetal life and is able to function at any point thereafter if the proper stimuli are present. Within a short time, however, the system undergoes profound inhibition and is kept in check until late in childhood or early teenage years, when it is reawakened.
GonadotropinReleasing Hormone
34
GnRH release, in pulsatile bursts, is the key to turning on the HPO axis system. GnRH is produced from neurons that migrate from the olfactory area into hypothalamic areas of the midbrain early in fetal development. Pulsatile release from these cells is coordinated by a mechanism called the GnRH pulse generator. The pulse generator is active in the newborn under the influence of maternal and placental hormonal exposure. The intensity and frequency of GnRH pulses (indirectly measured through LH pulse levels) are comparable to adults during this time. The pulse generator is quickly dampened and GnRH release is held in check throughout childhood. Inhibition of the pulse generator is achieved through upstream signaling from the brain and other outside sources. In girls, the small amount of estrogen produced by the ovary provides a strong negative feedback signal to the pulse generator. Estrogen is not the primary mechanism preventing GnRH pulse release, however. It has been shown in humans with nonfunctioning gonads and primate animal models with gonadectomies that GnRH pulse suppression in childhood and its release in adolescence are maintained. Although the mechanisms behind a primary pulse suppressor are not completely understood, there are currently two substances that seem to be leading candidates for that role—neuropeptide Y (NPY) and leptin. Male primate animal models (and female models to a lesser extent) have shown that NPY, a polypeptide produced in the hypothalamus, exerts suppressive effects on GnRH pulses. NPY plays a role in nutritional regulation. It is elevated in starvation states and stimulates a hyperphagic response thought to aid in caloric intake. NPY levels decrease as fat stores accumulate. This possible mechanism is intrinsically appealing because of its obvious bridge between nutritional status and reproductive function. Puberty is a time of intense metabolic expenditure (pregnancy being even greater). It is important to have adequate calorie supplies before initiating HPO axis function. Studies in female primates also have shown γ-aminobutyric acid to suppress GnRH pulse activity. Further studies are needed to understand better how NPY and γ-aminobutyric acid function in suppressing the reproductive system in childhood. In late childhood, the mechanism that was suppressing GnRH pulses is withdrawn, and the HPO axis reawakens. It has been known for some time that a link exists between nutrition and the initiation of puberty. The average age at menarche in the United States and the beginning of the 20th century was around 16 years. Currently, the average age is around 12½ years in the United States and other industrialized countries. Improved nutritional status over this time is thought to have a significant influence on pubertal timing. Some investigators linked an absolute weight or body mass index with the start of puberty. Other investigators thought that attaining a specific
Normal and Abnormal Puberty
fat proportion was necessary. The discovery of leptin and its interaction with NPY has led to research linking its role in release of GnRH suppression. Leptin is a polypeptide that is produced by the so-called “ob” gene in adipose cells. As fat accumulates with increased caloric intake, leptin levels increase. Leptin is thought to promote satiety by negative feedback signaling on NPY production from the hypothalamus. Nutritional homeostasis is influenced by their interaction. Initially, it was assumed that leptin was the signal that released the GnRH pulse generator from its suppression to initiate puberty. Researchers found that LH pulses begin after a critical level of leptin is attained, and administering adult doses of leptin to achieve GnRH pulse responses in agonadal states has achieved variable results. It is currently thought that leptin plays a permissive role in initiating the timing of puberty, but it is not the primary signal that restarts the GnRH pulse generator. As with its suppression, the mechanism behind the reawakening is not 35 completely understood, and further investigation is required.
Pituitary Gland
When suppression of the pulse generator is removed, the hypothalamus begins secreting GnRH into the portal blood system of the pituitary. Pituitary secretion of FSH and LH are detected. Gonadotropin pulses initially occur at night. Late in puberty, FSH and LH pulses are detected at night and during the day.
Ovary
LH receptors on theca cells in the stroma of the ovary stimulate the conversion of cholesterol to androgens. These androgens travel by diffusion to the granulosa cells within ovarian follicles. FSH binding in these cells stimulates aromatase enzyme activity to convert androgens into estrogens. Estradiol and androgen levels increase over time and result in end-organ stimulation and physical changes seen in puberty. Ovulatory cycles and progesterone production do not occur initially and may take up to 4½ years to develop.
Adrenal Gland
Although the physical sign of pubic and axillary hair growth occurs within the time frame of other pubertal changes, the androgen production that stimulates this seems to be separate from ovarian production. The maturation of the adrenal cortex, adrenarche, seems to be the source of androgens that produce sexual hair growth or pubarche. Adrenarche begins approximately 2 years before the reactivation of the HPO axis. In contrast to the gonad, which is quiet during childhood because of GnRH pulse suppression, the adrenal glands seem to increase androgen secretion steadily, but gradually, as the zona reticularis of the adrenal cortex matures. Dehydroepiandrosterone and dehydroepiandrosterone sulfate are the primary androgens secreted from this area of the adrenal gland. This process occurs in parallel with, but independent from, gonadal hormone production. Investigations supporting this view note that secondary hair growth continues in the face of gonadal agenesis and hypothalamic hypogonadism. Isolated premature pubarche is not associated with increased gonadal hormone production, and patients
Reproductive Endocrinology and Infertility
with adrenal insufficiency continue to go through the appropriate pubertal changes governed by gonadal hormone production.
Growth Hormone
36
Growth hormone (GH) plays an important role in pubertal development. Delays in growth are seen in patients with gonadal insufficiency or GHdeficient states highlighting the need of both systems to achieve optimal growth. Bone maturation is mediated by insulin-like growth factor produced by GH stimulation of the liver. GH secretion tends to remain steady during childhood, but increases fivefold at the onset of puberty. GH stimulation at puberty seems to be regulated by estrogen in girls and boys. Low levels of estrogen seem to increase GH activity, whereas high levels may exert an inhibitory response. The earlier onset of ovarian hormone production followed by relatively higher estradiol production in girls compared with boys explains the GH-mediated growth acceleration that occurs approximately 2 years earlier in girls and the extended growth period seen in boys leading to an average final height difference of 13 cm between genders. GH also plays a role in gametogenesis in the gonad and increased sensitivity of the follicle to gonadotropic stimulation.
PHYSICAL SIGNS OF PUBERTY The physical changes of puberty are produced by estrogens from gonadal production and androgens from the adrenal gland. Variations in onset of puberty are determined by genetic predisposition, environmental factors, gender, and ethnicity. Adrenarche, the increase in adrenal androgen production, begins around age 6. Ovarian estradiol production begins nearer to 8 years of age (Table 3-1).
Breast
The earliest physical sign of puberty is breast development, or thelarche. The median age of thelarche in the United States is 9.8, years, with differences seen between ethnic groups. The start of breast maturation can range from age 8 to 12. Tanner describes five stages of development from prepubertal to adult appearance (Box 3-1). Tanner stage I is prepubertal, II has small mounds of breast tissue under the areola, III has further enlargement, IV has a secondary mound of areola tissue above the breast, and V has a recession of the areola mound and final adult contour. Completion of breast development occurs over a 5-year period.
Sexual Hair
Although adrenal androgens begin to increase 2 years before ovarian hormones, pubarche is usually the second physical sign of puberty. Sexual hair growth becomes evident at a median age of 10.5 years in girls living in the United States. Timing of initial hair growth ranges from age 9 to 13. Tanner staging also describes progression of hair growth (Box 3-2). Stage I is prepubertal. Stage II has sparse hair along the labia majora. Stage III has dark,
Normal and Abnormal Puberty Table 3-1 Median Ages at Entry into Each Maturity Stage and Fiducial Limits (FL)* in Years for Pubic Hair and Breast Development in Girls by Race
Age at Entry Non-Hispanic White Stage
Median
Non-Hispanic Black
Mexican-American
FL
Median
FL
Median
FL
10.29-10.85 11.54-12.07 12.71-13.30 15.86-16.88
9.43† 10.57† 11.90† 14.70†
9.05-9.74 10.30-10.83 11.38-12.42 14.32-15.11
10.39 11.70† 13.19† 16.30†
— 11.14-12.27 12.88-13.52 15.90-16.76
Breast Development B2 10.38† 10.11-10.65 B3 11.75† 11.49-12.02 B4 13.29† 12.97-13.61 B5 15.47† 15.04-15.94
9.48† 10.79† 12.24† 13.92†
9.14-9.76 10.50-11.08 11.87-12.61 13.57-14.29
9.80 11.43 13.07† 14.70†
0-11.78 8.64-14.50 12.79-13.36 14.37-15.04
Pubic Hair PH2 10.57† PH3 11.80† PH4 13.00† PH5 16.33†
Calculated 98.3% FLs to adjust for multiple comparisons between races for an overall α of 0.05. † Significant pair-wise racial difference, P<.05. From Sun SS, Schubert CM, Chumlea WC, et al: National estimates of the timing of sexual maturation and racial differences among US children. Pediatrics 2002;110:911-919. *
coarse hair over the mons. Stage IV has abundant adult hair limited to the labia and mons. Stage V has adult type hair spread above the mons and over the inner thighs. Typically, complete hair development is seen within 3 years.
Growth Spurt
The median age of maximal growth velocity is 11½ years (range of 9½-14 years). Growth typically slows just before puberty, then accelerates approximately 2 years into puberty. A period of acceleration is seen for a little more than 2 years. Further growth ceases in girls when the bone age approaches 15 years, and the epiphyseal plates close. Girls begin their growth spurts approximately 2 years earlier than boys and gain an average of 25 cm during puberty. Significant weight gain also is seen during puberty. Fifty percent of
Box 3-1
Tanner Staging System for Breast Development
I—preadolescent, papilla elevation only II—breast bud palpable, increased areolar diameter III—breast contour diffusely enlarged IV—secondary mound formed by areola and papilla V—adult breast contour, areola and breast continuous
Box 3-2
Tanner Staging System for Pubic Hair Development
I—none II—sparse, long coarse hair on labia III—coarse, darkly pigmented, curly, spread to pubis IV—adult-quality hair over pubis V—adult distribution with spread to medial thighs
37
Reproductive Endocrinology and Infertility
adult body weight is gained during adolescence. Weight gain in boys parallels their growth spurt while lagging by 6 months compared with girls. Peak weight gain velocity reaches 8.3 kg/yr by 12.5 years of age, then decelerates with the deceleration in height velocity later in puberty.
Menarche
38
Continued estrogen exposure leads to increased endometrial cell mitosis and the proliferation of the endometrial layer in the uterus. Shedding of estrogen-primed endometrium, or menarche, occurs with variations in estrogen levels. Menarche is usually the last physical sign of puberty. The normal age range of menarche in the United States is 9 to 17½ years with a median age of 12½ years. Ethnic differences are associated with varying times of menarche. African-American girls achieve menarche an average of 8.5 months before white girls. The HPO axis does not mature immediately, and 12 to 18 months may pass before ovulation, progesterone production, and regular menstrual cycles occur.
INFLUENCES IN THE TIMING OF PUBERTY The onset of puberty in girls can be difficult to track because of various internal and external influences. Improvement in environmental conditions led to a steady decrease in timing of menarche from the early 1900s to the 1960s. A reduction of approximately 4 months per decade has been calculated. Since 1960, the timing of menarche has reached a plateau in industrialized countries. Although the overall variability is remarkably small (1 year), the range in age of menarche in industrialized countries may normally be 5 years. Studies comparing monozygotic twins, dizygotic twins, nontwin sisters, and unrelated groups note progressive variance in timing of menarche. These findings suggest that genetic factors, including ethnicity, constitute approximately three quarters of the influence on timing of puberty, whereas environmental factors contribute the remaining quarter. Environmental factors may include locale, climate, light-dark cycles, nutrition, intrauterine growth restriction, stress, illness, and toxin exposure.
ABNORMAL PUBERTAL DEVELOPMENT Abnormal pubertal development can be divided into conditions that initiate pubertal changes too early or prevent timely development. Early or precocious puberty can occur at any stage in childhood. Girls constitute most children with this condition. Delayed puberty is seen more frequently in boys.
Precocious Puberty
It has long been established that the lower limit of normal for pubertal initiation is 8 years of age. Normative curves in several populations have set this age limit. The Pediatric Research in Office Settings (PROS) study noted, however, that a large percentage of girls starting puberty when younger
Normal and Abnormal Puberty
than the established limit achieved normal adult height and had no longterm physical sequelae. This led the PROS authors to recommend redefining precocious puberty as thelarche beginning by age 6 in African-American girls and by age 7 in white girls. Other groups have not embraced this recommendation and continue to use 8 years of age as the lower limit of normal. They cite concerns regarding the accuracy of the study methods in dating thelarche. Multiple observers could have led to unreliable variance. Staging was decided using visual inspection of the breast instead of palpation. Visual inspection may not distinguish reliably true breast tissue development from visual changes of general increased adiposity in overweight children, inaccurately decreasing the age of thelarche. Other studies have noted that in children 6 to 8 years old who would have been classified as normal under the revised criteria, nearly half had an underlying disease. Concerns about the psychosocial impact that untreated pubertal changes may have on such 39 young children also have been raised. Precocious puberty may be divided into central or peripheral causes. Central precocious puberty (CPP) is mediated by the premature awakening of hypothalamic signals that stimulate ovarian hormone production. Most CPP, approximately three quarters, is idiopathic in etiology (Fig. 3-1). The remaining causes are due to a mass effect in the hypothalamic or pituitary
Figure 3-1 A 2-year-old girl with idiopathic central precocious puberty.
Reproductive Endocrinology and Infertility
areas of the brain leading to stimulation of GnRH or FSH and LH production. Because a brain mass may have serious consequences, idiopathic CPP should be a diagnosis of exclusion. Masses that arise from the brain to cause CPP include pituitary hamartomas (the most common tumor in CPP occurring in children <6 years old), craniopharyngiomas, gliomas, adenomas, and arachnoid cysts. Pressure and inflammation may stimulate gonadotropin release owing to hydrocephalus, abscess, sarcoidosis, tuberculosis, trauma, radiation, or chemotherapy (Table 3-2). Peripheral precocious puberty (PPP) does not depend on GnRH or pituitary hormone signaling to produce ovarian sex hormones. Causes include estrogen-producing tumors of ovary or adrenal glands and exogenous estrogen sources (Table 3-3). McCune-Albright syndrome is associated with excessive secretion of estrogen from the ovary and benign cyst formation, which also may secrete estrogen independent from gonadotropin signals (Fig. 3-2).
40
Diagnosis of Precocious Puberty
The physical signs of estrogen stimulation, breast development and pubic hair growth before age 8 years, may make the diagnosis of precocious puberty obvious. Occasionally, menarche may occur before breast and hair growth, however. Inspection of the vaginal tissue during the workup of childhood vaginal bleeding may reveal signs of estrogen stimulation of the Table 3-2
Etiology of Central Precocious Puberty (GonadotropinDependent, True)
Category
Underlying Disease
Permanent precocious puberty Idiopathic Sporadic Familial CNS abnormalities or lesions Hypothalamic hamartoma Tumors: astrocytoma, craniopharyngioma, ependymoma, glioma, LH-secreting adenoma, pinealoma Congenital malformations: arachnoid cyst, suprasellar cyst, phakomatosis, hydrocephalus (with or without spina bifida), septo-optic dysplasia Acquired disease: inflammatory CNS disease, abscess, radiation, chemotherapy, trauma Dysmorphic syndromes Williams-Beuren syndrome Klinefelter’s syndrome (rare) CNS maturation with central Congenital adrenal hyperplasia precocious puberty Sex steroid–producing tumors secondary to prolonged Male-limited precocious puberty (constitutively sex steroid exposure activated LH receptor Transient precocious puberty Sporadic Idiopathic Arachnoid cyst Hydrocephalus Variants of pubertal Premature thelarche development (partial Premature pubarche or incomplete precocity) Premature menarche CNS, central nervous system; LH, luteinizing hormone. From Partsch CJ, Sippell WG: Pathogenesis and epidemiology of precocious puberty. Effects of exogenous oestrogens. Hum Reprod Update 2001;7:292-302.
Normal and Abnormal Puberty Table 3-3 Etiology of Peripheral Precocious Puberty (GonadotropinIndependent, Pseudopuberty)
Category
Underlying Disease
Ovarian disorders
Granulosa cell tumor Theca cell tumor Other estrogen-secreting tumors: teratoma, teratocarcinoma, dysgerminoma, luteoma, mixed cell tumor, lipoid tumor Sex cord or Sertoli cell tumor of the ovary with annular tubuli seminiferi (SCTAT) and aromatase activity in Peutz-Jeghers syndrome McCune-Albright syndrome (ovarian cysts) Autonomous isolated ovarian cysts Testicular disorders Leydig cell adenoma Constitutively activating LH receptor mutation (male-limited precocious puberty = testotoxicosis) Adrenal disorders Adrenal adenoma Adrenal carcinoma (usually virilizing) Congenital adrenal hyperplasia (21-hydroxylase or 11β-hydroxylase deficiency) hCG-secreting Dysgerminoma, teratoma, chorioepithelioma, tumors choriocarcinoma, hepatoblastoma, pinealoma Exogenous Sex-steroid exposure: pills (estrogens, anabolics), food additives, cosmetics, creams Transient Autonomous isolated ovarian cysts (self-limiting) precocious Exogenous (interruption of exposure) puberty hCG, human chorionic gonadotropin. From Partsch CJ, Sippell WG: Pathogenesis and epidemiology of precocious puberty. Effects of exogenous oestrogens. Hum Reprod Update 2001;7:292-302.
mucosa (Box 3-3). A wet preparation of the mucosa may be done to perform a maturation index. Abundance of superficial epithelial cells suggests the presence of estrogen production. Growth curve plots may reveal acceleration in height and change to a higher percentile. Current estradiol assays are not always accurate in diagnosing precocious puberty. A bone age derived from wrist x-rays, compared with age-standardized films, helps to dif ferentiate progressive precocious puberty from more benign forms of early thelarche and pubarche. When the diagnosis of precocious puberty is suspected, LH and FSH levels should be drawn to differentiate between CPP and PPP. Elevated values into the pubertal range are consistent with CPP. Equivocal results may require a subsequent GnRH stimulation test. LH and FSH levels, drawn 30 minutes after a 100-μg injection of GnRH, lead to exaggerated serum levels in cases of CPP. A peak LH level of more than 15 IU/L or a peak LH-to-peak FSH ratio of more than 0.66 is consistent with a pubertal GnRH test with 96% sensitivity, 100% specificity, and no false-positive results. The independent estrogen production in PPP leads to suppressed LH and FSH levels. Imaging of the head should be performed in all cases of CPP to rule out a mass. Magnetic resonance imaging (MRI) has been shown to have the highest sensitivity in detecting masses in the pituitary and hypothalamic regions. When PPP is suspected, a thorough history should be taken to rule out exogenous estrogen consumption. Also, imaging of the ovary and adrenal glands should be performed to rule out a tumor in those organs.
41
Reproductive Endocrinology and Infertility Figure 3-2 A 4-year-old girl with McCune-Albright syndrome. Note caféau-lait spots on mons and inner thigh.
42
Box 3-3 ● ● ● ● ● ● ● ●
Treatment of Precocious Puberty
Useful Methodologies in the Diagnosis of Precocious Puberty
Maturation index of vaginal mucosa Growth curve Right radial bone age Serum LH, FSH GnRH stimulation test MRI of head Ovarian ultrasound Adrenal computed tomography
Any girl younger than age 8 with physical signs of puberty, significantly advanced bone age, decreased predicted height, and a pubertal response to GnRH stimulation should be treated to suppress CPP progression and improve adult height (Box 3-4). Surgical therapy is limited to a few cases of CPP in which there is a lesion present. Only lesions that arise from a pedunculated stalk are usually amenable to surgical removal. It may be too difficult to remove nonpedunculated lesions without sacrificing some normal tissue surrounding these lesions.
Normal and Abnormal Puberty
Box 3-4 ● ● ● ● ● ● ●
Possible Treatments of Precocious Puberty
Surgery if accessible central lesion identified GnRH-agonist therapy GH Removal of ovarian or adrenal tumors Removal of exogenous source of estrogen Removal of cysts in McCune-Albright syndrome Aromatase inhibitors in McCune-Albright syndrome
Medical therapy is the treatment of choice for most lesions and idiopathic CPP. Therapy involves continuous doses of GnRH agonists in the form of daily nasal spray inhalation or monthly or quarterly intramuscular injections. The continuous GnRH agonist levels override the pulsa- 43 tile GnRH signals coming from the hypothalamus and suppress ovarian hormone production. Serial examinations during treatment should reveal reversal of pubertal signs, decrease in growth velocity, and slowing of bone maturation. Laboratory values should revert to prepubertal values. This monitoring may include LH, FSH, and estradiol levels drawn 12 hours after the next monthly injection of GnRH agonists or a random ultrasensitive estradiol. GH secretion also may be suppressed when brain lesions are present. Decreased GH levels also have been noted in idiopathic CPP. Reduced GH stimulation of bone may reduce height velocity when GnRH treatment is initiated. If height velocity is suppressed, and a shortened adult height is predicted, GH administration combined with GnRH treatment may re-establish bone growth and improve final adult height. Treatment of PPP involves removal of the independent estrogen source through surgical removal in the cases of ovarian or adrenal tumors or discontinuation of an exogenous estrogen source. As estrogen levels begin to decrease with treatment, breast development and genital mucosal changes often revert to prepubertal appearance. Height acceleration should diminish, and if epiphyseal plate closure has not occurred, growth along the established curves should continue. Removal of cysts in patients with McCune-Albright syndrome may provide temporary reductions in estrogen production. Treatment with aromatase inhibitors has achieved limited success. Early diagnosis and treatment of precocious puberty is essential to optimize final adult height. When Tanner stage III breasts develop, it becomes difficult to achieve significant gains in height. Treatment of girls with short stature who began puberty on the early end of the normal age range does not result in additional final height.
Mixed Precocious Puberty
High levels of estrogen eventually can stimulate the hypothalamus to begin secreting GnRH pulses. An initial PPP etiology may lead to CPP. This combination of stimulation is known as mixed precocious puberty. Monitoring pubertal progression is important after treatment has been initiated to
Reproductive Endocrinology and Infertility
prevent overlooking this phenomenon. Initial laboratory tests noting an elevation in FSH and LH levels suggest a CPP. If progression in pubertal changes continues despite adequate GnRH suppression, however, an ovarian, adrenal, or exogenous source of estrogen should be ruled out. If a PPP source is initially found and treated, follow-up evaluations are needed to ensure the reversal of pubertal changes. If progression continues, a repeat evaluation of the FSH and LH levels should be considered to rule out secondary stimulation of the hypothalamus; this may require initiating GnRH treatment to address the new central source of ovarian stimulation.
Premature Thelarche
Premature thelarche is a benign condition that can be seen at a very early age. It consists of isolated breast tissue development. Areolar development usually is unaffected. It tends to be self-limited and does not show signs of progressive precocious puberty. Pubic hair growth, height and bone age acceleration, early epiphyseal closure, and shortened adult stature are not seen. The initial presentation of premature thelarche cannot be distinguished easily from early stages of progressive precocious puberty. Both conditions may show mild increases in serum estradiol, normal basal FSH levels, and an exaggerated FSH response to GnRH stimulation with a less drastic increase in LH levels. Elevated basal FSH and LH levels and predominant LH stimulation from GnRH administration do not occur until late stages of precocious puberty are established. Premature thelarche and central precocious puberty may represent different points of severity along a spectrum of early HPO axis activation. Serial monitoring of puberty changes, growth acceleration, and bone age may be needed to document stabilization or regression and to confirm the final diagnosis of isolated premature thelarche.
Premature Adrenarche
Premature adrenarche refers to early development of pubarche with no other signs of sexual development before the age 8 in girls and 9 in boys. Girls are affected more often than boys by a ratio of 10:1. Premature adrenarche is due to an early isolated maturation of the adrenal gland. Gonadotropins do not play a role in the development of premature adrenarche. Hair growth usually is limited to the labia majora, clitoral enlargement is usually absent, and breasts remain prepubertal. Mild increases in androgen levels, growth velocity, and bone age can be seen. Progressive androgenizing disorders, such as progressive precocious puberty, a virilizing adrenal or ovarian tumor, adult-onset congenital adrenal hyperplasia, and exogenous androgen administration, must be ruled out before making the diagnosis of isolated premature adrenarche. Acceleration in growth and bone maturation seems to be transient. There is no difference in onset of puberty or final adult height compared with controls. Premature adrenarche has been associated with hyperandrogenism, reduced ovulatory function, polycystic ovary syndrome, hyperinsulinemia, and alterations in triglyceride levels later in adulthood. Patients with premature adrenarche should be monitored for these conditions as they progress through adolescence.
44
Normal and Abnormal Puberty
Delayed Puberty
Delayed puberty is diagnosed when there is no breast development by 13.4 years in girls and no testicular development by 14 years in boys. Causes include constitutional delay, chronic illness, hypothalamic or pituitary failure from destructive lesions, hypothyroidism, hyperprolactinemia, excessive exercise, inadequate caloric intake, and ovarian failure. A constitutional delay is more common in boys. It should be a diagnosis of exclusion. Evaluation of delayed puberty is considered further in Chapter 4.
Abnormal Breast Development
Normal breast development begins early in fetal life. A primary mammary bud grows into surrounding mesenchyme from the epidermis of the pectoral region by week 6. In the second trimester, 15 to 25 secondary buds form and lead to lactiferous ducts that end at the nipple. Fibrous stroma and fat from the mesenchyme surround the duct systems. Late in the third trimester, the 45 nipple and areola arise from the mammary pit. The breast remains virtually unchanged during childhood. Pubertal breast development occurs over 3 to 5 years during puberty under the primary influence of estrogen. FSH, LH, GH, and adrenocorticotropic hormone contribute to duct growth. In most cases, an unknown mechanism arrests further breast development late in puberty. Breast hypoplasia describes a condition in which breast tissue fails to grow despite the presence of normal structures such as nipples. Amastia signifies the complete absence of breast tissue, including the nipples. Some asymmetry of the breasts can be seen in most women and does not require intervention. Significant asymmetry can be quite troubling and may warrant intervention. Hypoplasia has been associated with chromosomal aberrations, trauma, congenital defects of the pectoralis major muscle (Poland’s syndrome), and hormone receptor abnormalities. Attempts to stimulate growth with estrogen may provide some improvement in breast size, but surgical therapy with implants or autologous tissue may be required. Juvenile gigantomastia usually presents with rapid growth of one or both breasts to massive proportions. Enlargement begins during the early pubertal period. Accelerated growth lasts 3 to 6 months followed by slower, but steady growth indefinitely. Symptoms include breast pain, back and neck pain, slouching posture, shoulder grooving from bra straps, hygienic difficulties, and orthopnea. Physical changes may include skin necrosis and changes in spinal alignment. Psychosocial concerns also are significant. Breast reduction surgery is the primary initial treatment, but recurrent hypertrophy often occurs without additional therapy. Repeat reductive surgery is often required. Definitive treatment involves mastectomy with implants to prevent recurrence. Tamoxifen has shown some success in slowing recurrent growth after initial surgery.
Labial Hypertrophy
Before puberty, the labia minora appear as small prominences extending just inferior from the clitoral hood. Proliferation in size and shape occurs at puberty under the influence of estrogen. Asymmetry is common, and in
Reproductive Endocrinology and Infertility
some instances the tissue may grow quite large. Lengths of 4 to 5 cm are generally regarded as hypertrophic, but significance is related primarily to symptoms of pain with sitting or intercourse or patient concerns about appearance. Histologic examination shows dilated blood vessels and edematous stroma. Infiltration of lymphocytes in close proximity to blood vessels also suggests a possible inflammatory process. The cause of labial hypertrophy is unknown. Filaria sanguinis-hominis infection may cause blockage of the lymph channels, and consequently labial edema may occur to mimic true hypertrophy. Chronic stimulation from constant pulling, myelodysplasia, and chronic diaper use have been associated with the condition. Surgical correction is usually successful.
46
SUMMARY A complex pathway of signals between the brain, adrenal gland, and ovaries initiates puberty at the end of the first decade of life. The system has the ability to activate at any time in childhood, but is held in check by several regulatory mechanisms. Timing of puberty is influenced by genetics, nutrition, the environment, and health factors. Alterations in the timing of puberty are usually idiopathic, but can herald underlying lesions within the brain, adrenal gland, or ovary. Failure to identify these lesions may result in serious injury in the short-term. Failure to treat precocious puberty in a timely manner may affect potential height, sexual development, self-image, and social interactions later in life. Asymmetry of breast and labial tissue is common and in most cases does not require treatment. Surgical intervention usually is required to treat rare cases of severe, symptomatic growth abnormalities.
SUMMARY OF KEY POINTS 1.
2. 3.
4.
5.
The HPO axis has the capacity to function at any point after fetal life, but is kept in check until puberty by an unclear mechanism outside of the system. Nutritional homeostasis, regulated by NPY and leptin, may play a role in the timing of pubertal development. Adrenarche, and its subsequent development of sexual hair, occurs in parallel to, but separate from, secondary sexual developments regulated by the ovaries—breast development, growth spurt, and menarche. Pubertal changes typically begin with thelarche between ages 8 and 12. The time from early breast development until menarche is generally 2½ years. It may take another 2 years after menarche to begin ovulatory cycles. The timing of puberty in industrialized countries has stabilized since the 1960s with little variation in average age of pubertal development. Individual variations of pubertal timing range from 4 to 5 years within a group. Developing countries continue to have wider ranges of puberty timing secondary to various nutritional and environmental factors.
Normal and Abnormal Puberty
6. 7.
8.
9.
Precocious puberty is more common in girls. Delayed puberty is more common in boys. Idiopathic precocious puberty is the most common cause of early puberty, but should remain a diagnosis of exclusion until other, more health-threatening causes have been ruled out. GH levels should be monitored before treatment for CPP. Failure to diagnose and treat a coexistent GH deficiency hinders maximum growth potential. Serial monitoring should be performed during the treatment of precocious puberty to rule out a mixed etiology.
47
SUGGESTED READINGS Apter D, Butzow TL, Laughlin GA, Yen SSC: GnRH pulse generator activity during pubertal transition in girls: pulsatile and diurnal patterns of circulating gonadotropins. J Clin Endocrinol Metab 1993;76:940-949. Cunningham MJ, Clifton DK, Steiner RA: Leptin’s actions on the reproductive axis: perspectives and mechanisms. Biol Reprod 1999;60:216-222. Frisch RH: Pubertal adipose tissue: is it necessary for normal sexual maturation? Evidence from the rat and human female. Fed Proc 1980;39:2395-2400. Grumbach MM: Estrogen, bone, growth, and sex: a sea change in conventional wisdom. J Pediatr Endocrinol Metab 2000;13(suppl 6):1439-1455. Herman-Giddens ME, Slora EJ, Wasserman RC, et al: Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network. Pediatrics 1997;99:505-512. Jaffe RB: Fetal neuroendocrinology. In Mancusco S (ed): Achievements in Gynecology. Basel/ New York: Karger; 1989:104-110. Kaplowitz PB, Oberfield SE: Reexamination of the age limit for defining when puberty is precocious in girls in the United States: implications for evaluation and treatment. Drug and Therapeutics and Executive Committees of the Lawson Wilkins Pediatric Endocrine Society. Pediatrics 1999;104:936-941. Lazar L, Kauli R, Pertzelan A, Phillip M: Gonadotropin-suppressive therapy in girls with early and fast puberty affects the pace of puberty
but not total pubertal growth or final height. J Clin Endocrinol Metab 2002;87:2090-2094. Lee PA, Guo SS, Kulin HE: Age of puberty: data from the United States of America. APMIS 2001;109:81-88. Marshall WA, Tanner JM: Variations in patterns of pubertal changes in girls. Arch Dis Child 1969;44:291-303. Oerter KE, Uriarte MM, Rose SR, et al: Gonadotropin secretory dynamics during puberty in normal girls and boys. J Clin Endocrinol Metab 1990; 71:1251-1258. Pasquino AM, Municchi G, Pucarelli I, et al: Combined treatment with gonadotropin-releasing hormone analog and growth hormone in central precocious puberty. J Clin Endocrinol Metab 1996;81:948-951. Rosenbaum M, Leibel RL: Leptin: a molecule integrating somatic energy stores, energy expenditure and fertility. Trends Endocrinol Metab 1998;9:117-124. Spiliotis BE: Growth hormone insufficiency and its impact on ovarian function. Ann N Y Acad Sci 2003;997:77-84. Sun SS, Schubert CM, Chumlea WC, et al: National estimates of the timing of sexual maturation and racial differences among US children. Pediatrics 2002;110:911-919. Tanner JM: Fetus into Man: Physical Growth from Conception to Maturity. Cambridge, MA: Harvard University Press; 1989. Terasawa E, Fernandez DL: Neurobiological mechanisms of the onset of puberty in primates. Endocrinol Rev 2001;22:111-151.
4 EVALUATION AND TREATMENT OF AMENORRHEA Bruce R. Carr 49
DEFINITIONS Amenorrhea Androgen insensitivity syndrome Kallmann’s syndrome Sheehan’s syndrome
Cessation of menstrual flow Rare disorder resulting in external female appearance, but with absent uterus, ovaries, and a large part of the vagina, caused by the absence of functional androgen receptors Low gonadotropin levels, amenorrhea, and anosmia (absent sense of smell); the constellation is due to the failure of normal migration of olfactory and gonadotropin neurons during embryologic development Postpartum pituitary necrosis caused by hemorrhage and resulting profound hypovolemia
DEFINITION The usual definition of amenorrhea is the cessation of menstrual flow. Primary amenorrhea is a condition characterized by absence of menstruation by age 16 in phenotypic females, commonly due to gonadal dysgenesis. Secondary amenorrhea is a condition characterized by the cessation of menstruation for periods of 3 months or longer in a woman who previously has experienced spontaneous menstruation (Box 4-1). A common cause of secondary amenorrhea is polycystic ovarian syndrome (PCOS). Although these definitions are useful, there is significant overlap between different disorders that manifest with primary amenorrhea. Women with PCOS may present with a history of no bleeding, and women with gonadal dysgenesis may have occasional menses. We prefer to classify patients with amenorrhea in functional groups as described in Box 4-2 and Table 4-1.
CLASSIFICATIONS OF AMENORRHEA Women who present with delayed puberty also have amenorrhea and should not be considered as a separate entity. Women who present with
Reproductive Endocrinology and Infertility
Box 4-1 ● ●
Definition of Amenorrhea
Primary amenorrhea: failure of menarche by age 16 Secondary amenorrhea: absence of menstruation for 3 months in a woman with previous spontaneous menses
Box 4-2
Classifications of Amenorrhea
1. Gonadal failure 2. Chronic anovulation With estrogen present With estrogen absent 3. Defects of female reproductive tract
50 Table 4-1 Classification of Amenorrhea (Not Including Disorders of Congenital Sexual Ambiguity)
I. Anatomic defects (outflow tract) A. Labial agglutination/fusion B. Imperforate hymen C. Transverse vaginal septum D. Cervical agenesis—isolated E. Cervical stenosis—iatrogenic F. Vaginal agenesis—isolated G. Müllerian agenesis (Mayer-Rokitansky-Kuster-Hauser syndrome) H. Complete androgen resistance (testicular feminization) I. Endometrial hypoplasia or aplasia—congenital J. Asherman’s syndrome (uterine synechiae) II. Gonadal failure (hypergonadotropic hypogonadism) A. Gonadal agenesis B. Gonadal dysgenesis 1. Abnormal karyotype a. Turner’s syndrome 45,X b. Mosaicism 2. Normal karyotype a. Pure gonadal dysgenesis i. 46,XX ii. 46,XY (Swyer syndrome) C. Ovarian enzymatic deficiency 1. 17α-Hydroxylase deficiency 2. 17,20-Lyase deficiency D. Premature ovarian failure 1. Idiopathic—premature aging 2. Injury a. Mumps oophoritis b. Radiation c. Chemotherapy 3. Resistant ovary (Savage syndrome) 4. Autoimmune disease 5. Galactosemia III. Chronic anovulation with estrogen present A. Polycystic ovarian syndrome B. Adrenal disease 1. Cushing’s syndrome 2. Adult-onset adrenal hyperplasia
Evaluation and Treatment of Amenorrhea
C. Thyroid disease 1. Hypothyroidism 2. Hyperthyroidism D. Ovarian tumors 1. Granulosa-theca cell tumors 2. Brenner tumors 3. Cystic teratomas 4. Mucinous/serous cystadenomas 5. Krukenberg’s tumors IV. Chronic anovulation with estrogen absent (hypogonadotropic hypogonadism) A. Hypothalamic 1. Tumors a. Craniopharyngioma b. Germinoma c. Hamartoma d. Hand-Schüller-Christian disease e. Teratoma f. Endodermal sinus tumors g. Metastatic carcinoma 2. Infection and other disorders a. Tuberculosis b. Syphilis c. Encephalitis/meningitis d. Sarcoidosis e. Kallmann syndrome f. Idiopathic hypogonadotropic hypogonadism g. Chronic debilitating disease 3. Functional a. Stress b. Weight loss/diet c. Malnutrition d. Psychological i. Eating disorders (anorexia nervosa, bulimia) e. Exercise B. Pituitary 1. Tumors a. Prolactinomas b. Other hormone-secreting pituitary tumors (adrenocorticotropic hormone, thyrotropin-stimulating hormone, growth hormone) c. Nonfunctional tumors (craniopharyngioma) d. Metastatic carcinoma 2. Space-occupying lesions a. Empty sella b. Arterial aneurysm 3. Necrosis a. Sheehan’s syndrome b. Panhypopituitarism 4. Inflammatory/infiltrative a. Sarcoidosis b. Hemochromatosis From Carr BR: Disorders of the ovary and female reproductive tract. In Wilson JD, Foster D (eds): Williams Textbook of Endocrinology. Philadelphia: WB Saunders; 1992:764.
51
Reproductive Endocrinology and Infertility
sexual ambiguity since birth or significant virilization also may present with amenorrhea, but these should be evaluated as separate disorders. Using this approach, the diagnosis and treatment are simplified. Classifications consisting of primary and secondary amenorrhea are not used because they do not describe the pathophysiology. The largest category is chronic anovulation, which includes women who have the ability to ovulate but do not; subcategories include women who produce estrogen (eugonadotropism) and women who do not produce estrogen (hypogonadotropic hypogonadism). The second category is gonadal failure (hypergonadotropic hypogonadism), in which the germ cells are usually absent. The third category includes abnormalities and defects in development of the female reproductive tract. Table 4-1 lists all the possible disorders. 52
GONADAL FAILURE
Box 4-3 Gonadal Failure FSH >40 mIU/mL Age <35: Obtain chromosomes
Gonadal (ovarian) failure is associated with increased gonadotropins, and the term hypergonadotropic hypogonadism is used. The development of amenorrhea and hypoestrogenism associated with elevated gonadotropins before the age of 40 defines ovarian failure. Cessation of ovarian function as a result of loss of germ cells and follicles in the ovary can occur at any age, however, even in utero, such as in gonadal dysgenesis or ovarian agenesis. When ovarian failure occurs before puberty, the presentation is that of a phenotypic female with primary amenorrhea and lack of secondary sexual development. When it occurs after pubertal development, the presentation is secondary amenorrhea with the primary complaint being hot flashes. As is true for disorders of chronic anovulation, ovarian failure can result from several causes (see Table 4-1), including gonadal agenesis or dysgenesis. Gonadal dysgenesis can be associated with normal or abnormal karyotypes. Women harboring Y chromosome material have an increased risk of gonadal tumors, and the gonads should be removed (Box 4-3). Rare causes of ovarian failure include 17α-hydroxylase deficiency, resistant ovary syndrome, autoimmune disorders associated with galactosemia, and iatrogenic causes secondary to chemotherapy or radiation therapy. The diagnosis of ovarian failure should be suspected in all cases of primary amenorrhea and sexual infantilism and in women with secondary amenorrhea who develop hot flashes and other signs of estrogen deficiency. This diagnosis is confirmed by documenting an increased follicle-stimulating hormone (FSH) in the menopausal range (<30-40 IU/L).
CHRONIC ANOVULATION The major cause of amenorrhea is chronic anovulation. In this disorder, women have ovaries and follicles, but for various reasons do not ovulate normally. With appropriate therapy, however, they can ovulate and later conceive. In women with chronic anovulation, the ovaries do not secrete estrogen and progesterone in the normal cyclic pattern. Women who exhibit
Evaluation and Treatment of Amenorrhea
bleeding after receiving an oral or intramuscular progestin challenge are producing estrogen and fall into the category of chronic anovulation with estrogen present. Women who fail to exhibit a menstrual bleed after a progestin challenge have low levels of estrogen and are categorized as chronic anovulation with estrogen absent.
Chronic Anovulation with Estrogen Present
Box 4-4 Polycystic Ovarian Syndrome PCOS is a state of chronic anovulation with acyclic production of estrogen (estrone) formed by extraglandular aromatization of androgens (androstenedione).
Women with chronic anovulation who experience withdrawal menstrual bleeding after a progestin challenge and exhibit normal FSH levels are said to be in a chronic estrous cycle because of a cyclic production of estrogen. The ovarian follicles of women with this disorder do not secrete large amounts of estrogen, but instead secrete androgens, such as androstenedione, which are converted in peripheral tissues by extraglandular aromatase into the weaker estrogen, estrone. This condition may be due to problems primarily 53 in the ovary or in the hypothalamic-pituitary-gonadal feedback loops. The consequence is that these women fail to ovulate and produce estrogen and do not experience cyclic withdrawal bleeding. The primary cause of chronic anovulation with estrogen present is PCOS (Box 4-4). PCOS is a complex disorder (probably inherited and related to insulin resistance) characterized by the development of hirsutism or androgen excess; obesity; and menstrual disturbances, including amenorrhea, oligomenorrhea, or dysfunctional uterine bleeding at the time of expected puberty (Box 4-5). The clinical picture varies, and laboratory tests may be helpful, but are only supportive in confirming the diagnosis. In most women with PCOS, plasma luteinizing hormone (LH) levels are elevated at the same time the plasma FSH levels are normal or low. Some have suggested that a ratio of LH to FSH of greater than 2 to 3 may be a useful laboratory distinction. The evaluation of a single sample of gonadotropins may lead to the wrong diagnosis, however, and only 80% of women may exhibit this finding. In addition, most women with PCOS have moderately elevated serum androgen levels. An ultrasound showing multiple superficial small follicles surrounding the surface of the ovary in a ringlike pattern associated with increased stromal density in a woman with amenorrhea supports the diagnosis (Fig. 4-1). As stated previously, the diagnosis of PCOS is not based on pathologic changes in the ovaries or plasma hormone abnormalities, but is primarily based on the clinical evidence of chronic anovulation with varying degrees
Box 4-5
Polycystic Ovarian Syndrome Clinical Characteristics
1. Wide spectrum 2. At or just before menarche Androgen excess Obesity Menstrual disturbance ● Amenorrhea ● Oligomenorrhea ● Dysfunctional uterine bleeding Infertility Insulin resistance
Reproductive Endocrinology and Infertility Figure 4-1 Vaginal ultrasound shows classic polycystic ovaries. Note the peripheral location of multiple small ovarian cysts (ring surrounding ovarian stroma).
54
of androgen excess and menstrual disturbances. The etiology of this disorder is multifactorial and is not yet clearly understood. Chronic anovulation with estrogen present, obesity, hirsutism, and polycystic ovaries can be seen in a variety of other endocrine disorders in addition to PCOS (see Table 4- 1). These women may present with Cushing’s syndrome, hyperthyroidism, hypothyroidism, or late adult-onset adrenal hyperplasia secondary to 21-hydroxylase or 11β-hydroxylase deficiency. Rarely, patients with chronic anovulation with estrogen present have ovarian tumors, such as Brenner’s tumor or cystic teratomas and even ovarian cancers in which the ovary or tumor or both secrete increased amounts of androstenedione, which aromatize in extraglandular sites to estrogen. As a result, such patients may present with a pattern similar to that of a woman with PCOS that resolves at the time of the removal of the tumor or the treatment of the primary disorder.
Chronic Anovulation with Estrogen Absent
Women with chronic anovulation with estrogen absent owing to low or absent estrogen production fail to experience withdrawal bleeding or experience only vaginal spotting after a progestin challenge. Usually the FSH level is normal or low; this is an important point because evaluating the FSH level alone (if within the normal range, e.g., 4-8 IU/mL) does not confirm the cause of amenorrhea. Chronic anovulation with estrogen absent is a result of hypogonadotropic hypogonadism that is secondary to organic or functional disorders of the central nervous system hypothalamic-pituitary axis. It may be clinically helpful but not always practical to subdivide these into hypothalamic or pituitary causes (see Table 4-1). Hypothalamic tumors or other destructive disorders of the hypothalamus are relatively rare causes of
Evaluation and Treatment of Amenorrhea
amenorrhea and require radiographic evaluation, such as computed tomography (CT) or magnetic resonance imaging (MRI). In women with tumors, headaches and other neurologic symptoms and signs are often present. The most common cause of chronic anovulation with estrogen absent is a functional disorder of the hypothalamus or central nervous system in the presence of a normal MRI or CT study. In these cases, the diagnosis of chronic anovulation is one of exclusion. A history of stress or a stressful event often can be obtained. These events include loss of a loved one, entering a stressful work environment, or going off to college. In these cases, the stress reduces hypothalamic secretion of gonadotropin-releasing hormone (GnRH), leading to reduced gonadotropin secretion followed by reduced ovarian estrogen secretion, and amenorrhea results. This can happen even in women with normal body weight. Other causes related to stress and emotional disorders include weight loss 55 and dieting, which is particularly common in teenage girls. The most severe form of weight loss–induced amenorrhea is in anorexia nervosa, which is characterized by distorted attitudes toward eating and weight, self-induced vomiting, extreme emaciation, and distorted body images. Women who exercise excessively, such as marathon runners, ballet dancers, or extreme gym exercisers, and who use exogenous steroids to reduce percent body fat may develop amenorrhea. Amenorrhea is more likely to develop in women with a previous history of abnormalities in menstruation before the onset of excessive exercise or weight loss. Women who develop amenorrhea associated with stress, exercise, or dieting exhibit alterations in the menstrual cycle that are associated with the start of their new activities. Later, as the disorder progresses, problems in the luteal phase production of progesterone occur followed by anovulatory cycles associated with oligomenorrhea, and finally amenorrhea develops. In some of these women, a withdrawal bleed after progestin challenge may occur in the anovulatory phase with some estrogen being produced, but in most women the failure to exhibit a withdrawal bleed after a progestin challenge suggests that the disease is more severe. If untreated, it may lead to problems of estrogen deficiency, such as osteoporosis. After a reduction of stress or exercise and increased weight gain, reversal from amenorrhea to ovulatory menstrual cycles may occur requiring no further treatment. Other chronic debilitating diseases, such as acquired immunodeficiency syndrome, malabsorption, or cancer, may result in hypogonadotropic hypogonadism. A relatively rare cause of hypothalamic amenorrhea in women is due to Kallmann’s syndrome, which has been shown to be associated with defects in olfactory bulb development. GnRH neurons develop in the same rostral part of the brain as the olfactory bulbs, and women with Kallmann’s syndrome exhibit not only low gonadotropins and amenorrhea but also lack of the sense of smell, or anosmia. As stated previously, the diagnosis of functional disorders of the central nervous system hypothalamic-pituitary axis resulting in amenorrhea may be suggested by the history, but usually requires some form of imaging using MRI or CT. Disorders of the pituitary include not only tumors but also Sheehan’s syndrome, or postpartum necrosis of the pituitary, which is due to
Reproductive Endocrinology and Infertility
56
hemorrhage, spontaneous necrosis of the pituitary, congenital absence of the pituitary, empty sella, or inflammatory or infiltrative disorders (see Table 4-1). The most common causes of amenorrhea associated with the pituitary are disorders associated with increased prolactin secretion. Women present with amenorrhea plus galactorrhea associated with an increased prolactin level. In women with amenorrhea and elevated prolactin levels, imaging of the pituitary is required, and a thyrotropin level is obtained. Hyperprolactinemia and galactorrhea may be associated with antidepressant drugs or recent breastfeeding. Most women with hyperprolactinemia do not exhibit demonstrable pituitary tumors. It has often been questioned at what level of serum prolactin head imaging should begin. Some have suggested prolactin levels exceeding 50 μg/L. Women with prolactin levels greater than 50 μg/L have about a 20% chance of presenting with a pituitary tumor, whereas women who have 100 μg/L prolactin have a 50% risk, and women with greater than 200 μg/L prolactin have an approximately 90% to 100% chance of harboring a prolactin-secreting tumor (Box 4-6).
DEFECTS OF THE FEMALE REPRODUCTIVE TRACT Defects of the female reproductive tract can result in amenorrhea by obstruction or absence of endometrial tissue. Some of these defects may be developmental, and some may be due to iatrogenic causes. Women with anatomic defects have normal ovaries and ovarian function and develop secondary sexual characteristics. Ovulation can be proven by changes in the basal body temperature or by elevated serum progesterone levels in the luteal phase. These women also have a normal female 46,XX karyotype. The logical approach to the evaluation and classification of anatomic defects is to start from the lowest entry at the opening of the reproductive tract and move upward (Fig. 4-2). Anatomic causes include labial agglutination or labial fusion and imperforate hymen. If the obstruction is farther up into the vagina, it is known as a transverse vaginal septum. Rarely, a complete absence of the cervix may be suspected. Women with all of these conditions often present with increasing abdominal pain, which is the result of accumulation of blood behind the obstruction. In such instances, the pain is cyclic and predictable in nature associated with the onset of menstruation. If the diagnosis is delayed, endometriosis, adhesions, and infertility may result. Two additional disorders are not associated with obstruction and pain, but
Box 4-6
Hyperprolactinemia (Increased Prolactin)
1. Thyrotropin 2. Radiographic imaging (MRI) 3. Prolactin levels (ng/mL) correlated with tumor risk 20-50—5-10% tumor risk >50—20% tumor risk >100—50% tumor risk >200—90% tumor risk
Evaluation and Treatment of Amenorrhea Figure 4-2
5. Intrauterine adhesions (Asherman’s syndrome)
Diagrammatic representation of causes of amenorrhea resulting from defects of the female reproductive (outflow) tract.
6. Müllerian agenesis 4. Cervical stenosis 3. Transverse vagina septum
2. Imperforate hymen 1. Labial fusion-agglutination
result from absence of development of the uterus and vagina; these include müllerian agenesis or dysgenesis associated with a 46,XX karyotype and testicular feminization or complete androgen resistance, in which there is a testis and a 46,XY karyotype (Box 4-7). This diagnosis is easily confirmed, however, by the observation of the absence of pubic and axillary hair owing to the androgen resistance. Individuals with testicular feminization should have the testes removed to prevent tumor development after completion of breast development, which occurs at age 12 to 14. Rarely, a woman may have absence of the uterus and lack of female secondary sexual characteristics. In such individuals, a karyotype should be obtained. Individuals with a 46,XY karyotype have androgen deficiency most commonly as a result 17αhydroxylase, testicular regression, or gonadal dysgenesis. Individuals with
Box 4-7 Differential Diagnosis of Phenotypic Female with Secondary Sexual Development and No Uterus Feature 1. Occurrence 2. Hereditary pattern 3. Gonad 4. Chromosomes 5. Serum testosterone 6. Serum LH 7. Breasts 8. Pubic/axillary hair 9. Other anomalies
Müllerian Agenesis More common Sporadic Ovary 46,XX Low Normal Present Present Present
Complete Androgen Resistance (Testicular Feminization) Rare X-linked recessive Testis 46,XY Male Increased Present Absent Absent
57
Reproductive Endocrinology and Infertility
a 46,XX karyotype have müllerian agenesis plus another disorder, such as ovarian failure or hypogonadotropic hypogonadism or both. In addition, reproductive tract defects may be due to iatrogenic causes, such as scarring and stenosis of the cervix after dilation and curettage, conization, laser, or loop electrosurgical excision procedures to treat cervical dysplasia. Destruction of the endometrium after a vigorous curettage after postpartum hemorrhage or therapeutic abortion or after infection associated with a missed abortion results in scar tissue or uterine synechiae (Asherman’s syndrome). The diagnosis of this defect is rare in the absence of a previous surgical procedure or pregnancy. The diagnosis of female reproductive tract defects is established by history and physical examination. Labial agglutination, fusion, imperforate hymen, and transverse vaginal septum are easily recognized. An ultrasound can be obtained to confirm the location of the blockage and presence or absence of the uterus. To evaluate and confirm the diagnosis of Asherman’s syndrome, sonohysterography, office hysteroscopic procedure, or occasionally hysterosalpingography may be indicated. Rarely, a laparoscopy may be required to confirm the final diagnosis of the reproductive tract anomaly, particularly with regard to fundal appearance.
58
CLINICAL EVALUATION OF AMENORRHEA Evaluation of amenorrhea should begin with a thorough history and physical examination. If a woman presents with primary amenorrhea and absence of secondary sexual characteristics, this may suggest a primary gonadal problem or ovarian failure. In contrast, a woman who presents with previous regular menstrual periods but develops amenorrhea after a dilation and curettage for hemorrhage suggests the diagnosis of uterine adhesions. The evaluation of amenorrhea requires knowledge of the classification as vdescribed previously (see Table 4-1). Figure 4-3 shows a flow chart that aids in evaluating women with amenorrhea. This evaluation includes women with a female phenotype, but excludes women with disorders of virilization or sexual ambiguity (Box 4-8). Figure 4-3 1. History and physical examination Flow diagram used to evaluate amenorrhea.
2. R/O pregnancy 3. FSH, PRL, TSH 4. Progestin administration − Withdrawal menses
+ Withdrawal menses
FSH
PRL
FSH or
FSH
Chronic anovulation Radiographic Ovarian Estrogen present evaluation failure (PCOS) (gonadal Chronic anovulation dysgenesis Estrogen absent (functional hypothalamic amenorrhea, prolactinoma)
FSH
Anatomic defect (müllerian dysgenesis)
Steroids and Prostaglandins
Box 4-8 Amenorrhea— When to Evaluate 1. No menses by age 16 2. No evidence of sexual development (i.e., breasts) by age 14 3. If sexual ambiguity or virilization is present 4. If the patient or family is greatly concerned
Box 4-9 Initial Physical Examination for Amenorrhea 1. Degree of maturation of the breasts, pubic and axillary hair, and external genitalia 2. Current estrogen status 3. Presence or absence of a uterus
The laboratory tests required include a pregnancy test, FSH, prolactin and thyrotropin. We find it helpful to evaluate the estrogen status based on the progestin withdrawal test as discussed earlier. This evaluation is helpful before determining therapy for infertility as well. Evaluation of the estrogen status includes two parts: (1) The patient is examined looking for signs of previous estrogen secretion, such as breast development, and current estrogen secretion, which includes the presence of a well-rugated, moist vagina with abundant clear stretchable cervical mucus known as spinnbarkeit (Box 4-9). (2) The estrogen status can be confirmed by a progestin challenge using medroxyprogesterone acetate (5-10 mg daily for 5-10 days) or progesterone in oil (100-200 mg) administered intramuscularly. Intramuscular injection is useful, particularly when patient compliance is an issue (Box 4-10). Depo-Provera should not be used because this form of medroxyprogesterone acetate causes amenorrhea. 59 The one exception to this overall evaluation is a woman who is known on physical examination to have an absent uterus; in this case, it is more prudent and cost-effective to perform a few tests to confirm the diagnosis and to differentiate müllerian agenesis from complete testicular feminization syndrome. After the initial visit, the patient returns and the physician assesses the level of FSH, prolactin, and response to progestin challenge. If the FSH is elevated, the evaluation is directed toward ovarian failure or hypergonadotropic hypogonadism (Box 4-11). If the FSH is low or normal, the evaluation of the progestin challenge test is used to differentiate the two categories of chronic anovulation (Boxes 4-12 and 4-13). Finally, if the serum prolactin is Box 4-10
Progestin Challenge
Medroxyprogesterone acetate (Provera) 10 mg orally twice daily × 5-10 days Progesterone in oil 200 mg intramuscularly
Box 4-11
FSH Is Elevated − Withdrawal menses FSH
Ovarian failure (gonadal dysgenesis)
Box 4-12
FSH Is Low or Normal − Withdrawal menses PRL
FSH
or
Radiographic evaluation
Chronic anovulation, estrogen absent (functional hypothalamic amenorrhea, prolactinoma)
Reproductive Endocrinology and Infertility
Box 4-13
FSH Is Normal + Withdrawal menses FSH
Chronic anovulation, estrogen present (polycystic ovarian syndrome)
Box 4-14
60
Evaluation of Outflow Tract or Reproductive Tract
1. History and physical examination 2. Rule out pregnancy 3. FSH and prolactin 4. Progestin administration − Withdrawal menses
FSH
Anatomic defect (müllerian dysgenesis)
elevated, thyrotropin should be measured, and the pituitary should be evaluated further by MRI or CT. Most women with significant elevations of prolactin do not respond to a progestin challenge and are included in the category of chronic anovulation with estrogen absent. These women should experience withdrawal bleeding after a cycle of estrogen plus progestin, but this test and results are confusing because a high percentage of women would not bleed after one cycle of therapy. Evaluation of the outflow tract or reproductive tract is done on physical examination, and hysterosalpingography, ultrasound, or hysteroscopy is done if needed (Box 4-14). During the physical examination, if the patient exhibits a vagina, a patent cervix (which can be confirmed by uterine sounding), and a uterus without a history of pregnancy or operative procedure, a disorder of the female reproductive tract is unlikely. After disorders of the reproductive tract are ruled out, a normal or low FSH indicates a disorder of the hypothalamus or pituitary. Most of these women have functional disorders of the hypothalamus, although lesions of the hypothalamus and pituitary may be present. The use of MRI or CT, as discussed previously, depends on the history, clinical presentation, and prolactin level. The algorithm in Figure 4-3 is quite useful in most cases with the diagnosis simplified and easily obtained.
TREATMENT OPTIONS In general, the management of amenorrhea depends not only on the cause but also on the current desires of the patient.
Evaluation and Treatment of Amenorrhea
Gonadal Failure
Box 4-15 Treatment of Ovarian Failure Hormone replacement Donor egg—in vitro fertilization
Chronic Anovulation
Most cases of gonadal or ovarian failure are permanent, and patients should be started on hormone replacement therapy, particularly estrogen, as soon as possible (Box 4-15). Estrogen maintains secondary sexual characteristics and prevents premature osteoporosis and coronary heart disease. If the diagnosis of gonadal failure is made in a woman before breast development, such as in Turner’s syndrome, a regimen of low-dose estrogen gradually increased over time may be important in producing normal breast development. Growth hormone also may be used before estrogen therapy in achieving greater height if indicated. In women with gonadal dysgenesis, estrogen treatment begins with low-dose conjugated estrogens (0.3 mg) for 3 to 6 months, slowly increasing from 0.625 to 1.25 mg over 1 year to augment breast development. It is necessary to initiate progestin therapy after approximately 1 year of estrogen therapy to induce withdrawal bleeding to prevent endometrial hyperplasia. If progestin is started before initiation of breast 61 development, breast development may be abnormal. Women with disorders such as 17α-hydroxylase deficiency should be treated with glucocorticoids and hormone therapy. Women with autoimmune ovarian failure have been treated with a variety of medicines, but none seem to be successful, so hormone replacement therapy seems appropriate. Occasionally, repositioning of the ovary, or oophoropexy, may be helpful before a woman receives abdominal-pelvic radiation therapy. In addition, it has been hypothesized but not proven that pretreatment with GnRH analogues or oral contraceptive pills before chemotherapy may be successful in maintaining ovarian function. Women with amenorrhea resulting from ovarian failure are rarely able to conceive on their own. In some cases, ovarian follicular depletion may be incomplete, and spontaneous ovulation and a rare pregnancy may occur. The current treatment for infertility secondary to ovarian failure is to use donor oocytes obtained from normal ovulatory women that are retrieved followed by in vitro fertilization in which the sperm of the patient’s husband is used to fertilize the donor eggs. The fertilized embryo is transferred to the recipient with ovarian failure, who has been treated appropriately with exogenous estrogen and progesterone synchronized to mimic the normal ovulatory cycle.
The treatment of women with chronic anovulation can be subdivided to match the classification of women who produce estrogen and women who do not produce estrogen. In women who are producing estrogen but are not ovulating, the treatment depends on the desires of the patient. If the patient is obese, weight loss should be encouraged, and this may improve the overall clinical situation, including insulin resistance, if present, and hypercholesterolemia. If the woman is not hirsute and does not desire pregnancy, monthly withdrawal menses should be induced by progesterone therapy or more simply with oral contraceptive pills, which reduces the risk of hemorrhage secondary to dysfunctional uterine bleeding and endometrial neoplasia. If the woman is hirsute but does not desire pregnancy, excess male hormone production can be suppressed through oral contraceptive pills or antiandrogens or both. Oral contraceptives pills also are indicated if there
Reproductive Endocrinology and Infertility
Box 4-16 Treatment of Chronic Anovulation—Estrogen Present (Polycystic Ovarian Syndrome) What concerns the patient: 1. Amenorrhea—progestin withdrawal, oral contraceptive pills 2. Infertility—ovulation induction 3. Abnormal bleeding—oral contraceptive pills 4. Hirsutism—oral contraceptive pills, spironolactone 5. Insulin resistance—metformin
62
Box 4-17 Treatment of Chronic Anovulation— Estrogen Absent 1. Human menopausal gonadotropin/ human chorionic gonadotropin 2. GnRH pump 3. Long-term oral contraceptive pill/hormone replacement therapy
Defects of Female Reproductive Tract
are disorders in menstruation, such as dysfunctional uterine bleeding. Finally, if pregnancy is desired, ovulation can be induced with clomiphene citrate, metformin, or gonadotropins or occasionally laparoscopic ovarian wedge resection (Box 4-16). In women who are not producing estrogen with chronic anovulation, treatment needs to be directed at eliminating the primary cause, such as weight loss, exercise, or stress. Treatment in women with amenorrhea and low estrogen should be aggressive because this condition can lead to reduced bone mass development and early osteoporosis. In women with elevated prolactin levels but in the absence of prolactin-secreting tumors, cyclic estrogen-progestin therapy or, more commonly, oral contraceptive pills can be prescribed. Oral contraceptive pills and hormone replacement therapy not only prevent bone loss but also maintain secondary sexual characteristics. If pregnancy is desired, it is important that body weight and nutritional requirements for the potential developing fetus be returned to normal before induction of ovulation. If the amenorrhea persists despite reduction in stress, increasing body weight, and percent body fat, gonadotropins or pulsatile GnRH therapy is often successful in inducing ovulation and pregnancy. In women who present with pituitary tumors that secrete prolactin, the treatment of choice is pharmacologic using dopamine agonists such as bromocriptine (Box 4-17).
The primary treatment of outflow tract disorders is surgical, including the incision of labial fusion, imperforate hymen, and vaginal septum, and can lead to return of regular menstrual periods and fertility. With respect to specific disorders, chronic labial adhesions in children can be treated with intermittent estrogen cream. A functional vagina in women with müllerian agenesis or testicular feminization is more difficult to achieve. First, an attempt at nonsurgical dilation of a blind-ending vaginal pouch or perineal dimple is indicated. If this fails, reconstruction of the vagina using skin grafts is performed. Disorders of cervical obstruction can be treated by dilation of the cervix, and pregnancy can be achieved by intrauterine insemination. If the cervix is absent, a hysterectomy is usually required because retained blood behind the obstruction can cause significant pain and infection. Uterine scarring or Asherman’s syndrome is best treated by direct hysteroscopic resection of the adhesions.
Evaluation and Treatment of Amenorrhea
SUMMARY OF KEY POINTS 1.
2.
3. 4.
5.
Amenorrhea is best categorized functionally with chronic anovulation being the largest category; this category can be subdivided into women who produce estrogen and women who do not. A second category is women with gonadal (ovarian) failure (hypergonadotropic hypogonadism). Women with defects in the development of the reproductive tract constitute the third category. The phenotypic appearance of a woman and the extent of her secondary sexual development are related to the timing of ovarian failure in relation to her reproductive life. Women with chronic anovulation with normal estrogen levels are best diagnosed using progesterone withdrawal testing. Women with chronic anovulation and low estrogen levels (hypogonadotropic hypogonadism) should undergo CT or MRI to rule out the presence of central nervous system tumors. Defects of the female reproductive tract leading to amenorrhea often require surgical treatment.
SUGGESTED READINGS Abraham SF, Beaumont PJV, Fraser IS, et al: Body weight, exercise and menstrual status among ballet dancers in training. Br Obstet Gynaecol 1982;89:607. Blackwell RE, Boot LR, Goldenberg RL, Younger JB: Assessment of pituitary function in patients with serum prolactin levels greater than 100 ng/mL. Fertil Steril 1979;32:177. Rock JA, Zacur HA, Dlugi AM, et al: Pregnancy success following corrections of imperforate hymen and complete transverse vaginal septum. Obstet Gynecol 1982;59:448. Shangold MM, Levine HS: The effect of marathon training upon menstrual function. Am J Obstet Gynecol 1982;143:862.
Speroff L, Fritz MA (eds): Clinical Gynecologic Endocrinology and Infertility, 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2005:401-464. Stein IF, Leventhal ML: Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 1935;29:181. Turner HH: A syndrome of infantilism, congenital webbed neck, and cubitus valgus. Endocrinology 1938;23:66. Warren MP, Vande Wiele RL: Clinical and metabolic features of anorexia nervosa. J Obstet Gynecol 1973;117:435.
63
5 POLYCYSTIC OVARIAN SYNDROME Jani R. Jensen and Ruben Alvero
DEFINITIONS Androgens
Amenorrhea Anovulation Hirsutism
Oligomenorrhea Polycystic ovarian syndrome Virilization
65 Steroids that stimulate development of male secondary sexual characteristics; the major androgens are testosterone, dihydrotestosterone, androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate; in nonpregnant women, androgens are produced by the ovaries and adrenal glands and via peripheral conversion of steroid intermediates No menses for 3 or more consecutive months Failure of the development and release of a dominant ovarian follicle Excess, thickly pigmented, terminal hair growing in a male pattern, such as on the upper lip, chin, sideburns, periareolar region, upper abdomen, or inner thighs Fewer than nine menstrual periods per year, or menstrual cycles occurring more than 35 days apart A common endocrinopathy characterized by menstrual irregularity and hyperandrogenism Signs of severe androgen excess, which may include deepening of the voice, clitoromegaly, cystic acne, increased muscle mass, or male-pattern baldness
Polycystic ovarian syndrome (PCOS) is a common endocrinopathy characterized by menstrual irregularity and hyperandrogenism that is estimated to affect 5% to 10% of reproductive-age women. When initially described by Stein and Leventhal in the 1930s, the hallmarks of PCOS were reported to be hirsutism, oligomenorrhea, obesity, and the histopathologic finding of cystic ovaries. It is now recognized, however, that only about one third of patients with PCOS fulfill the classic clinical presentation, and the remaining women with this condition fall along a clinical spectrum. Although historically there has been confusion over the actual definition of PCOS, a 1990 National Institutes of Health consensus committee defined it as a condition characterized by oligo-ovulation and evidence of clinical or biochemical hyperandrogenism, with the exclusion of secondary causes, such as congenital adrenal hyperplasia (CAH) and Cushing’s syndrome. This is the definition that most clinicians and researchers in the United States use today.
Reproductive Endocrinology and Infertility
Box 5-1 ● ● ●
Menstrual irregularity owing to oligo-ovulation or anovulation Clinical or biochemical evidence of hyperandrogenism Exclusion of other causes of hyperandrogenism and menstrual irregularity
Box 5-2 ● ● ● ● ● ● ●
Polycystic Ovarian Syndrome Diagnostic Criteria
Differential Diagnosis of Polycystic Ovarian Syndrome
Exogenous androgenic steroid ingestion Thyroid disease (particularly hypothyroidism) Hyperprolactinemia Androgen-secreting ovarian or adrenal tumor Late-onset CAH (21α-hydroxylase deficiency) Cushing’s syndrome Ovarian hyperthecosis
66
Although the etiology of this condition is unknown, hypotheses include a dysregulated hypothalamic-pituitary axis, abnormal ovarian responsiveness, excess adrenal androgen production, and peripheral insulin resistance. PCOS is a diagnosis of exclusion after other causes of hyperandrogenism are eliminated. In addition, PCOS is a significant cause of infertility, largely owing to absence of ovulation (Boxes 5-1 and 5-2).
PHYSIOLOGY Although oligo-ovulation or anovulation is the hallmark of PCOS, the precise reason for ovulatory failure is unknown. For normal ovulation to occur, a single dominant graafian follicle grows from approximately 5 mm to about 24 mm in diameter, progressing through a series of hormonally controlled maturation steps until it is released from the ovary. In patients with PCOS, this orderly process does not occur. There is an arrest in follicular development, which prevents the follicle from completing the later stages of maturation required for successful ovulation. The progression from several developing follicles to the emergence of a single, dominant follicle destined for ovulation largely depends on serum follicle-stimulating hormone (FSH) levels, and there has been much discussion about the role of FSH in arrested follicular development. Serum FSH levels in PCOS patients are typically within the normal range, but the midcycle FSH surge may be lacking. Several studies have shown that ovulation can be induced by therapeutically increasing FSH levels, suggesting that a deficiency of FSH may be intrinsic to the arrest of follicular development. This mechanism alone is unlikely, however, to explain the abnormal pattern of follicle growth observed in PCOS patients. Researchers have suggested that hyperinsulinemia may be the cause of premature follicular arrest. Insulin may function as a secretagogue for ovarian androgens, disrupting the normally delicate balance among ovarian steroid hormones. With an increase in ovarian androgen secretion, which is peripherally aromatized to the weak estrogen, estrone, feedback to the pituitary leads to an increase in luteinizing hormone (LH) production; when
Polycystic Ovarian Syndrome
bound to ovarian theca cells, LH elicits the production of more androgens. With an increase in circulating androgens, there is also a decrease in sex hormone–binding globulin, which increases free androgen concentration, perpetuating the vicious cycle. The stunted development of numerous graafian follicles leads to the characteristic ultrasound appearance of ovaries containing multiple small follicles, none of which is usually greater than 8 mm in diameter. Histologic changes associated with PCOS include a thickened ovarian capsule containing multiple follicular cysts with a surrounding hypertrophic theca interna. Despite abnormal follicular growth, cystic ovaries are able to maintain the ability to convert some of the circulating serum androgens to estrogens. Likewise, peripheral adipose tissue is able to convert androgens to estrogens, and the combination of these results in a continuous state of mild hyperestrogenism. Elevated estrogen levels in the absence of progesterone lead to constant 67 stimulation of the uterine lining, placing women with PCOS at higher risk for endometrial hyperplasia or intermittent, unpredictable menstrual bleeding that is noncyclic in nature. Studies in the early 1980s first showed that many women with PCOS have higher circulating insulin levels than normal women. This observation is independent of body weight because obese and nonobese women with PCOS may have evidence of hyperinsulinism. Further studies linked hyperinsulinemia with underlying insulin resistance, and it is now estimated that 50% to 70% of women with PCOS have evidence of insulin resistance compared with age-matched controls. This observation translates to an increased risk of glucose intolerance or the development of type 2 diabetes, which is estimated to be 5-fold to 10-fold higher than in normal women. Several mechanisms have been proposed to explain this finding, including enhanced insulin first phase secretion, a defect in hepatic insulin sensitivity, abnormal insulin receptors, and increased abdominal obesity (central obesity) compared with controls. Although this is an active area of investigation, the molecular mechanisms behind insulin resistance currently are unknown. Women with PCOS usually have clinical evidence of hyperandrogenism, with the most common finding being hirsutism (excess terminal hair growth in a male pattern). Other physical manifestations of hyperandrogenism include acne, male-pattern baldness, voice deepening, increased muscle bulk, and clitoromegaly. Androgen excess directly leads to hair growth by the conversion of dehydroepiandrosterone (DHEA), androstenedione, and testosterone in the hair follicle by the enzyme 5α-reductase to dihydrotestosterone, a potent androgen that promotes increased hair growth and the conversion of vellus to terminal hair. Excess androgens also stimulate the sebaceous glands in the skin, resulting in increased oil production and development of acne.
CLINICAL PRESENTATION Although the classic description of a patient with PCOS is an obese, hirsute woman with oligomenorrhea or amenorrhea, the actual presentation varies. Women with PCOS typically present with menstrual disorders or infertility. An
Reproductive Endocrinology and Infertility
Box 5-3 Calculation of Body Mass Index Weight (kg)
68
Height (m)2
increased waist-to-hip ratio, often described as central obesity or “apple body” habitus, is commonly associated with PCOS. Review of the patient’s history should include careful questioning of menstrual history, including if the patient has ever had regular menstrual cycles. Other important information includes comorbidities (diabetes, thyroid disease, or other endocrine disorders), medication use (including use of exogenous androgens), lifestyle considerations (diet, exercise, smoking, and alcohol use), the onset and duration of signs of androgen excess, and family history (diabetes or dyslipidemia or other cardiovascular disease). The patient’s height and weight should be measured, and a body mass index should be calculated (Box 5-3). A body mass index greater than 25 indicates overweight, whereas a body mass index greater than 30 indicates obesity. Physical examination should look for evidence of hirsutism or other signs of hyperandrogenism. The degree of hirsutism can be determined using the Ferriman-Gallwey scoring system, which evaluates hair growth on the lip, chin, chest, arms, abdomen, inner thighs, back, and buttocks. The abdomen should be inspected for striae, particularly the purple variety associated with Cushing’s syndrome, and the vulva should be examined for clitoromegaly. Further screening for Cushing’s syndrome includes evaluation of blood pressure and assessment of the presence of a dorsocervical fat pad (so-called buffalo hump), centripetal obesity, and peripheral muscle wasting. Acanthosis nigricans, a condition characterized by thickened, velvety, and hyperpigmented skin, is a sign of insulin resistance that may be seen on the back of the neck, in the axillae, beneath the breasts or pannus, or on the vulva.
DIAGNOSTIC TESTING Diagnosis of PCOS is primarily clinical and is based on a patient having oligo-ovulation or anovulation and clinical or biochemical signs of hyperandrogenism. Other etiologies leading to similar symptoms must be excluded, such as late-onset CAH, thyroid disease, hyperprolactinemia, Cushing’s disease, ingestion of certain drugs (danazol or androgenic steroids), ovarian hyperthecosis, or an androgen-producing tumor. Signs of virilization, such as clitoromegaly or deepening of the voice, should prompt the clinician to search for an androgenic tumor because these manifestations occur rarely with PCOS. Many types of ovarian tumors can produce androgens or estrogens, including Sertoli-Leydig tumors, hilar (Leydig) tumors, granulosa cell tumors, Brenner’s tumors, Krukenberg’s tumors, cystadenoma, or cystadenocarcinoma. Adrenal tumors rarely may cause hirsutism. The most common lesion of the adrenal gland is an adenoma. Most adenomas are unilateral and greater than 1 cm in diameter. Adrenal adenomas can produce DHEA, dehydroepiandrosterone sulfate (DHEAS), or androstenedione. Androgen-producing adrenal or ovarian tumors can largely be ruled out by measuring serum DHEAS and total testosterone concentrations. Although historically DHEAS values of less than 700 μg/dL and total testosterone of 200 ng/dL were believed to rule out these conditions, the sensitivity and specificity of these levels have been called into question. If DHEAS is abnormal, an abdominal computed tomography scan should be performed.
Polycystic Ovarian Syndrome
Late-onset CAH is an autosomal recessive disorder that may be confused with PCOS. CAH is estimated to affect 1% to 5% of women who present with hirsutism and is more common in certain ethnic groups (Ashkenazi Jewish, Hispanic, Serbo-Croatian or American Eskimo). The most common form of CAH is characterized by a deficiency in 21α-hydroxylase enzyme activity, resulting in a failure to synthesize cortisol from its precursor 17α-hydroxyprogesterone. In response to low serum cortisol levels, the pituitary secretes excess adrenocorticotropic hormone (ACTH), which acts on the adrenals to produce intermediaries in the cortisol pathway. Because of inherited enzyme defects associated with CAH, however, the intermediaries build up and are variably diverted from the cortisol pathway and shuttled to produce excess androgens, resulting in increased serum concentrations of testosterone and androstenedione. A 17α-hydroxyprogesterone level should be drawn in the early morning, immediately on awakening. Normal levels are less than 200 69 ng/dL. Although a 17α-hydroxyprogesterone level greater than 400 ng/dL is associated with increased risk for late-onset CAH, an ACTH stimulation test should be performed to confirm the diagnosis. Unless there is compelling clinical evidence, Cushing’s syndrome is extremely rare, and testing for this condition with a 24-hour urine free cortisol should not be performed. Other laboratory tests to consider when evaluating a patient with suspected PCOS include free testosterone, thyrotropin, prolactin, fasting blood glucose and 2-hour blood glucose after a 75-g glucose load, and a fasting lipid panel. Approximately 75% of women with PCOS have elevated levels of circulating androgens, particularly free testosterone. Elevated thyrotropin levels are associated with hypothyroidism, and a free thyroxine level should be obtained to confirm the diagnosis. Prolactin may be modestly elevated in women with PCOS, but severe elevations (>100 μg/dL) warrant evaluation with central nervous system imaging for a prolactinoma. A 2-hour oral glucose tolerance test with a 75-g glucose load and fasting lipid panel are used to screen for type 2 diabetes and dyslipidemia (Box 5-4). Investigations suggest that 12% of PCOS subjects have type 2 diabetes mellitus. Insulin levels or complex tests of insulin resistance (e.g., euglycemic clamp test) are not required to make a diagnosis of PCOS. The 2-hour glucose tolerance test also is useful to assess insulin resistance (Box 5-5).
Box 5-4 ● ● ● ● ● ● ● ● ● ● ●
Laboratory Tests in the Evaluation of Polycystic Ovarian Syndrome
Urine pregnancy test Total testosterone Free testosterone DHEAS Prolactin Thyrotropin 17-Hydroxyprogesterone (basal) ACTH stimulation test if 17-hydroxyprogesterone level is elevated 2-hour oral glucose tolerance test with 75-g glucose load Fasting lipid panel Endometrial biopsy for prolonged oligoamenorrhea
Reproductive Endocrinology and Infertility
Box 5-5
Oral Glucose Tolerance Test
A fasting (baseline) blood glucose is measured, followed by ingestion of a 75-g oral glucose load. Serum glucose is remeasured 2 hours after ingestion. A fasting glucose >126 mg/dL or a 2-hour value >200 mg/dL indicates diabetes. A 2-hour value >140 mg/dL but <200 mg/dL indicates impaired glucose tolerance.
70
Although early discussions of PCOS included testing of serum LH and FSH, this is no longer routine. The classic finding suggesting PCOS was a ratio of LH to FSH of greater than 3:1, but 50% of women who otherwise would meet criteria for diagnosis of PCOS have normal serum LH values. Measurement of serum LH is of limited diagnostic value. According to the 1990 National Institutes of Health consensus criteria, radiologic imaging is not necessary to confirm or exclude a diagnosis of PCOS because 25% of normal women have polycystic-appearing ovaries on ultrasound. In Europe, diagnostic criteria may include radiologic imaging, with transvaginal ultrasound being the preferred modality to identify polycystic ovaries. Earlier descriptions of PCOS required the presence of eight or more small follicles (measuring 2-8 mm) in each ovary to make a diagnosis. The revised “Rotterdam” criteria now define PCOS with findings of 12 or more small (2-9 mm) follicles in each ovary or an ovarian volume of greater than 10 mL (calculated using the formula of ovarian length × width × thickness × 0.5). In the United States, the aforementioned ultrasound criteria are less often used to make a diagnosis of PCOS because these criteria alone are thought to be nonspecific. Hirsutism is an excess of thickly pigmented, terminal hair growing in a male pattern, such as on the upper lip, chin, sideburns, periareolar region, upper abdomen, or inner thighs. Most women with PCOS display some degree of hirsutism. Many patients attempt to remove unwanted or embarrassing hair growth through shaving, waxing, depilatory creams, laser treatments, or other modalities, so there may actually be little or no evidence of hirsutism on clinical examination. Patients should be asked directly if they have excess hair and what, if any, means of removal have been used. There also may be considerable ethnic differences in hirsutism, with women of Mediterranean descent having significantly greater degrees of hair growth than Northern European or Asian women. Women with PCOS also often have risk factors are adverse for atherosclerotic coronary artery disease. Elevated levels of total cholesterol, triglycerides, and low-density lipoprotein and low serum levels of high-density lipoprotein have been shown in women with PCOS. Screening of fasting serum lipids should be performed, with appropriate intervention initiated if dyslipidemia is identified.
THERAPEUTIC INTERVENTIONS Weight loss of 5% to 10% alone may be enough to restore ovulation, reduce serum testosterone, and improve fertility in women with PCOS. One study
Polycystic Ovarian Syndrome
reported that a mean weight loss of 9.7 kg (achieved through a low-calorie diet ranging from 1000 to 1500 kcal/day) was associated with a 45% decrease in serum LH, 40% decrease in fasting insulin, and 40% decrease in testosterone. Most of the women in the study also resumed ovulating, and some previously infertile women became pregnant. When fertility is not desired, the oligo-ovulation and oligomenorrhea associated with PCOS usually are treated with a combination oral contraceptive pill. Combination pills have been shown to increase the level of circulating sex hormone–binding globulin and suppress ovarian androgen secretion. An oral contraceptive pill containing 30 to 35 μg of ethinyl estradiol combined with a minimally androgenic progestin (e.g., norethindrone, desogestrel, norgestimate, or drospirenone) should be selected. Risks and side effects of oral contraceptive use are similar to those in normal women. Although one large study showed that combination oral contraceptive pill use was associ- 71 ated with increased triglyceride and high-density lipoprotein levels in PCOS patients, there is no evidence suggesting that women with PCOS have more adverse cardiovascular events while taking these pills than normal women. Cyclic oral progesterone also may be used to induce withdrawal bleeding, although these regimens do not have the antiandrogen benefits of oral contraceptive pills and do not provide contraception. Before initiating oral contraceptives, a urine pregnancy test should be performed to exclude pregnancy. If the patient has not had a menstrual period within the preceding 8 weeks, a course of medroxyprogesterone acetate (5-10 mg daily for 10 days) may be used to induce withdrawal bleeding before beginning therapy. Clomiphene citrate, a weak antiestrogenic compound that stimulates endogenous FSH secretion, is the first-line therapy for ovulation induction in PCOS patients desiring pregnancy. Clomiphene citrate is composed of two isomers, each of which has distinct estrogen receptor agonist-antagonist actions. The drug’s antiestrogen effects on the hypothalamus lead to increased gonadotropin-releasing hormone release, which drives increased LH and FSH output and pulsatility. Elevated peripheral FSH concentrations lead to the progressive development of ovarian follicles and increasing estradiol levels, which positively feed back to the hypothalamic-pituitary axis and result in an LH surge that triggers ovulation. Clomiphene is orally administered, usually beginning with a dose of 50 mg/day for menstrual cycle days 3 to 7 after a spontaneous or progesterone-induced withdrawal bleed. Follicle development and ovulation during the first cycle can be monitored via endovaginal ultrasound, home urinary LH predictor kits, or serum progesterone levels. Patients who fail to ovulate on the 50 mg/day dose of clomiphene can be titrated in a stepwise fashion to a maximum dose of 150 to 200 mg/ day during subsequent menstrual cycles. The lowest dose of clomiphene that allows the patient to ovulate should be used because increasing the clomiphene dose beyond what facilitates ovulation results in little gain in fecundity. Overall, ovulation occurs in approximately 75% of patients with clomiphene therapy, and 50% to 70% of women achieve pregnancy within six cycles. Women who fail to ovulate despite maximum dosage of clomiphene present a more difficult challenge. Induction of ovulation in PCOS women
Reproductive Endocrinology and Infertility
72
with conventional doses of exogenous gonadotropins has been associated with lower rates of ovulation and pregnancy, but with an increased chance of developing multiple follicles, ovarian hyperstimulation syndrome, and a higher rate of miscarriage compared with hypogonadotropic women. Many centers have advocated a low-dose regimen for ovulation induction in PCOS patients. Exogenous gonadotropin medications (human menopausal gonadotropin or recombinant FSH preparations) are administered in daily, usually subcutaneous, injections after the onset of spontaneous or progesterone-induced menses. Monitoring of ovarian response is achieved by serial transvaginal ultrasound and serum estradiol levels. When a dominant follicle emerges and reaches a diameter of about 20 mm, ovulation is triggered by an intramuscular dose of human chorionic gonadotropin. Although a variety of dosing regimens and protocols is available, overall estimates of ovulatory treatment cycles approach 70%. Pregnancy rates of 20% per cycle have been reported, with multiple gestation rates of approximately 6% to 25%. If the patient does not become pregnant after three to six cycles of injectable gonadotropins despite evidence of ovulation, most practitioners would recommend offering intrauterine inseminations or transition to in vitro fertilization. Successful in vitro pregnancy rates are similar for women with PCOS compared with women without PCOS. Metformin, a drug initially developed for use in patients with type 2 diabetes, has been used to treat adult and adolescent women with PCOS. Metformin is a biguanide oral antihyperglycemic agent with several therapeutic effects, including decreased hepatic glucose production and intestinal absorption of glucose and improved peripheral glucose uptake and use, which leads to increased insulin sensitivity. In contrast to sulfonylureas, metformin does not produce hypoglycemia. In addition to blood glucose regulation, metformin is reported to have other benefits in PCOS treatment. Several studies have shown that metformin can restore ovulation and regular menses in approximately 50% of women with PCOS. This observation was seen in lean and obese women with PCOS. Metformin also has been used in combination with clomiphene citrate to induce ovulation, usually in women with PCOS who have failed to achieve ovulation with clomiphene alone. Several randomized trials have shown that the combination of metformin plus clomiphene can achieve ovulatory rates of 90% in previously oligo-ovulatory or anovulatory women with PCOS. Metformin use during pregnancy also may decrease the rate of firsttrimester bleeding and pregnancy loss in women with PCOS. One study reported an early pregnancy loss rate of approximately 9% in women taking metformin in the first trimester, whereas women in the control group who did not take metformin had an early pregnancy loss rate of nearly 42%. This difference was even more pronounced in women who had a prior history of miscarriage; the early pregnancy loss rate was 11.1% in the metformin group compared with 58.3% in the control group. These results are still preliminary. Another prospective analysis of 126 women with PCOS who were treated with metformin throughout their pregnancy (1500-2550 mg
Polycystic Ovarian Syndrome
daily) reported a reduced rate of gestational diabetes compared with controls; showed no evidence of teratogenicity; and reported no adverse effects on birth length and weight, growth, or motor development of children in the first 18 months of life. These favorable findings suggest that in the future, metformin’s use in pregnancy may be expanded. Metformin is classified as a class B agent in pregnancy. Dosage of metformin is initiated at 500 mg orally per day, with titration to the usual effective dose of 1500 to 2550 mg daily. Metformin’s side effects are primarily gastrointestinal and include nausea, diarrhea, vomiting, indigestion, flatulence, and generalized abdominal cramping or discomfort. Rarely, lactic acidosis may occur, and metformin should not be used in patients with conditions predisposing them to this condition, such as chronic renal insufficiency, heart failure, or sepsis. A normal serum creatinine should be documented before initiating therapy to avoid lactic 73 acidosis. Laparoscopic ovarian drilling may be a therapeutic option for women with PCOS who fail to achieve pregnancy with medical ovulation induction alone. This procedure is associated with less postoperative adhesion formation than with ovarian wedge resection, a procedure requiring laparotomy that has largely now been abandoned. Various modalities have been used, including laser and electrosurgery, which have comparable efficacy. Laparoscopic ovarian drilling can be done as a same-day surgical procedure and results in impressive postoperative decreases in serum androstenedione and testosterone concentrations, but these effects are most often transient. Reported ovulation and pregnancy rates may be 80% and 50% to 60%, respectively. Hirsutism associated with PCOS may be treated with combination oral contraceptive pills alone or with antiandrogenic agents such as spironolactone or flutamide. Oral contraceptives work to lower serum testosterone levels by decreasing gonadotropin secretion and increasing sex hormone–binding globulin concentrations, which binds testosterone and lowers circulating free testosterone levels. There is a reported 50% to 60% decrease in hair growth in women taking oral contraceptive pills, although it may take several months before results are seen. Spironolactone is a diuretic with aldosterone antagonist actions, including inhibition of ovarian and adrenal androgen synthesis, direct inhibition of 5α-reductase activity (which converts testosterone to dihydrotestosterone), and competition for androgen receptors in the hair follicle. Spironolactone usually is given in a range of 50 to 200 mg daily, in divided doses. Higher doses of spironolactone have been associated with improved outcomes, with 200 mg daily being the most commonly used dose. Maximal effect usually occurs after 6 months of treatment. Known side effects include hypotension and hyperkalemia, although these are rarely seen. Flutamide is a nonsteroidal antiandrogen that competes for androgen receptor binding in target tissues. Although it is a highly effective treatment for hirsutism, it is usually reserved for difficult or resistant cases because it may rarely cause hepatotoxicity. Flutamide is typically given as 250 mg daily. Liver enzymes should be monitored periodically.
Reproductive Endocrinology and Infertility
Spironolactone and flutamide may be used in conjunction with oral contraceptives for maximal effect. Cyproterone acetate, an androgen receptor antagonist, has been used successfully in Europe to treat hirsutism. Efficacy rates of 50% to 75% have been reported, although there may be significant side effects, including the risk of hepatotoxicity. Cyproterone acetate is currently unavailable in the United States. Regardless of which treatment for hirsutism is selected, efficacy of therapy can be monitored by comparing pretreatment and current FerrimanGallwey scores or by measuring serum androgen levels. Because hair growth is cyclic, and treatment is effective only in the involutional phase, it may take several months for patients to see a clinical response. When patients embark on therapy, but before seeing results, unwanted hair may be removed or camouflaged with shaving, electrolysis, chemical depilatories, waxing, tweezing, or laser treatments. Eflornithine, an ornithine decarboxylase inhibitor, has been shown to be highly effective. An important long-term risk to patients with PCOS is the estimated 5fold to 10-fold increased risk of developing type 2 diabetes. Primary care providers should screen women with PCOS periodically for diabetes and dyslipidemia. Monitoring of blood pressure and smoking cessation should be encouraged to enhance cardiovascular protection because women with PCOS often have several risk factors for the development of atherosclerotic cardiac disease. Chronic anovulation and unopposed estrogen stimulation of the endometrium can lead to excess proliferation of the uterine lining, placing patients at risk for endometrial hyperplasia or cancer. Additionally, women with PCOS are often overweight or have evidence of diabetes, both of which are independent risk factors for endometrial cancer; their actual risk of developing abnormal endometrial pathology may be potentiated. Endometrial biopsy should be performed in all patients with long-standing anovulation and amenorrhea, almost regardless of age. Oral contraceptive pills or intermittent progesterone-induced withdrawal bleeds can be administered to decrease the risk of endometrial hyperplasia.
74
SUMMARY OF KEY POINTS 1.
2. 3. 4.
5.
PCOS is a common endocrinopathy characterized by menstrual irregularity and hyperandrogenism that is estimated to affect 5% to 10% of reproductive-age women. Diagnosis is based on clinical findings of menstrual irregularity and evidence of androgen excess. Secondary causes that may mimic PCOS, such as 21α-hydroxylase deficiency, should be excluded. The finding of polycystic ovaries on ultrasound is nonspecific and should not be used alone to make a diagnosis of PCOS because 25% of normal women may have polycystic-appearing ovaries on ultrasound. Health risks associated with PCOS include obesity, infertility, endometrial hyperplasia or cancer, type 2 diabetes, and hyperlipidemia.
Polycystic Ovary Syndrome
6.
7. 8. 9.
10.
Overall treatment goals include the induction of ovulation, normalization of the endometrium, prevention of hyperandrogenism and its sequelae, and decreasing insulin resistance. Weight loss of 5% to 10% of initial body weight can result in ovulation and improved fertility. Therapy should be individualized based on the patient’s symptoms and desire to attempt pregnancy. Treatment modalities may include weight loss and lifestyle modification, oral contraceptive pills, insulin-sensitizing agents, antiandrogens, or a combination of these. Hirsutism associated with PCOS may be treated with combination oral contraceptive pills or antiandrogenic agents, such as spironolactone or flutamide. Additionally, unwanted hair may be removed or camouflaged with shaving, electrolysis, chemical depilatories, waxing, tweezing, or laser treatments.
SUGGESTED READINGS Bayram N, van Wely M, van Der Veen F: Recombinant FSH versus urinary gonadotropins or recombinant FSH for ovulation induction in subfertility associated with polycystic ovary syndrome. Cochrane Database Syst Rev 2001;2:CD002121. Burghen GA, Givens JR, Kitabchi AE: Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease. J Clin Endocrinol Metab 1980;50:113-116. Dunaif A: Insulin resistance and the polycystic ovary syndrome: mechanism of action and implications for pathogenesis. Endocr Rev 1997;18:774-800. Ferriman D, Gallwey JD: Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 1961;21:1440-1447. Glueck CJ, Cameron D, Sieve-Smith L, Wang P: Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study. Fertil Steril 2001;75:46-52. Jakubowicz DA, Iuorno MJ, Jakubowicz S, et al: Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol Metab 2002;87:524-529. Moghetti P, Castello R, Negri C, et al: Metformin effects on clinical features, endocrine and metabolic profiles,
and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6month trial, followed by an open, long-term clinical evaluation. J Clin Endocrinol Metab 2000;85:139-146. National Institutes of Health Consensus Meeting on PCOS. In Dunaif A (ed): Current Issues in Endocrinology and Metabolism. Boston: Blackwell Scientific; 1992. Pasquali R, Casimirri F, Vicennati V: Weight control and its beneficial effect on fertility in women with obesity and polycystic ovary syndrome. Hum Reprod 1997;12(suppl 1):82-87. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004;19:41. Stein IF, Leventhal ML: Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 1935;29:181-191. Velazquez EM, Mendoza S, Hamer T, et al: Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 1994;43: 647-654.
75
6 ABNORMAL UTERINE BLEEDING Kirsten J. Lund DEFINITIONS Abnormal uterine bleeding Dysfunctional uterine bleeding Polycystic ovarian syndrome Menorrhagia Metrorrhagia Polymenorrhea Oligomenorrhea
Any bleeding that deviates from regular, cyclic (every 24-35 days) bleeding of normal amount (≤80 mL) and duration (2-8 days) Abnormal bleeding without clear anatomic cause Anovulation combined with clinical or laboratory evidence of hyperandrogenism Excessive uterine bleeding at regular intervals Bleeding between regular menstrual periods Irregular bleeding at frequent intervals Irregular bleeding at infrequent intervals
Abnormal uterine bleeding (AUB) is one of the most common complaints of patients seeking gynecologic care, whether through an obstetrics/gynecology specialist or a primary care provider. It is a frustrating symptom for the patient and the clinician. For patients, AUB can be a significant lifestyle issue and a health risk. Because uterine bleeding is a complex outcome of interactions between systemic hormones and an end organ, the uterus, there are myriad underlying causes of AUB. This wide differential diagnosis can lead clinicians to feel overwhelmed when attempting to evaluate and treat patients with AUB. In past decades, hysterectomy was a frequently used treatment for AUB, even when the uterus itself was absolutely normal. Heavy menstrual bleeding accounts for two thirds of all hysterectomies, and in 50% of those cases, no abnormality of the uterus is found on pathologic analysis. Although there is still much about the pathophysiology of uterine bleeding that is not well understood, it is possible through thoughtful history taking and judicious use of diagnostic tests to diagnose and treat most cases of AUB efficiently (Box 6-1).
PHYSIOLOGY The pathophysiology of AUB is complex, not entirely understood, and often multifactorial. Bleeding, whether normal or abnormal, results from
77
Reproductive Endocrinology and Infertility
Box 6-1
78
Abnormal Uterine Bleeding
Anatomic abnormality Submucous fibroid Endometrial polyp Hormonal dysfunction (dysfunctional uterine bleeding) Hyperandrogenic (PCOS) Hypothalamic anovulation Perimenopausal Thyroid Prolactin Coagulopathy von Willebrand’s disease Iatrogenic Long-term OCP use Medroxyprogesterone acetate (Depo-Provera) IUD
interactions between circulating reproductive hormones and the uterus. Abnormalities on either side of this interaction can lead to abnormal bleeding patterns. High levels of uterine prostaglandins have been associated with menorrhagia or excessive menstrual blood loss. It is helpful to review the physiology of normal, cyclic menstrual bleeding to understand deviations from this pattern. Cyclic bleeding of normal amount and duration indicates that not only is the hypothalamic-pituitary-ovarian (HPO) axis intact but also that the target organs, the uterus and endometrium, are responding in a normal way to hormonal input. (The physiology of the normal menstrual cycle is covered in greater depth in Chapter 2.) Generally, the menstrual cycle can be divided into follicular, ovulatory, and luteal phases. In the follicular phase, growth and maturation of ovarian follicles occurs under the influence of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) release from the pituitary. Selection of a dominant follicle results in increased estradiol production, which causes marked growth of the endometrial lining. Immediately before ovulation, there is a surge in gonadotropin-releasing hormone (GnRH) in response to high estradiol levels, resulting in a subsequent surge in LH and FSH levels and subsequent ovulation approximately 36 hours later. The corpus luteum, which remains at the site of the ovarian follicle, produces progesterone along with estradiol for the remainder of the ovarian cycle (the luteal phase). The luteal phase is characterized by high serum levels of progesterone and estrogen, which act on the endometrium to halt proliferation and induce secretory changes, making the endometrium an appropriate environment for implantation of a fertilized embryo. In the absence of implantation, the corpus luteum regresses, the endometrium deteriorates, and the resultant shedding of endometrium manifests as menstrual bleeding. Disruption of this normal ovarian cycle results in abnormal bleeding patterns. Anovulation is the most common cause of dysfunctional uterine bleeding. Women who do not ovulate regularly generally have significant estrogen production from ovarian follicles, and endometrial proliferation occurs similar to that seen in a normal follicular phase. Without ovulation
Abnormal Uterine Bleeding
and subsequent progesterone production, however, this proliferation continues without secretory changes and without a clear signal from the ovary for endometrial deterioration and shedding. The endometrium becomes thickened and unstable and may slough superficially and unpredictably. Anatomic abnormalities of the uterus also cause abnormal bleeding. The endometrium overlying an anatomic lesion, such as a fibroid, may receive differential perfusion and hormonal input and become unable to respond in a normal manner to cyclic ovarian hormone production. Finally, coagulation defects, such as von Willebrand’s disease, may give rise to menorrhagia.
CLINICAL PRESENTATION History
When evaluating and managing patients with AUB, it is imperative to 79 remember that AUB is a symptom, not a diagnosis, and warrants careful evaluation. Although the evaluation of any medical complaint begins with a good history, in the case of abnormal bleeding this part of the evaluation can be particularly challenging. Nevertheless, an accurate, focused history is crucial in guiding further workup. Frequently, patients are frustrated and tired of their bleeding before they arrive for their first appointment. It is the responsibility of the physician to guide the patient through a thorough review of the present complaint. Although there are many causes of AUB, they tend to “cluster” into a lesser number of interrelated categories, and a good history often points to the correct category of diagnosis. When obtaining a history of abnormal bleeding, several standard areas should be covered in addition to those that the individual patient may bring up.
Current Hormonal Status Knowledge of baseline hormonal status is an essential step in the evaluation of AUB. Is the patient premenopausal, perimenopausal, or postmenopausal? The average age of menopause is 50 to 52 years (range 48-55 years), and menopause is a clinical diagnosis consisting of 1 year of amenorrhea. Menopause is not a laboratory diagnosis, and often patients are referred for “postmenopausal bleeding” based on an elevated serum FSH, without ever having a diagnostic period of amenorrhea. Such patients should be considered premenopausal or perimenopausal for purposes of evaluation. Historical Bleeding Profile When did the patient go through menarche? Were cycles regular and predictable? If so, when exactly did this change? Was the change sudden or gradual? If the patient has had unpredictable cycles for a long time, what has changed to cause her to present for evaluation? Contraceptive and Hormonal History A good contraceptive history alerts the clinician to patients who may be at increased risk of pregnancy-related bleeding. It also often sheds light on the patient’s current complaint. What is the patient’s current method of contraception? Did this change at or around the time of the onset of
Reproductive Endocrinology and Infertility
AUB? Has the patient been on hormonal contraception in the past? Was she placed on oral contraceptive pills (OCPs) as an adolescent to “regulate her periods”? Many patients have been on some type of hormonal contraceptive for most of their lives, which obscures the natural history of a developing process of AUB.
History of Heavy Nonmenstrual Bleeding Coagulation defects should be considered in women who give a history of excessive bleeding during childbirth or with surgical procedures. Ensure That Physician and Patient Are Speaking the Same Language In addition to a working knowledge of the normal range of menstrual bleeding patterns, the physician must ensure that he or she and the patient are assigning the same meaning to the words used to describe bleeding. The physician should take time to ensure that when the patient states that menstrual periods are “irregular,” she means that the intervals between bleeding episodes are unpredictable. To many patients, “irregular” may simply mean bleeding that is different from their usual pattern. An increase in menstrual flow in the setting of 28-day cycles may qualify to a patient as “irregular.” Similarly, the amount of blood lost during a period of bleeding must be, as far as possible, quantifiable because patients often have differing perspectives on what “heavy” bleeding means. Although there are standardized pictorial scales for this estimation, by careful questioning one often can arrive at a fairly good idea of the amount of bleeding.
80
Physical Examination
After obtaining an adequate history, a physician may have generated a hypothesis as to the etiology of bleeding. In addition to an examination of uterine size and shape, the following elements are often skipped, but should be included in the physical examination.
Body Mass Index Because estrogens are produced in fatty tissue in amounts that may affect endometrial proliferation, the body mass index is a useful tool to guide differential diagnosis and to identify patients who may be at particular risk for endometrial hyperplasia. Examination of External Genitalia and Vagina Examination of the external genitalia and vagina not only rules out discrete lesions that may be contributing to bleeding but also provides information about the patient’s hormonal status. A thick, rugated vaginal mucosa indicates adequate circulating estrogen levels, whereas a thin, pale, smooth vaginal vault signals relative estrogen deficiency. Examination of the Cervix Not all bleeding is uterine in origin. Although the patient may be up to date on cervical cancer screening, one must look at the cervix to rule out cervical polyps and assess for clinical evidence of cervicitis.
Abnormal Uterine Bleeding
Differential Diagnosis
After the history and physical examination, the physician may tailor the diagnostic workup to the likely cause of the bleeding. It is useful to consider six major categories of AUB and the differential diagnosis suggested by each: pregnancy-related bleeding, disorders of coagulation, iatrogenic bleeding, ovulatory bleeding, oligo-ovulatory bleeding, and postmenopausal bleeding.
Disorders of Pregnancy Pregnancy should be ruled out in any woman of reproductive age. When combined with a thoughtful contraceptive history, a simple office urine pregnancy test is economical and highly sensitive. Although bleeding may occur in a normal intrauterine pregnancy, the possibility of an ectopic pregnancy or threatened abortion should be considered. Disorders of Coagulation 81 The classic presentation for patients with inherited clotting disorders is that of menorrhagia, associated with anemia, at the time of menarche. The prevalence of clotting disorders among patients admitted to the hospital for menorrhagia and severe anemia ranges from 19% to 45%. In addition to von Willebrand’s disease, other disorders of impaired platelet aggregation, including factor XI deficiency and thrombocytopenia, are common diagnoses in patients with menorrhagia. Although the classic presentation of von Willebrand’s disease is that of menorrhagia at menarche or obstetric hemorrhage, women may not be correctly diagnosed until later in the reproductive years. Iatrogenic Causes Patients on hormonal medications are at increased risk for abnormal bleeding patterns. This effect is most recognized with oral and injectable contraceptive preparations. The breakthrough bleeding patterns associated with hormonal contraceptives are thought to be due to endometrial atrophy associated with continuous, or near-continuous, progestin administration. Use of the intrauterine contraceptive device (IUD) also is associated with abnormal bleeding patterns. Perimenopausal patients who are placed on hormone replacement therapy for treatment of vasomotor symptoms also may exhibit abnormal bleeding patterns because standard hormone doses (in contrast to OCP doses) are insufficient to suppress the HPO axis in patients who are still ovulating, and hormone replacement therapy may destabilize the normal cyclic development of the endometrium. Finally, patients on anticoagulant therapy are prone to heavier bleeding because of the anticoagulation. Ovulatory Bleeding Patients who have an intact HPO axis and who ovulate regularly typically describe a cyclic pattern to their bleeding. This bleeding may manifest as simple menorrhagia; intermenstrual, premenstrual, or postmenstrual spotting; or ongoing bleeding with an identifiable “period” of heavier bleeding that occurs once per month or occasionally hormonal symptoms that suggest cyclic ovarian function in the setting of unpredictable bleeding. AUB that is ovulatory suggests a limited range of diagnoses.
Reproductive Endocrinology and Infertility
Anatomic Abnormalities of the Uterus
The uterus is an end organ for ovarian steroid hormones. A normal uterus should respond appropriately to cyclic hormonal input, with regular withdrawal bleeding as the corpus luteum regresses each month. An abnormal uterus may respond to cyclic hormones by bleeding more heavily during menses or by bleeding between menstrual periods. The exact pathophysiology by which anatomic abnormalities, such as uterine myomas, polyps, and adenomyosis, cause abnormal bleeding of the overlying endometrium is the subject of ongoing study.
Relative Estrogen Excess Related to Perimenopausal Changes
As women enter the later reproductive years, several interrelated changes occur in the HPO axis. Inhibin levels decrease, and ovaries become increasingly resistant to pituitary FSH. These changes result in higher follicular phase estradiol levels and higher levels overall throughout the cycle. In addition, corpus luteum function may become inadequate, leading to lower progesterone levels during the luteal phase and shorter luteal phase overall. Taken together, all these changes may result in a shift in the estrogen-progesterone balance during a menstrual cycle. Although patients still may ovulate regularly, menstrual blood loss becomes heavier, and cycle length may shorten.
Change in Contraceptive Method from Hormonal to Nonhormonal
It has been widely recognized that OCP use generally leads to decreased menstrual blood loss and to regular, 28-day withdrawal bleeding. Discontinuation of OCPs, conversely, may lead to a return of heavier menstrual bleeding. The onset of menorrhagia and dysmenorrhea after tubal ligation, dubbed “the post–tubal ligation syndrome,” was thought to be an effect of compromised ovarian blood supply after tubal sterilization. More recent studies and meta-analyses have not found any correlation between tubal sterilization and such symptoms. This phenomenon illustrates, however, that patients may experience changes in menstrual function when they change their contraceptive method.
82
Oligo-ovulatory Bleeding Patients who give a history of oligomenorrhea or unpredictable cycle intervals are likely to be anovulatory or to ovulate rarely. Anovulation may be a lifelong issue for some patients; for others, it may be a transient condition. The characteristic that distinguishes anovulatory bleeding is the lack of cyclic symptoms, such as cyclic bleeding or moliminal symptoms (e.g., breast tenderness). Anovulatory bleeding is caused by dysregulation of the normal cyclic hormone patterns, whether at the level of the hypothalamus, the pituitary, or the ovary. Hypothalamic anovulation is perhaps the least well-understood pathway for anovulatory bleeding. Patients who are under chronic stress, whether from chronic disease, poor diet, or excessive physical activity, may ovulate infrequently. The mechanism mediating the effect of stress on ovulation is poorly understood, but related to decreased pulsatile GnRH secretion. Patients with hypothalamic dysfunction may exhibit signs and symptoms of low estrogen status and often have amenorrhea rather than AUB. Thyroid dysfunction may be associated with abnormal menstrual bleeding patterns. Hyperthyroidism increases the rate of metabolism of ovarian steroid hormones, such as estradiol, and hypothyroidism increases thyrotropin
Abnormal Uterine Bleeding
from the hypothalamus (resulting in increased stimulation of thyrotropin and prolactin). Hyperprolactinemia is a well-recognized cause of oligo-ovulation among lactating women and among patients with pituitary prolactinomas. The syndrome of chronic estrogenized anovulation, with clinical or laboratory evidence of associated hyperandrogenism, is common and well described as polycystic ovarian syndrome (PCOS). A detailed discussion of PCOS is beyond the scope of this chapter (see Chapter 5), although it is a frequent cause of anovulatory bleeding. Because the ovaries produce estrogen from multiple follicles and do not produce progesterone on a monthly basis owing to anovulation, patients with PCOS-like anovulation are hyperestrogenic and at increased risk for endometrial hyperplasia. Anovulatory cycles occur frequently at the extremes of reproductive age. The HPO axis is not fully mature for 5 years after the onset of menarche. Similarly, decreasing ovarian function preceding menopause may result in 83 intermittent ovulation.
Postmenopausal Bleeding A clear history of menopause (>1 year of amenorrhea) shifts the differential diagnosis of AUB away from hormonal causes and toward anatomic causes. The exception is a patient who is taking exogenous hormones because uterine bleeding is a common side effect of hormone therapy. Aside from this, patients may have postmenopausal bleeding as a result of uterine hyperplasia or malignancy, myomata, polyps, or atrophy. Finally, when considering the likely category of diagnosis for AUB, the clinician should bear in mind that a patient may have more than one contributing factor for the bleeding. Patients with small uterine fibroids may have many years of normal cyclic bleeding, which changes as they reach the later reproductive years and begin to have intermittent anovulatory cycles. Although ultrasound evaluation diagnoses fibroids, perhaps for the first time, the patient might respond to medical treatment for the anovulation, rather than surgical treatment of the fibroids.
Diagnostic Testing
The workup of AUB is directed by the limited differential diagnosis generated by the history and physical examination. When pregnancy, coagulation disorders, and iatrogenic causes have been ruled out, a suggested workup is as follows. Patients who are ovulatory but who have AUB are more likely to have an anatomic lesion of the uterus, such as uterine polyps, fibroids, or adenomyosis. The best radiologic method for evaluating the uterus is pelvic ultrasound. Traditional endovaginal ultrasound is helpful for diagnosing most fibroids, although it is less sensitive in pinpointing whether the fibroids have a submucosal component (sensitivity 21-100%). When sonohysterography is performed, the sensitivity for detecting submucous fibroids increases to 57% to 100%, with specificity 96% to 100% (Fig. 6-1). The sensitivity of sonohysterography for diagnosis of intrauterine polyps (Fig. 6-2) is similarly high and approaches that of the gold standard, hysteroscopy, at a fraction of the cost and with less discomfort for the patient. In addition, myometrial defects are seen more easily than with hysteroscopy.
Reproductive Endocrinology and Infertility Figure 6-1 A, Fluid contrast ultrasound of submucous fibroid. B, Hysteroscopic view of same submucous fibroid.
84
Abnormal Uterine Bleeding Figure 6-2 A, Fluid contrast ultrasound of endometrial polyp. B, Hysteroscopic view of same endometrial polyp.
85
Reproductive Endocrinology and Infertility
A history of anovulation implies a hormonal cause for bleeding. The differential diagnosis of anovulatory bleeding is extensive (see earlier). Investigation of the HPO axis generally should include studies of thyroid and prolactin production. Clinical evidence of hyperandrogenism (hirsutism, acne) would be an indication for serum androgen testing, including free and total testosterone, dehydroepiandrosterone sulfate, and 17α-hydroxyprogesterone levels. In many patients, serum testing is normal, and there is no apparent cause for anovulation. Frequently, this anovulation is due to complex hypothalamic factors for which there are currently no practical diagnostic tests. Any patient who is anovulatory and has other risk factors for endometrial hyperplasia should undergo endometrial biopsy. In addition to chronic anovulation, risk factors for endometrial hyperplasia include any other condition that exposes the patient to high levels of estrogens. Such conditions include obesity, late menopause, and exposure to unopposed exogenous estrogens. If a patient seems clearly anovulatory by history, and the physical examination is not suggestive of an anatomic abnormality, such as uterine fibroids, it is reasonable (although uncommon) to embark on a course of treatment without obtaining a pelvic ultrasound. If the patient does not respond to adequate treatment as discussed subsequently, ultrasound may be useful in diagnosing a second, structural problem. Patients with postmenopausal bleeding, few or no risk factors for endometrial cancer, and a normal examination initially may be evaluated by pelvic ultrasound. Patients with risk factors initially may undergo endometrial biopsy, followed by ultrasound if the biopsy is negative for malignancy. Sonohysterography provides information regarding not only endometrial thickness but also the presence of benign causes of bleeding, such as myomata or uterine polyps. When the endometrial thickness is 5 mm or less on transvaginal ultrasound, the negative predictive value for detecting endometrial cancer is 96% and for detecting any endometrial pathology is 92%. Because this rate is less than 100%, however, any postmenopausal patient with a thin endometrium who continues to be symptomatic or who fails to respond to treatment should be considered for endometrial biopsy. Endometrial thickness in premenopausal women varies, and 5 mm or greater thickness is much less predictive of endometrial or uterine abnormalities.
86
THERAPEUTIC INTERVENTIONS Treatment modalities fall into two major categories: surgical therapy and hormonal therapy (Box 6-2).
Surgical Therapy
Surgical treatments are most useful for patients with structural abnormalities as the cause of bleeding. The list of surgical options is increasing in length each year as new technologies are tested and approved.
Abnormal Uterine Bleeding
Box 6-2
Treatment of Dysfunctional Uterine Bleeding
OCP therapy Progestin Oral Intrauterine GnRH agonist Uterine artery embolization Endometrial ablation Hysterectomy
Hysteroscopy with Resection Patients with uterine polyps or fibroids that are primarily intracavitary are 87 excellent candidates for hysteroscopic resection of lesions. Returning the uterine cavity to a normal shape allows the uterus to respond normally to cyclic ovarian steroid hormone output. Patients with fibroids that are primarily intramural are not good candidates for this procedure because it is impossible to resect most of the fibroid, and the recurrence rate of bleeding is higher. Uterine Artery Embolization Uterine artery embolization involves catheterizing the uterine artery, under radiologic guidance, then embolizing the uterine arteries or, in some cases, the single artery feeding the fibroid, with particles such as polyvinyl alcohol or gelatin microspheres. Analysis of uterine artery embolization has shown a decrease in menorrhagia for 80% to 90% of patients. Although there are reports of normal pregnancy outcomes after uterine artery embolization, there are no substantial data to predict the chances of successful pregnancy after the procedure. Uterine artery embolization is not recommended as a treatment of choice for patients wishing to preserve fertility. Global Endometrial Ablation Endometrial ablation may be an attractive alternative for patients with ovulatory bleeding and a relatively normal uterine cavity. The aim of endometrial ablation is to destroy as much of the endometrium as possible, rendering it unable to regenerate under the influence of ovarian steroid hormones. Traditional technologies, such as laser vaporization, rollerball ablation, and endometrial resection with electrocautery, have been joined by “second-generation” techniques, such as cryotherapy, microwave energy, and various forms of heated liquid. In practice, a few patients are amenorrheic after endometrial ablation, although most experience a return to “normal” or light menstrual flow. Patient satisfaction rate with most of these methods is generally high, ranging from 93% to 100%. A Cochrane review of endometrial destruction techniques did not find a significant difference between any of the techniques in reduction of heavy menstrual bleeding. Anovulatory patients at risk for endometrial hyperplasia generally are not
Reproductive Endocrinology and Infertility
considered good candidates for this procedure because cases of endometrial cancer after endometrial ablation have been reported, and the diagnosis is sometimes delayed by masking the uterine bleeding patterns.
Hysterectomy By definition, hysterectomy eliminates uterine bleeding in any patient. This procedure is a more invasive and costly option, however, with a higher risk of surgical complications. Patients who are finished with childbearing and who have significant anatomic abnormalities of the uterus are appropriate candidates for hysterectomy. Patients should be given appropriate counseling as to risks, benefits, and alternatives.
88
Hormonal Therapy
Medical treatment of AUB is particularly useful for patients with anovulatory bleeding or for patients who are ovulatory and have a relatively normal uterus. Occasionally, patients with structural abnormalities of the uterus also respond well to medical management. The list of possible medical treatments, similar to the list of surgical options, is growing as we begin to understand better the effects of various hormones on the endometrium.
Oral Contraceptive Pill Therapy It is well recognized that combination OCP use is associated with decreased menstrual flow. By providing progestins throughout the cycle, OCPs limit endometrial proliferation. OCP therapy is appropriate for patients who are anovulatory, to provide regular withdrawal bleeding, and for patients with menorrhagia, to decrease blood loss. There is now an overwhelming number of OCP brands on the market, but most combination OCPs work in similar ways (i.e., by ovarian suppression). Therapy should be tailored to the patient’s individual needs and side effect profile; almost any monophasic pill is appropriate for the treatment of AUB. Patients should be counseled to have a 3-month trial of therapy; if bleeding patterns are improved but side effects are unacceptable, a change in type of OCP may be considered at that time. Oral Progestin Therapy For patients in whom estrogen use is contraindicated, such as smokers older than age 35 or women with hypercoagulable states, progestins alone can control AUB. Any progestin dose with sufficient strength to suppress ovulation potentially renders a patient amenorrheic when used in continuous fashion. Although cyclic monthly progestin therapy also often is used in the treatment of AUB, it should be limited to patients who are truly chronically anovulatory. Treatment of ovulatory or oligo-ovulatory patients with progestins 10 to 14 days out of the month is likely to exacerbate AUB because it is difficult to synchronize the therapy with the patient’s own, sometimes unpredictable, luteal phase. There are at least four oral progestins currently on the market: medroxyprogesterone acetate, norethindrone, megestrol, and micronized progesterone. When prescribing progestins for control of AUB, the most important consideration is to administer a potent enough dose to control bleeding. These progestins differ widely in terms of potency
Abnormal Uterine Bleeding Table 6-1 Treatment Options for Abnormal Uterine Bleeding
Diagnosis Anovulatory Thyroid disease Prolactinoma
Treatment A
Treatment B
Treatment C
Treatment D
Thyroid replacement Suppression OCPs versus surgery OCPs Oral progestins LNG IUS
Idiopathic/ PCOS Ovulatory—anatomic Polyp Hysteroscopic resection Intracavitary Hysteroscopic myoma resection Intramural Open/ myoma laparoscopic resection Ovulatory— OCPs idiopathic Coagulation Factor disorder replacement PostmenoDiscontinue pausal, HRT normal uterus
Hysterectomy* UAE*
Hysterectomy* LNG IUS
Endometrial ablation* OCPs
LNG IUS
Change E/P ratio of HRT
Expectant/ reassurance
Oral progestins
*Incompatible with future fertility. E/P, estrogen/progestin; HRT, hormone replacement therapy; LNG IUS: levonorgestrel intrauterine system; OCPs, oral contraceptive pills; UAE, uterine artery embolization.
at the progesterone receptor and the amount necessary to induce secretory changes in endometrium (Table 6-1). Dosing of any progestin may be limited by patient side effects.
Intrauterine Progestin Patients with a relatively normal uterine cavity are excellent candidates for control of AUB with a progestin-containing intrauterine system. Although marketed as a contraceptive device, the levonorgestrel-containing intrauterine system is associated with a marked decrease in menstrual blood loss. Randomized studies have found that the efficacy of this method in terms of reducing heavy menstrual bleeding approaches that of thermal balloon endometrial ablation. By providing continuous progestin activity at the level of the endometrium, the risk of hyperplasia is greatly reduced for patients with chronic anovulation. Patients with ovulatory bleeding also may benefit from reduced blood loss. Because systemic levels of progestin are not as high as with the oral progestins, the intrauterine system is a good option for patients who cannot tolerate oral progestin side effects. Gonadotropin-Releasing Hormone Agonists GnRH agonists are extremely effective agents for control of bleeding, whether for anatomic or hormonal reasons. Their mechanism of action is through
89
Reproductive Endocrinology and Infertility
downregulation of pituitary GnRH receptors. This results in decreased output of FSH and LH and decreased stimulation of ovarian steroid hormone production. This marked decrease in estrogen and progesterone production brings with it potential undesirable side effects, however, including vasomotor symptoms, urogenital atrophy, and, when used over a long time, loss of bone density. Because of these side effects, GnRH agonists are not generally recommended as a long-term treatment for AUB. Ideal candidates for GnRH agonist therapy include patients who are perimenopausal and wish to attempt to control heavy bleeding until they are fully menopausal (although, as menopause is a retrospective diagnosis, it may be difficult to determine the length of treatment necessary). Patients with uterine myomata who wish to undergo less invasive surgical treatments are good candidates for a limited course of GnRH agonists. In randomized trials, GnRH agonists reduce uterine volume by 30% to 50% so that a patient with a moderately enlarged uterus may undergo a simple vaginal hysterectomy after GnRH agonist therapy, rather than an open or laparoscopic procedure. GnRH agonists also are associated with a significant decrease in bleeding, which allows patients to recover from anemia before a planned surgical procedure.
90
SUMMARY AUB can have many different causes. The clinician should attempt to identify the cause on the basis of history first. Lifelong abnormal menses may be related to coagulopathy. In the absence of clear features, a fluid contrast ultrasound can establish the presence of such anatomic causes as endometrial polyps or distorting fibroids. In the absence of any of these abnormalities, dysfunctional uterine bleeding secondary to hormonal disturbance is likely, and the patient can attempt exogenous hormones to control the bleeding. More aggressive therapies, such as the levonorgestrel-containing intrauterine system, uterine artery embolization, and endometrial ablation, can be attempted. Many of these modalities are incompatible with future childbearing. If all of these attempts fail, a hysterectomy can be considered in women who have completed childbearing.
SUMMARY OF KEY POINTS 1.
2.
3.
A thorough history needs to be taken, with particular attention to the presence or absence of risk factors for endometrial hyperplasia and to determining whether the patient is having ovulatory cycles. The diagnostic workup should be tailored to the individual patient’s presentation. If an anatomic cause for bleeding is suspected, imaging should be ordered first. If a hormonal etiology is suspected, treatable causes of anovulation should be ruled out first, such as thyroid or pituitary disease. Patients with a lifelong history of menorrhagia have a high incidence of coagulation defects, such as von Willebrand’s disease.
Abnormal Uterine Bleeding
4.
5.
Treatment of AUB should reflect and be consistent with the pathophysiology of the problem. Hormonal causes of bleeding, such as anovulation, are amenable to hormonal remediation. Patients with anatomic causes for bleeding respond best to the restoration of normal uterine anatomy. Because AUB can be a lifestyle issue and a health problem, it is important to include the individual needs of the patient and overall cost and risk in deciding on a course of therapy. Unless patients are at risk for cancer or severe anemia, one should err on the side of less invasive treatments or conceivably expectant management in a patient who is not greatly inconvenienced by her symptoms.
91
SUGGESTED READINGS Barington JW, Arunkalaivanan AS, Abdel-Fattah M: Comparison between the levonorgestrel intrauterine system (LNG-IUS) and thermal balloon ablation in the treatment of menorrhagia. Eur J Obstet Gynecol Reprod Biol 2003;108:72-74. Farquhar C, Ekerona A, Furness S, Arroll B: A systematic review of transvaginal ultrasonography, sonohysterography and hysteroscopy for the investigation of abnormal uterine bleeding in premenopausal women. Acta Obstet Gynaecol Scand 2003;82:493-504. Ferenczy A: Pathophysiology of endometrial bleeding. Maturitas 2003;45:1-14. Jensen JT, Speroff L: Health benefits of oral contraceptives. Obstet Gynecol Clin North Am 2000;27:705721.
Lethaby A, Hickey M: Endometrial destruction techniques for heavy menstrual bleeding: a Cochrane review. Hum Reprod 2002;17:2795-2806. McGurgan P, O’Donovan P: Endometrial ablation. Curr Opin Obstet Gynecol 2003;15:327-332. Oehler MK, Rees MC: Menorrhagia: an update. Acta Obstet Gynaecol Scand 2003;82:405-422. Strickand JL, Wall JW: Abnormal uterine bleeding in adolescents. Obstet Gynecol Clin North Am 2003;30:321-335. Worthington-Kirsch RL, Siskin GP: Uterine artery embolization for symptomatic myomata. J Intensive Care Med 2004;19:13-21.
7 THE CLIMACTERIC Michael D. Wittenberger and William H. Catherino DEFINITIONS Climacteric Perimenopause
Early perimenopause
Late perimenopause Menopause
Postmenopause
The period of a woman’s life when she is transitioning from the reproductive years to the postmenopausal years The variable period of time before complete cessation of menses characterized by menstrual irregularity in cycle length and amount of flow and increasing periods of amenorrhea; the World Health Organization has divided perimenopause into early and late phases Women with previously predictable cycles begin to experience alterations in their cycle regularity, but they have not gone for more than 3 months without menstruation; during this stage, women may or may not experience symptoms related to hormonal deprivation Absence of menstruation increases beyond 3 months Permanent cessation of menses determined retrospectively after 12 consecutive months of amenorrhea without any other underlying pathologic or physiologic cause; longitudinal studies supporting this definition show less than a 2% chance of spontaneous menstruation after 12 months of amenorrhea The period of time after the final menses, representing the state of permanent amenorrhea
Although the age of menarche has decreased over the years largely as a result of improvements in nutrition and general health, the age a woman transitions into reproductive senescence seems to be relatively unchanged. Most women begin to experience changes leading to menopause sometime during their 40s and 50s. With life expectancy for women entering the climacteric nearing 86 years, women can anticipate spending greater than one third of their lives in the postmenopausal period. Many women are poorly informed about the changes that occur in their bodies and the health concerns associated with these changes. They also may be uncertain about the potential interventions available and the true risks associated with them. The climacteric represents a singular opportunity for a woman’s health care provider to educate the patient and have a positive impact on the remainder of her life. Treatment and lifestyle interventions introduced at this crucial period of physiologic change could alleviate symptoms significantly, promote physical
93
Reproductive Endocrinology and Infertility
and psychological well-being, and potentially prevent chronic health problems related to the ensuing changes in the woman’s hormonal milieu. Because perimenopause represents the earliest opportunity to intervene, investigators have sought to clarify its onset and duration. The Massachusetts Women’s Health Study group followed a cohort of 2750 women age 45 to 55 over a 5-year period to determine the number who were perimenopausal and postmenopausal each year (Fig. 7-1). These investigators determined the median age of onset of perimenopause was 47.5 years, and the median age of menopause was 51.3 years. The median duration of perimenopause was 3.8 years. The investigators noted that 10% of the sample stopped menstruating abruptly without evidence of preceding cycle irregularity. Their findings suggested age, smoking, and nulliparity affected the onset and duration of perimenopause. Women who were older at the onset of perimenopause had shorter transitions to menopause, smokers had earlier onset and shorter transitions to menopause, and nulliparous women had earlier onset of perimenopause. Other studies have elucidated further factors that may be associated with early menopause, including family history of early menopause, history of regular cycles, shorter cycle length during adolescence, history of type 1 diabetes mellitus, unilateral oophorectomy, presence of a variant form of galactose 1-phosphate uridyltransferase, and presence of estrogen receptor polymorphisms. Regardless of the inherent interplay of patient genetics and specific risk factors, only about 2% of women have not entered into the climacteric by age 55. Armed with knowledge of when this important tran-
94
Figure 7-1 Perimenopausal Postmenopausal 100 90 80 70 60 Percent
Percentage of women entering perimenopause and postmenopause by age. By age 51, nearly half of all women have a cessation of menstrual periods. Nearly 9 of 10 women reach menopause by their mid-50s. (Adapted from McKinlay SM, Brambilla DJ, Posner JG: The normal menopause transition. Maturitas 1992;14:107.)
50 40 30 20 10 0 45
46
47
48
49
50 Age
51
52
53
54
55
The Climacteric
sition occurs and what factors influence its onset and duration, it is important to consider the physiologic processes at work in the climacteric period.
PHYSIOLOGY
Figure 7-2 45 40 Perimenopausal
35 30 FSH level
FSH levels in premenopausal and perimenopausal women. Because of decreasing negative feedback of estradiol, FSH levels remain elevated in perimenopausal women throughout the menstrual cycle. Using FSH levels to diagnose perimenopause can be misleading, however, because FSH measurements can reach premenopausal levels, and with infrequent menstrual periods, it may be difficult to time FSH measurements accurately. (Adapted from Santoro N, Brown JR, Adel T, Skurnick JH: Characterization of reproductive hormonal dynamics in the perimenopause. J Clin Endocrinol Metab 1996;81:1497.)
Although hormonal changes and ovarian physiology leading to the climacteric are not completely understood, it is known that there is a sharp decline in fertility rates beginning after age 30. In addition, there is a decline in the quality and quantity of oocytes associated with a concomitant increase in basal follicle-stimulating hormone (FSH) levels years before the onset of the climacteric. The climacteric presumably begins when a critical number of functional follicles are lost through the process of follicular atresia. During a woman’s reproductive years, hormone production by ovarian 95 follicles maintains a delicately balanced feedback system with the pituitary and the hypothalamus. As the production of ovarian hormones decreases, compensatory changes in the hypothalamus and the pituitary seek to reestablish homeostasis. At the onset of the climacteric (perimenopause), ovarian production of inhibins decreases, paralleling a decline in functional ovarian follicles. Initially, levels of inhibin B are affected. Normal levels of inhibin A are conserved until just before menopause. Because inhibins function to decrease the synthesis and secretion of FSH and to decrease the number of gonadotropin-releasing hormone receptors on pituitary gonadotropes, circulating levels of FSH begin to increase (Fig. 7-2). Despite elevated levels of
25 20 15 10
Premenopausal
5 0 −10 −9 −8 −7−6 −5 −4 −3 −2 −1 0 1 2 3 4 5 6 7 8 9 10 1112 13 14 15 16 17 18 Day of menstrual cycle
Reproductive Endocrinology and Infertility
FSH, ovarian response to FSH becomes progressively more blunted. Initially, the ovary responds to the elevated levels of FSH by increasing production of estradiol, resulting in levels greater than those seen during the reproductive years. Ovarian response per unit of FSH continues to decline, however, until estradiol levels are markedly reduced. In addition to fluctuations in estradiol, the perimenopause is marked by reduced progesterone production in the luteal phase until, with cessation of ovulation, progesterone production ends. This vacillation in ovarian hormone secretion continues until menopause, at which time a new steady state is reached. By menopause, estradiol and estrone are markedly decreased, FSH and luteinizing hormone (LH) are elevated, and testosterone is reduced by 20%. The most observable consequence of this hypothalamic-pituitaryovarian axis perturbation is the changes in a woman’s menstrual cycle. Perimenopause is characterized by ovulatory cycles interspersed with anovulatory cycles of varying lengths. Normal to elevated levels of estradiol and altered estradiol to progesterone levels may lead to menorrhagia, endometrial hyperplasia, dysfunctional uterine bleeding, and growth of uterine leiomyomata. Early on, there may be a shortening of the cycle by 2 to 7 days secondary to a shorter follicular phase as enhanced FSH recruitment of a dominant follicle occurs. There also may be increased quantity of menstrual bleeding as a result of luteal insufficiency and anovulation. Later, the cycle typically lengthens secondary to decreased follicular recruitment and further anovulation. Before menopause, menstrual bleeding decreases as estrogenic stimulation of the endometrium decreases; however, irregular spotting may increase. At menopause, the functional pool of follicles is depleted, and estradiol production declines further. As a result, there is minimal estrogenic stimulation of the uterus, the endometrium becomes atrophic, and menses cease.
96
CLINICAL PRESENTATION Although menstrual disorders are often cited as the most bothersome initial symptom of the climacteric, elsewhere in the body fluctuations and ultimate withdrawal of ovarian hormones are responsible for many clinical symptoms that have a significant impact on a woman’s life.
Vasomotor Disturbances
Vasomotor disturbances (hot flashes and night sweats) are common climacteric symptoms. Nearly 75% of perimenopausal and postmenopausal women report vasomotor symptoms. Hot flashes typically occur early in perimenopause, peak at menopause, and persist into postmenopause for approximately 1 to 5 years. They are characterized by a sudden sensation of heat in the upper body, especially the face, neck, and chest, which rapidly becomes generalized. Often they are associated with profuse sweating and palpitations and may be followed by shivering and chills. They last a few seconds to several minutes and occur several times per day. They may occur once per hour throughout the day and night. Physiologic studies show
The Climacteric
that hot flashes are associated with an inappropriate peripheral vasodilation with shunting of blood to the skin and perspiration resulting in rapid heat loss and a drop in core body temperature. Shivering ensues to restore the core body temperature to normal. The exact etiology of hot flashes is unknown, although there is evidence to suggest they arise secondary to a centrally mediated dysfunction in thermoregulation. This dysfunction is likely triggered by a decrease in estrogen during the climacteric years. The major thermoregulatory center in mammals (the medial preoptic area) lies in close proximity to a high density of gonadotropin-releasing hormone–secreting neurons in the hypothalamus. In addition, hot flashes are shown to have a temporal relationship to peaks in LH secretion—also dependent on gonadotropin-releasing hormone release. Women with Turner’s syndrome, who have constitutionally high levels of FSH and LH, do not experience hot flashes unless they are first treated with 97 and then withdrawn from estrogen. This finding suggests that it is not elevated FSH and LH per se, but estrogen withdrawal via its interplay with the hypothalamus that seems to play a major role in the mechanism of vasomotor symptoms.
Sleep Disturbances
Change in hormonal patterns that occur in the climacteric may contribute to sleep disturbances. Studies indicate that the number of women complaining of sleep disturbances increases after age 40 and plateaus by age 50. Sleep disturbances were increased only among perimenopausal and postmenopausal women who were not taking hormone replacement therapy. Nocturnal hot flashes invariably disrupt sleep, either by affecting sleep quality or by repetitive awakening. Perimenopausal and postmenopausal women who have hot flashes have decreased sleep efficiency and an increased latency to REM sleep. Because the restorative value of sleep is directly affected by sleep continuity (the ability to remain asleep) and the circadian phase (regulated by core body temperature cycles and melatonin) at which it occurs, disruptions caused by nocturnal hot flashes can lead to daytime drowsiness and fatigue and may exacerbate other problems common to the climacteric.
Depression
Although women do not develop depression during the climacteric transition, studies suggest that perimenopause is a period of increased susceptibility to depression. Studies are mixed on the relative importance of vasomotor symptoms in women with depression; some studies indicate women experiencing menopausal symptoms (irregular bleeding and vasomotor symptoms) have higher rates of depression than women who are symptom-free, whereas others report depression occurred independent of vasomotor symptoms. Regardless, one of the strongest predictors for depression during the climacteric is a preceding history of depression. Perimenopausal women have a variety of other psychosocial stressors that also may predispose them to depression. They may be at the peak of their professional careers, balancing career decisions with changes in family dynamics and caregiving responsibilities related to egress of older children and care of elderly
Reproductive Endocrinology and Infertility
family members. Women who view themselves primarily as mothers may mourn the loss of their reproductive years. Negative cultural images of the aging woman may promote pessimism in women undergoing this transition. Whether this increase in depression results from hormonal or life changes, the risk of depression seems to normalize in the postmenopausal years.
Urogenital Symptoms
As circulating estrogen levels decrease toward the end of the climacteric, numerous changes occur in the genitourinary system. Vaginal epithelium is relatively estrogen dependent, and estrogen depletion leads to thinning and atrophy of the vaginal mucosa. On examination, the vagina may appear pale with absence of normal rugae and presence of petechiae and superficial vessels. Vaginal elasticity also may decrease resulting in a loss of caliber and length unless sexual intercourse is maintained. In addition, there is decreased production of vaginal fluid and decreased glycogen production by vaginal epithelium. Lactobacilli, which previously suppressed competitive bacterial growth by metabolizing glycogen to acidic by-products, may be gradually replaced, and vaginal pH may increase. The increase in vaginal pH around menopause may promote growth of potential pathogenic organisms and increase the likelihood of infection. Collectively, all these changes introduced by estrogen depletion subsequently lead to vaginal irritation, pruritus, and dyspareunia. Similarly, estrogen depletion leads to atrophy of the superficial and intermediate layers of the urethra epithelium and to atrophy of the bladder trigone. Ensuing changes that occur may result in decreased urethral seal and tonicity and loss of bladder compliance and irritation, which result in dysuria from atrophic urethritis, urinary frequency, and incontinence. Combined with a change in vaginal flora favoring colonization by pathogenic or fecal organisms, postmenopausal women also are at increased risk for urinary tract infections. Risk for pelvic organ prolapse is another condition associated with estrogen deficiency. This malady is more likely to manifest itself after menopause, however, and usually is associated with several other risk factors. Other risk factors for pelvic organ prolapse include advanced age, multiparity, obesity, birth trauma associated with dystocia or operative vaginal delivery, prior pelvic surgery, connective tissue disorders, neurogenic dysfunction affecting the pelvic floor, chronic constipation secondary to anal atresia, and other conditions that chronically increase intra-abdominal pressure. Together with racial differences in the incidence of pelvic organ prolapse, these risk factors suggest that prolapse does not chiefly represent an estrogen deficiency syndrome, but injury of pelvic support structures that are exacerbated over time.
Sexual Dysfunction
Problems with sexual function are common among women in the climacteric period and may be associated with physiologic, emotional, and iatrogenic causes. Discomfort during intercourse may be exacerbated by vaginal atrophy, dryness, and decreased compliance resulting from estrogen deficiency.
98
The Climacteric
In addition, it is known in animals that estrogen deficiency also causes a reversible neuropathy in the distribution of the pudendal nerve. Similarly, estrogen deprivation may result in decreased skin sensitivity in the genital region in women. During the climacteric transition, libido also may be affected by the changing hormonal milieu. Although still controversial in its exact contribution to sexual function and dysfunction, androgen production is known to decline during this transition and may affect sexual interest and desire. Women also may have decreased interest in sexual activity if they are experiencing haphazard bleeding, hot flashes, and sleep disturbances. Emotional issues during this period also may interfere with normal sexual function. Body image concerns associated with weight gain during this phase, the availability of a functional partner, and the onset of chronic illnesses all may affect a woman’s sense of femininity and her sexual receptivity. Many medications given to treat these conditions actively interfere with 99 normal sexual functioning. Medications that affect the autonomic nervous system may affect desire and orgasm, whereas medications that affect the parasympathetic nervous system and alter concentrations of acetylcholine may affect arousal.
Connective Tissue Changes
As a woman ages, the amount of collagen in her skin and bones decreases. After the time of menopause, changes apparent in the skin include thinning, increased wrinkling, decreased hydration, decreased sebaceous secretion, and decreased elasticity. These changes are probably estrogen mediated because the skin is rich with estrogen receptors, and multiple studies have shown increased collagen content and thickness after estrogen therapy.
Osteoporosis
Although not typically associated with the early climacteric when estrogen levels are still conserved, osteoporosis is a significant health problem beginning with the menopausal and postmenopausal years. An individual’s ultimate bone mass seems to be influenced by heredity and hormonal factors and is amassed over a relatively short window of time during their reproductive life. With the onset of menopause and subsequent estrogen deprivation, bone remodeling increases with bone resorption by osteoclasts exceeding bone formation by osteoblasts. As a consequence, 1.5% of the total skeletal mass and 5% of trabecular bone can be lost per year in the first few years after menopause. Depending on the woman’s bone mass entering menopause, osteoporosis could occur in 10 years. Osteoporosis is characterized by low bone density and microarchitectural deterioration of bone tissue, with an increase in bone fragility and susceptibility to fracture. For measurement purposes, it is defined as greater than a 2.5 SD in bone mass from the average, same gender, peak bone mass. Osteopenia is defined as a reduction between 1 and 2.5 SDs from the average peak bone mass and, in the presence of other risk factors for osteoporosis or documented progressive bone loss, may represent an increased risk for fracture. Because trabecular bone in the axial skeleton experiences a greater decline in mass, it is particularly susceptible to fracture. Vertebral fractures may lead to chronic pain, loss of
Reproductive Endocrinology and Infertility
height, kyphosis (dowager’s hump), and other postural deformities with their attendant pulmonary, gastrointestinal, and bladder dysfunctions. Similarly, hip fracture is associated with significant morbidity and mortality. After hip fracture, approximately 20% of women die within 1 year, 25% require longterm care, and 50% experience long-term loss of mobility. Accelerated bone loss during the climacteric period represents a significant threat to health and quality of life for women at risk for osteoporosis. Osteoporosis is covered in greater detail in Chapter 8.
Cardiovascular Disease
Similar to osteoporosis, cardiovascular disease does not begin to increase until after menopause. Relative to age-matched men, women during their reproductive years show decreased risk for cardiovascular disease (Fig. 7-3). Progression through menopause is associated with an increase in total cholesterol, low-density lipoprotein cholesterol, and triglycerides—all risk factors for heart disease. The incidence of myocardial infarction also increases after menopause. Coronary heart disease is two to three times more likely to occur in women after menopause than in women of the same age who have not entered menopause; this has led many clinicians to postulate a protective role of estrogen in the prevention of cardiovascular disease.
Cognitive Decline
Aging is associated with a general decline in memory and cognition. In addition, there is a threefold increase in Alzheimer’s disease in women compared with men. In the brain, estrogen is believed to promote synaptic and neuronal growth and to guard against oxidative neuronal cytotoxicity and to
Incidence of myocardial infarction by age and sex. Before the climacteric (age 35-44), women have 1⁄10 the risk of myocardial infarction compared with agematched men. This risk increases to 1⁄7.5 at the climacteric and to less than ½ by age 80. (Adapted from Lerner DJ, Kannel WB: Patterns of coronary heart disease morbidity and mortality in the sexes: a 26year follow-up of the Framingham population. Am Heart J 1986;111:386.)
Figure 7-3
Men Women
35 30 Two year rate per 1000
100
25 20 15 10 5 0 35-44
45-54
55-64 Age at exa mination
65-74
75-84
The Climacteric
reduce the glycoprotein found in Alzheimer’s lesions. Despite this evidence, studies do not uniformly support a decline in cognition through the menopausal transition, and they do not show a protective effect of estrogen on cognitive decline or development of dementia.
Summary
Physiologic changes of the climacteric period can precipitate many clinical symptoms. These symptoms seem to be related to the short-term and longterm effects of ovarian hormone withdrawal. Symptom and risk factor recognition and subsequent initiation of therapy are paramount because of the impact these problems have on a woman’s general health and quality of life.
DIAGNOSTIC TESTING Markers for Menopause
Collectively, the many health issues associated with the climacteric can have a dramatic impact on current social functioning and long-term health. The diagnosis of menopause is made in hindsight, after a full year of ovarian quiescence. During this year, women experience many of the negative side effects of decreasing estrogen, including hot flashes, night sweats, and bone loss. Early identification of impending menopause would allow for preemptive intervention to prevent such symptoms. In the final stages of ovarian failure, the ovaries respond poorly to FSH stimulation. As a result, FSH levels increase to drive the ovarian follicles to produce estradiol. Ultimately, when the ovaries are exhausted of oocytes and are unable to produce estradiol, the FSH levels increase dramatically. Overproduction of FSH could serve as a marker for entry into menopause. FSH is not a reliable marker for the transition to menopause. This hormone is produced in a pulsatile fashion, and blood levels may be relatively low in menopausal women or relatively high in women who have not yet reached menopause, depending on whether FSH production is at its peak or nadir. Also, given this variability, it is difficult to select a clinically useful FSH level that can be used to diagnose menopause. If the FSH cutoff is too high, women reaching this level would most certainly be in menopause, but there would be many other women who experience the perimenopausal symptoms but do not achieve this cutoff. Conversely, if the level is too low, there would be women who have not reached menopause who would be incorrectly categorized as menopausal. It has been shown that there is no statistical increase in the likelihood of undergoing menopause over the next 10 years in women with a basal FSH of greater than 10 IU/L compared with women with basal FSH levels less than 10 IU/L. In the absence of an effective blood test to diagnose menopause accurately, clinicians are obliged to evaluate symptoms to determine whether their patients have progressed into and beyond the climacteric. Because this strategy can place a woman at risk for several months, it is important to use the established relationship between age and onset of perimenopause to begin screening for the health problems that she is likely to encounter and to intervene as necessary to minimize these risks.
101
Reproductive Endocrinology and Infertility
Osteoporosis Screening
Fracture risk, as described previously, represents one of the greatest risks of the menopausal period. The development of osteopenia and ultimately osteoporosis is relatively silent and inevitable with age, and patients frequently present with a life-threatening bone fracture. Current technology provides reasonable options for diagnosis and treatment of osteoporosis. The gold standard for assessment of bone loss is the dual-energy x-ray absorptiometry (DEXA) scan. DEXA involves exposure of x-rays at two different energies that are absorbed differently by bone of different densities. Results typically are presented as T-scores, which are simply SDs from the mean of the peak bone mass of an average young adult. Each SD from the mean increases the risk of fracture twofold. Data from DEXA scans also can be presented as Z-scores, which represent SDs from an age-matched mean. Z-scores can be misleading, in that mean bone mass decreases with age, and individuals who are elderly but near the mean are at increased risk of bone fracture. In addition to DEXA scanning, there are several blood and urine tests to identify products of bone turnover. Markers that increase with bone resorption include N-telopeptide, C-telopeptide, pyridinoline, deoxypyridinoline, and hydroxyproline, and markers that increase with bone formation include N-propeptide, C-propeptide, alkaline phosphatase, and osteocalcin. These markers may provide some information on the effectiveness of therapy, but there are currently no well-accepted measurements that can be used for prognosis.
Cardiovascular Risk Screening
As women progress through the climacteric period, their risk of cardiac and vascular disease rapidly approaches the risk encountered by men. Before the climacteric, men experience coronary heart disease at a rate 6.5 times greater than age-matched women (Box 7-1). By menopause, this ratio decreases to 3, and by 75 years of age or older, women carry the same risk as men. There remains a bias, however, that men are at risk of cardiovascular disease and that women are protected from it. In reality, cardiovascular disease is the most common cause of death in women from the climacteric and beyond. Typical symptoms that define impending myocardial infarction are well defined in men, but may differ in women. As a result, clinicians need to have a high level of suspicion when a perimenopausal or postmenopausal woman presents with vague symptoms. In an asymptomatic patient, studies such as electrocardiogram or exercise stress testing have low positive predictive value and are not helpful as screening tests. Evaluation of risk factors for cardiac disease such as cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides is warranted. For patients with symptoms, stress testing and electrocardiogram along with creatine kinase–MB and troponin blood testing provide invaluable information on current and future risk. Carotid artery Doppler also may be helpful in women who are experiencing central nervous system symptoms, such as transient ischemic attacks. Evidence of cardiovascular disease should be evaluated further and treated in conjunction with a cardiologist.
102
Box 7-1 Relative Risk of Cardiovascular Disease in Men Compared with Women by Age Preclimacteric—6.5 Menopause—3.0 ≥75 years—1.0
The Climacteric
THERAPEUTIC INTERVENTIONS Numerous management strategies exist to treat symptoms associated with the climacteric and to maintain the healthy functioning of a woman as she continues on into her postmenopausal years. These approaches consist of lifestyle interventions and hormonal and nonhormonal pharmacotherapy.
Lifestyle Intervention
The climacteric transition is an excellent opportunity to educate women and reinforce the concept of a healthy lifestyle. As part of a healthy lifestyle, women should be instructed in proper nutrition. With the cessation of ovarian hormone production, a woman’s metabolic requirements change. To maintain a desirable body weight and minimize her risk of different chronic diseases associated with obesity, her total caloric intake should be decreased 103 to 1900 calories per day. Approximately 30% of recommended calories should be fats with no more than 300 mg of cholesterol per day. High-fat diets may increase the risk of cardiac disease and are associated with several cancers. Conversely, dietary fiber is linked to a decreased risk for cardiac disease and cancer. Adequate intake of calcium and other minerals important in bone maintenance, such as zinc, magnesium, and phosphorus, also should be encouraged. Daily calcium intake should be increased from 1000 mg/day to 1500 mg/day, and vitamin D may be added if a patient has inadequate sun exposure. Caffeine and alcohol negatively affect bone density via calcium absorption and estrogen metabolism. Dietary changes that limit alcohol and caffeine may be helpful in ameliorating symptoms associated with osteoporosis. Because smoking increases a woman’s risk of cardiovascular disease, osteoporosis, bronchitis, emphysema, and cancer, smoking cessation during this period of increasing susceptibility should be strongly encouraged. Studies show that patients have greater success at quitting when physicians encourage them to stop. The health care provider’s effectiveness as determined by actual cessation rates depends, however, on a systematic approach to identifying smokers and supporting tobacco cessation. A woman’s health care provider should be prepared to assist with smoking cessation by introduction of behavioral therapy and supplementing with nicotine patch and bupropion therapy as needed. The positive effects of exercise on cardiovascular disease and bone mineral density are well documented. As a woman ages, cardiovascular endurance decreases at a rate of 1 mm3 oxygen/kg body weight per year, and maximum heart rate decreases by 1 beat/min per year. Although maximal heart rate does not change, cardiovascular endurance can be improved through physical activity. Studies indicate a 30% to 40% risk reduction in cardiovascular disease in women participating in vigorous physical activity such as brisk walking. In addition, exercise stimulates osteoblastic, or bone-forming, activity in bone and decreases the age-related decline in muscle mass. Regular physical activity should be encouraged. Physical activities should include a combination of aerobic weight-bearing and resistance exercises to maximize
Reproductive Endocrinology and Infertility
cardiovascular and musculoskeletal benefits. Posture and balance training also is important and may decrease the risk of falls as a woman ages. It is recommended that women get 30 minutes of cumulative physical activity at least 3 days per week. In addition to proper nutrition, smoking cessation, and exercise, health screening is an important component of lifestyle intervention. Various medical organizations have recommended health screening measures for women. The American College of Obstetrics and Gynecology has recommended the measures listed in Table 7-1 based on age groups and specific risk factors for asymptomatic women based on test accuracy, risks, and cost. Symptomatic women would require further evaluation as dictated by their complaint.
104 Hormonal Phar-
macotherapy
Many of the symptoms associated with the climacteric (hot flashes, night sweats, sleep disturbances, sexual dysfunction, and collagen changes) and some of the long-term health issues of the postmenopausal period (osteoporosis) result from hormone deprivation that occurs with ovarian failure. These symptoms and diseases can be minimized or eliminated with hormonal supplementation. Early retrospective studies suggested a wide range of benefits from hormone replacement therapy, including prevention
Table 7-1 Health Screening Recommendations for Women in the Climacteric
Evaluation
Timing
History—including full medical and family histories; evaluation of sexuality, fitness, and nutrition; psychosocial evaluation; and cardiovascular risk factors evaluation Physical—including measurement of height, weight, and blood pressure and oral cavity, thyroid, breast, abdomen, pelvic, and skin examinations Pap smear
Annually
Mammography Cholesterol testing Fecal occult blood testing Flexible sigmoidoscopy Or Colonoscopy Or Double-contrast barium enema Fasting glucose testing Influenza vaccine Tetanus-diphtheria booster
Annually
Annually, then physician discretion after 3 consecutive normal tests if low risk Every 1-2 yr until age 50, annually thereafter Every 5 yr beginning at age 45 Annually Every 5 yr beginning at age 50 Every 10 yr beginning at age 50 Every 5-10 yr beginning at age 50 Every 3 yr after age 45 Annually beginning at age 50 Every 10 yr
Modified from American College of Obstetricians and Gynecologists: Guidelines for Women’s Health Care, 2nd ed. Washington, D.C.: ACOG; 2002:130-131.
The Climacteric
of cardiovascular disease, dementia, and other long-term ailments. Various prospective trials have not validated these findings, however, and hormone replacement therapy can no longer be considered a panacea. Cardiovascular disease is the most common cause of morbidity and mortality in postmenopausal women, and early studies suggested that markers for long-term cardiovascular risk improved in women taking hormone replacement therapy. Placebo-controlled, randomized, prospective trials (Heart and Estrogen/progestin Replacement Study II and the Women’s Health Initiative) showed, however, that hormone replacement therapy provided no benefit for primary or secondary prevention of cardiovascular disease, stroke, or deep venous thromboembolus. The combination (Premarin/Provera) form of hormone replacement therapy used seemed to increase the risk of these outcomes, although overall mortality was no different in either arm of the study. 105 Although the Women’s Health Initiative validated hormone replacement therapy as reducing the risk of vertebral and hip fractures by 34%, these investigators concluded that overall risks outweighed the merits of hormone replacement therapy in this setting. Then what conditions should be treated preferentially with hormone replacement therapy? The above-mentioned studies did not, and by design could not, assess the impact of hormone replacement therapy on the vasomotor symptoms associated with the climacteric. Because of the dramatic improvement in hot flashes caused by hormone replacement therapy, it was impossible to do a blinded study. For women with severe hot flashes, night sweats, and sleep disturbances, hormone replacement therapy is an effective short-term therapeutic option. In addition, for women at high risk for osteoporosis, the risk/benefit assessment may favor hormone replacement therapy use. For women previously taking hormone replacement therapy primarily for nonvasomotor complaints, alternative formulations exist.
Other Pharmacotherapy
Other agents have not proved as effective in treating vasomotor symptoms. When evaluated by randomized placebo-controlled trials, only selective serotonin reuptake inhibitors and gabapentin have shown improvement in vasomotor symptoms over placebo. Because of the perceived danger in taking hormonal preparations, many women have resorted to using soy products, herbs, and other complementary and alternative therapies to manage menopausal symptoms. Although black cohosh and some phytoestrogen preparations initially appeared promising, randomized controlled trials have not borne out their efficacy. In addition, there are no long-term safety data for these formulations. Selective estrogen receptor modulators (SERMs) are one class of nonhormonal agents shown to be beneficial in remedying some of the effects of ovarian hormone withdrawal. SERMs selectively bind estrogen receptors and, based on the tissue type, may exert an agonistic or antagonistic response. Raloxifene has been shown to maintain bone density in postmenopausal women without adverse stimulation of the breast or endometrium. In addition, raloxifene was associated with reduced risk for breast cancer.
Reproductive Endocrinology and Infertility
It also was associated with an increase in thromboembolic events and a significant increased risk of hot flashes, however. At this time, no commercially available SERM has proved effective at relieving vasomotor symptoms. Bisphosphonates are another group of medications that have shown efficacy in increasing bone mass and reducing fractures when used to treat osteoporosis. These agents preferentially bind hydroxyapatite crystals in mineralized bone matrix and inhibit osteoclastic activity. Bisphosphonates approved for use in the United States include alendronate, risedronate, and ibandronate. For patients at risk for osteoporosis-related fractures who are unable to tolerate bisphosphonates, calcitonin and teriparatide (an injectable parathyroid hormone) may be viable options.
106
Summary
Multiple therapeutic modalities exist to treat the short-term and long-term effects of ovarian hormone withdrawal initiated in the climacteric period. Early diagnosis and intervention potentially can prevent significant morbidity and preserve overall well-being of women reaching this transition point in life.
SUMMARY OF KEY POINTS 1. 2.
3. 4.
5.
It is important to identify the beginning of the climacteric period to intervene appropriately. Fluctuations of estradiol during perimenopause potentially may lead to pathologic conditions, such as endometrial hyperplasia, dysfunctional uterine bleeding, and enlargement of uterine tumors. Bleeding during perimenopause needs to be investigated with endometrial sampling. Estrogen deprivation underlies most of the physical symptoms experienced by women passing through the climacteric. Long-term hormonal replacement may not be beneficial, but short-term use may be justified to control symptoms related to hormonal deprivation. Alternatives to hormonal supplementation exist, but the benefits of some of these products, particularly those sold without prescription, have not been carefully evaluated.
SUGGESTED READINGS American College of Obstetricians and Gynecologists: Clinical updates in women’s health care—care of aging women. ACOG vol III, no 1; January 2004. Barbieri RL, Berga SL, Chang RJ, Santoro NF (eds): APGO Educational Series on Women’s Health Issues: Managing the Perimenopause. Beachwood, Ohio: Current Therapeutics; 2001.
Barbieri RL, Derman RJ, Gass MLS, et al (eds): APGO Educational Series on Women’s Health Issues: Current Strategies for Managing Osteoporosis. Beachwood, Ohio: Current Therapeutics; 2003. Barbieri RL, Lobo RA, Walsch BW, Santoro NF (eds): APGO Educational Series on Women’s Health Issues: Improving Quality of Life during Menopause:
The Climacteric The Role for Hormone Replacement Therapy. Beachwood, Ohio: Current Therapeutics; 2002. Diagnosis and clinical manifestations of menopause. UpToDate Online Version 12.2; 2004. Grady D, Herrington D, Bittner V, et al: Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). HERS Research Group. JAMA 2002;288:49-57. Ling FW, Buysse DJ, Ciotti MC, et al (eds): APGO Educational Series on Women’s Health Issues:
Managing Insomnia and Sleep Disorders in Women. Beachwood, Ohio: Current Therapeutics; 2000. Speroff L, Fritz RA (eds): Menopause and the perimenopausal transition. In Clinical Gynecologic Endocrinology and Infertility, 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2005:621-688. Writing Group for the Women’s Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288:321-333.
107
8 OSTEOPOROSIS AND BONE METABOLISM Rocio I. Pereira and Linda A. Barbour DEFINITIONS Bisphosphonates Bone strength
Osteomalacia
Osteopenia Osteoporosis
T-score Z-score
Pharmacologic agents that bind to hydroxyapatite at active sites in the bone and inhibit osteoclastic activity The characteristic of bone that, when compromised, predisposes patients to increased fracture risk; bone strength depends on bone mineral density and bone quality (determined by architecture, mineralization, microdamage accumulation, and turnover rate) A condition of defective mineralization of mature bone that occurs in adults when insufficient calcium or phosphorus is available for the formation of the primary bone mineral, hydroxyapatite Bone mineral density compromise with a T-score of −1 to −2.5 A skeletal disorder characterized by compromised bone strength, predisposing an individual to increased risk of bone fracture, defined by the World Health Organization as a T-score of −2.5 or less Bone mineral density reported as the number of SDs from the normal young adult mean density value Bone mineral density reported as the number of SDs from the normal mean value for age-matched and sex-matched control subjects
Osteoporosis affects numerous individuals who often are not diagnosed until significant morbidity occurs. Although osteoporosis most often affects white women, men and women of all races and ethnic backgrounds can be affected. According to the World Health Organization, one in three postmenopausal women have osteoporosis, but 70% are undiagnosed and untreated. The cumulative lifetime fracture risk for whites is approximately 50%. One in five postmenopausal women have vertebral fractures, usually with no symptoms, yet this single event increases their relative risk of mortality eightfold. Most women are deeply concerned about the effects of bone fracture on quality of life, as evidenced by the finding that owing to the unfavorable prospect of nursing home placement, 80% of women older than 75 years preferred death to a bad hip fracture. Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing an individual to increased risk of bone fracture. Bone strength depends on bone mineral density (BMD) and bone
109
Reproductive Endocrinology and Infertility
quality (determined by architecture, mineralization, microdamage accumulation, and turnover rate). BMD accounts for 70% of bone strength and is used as a proxy measure of overall bone strength. Osteoporosis can be classified as primary, secondary, or idiopathic. Primary osteoporosis results from an age-related acceleration of bone resorption. It can affect men and women, but most often affects postmenopausal women. Secondary osteoporosis is unrelated to menopause and results from medications or certain clinical disorders. Idiopathic osteoporosis results from an inability to achieve adequate peak bone mass during childhood and adolescence. Osteoporosis-associated fractures can occur in any bone, but usually occur at sites of low bone mass and are related to a fall or injury. A fragility fracture is a fracture occurring from trauma that usually would not cause a fracture or from a force less than or equal to that resulting from a fall from standing height. Common sites of fractures are the vertebral bodies (vertebral compression fracture), proximal femur (hip fracture), and distal forearm (Colles’ fracture). Vertebral compression fractures are diagnosed by a 15% to 20% reduction in anterior, mid, or posterior vertebral body height. Possible adverse effects related to vertebral fractures include loss of height, kyphosis, crowding of internal organs, back pain (acute and chronic), prolonged disability, and increased mortality. Hip fractures are the most serious complication of osteoporosis, resulting in pain, disability, and greatly increased mortality. Among women with hip fractures, approximately 25% die within 1 year, greater than 50% spend time in a nursing home, and 90% are no longer able to climb stairs independently. The risk of fracturing the opposite hip is approximately 30%.
110
PHYSIOLOGY Bone remodeling is the ongoing process of bone formation and breakdown (resorption) necessary for the skeleton to provide optimal support and for the repair of damage occurring from daily activities. During childhood and adolescence, bone formation predominates, and bone mass gradually increases. Peak bone mass is achieved by 30 years of age in men and women. Peak bone mass is determined by multiple factors, including genetics (50-80% contribution), nutrition, physical activity, health, and sex hormones. In healthy young adults, the bone remodeling process is in balance, and bone density remains stable. The highest rate of calcium accrual occurs at age 12 to 13 years in girls, and many do not achieve their predicted peak bone mass because of an increase in the incidence of calcium and vitamin D deficiency in children. With menopause and aging, bone resorption occurs at a greater rate than bone formation, and a loss in bone density occurs. An accelerated decline in bone density of 1% to 3% loss per year is seen for the first 5 to 10 years after menopause and tapers to approximately 0.75% per year in the elderly. Risk factors for developing low bone mass can be categorized as modifiable or nonmodifiable (Table 8-1). Although nonmodifiable risk factors, such as
Osteoporosis and Bone Metabolism Table 8-1 Modifiable and Nonmodifiable Risk Factors for Low Bone Mass
Modifiable Risk Factors
Nonmodifiable Risk Factors
Calcium deficiency (vitamin D deficiency, malabsorption, hypercalciuria) Smoking Low weight (<127 lb) and body mass index Estrogen deficiency (menopause <45 yr, amenorrhea) Alcohol intake (>2 drinks/day) Chronic diseases (see Box 8-1) Medications (see Box 8-2) Low activity level and muscle strength Balance problems Poor vision
Female gender Age >50 yr White race Family history History of prior fracture History of falls Dementia
111
genetic makeup and age, account for most osteoporosis risk, modifiable factors, such as inadequate vitamin D and calcium, smoking, excess alcohol and caffeine intake, and inactivity, should be identified and addressed in all women receiving routine medical care. Multiple medical conditions and medications also have been associated with an increased risk of osteoporosis (Boxes 8-1 and 8-2). Early identification of these risk factors and appropriate intervention can help prevent the development of secondary osteoporosis in these patients. Although BMD is an important predictor of fracture risk, the propensity to fall also contributes markedly to the overall risk of osteoporotic fracture in postmenopausal women. Age is the most powerful risk factor. Despite the exact same bone density measurements, an 85-year-old woman has four times the fracture risk compared with a 65-year-old woman, and hip fracture risk increases more than 10-fold from age 50 to age 70. In women with known osteoporosis, it is important to address other risk factors for falls, including poor eyesight, frailty, alcoholism, balance problems, and dementia.
Box 8-1 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●
Chronic Diseases Associated with an Increased Risk of Osteoporosis
Anorexia/bulimia Celiac sprue Cerebrovascular accident Chronic obstructive pulmonary disease Chronic renal insufficiency Cushing’s syndrome Hyperparathyroidism Hyperthyroidism Hypogonadism Inflammatory bowel disease Liver disease Multiple myeloma Multiple sclerosis Rheumatoid arthritis Type 1 diabetes
Reproductive Endocrinology and Infertility
Box 8-2 ● ● ● ● ● ● ● ● ● ●
Medications Associated with an Increased Risk of Osteoporosis
Aluminum Medroxyprogesterone Glucocorticoids Heparin Immunosuppressants Lithium Phenobarbital Phenytoin Sedatives Supraphysiologic thyroxine replacement
112 CLINICAL PRESENTATION
Osteoporosis is most commonly silent, and the diagnosis is often not made until an individual sustains a fragility fracture. Even when a patient is hospitalized for a fragility fracture, only approximately 25% of patients undergo the appropriate diagnostic evaluation and treatment for osteoporosis. Vertebral fractures may present as an insidious loss of height or as acute and chronic pain associated with a stooped posture. African-American women have a higher bone density than white nonHispanic women throughout their life and experience lower hip fracture rates. Japanese women often have a lower peak bone density than white women, but for unclear reasons, they have a lower hip fracture rate. MexicanAmerican women have bone densities intermediate between those of white non-Hispanic women and African-American women. Limited available information on Native American women suggests they have a lower BMD than white non-Hispanic women.
DIAGNOSTIC TESTING Bone Mineral Density Measurements
Measurement of BMD is integral to the evaluation of osteoporosis and should be performed on all younger postmenopausal women (>50 years) who have risk factors and in all women 65 years old or older (Box 8-3). Several different techniques have been developed for measuring BMD, including dualenergy x-ray absorptiometry (DEXA), quantitative computed tomography (CT), peripheral quantitative CT, single x-ray absorptiometry, quantitative ultrasonography, and radiographic absorptiometry. Measurements of central BMD (hip and spine) done by DEXA and quantitative CT are most sensitive and most useful in the diagnosis of osteoporosis and in assessing a response to treatment. DEXA has become the technical standard for measurement of BMD because of its ability to measure clinically important sites, relative affordability, reproducibility, and low exposure to radiation. Quantitative CT of the spine is measured in three dimensions (g/cm3) rather than in two dimensions. Although most sensitive, its precision may not be as high as DEXA, and it is mainly used as a research tool
Osteoporosis and Bone Metabolism
Box 8-3
National Osteoporosis Guidelines for Bone Density Measurement
All women >65 years old All women with a history of fragility fracture Postmenopausal women <65 years old with at least one risk factor other than menopause or white race Patients receiving glucocorticoids for >3 months Monitoring therapy
because of its high cost (three times the cost of DEXA) and significant radiation. Measurements of peripheral (e.g., forearm, heel) BMD by the other techniques are less sensitive but less expensive and more widely available. Peripheral BMD measurement can be useful in screening for fracture risk when DEXA is unavailable and in low-risk populations. Peripheral measure- 113 ments cannot be used to monitor response to therapy, however, because of lower sensitivity and the small changes seen in peripheral bone density compared with the precision of the device. Until standards of comparability of different devices and sites for assessing fracture are established, DEXA remains the gold standard to confirm the diagnosis of osteoporosis and to monitor the response to treatment. BMD data are reported as T-scores, representing the number of SDs from the normal young adult mean density values; Z-scores, representing the number of SDs from the normal mean value for age-matched and sexmatched control subjects; and absolute BMD (Figs. 8-1 and 8-2). The T-score
Figure 8-1 0
−0.5 −1 −1.5 SD (T-score)
Bone densitometry report: T-score calculation. The T-score represents the number of SDs from the normal young adult mean density value. The T-score predicts fracture risk.
−2 −2.5 T-score = −3.0
−3
X
−3.5 −4 20
30
40
50
60 70 Age (years)
80
90
100
Reproductive Endocrinology and Infertility Figure 8-2
114
0
−0.5 −1 −1.5 SD (Z-score)
Bone densitometry report: Z-score calculation. The Z-score represents the number of SDs from the mean density value for age-matched and sex-matched control subjects. The Z-score predicts likelihood of secondary cause.
−2 −2.5 Z-score = −1.5
−3
X
−3.5 −4 20
30
40
50
60
70
80
90
100
Age (years)
is used to diagnose osteoporosis or osteopenia and is useful in predicting fracture risk. The World Health Organization has defined osteopenia as a T-score of −1 to −2.5 and osteoporosis as a T-score of equal to or less than −2.5 (Box 8-4). These definitions are based on normal values for DEXA hip scores in white postmenopausal women, but have become generalized to other patient groups, including men and nonwhite women. In women older than 60 years of age, fracture risk doubles with each unit decrease in T-score (Fig. 8-3). The presence of a vertebral fracture doubles this risk further. T-scores from peripheral measurements do not correlate well with central DEXA T-scores and should not be used for true World Health Organization classification of osteoporosis or osteopenia. The Z-score compares a patient’s BMD with that of age-matched controls and is useful in identifying patients with abnormally low BMD for their age. Women with Z-scores less than 2 should undergo comprehensive evaluations for secondary causes of bone loss. Premenopausal women with signifi-
Box 8-4 Bone Density Criteria for Diagnosis of Osteoporosis in Postmenopausal Women Normal: T-score >−1.0 Osteopenia: T-score −1.0 to −2.5 Osteoporosis: T-score ≤−2.5 Premenopausal women: not established; use Z-scores
Osteoporosis and Bone Metabolism Figure 8-3 Bone density and fracture risk. The T-score can be used to determine relative fracture risk in women older than 60 years.
16 Osteoporosis 14
Relative fracture risk
12
10
8
6
115
4
2
0 −4
−3
−2 Bone mineral density (T-score)
−1
0
cant underlying medical diseases placing them at high risk for osteoporosis should be diagnosed using a Z-score rather than a T-score. The absolute BMD value is expressed in g/cm2 and can be used to determine whether a change in BMD is likely a true change or due to the precision error of the instrument. The precision error for DEXA equipment is usually approximately 1.5% to 2%. To be confident that a true change in bone mass has occurred, the change must be greater than 2.5 times the precision error, which often translates into a 3% to 4% change overall. If possible, serial measurements over time are most accurately assessed using the same DEXA machine.
Bone Turnover Markers
Bone turnover markers provide useful information in identifying patients with high bone turnover and evaluating response to treatment. These markers cannot replace BMD measurements, however, and do not make a diagnosis of osteoporosis. Bone formation can be assessed by measurement of serum bone-specific alkaline phosphatase, serum osteocalcin, and serum procollagen I extension peptides. Bone resorption can be assessed through measurement of urinary and serum N-telopeptides, collagen crosslinks, and urinary deoxypyridinoline and hydroxyproline. A therapy-induced decrease in bone resorption markers can indicate response to therapy even before significant changes in BMD are observed. A patient with osteopenia by DEXA and increased resorption markers seems to have a higher likelihood of developing more rapid bone loss over time, but there are inadequate fracture data to recommend the use of bone markers in routine clinical practice at this time.
Reproductive Endocrinology and Infertility
SCREENING
116
The most significant barrier to osteoporotic fracture risk reduction is the failure of primary and specialty care physicians to implement screening in appropriate populations. Fewer than 30% of “high-risk” women receive bone density testing, and fewer than 2% of women older than 60 years of age were diagnosed by their primary care physicians with osteoporosis (although the expected prevalence is approximately 20-30%). The National Osteoporosis Foundation recommends BMD testing for all women age 65 and older regardless of risk factors, younger postmenopausal women with one or more risk factors (other than being white, postmenopausal, and female), and postmenopausal women who present with fractures (to confirm diagnosis and determine disease severity). In addition, BMD can be useful when monitoring therapy to ensure that there is no decrease in BMD (see Box 8-3). Women receiving hormone replacement therapy should be followed especially closely because 25% have a decrease in bone density on therapy. Measurement of BMD also should be considered when it might help the patient to decide whether to institute a treatment that might prevent a fracture. Age is the most powerful risk factor for fracture and is the reason that screening strategies prioritize obtaining bone density measurements for women older than 60 to 65 years of age. Screening 10,000 women age 70 to 74 would result in identifying 2025 women with T-scores of −2.5, and the number needed to treat to prevent one hip fracture is 51. Screening the same number of women age 55 to 59 would result in identifying 445 women with T-scores of −2.5, and the number needed to treat to prevent one hip fracture is 193. Owing to a paucity of prospective trials on screening and treatment in premenopausal women and the rarity of fragility fractures, bone density measurements should be reserved for premenopausal women who have high-risk medical conditions (including amenorrhea) or who are taking medications associated with bone loss. Changes in postmenopausal bone density occur first at the spine as a result of the high metabolic activity of vertebral trabecular bone. To detect early postmenopausal changes in bone loss, central spine bone density is most sensitive until about age 65 years, when degenerative joint disease can falsely elevate the measurement. Given that a spine bone density can overestimate bone mass after age 65 years, it should not be used as the sole site for screening in this age group. Hyperparathyroidism may affect cortical bone before trabecular bone, and a wrist DEXA is the most sensitive measurement in this subset of patients at a high risk for osteoporosis. A low central or peripheral bone density predicts risk of fracture at other sites. However, low BMD of the hip is the best predictor of future hip fracture. Screening should be done with DEXA of the spine and hip, unless this technique is unavailable. Peripheral BMD measurement can be used to screen low-risk populations for fracture risk, but should not be used in the high-risk groups mentioned previously or to diagnose osteoporosis. Women with normal peripheral BMD still should be considered for follow-up central DEXA if they have significant risk factors (Box 8-5).
Osteoporosis and Bone Metabolism
Box 8-5 Who Should Have a Central Measurement with Normal Peripheral Bone Density ● ● ● ● ●
Postmenopausal women >65 years old not on estrogen replacement therapy who would consider treatment Women with history of fragility fractures Women with two or more risk factors for bone loss other than menopause Women with medical conditions associated with bone loss Women taking medications that cause bone loss
EVALUATION All women with postmenopausal osteoporosis should have an evaluation to exclude other common causes of low BMD (e.g., vitamin D deficiency, hyper117 thyroidism, or hyperparathyroidism) and to detect coexisting medical conditions or factors contributing to low BMD. Secondary causes of decreased BMD include endocrine disorders, medications, immobilization, renal failure, and malignancy (see Table 8-1). Osteomalacia is a condition of defective mineralization of mature bone that occurs in adults when insufficient calcium or phosphorus is available for the formation of the primary bone mineral hydroxyapatite; this results in inadequate or delayed mineralization of newly formed osteoid (bone protein matrix). Rickets is the same process, but it occurs in immature bone in children. Rickets causes defective mineralization in the bones and in the cartilage of epiphyseal growth plates, resulting in growth retardation and skeletal deformities not seen in osteomalacia. More than 50 different diseases and conditions associated with abnormal vitamin D metabolism or action or abnormalities of phosphorus may result in osteomalacia or rickets. Vitamin D deficiency is extremely common in the outpatient and inpatient populations and occurs in 50% of patients on medical wards and 80% in nursing homes.
SECONDARY CAUSES OF OSTEOPOROSIS Secondary causes are present in more than 50% of cases of perimenopausal osteoporosis and should be sought in patients with a T-score less than −2.5 and especially in patients with a Z-score less than −2.0. Before osteoporosis treatment, the following conditions should be ruled out: idiopathic hypercalciuria, hyperparathyroidism, hyperthyroidism, premature hypogonadism, low vitamin D levels or calcium malabsorption, and chronic medical conditions or medications that can cause osteoporosis. Minimum laboratory studies should include calcium and phosphorus (to evaluate for hyperparathyroidism or severe vitamin D deficiency), alkaline phosphatase (to determine increased bone turnover or metastatic disease), serum creatinine (to screen for renal failure), thyrotropin (to rule out hyperthyroidism), and a complete blood count and erythrocyte sedimentation rate to screen for malignancy (Box 8-6). In younger patients with limited sun exposure
Reproductive Endocrinology and Infertility
Box 8-6
Evaluation for Postmenopausal Osteoporosis
Serum laboratory values, including calcium, phosphorus, alkaline phosphatase, creatinine, thyrotropin, complete blood count, PTH Consider 25-hydroxyvitamin D and serum protein electrophoresis for older women Consider 24-hour urine for calcium and creatinine Lateral spine films if any history of height loss
118
and poor nutrition and in all older patients, a 25-hydroxyvitamin D level should be checked. A 24-hour urine is extremely useful to rule out hypercalciuria (which can occur in approximately 10% of patients with secondary causes and is effectively treated with hydrochlorothiazide diuretics), hyperparathyroidism (normal to high 24-hour calcium excretion), and vitamin D deficiency (low 24-hour calcium excretion). For patients with unexplained vitamin D deficiency, consideration should be given to rule out celiac sprue, especially in patients with affected first-degree relatives, patients with type 1 diabetes, patients with hypothyroidism, and any patient with weight loss or diarrhea. Older patients with unexplained osteoporosis should have a serum protein electrophoresis study to rule out multiple myeloma. Women who could be perimenopausal may benefit from having folliclestimulating hormone and estradiol levels ordered because estradiol levels less than 30 to 50 pg/mL place women at risk for estrogen deficiency–related bone loss. Estradiol levels may decrease below this level even before menses ceases in perimenopausal women and before hot flashes occur in women with a hysterectomy. Women with estradiol levels less than 5 pg/mL have a seven to eight times increased risk of hip and spine fracture. The most common offending medications causing osteoporosis include excess thyroid hormone supplementation, anticonvulsants, glucocorticoid therapy, and immunosuppressant agents (see Box 8-2). Even subclinical hyperthyroidism (suppressed thyrotropin but normal levels of thyroid hormones) can cause postmenopausal osteoporosis. Glucocorticoids are potent direct antiresorptive agents and cause calcium wasting and decreased calcium absorption. Patients treated with only 10 mg of prednisone for 20 weeks experienced an 8% loss of spine bone density. Many experts suggest that any patient receiving the daily equivalent of 5 mg of prednisone for more than 3 months is at high risk for excessive bone loss. Lateral spine films should be obtained to rule out asymptomatic vertebral fractures in patients with height loss. More than 50% of vertebral fractures are asymptomatic. The presence of a vertebral fracture is sufficient to diagnose osteoporosis regardless of T-score value. Bone remodeling markers may be useful to determine whether a patient has “high turnover” or “low turnover” osteoporosis and possibly for monitoring the effectiveness of antiresorptive therapy. Bone resorption can be assessed through measurement of urine N-telopeptides and C-telopeptides, which are collagen degradation products of osteoclasts. Urine crosslinked deoxypyridinoline can be collected at the same time that calcium excretion is evaluated to rule out hyperparathyroidism, hypercalciuria, or vitamin D deficiency.
Osteoporosis and Bone Metabolism
High-turnover osteoporosis (high bone resorption with normal or high bone formation) is found in one third of patients and seems to be a risk factor for fractures independent of bone density compared with low turnover osteoporosis (low-normal or low bone resorption with low bone formation). Highturnover osteoporosis is associated with a rapid bone loss of 3% to 5% per year and may result in increased bone fragility independent of bone mass owing to an increase in resorptive depth of individual bone remodeling units, with disruption of the trabecular framework. High-turnover osteoporosis may be more responsive to antiresorptive treatment than low-turnover osteoporosis. In patients with suspected osteomalacia, the disease can be confirmed with a bone biopsy using tetracycline labeling. Histologic features of osteomalacia include wide osteoid seams and an increased mineralization lag time (time necessary for newly deposited matrix to mineralize). Mineralization lag time is assessed by administering two short courses of tetracycline several weeks 119 apart and measuring the distance between the two tetracycline-labeled mineralization fronts in the biopsy specimen.
PREVENTION AND TREATMENT Prevention of Osteoporosis and Bone Fracture
The National Osteoporosis Foundation recommends several interventions to reduce fracture risk in the general population, including adequate calcium and vitamin D intake, regular weight-bearing exercise, fall prevention, and avoidance of tobacco use and alcohol abuse. All individuals should be advised to obtain at least 1200 mg/day of calcium and 400 to 800 IU/day of vitamin D. Adequate calcium intake during the first 2 decades of life is essential for the acquisition of peak bone mass. In addition, continued adequate calcium intake after peak bone mass is achieved is necessary to prevent accelerated bone resorption. Postmenopausal women should receive at least 1500 mg/ day of calcium, including supplements if necessary, and 400 to 800 IU/day of vitamin D. Adequate calcium and vitamin D therapy can prevent secondary hyperparathyroidism and the accelerated resorption that occurs in this condition. Elderly women are at increased risk of vitamin D deficiency because of low sunlight exposure, decreased skin synthesis of vitamin D, and low vitamin D intake. Randomized controlled trials have shown that therapy with 800 IU of vitamin D and 1200 mg of calcium decreased hip fractures in elderly women, many of whom had vitamin D levels less than 15 ng/mL. Calcium is present in a variety of foods, but the major bioavailable sources are dairy products and calcium-fortified drinks. Increasing the consumption of low-fat dairy products is the safest way to increase calcium intake without increasing the risk of kidney stones. The approximate calcium content of 1 oz of cheese or 8 oz of milk, yogurt, or fruit juice with calcium is 200 to 300 mg (Box 8-7). These sources along with 300 mg of calcium from the nondairy diet (owing to small amounts of calcium in an assortment of foods) give a reasonable estimate of dietary calcium intake. The chief dietary sources of vitamin D are vitamin D–fortified milk (400 IU per quart) and cereals (40-50 IU per serving).
Reproductive Endocrinology and Infertility
Box 8-7
Calcium Content of Foods
1 cup milk (125 IU vitamin D) 8 oz yogurt 1 oz cheese ½ cup raw tofu 6 oz calcium-fortified orange juice 1 cup cottage cheese ½ cup broccoli
~300 mg ~300 mg ~200 mg ~250 mg ~200 mg ~125 mg ~35 mg
All women should be encouraged to participate in weight-bearing exercises and muscle-strengthening exercises. Bone is a dynamic tissue, which is constantly being formed and resorbed. Weight-bearing exercise stimulates the accrual of bone mineral content in the skeleton. In addition, exercise can decrease fall risk by improving agility, strength, and balance. Sit-ups should be avoided in women with osteoporosis of the spine or vertebral fractures because this type of exercise puts excessive pressure on the anterior vertebral bodies. Preventing osteoporotic fractures depends not only on maintaining BMD but also on fall prevention. Factors that increase the risk of falls (poor eyesight, physical obstacles in the living space, orthostatic hypotension, balance problems, and sedating medications) should be identified and corrected if possible. Also, in frail, elderly women with high risk for fracture, hip protectors (SAFEHIP, HIPS, HipGuard, all from e-pill, B wellestey, MA; ImpactWear, from High Tech Bodywear Lt Auckland, New Zeal) have been shown to decrease hip fractures by approximately 60%. In addition to calcium and vitamin D, several pharmacologic agents have been approved by the U.S. Food and Drug Administration (FDA) for the prevention of osteoporosis, including bisphosphonates, estrogen, and selective estrogen receptor modulators. These agents are discussed subsequently.
120
Indications for Treatment
The National Ambulatory Medical Care Survey found that appropriate therapy for osteoporosis is offered to only approximately one third of all diagnosed patients. Therapy for osteoporosis should be initiated in all postmenopausal women with DEXA T-scores of −2.0 or less (Box 8-8). Women with one or more risk factors for osteoporosis other than menopause should begin treatment when the T-score is equal to or less than −1.5. Therapy for prevention of osteoporosis should be started when the T-score is equal to or less than −1.0 in patients on a glucocorticoid regimen equivalent to 5 mg/ day of prednisone or in patients who will be receiving glucocorticoids for more than 3 months. Women who have sustained a vertebral or hip fracture Box 8-8
When to Initiate Treatment
T-score −2.0 in all postmenopausal women T-score ≥−1.5 with risk factors (other than menopause) T-score ≥−1.0 in patients on steroids or if duration >3 months
Osteoporosis and Bone Metabolism
should be assumed to have osteoporosis and started on treatment regardless of T-score. Some experts would consider initiating pharmacologic intervention in osteopenic women with high rates of bone resorption (as identified by urinary N-telopeptides >1 SD above the limit of normal for the premenopausal population). These women seem to be at risk for losing bone more quickly, and rates of bone loss may not be constant. It is never too late to initiate therapy in a woman with osteoporosis. Bisphosphonate studies show a decrease in hip fracture rate by 18 months after initiation of therapy. Bisphosphonate therapy should be considered in elderly women with osteoporosis as long as life expectancy is more than 2 to 3 years.
Pharmacologic Agents
Therapeutic agents for the prevention and treatment of osteoporosis fall into 121 two main categories: antiresorptive agents, which inhibit bone resorption (including estrogens, bisphosphonates, calcitonin, and raloxifene), and anabolic agents, which stimulate bone formation (including sodium fluoride, androgens, parathyroid hormone [PTH], growth hormone, and growth factors). Antiresorptive agents significantly reduce bone resorption without initially affecting bone formation. As a result, bone formation temporarily exceeds bone resorption, and bone mass increases. This increase in bone mass is greater in patients with high-turnover osteoporosis than in patients with low-turnover osteoporosis. Six to 18 months after the initiation of therapy, bone formation rates gradually decline to the level of resorption, and bone mass stabilizes.
Calcium and Vitamin D As discussed previously, adequate calcium and vitamin D intake is essential for the maintenance of healthy bone. The most common side effects of calcium are intestinal gas and constipation. These problems occur most frequently with calcium carbonate and are less likely with calcium citrate. Calcium and vitamin D therapy can slow down, but not prevent, the progression of cortical bone resorption and does not prevent spine fractures. Calcium and vitamin D therapy should not be used as single therapy in patients with known osteoporosis. Women with documented vitamin D deficiency should be treated with higher doses of vitamin D (ergocalciferol) than that used for prevention or with 25-hydroxyvitamin D (calcifediol) or 1,25-hydroxyvitamin D (calcitriol). Hypercalcemia, hyperphosphatemia, and hypercalciuria can occur unless 25-hydroxyvitamin D levels and 24-hour calcium excretion are carefully monitored. Bisphosphonates Bisphosphonates are currently the first-line therapy for osteoporosis and the most powerful antiresorptive agents. These agents bind to hydroxyapatite at active sites of remodeling on the bone surface and inhibit osteoclastic activity by reducing the production of hydrogen ions and lysosomal enzymes. Bisphosphonates also inhibit the differentiation of osteoclasts and induce osteoclast apoptosis. By reducing the activation frequency
Reproductive Endocrinology and Infertility
122
(rate of formation of bone remodeling units), bisphosphonates reduce the depth of resorption, which may result in improved bone quality and maintenance of BMD. The two oral bisphosphonates currently approved by the FDA for osteoporosis treatment are alendronate (Fosamax) and risedronate (Actonel). Alendronate can be used in doses of 5 mg daily or 35 mg weekly for prevention and 10 mg daily or 70 mg weekly for treatment of osteoporosis. This agent increases bone density by 8% to 9% in the spine and 6% in the femoral neck after 2 years. Alendronate reduces the incidence of spine and hip fracture by about 50% over 3 years in patients with or without prior fractures. Risedronate is approved for the prevention and treatment of osteoporosis at doses of 5 mg daily and 35 mg weekly and has been shown to increase BMD by 6% in the spine and 5% in the femoral neck over 2 years. Risedronate has fracture data comparable to that of alendronate, with a reduced incidence of spine and hip fractures by 40% to 50%. Alendronate and risedronate are approved for treatment of steroid-induced osteoporosis and decrease vertebral fractures by 60% to 70% after 2 years of treatment in patients receiving long-term steroids. Because of their poor intestinal absorption and potential for gastrointestinal toxicity, alendronate and risedronate must be given on an empty stomach, first thing in the morning, with 8 oz of water and with the patient remaining upright for at least 30 minutes after the dose. Large clinical trials have failed to show an increased incidence of side effects in patients treated with alendronate or risedronate compared with placebo. Clinical experience suggests, however, that these drugs may cause some gastrointestinal symptoms, including heartburn, indigestion, and rarely esophageal ulceration or bleeding. Once-weekly administration of either agent results in similar bone density increases with fewer gastrointestinal side effects. Patients who are unable to tolerate treatment with oral bisphosphonates or who are unable to absorb oral bisphosphonates because of gastrointestinal disease can be considered for treatment with an intravenous bisphosphonate. Currently available intravenous bisphosphonates are pamidronate (Aredia) and zoledronic acid (Zometa). These agents have not been approved by the FDA for prevention or treatment of osteoporosis and are currently used “off label” when necessary. Pamidronate can be given by intravenous infusion, 30 mg over 2 hours, followed by a 30-mg infusion every third month. Zoledronic acid, when given at a dose of 2 mg every 6 months or 4 mg every year, increased bone density in the spine by approximately 5%, but there are fewer data compared with pamidronate. Patients should be given 1000 mg of calcium at the beginning of the intravenous infusion because of the hypocalcemic effect of these drugs. The duration of therapy for bisphosphonates is a subject of ongoing study. Stable bone markers and bone density persist at least for 2 years in postmenopausal women. A study showed, however, that discontinuation of alendronate after 5 years resulted in a loss of bone density at years 6 to 10 associated with an increase in bone resorptive markers compared with women who remained on the bisphosphonate for 10 years. Until more definitive studies are available, bisphosphonates probably should be continued
Osteoporosis and Bone Metabolism
indefinitely unless financial concerns are prohibitive. If bisphosphonates are discontinued after 5 years of therapy, bone resorption markers and bone density should be monitored, and if these are increased, therapy should be reinstituted.
Estrogens Estrogens probably inhibit osteoclastic bone resorption by inhibiting cytokines, which activate and promote the growth of osteoclasts or alter the expression of molecules directly involved in osteoclast differentiation. Estrogen in oral, transdermal, and combined estrogen/progesterone (hormone replacement therapy) formulations are FDA approved for the prevention of bone loss in recently menopausal women. The usual dose of conjugated estrogens prescribed for prevention of osteoporosis is 0.625 mg daily, but lower doses also may be effective. 123 The Women’s Health Initiative, a prospective, randomized, double-blind, placebo-controlled trial that studied more than 16,000 postmenopausal women, showed a 34% reduction in vertebral and hip fractures after 5 years of hormone replacement therapy (specifically, conjugated equine estrogen, 0.625 mg, plus medroxyprogesterone acetate, 2.5 mg daily [Prempro]). Clinical experience has shown, however, that approximately 25% of women on estrogen or hormone replacement therapy still sustain an osteoporotic fracture. The Women’s Health Initiative also reported an increased risk of myocardial infarction, stroke, pulmonary emboli, and breast cancer in women treated with Prempro. Although the absolute number of women affected was small, these results have led most expert panels to recommend that the use of estrogen and hormone replacement therapy be limited to the lowest possible doses for the shortest possible duration necessary to control hot flashes. Estrogen should not be used in patients with breast cancer or in patients with thrombophlebitis or thromboembolic disease. It also is recommended that other approved nonestrogen agents be considered first before starting women on estrogen or hormone replacement therapy solely for the purpose of treating osteoporosis. Phytoestrogens Phytoestrogens are mixed estrogen agonists and antagonists consisting of more than 20 different compounds found in parsley, garlic, soybeans, wheat, rice, dates, pomegranate, cherries, coffee, and many herbs. Phytoestrogens are usually much weaker than natural estrogens, are easily broken down, and are not stored in the tissues. No reduction in fractures has ever been documented with the use of phytoestrogens. Isoflavonoids are a class of soybean-based foods that have estrogen-like activity. One small study of 56 women less than 5 years postmenopausal with low BMD showed no loss of BMD (0.4% increase versus a 5% loss in the placebo group) in women treated with ipriflavone (a synthetic derivative of a natural isoflavone). Many early menopausal women lose bone density despite treatment with phytoestrogens. The effects of phytoestrogens on the uterus, heart, brain, and breast are still unknown.
Reproductive Endocrinology and Infertility
124
Selective Estrogen Receptor Modulators Selective estrogen receptor modulators work by binding to the estrogen receptors in target organs and have estrogen agonist effects in some tissues, but estrogen antagonist effects in other tissues. Raloxifene (Evista) has been approved by the FDA for the prevention and treatment of postmenopausal osteoporosis. This agent has been shown to decrease vertebral fractures by about 40% after 3 years of treatment in women with and without prior vertebral fracture. At 3 years, raloxifene increased BMD in the spine by 2.6% and in the femoral neck by 2.1%. Raloxifene also has been found to reduce bone turnover markers to premenopausal levels. No hip fracture data are available yet. Raloxifene should be given as 60 mg daily for the treatment of osteoporosis. Minor side effects attributed to raloxifene include hot flashes, leg cramps, and peripheral edema. In contrast to estrogen, which may increase breast cancer risk, raloxifene has been shown to decrease the incidence of breast cancer and can be considered for patients who wish to stop hormone replacement therapy because of concern for breast cancer. The same thromboembolic risk of estrogen has been observed with raloxifene, and cardiovascular disease end points currently are being studied. Calcitonin Salmon calcitonin (Miacalcin) works by inhibiting osteoclastic bone resorption and is FDA approved for the treatment of osteoporosis in women who are postmenopausal. It is available as an intranasal spray (200 IU [one spray] daily) and a subcutaneous or intramuscular injection (100 IU/every other day). Several prospective, randomized, double-blind, placebo-controlled trials have shown the injectable formulation of calcitonin to increase BMD modestly, but there are no fracture data. The 200-IU intranasal formulation of calcitonin decreased vertebral fractures by approximately 40%, although bone density did not significantly change. There was no dose-response relationship, and no such benefit was seen with either the 100-IU or 400-IU dose. Studies have not yet been done to look at the effect of intranasal calcitonin on hip or other nonvertebral fractures, and the preparation should be considered a third-line treatment. Combination Therapy Small additional increments in bone density occur (1-3%) when bisphosphonates are combined with estrogen or raloxifene, but the effects are not additive or synergistic. When bone turnover is normalized by one antiresorptive drug, there is little left for an additional agent to accomplish. Whether the small increases in bone density translate to any fracture benefit is unproven. It is unclear whether further suppression of bone remodeling is beneficial, or whether this promotes or harms bone health. Combining a bisphosphonate with an anabolic agent (PTH) is not recommended because of what seems to be a blunting of the bone formation effect when given simultaneously. Parathyroid Hormone Recombinant human PTH (teriparatide) is the only anabolic agent approved by the FDA for the treatment of osteoporosis in postmenopausal women.
Osteoporosis and Bone Metabolism
PTH stimulates bone resorption and bone formation, but when given as daily injections its effect on bone formation is greater than that on bone resorption, resulting in significant increases in BMD. Teriparatide (Fortéo) is given in a daily dose of 20 μg injected subcutaneously and is supplied in a disposable multiple-dose pen device, which holds 28 doses of the drug. Teriparatide given at the approved therapeutic dose has been shown to decrease the risk of vertebral fractures by 65% and of nonvertebral fractures by 53% in postmenopausal women treated for 19 months. Spine bone density increased by 9% and hip bone density by 3%. Mild side effects, including nausea and orthostatic hypotension, have been observed with teriparatide treatment. These side effects tend to occur only with the first few doses of the drug and do not usually require the discontinuation of therapy. Transient asymptomatic calcium elevations also have been observed. Teriparatide caused an increased incidence of osteosarcoma when studied 125 in rats, although this complication has not been seen in humans. Because of this observation, the use of teriparatide is contraindicated in patients at increased risk of osteosarcoma, including patients with Paget’s disease, open epiphyses, bone metastases, hypercalcemia, a history of radiation therapy to the skeleton, or an elevation in bone-specific alkaline phosphatase. Teriparatide is approved by the FDA for individuals at “high risk” for fracture and in patients who fail to respond to antiresorptive therapy for 2 years or more. It was shown in two trials that combining PTH with alendronate was inferior to using PTH alone to increase the density of the trabecular bone at the spine. Alendronate seemed to impair the ability of PTH to induce bone formation by decreasing bone turnover. If teriparatide is used, all antiresorptive agents, including bisphosphonates, should be discontinued before starting therapy.
Monitoring Treatment
It is recommended to assess the response to therapy by repeating central BMD measurements every 1 to 2 years. Because the average increase in BMD in the spine is 5% to 8% and only modestly exceeds the smallest change between two measurements that can be detected in individual subjects (3-4%), many patients seem to have no appreciable increase in bone density with treatment. No appreciable response is usually seen in the proximal femur. BMD in patients using bisphosphonates did not predict fracture prevention. Patients who seemed to lose bone density in the first year after alendronate therapy still had a 48% lower fracture rate and often gained it in the second year. Patients who gain bone density in the first 2 years usually have no further significant increase, and bone density remains stable over subsequent years. Patients who do not show an increase in bone density on bisphosphonates should not be considered nonresponders. Not observing a response is not indicative of treatment failure, but compliance should be questioned, and a search for metabolic factors that could impair the response should be considered (Box 8-9). In addition to noncompliance, the most common underlying disorder not initially identified is vitamin D deficiency resulting in secondary hyperparathyroidism. It may be useful to obtain a 24-hour urine for
Reproductive Endocrinology and Infertility
Box 8-9
Osteoporosis Treatment Failures
Taking medication improperly Poor compliance with medication Underlying disorder not identified Secondary hyperparathyroidism from vitamin D deficiency Patient is actually responding (regression to the mean)
calcium and bone resorption markers. If the 24-hour urine shows hypocalciuria, inadequate calcium and vitamin D should be suspected. If the calcium excretion is normal, but bone resorption markers are not suppressed, the possibility of other metabolic conditions or drug noncompliance should be re-examined. BMD should not be measured more frequently than every 1 to 2 years except in patients on glucocorticoids, who are likely to have significant changes in 6 months. Urinary markers of bone resorption may be useful in evaluating the response to antiresorptive therapy 3 to 6 months after treatment. Bone resorptive markers should decrease by greater than 30% compared with baseline or to within the premenopausal reference range. Because of the precision errors of the markers, however, the study may need to be repeated before concluding a nonresponse.
126
SUMMARY OF KEY POINTS 1. 2. 3.
4.
5. 6. 7.
8.
Age is a more powerful risk factor for fracture than bone density. Approximately 50% of perimenopausal women with osteoporosis have underlying secondary causes. Approximately 50% of vertebral fractures are asymptomatic, but their occurrence doubles the risk of sustaining a hip fracture and increases mortality by eightfold. Vitamin D deficiency resulting in secondary hyperparathyroidism is a common cause of bone loss in older women or an inadequate response to therapy. Bisphosphonates are the most powerful antiresorptive agents currently available. Combination therapy with two antiresorptive agents results in only a modest increase in bone density. An absence of change in bone density after 1 to 2 years of treatment with an antiresorptive agent does not indicate a lack of response to therapy. Teriparatide (PTH) is the first anabolic agent to be FDA approved, but it should not be combined with an antiresorptive agent.
Osteoporosis and Bone Metabolism
SUGGESTED READINGS American Association of Clinical Endocrinologists (AACE) Osteoporosis Task Force: American Association of Clinical Endocrinologists medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis: 2001 edition, with selected updates for 2003. Endocr Practice 2003;9:545-563. Black DM, Greenspan SL, Ensrud KE: The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 2003;349:1207-1215. Bone HG, Hosking D, Devogelaer JP: Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 2004;350: 1189-1199. Evio S, Titinen A, Laitinen K, et al: Effects of alendronate and hormone replacement therapy, alone and
in combination, on bone mass and markers of bone turnover in elderly women with osteoporosis. J Clin Endocrinol Metab 2004;89:626-631. Hodsman AB, Hanley DA, Ettinger MP: Efficacy and safety of human parathyroid hormone-(1-84) in increasing bone mineral density in postmenopausal osteoporosis. J Clin Endocrinol Metab 2003;88:5212-5220. McClung MR: Bisphosphonates. Endocrinol Metab Clin N Am 2003;32:253-271. National Institutes of Health: Osteoporosis, prevention, diagnosis, and therapy. NIH Consensus statement, vol 17, no 1; March 27-29, 2000. Simon JA: Osteoporosis. ACOG practice bulletin, no 127 50; January 2004. Stein E, Shane E: Secondary osteoporosis. Endocrinol Metab Clin N Am 2003;32:115-134.
9 HUMAN SEXUALITY William D. Petok DEFINITIONS Sex
Males Females Gender
Gender identity
A fundamental difference to distinguish is between sex and gender. Sex can refer to a physical activity and to physical characteristics. The latter definition often is confused with gender or the sense of maleness or femaleness that individuals experience. With regard to physical characteristics, sex is the anatomic and physiologic difference between males and females. The genome for most males contains an X and a Y chromosome. Females have two X chromosomes. Gender is perceived on an internal level and is the combination of socially learned behavior, meanings, and cues that are a reflection of society’s notion of masculine and feminine. Gender is the biologic sex and the more subjective sense one has of being either masculine or feminine. Because the male sex is defined by physical characteristics such as penile development, and male gender is defined by social and psychological issues, there is room for confusion. On a psychological level, an individual’s gender identity is the individual’s subjective perception of maleness and femaleness. Consequently, an individual’s gender identity is psychological in nature. A physiologic male can perceive himself as female and vice versa.
Sexual function is an important component of the lives of most adults. Generally, sexual activity serves three primary purposes: procreation, relationship enhancement, and pleasure. Members of each gender seem to differ in what is most important to them in their sexual relationships. Men seem to value the physical release component of sex, whereas women tend to desire intimacy as the end goal. Although the differences are obvious, many couples are capable of integrating them into mutually satisfying interactions and find great comfort and pleasure in their sexual interactions. Sex is not one-dimensional and comprises more than intercourse leading to orgasm. A wide variety of behaviors, which include tactile stimulation of many erogenous zones on the body, kissing, and loving words, are included in sexual activity. All of these activities can lead to sexual satisfaction.
129
Reproductive Endocrinology and Infertility
SEXUAL ANATOMY Male external reproductive organs consist of the penis, scrotum, and testes (Fig. 9-1). The penis is composed of two parts: the shaft and the glans. The glans is highly enervated and is very sensitive to tactile stimulation. Uncircumcised men have a prepuce or foreskin that covers a portion of the glans. The prepuce retracts when the penis becomes erect. The penis is composed of three cylindrical bodies that allow for erection. The two corpora cavernosa are located dorsally. They are surrounded by a sheathlike membrane, the tunica albuginea. The third body, the corpus spongiosum, lies on the ventral plane and contains the urethra. Vasocongestion, the result of physical or psychological stimulation or both, occurs rapidly. As the erectile tissue expands, it presses against the tunica albuginea and mechanically prevents outflow of blood through veins and capillaries. Erections are maintained as long as the smooth muscles surrounding the corpora cavernosa remain relaxed, keeping blood trapped within. The scrotum, a thin sack of skin, forms a pouch that contains the testes. The outer layer of skin is darker than the body and contains sweat glands. The inner layer is composed of involuntary muscle that contracts with sexual excitement, cold weather, or exercise. The muscle layer relaxes when the body becomes hot. This relaxing and contracting function allows for temperature regulation of the testes and protects sperm, which are sensitive to extreme temperature change. The scrotal sac is partitioned into two components, which each contains a testis, epididymis, and spermatic cord. The cord supports the testis and con-
130
Figure 9-1
Seminal vesicle
Male genitalia. (From Lauver D, Welch MB: A biopsychosocial approach to sexuality. In Fogel CI, Lauver D [eds]: Sexual Health Promotion. Philadelphia: WB Saunders; 1990:41.)
Rectum
Ureter Bladder
Ejaculatory duct
Urethra Vas deferens Corpus cavernosum Corpus spongiosum
Prostate Epididymis
Pupuce (foreskin) Scrotum
Testis
Penile bulb
Bulbourethral gland (Cowper’s gland)
Human Sexuality
tains the vas deferens, blood vessels, nerves, and muscle fiber. The vas deferens provides the duct for sperm delivery from the scrotum to the ejaculatory duct. In addition to sperm production, the testes are responsible for secretion of testosterone, made in Leydig cells. These bodies are located between the seminiferous tubules in the scrotum. Three additional organs are important to male sexual functioning: the prostate, seminal vesicles, and Cowper’s glands. The prostate produces alkaline prostatic fluid, which composes 20% of ejaculate. Sperm are protected from the acidity of the vagina by this fluid. Sixty percent of the ejaculate is seminal fluid produced in the seminal vesicles, which join at the vas deferens to form the ejaculatory duct. Contained in the seminal fluid are prostaglandins that may stimulate uterine contractions and subsequent migration of the sperm to the fallopian tubes. Cowper’s glands, located inferior to the prostate, secrete a small amount of pre-ejaculatory fluid that is also alkaline 131 in nature. This fluid protects sperm from the acidity of the urethra. Female external sexual organs include the vulva comprising the mons pubis, labia majora and minora, vaginal orifice, and clitoris (Fig. 9-2). The mons pubis is a fatty tissue that becomes more pronounced with puberty. It provides some cushioning during the thrusting of intercourse. Sensitive to pressure and touch, stimulation of this area can be very arousing for some women. Labia majora cover the outer entrance to the vagina. Sweat and sebaceous glands cover their lateral and medial surfaces. The labia majora provide a protective covering for the urethra and vagina. Interior to and between the labia majora are the labia minora. At their anterior aspect, they join to form the clitoral hood. Posterior and slightly deeper is the frenulum or lower fold of the clitoris. The labia minora also cover the urethral opening, vaginal opening, and openings of Bartholin’s glands. The sebaceous glands contained on them provide some lubrication. Highly vascularized and containing many tactile nerve endings, the labia minora are very sensitive. The clitoris, from the Greek for “key,” is an extremely erotic area for women. Composed of a body and a glans, it is ½ to 1 inch long. Similar to the penis, it is composed of erectile tissue and is richly vascularized and innervated. The only known function of the clitoris is to provide sexual pleasure. At the entrance to the vaginal opening is the hymen. Normally perforated to allow for menses, the hymen can be visualized as an irregular fold around the introitus. It serves no physiologic purpose. It can be broken during vigorous exercise or remain intact even with intercourse. Much cultural and emotional importance has been attached to an intact hymen. The belief that a woman with a torn hymen must not be a virgin is false. Two sets of glands are contained in the female genitalia: Bartholin’s and Skene’s glands. Bartholin’s glands, located at the posterior surface of the vaginal introitus, are analogous to Cowper’s glands in the male. They secrete a drop or two of fluid when a woman is sexually aroused, slightly moistening the labia. Skene’s glands are located on either side of the urethra. Skene’s glands can vary in size from woman to woman. Fluid released by Skene’s glands has been described as analogous to prostatic fluid and seems to be similar in chemical makeup. Some believe that release of this fluid occurs during
Reproductive Endocrinology and Infertility Figure 9-2 A and B, Female genitalia. (From Lauver D, Welch MB: A biopsychosocial approach to sexuality. In Fogel CI, Lauver D [eds]: Sexual Health Promotion. Philadelphia: WB Saunders; 1990:431.)
A
Mons pubis Clitoral shaft Clitoral hood
Urethra
Clitoral head (glans)
Skene’s glands
Labium majus
132
Location of Bartholin’s glands
Labium minus Vagina
Perineum
Hymenal caruncles
Anus
B Urethra Position of Skene’s glands Vagina
Rectum
female ejaculation, a controversial topic. No other known purpose for Skene’s glands exists. Internal female reproductive organs consist of the ovaries, fallopian tubes, uterus, and vagina. The vagina is the conduit between the internal and external structures. With sexual excitement, the walls of the vagina become distended. Its length and diameter can increase 50% during arousal. A multilayer structure, the vagina’s inner layer is mucosal in nature and
Human Sexuality
well supplied with blood and is affected by hormonal levels. The lining thins dramatically with the onset of menopause and can become a source of pain during intercourse. The middle layer is musculature and allows for expansion and contraction that occur with childbirth. Pubococcygeal muscles circle the outer one third to one half of the vagina. The inner two thirds contain a limited amount of tactile receptors and are more sensitive to pressure. The outermost layer is thin mucosa. The entire vagina is lined with squamous epithelium cells that are the source of vaginal lubrication or transudate. Internal female reproductive structures include two ovaries that are responsible for producing ova and estrogen and progesterone. Testosterone also is produced in the ovaries and the adrenal glands. The fallopian tubes, although essential for conception, have nothing to do with the pleasure component of sexual behavior. The uterus can experience contractions during orgasm. Otherwise, its role 133 in sexual expression is physiologically negligible. Psychologically and sociologically, the uterus can carry great importance because of its association with the onset of reproductive sexuality via menstruation and pregnancy.
SEXUAL RESPONSE Masters and Johnson’s Sexual Response Cycle
According to Masters and Johnson, human sexual response proceeds in an invariable linear fashion. Although the assumptions, sampling variables, and other components of their research have been criticized, it remains groundbreaking in nature and provides the first scientific data on sexual response. Four stages of the response cycle are described for men and women. The typical pattern of male response is shown in Figure 9-3. Female response shows greater variability than male response. Examples are shown in Figure 9-4. Excitement is characterized by the onset of erotic feeling (erection in men and vaginal lubrication in women); sexual tension, which also is characterized by vasocongestion and myotonia; increased respiration rate; increased heart rate; blood pressure elevation; and certain changes in skin coloring. This skin response, called mottling, is often observed more easily in women than in men. In addition, female breasts swell, and nipples become erect. Men also can experience nipple erection. Some women also experience a
Figure 9-3 Orgasm Refractory period
Plateau
n lutio
ion olut R es
Excitement
Refractory period
o Res
The male sexual response cycle per Masters and Johnson. (From Masters W, Johnson V: Human Sexual Response. Boston: Little, Brown; 1966:5.
Reproductive Endocrinology and Infertility Figure 9-4 The female sexual response cycle per Masters and Johnson. (From Masters W, Johnson V: Human Sexual Response. Boston: Little, Brown; 1966:5.
Orgasm
Plateau
Re
so
s ol u Re
tion
Resolutio
Excitement
lut
ion
(B)
n
134 A B C
(C)
(A)
clitoral erection from vasocongestion within this structure. In preparation for coitus, several pelvic changes take place. The uterus becomes enlarged and begins to rise from its resting position on the pelvic floor, and the vagina enlarges to accept an erect penis more easily. Vaginal lubrication, a distinct sign of female response, results from a transudate, caused by vascular engorgement of the vaginal walls. Transudate typically forms within 10 to 30 seconds after the onset of sexual stimulation. Additional changes in men include elevation and swelling of the testicles, tightening of the scrotal sac, and secretion of a lubricating liquid by the Cowper’s glands. Plateau, in which the maximum level of arousal is reached, is a misleading label because during this phase the arousal is not continuously high, but fluctuates on the way to orgasm. Vasocongestion peaks in this stage. Maximum genital vasocongestion in the woman causes swelling and deepened coloration in the labia minora, and a thickened plate of congested tissue (the “orgasmic platform”) surrounds the entrance to the lower portion of the vagina; the erect clitoris retracts behind the symphysis pubis just before orgasm. Orgasm is the most intensely pleasurable of the four stages. Involuntary muscle contractions, heightened blood pressure and heart rate, rapid intake of oxygen, and sudden forceful release of sexual tension characterize the orgasmic phase. Male ejaculation consists of two steps. During the first step, or emission, seminal fluid builds up in the urethral bulb of the prostate. As the fluid accumulates, the man senses he is about to ejaculate, sometimes known as the point of ejaculatory inevitability. During the second step, or expulsion, the urinary bladder closes to block the possibility of urine mixing with semen. At this point, muscles at the base of the penis begin a steady rhythmic contraction that expels the semen from the urethral opening at the head of the penis. After ejaculation, men enter a refractory period during which further response to stimulation is not possible. Women do not experience a refractory period and are capable of multiple orgasms during a single period of stimulation. Contractions of the circumvaginal and
Human Sexuality
perineal muscles at rhythmic 0.8-second intervals characterize this stage for women. Despite the touted social mythology of the “vaginal orgasm,” it seems that female orgasm is almost always the result of some form of clitoral stimulation. Resolution is the final stage defined by Masters and Johnson. During this phase, all sex-specific responses subside, and the body returns to its basal state; somatic responses to sexual stimuli diminish rapidly; heart rate, blood pressure, respiration, and skin vascularity become normal within minutes. Postorgasm, somatic responses recede rapidly, and the clitoris returns to its normal position within 5 to 10 seconds. Although the vagina may take 10 to 15 minutes to return to its normal state, the orgasmic platform rapidly becomes detumescent. Probably as a result of blood draining from the genital area, the labia minora revert to normal coloration within 10 to 15 seconds after the end of orgasmic contractions. The resolution phase is marked 135 by a general sense of well-being and enhanced intimacy and possibly fatigue. Men, especially as they age, experience a refractory period of varying duration after orgasm during which they cannot achieve orgasm, although partial or full erection sometimes may be maintained. The duration of the refractory period varies from a few minutes to several days. There is great variability in the length of the refractory period within and between men.
Kaplan and Desire
Desire, which sets the stage for further sexual activity, is discrete and separate from the genital components of sexuality according to Kaplan. Her contribution to theory is the result of examining the limitations of the original theory of the human sexual response cycle. She found that many patients had little desire for sexual activity, and no amount of intervention for other problems would effectively help them. Sexual desire can be influenced by physiologic drive, mood states, psychological perceptions, and sociocultural factors. In addition, sexually explicit material from visual images, sounds, or internal fantasies can elicit arousal. Sexual desire can be conceptualized, regardless of its source, as the stimulus that leads the individual to initiate or be receptive to sexual activity. Physical activation of a specific neural system produces the desire or libido that drives the individual for sexual activity. A “horny” person has such an active system and can feel genital sensation or just vaguely sexy. This appetite for sexual activity is the trigger for the remaining sexual responses. Following Kaplan’s contribution, the human sexual response cycle can be organized as a triphasic grid (Table 9-1).
Table 9-1 Sexual Response Cycle as Redefined by Kaplan
Stage
Components
Desire
Cognitive and hormonal motivating factors leading to an interest in sexual activity Vasocongestion of the genitalia, associated changes in respiration, attention focused on erotic stimuli Release of vasocongestion and myotonia developed in the prior stages
Arousal Orgasm
Reproductive Endocrinology and Infertility
Unique Components of Women’s Sexual Response
Noting that many women in long-term monogamous relationships are not motivated in the same way as men with regard to sexual interaction, Basson proposed a different model of female sexual response (Fig. 9-5). Receptivity to sexual stimulation is not preceded by sexual thoughts or fantasies. Emotional intimacy is the goal that women seek from their sexual interactions in this model. Intimacy is enhanced by the emotional and physically rewarding outcomes and is necessary in a sexual experience. The nongenital components of a woman’s sexual experience lead to her satisfaction and are driven by intimacy needs and nurture intimacy. A lack of tenderness, excessive focus on intercourse, physical and emotional discomfort, and other factors can prohibit the attainment of the overriding goal of enhanced intimacy. Finally, this desire, primarily receptive in nature, depends on whatever sexual stimuli are necessary for a particular woman. Context may be more
136 Figure 9-5 Orgasm
Sexual excitement/tension
Traditional sex response cycle of Masters, Johnson, and Kaplan, alongside new intimacy-based female sex response cycle. (From Basson R: Female sexual response: the role of drugs in the management of sexual dysfunction. Obstet Gynecol 2001;98:351.)
Plateau
Arousal
Resolution Desire Time
Emotional intimacy
+ motivates the sexually neutral woman
+ Emotional and physical satisfaction
to find/be responsive to
Sexual stimuli Arousal and sexual desire
psychological and biological factors govern “arousablity” Sexual arousal
Human Sexuality
important to a woman in terms of the effectiveness of sexual stimulation than the stimulation itself.
Neuronal Influences on Sexual Response
The vasocongestive and orgasmic reflexes that compose the sexual response can be found in separate but related portions of the nervous system. The innervation of the genitals is somatic and autonomic in nature. Sensory afferents provide information on tactile stimulation that instigate the local sexual responses that are vascular and glandular after their synapse in the sacral portion of the spinal cord. Information of a sensory nature is projected to suprasacral regions and contributes to additional reflex activity that influences awareness and sexual excitation. In men, erectile response is initiated by parasympathetic efferents that travel through the pelvic plexus and the cavernosal nerves. It is possible 137 for an erectile pathway to be formed via the hypogastric nerves. This phenomenon has been observed in men with lesions to sacral and pelvic nerve segments and is termed psychogenic erection. Ejaculation seems to be served by portions of T11-L2 nerve segments that are sympathetic in nature. Continued stimulation of the penis triggers orgasm with seminal emission and the rhythmic 0.8-second contractions of the perineal and pelvic floor muscles. Emission begins during arousal. Smooth muscle contraction of the seminal vesicles, vas deferens, and prostate is influenced by sympathetic outflow producing emission. Similarly, smooth muscle contraction in the bladder neck prevents retrograde ejaculation. Higher centers of the brain can modify, augment, or inhibit genital vasocongestion and orgasm. Genital neuromuscular activation of female sexual response seems to be similarly controlled. Parasympathetic activity produces clitoral erection, labial engorgement, and vaginal lubrication. Sympathetic activity produces orgasmic contractions, at 0.8-second intervals, of the uterus, fallopian tubes, and paraurethral glands and contractions of the pelvic floor muscles. Several neural pathways have been proposed as important in female sexual response: the pudendal nerve for clitoral stimulation, the hypogastric plexus and pelvic nerve for vaginal stimulation, and potentially the vagus nerve directly from the cervix to the brain. Similar to male response, female sexual response is influenced by the brain. Research has shown women’s ability to have orgasm through fantasy alone and hypnotically induced and direct stimulation of brain areas.
Hormonal Influences on Sexual Response
Knowledge of the hormonal influences on sexual response is growing. An exhaustive review of the data is not possible in this chapter. Androgens and estrogen play an important role in sexual response of men and women. Androgens increase sensitivity for sexual stimuli and seem to have important effects on women’s sexual fantasies, desire, and arousal. Androstenedione is the major androgen in the serum of cycling women. Most androstenedione circulates bound to sex hormone–binding globulin and albumin. Half is produced in the ovaries and half in the adrenal glands. Testosterone is the
Reproductive Endocrinology and Infertility
138
other major circulating androgen in cycling women. The ovaries produce about 25% of testosterone. The remainder is produced in approximately equal proportions by conversion from androstenedione in the liver, spleen, and adipose tissue and adrenal secretion. There is an age-related decline in female testosterone levels by a factor of 50% between ages 20 and 40. Research data indicate that surgically menopausal women experience a decline in desire from presurgical levels that can be restored with the addition of supraphysiologic levels of testosterone. Naturally menopausal women have sexual interest that is positively correlated with their androgen levels. The picture is less clear with premenopausal healthy women. Androgen levels influence sexual desire, but androgens alone are insufficient for the experience of sexual desire. The effects of testosterone on female arousal are similarly unclear with some data supporting a positive role for higher levels of vaginal blood flow in response to erotic stimuli with higher versus lower levels of circulating testosterone. At the same time, other research reported no differences in subjective levels of arousal or vaginal blood flow in women administered acute levels of dehydroepiandrosterone versus placebo controls. There are abundant data with hypogonadal men that show reduced levels of testosterone produce a rapid and marked decrease in sexual interest. Adolescent boys’ level of sexual thoughts can be predicted by level of free testosterone. In normal men, wide individual variability exists in the level of circulating testosterone and levels of drive or sexual behavior. It is believed that the level of testosterone necessary for sexual interest and activity in men is lower than the levels of circulating testosterone found in normal men. Variability above threshold levels in testosterone would not produce sexual interest or behavior. Testosterone restores erectile responses in hypogonadal men with impaired nocturnal penile tumescence. In men with normal testosterone levels, additional testosterone has not been shown to aid erection. Estrogen has a role in sexuality for men and women. Relatively high levels of exogenous estrogen have been useful in suppressing sexual desire in sex offenders and men with uncontrollable sexual urges. Estrogen seems to play a minimal role in female sexual desire with studies finding fluctuations in desire across the menstrual cycle to be independent of estrogen levels. The estrogen deficiency that occurs after menopause is related, however, to deficits in genital vasocongestion and lubrication and reductions in the thickness of the vaginal epithelium. These changes can impair physiologic arousal in women and lead to dyspareunia; they also can have an adverse effect on arousal as it is experienced psychologically. The effect of progesterone on male sexuality has been poorly studied. Increased levels of progesterone from certain oral contraceptives are correlated with decreased sexual desire in women. It is generally agreed, however, that progesterone treatment does not substantially influence sexual desire in premenopausal or postmenopausal women. Abnormally high levels of prolactin can lead to reports of decreased sexual interest in men and women. Additional data suggest that lactating women evidence decreased desire compared with their prepregnancy reports. Other psychological factors could be at work given the research that associates mood disturbances, including anxiety and depression, with high levels of
Human Sexuality
prolactin. Erectile problems have been noted in men with elevated and lowered prolactin levels. Some evidence exists that prolactin levels decrease immediately after sexual arousal. Contradictory evidence from more precisely controlled research showed increased prolactin levels after masturbation-induced sexual arousal in men. A doubling of prolactin levels after orgasm in women also has been shown. Oxytocin increases during sexual arousal and orgasm have been shown in men and women. Oxytocin seems to have positive erection effects because it activates excitatory nerve pathways from the spinal erection-generating center to the penis. Intensity of orgasmic contractions, but not their duration, also has been correlated positively with oxytocin levels in both genders. Some evidence exists that inasmuch as positive mood and sexual desire may be related, oxytocin could play an indirect role in sexual desire. Nitric oxide is essential to the production of penile erections. It also may 139 play a role in clitoral vasocongestion. The primary effect of nitric oxide is that it stimulates the release of guanylate cyclase, which converts guanosine triphosphate to cyclic guanosine monophosphate (cGMP), which enhances relaxation of the smooth muscles of the penile arteries and corpus cavernosum yielding increased blood flow into the penis. Men with erectile dysfunction may have a disruption in this process. Phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil, vardenafil, and tadalafil, prolong the action of cGMP by inhibiting its metabolism, resulting in more stable erections. A significant body of literature exists establishing the effectiveness of PDE5 inhibitors for male erectile dysfunction. There is no similarly well-controlled research supporting the use of PDE5 inhibitors in women with sexual dysfunction. The use of PDE5 inhibitors does not produce an erection in the absence of effective psychological or sensory sexual stimulation.
CLINICAL PRESENTATION AND THERAPEUTIC INTERVENTIONS Many individuals have difficulty with their sexual lives. National probability survey data suggest that 43% of women and 31% of men between the ages of 18 and 59 experienced some form of sexual dysfunction in the year preceding the survey. Sources of these difficulties can be complex and usually are multiply determined. Sources can include inadequate sexuality education, conflicting values and beliefs, medical problems, medication side effects (Box 9-1), and relationship problems. Consequently, the remediation of
Box 9-1 ●
● ●
Medication Side Effects on Sexual Function
Reduced libido—alcohol, anticonvulsants, antipsychotics (chlorpromazine, thioridazine, haloperidol, thiothixene), benzodiazepines, β-blockers, diuretics, MAOIs, opiates, SSRIs, tricyclic antidepressants Reduced arousal—alcohol, anticholinergics, antihistamines, β-blockers, MAOIs Reduced orgasm—β-blockers, clomipramine, SSRIs (men and women), thioridazine (men)
MAOIs, monoamine oxidase inhibitors; SSRIs, selective serotonin reuptake inhibitors.
Reproductive Endocrinology and Infertility
these problems can require interventions that involve medical and psychosocial components. In addition, most sexual problems are best treated in the context of a couple because they involve interaction between partners. It is essential that patients have reasonable expectations about sexual function. Popular cultural representations of sexual interactions tend to misrepresent reality. Mind-numbing, explosive orgasms are not the norm, and mutual orgasm with penile thrusting occurs in a small percentage of instances. Similarly, myths about erections that are “rock hard and instantly ready” have literary value, but do not approach actual experience. Some therapists suggest that, at best, 20% of sexual interactions reach the heights suggested by movies, magazines, or television. More realistically, 60% to 70% of sexual interactions may be “good enough.” An additional 10% to 20% may be unsatisfying. It is best to focus patients on non–performanceoriented goals for therapy. Mutual satisfaction and sexual comfort are more appropriate outcomes at which to direct patients than frequency or intensity objectives. Patients frequently consider only intercourse leading to orgasm as “sex.” It is good practice to educate patients that being sexual comprises a wide range of behaviors that can include but is not limited to hugging, caressing, kissing, manual and oral stimulation of erogenous zones that include genitals, and intercourse. An expanded range of options can increase the probability that patients will be able to achieve treatment goals of mutual comfort and satisfaction. Sexual problems are best categorized based on where in the sexual response cycle they occur. Table 9-2 presents a schema for this categorization. In addition to descriptive categories, sexual dysfunction can be conceptualized along two additional dimensions (Table 9-3). First, sexual problems can be primary, meaning they are lifelong, or secondary, meaning they are acquired. Second,
140
Table 9-2 Categories of Sexual Dysfunction
Stage of Response Cycle Involved Desire
Arousal Orgasm Pain
Male
Female
Hypoactive sexual desire disorder Sexual aversion disorder Erectile disorder Male orgasmic disorder Premature ejaculation Dyspareunia
Hypoactive sexual desire disorder Sexual aversion disorder Female arousal disorder Female orgasmic disorder
Table 9-3 General Subtypes of Sexual Dysfunction
Type of Onset
Type of Context
Lifelong Acquired
Generalized Situational
Dyspareunia Vaginismus
Human Sexuality
sexual problems can be generalized and occur in all situations or situational and be limited to certain environments or specific partners.
Desire Phase Disorders
Hypoactive sexual desire disorder (HSDD) can occur in men and women and is most often multiply determined. HSDD can be secondary to other dysfunctions. A woman with dyspareunia may develop HSDD in response to the pain she experiences during intercourse. HSDD occurs clinically with a high frequency and is one of the most difficult disorders to treat. HSDD patients do not normally have sexual fantasies or any desire for sexual activity. Although hormone levels, medication side effects, developmental stage of life, illness, and other medical factors all can play a role in the HSDD development and maintenance, psychological factors are often intertwined with these physical sources of the disorder. Religious orthodoxy, anhedonic or obsessive- 141 compulsive disorder, gender identity or sexual object choice, fear of loss of control over sexual urges, depression, and age-related concerns all could be implicated. Relationship factors also can contribute to HSDD development and maintenance. Lack of attraction to a partner, poor partner sexual skills, marital conflict, couple differences regarding the point of optimal closeness and other factors appear in the literature. Treatment, often lengthy owing to the multivariate nature of potential causes, can be complicated. Referral to a specialist is often advisable. Work with testosterone and estrogen/testosterone combinations in naturally and surgically postmenopausal women has shown promise for HSDD. Hormonal therapies without exploration of other factors may be ineffective, however, because, for example, no amount of hormonal intervention can override the effects of an abusive relationship with a partner. Additional interventions of a psychosocial nature can include correction of misinformation about sex, cognitive therapies, development of positive sexual experiences and expectations through the use of sensate focus exercises (originally developed by Masters and Johnson), and fantasy material. Sexual aversion disorder (SAD), although rare, can occur in men and women. SAD patients have or develop an aversion to all genital sexual contact with a sexual partner. The aversion may manifest itself as revulsion, fear, or anger. Patients with SAD do not present saying they are averse to sex. Women are likely to report dyspareunia or vaginismus instead. These conditions may be secondary to the aversion. Physical causes of SAD include any illness or other condition that might cause genital pain. Vulvar vestibulitis may cause such excruciating pain that a woman shudders at the mere thought of someone touching her genitals. When well established, this aversion to genital contact may persist long after the physical cause has been resolved. Case reports of men who have impaled their penises on the tail of an improperly trimmed intrauterine device and subsequently become averse to sexual activity are found in the literature. Survivors of rape or other sexual trauma, including men who have been sexually assaulted, are particularly vulnerable to SAD. Symptoms may include flashbacks similar to those in post-traumatic stress disorder. In some cases, each attempt at sex reactivates the memory of the traumatizing event,
Reproductive Endocrinology and Infertility
resulting in flashbacks when a partner attempts to be physically intimate in any way. Naturally, such patients work very hard to avoid sex.
Arousal Phase Problems
142
Erectile disorder is the best understood of the sexual dysfunctions. It is defined as the inability to obtain or maintain an erection satisfactory for the completion of sexual activity. As men age, normal changes occur in erectile capacity as a result of changing vascular, neurologic, and endocrine factors. Many men believe that their youthful sexual experiences, when erection was autonomous and stimulation from a partner was unnecessary, will last forever. If a man is unaware that it is normal for an older man (45-50 years old) to require more physical stimulation to achieve the same type of erection, he can become frustrated and anxious. Anxiety is a contributor to many instances of erectile disorder, and performance anxiety can maintain it. Consequently, some education about what is normal can have a positive therapeutic effect. Medical treatments for erectile disorder may include the use of vasoactive intracavernosal injections of agents such as alprostadil, papaverine hydrochloride, phentolamine mesylate, and prostaglandin E1. All of these agents have proved effective for erectile dysfunction and have a significant dose-response relationship: the higher the dose, the stronger the erection. Transurethral suppositories also have been used with limited success and reports of discomfort from patients. These treatments focus on performance, rather than on enhancement of the broader intimate relationship between the partners. Some men define their sexuality as their ability to maintain an erection sufficient for intercourse and intravaginal orgasm. PDE5 inhibitors have become a first-line therapy for many men with erectile disorder. Dropout rates and outcome satisfaction can be influenced by carefully explaining the proper use of these agents relative to the expected onset of effects, expected half-life, and the fact it is rare for a man to achieve 100% effectiveness as evidenced by an erection sufficient for penetration. Interpersonal and intrapersonal variability is more likely and to be expected. PDE5 inhibitors can be a useful adjunct in treating men with psychosocial erectile dysfunction. It is useful to advise patients to test out their response with masturbation to determine what, if any, side effects may exist and to get used to the medication. PDE5 inhibitors are contraindicated for anyone taking nitrate-based medications and for men with retinitis pigmentosa. Surgical treatments for erectile dysfunction include implantable prostheses, penile arterial revascularization, and penile venous ligation. The data on outcomes with these procedures are usually limited to nondescriptive “satisfactory” and “unsatisfactory.” When comparing vascular surgery with implants with vascular surgery that is effective, the patient has “normal” erections when he desires sex and there is sufficient erotic stimulation. Implant patients are able to achieve erection whenever they wish. Some men and their partners are dissatisfied because the erotic or affection components of sex are not a necessary component. For many patients for whom medication interventions are inappropriate, surgical interventions are highly desirable.
Human Sexuality
Vacuum device therapy is another treatment for erectile dysfunction. In this treatment, a tube is placed over the flaccid penis, and after a tight seal is made, the air is pumped out. The resulting change in pressure draws blood into the penis. The blood is trapped with a constricting device. This procedure requires some degree of manual dexterity to make the seal, pump the device, and get the band off the device and onto the penis. The band may be uncomfortable, and some men report bruising with this technique. Interfering thoughts and emotional issues can accompany erectile dysfunction. Men can become upset and embarrassed about this problem. Men who experience normal arousal and erection usually think erotic thoughts that focus on their or their partner’s body parts, seductive behavior, and anticipation of arousal and pleasure. A man with interfering thoughts is focused on the firmness of his erection; his partner being disappointed, angry, or even ridiculing; and palpable feelings of anxiety, embarrassment, 143 and depression. Cognitive-behavioral interventions can be employed in conjunction with medication therapies and may provide a more powerful treatment than one or the other in isolation. It is important to work with partners in these cases. Frequently, partners have their own set of interfering thoughts about the dysfunction. Common problematic thoughts have to do with the partner’s attractiveness to the patient, loss of love, infidelity, or loss of desire for the partner. Asking the partner what he or she thinks is the cause of the erectile dysfunction can allow explanations of likely etiology and clear up any misunderstandings. Female sexual arousal disorder (FSAD) refers to arousal phase problems of the engorgement-lubrication response. Because the primary location for these phenomena is internal, however, women are less likely than men to notice a physiologic arousal deficiency. Diagnosis of the physiologic changes that occur during arousal is difficult. Vasocongestion is monitored most accurately by vaginal photoplethysmograph measurements obtained while the patient is exposed to erotic and neutral stimuli. In addition, research indicates that physiologic measures of female arousal have a limited or nonsignificant correlation with subjective measures. When questioned, patients complaining of FSAD say they rarely, if ever, think about sex or get “turned on.” They may be interested in sex—but in a theoretical, conceptual way. Patients may present for treatment when they notice reduced arousal in the genital region. More likely, they seek therapy because they are not having “sexy” thoughts. FSAD patients have a hard time focusing on erotic stimuli, such as fantasies or sexual cues from a partner, and seldom report having the experiences of sexual excitement, pleasure, and romance that other people report. Treatment of premenopausal women rarely employs medical intervention. Women with estrogen deficiency and impaired arousal can benefit from hormone replacement therapy, however. A variety of artificial lubricants also are available to help these patients. The psychological portion of treatment is directed at teaching how to focus on pleasurable thoughts and feelings about sex and methods of improving intimacy. Because electric and battery operated vibrators can be effective in enhancing all phases of female sexual response, they may prove useful for FSAD treatment. An integrated
Reproductive Endocrinology and Infertility
approach of medical and psychosocial interventions is considered the most effective therapy.
Orgasm Phase Problems
144
Premature ejaculation, more recently termed rapid ejaculation, is the most common male sexual problem. Early in their sexual experience, before they acquire ejaculatory control, most men ejaculate sooner than they or their partners would wish. About 30% of sexually experienced men have this problem. Definitional differences have limited the complete understanding of rapid ejaculation from a research point of view. Popular myths about the length of the average intercourse event create unrealistic expectations in many men and their partners about what is “normal.” A good definition of rapid ejaculation is that the man does not have voluntary, conscious control or the ability to choose in most encounters when to ejaculate. From a skill-based point of view, men with rapid ejaculation have difficulty identifying the point of ejaculatory inevitability at which orgasm is no longer voluntary. The abilities to relax during sexual encounters, focus on pleasure and arousal in his own body, and use arousal pacing strategies are essential for ejaculatory control. In addition, anxiety disorders, obsessivecompulsive disorder, and fear of pregnancy are possible etiologic factors. Relationship factors can have a role in the onset and maintenance of rapid ejaculation that is acquired. Nonpsychological explanations also are possible. Physiologic predisposition to rapid ejaculation has been linked to greater penile sensitivity and a shorter bulbocavernosus reflex nerve response latency. Medical problems, such as prostatitis, can predispose a man to rapid ejaculation. Certain physical injuries, neurologic trauma, and pelvic surgeries also can have an impact. Use of or withdrawal from some medications can produce a rapid ejaculation as well. Nonscientific remedies for rapid ejaculation have existed for decades. Men have been encouraged to think “nonsexy” thoughts or apply anesthetic creams to their penises. Inevitably, these interventions fail or produce discomfort or lack of pleasure for the man and his partner. Behavioral strategies, such as the stop-start or squeeze technique, have been employed with a good deal of initial success, although their long-term effectiveness has come into question. In each of these therapies, the man’s partner stimulates his penis until just before the point of ejaculatory inevitability. He tells her when he reaches that point, and she either stops stimulation or squeezes the head of the penis below the glans between her thumb and forefinger. After a period of nonstimulation, she resumes for a second and then third trial. On the third trial, he is allowed to reach ejaculation. Over time, the man learns to predict his ejaculation better and control his behavior to prolong it. Selective serotonin reuptake inhibitors (SSRIs) have known side effects on sexual response. Increased serotonin levels are thought to inhibit ejaculation. Tricyclic antidepressants also have been used with effectiveness, but tend to have other less desirable side effects than SSRIs. Because withdrawal of these medications can cause a reversion to prior patterns of ejaculation, a combination of behavioral and pharmacologic interventions may be more
Human Sexuality
powerful. Inclusion of the partner in therapy is essential because ejaculatory problems can distress relationships. Male orgasm disorder is a persistent difficulty in attaining orgasm despite adequate physical and cognitive/erotic stimulation. Most men are readily orgasmic. Consequently, it is unusual for a man not to experience orgasm with proper stimulation. These men obtain erections with sexual stimulation. This stimulation is apparently insufficient, however, to produce an orgasm. It is not unusual for men to describe a history that is low in sex drive or interest or filled with negative sex messages. They also may participate in sex without allowing adequate time to create a sexual mood. It is not unusual for such men to have developed idiosyncratic masturbatory methods of vigorous stimulation that cannot be replicated in intercourse. Psychological factors, such as conflict about sexual activity, fear of pregnancy, or obsessive-compulsive or passive-aggressive personality traits, can contribute to 145 the etiology. Finally, surgical disruption or diseases that interfere with the sympathetic nervous system, such as diabetes, multiple sclerosis, and alcoholic neuropathy, can be implicated. When no biologic or pharmacologic causal explanations exist, male orgasm disorder is difficult to treat. It is not unusual for a man to present for therapy when his partner insists on it, often because she wants to get pregnant. Therapy for male orgasm disorder frequently addresses the issue of creating and maintaining a sexual mood and allowing sufficient time and increasing erotic input. Erotic components might include fantasy, lubrication, vibrators, or sex play. These therapeutic interventions are based on a belief that men with delayed orgasm do not take the time to focus on their own eroticism. Orgasmic responsiveness is something that women tend to develop over time. They learn how to be orgasmic alone or with a partner and adapt their sexual interaction to achieve release. Female orgasmic disorder can be the psychological mirror of erectile dysfunction. Performance anxiety can play a major role in maintaining the problem. Worry about the outcome interferes with enjoyment of the total sexual experience, and the harder the woman tries to reach the goal of orgasm, the more difficult it is to achieve. Because the dysfunction can be so frustrating, it can lead a woman to avoid all sexual interaction. Orgasm in men is readily detected because it typically is accompanied with ejaculation. Female orgasm is a more subjective experience even though muscular contractions occur when it is achieved. The normal range of stimulation required to trigger orgasm is wide. Consequently, the diagnosis of this disorder must take into account whether the woman’s orgasmic capacity is less than would reasonably be expected, based on her age, her sexual experience, and the adequacy of the stimulation she receives. A woman may be orgasmic during masturbation, but not during intercourse, or she may be orgasmic with one partner, but not with another. Possible etiologic factors for female orgasmic disorder include abnormal pubococcygeus muscle tone, hormonal imbalances, diabetes, and spinal cord injuries. Psychiatric medications, such as SSRIs, antipsychotics, and anxiolytics, and antihypertensives can produce anorgasmia. Psychological
Reproductive Endocrinology and Infertility
explanations have not been consistently supported by adequate research. Although relationship variables can play a role, they have not been quantified adequately to be meaningful. When female orgasmic disorder is lifelong and generalized, directed masturbation is a preferred treatment technique. Education, self-exploration and body awareness, and encouraging the patient to masturbate to experience orgasm initially on her own before she does with a partner are sequential components of the therapy. The objective is for the woman to become comfortable with orgasm when alone and transfer that comfort to partnerrelated sexual activity that can include manual or oral stimulation or intercourse. In addition, by learning how to bring herself to orgasm she is more able to teach her partner how to do the same. Several books and videotapes describe this empirically validated approach. Acquired or situation-specific female orgasmic disorder is infrequent in healthy women. Investigation of medication-related or health-related issues should guide intervention efforts.
146
Pain Problems
Controversy exists about the inclusion of pain during sex as a sexual dysfunction. It is unclear why painful genital sexual activity is a sexual dysfunction when other pain syndromes that interfere with sexual activity, such as low back pain, are not so classified. Nevertheless, the sexual pain problems of dyspareunia and vaginismus are diagnosed as sexual problems, rather than pain problems. There is significant overlap between female dyspareunia and vaginismus. Vaginismus can be secondary to painful intercourse. Although it is quite rare, male dyspareunia can be the result of Peyronie’s disease. Plaques develop on the midshaft of the penis and cause it to bow. Sexual activity, including masturbation and intercourse, can be painful. There is no generally accepted, standard nonsurgical treatment for Peyronie’s disease. In addition, the success of treatment may be difficult to determine because 20% to 50% of patients with Peyronie’s disease experience spontaneous resolution. Other causes of penile pain include prostatitis and urinary tract infections. Obstructed ejaculatory ducts can cause testicular pain. It is rare for a man to experience testicular pain solely in conjunction with sex and not at other times. Recurrent or persistent female genital pain on intercourse often has a medical etiology. Dyspareunia also places a woman at risk, however, for developing vaginismus and secondary disorders of desire, arousal, and orgasm. An accurate diagnosis requires a thorough physical examination. Sometimes, patients whose examinations are negative for physical factors still complain of pain. Whatever their cause, pain symptoms can cause the patient to avoid sexual encounters with a partner, stressing the relationship. Most often, dyspareunia has multiple etiologies. Numerous physical factors require consideration when making the diagnosis: hymenal remnants; pelvic tumor; endometriosis; prolapsed ovaries; pelvic inflammatory disease; vulvar vestibulitis; surgical scar tissue from episiotomy; and infections of the vagina, lower urinary tract, cervix, or fallopian tubes. Anatomic relationships, such as ovarian fixation to a retroverted uterus, also may be the source of the pain. Postmenopausal women can experience dyspareunia as
Human Sexuality
a result of changes to the vulvovaginal area, including reduced vaginal transudate during sexual arousal, owing to decreasing estrogen levels. Cancer treatments that involve radiation to the pelvic region also reduce estrogen production with similar results. Psychological factors also may drive or contribute to the etiology of the disorder. Many patients complaining of dyspareunia report guilt or shame about sex, religious proscriptions that arouse shame or guilt, poor body image, or a combination of those factors. Sexual trauma also may contribute and should be carefully and gently investigated. Sometimes patients complain that a partner does not provide enough foreplay to produce adequate arousal. Other presenting issues include a partner’s lack of sexual skill, feelings of resentment toward a partner, and anxiety about sex. Detailed information about the location and quality of pain are essential diagnostic components. Other factors evaluated include the degree of 147 interference with sexuality, relationships, and well-being of the patient. Assessment by a physical therapist who specializes in pelvic floor musculature also is advisable. Cognitive-behavioral techniques for pain management, biofeedback, vestibulectomy, trigger point injections, topical and systemic medications, and lubricants all have been used for treatment of dyspareunia. Inclusion of the partner in treatment planning is advisable because the pain typically affects the sexual relationship between the two. Patients with vaginismus experience a recurrent or persistent involuntary spasm of the perineal and levator ani muscles of the outer third of the vagina. When her partner attempts intromission, these muscles clamp down preventing intercourse. These women may report fear not only of coitus, but also of vaginal penetration of any kind, making routine vaginal examination impossible. Vaginismus patients frequently can be aroused by sexual stimuli and achieve orgasm via masturbation or stimulation from a partner. This can make the problem all the more frustrating for them and their partners. Etiologic hypotheses include the contribution of many physical factors, including atrophic vaginitis, episiotomy, prior surgery, Monilia or Trichomonas vaginitis, constipation, pelvic congestion, a rigid hymen, pelvic inflammatory disease, hemorrhoids, stenosis of the vagina, pelvic tumors, childbirth pathologies, and urethral carbuncle. These physiologic conditions seldom are the direct cause of the vaginismus, but can become associated with the disorder through a classic conditioning paradigm: The pain the patient experiences initially becomes associated with intercourse; she reports that her vaginal muscles clamp down, almost automatically, when her partner approaches her for sex; sometimes even thoughts about intercourse can initiate this conditioned muscle response. The psychological etiology of vaginismus can include inhibitions introduced via religious orthodoxy, prior sexual trauma, fear of pregnancy or parenting, or response to a partner’s sexual dysfunction. If local pathology is the cause of the vaginismus, it must be ameliorated before treatment of any underlying psychological causes or contributors can be attempted. The goal of treatment for vaginismus is the elimination of the reflexive muscle spasms through a series of treatments, including relaxation
Reproductive Endocrinology and Infertility
techniques to help control the onset of muscle spasms and physical dilation of the vaginal entrance. This constitutes an in vivo desensitization. Patients also may receive pelvic floor physical therapy. Graduated dilator sets are used in the patient’s home with specific directions on how to lubricate and insert them. Eventually, the partner can be introduced to the process, inserting the dilator under the patient’s guidance. It may be more comfortable for patients to have digital insertion rather than dilators and move to penile insertion without thrusting.
148
Obtaining Historical and Diagnostic Information
It is clear that patients want to discuss their sexual problems with health care professionals. They expect physicians to take the lead in asking about sexual health matters. The impetus for screening for sexual health problems includes not only concern about sexually transmitted diseases and HIV/AIDS but also the ability of physicians to reduce their incidence through preventive education. Screening also pays attention to the fact that other disorders, such as depression and diabetes, can have an impact on sexual function. Finally, evidence exists that sexual activity and good health are related. Taking a complete sex history may be precluded by time limitations in general practice. It is useful, however, to have a set of screening questions to initiate discussion about sexuality issues. Screening for sexual problems is best accomplished during a review of systems or during a personal and social history. Finally, sex-related questions can be introduced during a physical examination, although it is the least desirable time of the three because the unclothed patient is the most defenseless, and the appearance of impropriety exists. When taking a history, screening for sexual problems, or initiating therapeutic interventions, some basic assumptions can guide a physician’s behavior. Basic assumptions about patients when taking a history are listed in Box 9- 2. Four screening questions for sexual problems are listed in Box 9-3; these questions are brief and direct. It is essential first to obtain permission to ask about sexual matters. All other questions flow from this starting point. The specificity Box 9-2
Basic Assumptions About Patients
1. Patients are embarrassed about and have difficulty discussing sexual matters. 2. Patients have a limited understanding of and do not use medically accurate terminology. 3. Patients are misinformed about sexual functioning. 4. Patient couples have not been open with each other and do not discuss sexual matters easily.
Box 9-3
Sex Screening Questions
1. Can I ask you a few questions about sexual matters? 2. Have you been sexually active (or involved) with a partner in the past 6 months? 3. Have you been sexually active with women, with men, or both? 4. Do you or your partner have any sexual difficulties, (for a man) such as with your level of interest, erections, or ejaculations, (for a woman) such as with your level of interest, vaginal lubrication, orgasms, or intercourse pain?
Human Sexuality
of the questions is designed to elicit the maximum amount of information. The second question gives the option of “active” or “involved.” Some patients may not understand active and think of it as the opposite of “passive” and may be confused. If the patient responds affirmatively, the third question provides information about the gender of the patient’s partner or partners. Finally, the fourth question provides detailed information from which more detailed information can flow. If little time is available, the fourth question is the single best question to ask. More detailed questionnaires and instruments have been devised for obtaining sexual history and sexual problem description. Examples are listed in Box 9-4. Finally, many sexual problems are best treated by specialists. Resources for making a referral and finding out more information about sexuality and sexual problems are listed in Box 9-5. 149
Infertility and Sexuality
Infertility, with its direct link to procreative sexual behavior, is a life crisis that is ripe for sexual dysfunction. The infertile couple in treatment is faced with a failure experience every time they have intercourse and do not become
Box 9-4
Representative Sexuality Questionnaires
Brief Index of Sexual Functioning for Women (BISF-W). Taylor JF, Rosen RC, Leiblum SR: Self-report assessment of female sexual function: psychometric evaluation of the Brief Index of Sexual Functioning for women. Arch Sex Behav 1994;23:627-643. Derogatis Sexual Functioning Inventory (DSFI). Derogatis LR, Melisaratos N: The DSFI: a multidimensional measure of sexual functioning. J Sex Marital Ther 1979;5:244-281. Female Sexual Function Index (FSFI). Rosen R, Brown C, Heiman J, et al: The Female Sexual Function Index (FSFI): a multidimensional self-report instrument for the assessment of female sexual function. J Sex Marital Ther 2000;26: 191-208. International Index of Erectile Function (IIEF). Rosen RC, Riley A, Wagner G, et al: The International Index of Erectile Function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 1997;49:822-830. Sexual Desire Inventory (SDI). Spector IP, Carey MP, Steinberg L: The Sexual Desire Inventory: development, factor structure, and evidence of reliability. J Sex Marital Ther 1996;22:175-190.
Box 9-5
Referral Sources for Sex Therapy Specialists
American Association of Sexuality Educators, Counselors, and Therapists: Available at: http://www.aasect.org/ The American Board of Sexology: Available at: http://www.sexologist.org/ The Society for the Scientific Study of Sexuality: Available at: http://www.ssc.wisc. edu/ssss/ SSTAR—Society for Sex Therapy and Research: Available at: http://www.sstarnet. org/ International Society for the Study of Women’s Sexual Health: Available at: http:// www.isswsh.org/
Reproductive Endocrinology and Infertility Table 9-4 Interface of Sexual Dysfunction and Infertility
Infertility causing sexual dysfunction
Sexual dysfunction causing infertility
Incidental findings
Hypoactive sexual desire disorder Female orgasmic disorder Erectile dysfunction Vaginismus Erectile dysfunction Male orgasmic disorder Premature ejaculation Reduced sexual satisfaction Guilt about sex Impaired marital adjustment
Based on Elstein M: Effect of infertility on psychosexual function. BMJ 1975;3:296-299.
150
pregnant. It would be difficult to imagine that the repeated pairing of sex and failure would not begin to take a toll on the sexual image and behavior of the individuals involved. Sex can become routine, lacking in emotion and devoid of excitement, when couples are in infertility treatment. Patients talk about it as though the physician was with them in the bedroom. Romance, intimacy, and spontaneity can evaporate under such circumstances. Estimates of sexual dysfunction in the infertile population range from 10% to 37%. At the same time, infertile couples can score in the normal range on measures of marital and sexual satisfaction. For men, increasing age is positively associated with erectile problems and a decreased desire for sexual interaction. National survey data found that the oldest group of men (50-59) was more than three times as likely to experience erection difficulties and to report low desire as the cohort of men 18 to 29 years of age. The opposite is true for women, whose sexual problems, with the exception of trouble with lubrication, tend to decrease with age. Given that the infertile population tends to be younger than the overall population studied in these more recent national estimates of sexual function disturbance, the estimates for sexual dysfunction with infertile individuals may reflect a more significant problem because lower rates of dysfunction would be expected, at least for men. It is possible to conceptualize the interface of sexual dysfunction and infertility as the matrix displayed in Table 9-4, with possible presentations of infertility leading to sexual dysfunction, sexual dysfunctions leading to a diagnosis of infertility, and finally incidental findings of sexual problems in cases of infertility.
SUMMARY OF KEY POINTS 1.
2.
Sexual interaction is multidimensional. It is more than intercourse leading to orgasm and can include a wide range of erotic behavior. Men and women seem to find different aspects of sexual interaction important. Human reproductive organs are located internally and externally, suggesting that internal structures function more for reproduction, whereas external structures function more for physical pleasure.
Human Sexuality
3.
4.
5.
Sexual response can be conceptualized in three phases: desire, arousal, and orgasm. Diagnosis of a problem based on where it occurs in the response cycle guides intervention strategies. Neuronal, hormonal, physical, and psychological factors all play important roles in sexual response, and all must be taken into account when diagnosing problems and providing interventions. Infertility, with its focus on sexual interaction and the failure to reproduce, can be the source of sexual problems.
SUGGESTED READINGS Basson R: Using a different model for sexual response to address women’s problematic low sexual desire. J Sex Marital Ther 2001;27:395-403. Basson R: Female sexual response: the role of drugs in the management of sexual dysfunction. Obstet Gynecol 2001;98:350-353. Burns LH: Sexual counseling and infertility. In Burns LH, Covington SN (eds): Infertility Counseling. New York: Parthenon; 1999:149-178. Crenshaw TL, Goldberg JP: Sexual Pharmacology: Drugs That Affect Sexual Function. New York: Norton; 1996. Heiman JR, LoPiccolo J: Becoming Orgasmic: A Sexual and Personal Growth Program for Women, rev ed. New York: Prentice Hall; 1988. Leiblum SR, Rosen RC (eds): Principles and Practice of Sex Therapy, 3rd ed. New York: Guilford; 2000. Kaplan HS: The New Sex Therapy. New York: Bruner/ Mazel; 1974. Kaplan HS: Disorders of Sexual Desire. New York: Bruner/Mazel; 1979. Masters W, Johnson V: Human Sexual Response. Boston: Little, Brown; 1966.
151 McCarthy B, McCarthy E: Couple Sexual Awareness. New York: Carroll & Graf; 1998. Meston C: The psychophysiological assessment of female sexual function. J Sex Educ Ther 2000;25: 6-16. Meston CM, Frolich PF: The neurobiology of sexual function. Arch Gen Psychiatry 2000;57:1012-1030. Metz ME, Pryor JL: Premature ejaculation: a psychophysiological approach for assessment and management. J Sex Educ Ther 2000;26:293-320. Reissing ED, Binik YM, Khalife S: Does vaginismus exist? A critical review of the literature. J Nerv Ment Dis 1999;187:261-274. Schover LR, Jensen SB: Sexuality and Chronic Illness: A Comprehensive Approach. New York: Guilford; 1988. Tiefer L: Historic, scientific, clinical and feminist criticisms of “the human sexual response cycle” model. Ann Rev Sex Res 1991;2:1-23. Weeks GR, Gambescia N: Erectile Dysfunction: Integrating Couple Therapy, Sex Therapy and Medical Treatment. New York: Norton; 2000. Zilbergeld B: The New Male Sexuality, rev ed. New York: Bantam; 1999.
10 EVALUATION OF FEMALE INFERTILITY Seth G. Derman and David B. Seifer DEFINITIONS Clomiphene citrate challenge test Diminished ovarian reserve Hysterosalpingogram Infertility
Sims-Huhner test
Saline infusion sonography
A test of ovarian reserve in which a menstrual day 3 and day 10 serum follicle-stimulating hormone (FSH) is drawn, and clomiphene citrate at a dose of 100 mg is given daily on days 5 through 9; its advantage is improved sensitivity compared with basal FSH alone Reduction in female fecundity owing to loss of reproductively competent oocytes A radiologic procedure using iodine-based contrast material and fluoroscopy to assess intrauterine anatomy and tubal patency and anatomy The inability to conceive despite 1 year of adequately timed intercourse; an evaluation may be started earlier if the female patient is older (≥35 years old) or the couple has an obvious defect A test to assess sperm–cervical mucus interaction, performed after intercourse at the midcycle; the mucus is assessed for stretchability and motile sperm; this test has largely fallen out of favor because of poor predictive value A radiologic test to assess the anatomic integrity of the uterine cavity; the test uses ultrasonography and instillation of saline into the cavity via a small catheter
Infertility, defined as the inability to conceive after 1 year of unprotected intercourse, is a common problem in gynecologic practice. This problem has been estimated to affect one in six couples at some point in their lives. With more couples delaying childbearing, infertility has become more common. As modern therapies have become more successful and more commonly discussed in the media and in casual conversation, infertile couples are more likely to seek out care. An understanding of how to evaluate an infertile couple is important to the practicing obstetrician/gynecologist. Reproductive failure may be due to the man or the woman, or a combination of the two. It has been estimated that 40% of human infertility is attributable to female causes, 40% to male causes, and the other 20% to a combination of male and female causes. Evaluation of male and female causes for infertility is essential in the evaluation of an infertile couple. Evaluation of the male
155
Reproductive Endocrinology and Infertility
partner, including semen analysis and other diagnostic modalities, is discussed in Chapter 11. This chapter reviews the essential components of the workup of the female partner of the infertile couple. The essential components of the history and physical examination, the various diagnostic tests available, and the physiologic basis of these tests are discussed.
NORMAL HUMAN REPRODUCTION AND REPRODUCTIVE FAILURE
156
To understand best how to approach the evaluation of an infertile couple, it is essential to understand the physiologic events that accompany normal human reproduction. In a woman with normal regular menstrual cycles, an oocyte is released from one of the ovaries at midcycle. In a woman with 28-day menstrual cycles, ovulation usually occurs on or around day 14. As the dominant follicle reaches maturity, circulating estradiol levels increase, which, through a positive feedback mechanism, leads to a surge in luteinizing hormone (LH). Shortly after ovulation, the oocyte is picked up by the fimbriated end of the ipsilateral fallopian tube, and the oocyte begins its journey down toward the uterus. This transport is facilitated by the cilia in the endosalpinx, and its viability is supported by endosalpingeal secretions. Around the same time, the couple has intercourse, and the male partner releases an ejaculate into the vagina. This ejaculate contains tens, or even hundreds, of millions of motile sperm. These sperm travel into the cervix where the mucus has become thin, watery, and generally hospitable to sperm (in contrast to the vagina). Some of these sperm find their way into the glandular crypts of the endocervix, whereas others enter the uterus and eventually the fallopian tubes. Although scores of sperm surround the oocyte and attempt to penetrate, only a single sperm actually penetrates the zona pellucida and fertilizes the mature oocyte. After fertilization, the oocyte completes the second meiotic division and continues its journey down through the fallopian tube. Embryo migration lasts approximately 6 days, and the zygote progresses from the pronuclear to the blastocyst stage. At the end of the trip, the blastocyst begins to implant itself into the endometrium, the lining of the uterus. This process is facilitated by hormones from the ovary. After ovulation, the ovarian follicle, which contains steroidogenic cells, becomes the corpus luteum, which produces high levels of the steroid hormones that help support the early pregnancy. Chief among these luteal hormones are progesterone and estradiol. If a pregnancy is not established, the cells of the corpus luteum undergo apoptosis, or programmed cell death, and the progesterone levels wane. If a conceptus implants, the trophoblast begins to secrete human chorionic gonadotropin. Human chorionic gonadotropin acts to rescue the corpus luteum, steroid secretion continues, and the pregnancy is maintained. There are many steps at which this process can be interrupted, any of which may result in infertility. The causes for infertility are summarized in Box 10-1. One can encounter disruption of the ovulatory process. It is possible that an egg may not be released at all, or that ovulation occurs on an infrequent basis, significantly lowering the odds for conception. It also
Evaluation of Female Infertility
Box 10-1
Causes of Infertility
Ovulatory Polycystic ovarian syndrome Hypothalamic amenorrhea Prolactinoma Other endocrinopathies Luteal phase deficiency Tubal/Peritoneal Proximal tubal obstruction Hydrosalpinx Peritubal adhesions Endometriosis Uterine Submucosal fibroids Synechiae Septum/congenital anomalies Luteal phase deficiency Cervical Hostile mucus Antisperm antibodies Ovarian Reserve Ovarian failure/menopause Diminished ovarian reserve
is possible that the oocyte quality may be poor because of an unfavorable hormonal milieu in the ovarian follicle (e.g., as a result of hyperandrogenism) or because of an aged oocyte. The corpus luteum also may be unable to produce adequate levels of progesterone to support the early pregnancy. The latter situation is referred to as a luteal phase deficiency. The fallopian tubes may be absent or damaged by infectious or fibrotic processes. This situation may result in mechanical inability for the oocyte and sperm to come in contact or result in the inability of the fertilized pre-embryo to be transported out of the fallopian tube into the uterus. Endometriosis, defined as the presence of endometrial glands and stroma in an ectopic location, also may contribute to this process. Advanced cases of endometriosis may result in mechanical barriers to conception, as described previously. There are numerous theories on why minimal and mild cases of endometriosis might cause infertility, such as abnormalities in fertilization and luteal phase deficiency; none of these has been proven. In the male partner, there may be a defect in sperm production in quantity or quality. There also may be difficulty in ejaculation or intercourse. The causes of male reproductive failure are discussed in Chapter 11. The cervix also may be a barrier to conception. It may be stenotic or have sustained damage to the endocervical glands from surgical treatment of cervical dysplasia (e.g., cryosurgery or loop electrosurgical excision procedures). Such damage may prevent the production of adequate mucus from
157
Reproductive Endocrinology and Infertility
the endocervical glands. The presence of thick hostile mucus may prevent sperm from being able to penetrate the cervix and survive for prolonged periods in the endocervical crypts. Many investigators also believe that antisperm antibodies may prevent viable sperm from reaching the oocyte. When the oocyte is fertilized and migrates to the uterus, several problems still may be encountered. There may be anatomic defects inside the uterus that prevent proper implantation or do not provide for sufficient blood supply to allow the pregnancy to develop to the clinical stage. Submucosal fibroids, synechiae (intrauterine adhesions), and uterine septa are examples of such intrauterine anomalies. Additionally, a luteal phase insufficiency owing to inadequate progesterone production may prevent the conceptus from surviving to the point where a pregnancy can be detected. 158
HISTORY AND PHYSICAL EXAMINATION One cannot overstate the importance of obtaining a thorough history on the infertile couple. Physical examination also may be helpful in determining the causes for infertility, although to a lesser degree than the history. The salient points in obtaining a history in the infertile couple are listed in Box 10-2. The infertility history begins with a discussion of the age of the male and female partners and the duration of their infertility. The age of the female partner is crucial. A woman in her mid to late 40s is unlikely to conceive (without use of donated oocytes), whereas a woman in her 20s is far more likely to have issues other than oocyte age as the cause for her infertility. The female partner’s age also determines at which point a workup might be appropriate. Infertility generally is considered to exist when pregnancy fails to occur after 1 year of unprotected intercourse. In patients older than 35 years of age, it is common to begin the workup after 6 months of unprotected intercourse. It is important to obtain a complete menstrual history, including the age of menarche, the cycle length and duration, the regularity and predictability of the cycle, and the presence or absence of moliminal symptoms and dysmenorrhea, which suggest adequate ovulation. Additionally, it is important to inquire about symptoms of menorrhagia, metrorrhagia, severe dysmenorrhea, and dyspareunia, which are associated with pathologic conditions.
Box 10-2 ● ● ● ● ● ● ● ● ● ●
Essential Components in the Infertility History
Age Detailed pregnancy history Menstrual history Sexually transmitted disease and pelvic infections Androgenic symptoms Medical history Surgical history Substance abuse Infertility testing Treatment
Evaluation of Female Infertility
The clinician also should inquire about history of intrauterine device use, sexually transmitted diseases, or history of pelvic inflammatory disease. Irregularity of the cycle suggests ovulatory disturbance, whereas symptoms of severe dysmenorrhea and dyspareunia are seen frequently with endometriosis. A history of sexually transmitted diseases, such as chlamydia or gonorrhea, or of pelvic inflammatory disease should alert the physician to the possibility of tubal causes for a couple’s inability to conceive. The clinician should inquire about other symptoms of endocrinopathies, such as those of hyperandrogenism. Hyperandrogenic women, such as women who have polycystic ovarian syndrome, may complain of hirsutism, male-pattern alopecia, and acne. Additionally, the clinician should inquire about the symptoms of hypoglycemia and thyroid disease and galactorrhea. Symptoms of hyperandrogenism or hyperinsulinemia suggest the possibility of polycystic ovarian syndrome, whereas galactorrhea suggests the possibil- 159 ity of hyperprolactinemia. A thorough obstetric history is important, including history of all pregnancies, the method of delivery, and any complications related to the pregnancy. This history includes vaginal births, cesarean sections, spontaneous abortions, ectopic gestations, and elective terminations of pregnancy. Certain complications during the pregnancy may suggest various endocrine disturbances or pelvic infections. Women who develop gestational diabetes are more likely to be insulin resistant, a metabolic state that frequently coexists with polycystic ovarian syndrome. A postpartum or postabortal fever or curettage may result in tubal damage or the development of intrauterine synechiae. Patients with recurrent spontaneous abortions require further evaluation (see Chapter 16). Past medical and surgical histories also are relevant. Abdominal or pelvic surgeries may suggest the possibility of tubal damage or pelvic adhesive disease. A history of surgical intervention, such as cryosurgery or cone biopsy of the cervix, may suggest the possibility of cervical etiologies for infertility. Additionally, one should inquire about abdominal pain and any family history of reproductive failure, genetic anomalies, or mental retardation. It is important to obtain a sexual history, including the frequency and timing of intercourse. A couple who is not sexually active during the periovulatory period will not conceive, regardless of how often they have intercourse throughout the remainder of the month. Additionally, when the male partner is unable to ejaculate reliably during coitus, pregnancy is far less likely to occur. Obtaining a sexual history also provides an opportunity to counsel the couple on when to have intercourse. In general, the couple should be advised to start having intercourse 2 to 3 days before anticipated ovulation and continue until the day after ovulation. Some physicians recommend daily intercourse to maximize the number of available sperm, whereas others recommend every-other-day intercourse to maximize counts. The total exposure to sperm (or total area under the curve) seems to be the most important predictor of success. Physical examination of the female partner should not be limited to gynecologic examination. On general examination, the examiner should take note
Reproductive Endocrinology and Infertility
160
of the patient’s weight and body mass index. Examination of skin may reveal acanthosis nigricans (a sign of insulin resistance), hirsutism, male-pattern alopecia, or acne, all of which suggest a hyperandrogenic state. Additionally, signs of other endocrinopathies, such as thyromegaly and abdominal striae (suggestive of cortisol excess), should be noted. Breast examination should be performed to look for masses, tenderness, and lymphadenopathy and to evaluate for discharge. Any breast discharge expressed should be examined under the microscope for fat droplets diagnostic of galactorrhea. The most important part of the physical examination is the pelvic examination. The clinician should inspect for clitoromegaly (a sign of hyperandrogenism) and evidence of congenital defects, such as an imperforate hymen or a transverse or longitudinal vaginal septum. The uterus and adenexa should be evaluated for shape, size, position, and tenderness. Additionally, the cul-de-sac should be palpated for nodularity and tenderness, which may be more apparent on rectovaginal examination. The presence of pelvic tenderness or nodularity suggests the possibility of endometriosis. Tenderness also may be found in patients with prior or recent infectious processes, such as pelvic inflammatory disease. If the patient’s history and physical examination point to a specific etiology, it is appropriate to focus the workup in that direction. If the history does not point to any specific issue, a more comprehensive evaluation is in order.
EVALUATION OF OVULATION AND THE LUTEAL PHASE As described earlier, ovulation is essential for normal human conception. Most women with predictable menstrual cycles have regular cyclic ovulation. Nevertheless, it is still possible, albeit unlikely, that such patients may be anovulatory. Many different modalities are available to the clinician in the office setting and patient at home to confirm the presence of ovulation (Box 10-3). One of the simplest and least expensive methods for evaluating ovulation is the basal body temperature chart. The patient checks her temperature by a basal thermometer on first rising in the morning, before getting out of bed, on a daily basis. Several days after ovulation, there may be an increase in the temperature (approximately 0.5°C) mediated by an increase in serum progesterone levels, a finding that strongly suggests ovulation. The advantages of basal body temperature testing are its relatively low cost and simplicity. There are, however, several drawbacks to basal body temperature testing. A woman who takes her temperature on first rising in the morning starts
Box 10-3 ● ● ● ● ●
Methods to Document Ovulation
Basal body temperature charts Urine LH kits Clear Plan Easy device (Unipath, Waltham, MA) Midluteal serum progesterone Endometrial biopsy
Evaluation of Female Infertility
each day reminded that she and her partner have been unable to have children. It has been well established that stress may contribute to infertility, and temperature charting in itself is likely to increase the patient’s stress levels. Basal body testing cannot direct the timing of intercourse because the temperature increase occurs after the peak fertility period is complete. Ovulation also may be confirmed by an over-the-counter ovulation prediction kit. These kits work by detecting the midcycle LH surge in the urine. In response to the preovulatory increase in estradiol, LH levels surge in the bloodstream and spill into the urine. Each of the test kits measures the LH as it accumulates in the urine. Ovulation prediction kits are made by various manufacturers and have varying levels of reliability. These home kits confirm the presence of an LH surge only and do not directly confirm ovulation. Women with chronically elevated LH levels, such as patients with polycystic ovarian syndrome, may have kits that indicate a positive LH surge every day 161 of the month, rendering them less useful in such patients. A fertility monitor called the Clear Plan Easy device (Unipath, Waltham, MA) measures LH along with a metabolite of estradiol in the urine. The monitor indicates periods of elevated fertility and peak fertility. These are reflective of LH and estriol glucuronide (an estradiol metabolite) levels only and are not direct measures of ovulation. Even though the monitor and ovulation prediction kits indicate several days of “peak” fertility, the true window for fertilization actually is short (usually <24 hours). The ability of sperm to be stored in the cervical mucus for 72 hours explains the fertility period that extends beyond this narrow window. Many couples find the ovulation prediction kits useful in helping them time intercourse. Nevertheless, the fertile period in women with regular, predictable cycles can be predicted easily using menstrual cycle timing alone. Women with longer cycles are more likely to benefit from urinary LH testing. Ovulation also may be confirmed by serum testing of progesterone levels in the midluteal phase. It is widely believed that a level of 3 ng/mL is confirmatory of ovulation. Nevertheless, such low levels may not be associated with pregnancy cycles, and many clinicians consider levels of 10 ng/mL indicative of an adequate luteal phase. Levels of 10 ng/mL correlate well with normal in-phase endometrial histology. When interpreting progesterone levels, one should keep in mind that serum progesterone levels vary considerably based on the laboratory technique used (e.g., radioimmunoassay, sandwich assay) and the day of the cycle on which they are drawn. Historically, clinicians used endometrial histology to diagnose luteal phase insufficiency, which is essentially a mild ovulatory defect. The expense, discomfort, and relatively poor reliability of the endometrial biopsy make it an increasingly unpopular test. It is important to inquire about ovulation when obtaining a history and use an objective method to confirm the presence of ovulation even in patients whose history suggests they are ovulatory. Many modalities are available to investigate this. Basal body temperature charting and over-the-counter ovulation prediction kits are easily accessible to patients. Midluteal serum progesterone levels provide the clinician with more definite proof of ovulation. Endometrial histology is less commonly used in clinical practice.
Reproductive Endocrinology and Infertility
EVALUATION OF THE FALLOPIAN TUBE AND PERITONEUM
162
Tubal patency and proper tubal function are essential to enable transport of the sperm to the oocyte and to allow the fertilized zygote to travel back to the uterus. The patient history may help in determining which patients are likely to have tubal causes for infertility. Patients with prior pelvic inflammatory disease, sexually transmitted diseases such as gonorrhea or Chlamydia trachomatis, or a history of septic abortions are most likely to have tubal disease. Serum antibody testing for chlamydia (IgG) may help alert the clinician to the possibility of an undiagnosed infection in the past. Many patients with extensive tubal disease have an unremarkable history. With the possible exception of ovulatory dysfunction and azoospermia, all patients who are seeking evaluation for infertility at some point need to have fallopian tube patency established. Even anovulatory patients should be assessed if infertility persists despite successful ovulation induction. Couples who use donor sperm insemination for azoospermia also should be assessed if they do not conceive after several treatment cycles. The most common test for determining tubal patency is hysterosalpingography (HSG). With this procedure, a catheter is introduced into the cervix and iodine-based contrast material is injected into the uterus under fluoroscopic evaluation. The physician is able to observe filling of the uterus, evaluate the uterine cavity, and observe the radiopaque dye passing into the fallopian tubes and freely spilling into the peritoneum. The dye may be water-based or oil-based. Because of concerns about the risks of emboli from oil-based dye, most physicians use only water-based contrast media. Examples of HSG images are shown in Figure 10-1. Tubal problems, such as proximal or distal tubal obstruction with or without hydrosalpinx, may be diagnosed. In some cases, intratubal and extratubal adhesions may be noted. An obstruction of the fallopian tube diagnosed on HSG profoundly affects the direction of evaluation and treatment. Although HSG is excellent at determining tubal patency, occasionally the fallopian tubes appear to be patent on HSG, but there are significant pelvic adhesions present. Post-tubal loculations also can be suspected on the basis of retention of contrast material in what appear to be pockets near the tubal fimbriae. HSG carries a low risk of pelvic infection, and many physicians instruct the patient to take prophylactic antibiotics. The gold standard in evaluating the fallopian tube is laparoscopy. This surgical procedure, with which most obstetrician/gynecologists and general surgeons are quite familiar, involves insufflation of the abdominal cavity with carbon dioxide gas followed by introduction of a trochar and laparoscope into the abdominal cavity. A uterine manipulator, such as a Humi or Jarcho catheter, is inserted into the cervix. The external surface of the ovaries, fallopian tube, uterus, and cul-de-sac may be evaluated to an extent that is impossible with HSG. As with HSG, tubal patency can be confirmed. In contrast to HSG, the external surface of the fallopian tube may be visualized as well; pelvic adhesions can be clearly diagnosed and treated. The health of the fimbriated end of the tube may be assessed. It is possible to have patent tubes with fimbriae that are incapable of ovum pickup.
Evaluation of Female Infertility Figure 10-1 HSG findings. A, Normal. B, Midsegment obstruction. C, Hydrosalpinx. D, Submucosal fibroids.
A
Normal
C
B
Midsegment obstruction
D Hydrosalpinx
Submucosal fibroids
Equally important, endometriosis can be diagnosed at the time of laparoscopy. Endometriosis is a condition in which glands and stroma that line the uterus are located in ectopic locations (see Chapter 14). The most common of these locations is around the ovary, in the cul-de-sac, and on the uterosacral ligaments. These structures can be visualized directly at the time of laparoscopy. Laparoscopy also provides the opportunity for fulguration or excision of such lesions. Patients with moderate or severe endometriosis benefit from surgical treatment of endometriosis. There is also likely a benefit to patients with minimal to mild disease, although more study is warranted. Discussion of the relationship between endometriosis and infertility is beyond the focus of this chapter. Other factors that should be noted with laparoscopy include the presence of abdominal and perihepatic adhesions, which suggest previous pelvic inflammatory disease. Laparoscopy carries with it the risks of general anesthesia, bleeding, infection, and damage to the adjacent organs. Because of the risks and costs associated with laparoscopy and the increasing success of in vitro fertilization, many reproductive endocrinologists are abandoning routine laparoscopy in infertility patients with no abnormal findings in their workup. There are other ways to evaluate tubal patency, although some of these methods are not established to be of benefit. Sonohysterography is a procedure
163
Reproductive Endocrinology and Infertility
164
commonly used to evaluate the uterine cavity in which saline is infused into the uterus at the time of pelvic sonography. Although visualization of the uterine cavity is excellent, it is more difficult to visualize the fallopian tube at ultrasound. There has been some success in using albumin mixed in with saline infusion and color flow Doppler to visualize the tubes. At this time, sonohysterography is not used routinely to document tubal patency. Additionally, evaluation of the fallopian tube, whether by HSG or laparoscopy, does not adequately visualize the interior of the fallopian tube. The cilia and function of the tube are essential to proper tubal function. Techniques such as falloposcopy and salpingoscopy have been developed to visualize the endosalpinx, and some centers use these techniques to evaluate the fallopian tube. The increasing success rate of in vitro fertilization as a treatment for tubal disease has made the importance of such an evaluation less important. It is essential to establish that the fallopian tubes are patent as part of a complete infertility evaluation. Most commonly, this is done by use of HSG or laparoscopy.
EVALUATION OF THE UTERINE CAVITY The uterine cavity plays an important role in normal human reproduction. A normal endometrium allows the fertilized embryo to implant, allowing the conceptus to continue to develop. There are two aspects of uterine function that are of interest to the clinician evaluating an infertile couple. One concerns the cyclic changes that occur in the endometrial thickness and histology in response to hormonal fluctuations throughout the menstrual cycle. Such changes in endometrial receptivity are largely related to ovarian rather than uterine function; evaluation of endometrial histology and progesterone was considered earlier in this chapter. The second aspect of uterine function relevant to reproduction is anatomic integrity. Anatomic abnormalities in the endometrium, such as submucosal fibroids, endometrial polyps, uterine septa, and uterine synechiae, may interfere with the implantation process. Although many congenital uterine anomalies have not been associated with infertility, most have been associated with recurrent pregnancy loss and are still important in the management of an infertile couple. The most commonly used test to evaluate the uterine cavity anatomy is HSG. HSG is effective at determining tubal patency and delineating uterine anatomy. Even more sensitive and specific for evaluation of the cavity is sonohysterography, also known as the saline infusion sonography. A soft plastic catheter is inserted into the internal os, saline is injected, and transvaginal sonography is performed preinfusion and postinfusion. Sonohysterography provides an excellent view of the uterus in general and the endometrial cavity in particular. Alternatively, one may perform hysteroscopy, in which an endoscope is introduced into the uterine cavity along with gas (carbon dioxide) or liquid (saline, glycine, sorbitol) distending medium. Both procedures provide excellent imaging of the endometrium, but they are of limited or no use in evaluating tubal patency. Additionally, major müllerian
Evaluation of Female Infertility
anomalies may be diagnosed reliably by pelvic magnetic resonance imaging or three-dimensional sonography.
EVALUATION OF CERVICAL FUNCTION The postcoital test is performed by aspirating a sample of cervical mucus via a hollow catheter, such as an intravenous angiocatheter. The aspirate is evaluated for stretchability (also known as spinnbarkeit), pH, and volume. Under the microscope, the clinician looks for the presence of sperm and confirms that the sperm are motile and forwardly progressive. Although standards vary from center to center, the clinician should look for forwardly progressive sperm, adequate volume, and spinnbarkeit of at least 10 cm. The problem with this test is that it is not uniformly predictive for pregnancy. 165 Many women with abnormal postcoital tests go on to achieve pregnancy. Additionally, there remain a variety of normal values in the medical literature and little consensus on what constitutes a normal test. If the postcoital test is not performed at precisely the right time, even a patient with excellent quality cervical mucus would have an abnormal postcoital test. As a result of the poor reproducibility and a low positive predictive value, the postcoital test has largely fallen out of favor with reproductive endocrinologists and is not recommended for routine use by the American Society for Reproductive Medicine. Many reproductive endocrinologists also check infertile couples for antisperm antibodies. Antibodies directed at the sperm are thought to prevent adequate numbers of sperm from passing through the cervical mucus and reaching the oocyte and prevent the sperm that do manage to get through from fertilizing the egg. Antisperm antibodies may be assayed in the female partner by serum testing or in the man by testing of serum or seminal fluid. The validity of such testing in predicting infertility is controversial.
EVALUATION OF OVARIAN RESERVE In recent years, reproductive endocrinologists have come to realize the importance of the role that ovarian aging plays when assessing an infertile couple. Many women with otherwise unexplained infertility may be unable to conceive because of diminished numbers or quality of the remaining oocyte pool. Although natural fertility potential and pregnancy rates from in vitro fertilization are quite good in women in their early 20s, they are poor in women in their late 40s, a phenomenon clearly related to aging of the cohort of ovarian follicles. This aging of the ovary is known as diminished ovarian reserve, and a battery of tests has been devised to provide a quantitative estimate of ovarian reserve (Box 10-4). The most long-standing test for determining ovarian reserve is the basal follicle-stimulating hormone (FSH) level. Serum is drawn on day 2 or 3 in the early follicular phase for FSH assay. A normal value in most centers is considered to be less than 10 mIU/mL and is considered diagnostic of normal
Reproductive Endocrinology and Infertility
Box 10-4 ● ● ● ● ● ●
166
Methods to Assess Ovarian Reserve
Basal FSH levels Basal estradiol levels Clomiphene citrate challenge test Ultrasound Inhibin levels MIS/antimüllerian hormone levels
ovarian reserve, although each clinic should determine its own normative values. Elevated basal FSH levels in older patients indicate significantly diminished chances for success with assisted reproductive technology and in spontaneous conception. In younger patients, it is unclear whether an elevated basal FSH level is indicative of lower pregnancy rates, or whether such patients simply have poorer responses to gonadotropin treatment and a higher chance for cycle cancellation. More significantly, basal FSH levels can be interpreted only in light of the laboratory in which the assay is run, and there is significant intercycle variability among patients. Individuals with even one elevated basal FSH value have a markedly decreased chance for success. Taking the basal FSH concept a step further, the clomiphene citrate challenge test was developed in 1987. This is a provocative test of ovarian reserve during which basal FSH levels are drawn. The patient is given clomiphene, 100 mg/day, on days 5 to 9 of the cycle, and repeat FSH levels are checked on day 10. The basis of this test is that patients with normal ovarian reserve with a normal cohort of follicles producing adequate estradiol and inhibin levels are able to suppress FSH levels back into the normal range between days 9 and 10. This test has been shown to be predictive for a general infertility population and patients undergoing in vitro fertilization. It seems to be much more sensitive than the basal FSH alone. Other tests have been developed for evaluation of ovarian reserve in addition to the basal FSH and clomiphene citrate challenge test. Estradiol levels frequently are obtained with the basal FSH, and women with elevated basal estradiol levels have been shown to have reduced fertility. It is unclear at this time whether an elevated basal estradiol level is suppressing the FSH level or is itself predictive of diminished ovarian reserve. Inhibin B also has been studied as a measure of diminished ovarian reserve. This peptide growth factor from the transforming growth factor-β superfamily is produced by granulosa cells and expressed in the ovarian follicle. Diminished inhibin B production is the physiologic basis of elevated FSH levels noted in patients with diminished ovarian reserve and the clomiphene citrate challenge test. The decrease in inhibin B occurs before elevations in basal FSH, suggesting that diminished inhibin B levels may be an earlier sign of diminished ovarian reserve. Another member of the transforming growth factor-β superfamily, müllerian inhibin substance (MIS), also known as antimüllerian hormone, may be used to test for ovarian reserve. MIS is best known for its role in embryonic sexual differentiation. The hormone is produced in follicles at various stages
Evaluation of Female Infertility
of development and is unlikely to be affected by the cycle. In the available studies, low MIS levels suggested poor response to gonadotropin therapy. Nonetheless, MIS remains an experimental diagnostic test. Ultrasound evaluation of ovarian reserve also has been studied. Various authors have looked at total ovarian volume, volume of the largest ovary, and the investigators noted that patients with smaller ovaries produced smaller numbers of follicles. What is unclear is whether patients with diminished ovarian size on ultrasound have diminished pregnancy rates or only poor oocyte yields at in vitro fertilization. Additionally, ultrasound can be used to perform counts of early antral follicles. Antral follicle counts seem to correlate with ovarian response to stimulation and perhaps with pregnancy outcome.
CONCLUSION
167
Infertility is a common problem among women of reproductive age. A couple who has been attempting pregnancy for 1 year should undergo evaluation; couples in whom the female partner is older than age 35 should undergo evaluation after attempting pregnancy for 6 months. Various tests have been used to evaluate infertility. As in all areas of clinical medicine, the first step is to obtain an adequate history. Evaluation of the female partner of an infertile couple typically includes evaluation of ovulation, confirmation of tubal patency, evaluation of the semen, and evaluation of ovarian reserve. In many modern reproductive centers, the workup has often been pared down to a basal FSH, midluteal progesterone, semen analysis, and HSG. The postcoital test, a standard for infertility testing over the past century, has generally fallen out of favor. It is helpful for the clinician and the patient to understand the reasons for reproductive failure before beginning therapy. This information may direct therapy, avoid treatments that are likely to be ineffective, and make the infertile couple active participants in their care. Despite diagnostic efforts, however, about 10% of couples have unexplained infertility. In these couples, empiric therapy with clomiphene citrate or gonadotropin superovulation may be effective. Patient age plays an important role, and in vitro fertilization should be considered early in couples in whom the woman is older than 35 years old.
SUMMARY OF KEY POINTS 1. 2. 3. 4.
Female causes and mixed male and female causes account for more than half of the cases of human infertility. Evaluation of the female partner is essential in determining the cause of a couple’s infertility and directing the course of therapy. A thorough history can help to pare down the workup, reduce costs, and bring the patient to treatment sooner. Minimal evaluation of the female partner includes confirmation of ovulation, tubal patency, and adequate ovarian reserve.
Reproductive Endocrinology and Infertility
5. 6.
7. 8.
The use of the postcoital test in evaluation for cervical causes in infertility is controversial. Ovulation may be confirmed by various means, including basal body temperature charting, urinary LH testing, midluteal progesterone levels, and endometrial biopsy. Tubal patency may be shown by HSG or chromoperturbation at the time of laparoscopy. Ovarian reserve is a measure of aging of the ovaries and can predict a woman’s ability to conceive with contemporary therapies. It is commonly assessed using a basal FSH and estradiol level or a clomiphene citrate challenge test.
168
SUGGESTED READINGS ASRM Practice Committee Report: Optimal evaluation of the infertile female. Birmingham, AL: American Society of Reproductive Medicine; June 2000. Griffith CS, Grimes DA: The validity of the postcoital test. Am J Obstet Gynecol 1990;162:615-620. Mosher WD, Pratt WF: Fecundity and infertility in the United States: incidents and trends. Fertil Steril 1991;56:192. Noyes RW, Hertig AW, Rock J: Dating the endometrial biopsy. Fertil Steril 1950;1:3. Sharara FI, Scott RT Jr, Seifer DB: The detection of diminished ovarian reserve in infertile women. Am J Obstet Gynecol 1998;179(3 pt 1):804-812.
Wathen NC, Perry L, Lilford RJ, Chard T: Interpretation of single progesterone measurement in a diagnosis of anovulation and defective luteal phase: observations on analysis of the normal range. BMJ 1984;288:7. Wilcox AJ, Weinberg CR, Baird DD: Timing of sexual intercourse in relation to ovulation—effects on the probability conception, survival of the pregnancy and sex of the baby. N Engl J Med 1995;333:1517.
11 EVALUATION AND TREATMENT OF MALE INFERTILITY Jesse N. Mills, Sheri M. Dey, and Randall B. Meacham 169
DEFINITIONS Oligospermia Asthenozoospermia Severe asthenozoospermia Teratozoospermia Azoospermia
Sperm density less than 20 million/mL Sperm motility less than 50% Total motility of 0% to 5% Normal sperm morphology less than 15% Absence of sperm in the ejaculate
Primary infertility affects approximately 15% to 18% of couples. Male infertility is responsible for approximately 40% of these cases. This chapter discusses the evaluation, including history, physical examination, laboratory testing, and radiologic evaluation, and treatment of male factor infertility. A section on genetic factors of male infertility and genetic screening considerations is included.
HISTORY Evaluation of an infertile man begins with a detailed history. The patient should be asked about childhood illnesses and abnormalities, including the presence of an undescended testicle, performance of an orchiopexy, testicular torsion, and trauma. Men with a history of testicular cancer also may have impaired fertility. Testicular cancer is an independent risk factor for infertility, and the various treatment options can result in impaired fertility. Chemotherapy, radiotherapy, and retroperitoneal lymph node dissection all can adversely affect sperm function and transport. The effects of chemotherapy and radiation can last 5 years post-treatment, and improvement after that time is rare. Retroperitoneal lymph node dissection can interrupt
Reproductive Endocrinology and Infertility
170
the sympathetic chain and cause absence of seminal emission or retrograde ejaculation. The history should include questions about past and current medical problems. Chronic respiratory infections may suggest a diagnosis of immotile cilia syndrome, Kartagener’s syndrome, cystic fibrosis, or Young’s syndrome. Young’s syndrome produces an obstructive azoospermia by blocking the epididymis with inspissated debris. Immotile cilia syndrome and Kartagener’s syndrome, a subset of immotile cilia syndrome associated with situs inversus, affects sperm motility. Cystic fibrosis can show variable penetrance in which the patient may experience only frequent respiratory infections or be completely asymptomatic. Physical examination subsequently may reveal congenital absence of the vas deferens. This finding has a strong correlation with a mutation of the cystic fibrosis transmembrane receptor (CFTR) gene. Endocrine abnormalities are responsible for some cases of male infertility. Congenital adrenal hyperplasia is associated with precocious puberty and impaired fertility. Family and personal history of diabetes mellitus may manifest as disturbances in emission or retrograde ejaculation. It has been reported that men with diabetes mellitus can present with decreased ejaculate volume as the sole complaint. Delayed puberty can be a sign of hypogonadotropic hypogonadism. Patients with Kallmann’s syndrome, a form of hypogonadotropic hypogonadism associated with anosmia, can present with a history of decreased olfaction. Hyperthyroidism can cause reversible reduction in sperm motility. Hypothyroidism, rare in men, is less likely to contribute to infertility. It was found, however, that 3% of men with idiopathic infertility had subclinical hypothyroidism. A subset of these men was found to have positive thyroid autoantibodies and decreased sperm counts. Visual disturbances, galactorrhea, anosmia, and sudden decrease in libido suggest the presence of a pituitary tumor. Scrotal trauma, whether surgically corrected or not, is a reported cause of infertility. Past scrotal and inguinal surgeries are important to investigate. More recent literature has focused on bilateral inguinal hernia repairs as a cause of infertility. In one study, 14% of men with severe oligozoospermia had undergone bilateral inguinal hernia repairs. Men who have low-volume ejaculate and sperm in a postejaculatory urine specimen may have undergone bladder neck surgery in their childhood. History of recent illnesses also must be elicited. Fever or viremia can cause impaired testicular function that may last 3 months after the initial insult. This delay in recovery is due to the normal time course of sperm maturation because it takes approximately 74 days for immature spermatogonia to develop into spermatozoa in the ejaculate. When a man gives a history of recent illness and his semen quality is subnormal, he should return in 4 months for re-evaluation. Sexually transmitted diseases in men can cause obstructive azoospermia, ranging in cause from a strictured urethra to obstructed vas deferens or epididymis. Although far less common in the United States, genitourinary tuberculosis can lead to obstruction of the vas deferens and epididymis. Much has been made of environmental toxins causing abnormal and reduced semen parameters. A widely discussed article from 1992 asserted
Evaluation and Treatment of Male Infertility
that sperm quantity and quality had declined over the last half of the 20th century. This study was a meta-analysis of semen quality from European and American fertility centers, which showed average sperm densities in 1940 were 113 × 106 mL and in 1990 were 66 × 106 mL. Many authors challenged the study’s methodology, and the topic remains controversial. Although a responsible agent has yet to be identified, possible toxins include pesticides, particularly the nematocide dibromochloropropane, ethylene dibromide, carbaril, lead, and chlordecone. Occupations in which these chemicals are encountered include agriculture, welding, and ceramics. Numerous lifestyle factors can contribute to male infertility. The most quoted in the popular literature and least scientifically supported is the type of underwear a man wears. Wearing boxer shorts instead of briefs offers no advantage to successful procreation. Other hyperthermic environments may play a minor role, however. Discontinuing use of saunas and hot tubs is prudent advice for a 171 man with borderline semen parameters. Long-distance cycling often has been associated with male infertility, although the evidence is scant. One study identified reduced sperm motility during the training season of professional cyclists with return to normal parameters in the off-season. Smoking seems to have relatively little effect on semen quality. Data suggest that smoking causes oxidative DNA damage in human spermatozoa, which may lead to birth defects and an increased cancer risk in offspring. This information offers another opportunity for the clinician to advise a patient to quit smoking. Obesity is a potential risk factor. Excess fat enhances peripheral conversion of testosterone to estrogen via aromatase. There also is an increased prevalence of varicocele, diabetes, and erectile dysfunction in obese men. It is important to inquire about erectile function early in the history to rule out inadequate vaginal penetration as a cause of male factor infertility. The diagnosis of erectile dysfunction often has a significant impact on male self-esteem, which can lead to significant relationship stressors and couple anxiety. Similarly, premature ejaculation is rarely a source of infertility, but is often a source of male reproductive anxiety. Many medications have been implicated. Recreational and illicit drugs potentially contributing to male infertility include marijuana, opiates, cocaine, and alcohol. Acute alcohol intoxication can transiently impair sperm morphology. Chronic alcoholism alters testosterone clearance by the liver and causes gynecomastia and feminization. There is no evidence, however, that moderate alcohol consumption is detrimental to sperm quality. Anabolic steroids, such as those taken by bodybuilders, have direct gonadotoxic effects in addition to altering the hypothalamic-pituitary-gonadal axis. Testosterone supplementation is an increasingly common practice for men with subclinical hypogonadism and can impair spermatogenesis by feedback inhibition, altering the function of the hypothalamic-pituitary-gonadal axis. Men with decreased serum testosterone who wish to achieve conception should not be treated with testosterone. Chemotherapeutic regimens have variable effects on fertility. As a class, all chemotherapeutic agents are potentially gonadotoxic, but some are more detrimental than others. Recovery of fertility is better with doxorubicin,
Reproductive Endocrinology and Infertility
172
methotrexate, estrogens, and androgens. Improvement is less likely after vincristine and the testicular cancer combination of bleomycin, etoposide, and cisplatin. There is a poor chance of recovery after cyclophosphamide, chlorambucil, procarbazine, and the combination of nitrogen mustard, vincristine, procarbazine, and prednisone, a regimen used in Hodgkin’s lymphoma. Men anticipating cancer chemotherapy should be counseled to consider cryopreserving sperm. Antihypertensives as a class have deleterious effects on penile erections, with nonselective β-blockers, such as propranolol, being the worst offenders. Calcium channel blockers may interfere directly with the capacitation process and acrosome reaction; there is a case report of a previously infertile couple conceiving after the man stopped his calcium channel blocker. The α-blocker agents, a class of antihypertensives and prostatic smooth muscle relaxants, cause retrograde ejaculation in approximately 10% of patients. Angiotensin-converting enzyme inhibitors, including enalapril and lisinopril, do not seem to have any adverse effects on fertility or male sexual function. Antipsychotics and antidepressants can lead to infertility by inhibiting erectile function. Most antipsychotics act on central dopamine pathways, which can suppress the hypothalamic-pituitary-gonadal axis and depress libido. Selective serotonin reuptake inhibitors are commonly prescribed for even mild depression because of their excellent safety profile. They may have a marked impact on decreasing libido, however, and leading to delayed ejaculation or even anejaculation. Fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft) are so effective in delaying ejaculation that clinicians prescribe these medications to men with premature ejaculation. These agents also can cause hyperprolactinemia, which can impair sexual function and semen quality. Antibiotics also can contribute to infertility. High doses of nitrofurantoin cause maturation arrest. Erythromycin and tetracycline can affect sperm motility. Spermatogenesis can be inhibited by gentamicin and neomycin. A few commonly prescribed miscellaneous drugs can affect fertility. Cimetidine, a common H2 blocker, interrupts the pulsatile release of luteinizing hormone (LH) from the anterior pituitary. The gout medications colchicine and allopurinol impair the sperm’s ability to penetrate the egg. Sulfasalazine, a common treatment for inflammatory bowel disease, decreases sperm density and motility and alters morphology. Mesalazine, an alternative drug, does not seem to have these adverse effects. There has been some concern over the statin class of cholesterol-lowering drugs. The hypothesis is that these medications reduce the availability of cholesterol, an essential component in steroidogenesis. Animal and human studies have not supported these concerns. Table 11-1 summarizes the effects of commonly used drugs on fertility.
PHYSICAL EXAMINATION A brief but thorough general physical examination must be included in the evaluation of an infertile man, followed by a more detailed examination of the genitalia. Inadequate virilization can be suggested by scant body hair,
Evaluation and Treatment of Male Infertility Table 11-1 Medications and Recreational Drugs and Their Impact on the Male Reproductive Axis and Sexual Function
Medication/Drug
Gonadotoxic
Alcohol Tobacco Marijuana β-blockers Calcium channel blockers
Yes Yes Yes No No, but can inhibit capacitation No Yes Yes Yes Yes Yes
SSRIs Anabolic steroids Chemotherapy Nitrofurantoin Cimetidine Sulfasalazine
Altered HPG Axis
Decreased Libido
Erectile Dysfunction
Yes No No No No
Yes No No Yes No
Yes Yes No Yes No
No Yes No Yes Yes Yes
Yes No No No No No
Yes Yes No No No No
HPG, hypothalamic-pituitary-gonadal; SSRIs, selective serotonin reuptake inhibitors.
gynecomastia, and a eunuchoid appearance. Examination of the penis should assess curvature, plaques, and position of the meatus. Hypospadias, if proximal enough, can result in inadequate deposition of semen in the vagina. The scrotum is examined with the patient standing for testicular size and consistency. The adult testicle in a normospermic man should be greater than 4 cm in length with an estimated volume greater than 20 mL. Testes smaller than this suggest abnormal spermatogenesis. By volume, 85% of the testis is involved in spermatogenesis. The testes also should be palpated for tumors. Testicular cancer is the most common malignancy in men younger than age 35, the prime age for infertility. Testicular cancer is associated with subfertility, and the subfertility often manifests before the cancer. The scrotal examination also includes assessment for the presence of a varicocele and palpation of the vasa deferentia. Varicoceles, thought to result from engorgement of the pampiniform complex secondary to faulty venous valves, are thought by some to cause defects in sperm motility. Of men presenting with primary infertility, 40% have a varicocele. Varicocele represents a surgically correctable cause of infertility; this is controversial because a substantial percentage of fertile men also have varicoceles. As a result of the drainage of the left testicular venous system into the left renal vein, varicoceles are more common on the left. Occasionally, a unilateral right-sided varicocele can indicate abdominal pathology, which needs evaluation by computed tomography scan. The vasa must be identified on physical examination because congenital bilateral absence of the vas deferens occurs in 1.4% of infertile men. Finally, a digital rectal examination should be performed to evaluate the prostate and the seminal vesicles. Enlarged seminal vesicles or a midline prostatic cyst may indicate obstructive azoospermia necessitating transrectal ultrasound for further evaluation.
173
Reproductive Endocrinology and Infertility
LABORATORY EVALUATION
174
A thorough history and physical examination should guide the clinician in performing a focused laboratory evaluation. Endocrine panels including follicle-stimulating hormone (FSH), LH, and prolactin are often ordered, but frequently are not helpful. In one study involving two infertility centers, less than 10% of more than 1000 subfertile men were found to have any endocrinologic abnormalities. Most of these men had isolated elevated levels of FSH. Less than 2% had a clinically relevant finding that could affect fertility treatment. Although general endocrine screening may not yield many patients, directed serum assays may be useful. Men presenting with delayed puberty, low libido, or erectile dysfunction should have testosterone, FSH, and LH drawn to investigate hypogonadotropic hypogonadism. A man presenting with visual disturbances and galactorrhea needs a serum prolactin assessment to rule out pituitary tumors. Although serum hormone assessments may not often prove useful, the semen analysis is an essential component of the male infertility evaluation. The quality of semen analyses is influenced by the collection technique (Box 11-1). The patient should not have ejaculated for 48 to 72 hours before collecting the sample. Prolonged abstinence beyond 72 hours also may be detrimental to sperm quality. Specimens should be brought to the evaluating facility within 1 hour of ejaculation. Suitable containers must be clean, but not sterile. Masturbation is the preferred method of collection, but intercourse with a spermicide-free condom is acceptable. Initial evaluation should consist of at least two separate semen analyses. The semen parameters of greatest interest are outlined in Table 11-2. Briefly, volume measured to the nearest 0.1 mL, sperm density, percent motile sperm, forward progression, and percent normal morphology are assessed. Sperm density is determined with a microscope at 400× power using an appropriate counting chamber on the device’s stage. All equipment, including pipettes used to prepare the sperm, should be calibrated periodically to ensure accuracy. Motility is a quantification of the average percentage of sperm moving in 10 randomly selected high-power fields. Forward progression, a subset of motility, is classified using a variety of scales. One commonly used scheme designates “a” as rapidly progressive, “b” as progressive, “c” as motile but not progressive, and “d” as nonmotile. An alternative but similar score grades the sperm from 0 to 4+, with each increment indicating an improvement in forward motility. Morphology is a more complex assessment to make. The World Health Organization (WHO) requires that even slightly aberrant sperm are assigned Box 11-1 ● ● ● ● ●
Semen Collection
Abstinence for 2 to 3 days Delivery to laboratory within 1 hour of collection Keep sample at body temperature (37°C) Masturbation preferred Avoid normal condoms or lubricants
Evaluation and Treatment of Male Infertility Table 11-2 World Health Organization (WHO) Criteria for Semen Analysis
Parameter
Normal Value (WHO)
Ejaculate volume Sperm density Motility Morphology pH
>2 mL >20 million/mL >50% ≥15% normal 7.5-8.5
Adapted from World Health Organization: WHO Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Interaction, 4th ed. Cambridge: Cambridge University Press; 1999.
as abnormal. A normal semen analysis should contain greater than 14% of sperm with normal morphology using the WHO criteria. These criteria are increasingly employed, particularly in laboratories that support assisted repro- 175 ductive technique centers, abandoning the older methods that assess sperm morphology using moving sperm. With the so-called strict criteria, sperm are immobilized and evaluated; using this standard, 15% or greater normal forms constitutes a normal assay. Providers should be aware of which criteria their laboratory uses. There should be few white blood cells in a normal semen specimen. The WHO allows for 1 × 106 white blood cells/mL. In one study, 23% of infertile men had white blood cell counts higher than the WHO criteria, suggesting that pyospermia contributes to male infertility. Although normal values are specified when semen analyses are performed, the provider should understand that, other than azoospermia, deviation from these standards does not suggest sterility, but rather an increase in the relative risk of subfertility.
RADIOGRAPHIC EVALUATION Men with low-volume ejaculate who are found not to have retrograde ejaculation should undergo transrectal ultrasound evaluation to assess for the presence of ejaculatory duct obstruction. Cysts of wolffian or müllerian origin can be found in the midline of the prostate and may be associated with ejaculatory duct obstruction. One controlled study found müllerian duct cysts in 11% of infertile men with an incidence of 0% in the control group. Ejaculatory duct obstruction can be treated successfully with a transurethral repair. Vasography is an invasive diagnostic procedure that also can diagnose an obstructive process. Its risks include vasal scarring, which can lead to obstruction. Because of the success of transrectal ultrasound in diagnosing distal obstructions, vasography typically is reserved for detecting obstruction of the inguinal vas. It also may be performed at the time of a microscopic vasovasostomy or vasoepididymostomy to ensure a patent system.
TREATMENT OF INFERTILITY Treatment of male factor infertility should begin with identifying reversible medical conditions amenable to pharmacologic management. Treatable
Reproductive Endocrinology and Infertility
176
conditions include hyperthyroidism or hypothyroidism, isolated testosterone deficiency, hypogonadotropic hypogonadism, congenital adrenal hyperplasia, hyperprolactinemia, retrograde ejaculation, and genital tract infection. If the history suggests a diagnosis of hypogonadism, targeted therapies can help restore fertility. Although sexual dysfunction associated with isolated testosterone deficiency may respond to testosterone replacement therapy, induction of spermatogenesis is unlikely. Patients with hypogonadotropic hypogonadism often respond to injections of human chorionic gonadotropin, 1500 IU three times weekly, and human menopausal gonadotropin, 75 IU three times weekly. Congenital adrenal hyperplasia causes elevated androgen levels that suppress gonadotropin production by the pituitary and inhibits spermatogenesis. This disease is rare in adults, but there are case reports of glucocorticoid therapy inducing spermatogenesis in affected men. Hyperprolactinemia, almost as uncommon as congenital adrenal hyperplasia, also can adversely affect fertility. Pituitary tumors, hypothyroidism, liver disease, and various medications (e.g., tricyclic antidepressants, phenothiazines) can cause hyperprolactinemia. After ruling out a pituitary tumor by computed tomography or magnetic resonance imaging, a trial of bromocriptine (5-10 mg/day), a dopamine agonist, can reduce serum prolactin and lead to an increase in sperm counts. Antisperm antibodies, seen in high titers in men with a history of testicular cancer, genitourinary infections, or after vasectomy, can cause decreased sperm motility and inability to penetrate the oocyte. Treatment with corticosteroids is usually ineffective and can lead to untoward side effects, including hyperglycemia, acne, and aseptic necrosis of the hip. Because of this, many fertility centers use intracytoplasmic sperm injection (ICSI) in the management of this condition. Retrograde ejaculation, a condition seen in men with a history of testicular cancer and subsequent retroperitoneal lymph node dissection, bladder neck surgery, spinal cord injury, or diabetes mellitus, is an identifiable cause of infertility that can be addressed with medication. The aim of pharmacologic therapy is to increase adrenergic activity at the bladder neck and propel semen forward. Common agents include phenylpropanolamine (75 mg twice daily), pseudoephedrine (60 mg four times daily), ephedrine sulfate (50 mg four times daily), and imipramine hydrochloride (50 mg at bedtime), to be started 1 week before the start of ovulation and continued 3 days beyond. Success with this therapy may be 40%. If medical management is unsuccessful, retrieval of sperm from the bladder can be used in combination with sperm processing and intrauterine insemination or assisted reproductive techniques. If a thorough evaluation fails to identify a treatable cause of oligozoospermia, empiric therapy historically has been considered. Empiric therapy generally has provided inconsistent results at best. Clomiphene citrate, an antiestrogen that increases gonadotropin production and increases serum testosterone, has been used empirically to treat male infertility. Numerous small trials have suggested efficacy with various dosages and dosing intervals. A well-performed randomized controlled trial showed no efficacy, how-
Evaluation and Treatment of Male Infertility
ever. Tamoxifen, similar in its endocrine function, but devoid of the estrogenic side effects, also has been used in the treatment of idiopathic oligozoospermia. It too has undergone close scrutiny with poor results. Empiric medical therapy has no place in modern male factor infertility treatments.
SURGICAL TREATMENT As previously mentioned, varicocele is the most common surgically correctable abnormality in an infertile man, but significant controversy exists as to its efficacy. Three main surgical approaches are available for varicocele repair: scrotal, inguinal, and retroperitoneal. Scrotal repairs are hindered by the uncertainty of the venous plexus anatomy at that level. There are multiple veins within the pampiniform plexus, and it may be difficult to ascer- 177 tain whether all veins contributing to the varicocele have been ligated. The scrotal approach is the least popular of the three approaches. The retroperitoneal, or high ligation, approach is performed through a transverse incision made just medial to the anterior superior iliac spine at the level of the internal ring. Dissection is carried through the external oblique fascia, and the dilated veins usually are found adherent to the reflected peritoneum. The inguinal, or low ligation, approach is performed through an incision approximately 3 to 4 cm above and lateral to the symphysis pubis. The spermatic cord is identified and mobilized, and the dilated veins are identified. Each vein is ligated. Use of intraoperative Doppler can help identify the arterial supply to the testis and avoid its ligation. Laparoscopic varicocelectomy also has been described. More recent data suggest the laparoscopic approach offers shorter operative and recovery time and decreased surgical costs. Other varicocele repair techniques include percutaneous embolization. Interventional radiologists can localize venographically the varicocele and inject wire coils or sclerosing agents to occlude the vessels. Some retrospective reviews of surgically treated patients show a 50% to 70% improvement in semen parameters and a 30% to 50% rate of pregnancy within 6 to 9 months of surgery. Many studies are uncontrolled, however. The literature suggests that azoospermic men with unilateral or bilateral varicoceles may benefit from repair. In one series, 43% of azoospermic men with varicoceles were noted to have return of sperm to the ejaculate after repair. Approximately 500,000 vasectomies are performed yearly in the United States. Approximately 50% to 67% of first marriages end in divorce, so it is not surprising that vasovasostomy is a relatively common surgical procedure. The most important factor in predicting the success of a vasovasostomy is time since the original vasectomy. The greatest success is achieved with an interval less than 3 years, with a patency rate of 97% and a pregnancy rate of 76%. The least successful interval is greater than 15 years, with a patency rate of 71% and a pregnancy rate of 30%. At the time of vasectomy reversal, men should be offered the option of sperm extraction and cryopreservation for future use in assisted reproductive technologies in the event that the
Reproductive Endocrinology and Infertility
vasectomy reversal is unsuccessful. Occasionally, the surgeon performing a vasectomy reversal encounters obstruction at the level of the epididymis gland. Performance of an epididymovasostomy is indicated to bypass the obstruction. Although more technically demanding than a vasovasostomy, in experienced hands, epididymovasostomy still can yield favorable results. The pregnancy rates for this procedure approach 30% to 40%. Motile sperm often return to the ejaculate within 2 months after vasovasostomy and 6 months after epididymovasostomy. The time course varies, however, so it is prudent to wait 6 months after vasovasostomy and 1 year after epididymovasostomy before intervening for persistent azoospermia. The growing success of in vitro fertilization and ICSI has fostered increased interest in sperm retrieval. Many methods are available to obtain sperm from azoospermic men (Table 11-3). Microsurgical epididymal sperm aspiration (MESA) entails an incision in the scrotum and aspiration of sperm under direct vision. The technique of MESA usually involves working from the distal epididymis to the proximal portion or caput in search of viable sperm. This technique allows for minimal disruption of normal tissue. The procedure can be done under general anesthesia or conscious sedation and local anesthetic. The main advantage of MESA is the ability to retrieve large amounts of sperm sufficient for multiple cycles of in vitro fertilization. Because it is an open procedure, MESA also minimizes trauma to normal structures. The downsides to MESA compared with percutaneous procedures are the need for an incision, longer recovery time (2-3 days), and added expense. Percutaneous epididymal sperm aspiration employs a 21-gauge or 23-gauge needle to extract sperm from the epididymis. The patient undergoes conscious sedation and local anesthetic, and the surgeon makes multiple passes with the needle under negative pressure into the epididymis. The aspirate is placed in sperm buffer and analyzed. Percutaneous epididymal sperm aspiration is an office procedure, and because no incision is made, it is less expensive than MESA. Because there is no incision, it is by nature a blind approach. This potentially increases the risk of damaging the epididymis to
178
Table 11-3 Invasive Sperm Retrieval Techniques
Technique
Advantages
Disadvantages
Pregnancy Rate
Microsurgical epididymal sperm aspiration Percutaneous epididymal sperm aspiration Testicular sperm extraction
High sperm yield, technically precise
Open surgery, expensive
30%
Fast recovery, office procedure
30%
Testicular sperm aspiration
Office procedure, reduced costs
Epididymal scarring, lower sperm yield Open surgery, risk of testicular atrophy Multiple procedures, hematoma
Diagnostic ability, good sperm yield
ICSI, intracytoplasmic sperm injection.
33%
11% with ICSI
Evaluation and Treatment of Male Infertility
the point where reconstructive procedures are impossible. The quantity of sperm retrieved is usually less than with MESA, making the need for repeat procedures more likely. Testicular epididymal sperm aspiration is a percutaneous approach similar to percutaneous epididymal sperm aspiration. The testis is aspirated with multiple passes under negative pressure with a finegauge needle. The yield of sperm is low with this technique, and multiple procedures may be required. The above-described procedures for sperm harvesting are applicable only to men with obstructive azoospermia. Testicular epididymal sperm extraction performed through an open testicular biopsy is an option, however, for some men with testicular failure. Testicular epididymal sperm extraction offers diagnostic information regarding the nature of the patient’s testicular failure in addition to providing tissue for attempted sperm extraction. If there is asymmetry between the testicles, the larger testicle typically is selected 179 for biopsy and sperm extraction first. There is some controversy regarding whether to perform bilateral biopsies automatically on all men undergoing this procedure. Approximately 30% of the time, there can be major histologic differences between the right and left testicle. Focal spermatogenesis can be missed in unilateral biopsies.
GENETIC CONSIDERATIONS IN AZOOSPERMIC OR SEVERELY OLIGOZOOSPERMIC MEN Genetic abnormalities accounted for 5.8% of male factor infertility in one survey of 9766 infertile men. Of these men, 4.2% showed sex chromosome abnormalities, and 1.5% had autosomal abnormalities. A large percentage of subfertile men (approximately 30-40%) are labeled as having idiopathic infertility; genetic factors probably contribute to many of these cases. Efforts have been made to bridge the gap between basic science and clinical practice in dealing with genetic causes of male infertility. In 1998, the Practice Guidelines Committee of the American Urological Association, Inc., commissioned a team to provide recommendations for the optimal evaluation of the infertile man. These guidelines provide urologists, gynecologists, and other health care providers practical assistance in newer, less standardized, and rapidly changing areas of male infertility. It is recommended that men with azoospermia secondary to testicular failure and men with severe oligospermia undergo genetic evaluation. One purpose of genetic testing in such patients is to identify uncorrectable conditions. Identification of men in this group allows counseling on therapeutic donor insemination and adoption, while saving the couple the inconvenience, expense, and risk associated with invasive procedures if the potential for sperm acquisition is extremely low. In addition, genetic testing and counseling allow couples to be informed regarding potential genetic transmission of anomalies to offspring. In one study, it was observed that many infertile men fear that they are responsible for their infertility problem by their own behaviors, environmental factors, or previous sexual experiences and were relieved to learn their infertility was a result of genetic factors.
Reproductive Endocrinology and Infertility
180
When considering genetic abnormalities, it is helpful to categorize disorders into the following categories: numerical chromosomal abnormalities; structural chromosomal abnormalities; and pretesticular, testicular, and post-testicular genetic causes of infertility. The most common numerical chromosomal disorder encountered in practice is Klinefelter’s syndrome. Klinefelter’s syndrome has an overall incidence of 1 in 500 live male births and contributes to 14% of all cases of azoospermia. The syndrome is a result of nondisjunction of either the maternal or the paternal chromosome. Most cases result in a 47XXY configuration that is easily detected on karyotyping. Mosaic patterns have been described and are associated with less severe phenotypes. Men with Klinefelter’s syndrome may present with increased height, deficient maturation of secondary sexual characteristics, small firm testes, gynecomastia, obesity, decreased intelligence, and infertility. Laboratory studies may show increased FSH, normal or increased estradiol and testosterone, and decreased or absent spermatogenesis. Klinefelter’s mosaic patients may be treated with assisted reproductive techniques including ICSI with the option of preimplantation genetic testing of the embryo to ensure a normal karyotype before implantation. Men with XYY karyotype are another relatively common numerical chromosomal anomaly with an incidence of 1 in 1000 live births. Males are usually phenotypically normal, although of increased stature and possibly lower than average IQ. Infertility is associated with spermatogenic impairment and may be associated with hormonal abnormalities. Less common is mixed gonadal dysgenesis with a mosaic pattern of 45X/46XY. These individuals can present with a male, female, or ambiguous phenotype. Patients with ambiguous phenotypes often have intra-abdominal testes, which carry a high risk of malignancy. Structural chromosomal abnormalities resulting in defective sperm function and production can result from translocations, reciprocal exchange of visible lengths between two or more autosomes or sex chromosomes, or reciprocal attachment of the long arms of two acrocentric chromosomes, termed robertsonian translocation. Y chromosome microdeletions that are not detectable through normal karyotyping but are detectable through polymerase chain reaction testing have shown that the long arm of the Y chromosome is required for spermatogenesis. Microdeletions result in variable sperm production. The most common microdeletions include abnormalities of the SRY (sex determining region on the Y chromosome) and DAZ (deleted in azoospermia) regions. More than 30 deletions have been identified, and testing is currently available at specialized facilities. Men with Y chromosomal microdeletions are phenotypically normal but often infertile and may be candidates for reproductive assistance with counseling that the genetic abnormality may be transmitted to their offspring. One case series evaluated the four sons, products of ICSI, of three men with Y chromosomal microdeletions who all expressed the same Y microdeletion. Another study indicated that 7% of azoospermic or severely oligozoospermic men without non–sex chromosomal abnormalities, endocrinopathies, or obstructive azoospermia have a Y chromosomal microdeletion. These authors recommend routine screening of azoospermic
Evaluation and Treatment of Male Infertility
and severely oligozoospermic men for Y microdeletions owing to the high prevalence in that population. Another example of a structural chromosomal abnormality associated with male infertility is the XX male syndrome with an incidence of 1 in 20,000 births. The SRY is believed to be translocated to the X chromosome. Phenotypically, individuals present as men in 90% of cases and with ambiguous genitalia in 10% of cases. All affected individuals, regardless of phenotype, are azoospermic. Defects, mutations, deletions, or polymorphic expansions of genes that determine function at any point in the hypothalamic-pituitary-gonadal axis can have an impact on spermatogenesis. These pretesticular causes of infertility can be detected by abnormalities in testosterone, LH, FSH, estradiol, and prolactin. The most common X-linked disorder associated with infertility is Kallmann’s syndrome, which results in hypogonadotropic hypogonadism and has an inci- 181 dence of 1 in 10,000 to 1 in 60,000 births. The deficiency in this syndrome is a failure of gonadotropin-releasing hormone secretion from the hypothalamus as a result of a mutation in KAL-1, which is thought to code for neuronal cell adhesion. Patients often present with failure to initiate puberty. Physical signs of Kallmann’s include increased stature, small testes, micropenis, anosmia, and cryptorchidism. Treatment is with testosterone to allow maturation and sexual function and gonadotropin therapy if fertility is desired. Genetic factors also may manifest as post-testicular ductal and ejaculatory system abnormalities. As mentioned previously, congenital bilateral absence of the vas deferens is commonly associated with cystic fibrosis. Cystic fibrosis is an autosomal recessive disorder affecting 1 in 2000 live births. To date, more than 500 mutations in the large CFTR have been identified. Patients with cystic fibrosis mutations can present with hypoplastic, nonfunctional seminal vesicles and absent vasa. Other, less common disorders associated with male infertility include Young’s syndrome, which is associated with respiratory tract abnormalities, including chronic sinusitis and bronchiectasis; epididymal obstruction; spina bifida, which is associated with failure of normal ejaculation and defects in spermatogenesis; prune belly syndrome; and genitourinary tract malformations, such as bilateral cryptorchidism and bladder exstrophy/epispadias. Impairments of sperm production and function can be related to disorders such as muscular dystrophy that cause seminiferous tubule damage. Sperm motility also can be affected by primary ciliary dyskinesia in syndromes such as Kartagener’s syndrome and Usher’s syndrome. These also cause extratesticular problems, such as chronic sinusitis, bronchiectasis, and deafness. Both of these disorders can be treated by ICSI and in vitro fertilization because the problem is one of motility and not production. Systemic disorders that damage the testis or the pituitary can result in infertility. Common examples include sickle cell anemia and β-thalassemia. These disorders themselves do not cause infertility, but treatment with multiple blood transfusions increases total body iron, which can be deposited in the testis and pituitary. Hematochromatosis can result in infertility by a similar mechanism.
Reproductive Endocrinology and Infertility
SUMMARY Male factor infertility is a common cause of infertility in couples and comprises many diagnoses. Idiopathic male factor infertility is one of the most common subcategories of this disorder, although a genetic cause for many of these individuals is suggested. When no correctable diagnosis is identified, empiric therapy with techniques such as intrauterine insemination may be attempted. Realistically, ICSI should be attempted from the outset with moderate to severe male factor patients or when intrauterine insemination fails. ICSI has revolutionized male factor treatment, improving what was previously a dismal success rate to parity with all other diagnoses using assisted reproductive techniques. Nevertheless, concern has arisen that genetic transmission of disorders now may be possible because ICSI bypasses one of the barriers to fertilization in these previously infertile individuals. Further research is needed to address these concerns.
182
SUMMARY OF KEY POINTS 1. 2. 3. 4. 5.
Male infertility is responsible for 40% of all cases of difficulty conceiving. Endocrine abnormalities are an unusual cause of male factor infertility. Intracytoplasmic sperm injection has dramatically improved the success rates of moderate-to-severe male factor patients. Men with severe oligospermia or azoospermia should be offered genetic testing. The semen analysis is crucial in assessing an infertile couple and should be performed in virtually all men involved in an infertile relationship.
SUGGESTED READINGS Anguiano A, Oates RD, Amos JA, et al: Congenital bilateral absence of the vas deferens: a primarily genital form of cystic fibrosis. JAMA 1992; 267:1794. Carlsen E, Giwercman A, Keiding N, et al: Evidence for decreasing quality of semen during past 50 years. BMJ 1992;305:609. Howell SJ, Shalet SM: Testicular function following chemotherapy. Hum Reprod Update 2001; 7:363-369. Jarow J, Sharlip I, Belker A, et al: Best practice policies for male infertility. J Urol 2002;167:2138-2144. Joffe M: Infertility and environmental pollutants. Br Med Bull 2003;68:47-70. Johnson MD: Genetic risks of intracytoplasmic sperm injection in the treatment of male infertility: recommendations for genetic counseling and screening. Fertil Steril 1998;70:397.
Lenzi A, Lombardo F, Salacone P, et al: Stress, sexual dysfunctions, and male infertility. J Endocrinol Invest 2003;26(3 suppl):72-76. Maduro MR, Lamb DJ: Understanding the new genetics of male infertility. J Urol 2002;168:2197-2205. Meacham RB, Lipshultz LI, Howards SS: Male infertility. In Gillenwater JY, Grayhack JT, Howards SS, Duckett JW (eds): Adult and Pediatric Urology, 4 ed. Philadelphia: Lippincott Williams & Wilkins; 2002: 1747-1802. Munkelwitz R, Gilbert BR: Are boxer shorts really better? A critical analysis of the role of underwear type in male subfertility. J Urol 1998;160:1329. Mydlo J: The impact of obesity in urology. Urol Clin North Am 2004;31:275-287. Nudell D, Monoski M, Lipshultz L: Common medications and drugs: how they affect male fertility. Urol Clin North Am 2002;29:965-973.
Evaluation and Treatment of Male Infertility Oates RD, Amos JA: Congenital bilateral absence of the vas deferens in cystic fibrosis. World J Urol 1993;11:82. Rucker G, Mielnik A, King P, et al: Preoperative screen for genetic abnormalities in men with nonobstructive azoospermia before testicular sperm extraction. J Urol 1998;160:2068-2071. Sigman M, Lipshultz LI, Howards SS: Evaluation of the subfertile male. In Lipshultz LI, Howards
SS (eds): Infertility in the Male, 3rd ed. St. Louis: Mosby; 1997:530. Thompson ST: Prevention of male infertility: an update. Urol Clin North Am 1994;21:365-376. World Health Organization: WHO Laboratory Manual for the Examination of Human Semen and SpermCervical Interaction, 4th ed. Cambridge: Cambridge University Press; 1999.
183
12 OVULATION INDUCTION Lynda J. Wolf 185
DEFINITIONS Aromatase inhibitor Clomiphene citrate
Human chorionic gonadotropin Human menopausal gonadotropin
Ovulation
An alternative to clomiphene citrate ovulation induction; when estrogen levels are suppressed by the medication, the pituitary increases release of follicle-stimulating hormone to enhance follicular development A selective estrogen receptor modulator with a structure that allows it to bind to hypothalamic estrogen receptors; the hypothalamus is deceived into sensing a hypoestrogenic state, which enhances pulsatile gonadotropin-releasing hormone secretion A naturally occurring glycoprotein that is used as a luteinizing hormone surrogate to “trigger” ovulation when a mature graafian follicle is identified A glycoprotein derived from postmenopausal women or synthesized with recombinant technologies; consisting of either follicle-stimulating hormone (FSH) alone or a combination of FSH and luteinizing hormone, the glycoprotein is used to stimulate anovulatory women or hyperstimulate them for use in assisted reproductive technologies The precise coordination of hypothalamic, pituitary, and ovarian hormonal events to facilitate the expulsion of a fertilizable oocyte from the ovary
Ovulation requires the precise coordination of hormonal events in three locations: hypothalamus, pituitary gland, and ovary. Any interference in the complex interactions between these three organs results in the failure to develop and release an egg (Box 12-1). Ovulatory cycles vary from 24 to 35 days. Anovulatory cycles can be shorter or longer. Women with anovulation often have oligomenorrhea, or fewer than six spontaneous menstrual cycles in a year. The reduction in the number of ovulatory events prolongs the interval to conception. The goal of ovulation induction is to optimize the environment within the follicle to facilitate ovulation during each menstrual cycle.
Reproductive Endocrinology and Infertility
Box 12-1
World Health Organization Classification of Ovulatory Deficiencies
Type I: hypothalamic-pituitary failure/hypogonadotropic hypogonadism Hypothalamic amenorrhea Kallmann’s syndrome Isolated gonadotropin deficiency Type II: hypothalamic-pituitary dysfunction Normogonadotropic normogonadism Chronic anovulation secondary to hyperandrogenism (polycystic ovarian syndrome) Type III: ovarian failure/hypergonadotropic hypogonadism
Couples attempting to conceive during a spontaneous ovulatory cycle with a fertile male partner and patent fallopian tubes achieve a pregnancy in only 15% to 25% of cycles. It may take multiple attempts at ovulation induction to achieve a pregnancy.
186
EVALUATION The first step in the treatment of anovulation is the screening and correction of occult underlying medical conditions. A single fasting serum sample of thyroid-stimulating hormone, prolactin, dehydroepiandrosterone sulfate, 2-hour glucose tolerance test, and insulin are reasonable first steps. In women who have experienced prolonged anovulation without progestin treatment alone or with combined oral contraceptive preparations, an endometrial sampling to assess for endometrial hyperplasia is performed before initiating ovulation induction. Male partners are evaluated with a semen analysis. Tubal patency may be confirmed by hysterosalpingography, but some practitioners defer this until ovulation is established.
PHYSIOLOGY Ovulatory dysfunction is the cause of infertility in 40% of women presenting for treatment. Most of these women have hyperandrogenism resulting in anovulation, a condition referred to as polycystic ovarian syndrome (Fig. 12-1). Insulin resistance is the most common cause of hyperandrogenism. Obesity often exacerbates hyperandrogenism and must be treated to optimize therapy. Obesity impairs insulin receptor sensitivity. To compensate, the pancreas overproduces insulin, resulting in sustained elevations of circulating insulin levels (hyperinsulinemia). As weight increases, so does insulin resistance. Insulin receptors are ubiquitous, and chronic stimulation of these receptors leads to widespread pathology. In the liver, excess insulin suppresses the production of sex hormone–binding globulin resulting in a higher percentage of free circulating testosterone. In addition, insulin decreases hepatic insulin-like growth factor binding protein I production leading to increased bioavailable insulin-like growth factor I contributing to anovulation. In the ovary, insulin stimulates stromal cell
Ovulation Induction Figure 12-1 A and B, Unstimulated ultrasound appearance of the ovaries in a woman with chronic anovulation secondary to hyperandrogenism (polycystic ovarian syndrome).
187
Reproductive Endocrinology and Infertility
proliferation. The combination of elevated insulin levels and normal luteinizing hormone (LH) release from the hypothalamus amplifies the production of testosterone by thecal cells and contributes to premature arrest of follicular growth. In the adrenal gland, insulin increases sensitivity to adrenocorticotropic hormone stimulation, increasing the production and release of dehydroepiandrosterone sulfate.
TREATMENT OF CHRONIC ANOVULATION SECONDARY TO HYPERANDROGENISM Lifestyle Alterations
For an obese insulin-resistant woman undergoing ovulation induction, lifestyle alterations to bring about weight loss are an important part of therapy. Dietary interventions should focus on restricting calories and simple carbohydrates and increasing protein and fiber. Sustained physical activity is essential for weight loss. A minimum of 30 minutes of moderately intense exercise at least three times per week is recommended; daily exercise is strongly encouraged. Daily exercise promotes the uptake of insulin by the skeletal muscle. The sequestered insulin can remain in the skeletal muscle for 24 hours. Women participating in structured weight loss programs that include a behavior modification component do better than women attempting weight loss on their own. Women participating in a structured weight loss program of 6 months’ duration experienced an average weight loss of 15 lb. These previously anovulatory women had a 92% spontaneous ovulation rate and a 33% to 45% spontaneous pregnancy rate. Spontaneous abortions were reduced from 75% to 18%. These findings prove that lifestyle alterations that lead to weight loss of even a small percentage of the woman’s total weight can have a dramatic impact on the ability to achieve and carry a pregnancy.
InsulinSensitizing Agents
Metformin is an oral biguanide insulin-sensitizing agent that improves the action of insulin at the cellular level without affecting insulin secretion. It works through second messengers within the cells. Metformin inhibits hepatic glucose production without inducing hypoglycemia, while enhancing glucose uptake by skeletal muscle. Metformin decreases intestinal absorption of glucose. This action leads to an increase in the severity of gastrointestinal symptoms when the patient ingests meals high in simple carbohydrates. Gastrointestinal symptoms, including nausea, vomiting, bloating, and diarrhea, are common when initiating therapy. Taking metformin with meals, increasing the dosage slowly to 1.5 to 2 g/day, or changing to an extended-release formulation can reduce side effects. Reducing the ingestion of simple carbohydrates also reduces gastrointestinal symptoms. Many women taking metformin experience weight loss; women taking it for more than 6 months experienced an average weight loss of 16 lb. Many women taking metformin have an increase in sex hormone–binding globulin and a decline in insulin and androgen levels, which improve menstrual
188
Ovulation Induction
cyclicity. Spontaneous ovulation rates of 87% have been reported with pregnancy rates of 5% to 20%. Several small studies have shown a reduction in spontaneous abortion.
Clomiphene Citrate
Clomiphene citrate is a selective estrogen receptor modulator with a structure that allows it to bind to estrogen receptors. Clomiphene citrate occupies the receptor for weeks rather than hours. This prolonged binding interferes with estrogen receptor replenishment within the hypothalamus. With the binding of clomiphene citrate, the hypothalamus is unable to recognize the endogenous estrogen level and mistakenly interprets it as low. In response, the hypothalamus alters the pulsatility of the gonadotropin-releasing hormone secretion, resulting in increased pituitary release of follicle-stimulating hormone (FSH). This increased FSH initiates ste- 189 roidogenesis and folliculogenesis, resulting in growth of the ovarian follicle and an increase in the circulating level of estradiol. Ovulation occurs 5 to 10 days after the last pill in each course of therapy. After ovulation, progesterone and estradiol levels increase and decrease as they would in a normal ovulatory cycle. The actions of clomiphene citrate facilitate ovulation in 80% of women. Although not absolute, weight influences the dose at which an ovulatory response can be expected. Empirically, clomiphene citrate is initiated at a dose of 50 mg for 5 days during the early follicular phase (cycle days 3-5). In obese women weighing more than 200 lb, less than 20% ovulate when treated with a 50-mg course, with most requiring much larger doses. In these women, initiating therapy at a dose greater than 50 mg is acceptable. The dose of clomiphene citrate is increased by 50-mg increments to a maximum dose of 250 mg until ovulation is achieved. The package insert for clomiphene citrate stipulates that increasing the dose beyond 100 mg for 5 days is not recommended, and that if ovulation does not occur after three courses of therapy, further treatment is not recommended. In clinical practice, these recommendations would exclude from optimizing treatment many patients who ultimately conceive with clomiphene citrate. Doses of clomiphene citrate of 150 to 250 mg are used commonly and safely, although outside the dose approved by the Food and Drug Administration. In women who conceive with clomiphene citrate, 75% of pregnancies occur in the first three ovulatory cycles. Urinary LH surge detection is more sensitive than basal body temperature charting to confirm ovulation. In addition to home urinary LH screening, ultrasound may be used to help ascertain the appropriate dose to facilitate ovulation. To optimize the information gained from a single ultrasound study, it is best scheduled at least 5 days after the last pill of the clomiphene citrate course. Important indicators of a conception cycle include the number and size of preovulatory follicles. The lead follicle in a clomiphene citrate cycle grows to a larger mean diameter before the ovum is ready for release compared with a spontaneous cycle (Fig. 12-2). During the clomiphene citrate cycle, the preovulatory follicle reaches a mean diameter of 25 mm compared with 19 mm in a spontaneous ovulatory cycle. In ovulatory clomiphene citrate cycles in which the endometrium
Reproductive Endocrinology and Infertility Figure 12-2 Lead follicle in an ovulatory clomiphene citrate cycle with a mean diameter of 24 mm.
190
has been exposed to appropriate estrogen levels for an adequate duration, the endometrial lining has the same thickness compared with spontaneous ovulatory cycles, reaching an average thickness of 11 mm (Fig. 12-3). Even with an approximately 30% rate of multifollicular development, pregnancies achieved with clomiphene citrate are usually singletons, with a multiple pregnancy rate of only 8%. Most multiple pregnancies are twins. Triplet pregnancies account for only 0.5% of pregnancies, and quadruplets account for only 0.3% of pregnancies. The most common side effect of clomiphene citrate is hot flashes. Uncommonly, women taking clomiphene citrate may experience visual changes. The visual changes resolve without intervention by 1 week after the last pill. Headaches are another common side effect of clomiphene citrate. After ovulation, women may report discomfort including a sensation of abdominal fullness or bloating, pelvic pain, breast tenderness, and menorrhagia in a nonconception cycle. After a nonconception cycle, there may be a persistence of one or more corpora lutea cysts. These cysts are usually asymptomatic. There are no studies on the effect of these cysts on the outcome of subsequent clomiphene citrate cycles. Stimulation of an existing large ovarian cyst prevents resolution, however. A 1-month hiatus from clomiphene citrate allows for spontaneous resolution of the cyst. There is no role for the use of combined oral contraceptives to suppress ovarian cysts because they do not resolve the cyst any faster. Ovarian cysts that persist for more than 9 weeks are neoplasms or endometriomas rather than physiologic cysts. These persistent ovarian cysts should be removed before proceeding with additional ovulation induction.
Ovulation Induction Figure 12-3 Endometrial thickness in an ovulatory clomiphene citrate cycle.
191
Clomiphene Citrate and Ovarian Cancer The relationship between the use of clomiphene citrate and the subsequent development of ovarian cancer is controversial. Infertility may be the early expression of an underlying process that increases the risk of ovarian cancer. Women who are never able to conceive have an increased incidence of ovarian cancer. There are likely many cellular processes that culminate in ovarian cancer. Genetic, environmental, hormonal, and viral etiologies all have been implicated in the development of ovarian cancer. Clomiphene citrate induces ovulation disrupting the ovarian epithelium. The process of ovarian repair involves the invagination and entrapment of the surface epithelium rendering the epithelial cells vulnerable to malignant transformation. Other theories suggest that stimulation by estrogen, growth factors, follicular fluid, or gonadotropins may result in differentiation, proliferation, and ultimately malignant transformation. The published literature is contradictory. The most commonly cited study showing an increased risk of ovarian cancer in women exposed to clomiphene citrate is a retrospective study. The investigators relied on patient recall to ascertain the clomiphene citrate exposure. This study suggested that the use of 12 or more cycles of clomiphene citrate increased the risk of developing ovarian cancer. In this study, exposure to 1 to 11 cycles decreased the risk of ovarian cancer. The risk of ovarian cancer was increased only when borderline (low malignant potential) tumors were included, but the incidence of invasive cancer was not increased. Additional studies investigating clomiphene citrate use and the subsequent formation of borderline ovarian neoplasms have shown no increased risk. Many studies that have followed
Reproductive Endocrinology and Infertility
fertility patients and monitored them for the development of ovarian cancer have found no increased risk of invasive ovarian cancer. Patients receiving clomiphene citrate for ovulation induction should be advised of a potential increased risk of ovarian cancer if they never conceive. Pregnancy reduces this risk, likely offsetting any risk incurred by the use of clomiphene citrate. The uninterrupted extended use of clomiphene citrate is discouraged. Some patients repeat therapy after a pregnancy; risk of ovarian cancer in these patients is lowered by the previous pregnancy, and it is appropriate to repeat the clomiphene. When previous users of clomiphene citrate are not actively attempting to conceive, the use of combined oral contraceptives reduces their risk of ovarian cancer.
Adjuvants to Clomiphene Citrate Therapy 192
Glucocorticoids
The first medical treatment of chronic anovulation was adrenal suppression with cortisone. Since the introduction of clomiphene citrate, it has been combined with adrenal suppression to optimize ovulation induction. Adrenal androgens, particularly dehydroepiandrosterone sulfate and androstenedione, along with their metabolites estrone and testosterone, interfere with the hypothalamic-pituitary-ovarian axis. Suppression of the adrenal androgens is theorized to augment clomiphene citrate’s actions on the hypothalamus. In addition to suppressing adrenal androgens, glucocorticoids exacerbate insulin resistance. Hyperinsulinemia is detrimental to the developing follicle. The adjuvant use of glucocorticoids should be limited to patients with low insulin levels and high adrenal androgens.
Human Chorionic Gonadotropins
Human chorionic gonadotropin as an LH surrogate is an appropriate adjuvant to clomiphene citrate therapy in women without a detectable urinary LH surge despite ultrasound-confirmed adequate follicular development and endometrial proliferation. It is given as a 5000-U or 10,000-U intramuscular injection when a mature graafian follicle is identified.
Human Menopausal Gonadotropins
A threshold of FSH is required to support follicular development through ovulation. Some clomiphene citrate nonresponders initiate follicular development, but are unable to sustain adequate FSH to reach ovulation. These women may benefit from sequential clomiphene citrate and human menopausal gonadotropins (HMG). Clomiphene citrate is administered in the early follicular phase for 5 days immediately followed by a daily injection of HMG. Sequential cycles require careful monitoring to minimize the risk of multiple pregnancies and ovarian hyperstimulation syndrome. Monitoring with ultrasound is initiated after the fourth injection and continued until adequate follicular development is documented.
Aromatase Inhibitors for Ovulation Induction
The aromatase enzyme is the last step in the formation of estrogens. Blockage of the aromatase enzyme suppresses estrogen synthesis, resulting in markedly lower levels of estradiol and estrone. Administration of aromatase inhibitors in the early part of the menstrual cycles reduces estrogen
Ovulation Induction
levels, and in response the hypothalamus increases pituitary release of FSH, which enhances ovarian follicular development. Aromatase inhibitors have a shorter half-life than clomiphene citrate. There is no downregulation of estrogen receptors. Early studies using aromatase inhibitors showed ovulation in clomiphene citrate–resistant women.
Superovulation
Some women with chronic anovulation secondary to hyperandrogenism do not respond to clomiphene citrate despite the appropriate use of adjuvants or aromatase inhibitors or both. These women require HMG. Caution must be used in the administration of these preparations because of the large pool of recruitable follicles. These preparations have a narrow therapeutic range; the difference between the dose required to support adequate follicular development and hyperstimulation is small. Ovulation 193 induction with HMG requires careful monitoring. The judicious use of ultrasound and estradiol levels optimizes pregnancy rates, while minimizing complications. Severe ovarian hyperstimulation syndrome complicates 1% to 2% of HMG cycles. This syndrome is characterized by an increase in ovarian and peritoneal capillary permeability resulting in a fluid shift from the intravascular space to third space compartments. Vascular endothelial growth factor is one protein implicated in this process. This protein is produced in spontaneous ovulatory cycles to promote the rapid ingrowth of blood vessels into the corpus luteum to facilitate progesterone transport to the endothelium for secretory transformation, embryo attachment and implantation, and placentation. Ovarian hyperstimulation syndrome is a life-threatening condition (Box 12-2). It must be diagnosed and treated early (Box 12-3).
Box 12-2 ● ● ● ● ● ● ● ● ●
Pain Rapid weight gain Ascites Orthostatic hypotension Tachycardia Tachypnea Oliguria Hyponatremia Hyperkalemia
Box 12-3 ● ● ● ●
Clinical Features of Severe Ovarian Hyperstimulation Syndrome
Management of Severe Ovarian Hyperstimulation Syndrome
Intravenous hydration with normal saline Antiemetics Analgesics Paracentesis/culdocentesis
Reproductive Endocrinology and Infertility
OVULATION INDUCTION IN WOMEN WITH HYPOTHALAMIC AMENORRHEA Options for ovulation induction in women with hypothalamic amenorrhea are limited to HMG or gonadotropin-releasing hormones. Exogenous HMG response in women with hypothalamic amenorrhea varies. Some women are sensitive to low doses for a short time. Many women with hypothalamic amenorrhea require a prolonged stimulation, however, and high doses to prime the follicles. Women with hypothalamic amenorrhea also are at risk of multiple pregnancy and ovarian hyperstimulation syndrome and must be monitored appropriately with ultrasound studies and estradiol levels. Luteal phase and early pregnancy support is required for women with hypothalamic amenorrhea. The pituitary gland is unable to release LH, which is required to maintain the corpus luteum for progesterone production to prepare the endometrium for attachment, implantation, and early placentation. Progesterone alone or in combination with repeated lowdose human chorionic gonadotropins may be used for this necessary luteal support. Gonadotropin-releasing hormone is administered in pulses by a portable pump with an intravenous needle. Monitoring is similar to that required for HMG cycles. The pump, human chorionic gonadotropin, or progesterone can provide luteal support.
194
SUMMARY Anovulation is a common cause of infertility. Women with chronic anovulation secondary to hyperandrogenism are often able to conceive with a combination of lifestyle alterations and clomiphene citrate. In women who are resistant to clomiphene citrate, the use of combination therapy or aromatase inhibitors often results in pregnancy. Some women respond only to HMG. These women are at a higher risk of ovarian hyperstimulation syndrome and multiple pregnancies. In contrast, women with hypothalamic amenorrhea have limited options for ovulation induction, and their luteal phase and early pregnancy must be supported with hormones.
SUMMARY OF KEY POINTS 1. 2.
3. 4.
The goal of ovulation induction is to optimize the environment within the follicle to facilitate ovulation during each menstrual cycle. The first step in the treatment of anovulation is the screening and correction of occult underlying medical conditions, including insulin resistance, which is common. Lifestyle alterations, including dietary interventions and exercise that lead to weight loss, are an important part of therapy. Insulin-sensitizing drugs work in synergy with ovulation induction agents.
Ovulation Induction
5.
6. 7. 8.
Clomiphene citrate is a first-line agent in the treatment of anovulation in women with chronic anovulation secondary to hyperandrogenism. If clomiphene citrate alone is unsuccessful, adjuvants can be used to facilitate ovulation. Aromatase inhibitors can be used for ovulation induction in clomiphene citrate–resistant women. Superovulation with human menopausal gonadotropins has the highest risk of ovarian hyperstimulation syndrome and multiple pregnancy. Women with hypothalamic amenorrhea have limited options for ovulation induction, and their luteal phase and early pregnancy must be supported with hormones. 195
SUGGESTED READINGS Balen AH, Braat DDM, West C, et al: Cumulative conception and live birth rates after the treatment of anovulatory infertility: safety and efficacy of ovulation induction in 200 patients. Hum Reprod 1994;9:1563. Daly DC, Walters CA, Soto-Albors CE, et al: A randomized study of dexamethasone in ovulation induction with clomiphene citrate. Fertil Steril 1984;41:844. Dickey RP, Olar TT, Taylor SN, et al: Relationship of endometrial thickness and pattern to fecundity in ovulation induction cycles: effect of clomiphene citrate alone and with human menopausal gonadotropin. Fertil Steril 1993;59:756. Filicori M, Flamigni C, Dellai P, et al: Treatment of anovulation with pulsatile gonadotropin-releasing hormone: prognostic factors and clinical results in 600 cycles. J Clin Endocrinol Metab 1994;79(04):1215. Hoeger KM, Kochman L, Wixom N, et al: A randomized, 48-week, placebo-controlled trial of intensive lifestyle modification and/or metformin therapy in overweight women with polycystic ovary syndrome: a pilot study. Fertil Steril 2004;82:421.
Mitwally MFM, Casper RF: Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate. Fertil Steril 2001;75:305. Mosgaard BJ, Lidegaard O, Kjaer SK, et al: Infertility, fertility drugs, and invasive ovarian cancer, a casecontrol study. Fertil Steril 1997;67:1005. Novat D, Goldstein N, Mor-Joseph S, et al: Multiple pregnancies: risk factors and prognostic variables during ovulation induction with human menopausal gonadotropins. Hum Reprod 1991;6:1152. Opsahl MS, Robins ED, O’Connor DM, et al: Characteristics of gonadotropin response, follicular development, and endometrial growth and maturation across consecutive cycles of clomiphene citrate treatment. Fertil Steril 1996;6:533. Practice Committee of the American Society for Reproductive Medicine: Ovarian hyperstimulation syndrome. Fertil Steril 2003;80:1309. Steinkampf MP, Hammond KR, Blackwell RE, et al: Hormonal treatment of functional ovarian cysts: a randomized, prospective study. Fertil Steril 1990;54:775.
13 ANATOMIC INFERTILITY Mark Payson and Alicia Armstrong DEFINITIONS Diethylstilbestrol
Endometrial polyps Hysterosalpingogram Leiomyomata uteri
Saline sonohysterography Salpingitis isthmica nodosa Synechiae Uterine septa
An oral estrogen used from the 1930s to the early 1970s for relief of menopausal symptoms, spontaneous abortion, preterm labor, and preeclampsia; despite no convincing data of its efficacy, it was widely used and resulted in significant adverse outcomes in female infants exposed in utero Overproliferation of endometrial glands and stroma; may be associated with abnormal bleeding and impaired fertility A radiologic study employing fluoroscopy and plain film x-rays to assess the uterine cavity and patency of the fallopian tubes Benign smooth muscle tumors of the uterus, otherwise known as fibroids; although benign, their location in critical areas of the uterus, such as the endometrial cavity, may be associated with abnormal bleeding, infertility, and miscarriage An ultrasound procedure that employs normal saline in the endometrial cavity to delineate better irregularities in contour of the cavity that may suggest abnormalities such as polyps and fibroids Small diverticuli found in the proximal fallopian tube and associated with infertility Intrauterine adhesions resulting from prior surgical trauma or infection Failure of the embryologic septum to resorb, resulting in a fibrous midline structure variably separating the two sides of the uterine cavity; associated with recurrent spontaneous abortion
The technical definition of infertility requires 1 year of unprotected coitus without conception, but the criteria for initiating an evaluation also should consider the patient’s age and relevant medical diagnoses. Infertility is a widespread problem that affects millions worldwide; nearly 15% of couples attempting conception experience difficulty. The increase in the number of visits from less than 1 million in the late 1960s to more than 2 million in the early 1980s is evidence of the enormous impact of this diagnosis among reproductive-age couples. By the mid-1990s, approximately 17% of reproductive-age women sought medical help during their lifetimes as a result of infertility; an estimated 5 million couples in the United States alone sought help.
197
Reproductive Endocrinology and Infertility
Excluding the category of idiopathic infertility, a diagnosis for infertility can be made approximately 80% of the time. These diagnoses are divided equally between male factor and female factor. Approximately 60% of women younger than age 35 have anatomic infertility as the primary cause; most of these women have tubal factor, with 5% or less having a diagnosis of cervical factor. Together, tubal and pelvic pathologies are responsible for nearly half of female factor infertility. Numerous societal factors have played a pivotal role in the rise in tubal factor infertility. The dramatic increase in sexually transmitted disease in the last several decades is clearly linked to the increasing numbers of women with tubal infertility. The impact of infections on future fertility has been well documented by multiple investigators. One widely cited study indicated that the incidence of tubal infertility is 12% after one pelvic infection, increasing to 23% after two infections and 54% after three infections. In addition to infertility, there is a sixfold to sevenfold increase in the risk of ectopic pregnancy, which remains a major cause of maternal mortality in the first trimester. Despite the threat of HIV transmission, at-risk sexual behavior continues to contribute to the high prevalence of chlamydia and gonorrhea among young adults, which contributes to the ever-increasing numbers of women with tubal and pelvic pathologies. Although the incidence of tubal factor is far greater than that of cervical or uterine factors, evaluation for these causes of infertility is a crucial part of the basic infertility evaluation. This chapter reviews the following topics:
198
1. Normal anatomy and congenital anomalies of the female reproductive tract 2. Acquired pathology of the uterus, cervix, and fallopian tubes 3. Evaluation of anatomic infertility 4. New and future therapies
ANATOMY, PHYSIOLOGY, AND CLINICAL PRESENTATION OF UTERINE FACTOR INFERTILITY Anatomy and Physiology of Congenital Anomalies
Congenital abnormalities of the reproductive tract occur in 1 in 200 women. These disorders may manifest first as reproductive problems, such as infertility or recurrent pregnancy loss. Although not a common cause of infertility, it is easy to screen for these frequently treatable anomalies in the initial infertility evaluation.
Embryology
A basic understanding of reproductive system embryology simplifies an otherwise confusing array of congenital defects. These problems are the result of failures at various stages of ontogeny: (1) failures of development, (2) failure of descent, and (3) failure of fusion or resorption or both.
Normal Development
The genital structures begin at the indifferent stage (7 weeks) with female and male embryos having two pairs of genital ducts. The mesonephric (wolffian
Anatomic Infertility
ducts) remain and develop male gonads in the presence of Y chromosome encoded testis determining factor. In contrast, the paramesonephric (müllerian ducts) persist if there is an absence of a signal to differentiate along the male pathway. In the female, the wolffian ducts disappear, and the müllerian ducts give rise to the fallopian tubes, uterus, and superior vagina. The genital ducts lengthen into paired tubular structures, which fuse in the midline. At their caudal end, they join the urogenital sinus. The wall between the two uterine tubes is resorbed producing the uterus, and the tissue between the distal end of the wolffian ducts and the urogenital sinus canalizes forming a patent vagina (Fig. 13-1).
Congenital Anomalies
Congenital Anomalies and Infertility
The most severe anomaly is congenital absence of müllerian structures. 199 Mayer-Rokitansky-Küster-Hauser syndrome has an incidence of 1 in 4000. Individuals with this disorder have absence of the uterus and fallopian tubes with a foreshortened vaginal pouch. As a result of the presence of normal ovaries, affected individuals otherwise develop as phenotypically normal women and present with primary amenorrhea. Genetic offspring are possible through the use of the patient’s oocytes and a surrogate carrier. Failure of one of the müllerian ducts to develop produces a unicornuate uterus on the contralateral side. If there is partial development of one side, there is a rudimentary horn adjacent to the “normal” side. If the uterine horns form normally, failure of the septum to resorb can leave residual tissue that ranges from the clinically insignificant arcuate uterus to a uterine septum of variable length that may extend to the vagina. Failure of the vagina to canalize results in a transverse vaginal septum, which can range from a thin layer of tissue to extensive replacement of the vagina with fibrous tissue. In the evaluation of a patient discovered to have a müllerian abnormality, it is important to evaluate the renal system because these patients are prone to have abnormalities of the kidneys and ureters. When renal anomalies do occur, they are likely to be ipsilateral to the müllerian abnormality because of the intertwined development of the urinary and genital systems. Müllerian abnormalities arise from disorders of embryologic development, and these structural aberrations may not be discrete from each other. These disorders occur on a continuum, and they can be seen in combination with each other. They can be understood by applying the principles of embryologic development. This explains the periodic case reports of “new” variants that do not seem to fit classic patterns.
The impact on fertility of disorders such as outflow tract obstruction and uterine agenesis is clear. Most of these patients are diagnosed before attempts at conception, either as children or when they present with primary amenorrhea. More difficult are uterine abnormalities diagnosed because of difficulty with conception or after recurrent pregnancy loss. Generally, any structural abnormality in the uterus leads to a decrease in fertility and an increase in abortion and preterm delivery. The diagnosis and management of anomalies
Reproductive Endocrinology and Infertility Figure 13-1 Embryology and congenital abnormalities of the uterus. A, The müllerian horns have fused side-to-side, leaving a septum still in place and abutting the urogenital sinus (9 weeks). B, The septum has resorbed, but the cervix has not resorbed (12 weeks). C, Normally formed uterus with cervix 200 patent to vagina. D, Unicornuate uterus (right-sided) representing a fully developed onehorned uterus. E, Bicornuate uterus. Uterine horns fused only at the level of the cervix. F, Septate uterus secondary to lack of complete resorption of septum (seen in A).
A
D
B
C
E
F
that become evident as a result of an infertility evaluation or the investigation of recurrent pregnancy loss are more difficult to evaluate and to treat.
Impact of Diethylstilbestrol
Diethylstilbestrol (DES), an oral estrogen, was first synthesized in 1933. It was used for the control of menopausal symptoms, primarily hot flashes, in the 1930s and 1940s. In 1948, its efficacy in preventing miscarriage, preterm labor, and preeclampsia was publicized. DES became widely used in pregnant women in the United States in the 1950s and 1960s, despite a series of randomized trials that showed no efficacy. DES was even included in some prenatal vitamin formulations. Use of DES was halted in 1971 with the discovery of an association between clear cell adenocarcinoma of the vagina and in utero exposure to the drug. It is estimated that 2 million U.S. women used DES during their pregnancy. DES also caused several reproductive tract abnormalities. The uterus may be malformed with a T-shaped hypoplastic cavity or with intrauterine adhesions (synechiae). Abnormality of fallopian tubes and an increase in ectopic pregnancy have been reported. A “cockscomb cervix” or a cervix with pseudopolyps also is often present. In the absence of reproductive tract abnormalities, the effect of in utero DES exposure on infertility is controversial, with most women with DES
Anatomic Infertility
exposure having little difficulty with reproduction. In the presence of structural abnormalities, these patients have problems with maintenance of pregnancy often seen in patients with structural uterine anomalies. In 2005, the youngest DES-exposed women were 34 years old. Although this cohort of women will be seen less and less often in the evaluation of infertility, the lessons of DES should not be forgotten: It is crucial to test new medications properly and to adhere to careful study design.
Acquired Anomalies
Similar to congenital abnormalities, acquired abnormalities of müllerian structures can affect reproductive outcomes. Uterine fibroids can interfere with implantation, and fallopian tube damage can inhibit egg transport. The two most common causes of acquired anatomic infertility are fibroids and infection. 201
Uterine Synechiae In 1948, Asherman described intrauterine adhesions (synechiae) after uterine curettage. This syndrome frequently is associated with a clinical history of menstrual irregularities, abortion, and infertility. The severity of the synechiae is measured by the degree of obliteration of the cavity (Fig. 13-2). Most cases of Asherman’s syndrome develop after dilation and curettage, as part of a termination procedure, a missed abortion, or postpartum for retained placenta. The instrumentation of the endometrium at this sensitive phase predisposes to anterior-to-posterior scarring of the uterus. Infection in the form of endometritis can cause adhesions, and instrumentation in the face of infection is a particularly high-risk setting. Dilation and curettage for a septic abortion presents the highest risk of developing Asherman’s syndrome. A scoring system for assessment of the severity of uterine synechiae was published by the American Fertility Society. Polyps Endometrial polyps, overproliferation of endometrial glands and stroma, are found in about 15% of asymptomatic women. These lesions are usually benign and often regress spontaneously. The most common symptom associated with these lesions is the development of abnormal uterine bleeding. Similar to intracavitary fibroids, polyps may interfere with fertility, presumably through an effect on implantation. The ultrasound appearance of polyps also can be similar to intracavitary fibroids. It is standard practice in many in vitro fertilization (IVF) centers to screen for and remove any polyps found before assisted reproductive technique procedures. It also is important that polyps be evaluated to rule out hyperplasia or malignancy, particularly in postmenopausal women. Leiomyomata Commonly known as fibroids, leiomyomata are benign smooth muscle tumors of the uterus. Leiomyomata represent an extremely common disorder; 25% of women have symptoms of fibroids at some time in their life.
Reproductive Endocrinology and Infertility Figure 13-2 HSG of Asherman’s syndrome. Note the central obliteration of the uterine cavity.
202
The cause of fibroids is unknown; they are monoclonal and can range from many small tumors to tumors that fill the abdominal cavity and weigh several kilograms. Fibroids can be found in multiple locations within the uterus. They can be polypoid masses in the uterine cavity (intracavitary), immediately beneath the endometrium (submucosal), within the wall of the uterus (intramural), immediately beneath the uterine serosa (subserosal), arising from the surface of the uterus (pedunculated), in the cervix, or in the broad ligament. Rate of growth and size vary (Fig. 13-3). Depending on size and location, fibroids can cause menorrhagia, pressure, pain, and urinary frequency, all of which are gynecologic indications for intervention. From a fertility point of view, the clinical impact of fibroids likely is determined by their location. An intracavitary fibroid can function as an intrauterine device and prevent pregnancy. A fibroid that pushes into the endometrial cavity and distorts it decreases fecundity and leads to an increased risk of abortion or preterm delivery. Intramural fibroids greater than 2.5 cm in diameter may decrease pregnancy rates in IVF by interfering with implantation. Fibroids distorting the cervix can lead to cervical incompetence or labor dystocia. Leiomyomata also can increase markedly the complexity and morbidity of cesarean section. Most studies evaluating
Anatomic Infertility Figure 13-3 MRI of fibroid.
203
the impact of fibroids on infertility are uncontrolled, so it is difficult to assess their true importance. The imaging study of choice for fibroids is transvaginal ultrasound followed by saline sonography. The location and position of fibroids and any distortion of the cavity can be documented, and impact of the fibroids on the cavity can be assessed. If there are no large intramural fibroids, and the uterine cavity distends normally, the patient can be reassured that fibroids should not have a significant effect on fertility. Fibroids typically increase in size during reproductive life, although the rate of growth varies.
ANATOMY, PHYSIOLOGY, AND CLINICAL PRESENTATION OF TUBAL INFERTILITY The fallopian tubes are more than conduits for oocytes. As the site of fertilization, fallopian tubes must facilitate the passage of ova and sperm in opposite
Reproductive Endocrinology and Infertility
directions and transport the zygote to the uterus. Internal and external damage of the fallopian tube can inhibit these functions. Obstruction of the fimbriated end of the fallopian tube prevents egg transport and causes infertility. Intrapelvic inflammation, from any cause, often leads to adhesions and distortion of anatomy. This anatomic distortion can be caused by a ruptured appendix, pelvic infection, intraperitoneal spread of infection arising from the fallopian tubes, or endometriosis. A ruptured appendix rarely causes infertility and usually does not cause more than a unilateral (right) tubal blockage. Endometriosis can cause significant damage to the distal fallopian tube and ovaries, which are further evidence for the theory of retrograde menstruation as a cause of endometriosis. Pelvic inflammatory disease may cause adhesions throughout the pelvis. The presence of adhesions localized to the liver (Fitz-Hugh-Curtis syndrome) should be considered anatomic evidence of a history of chlamydial pelvic infection.
204
Intraluminal Tubal Disease
The most common form of tubal disease occurs within the fallopian tube and is often the result of a chlamydial infection. Many cases of chlamydial salpingitis are clinically silent, and the patient may not be aware of past infection. The disruption of tubal microarchitecture, important for normal reproductive function, not only increases the risk of infertility, but also the risk of ectopic pregnancy. It is estimated that after one episode of pelvic inflammatory disease the rate of infertility is 12%, increasing to 25% and 50% after the second and third infections. The risk of ectopic pregnancy increases in a similar fashion. The classic finding of tubal disease is a hydrosalpinx, a fallopian tube that has been dilated to many times its normal diameter and is filled with fluid. The presence of a hydrosalpinx not only may explain the cause of a woman’s infertility, but it also interferes with the success of assisted reproductive techniques; the presence of a hydrosalpinx decreases the success rate of IVF by 30% (Fig. 13-4). Although less common than distal tubal occlusion, disease arising in the proximal portion of the fallopian tube is also an important cause of anatomic infertility. Salpingitis isthmica nodosa, a rare condition, is diagnosed by the finding of small diverticuli along the proximal portion of the tube on hysterosalpingogram (HSG). Its etiology is unknown. Salpingitis isthmica nodosa is seen in 60% of tubal specimens removed as a result of ectopic pregnancy, and it has been associated with infertility (Fig. 13-5). Tubal disease is diagnosed by HSG, which is the best method to establish intraluminal disease. External tubal adhesive disease may be suspected on HSG, but is best confirmed with laparoscopy.
Anatomic Infertility Figure 13-4 HSG of hydrosalpinx. Note the sausageshaped fallopian tubes.
205
Figure 13-5 HSG of salpingitis isthmica nodosa (arrows). (From Letterie G: Structural Abnormalities and Reproductive Failure. Blackwell Scientific, Malden, MA: Publications; 1998:377.)
Reproductive Endocrinology and Infertility
ANATOMY, PHYSIOLOGY, AND CLINICAL PRESENTATION OF CERVICAL FACTOR INFERTILITY The cervix is more than the anatomic path between the vagina and cervix. It also serves as a barrier to ascending infection and serves as a filter and reservoir of sperm in the periovulatory period. During this period in the cycle, the cervical mucus increases in quantity and decreases in viscosity, further facilitating sperm transport. The concept of “cervical factor infertility” is controversial. Cervical factor infertility is based on the theoretical principle that there may be some abnormality in the sperm–cervical mucus interaction that is responsible for the disruption of normal sperm transport; this is evaluated by the postcoital test, an examination that has little scientific support. The test involves sampling periovulatory cervical mucus for ferning, cervical mucus consistency, and the presence of motile sperm within 12 hours of intercourse. This test is rarely used in the evaluation of infertile couples because of poor sensitivity, poor specificity, high percentage of abnormal tests in fertile couples, and lack of reproducibility. Perhaps the only useful purpose of the test is to document that intercourse successfully occurred. The one cervical abnormality that has been clearly linked to poor obstetric outcomes is cervical incompetence. Women with this disorder experience painless dilation that can lead to multiple early pregnancy losses or preterm birth. A complex problem managed by perinatologists, cervical incompetence often requires ultrasound surveillance of cervical length. Prophylactic and emergent management frequently require operative intervention using cervical cerclage and tocolytics. Cervical incompetence is not a cause of infertility, but a cause of recurrent pregnancy loss. Recurrent pregnancy loss is discussed in greater detail in Chapter 16. Surgery or trauma to the cervix, whether from delivery, cesarean section, or removal of a portion of the cervix for treatment of precancerous lesions, may cause cervical incompetence, but has little effect on fertility.
206
DIAGNOSTIC TESTING FOR ANATOMIC INFERTILITY Uterine anomalies may be suspected by a history of amenorrhea, pain, or reproductive difficulties. A physical examination determines normal external genitalia, vagina, cervix, and the presence of a uterus. HSG delineates whether or not the uterine cavity and tubal architecture are normal. If there is an abnormal finding on physical examination or HSG, it is prudent to evaluate further with a transvaginal ultrasound and saline sonogram. In some cases associated with developmental abnormalities, magnetic resonance imaging (MRI) may be necessary (Fig. 13-6 and 13-7).
Hysterosalpingogram
HSG is a crucial part of the initial infertility evaluation and should be offered to most patients. The study should be performed in the early follicular phase after the cessation of menses. If tenderness or masses are present on physical
Anatomic Infertility Figure 13-6 MRI of bicornuate uterus (arrow and arrowheads). (From Letterie G: Structural Abnormalities and Reproductive Failure. Blackwell Scientific, Malden, MA: Publications; 1998:1550.)
207
Flow chart for evaluation of anatomic infertility.
Figure 13-7 HSG
Severe tubal disease patient > 36 even if minimal
Minimal tubal disease patient < 35
IVF
Laparoscopy
Uterine cavity abnormality
Saline sonography with abnormal cavity
Hysteroscopic polypectomy or myomectomy
Myomectomy for intramural or large Leiomyoma
MRI confirmation congenital abnormalities
Surgical correction septum; rudimentary uterine horn
Reproductive Endocrinology and Infertility
examination, or if the patient has a history of tubo-ovarian abscesses, pelvic anatomy should be evaluated by laparoscopy. A history of pelvic infections is not an absolute contraindication to HSG because even high-risk patients have a less than 5% chance of serious infections. Patients with risk factors should receive antibiotics before the HSG, however, and patients who have evidence of tubal disease should receive postprocedure antibiotic therapy. Doxycycline, 100 mg twice daily the day before, the day of, and the day after the procedure, should suffice. Numerous radiographic findings on HSG are possible in the presence of tubal disease. Distal tubal disease can be manifested as mild dilation or large hydrosalpinges with absent mucosal folds. Salpingitis isthmica nodosum usually is evidenced by radiographic findings in the proximal tube. Many congenital anomalies, such as uterus didelphys, require additional studies for confirmation. Two common abnormalities, uterine synechiae and a uterine septum, frequently can be detected by HSG. As previously mentioned, not all uterine anomalies should be surgically corrected, underscoring the importance of an accurate diagnosis. Cavitary abnormalities, including leiomyomata, which distort the cavity, may be suggested by transvaginal ultrasound, but are best documented by saline sonohysterography. Cavitary abnormalities found on saline sonohysterography can be confirmed and frequently corrected by hysteroscopy. Hysteroscopy is best reserved for patients who are likely to need surgical intervention.
208
Magnetic Resonance Imaging
MRI is a noninvasive method for evaluating further uterine anomalies found on HSG or ultrasound. Before the widespread use of this radiographic technique, laparoscopy or laparotomy was often required to differentiate such entities as bicornuate uterus and uterine septum. Because management depends on diagnosis, a radiographic test that does not carry the risk and cost of surgery is invaluable. HSG technique should be part of residency training and is one of the Council on Resident Education in Obstetrics and Gynecology educational objectives
THERAPEUTIC INTERVENTIONS Abnormalities of the Uterus
Unicornuate Uterus Although term pregnancy may be achieved in the presence of a unicornuate uterus, there is an increased risk of preterm birth and malpresentation. Unicornuate uterus probably does not decrease long-term fertility, but may reduce fecundity or the ability to achieve a live birth within one menstrual cycle by increasing the time to conception. The possibility of a uterine anomaly always should be considered in a term infant that is persistently breech. In a woman with multiple early losses and a unicornuate uterus, cervical cerclage can be considered, but because of the potential morbidity of such a procedure, its prophylactic use in a first pregnancy is controversial.
Anatomic Infertility
A unicornuate uterus with a rudimentary horn presents a greater problem. If the horn does not communicate with the vagina, it can be a source of pain owing to retained menstrual bleeding and can lead to pain through endometriosis that results from retrograde menstruation. Pregnancy may occur because sperm can transmigrate from the contralateral fallopian tube, leading to a pregnancy in the rudimentary horn. A pregnancy in the rudimentary uterus can be life-threatening if rupture and hemorrhage occur. It is recommended that a rudimentary horn be removed because of these potential morbidities; this procedure often can be accomplished laparoscopically. A bicornuate uterus should not be surgically corrected. Various attempts at uterine reunification procedures have only worsened morbidity and outcomes. Similar to women with a unicornuate uterus, these women have the potential for normal obstetric outcomes. 209
Uterine Septa Uterine septa, which are a common anomaly, have a similar appearance to a bicornuate uterus on HSG and frequently are associated with miscarriage. After confirmation of the diagnosis, which often includes studies such as ultrasound and MRI, a careful resection of the septum can be undertaken. This is generally a hysteroscopic procedure. Laparoscopy can aid in the prevention of and early recognition of injuries in complex cases. The finding of “arcuate uterus,” or an indentation of the myometrium into the fundal portion of uterine cavity, should be considered a normal variant. Although embryologically it may be the mildest form of septum, it does not have adverse reproductive consequences, and patients should be reassured that surgical intervention is unnecessary. Uterine Synechiae Patients who have radiographic evidence of uterine synechiae are best managed surgically. Hysteroscopic lysis of adhesions, followed by estrogen therapy to promote regeneration of the endometrium, is the recommended therapy for patients with this diagnosis. Hysteroscopy frequently is performed under laparoscopic guidance to decrease the likelihood of uterine injury and to facilitate the early recognition of uterine perforation. Patients should be counseled that they may require multiple hysteroscopic procedures as a result of adhesion reformation. In severe cases, it may not be possible to restore a functional endometrium. Leiomyoma If the primary indication for treatment of leiomyoma is fertility or pregnancy loss, surgical removal is the treatment of choice. Intracavitary and submucosal fibroids that protrude 50% or more into the cavity can be removed hysteroscopically. Larger fibroids and intramural fibroids often require laparotomy and extensive dissection into the myometrium. In most cases, the removal of intramural fibroids or any procedure that requires deep dissection into the myometrium requires all future births to be via cesarean section because of an unacceptably increased risk of uterine rupture in labor.
Reproductive Endocrinology and Infertility
Cervical Abnormalities
Cervical stenosis and its impact on sperm transport and fertility have been poorly studied. If the cervix remains sufficiently patent to permit menstruation, sperm transport also should be possible. The use of intrauterine insemination bypasses the cervix and is a simple and minimally invasive treatment for infertility that is possible in most couples except in cases of severe stenosis. Intrauterine insemination obviates the cervix as a possible cause of infertility and eliminates the need for testing, which is inconvenient and lacks scientific evidence.
Abnormalities of the Fallopian Tube
The surgical treatment of tubal disease is often disappointing, and many patients are best served by proceeding to IVF rather than surgery. When performed properly, laparoscopy has been found to be just as effective as laparotomy in pregnancy rates achieved based on the extent of adhesions found at the time of surgery. As would be expected, mild disease is associated with the best outcomes, and approximately two thirds of these women achieve a pregnancy within 3 years of the surgery. Moderate disease has an intermediate response with 30% to 40% of women achieving pregnancy within the same time period. Women with severe disease rarely get pregnant, regardless of the length of observation. Operative correction of tubal disease does not restore pregnancy rates to baseline. Surgery not only is associated with lower pregnancy rates compared with IVF, but it also is associated with an increased risk of ectopic pregnancy. Pelvic infection is rarely a unilateral disease. If there is gross evidence of unilateral tubal damage, bilateral tubal damage should be assumed. The “unaffected” tube is likely to have histologic evidence of disruption of the microarchitecture and would not be a normal conduit for a pregnancy. As previously noted, the treatment of mild tubal disease with relatively normalappearing fimbria in a patient younger than 35 years old may be beneficial. In light of the 30% decrease in IVF pregnancy rates associated with hydrosalpinges, salpingectomy or proximal tubal occlusion should be considered when they are shown by ultrasound before IVF. Although the ectopic pregnancy rate associated with IVF is lower than the rate associated with tubal surgery, salpingectomy can decrease that risk further.
210
SUMMARY OF KEY POINTS 1.
2. 3.
4.
Congenital abnormalities are due to embryologic failure of development and fusion of the paired müllerian ducts and can lead to infertility and premature delivery. Not all anomalies require surgical correction, and management and counseling should be based on the type of anomaly. DES, a synthetic estrogen, was widely used in the 1950s and 1960s. In utero exposure leads to an increased risk of clear cell adenocarcinoma of the vagina and structural abnormalities of the uterus, cervix, and fallopian tubes. HSG is the best screening method for tubal disease.
Anatomic Infertility
5. 6.
7. 8.
Patients older than age 35 and all patients with severe tubal disease have higher pregnancy rates and lower ectopic pregnancy rates with IVF. HSG is the initial screening method of choice for acquired uterine abnormalities. Saline sonohysterography frequently is needed to confirm these findings before hysteroscopic correction. The management of a leiomyoma that affects fertility depends on size, location, reproductive history, and future plans for achieving conception. Intrauterine insemination obviates the cervix as a possible cause of infertility and eliminates the need for testing, which is inconvenient and lacks scientific evidence.
211
SUGGESTED READINGS Council on Resident Education in Obstetrics and Gynecology: Core Curriculum in Obstetrics and Gynecology, 7th ed. Washington, DC: Council on Resident Education in Obstetrics and Gynecology; 2002. Donnez J, Nisolle M: An Atlas of Operative Laparoscopy and Hysteroscopy, 2nd ed. New York: Parthenon Publishing Group; 2001. Lepine LA, Hillis SD, Marchbanks PA, et al: Severity of pelvic inflammatory disease as a predictor of the probability of live birth. Am J Obstet Gynecol 1998;178:977-981.
Letterie, G: Structural Abnormalities and Reproductive Failure. Malden, MA: Blackwell Science;1998. Peterson H, Walker CK, Kahn JG, et al: Pelvic inflammatory disease: key treatment issues and options. JAMA 1991;266:2605-2611. Speroff L, Fritz MA (eds): Clinical Gynecologic Endocrinology and Infertility, 7th ed. Philadelphia: Lippincott, Williams & Wilkins; 2005.
14 ENDOMETRIOSIS Richard Scott Lucidi and Craig A. Witz DEFINITIONS Dyschezia Dysmenorrhea Dyspareunia Fecundability Fecundity
The presence of pain with defecation Pain or discomfort associated with menstruation The presence of pain during intercourse The probability of conceiving a pregnancy in one cycle The probability of conceiving a pregnancy that results in a live birth in one cycle
Endometriosis, defined as the presence of endometrial glands and stroma outside of the uterine cavity (Fig. 14-1), is a common benign gynecologic disorder, affecting approximately 5% of the general population and 30% or more of infertile women. It was first described as a disease process 300 years ago. In the late 17th century, it was recognized as peritoneal “ulcers” occurring on the surface of the bladder, intestine, and surface of the uterus. Von Rokitansky described the disease in detail in 1860. With improvements in microscopy, the growth of ectopic endometrial tissue was identified as the cause of these lesions.
PATHOPHYSIOLOGY Theories
Although the cause of endometriotic lesions remains undefined, various theories have been promulgated to explain the pathogenesis of endometriosis. This section describes the different theories of histogenesis and discusses current understanding of the contribution of the immune system to the etiology of endometriosis.
Implantation Theory The implantation theory proposes that endometrial tissue passes through the fallopian tubes then attaches and proliferates at ectopic sites in the peritoneal cavity. This mechanism of histogenesis is often referred to as Sampson’s theory and suggests that endometriotic implants result from menstrual flow through the fallopian tubes. More recent studies using laparoscopy have shown that retrograde menstruation is a nearly universal phenomenon in women with patent fallopian tubes, showing that endometrial cells can access the peritoneal cavity through the fallopian tubes. Other studies have
213
Reproductive Endocrinology and Infertility Figure 14-1
214
Histologic appearance of endometriosis. The specimen is from a resection of the anterior rectal wall. Endometriosis was seen throughout the bowel wall from serosa to rectal mucosa. Endometrial glands and stroma are seen in this micrograph. (Original magnification ×100.)
shown that sloughed menstrual endometrial cells remain viable and have the capacity to implant at ectopic sites. Cases of iatrogenically derived endometriosis resulting from mechanical transplantation of endometrium also support the implantation theory. There are numerous case reports of endometriosis in episiotomy and laparotomy scars after vaginal delivery and cesarean section. Similarly, endometriosis has occurred remote from pregnancy in umbilical incisions after laparoscopic tubal ligation and in needle tracts after amniocentesis. Several “natural experiments” support the implantation model of peritoneal endometriosis. Patients with müllerian anomalies and obstructed menstrual flow through the vagina have an increased risk of endometriosis. The anatomic distribution of endometriosis also provides evidence for Sampson’s theory with an increased frequency of endometriotic implants in the dependent areas of the pelvis where pooling of menstrual debris is expected.
Coelomic Metaplasia Theory The theory of coelomic metaplasia holds that endometriosis develops from metaplasia of cells lining the pelvic peritoneum. Iwanoff and Meyer are recognized as the originators of this theory. This theory is based on embryologic studies showing that müllerian ducts, germinal epithelium of the ovary, and pelvic peritoneum all are derived from the same embryologic precursor. A prerequisite of the coelomic metaplasia theory is that germinal epithelium and pelvic peritoneum contain cells capable of differentiating into endometrial cells or that these cells may dedifferentiate and later acquire the capacity for further development into endometrium. The coelomic metaplasia theory is attractive in that it can account for the occurrence of endometriosis anywhere in the abdominal cavity and in the
Endometriosis
thoracic cavity. In cases of pulmonary endometriosis, the pleura are most commonly affected. Pleural endometriosis could result from local metaplasia of pleural epithelium. It also could result from transdiaphragmatic passage of peritoneal fragments of endometrium and vascular metastasis of endometrium. The rare occurrence of endometriosis in men is often taken as proof of the coelomic metaplasia theory. In these reported cases of endometriosis, however, the men all were undergoing estrogen therapy, and the location of endometriosis did not exclude the possibility that it resulted from müllerian rests stimulated by exogenous hormones.
Induction Theory The induction theory is an extension of the coelomic metaplasia theory. This theory postulates that retrograde menstruated endometrium produces 215 substances that induce peritoneal tissues to form endometriosis by dedifferentiation and subsequent metaplasia. Embryonic Rests Theory Von Recklinghausen and Russell are credited with the theory that endometriosis results from embryonic cell rests. This theory suggests that, in the presence of a specific stimulus, cell rests of müllerian origin could be activated to form functioning endometrium. Although embryonic cell rests are common in the ovary, there is no evidence that they develop into endometriosis. As described previously, however, rare cases of endometriosis have been reported in men, and transformation of embryonic rests is a plausible explanation for this phenomenon. Lymphatic and Vascular Metastasis Theories The lymphatic metastasis theory of endometriosis often is referred to as Halban’s theory. Halban reported that endometriosis could arise in the retroperitoneum and in sites not directly apposed to peritoneum. Sampson also had suggested that endometriosis could result from lymphatic and hematogenous dissemination of endometrial cells. Subsequently, considerable evidence has accumulated suggesting that endometrial cells can metastasize via lymphatic and hematogenous routes. An extensive communication of lymphatics has been shown between the uterus, ovaries, tubes, pelvic and vaginal lymph nodes, kidney, and umbilicus. Metastasis of endometrial cells via the lymphatic system to these areas is anatomically possible. Venous and lymphatic transportation of intrauterine contents (i.e., trophoblasts, amniotic fluid, and fetal squames) is now a well-recognized phenomenon. Experimental demonstration that intravenous injection of endometrium can produce pulmonary endometriosis in the rabbit further supports the theory of venous metastasis. Lymphatic and vascular metastasis of endometrium has been offered as an explanation for rare cases of endometriosis occurring in locations remote from the peritoneal cavity. In addition to pleural tissue, endometriosis has been reported in pulmonary parenchyma, bone, muscle, peripheral nerves, and the brain.
Reproductive Endocrinology and Infertility
Composite Theory Javert proposed a composite theory of the histogenesis of endometriosis that combines implantation and vascular/lymphatic metastasis and a theory of direct extension of endometrial tissue through the myometrium. According to the composite theory, the histogenesis of endometriosis depends on the location and “type” of the endometriotic implant. Peritoneal endometriosis can be explained by the implantation theory. Ovarian endometriomas could be the result of coelomic metaplasia of invaginated ovarian epithelial inclusions. Rectovaginal endometriosis, which often resembles adenomyosis, could result from metaplasia of müllerian remnants located in the rectovaginal septum. The composite theory is attractive in that it recognizes a multifaceted mechanism of histogenesis. It seems logical that a disease with such protean manifestations may originate via several mechanisms, and that no single theory can explain every case of endometriosis.
216
Genetic Factors
It has long been thought that endometriosis has a genetic basis. Although there does not seem to be an association with HLA haplotypes, there is an increased prevalence of endometriosis in first-degree relatives of affected women compared with the general population. In addition, monozygotic twins have 88% concordance for endometriosis. It has been suggested that endometriosis is a genetically transmitted disorder that results from an altered immune surveillance that allows for the attachment and growth of ectopic endometrium.
Immune Factors
Convincing data exist to suggest that retrograde menstruation and implantation of endometrial fragments is the most likely means of developing endometriosis in the peritoneal cavity. Although retrograde menstruation is a nearly universal phenomenon in women with patent fallopian tubes, the development of endometriosis is far less common. Alterations in immunologic response to this tissue have been implicated in the genesis and maintenance of the endometriotic lesion. To evaluate the role of the immune system in the pathogenesis of endometriosis, investigators studied immune cells and their secretory products in peritoneal fluid. Examination of the cellular and biochemical composition of peritoneal fluid revealed differences between women with endometriosis and without endometriosis. Macrophages are the predominant cell type in peritoneal fluid and are found in higher concentrations in women with endometriosis. They are thought to contribute to the pathogenesis of endometriosis by secreting growth factors and cytokines. Elevated levels of macrophage-derived growth factor, tumor necrosis factor-α, interleukin-1, interleukin-6, interleukin-8, transforming growth factor-β, and other cytokines have been found in the peritoneal fluid of women with endometriosis. It is currently unclear whether the increased concentration of macrophages and cytokines contributes to the creation of endometriotic lesions, or whether these findings represent an immunologic response to endometriosis. More recent
Endometriosis
reports have suggested evidence for a role of cytokines in the establishment and maintenance of endometriotic lesions.
CLINICAL PRESENTATION Most women with endometriosis are asymptomatic. When present, the symptoms may take a variety of forms (Box 14-1). The type and severity depend on the extent and location of the disease; even limited disease can cause significant symptoms.
Pain
Infertility
Pain symptoms in women with endometriosis range from increasing dysmenorrhea to chronic pelvic pain and dyspareunia. The mechanism of 217 worsening dysmenorrhea is unknown, but may be related to increased prostaglandin and cytokines present in peritoneal fluid of women with endometriosis. Pain secondary to peritoneal disease is mediated by somatic afferent fibers that sense stretching, irritation, or injury. Endometriosis-related pain also may be perceived by sympathetic or parasympathetic visceral nerves that innervate the pelvic organs and are sensitive to distention, distortion, or impression. Dyspareunia is more common in women with endometriosis and deep posterior cul-de-sac disease.
Retrospective data demonstrate that 30% to 50% of women with endometriosis may be infertile. Severe disease may cause infertility by distorting pelvic anatomy. Severe pelvic adhesions may impair egg release from the ovary, block sperm entry into the distal fallopian tube, and inhibit ovum pickup. In animal models of endometriosis, pelvic adhesions seem to contribute to the observed decreased fecundity noted in animals with advanced endometriosis. The cause in less severe cases is controversial, and the literature contains many theories regarding possible mechanisms to explain endometriosis-associated infertility (Box 14-2). Many studies show that women
Box 14-1
Signs and Symptoms of Endometriosis
Signs Tenderness in the cul-de-sac or uterosacral ligaments Nodularity along the uterosacral ligaments Adnexal tenderness Pelvic masses Symptoms Worsening dysmenorrhea Pelvic pain Dyspareunia, especially with deep thrust Dysuria Hematuria Dyschezia Infertility
Reproductive Endocrinology and Infertility
Box 14-2 ● ● ● ● ● ● ● ● ● ●
Possible Mechanisms of Endometriosis-Associated Infertility*
Anatomic distortion and tubal obstruction Anovulation Autoimmunity/immune dysfunction Corpus luteum insufficiency Decreased ovarian reserve Embryotoxicity of peritoneal fluid Granulosa cell apoptosis Implantation defects Luteinized unruptured follicle syndrome Sperm toxicity of peritoneal or follicular fluid
*For a complete discussion of these mechanisms, see the article by Burns and Schenken in Suggested Readings.
218
with endometriosis have an increased volume of peritoneal fluid; increased macrophage concentration and function; and increased peritoneal fluid concentrations of prostaglandin, interleukin-l, tumor necrosis factor, and proteases. These alterations may impair oocyte, sperm, embryo, and fallopian tube function. It also has been proposed that numerous endocrine and ovulatory disorders may be present in women with endometriosis, including luteinized unruptured follicle syndrome, luteal phase dysfunction, abnormal follicular growth, and premature or multiple luteinizing hormone surges. IgG and IgA antibodies and lymphocytes may be increased in the endometrium of women with endometriosis. These abnormalities may alter endometrial receptivity to embryo implantation. In women with endometriosis, it is unclear whether implantation failure contributes to decreased fecundity. Some women with endometriosis lack endometrial αvβ3 integrin expression. This decreased endometrial integrin production in the midluteal phase may cause infertility by impairing implantation. These observations support the concept that endometriosis may represent one component of a disease that is characterized by dysfunction in multiple components, including the ovary, endometrium, fallopian tubes, and peritoneum.
DIAGNOSIS Endometriosis should be suspected when patients present with the previously noted symptoms. Signs of endometriosis include pelvic tenderness with nodularity, particularly over the uterosacral ligaments; pain with uterine movement; uterine retroversion with decreased mobility; and adnexal enlargement with tenderness. Many symptomatic women have normal pelvic examinations. No one constellation of signs or symptoms is pathognomonic of endometriosis. Serum antigen CA 125 levels are helpful in detecting and monitoring more severe cases, but are not specific to this condition. Transvaginal ultrasound is helpful to confirm the presence of endometriomas (Fig. 14-2). They appear as intraovarian cystic structures, usually unilocular with hazy borders and internal echoes.
Endometriosis Figure 14-2 Pelvic ultrasound shows an ovarian endometrioma.
219
The diagnosis can be substantiated only by laparoscopy or laparotomy. Endometriotic lesions can have multiple appearances (Box 14-3). Peritoneal biopsy is desirable because many other lesions can mimic endometriosis (Box 14-4), and because the positive predictive value of a visual diagnosis is only 45%.
Box 14-3 ● ● ● ● ● ● ● ● ●
Clear vesicles White lesions Red lesions Red polypoid lesions Yellow lesions Powder burn lesions Black lesions Chocolate ovarian cysts Peritoneal windows
Box 14-4 ● ● ● ● ● ● ●
Common Appearances of Endometriotic Lesions
Lesions That Visually Mimic Endometriotic Implants
Carbon residual from prior surgical ablation Endosalpingiosis Hemangiomas Hemosiderin deposits Inflammatory changes Mesothelial hyperplasia Splenosis
Reproductive Endocrinology and Infertility
It is important to assess correctly the presence and extent of disease. Endometriosis should be documented carefully by using the revised classification of endometriosis recommended by the American Society for Reproductive Medicine (Fig. 14-3). Although this classification scheme has not been prospectively validated, and the score assigned to various lesions and adhesions produced by endometriosis is arbitrary, it serves as a partially objective means of determining the extent of the disease and provides a quantifiable basis for follow-up comparisons.
THERAPY Individual treatment of endometriosis should be based on the extent of the disease, the severity of symptoms, the patient’s desire for childbearing, the patient’s age, and other coexisting medical and surgical factors. Available treatment modalities are expectant, hormonal, surgical, and combined medical/surgical. Expectant management of infertile women with mild endometriosis has been previously recommended. More recent data suggest that treatment at the time of laparoscopy maginally improves pregnancy rates.
220
Medical Treatment
Endometriotic implant growth usually depends on ovarian steroids. Medications that suppress ovarian function appear to be beneficial. Ovarian suppression has not been shown to improve pregnancy rates for infertile women with mild or moderate endometriosis; several studies have reported a decreased pregnancy rate with medical management likely as a result of the period of anovulation associated with use of these agents. Medical therapy should not be used to enhance fertility. Medical therapy has been shown, however, to relieve pain and reduce the amount of endometriosis visible at laparoscopy. Medical therapy may be indicated for women with pain. Analgesics, oral contraceptives, progestins, danazol, and gonadotropin-releasing hormone (GnRH) agonists all seem to be effective in reducing pelvic pain (Table 14-1). Medical therapy also may be effective in reducing the progression of disease, but this benefit is not as well documented. Hormonal therapy is ineffective in resolving endometriomas and has no effect on adhesion formation. Contraindications to medical therapy include hypersensitivity to any of the individual agents and undiagnosed abnormal vaginal bleeding. Medical therapy has been employed before and after conservative surgical treatment of endometriosis. There is no good evidence that preoperative treatment reduces operating time or bleeding. It has no benefit over surgery alone for endometriosis-associated pain or infertility. Postoperative treatment may be beneficial for delaying pain recurrence.
Analgesics Prostaglandin synthesis by ectopic endometrium may be responsible for characteristic symptoms of endometriosis, such as pelvic pain and dysmenorrhea. Nonsteroidal anti-inflammatory drugs inhibit biosynthesis of prostaglandins and alleviate these symptoms. These drugs are well tolerated, safe,
Endometriosis Figure 14-3 American Society for Reproductive Medicine revised classification scale for endometriosis. (Courtesy of American Society for Reproductive Medicine.)
221
Continued
Reproductive Endocrinology and Infertility Figure 14-3—Cont’d
222
and inexpensive and are recommended as first-line treatment in women with mild symptoms.
Oral Contraceptive Pills Specific contraindications to taking oral contraceptives include being a smoker older than age 35 years and having a history of thromboembolic disease. Treatment usually involves the use of low-dose (20–35 μg of ethinyl estradiol) oral contraceptives continuously for 6 to 9 months. The treatment usually is begun with one tablet daily and increased to two tablets per day only if breakthrough bleeding occurs. The administration of more than two pills is not recommended because of increasing undesirable side effects. The lowest dose of hormone that produces amenorrhea is maintained during the course of
Endometriosis Table 14-1 Medications Commonly Used to Treat Endometriosis
Medication
Dose
Route
Nonsteroidal antiinflammatory drugs Oral contraceptives
Varies
Oral
1-2 pills daily continuous dosing 20-100 mg daily
Oral
150 mg (3 mo)
Depot injection
40 mg daily 5-15 mg daily (start at 5 mg daily and increase dose every 2 wk if needed) 200-800 mg daily 3.75 mg (1 mo); 11.25 mg (3 mo) 200 μg twice daily
Oral Oral
Medroxyprogesteone acetate Depot medroxyprogesterone Megestrol acetate Norethindrone acetate Danazol Leuprolide acetate Nafarelin acetate
Oral
Oral Depot injection 223 Intranasal
therapy. During the initial 2 to 3 months of treatment, many patients experience worsening symptoms referable to the endometriosis.
Progestins Medroxyprogesterone acetate is the most commonly used progestin to treat endometriosis. Oral medroxyprogesterone acetate, 20 to 100 mg/day, or injection of depot medroxyprogesterone acetate, 150 mg every 3 months, results in significant amelioration of pain symptoms. A drawback to the use of depot medroxyprogesterone acetate is the prolonged interval to resumption of ovulation after cessation of therapy, which may be 1 year. The depot form should not be used in women who desire pregnancy in the near future and should be reserved for patients who do not want to conceive. The most prominent side effects consist of spotting and breakthrough bleeding, depression, weight gain, and bloating. Megestrol acetate and norethindrone acetate may also be used with similar side effects. Danazol Danazol is a derivative of the synthetic steroid 17α-ethinyl testosterone, which is known to have progestagenic and androgenic effects. It has a mild suppressive effect on gonadotropin secretion, abolishes the luteinizing hormone surge, and has an inhibitory effect on ovarian steroidogenic enzymes and the growth of normal and ectopic endometrium. The drug creates an anovulatory amenorrheic, high-androgen, low-estrogen milieu that is hostile to the growth of endometriotic implants. Specific contraindications to danazol include impaired hepatic, renal, or cardiac function. A dosage of 600 mg/day for 6 months is recommended and seems to be effective in relieving symptoms and suppressing endometriotic lesions. In practice, the dosage of danazol should be individualized and adjusted to the need of the patient, extent of the disease, and severity of side effects. The medication should be started after the completion of a normal
Reproductive Endocrinology and Infertility
224
menstruation. Danazol should not be administered to pregnant women because it may cause virilization of the external genitalia of a female fetus. In patients with irregular or abnormal menstrual cycles, the presence of an early pregnancy should be excluded before this medication is given. Patients receiving danazol therapy should use barrier contraceptives during the course of treatment. Menses usually recur within 6 weeks of stopping danazol therapy. Danazol use results in side effects associated with a hyperandrogenic state, including weight gain, acne, hirsutism, oily skin, a decrease in breast size and, rarely, a deepening of the voice. Other side effects include muscle cramps, flushing, mood changes, depression, and edema. Patients receiving danazol are usually amenorrheic; however, breakthrough bleeding may occur when doses of 400 mg or less are given. Because of the significant side-effect profile, danazol is rarely used today.
Gonadotropin-Releasing Hormone Agonists Administration of GnRH agonists produces an initial stimulation of pituitary gonadotropes that results in secretion of follicle-stimulating hormone and luteinizing hormone and the expected gonadal response. Continuous or repeated administration of an agonist at supra-physiologic doses produces an inhibition of the pituitary-gonadal axis, however. Functional changes resulting from this inhibition include pituitary GnRH receptor downregulation, gonadal gonadotropin receptor downregulation, attenuated gonadotropin secretion, and decreased steroidogenesis. The inhibitory effects of agonists are fully reversible. The ability of GnRH agonists to produce amenorrhea and anovulation has provided the basis for their use in the management of endometriosis. Side effects associated with GnRH agonist therapy are those attributable to hypoestrogenism, including hot flashes, vaginal dryness, and some largely reversible loss of bone mineral density. Treatment usually is limited to one 6-month course. Women who develop side effects on GnRH agonists, who require treatment for longer than 6 months, or who require repeat treatments may be candidates for “add-back” therapy. This consists of progestin or combination low-dose estrogen and progestin. Many regimens are commonly used (Box 14-5). Use of oral contraceptive pills for add-back therapy may negate the effect of GnRH agonist treatment because of the supraphysiologic estrogen dose. Add-back therapy usually decreases side effects, but may not completely prevent bone loss. Menses may take 8 to 10 weeks to be re-established after GnRH agonist therapy. Aromatase Inhibitors Aromatase is an enzyme involved in the production of estrogen that acts by catalyzing the conversion of testosterone to estradiol. Aromatase is located in estrogen-producing cells in the adrenal glands, ovaries, placenta, testicles, adipose tissue, and brain. Third-generation aromatase inhibitors act by inhibiting the enzyme aromatase, which suppresses estrogen production locally and systemically, and are used to treat estrogen-dependent breast cancer. Because GnRH analogue
Endometriosis
Box 14-5 Common Add-Back Regimens for Use with GonadotropinReleasing Hormone Agonists CEE 0.625 mg + MPA 2.5–5 mg CEE 0.3 mg + MPA 2.5–5 mg 17β-E2 1 mg + MPA 2.5–5 mg NE 5 mg ± CEE MPA 20 mg NE 5 mg + etidronate CEE, conjugated equine estrogen; E2, estradiol; MPA, medroxyprogesterone acetate; NE, norethindrone acetate.
therapy inhibits estrogen production in the ovary, but not locally in the 225 endometriotic lesion, aromatase inhibitors are currently being evaluated for treatment of refractory cases of endometriosis. Letrozole, 2.5 mg daily for 6 months, showed promising results in a small study. Side effects of letrozole include hot flashes and bone pain. Because bone loss is a theoretical risk of prolonged therapy secondary to the hypoestrogenic state induced, add-back therapy with norethindrone acetate may be given.
Surgical Treatment
Surgical treatment usually can be accomplished at the initial laparoscopy undertaken to diagnose the disease. Conservative or limited surgery is appropriate for women desiring future fertility and for women with pelvic pain. Conservative procedures include excision, vaporization, and coagulation of endometrial implants; excision of ovarian endometriomas; and lysis of adhesions. These can be accomplished at laparoscopy with surgical excision, laser (carbon dioxide, argon, potassium titanyl phosphate [KTP], or neodymium: yttrium-aluminum-garnet [Nd:YAG]), and monopolar or bipolar electrocautery. Treatment outcomes using sharp excision, carbon dioxide laser, argon laser, KTP laser, and electrosurgery during laparoscopy seem to be comparable. Conservative surgery is most often performed through the laparoscope; however, in the case of extensive disease with cul-de-sac obliteration and dense scarring of the ovaries to the pelvic sidewalls, or when removal of large endometriomas, enterostomy, extensive enterolysis, bowel resection, or other situations deemed too complex for the laparoscope are required, laparotomy may be necessary. Adjunct procedures, including presacral neurectomy and uterosacral nerve ablation, have been recommended for relief of central pelvic pain. The long-term benefit of these procedures has not been conclusively shown. Uterosacral plication, uterine suspension, and oophoropexy have even less clearly defined benefits. Patients with significant bowel involvement may require resection of the affected segment and anastomosis. Pregnancy rates are acceptable after laparoscopic surgery for endometriosis (Table 14-2). Two randomized, controlled studies on the effectiveness of laparoscopic conservative surgery report conflicting results in women with less severe stages of endometriosis. The effectiveness of surgery for minimal or mild endometriosis has been difficult to show. The Canadian Collaborative
Reproductive Endocrinology and Infertility
Table 14-2 Pregnancy Rates After Laparoscopic Surgery for EndometriosisAssociated Infertility
Endometriosis Stage Without surgery After surgery
Minimal/Mild
Moderate/Severe
37.4% 51.7%
3.1% 41.3%
Group on Endometriosis reported a randomized trial of laparoscopy with and without treatment in 341 women with minimal or mild disease. The fecundity rate in treated patients was 4.7 versus 2.4 per 100 person-months in controls (95% confidence interval 1.2–3.1). The Gruppo Italiano per lo Studio dell’ Endometriosis conducted a similar study in 111 patients with stage I or stage II endometriosis. One year after surgery, the pregnancy rate was 29% in the no treatment group and 24% in the ablation/resection group. These conflicting studies show the controversy regarding the value of surgery for patients with mild disease. If lesions are observed at the time of laparoscopy, however, destruction or excision of these lesions may improve fecundity and is unlikely to cause significant morbidity. Definitive therapy, total abdominal hysterectomy, and bilateral salpingooophorectomy are indicated for patients who have completed childbearing or have significant persistent pelvic pain after conservative treatment. One or both ovaries may be spared if they are completely uninvolved and the endometriosis can be resected completely. Approximately one third of women treated conservatively have recurrent endometriosis and require additional surgery within 5 years. After bilateral oophorectomy, estrogen replacement therapy may be initiated immediately with little risk of reactivating residual disease. There is no reason to delay replacement therapy after surgery.
226
Assisted Reproduction
In patients with persistent infertility associated with endometriosis, superovulation (with and without intrauterine inseminations) and assisted reproductive technologies offer some promise. Spontaneous monthly fecundity rates of 0.10 for stage I, 0.09 for stage II, 0.18 for stage III, and 0.0 for stage IV endometriosis have been reported. A significant increase in cycle fecundity was seen with four cycles of clomiphene citrate and intrauterine insemination compared with controls having intercourse (0.095 versus 0.033). Cycle fecundity for gonadotropins and intrauterine insemination also compare favorably with no treatment for women with stage I or stage II endometriosis and infertility (0.15 and 0.045). A report on the effects of expectant management, clomiphene citrate and intrauterine insemination, gonadotropins and intrauterine insemination, or in vitro fertilization and embryo transfer (IVF/ET) on cycle fecundity in women with infertility and minimal or mild endometriosis showed improved cycle fecundity rates with treatment (Table 14-3). The effect of endometriosis on the outcome of IVF is controversial. Overall, the diagnosis of endometriosis (especially previously treated disease) does not seem to decrease pregnancy rates in patients with less severe
Endometriosis Table 14-3 Effect of Treatment on Fecundity in Women with Minimal or Mild Endometriosis
Treatment None Clomiphene citrate and IUI Gonadotropins and IUI IVF/ET
Fecundity 0.028 0.066 0.114 0.320
IUI, intrauterine insemination.
stages of disease. Some investigators have suggested, however, that patients with endometriosis undergoing IVF have a reduced implantation rate, possibly secondary to endometrial dysfunction or an embryotoxic environment. Women with advanced endometriosis and a history of a previous oophorec- 227 tomy and a contralateral ovarian cystectomy seem to do poorly in IVF/ET programs. It is possible that the previous ovarian surgery has depleted the available oocyte pool, making the women perimenopausal. Women with large endometriomas at the start of an IVF/ET cycle also may be at risk for a poor cycle outcome. Resection of an endometrioma should be considered before initiation of an IVF/ET cycle.
SUMMARY OF KEY POINTS 1. 2.
3.
4.
5.
Although many theories have been proposed, the etiology of endometriosis remains unclear. Medical therapy effectively treats endometriosis-associated pain symptoms, but is of no value for the treatment of endometriosis-associated infertility. A causal relationship between moderate or severe disease with distortion of pelvic anatomy and infertility is clear; however, the relationship between minimal or mild disease and infertility is controversial. There is controversy regarding the value of surgery for patients with mild disease; however, if lesions are observed at the time of laparoscopy, destruction or excision of these lesions may marginally improve fertility. Superovulation, with or without intrauterine insemination, and assisted reproductive technologies improve fecundity in patients with endometriosis-associated infertility.
SUGGESTED READINGS ACOG practice bulletin: medical management of endometriosis. Number 11, December 1999. Burns WN, Schenken RS: Pathophysiology of endometriosis-associated infertility. Clin Obstet Gynecol 1999;42:586-610.
Gambone JC, Mittman BS, Munro MG, et al: Consensus statement for the management of chronic pelvic pain and endometriosis: proceedings of an expert-panel consensus process. Fertil Steril 2002;78:961-972.
Reproductive Endocrinology and Infertility Marcoux S, Maheux R, Berube S: Laparoscopic surgery in infertile women with minimal or mild endometriosis. Canadian Collaborative Group on Endometriosis. N Engl J Med 1997;337:217-222. Surrey ES, Hornstein MD: Prolonged GnRH agonist and add-back therapy for symptomatic endometriosis: long-term follow-up. Obstet Gynecol 2002;99:709-719.
228
Winkel CA: Evaluation and management of women with endometriosis. Obstet Gynecol 2003;102: 397-408. Witz CA: Pathogenesis of endometriosis. Gynecol Obstet Invest 2002;53(suppl 1):52-62. Witz CA, Burns WN: Endometriosis and infertility: is there a cause and effect relationship? Gynecol Obstet Invest 2002;53(suppl 1):2-11.
15 DIMINISHED OVARIAN RESERVE Andrew J. Levi
229
The evaluation and treatment of an infertile couple can be complex. In the female partner, success of treatment relies on competent oocytes that are capable of being fertilized and subsequently are able to implant and differentiate successfully. As women age, the likelihood of conception decreases, with a steep decline in pregnancy rates as women enter their mid to late 30s (Fig. 15-1); this is usually secondary to the absence of competent oocytes. Oocytes of poor quality may be a cause of in vivo or in vitro fertilization failure, implantation failure, or early pregnancy loss. When evaluating a subfertile woman, an evaluation of whether there exists a potential problem with oocyte quality or quantity (which often goes hand-in-hand with subfertility) should be performed. This investigation is termed ovarian reserve screening or screening for diminished ovarian reserve (DOR).
FOLLICULOGENESIS AND OVARIAN AGING A thorough understanding of ovarian physiology and folliculogenesis is important to comprehend the rationale behind ovarian reserve screening. During fetal life, the ovaries contain approximately 6 million oocytes; only a few million of these oocytes are present at birth. By menarche, only around 250,000 oocytes remain. When a woman reaches the menopause, approximately 500 ovulations have occurred, yet the oocyte pool is depleted (Fig. 15-2). During a woman’s reproductive life, most oocytes are consumed not through ovulation, but rather through the processes of apoptosis (programmed cell death) and atresia. In some women, this rate of oocyte atresia can occur rapidly and prematurely, leading to a decrease in available oocytes (quantity) and competent oocytes (quality). Ovarian reserve screening seeks to identify women who may be subfertile because of issues related to diminishing oocyte quantity or quality or both.
Reproductive Endocrinology and Infertility Figure 15-1 400
300
Number pregnant
Historical fertility rates in women as a function of age. The natural decline in fertility as women age is well documented. Note the steep decline in conception rates as women enter their 30s. This natural decline in fertility is due to diminishing oocyte quantity and quality. Although 230 chronologic aging and reproductive aging often progress in parallel, the rate of decline varies among individuals. Women with DOR often have a rapid decline in fertility potential, sometimes at an early age. (Adapted from Menken J, Trussell J, Larsen U: Age and infertility. Science 1986;233:1389– 1394.)
200
100
0 20
25
30 35 Female age (years)
40
45
50
Early in fetal life, germ cell migration from the yolk sac to the gonadal ridge forms gonadal tissue. In female gonads, the primordial follicles are the first follicles produced. These early follicles are the follicles that are recruited first in the process of folliculogenesis and subsequently develop into preantral follicles. The development of preantral follicles from primordial follicles occurs in the absence of gonadotropin stimulation, also known as the gonadotropin-independent period of folliculogenesis. Later, these preantral follicles enlarge and fill with fluid, becoming antral follicles; in contrast to preantral follicles, antral follicles respond to tropic pituitary hormones. This part of follicle development is appropriately termed the gonadotropin-dependent period of folliculogenesis. In a given menstrual cycle, a cohort of ovarian follicles (depending on age) is recruited in the late luteal phase under the selective stimulation of folliclestimulating hormone (FSH) during the stage of gonadotropin-dependent folliculogenesis. As the corpus luteum regresses in a nonpregnant cycle, estradiol, progesterone, and inhibin levels decrease, and suppression of the hypothalamic-pituitary-ovarian axis no longer occurs. In the days that follow, FSH levels increase as inhibin levels wane, and selection of the dominant follicle occurs. The dominant follicle rapidly grows under the influence of FSH in its unique microenvironment, whereas unselected follicles undergo atresia secondary to apoptotic events that are not completely understood. Inhibin plays an important role in the process of folliculogenesis because its withdrawal in the early follicular phase of the menstrual cycle allows FSH levels to increase and it directly and indirectly plays a role in follicular atresia
Diminished Ovarian Reserve Figure 15-2 10000000
Birth 1000000
Number of eggs
Decline in oocyte quantity as a function of chronologic aging. Oocytes are constantly lost through the processes of apoptosis and atresia as a woman ages. By the time a woman is 37 years old, only a small fraction of oocytes remain compared with the number of oocytes present in early adulthood. In women with DOR, the oocyte pool is typically small and may consist of oocytes of poor quality. Among younger women with DOR, the graph is shifted to the left, consistent with premature ovarian senescence. (Adapted from te Velde ER, Scheffer GJ, Dorland M, et al: Developmental and endocrine aspects of normal ovarian aging. Mol Cell Endocrinol 1998;145:67–73.)
Optimal fertility Decreasing fertility
100000
End of fertility
231
10000
Menopause 1000 0
18
31
37
41
45
51
Age
among unselected follicles. In this way, a multitude of oocytes undergo apoptosis and atresia during the period of follicular recruitment, selection of the dominant follicle, and ovulation. In some women, these processes are magnified and can lead to the accelerated loss of ovarian follicles and subsequent DOR. In many patients, DOR is manifested as subfertility and diagnosed during ovarian reserve screening. Chronologic aging and reproductive aging do not always go together. Rather, in some patients, the accelerated loss of ovarian follicles can lead to ovarian senescence at an early reproductive age. Whether this loss occurs through apoptosis, as a consequence of environmental factors (e.g., reactive oxygen species), or through other mechanisms is unknown. In some patients, ovarian aging can occur rapidly, leading to infertility at an early chronologic age. It is important to consider DOR as a potential diagnosis in “young” patients with apparent unexplained infertility.
OVARIAN RESERVE SCREENING Many screening tests exist that seek to detect DOR as a cause of subfertility in women (Box 15-1). The fact that multiple tests exist underscores the point that no one test possesses the sensitivity and specificity to serve as “the” screening test for prospective detection of declining ovarian function. In many cases, abnormalities in testing portend a poor outcome. Because many of these tests lack specificity, however, patients should not be assured that “normal” ovarian reserve screening implies that fertility is a certainty.
Reproductive Endocrinology and Infertility
Box 15-1 ● ● ● ● ● ● ●
Ovarian Reserve Screening Tests
Basal FSH measurements CCCT Basal AFC Measurement of mean ovarian volume Basal estradiol levels Basal inhibin B levels Ovarian biopsy
The results of the following tests commonly are employed by clinicians to identify and counsel patients whose subfertility is likely secondary to declining ovarian reserve. 232
Basal FollicleStimulating Hormone Levels
The measurement of basal FSH levels has been the most widely studied and the best characterized screening test for the detection of DOR in subfertile women. The premise for measuring basal FSH levels in the early follicular phase of the menstrual cycle (on day 2, 3, or 4) stems from the findings that as women age, mild elevations in basal FSH concentrations occur; these elevations are commonly observed in women during their mid-30s. The early manifestations of DOR may be reflected solely as increases in basal FSH levels. FSH levels likely begin to increase secondary to waning granulosa cell function, which is manifested by lower concentrations of follicular inhibin levels. FSH levels, which are normally “inhibited” by serum inhibin, consequently increase in the early follicular phase. This phenomenon led many investigators to study the relationship between basal FSH levels and ovarian response to exogenous gonadotropin stimulation and subsequent reproductive outcome. The initial studies investigating basal FSH as a screening test for DOR were performed in the late 1980s and 1990s. Most of these reports were from populations of patients undergoing in vitro fertilization (IVF). Although most of these studies were retrospective, numerous investigators showed that as basal FSH levels increased, the odds of a successful pregnancy dramatically decreased. At a defined FSH threshold level, ongoing pregnancy rates and live birth rates were low. These declining pregnancy rates were attributed to DOR because patients with elevated basal FSH levels who underwent IVF were often poor responders to exogenous FSH (as manifested by fewer ovarian follicles visualized by ultrasound), had fewer oocytes retrieved, and developed fewer embryos that were ultimately available for transfer compared with controls. Patient age did not predict clinical response (ovarian responsiveness and number of embryos) or the chances of an ongoing pregnancy as well as did basal FSH concentrations. Although pregnancy rates declined with advancing age, basal FSH levels were shown to predict outcome best, independent of age. These findings were shown in subfertile women; basal FSH levels were not a reliable screening tool in women of reproductive age who had not yet attempted to conceive.
Diminished Ovarian Reserve
Subsequent studies showed other significant findings. First, FSH levels on day 2, 3, or 4 were equivalent in terms of predicting reproductive outcome. In addition, basal FSH levels had significant intercycle variability; FSH levels could be within the “normal” range in one cycle, but could be deemed as “abnormal” in a subsequent cycle. Women with significant DOR had the largest deviations from cycle to cycle. Outcome in a given patient was similar in cycles when FSH levels were elevated compared with cycles when FSH levels were normal. Pregnancy rates were not enhanced by treating patients in cycles when the FSH was normal; clinical responsiveness and outcome was defined by patients’ highest FSH levels noted during prior screening. Further studies suggested that women with DOR not only might have problems conceiving, but also might have a propensity toward miscarriage. Investigators showed that women with elevated basal FSH levels have significantly higher miscarriage rates compared with age-matched controls. In 233 one study, women older than 40 with elevated basal FSH levels had miscarriage rates of 90%. It has been suggested that DOR, as manifested by elevated basal FSH concentrations, may be an explanation for “unexplained” recurrent pregnancy loss. Among these patients, it is hypothesized that fertilized oocytes of poor quality give rise to aneuploid embryos that ultimately miscarry. In these clinical scenarios, screening for DOR with basal FSH levels becomes useful not only in predicting outcome, but also for preconceptual counseling. Despite the multitude of studies examining the relationship between elevated basal FSH levels and poor ovarian responsiveness and reproductive outcome, follow-up studies suggested that in some clinical scenarios, elevated basal FSH levels did not always predict a poor prognosis. Some investigators strongly support the notion that elevated FSH levels should not be used to exclude subfertile patients from ART. Although patients with grossly elevated basal FSH values generally have a poor chance of achieving an ongoing pregnancy, patients with borderline elevated test results ultimately may achieve a live birth. It may be that patients with moderately elevated basal FSH concentrations can achieve a pregnancy, provided that they respond well to exogenous gonadotropins. It may be that the results of ovarian reserve screening by way of basal FSH concentrations should be reserved for patient counseling, rather than used to dissuade these patients from considering ART as a means to conceive.
Clomiphene Citrate Challenge Test
The clomiphene citrate challenge test (CCCT) was next investigated as a possible screening test for DOR. Studied in 1987 in subfertile women older than 35 years, the CCCT relied on the principle that some women might have DOR despite a “normal” screening basal FSH level (false-negative test result). As originally described, the CCCT involved measuring the basal FSH concentration (typically on day 3) followed by the administration of clomiphene citrate, 100 mg/day, on days 5 to 9 of the cycle; the FSH level was measured again on day 10 (Box 15-2). The physiologic principle behind the CCCT was that clomiphene citrate would increase the patient’s FSH level
Reproductive Endocrinology and Infertility
Box 15-2
Clomiphene Citrate Challenge Test
Measure serum basal FSH concentration on cycle day 2, 3, or 4 Administer clomiphene citrate, 100 mg/day, from cycle day 5 through cycle day 9 Measure serum basal FSH concentration on cycle day 10
during the course of administration, and in patients with normal ovarian reserve, the FSH level would return to baseline on day 10 after the 5 days of treatment. Studies of the CCCT in subfertile women showed that although many patients had a “normal” basal FSH level, some had an elevated level on day 10 of a CCCT. Study results showed that among patients with “normal” basal FSH concentrations who underwent the CCCT, of women who then had an abnormal day 10 level, only 6% conceived during the study period, whereas of women with a normal day 10 value, 42% conceived. Additional studies evaluating the CCCT as a screening test for patients undergoing ART followed, and results from those investigations corroborated what was originally surmised: that patients with abnormal day 10 FSH levels after a course of clomiphene citrate, despite “normal” basal FSH levels, frequently responded poorly to exogenous gonadotropins or did not become pregnant. Similar to basal FSH screening for DOR, the CCCT was independent of patient age. Many patients who originally had been diagnosed with unexplained infertility had significant DOR as manifested by an abnormal CCCT. Clinics should develop their own database and determine normal values for FSH screening. Populations and testing technique vary, so individual clinic experience should be the primary determinant for counseling patients regarding their results.
234
Basal Antral Follicle Counts
Investigators have sought to determine whether the number of basal antral follicles, defined as follicles visualized in the early follicular phase of the menstrual cycle, measuring 4 mm or less in diameter when observed by transvaginal ultrasound, might predict ovarian responsiveness and pregnancy outcome. The premise behind the significance of basal antral follicle counts (AFCs) is that in patients with DOR, fewer antral follicles are available for recruitment in a given menstrual cycle. It was postulated that basal AFCs could be another method to prospectively identify patients at risk for poor ovarian response and a low probability of conception. Multiple studies have been performed seeking to identify a threshold basal AFC that might predict pregnancy. Such an AFC threshold value has yet to be ascertained. In examining the basal AFC in patients undergoing IVF, patients with lower numbers of antral follicles had higher cycle cancellation rates, and if they were not cancelled, these patients had lower pregnancy rates compared with controls. The total number of antral follicles was noted to be of greatest importance, regardless of whether more antral follicles were visualized in one ovary or the other. In addition, basal AFCs seemed to vary little from cycle to cycle. Although a threshold basal AFC that might predict
Diminished Ovarian Reserve
IVF cycle cancellation, poor ovarian response to exogenous gonadotropins, or poor pregnancy outcome was not delineated, study results suggested that patients with fewer than four to six total antral follicles had poor outcomes relative to patients with higher AFCs. Basal AFCs may be used to counsel patients regarding the likelihood of IVF cycle cancellation before starting gonadotropins and may be used to alter treatment regimens before ovarian stimulation for IVF, for instance increasing gonadotropin dose during ovarian hyperstimulation. AFCs also can be useful as a counseling tool in the context of an abnormal basal FSH level or abnormal CCCT; taken together, these results may deter a patient from proceeding with IVF based on the high likelihood of cycle cancellation and poor pregnancy outcome. The patient may proceed instead with a donor oocyte protocol. 235
Measurement of Mean Ovarian Volume
Measuring the volume of the ovaries in the early follicular phase of the menstrual cycle also has been investigated as a potential predictor of ovarian responsiveness. Investigators first recognized that women with DOR had smaller ovarian volumes compared with controls. Studies suggested that women with smaller mean ovarian volumes (<2 cm3) had higher cycle cancellation rates and lower pregnancy rates compared with women with mean ovarian volumes greater than 2 cm. These findings were observed when controlling for age. One group of investigators hypothesized that the mean ovarian volume reflected the number of primordial follicles remaining and could predict ovarian reserve and reproductive age. Although this is not an absolute, the mean ovarian volume, similar to the basal AFC, can be used in conjunction with other ovarian reserve screening tests to better counsel infertility patients regarding their chances of ovarian response to treatment.
Basal Estradiol Levels
When measuring basal FSH levels, it is appropriate to measure the FSH and estradiol concentrations to confirm that testing is being performed at the appropriate time of the menstrual cycle (i.e., in the earlier follicular phase). Some patients, despite screening in the early follicular phase, have surprisingly high serum estradiol levels. Investigators postulated that in some patients, the prematurely elevated estradiol levels could be suppressing basal FSH levels into the normal range, perhaps “masking” abnormal FSH levels in patients with occult DOR. In 1995, one study suggested that in patients undergoing IVF, a basal estradiol concentration of greater than 80 pg/mL correlated with poor IVF outcome. Follow-up studies with larger sample sizes failed to identify a relationship between basal estradiol levels and pregnancy rates, however. Basal estradiol levels did not predict pregnancy outcome in patients undergoing IVF when controlling for basal FSH (i.e., basal estradiol levels were inconsequential in the face of a normal basal FSH). Although measuring the basal estradiol level in conjunction with FSH is important to confirm the part of the menstrual cycle in which a blood sample is collected, its validity as a screening test for DOR remains to be proven.
Reproductive Endocrinology and Infertility
Basal Inhibin B Levels
Inhibin B is a granulosa cell product from antral follicles that directly suppresses pituitary FSH secretion. Investigators surmised that as ovarian function waned, early follicular inhibin B concentrations would decrease and fail to suppress FSH secretion. Changes in inhibin B concentrations might occur before fluctuations in basal FSH levels, and inhibin B levels might be a more “direct” assessment of granulosa cell function. Based on this premise, it was thought that measurements of basal inhibin B concentrations might be an excellent screening test for DOR. Although results from one of the first studies of inhibin B as a screening test for DOR determined a threshold level for which ART outcome was poor, it failed to control for basal FSH levels. A follow-up study showed that basal inhibin B levels increased before basal FSH levels did; however, in patients with normal basal FSH levels, inhibin B levels in the same patients did not prognosticate ovarian response or pregnancy outcome. Similar to AFCs or ovarian volume measurements, basal inhibin B concentrations may be used in conjunction with other screening tests for patient counseling. Although women with diminished ovarian reserve typically have lower inhibin B levels compared with women who respond well to exogenous gonadotropin administration, inhibin B levels are not by themselves predictive of reproductive outcome. Although the hypothesis behind screening for DOR with inhibin B levels makes physiologic sense, screening patients with basal inhibin B levels seems to be inferior to other screening tests for DOR.
Ovarian Biopsy
It has been suggested by some investigators that ovarian biopsy should be a part of the infertility evaluation to rule out depletion of the pool of primordial follicles as a source of declining ovarian function. Investigators observed that patients with unexplained infertility had lower ovarian follicular density and fewer total follicles compared with patients with discernible etiologies for infertility. This observation led to the notion of ovarian biopsy as a diagnostic tool during the infertility investigation. Ovarian biopsy is invasive, requiring diagnostic laparoscopy. In addition, the risk of future adhesions and further decreasing ovarian reserve as a result of the biopsy itself exists. Perhaps most important, although the presence of appropriate numbers of follicles was reassuring for sufficient ovarian reserve, a biopsy specimen showing empty cortex or few follicles was not always consistent with declining ovarian function. The risks of ovarian biopsy and its uncertain role as a sensitive and specific screening test for DOR prevent this procedure from being recommended at this time.
236
TREATMENT AND PATIENT COUNSELING As mentioned previously, DOR implies a significant decline in oocyte quantity or quality or, in many cases, both. Although treatment options exist (Box 15-3), there are no safe, effective, proven therapies that can improve oocyte quality. When testing suggests a diagnosis of DOR, therapy usually consists of ovarian hyperstimulation in the hopes of recruiting multiple ovarian
Diminished Ovarian Reserve
Box 15-3 ● ● ●
Treatment Options for Patients with Diminished Ovarian Reserve
Gonadotropin stimulation with intrauterine insemination IVF Oocyte donation
follicles. Viable options include treatment with exogenous gonadotropins followed by (1) intrauterine inseminations or (2) oocyte retrieval and IVF. In cases of borderline DOR in which response to ovarian stimulation is adequate, pregnancies do occur. Studies have shown that women with DOR (as manifested by abnormal basal FSH or CCCT) have significantly lower pregnancy rates and higher miscarriage rates compared with controls; however, investigators also have suggested that moderately elevated FSH levels should not lead to the exclusion of subfertile patients from treatment. In one study, 237 although the pregnancy rate was lower among patients with moderately elevated FSH levels compared with controls, the pregnancy rate was still an acceptable 28% among patients with abnormal basal FSH levels. Based on their data, the authors concluded that pregnancy rates were acceptable as long as patients responded to exogenous gonadotropins and had a basal FSH of less than 20 IU/L. Ovarian reserve testing generally should be used as a screening and counseling tool, but should not be used routinely as a way to dissuade patients from undergoing fertility treatment. In patients with DOR who experience poor response to gonadotropins or poor reproductive outcome, conceiving with donor eggs is a viable option. Studies have unequivocally shown that the age of the oocyte, not the age of the uterus, is more important (Fig. 15–3). In brief, egg donation can be performed anonymously (through a clinic or agency) or directed (a known donor, such as a friend or relative). Egg donors are extensively screened medically, genetically, and psychologically before being selected by a recipient couple and undergoing the egg donation process. An egg donor undergoes ovarian stimulation and oocyte retrieval; the donor oocytes are fertilized with the recipient partner’s sperm, and the resulting embryos are transferred to the donor egg recipient. Before stimulating the egg donor, the recipient takes sequential estrogen and progesterone supplementation to simulate the midluteal phase so that implantation occurs after embryo transfer. In this way, extremely high live birth rates are achieved in patients who otherwise would have been unable to conceive. Experimental methods involving cytoplasm (ooplasm) donation have been investigated; cytoplasm is transferred from a donor oocyte to a recipient oocyte in an attempt to enhance embryo quality and improve ART outcome in patients with poor oocyte quality. Cytoplasm donation was first investigated in the late 1990s in patients with “recurrent implantation failure.” In these patients, small amounts of donor cytoplasm were injected into recipient oocytes; mitochondria from the donor cytoplasm were thought to improve respiratory processes in recipient oocytes and to enhance implantation. Although healthy children resulted from this technique, an alarmingly increased rate of Turner’s syndrome and Down syndrome was observed in humans; this could be due to epigenetic defects intrinsic to impaired
Reproductive Endocrinology and Infertility Figure 15-3 40
35 Donor eggs
30 Live births per transfer
Live birth rate after embryo transfer using a patient’s own eggs versus using donor eggs. In patients undergoing IVF using their own eggs, there is a significant decrease in live birth rates after the age of 37. The live birth rate remains high regardless of age in women who conceive using donor 238 eggs. This illustrates the fact that (1) egg quality decreases with advancing age, and (2) the age of the uterus plays a minor role in reproduction. (Adapted from the CDC 2001 ART Success Rates, National Summary and Fertility Clinic Reports, 48.)
25 Own eggs 20
15
10
5
0 25
27
29
31
33
35
37
39
41
43
45
Age
recipient oocytes that seemingly were “rescued” by donor cytoplasmic transfer. Although initial studies were promising, the safety and efficacy of this technique has not yet been convincingly addressed. Additional research into cytoplasmic donation in animals and humans is necessary before this method to enhance oocyte quality is used further. More recently, ovarian tissue and oocyte cryopreservation have emerged as a means to “bank” tissue or gametes before ovarian failure; at this time, these technologies are being considered for patients before undergoing chemotherapy or radiation therapy and warrant further investigation.
CONCLUSION Aging, ovarian and chronologic, remains the enemy of reproduction. Numerous ovarian screening tests exist, and they should be interpreted in such a way that their results can be used to affect treatment and to better counsel patients regarding their chances of conception and achieving a live birth. In general, the possibility of DOR should not exclude patients from care, unless the results of testing are grossly abnormal, or patients respond poorly to treatment, because studies have shown that patients with moderately abnormal test results can conceive. The role of cytoplasmic donation needs to be investigated further. Patients with suspected DOR as a rule should be treated aggressively because their window of opportunity before complete ovarian senescence occurs may be a small one. In some patients, conceiving with donor eggs is a viable option. Lastly and perhaps most importantly,
Diminished Ovarian Reserve
patient age always should be taken into account because age remains a powerful predictor of reproductive outcome. Patients older than age 37 (if not younger) should not be given a false sense of security from clinicians if their ovarian reserve screening is “normal”; in these patients, advancing age by itself portends that there may be “bumps in the road” as patients try to conceive.
SUMMARY OF KEY POINTS 1.
2.
3. 4.
5.
6.
7.
8.
Ovarian aging and oocyte atresia is a normal part of reproductive life. Rates of oocyte loss vary, however, among women. Women with accelerated oocyte atresia may encounter problems conceiving at an early age. It is unknown why some women experience reproductive senescence earlier than others. Declining oocyte quantity and poor oocyte quality contribute to DOR, which can be a cause of subfertility and miscarriage. DOR also is thought to be a possible cause of “unexplained” recurrent miscarriage. Patient age always should be taken into consideration when interpreting results from ovarian reserve testing because age alone is a predictor of DOR. Numerous testing methods have been proposed to detect declining ovarian function in subfertile patients. No one test has been shown to be the ideal screening test for detecting DOR. In many cases, a combination of different studies (i.e., the CCCT in conjunction with AFC and/or ovarian volume), rather than a single test (basal FSH measurement), may better detect DOR. Ovarian reserve screening should be reserved for patients with a diagnosis of infertility. These tests have not been studied in patients who have not yet attempted to conceive and should be interpreted with caution in such patients. Abnormal test results are usually predictive of poor reproductive outcome. “Normal” ovarian reserve testing, although reassuring, does not imply that a patient is fertile because some tests are subject to intracycle variability and lack adequate specificity. There are no safe, effective, proven treatments to improve oocyte quality. Treatment with exogenous gonadotropin to recruit multiple ovarian follicles (possibly in conjunction with IVF) may be beneficial in some cases, although reproductive outcome tends to be poor. Oocyte donation may be a possible option for patients in cases in which pregnancy cannot be achieved using their own eggs. The results of ovarian reserve screening tests should be used to counsel patients regarding their chances of success with infertility treatment. Abnormal testing is predictive of an increased likelihood of poor response to ovarian stimulation, IVF cycle cancellation, and poor reproductive outcome. Abnormal test results should not be used to deny patients care; rather, test results should be discussed with patients in the context of whether or not the probability of achieving a pregnancy warrants proceeding with treatment.
239
Reproductive Endocrinology and Infertility
SUGGESTED READINGS Barnhart K, Osheroff J: Follicle stimulating hormone as a predictor of fertility. Curr Opin Obstet Gynecol 1998;10:227-232. Cohen J, Scott R, Alikani M, et al: Ooplasmic transfer in mature human oocytes. Mol Hum Reprod 1998;4:269-280. Frattarelli JL, Bergh PA, Drews MR, et al: Evaluation of basal estradiol levels in assisted reproductive technology cycles. Fertil Steril 2000;74:518-524. Frattarelli JL, Lauria-Costab DF, Miller BT, et al: Basal antral follicle number and mean ovarian diameter predict cycle cancellation and ovarian responsiveness in assisted reproductive technology cycles. Fertil Steril 2000;74:512-517. 240 Frattarelli JL, Levi AJ, Miller BT, Segars JH: A prospective assessment of the predictive value of basal antral follicles in in vitro fertilization cycles. Fertil Steril 2003;80:350-355. Frattarelli JL, Levi AJ, Miller BT, Segars JH: Prognostic use of mean ovarian volume in in vitro fertilization cycles: a prospective assessment. Fertil Steril 2004;82:811-815. Hawes SM, Sapienza C, Latham KE: Ooplasmic donation in humans: the potential for epigenic modifications. Hum Reprod 2002;17:850-852. Hofmann GE, Danforth DR, Seifer DB: Inhibin-B: the physiologic basis of the clomiphene citrate challenge test for ovarian reserve screening. Fertil Steril 1998;69:474-477. Hofmann GE, Khoury J, Thie J: Recurrent pregnancy loss and diminished ovarian reserve. Fertil Steril 2000;74:1192-1195. Levi AJ, Raynault MF, Bergh PA, et al: Reproductive outcome in patients with diminished ovarian reserve. Fertil Steril 2001;76:666-669. Navot D, Drews MR, Bergh PA, et al: Age-related decline in female fertility is not due to diminished capacity of the uterus to sustain embryo implantation. Fertil Steril 1994;61:97-101. Navot D, Rosenwaks Z, Margalioth EJ: Prognostic assessment of female fecundity. Lancet 1987;2:645-647. Practice Committee of the American Society for Reproductive Medicine: Ovarian tissue and oocyte cryopreservation. Fertil Steril 2004;82:993-998.
Scott RT Jr, Hofmann GE, Oehninger S, Muasher SJ: Intercycle variability of day 3 follicle-stimulating hormone levels and its effect on stimulation quality in in vitro fertilization. Fertil Steril 1990;54:297-302. Scott RT, Leonardi MR, Hofmann GE, et al: A prospective evaluation of clomiphene citrate challenge test screening of the general infertility population. Obstet Gynecol 1993;82(4 Pt 1):539-544. Scott RT, Toner JP, Muasher SJ, et al: Follicle-stimulating hormone levels on cycle day 3 are predictive of in vitro fertilization outcome. Fertil Steril 1989;51:651-654. Seifer DB, Gardiner AC, Ferreira KA, Peluso JJ: Apoptosis as a function of ovarian reserve in women undergoing in vitro fertilization. Fertil Steril 1996;66:593-598. Seifer DB, Lambert-Messerlian G, Hogan JW, et al: Day 3 serum inhibin-B is predictive of assisted reproductive technologies outcome. Fertil Steril 1997;67:110-114. Seifer DB, Scott RT Jr, Bergh PA, et al: Women with declining ovarian reserve may demonstrate a decrease in day 3 serum inhibin B before a rise in day 3 folliclestimulating hormone. Fertil Steril 1999;72:63-65. Sharara FI, Scott RT: Assessment of ovarian reserve: is there still a role for ovarian biopsy? First do no harm! Hum Reprod 2004;19:470-471. Sharara FI, Scott RT Jr, Seifer DB: The detection of diminished ovarian reserve in infertile women. Am J Obstet Gynecol 1998;179(3 Pt 1):804-812. Smotrich DB, Widra EA, Gindoff PR, et al: Prognostic value of day 3 estradiol on in vitro fertilization outcome. Fertil Steril 1995;64:1136-1140. Trout SW, Seifer DB: Do women with unexplained recurrent pregnancy loss have higher day 3 serum FSH and estradiol values? Fertil Steril 2000;74:335-337. te Velde ER, Scheffer GJ, Dorland M, et al: Developmental and endocrine aspects of normal ovarian aging. Mol Cell Endocrinol 1998;145(1–2): 67-73. van Rooij IA, de Jong E, Broekmans FJ, et al: High follicle-stimulating hormone levels should not necessarily lead to the exclusion of subfertile patients from treatment. Fertil Steril 2004;81:1478-1485.
16 RECURRENT PREGNANCY LOSS Stacey Leigh Rubin and Randall Odem Recurrent pregnancy loss (RPL) is a devastating medical problem with far-reaching effects on the couple, their support system, and their caregivers. Few problems strike the heart of a relationship as forcefully as pregnancy 241 loss. These emotional issues may contribute to divorce or the decision to abandon prematurely further pregnancy attempts. To help couples work through the fear of future pregnancies, the clinician should provide accurate facts, an appropriate evaluation, close follow-up in subsequent pregnancies, and continued emotional support. RPL is defined as three or more consecutive pregnancy losses of less than 20 weeks’ gestation. Many physicians apply this diagnosis to nonconsecutive losses before 28 weeks’ gestation. Others argue that a RPL workup should be initiated after two consecutive miscarriages because the risk of subsequent spontaneous abortion after two losses is similar to the risk after three or more. For this reason, many clinical trials investigating habitual abortion include patients with two pregnancy losses. Of all clinically recognized pregnancies, 12% end in spontaneous abortion; the miscarriage rate is 30% when unrecognized pregnancies are taken into account. Overall, 1% of reproductive-age women have experienced three or more losses, 5% of women have experienced two losses, and 15% to 40% of women have experienced at least one pregnancy loss. RPL may have an etiology distinct from sporadic spontaneous abortions, with an inherent factor placing some couples at greater risk for further pregnancy loss. Numerous etiologies have been suggested by retrospective studies, and prospective trials continue to yield additional information. Despite a thorough evaluation, no etiology is identified in 30% to 40% of habitual abortion cases. Even without treatment, a 65% to 70% chance exists of subsequently achieving a live birth. Obstetric history is significant in predicting future risk of spontaneous abortion. Even a single miscarriage, without history of a viable pregnancy, increases the risk that the next pregnancy will terminate in abortion from 12% to 20%. Two miscarriages without a live birth result in a 35% risk of subsequent spontaneous abortion, and three miscarriages without a live birth confer a 47% risk of subsequent loss. A history of one prior live birth reduces the risk of miscarriage by approximately 10%.
Reproductive Endocrinology and Infertility
The routine workup for RPL begins with a detailed history and physical examination. Box 16-1 lists pertinent information to be collected. This chapter addresses the various genetic, uterine, endocrine, infectious, thrombophilic, immune, and environmental causes of RPL.
GENETIC ERROR
242
Fifteen percent of all clinically recognized pregnancies end in spontaneous abortion, and more than half of these are due to lethal genetic defects in the conceptus. Genetic anomalies account for 60% of first-trimester miscarriages, 6% of second-trimester miscarriages, and 0.6% of third-trimester miscarriages. Genetic errors likely cause many additional early abortions occurring before clinical detection. More than 50% of RPL results from genetic etiologies, including aneuploidies, chromosomal abnormalities, and single gene mutations.
Box 16-1 Pertinent History, Physical Examination, and Laboratory Tests for Recurrent Pregnancy Loss History Detailed obstetric history Pattern and trimester of previous pregnancy losses Presence or absence of live embryos Serial human chorionic gonadotropin levels Ultrasound findings Pathology reports of abortuses (e.g., karyotypes) Family history of RPL Menstrual abnormalities, including history of amenorrhea, oligomenorrhea, and LPD Gynecologic or obstetric infections Exposure to occupational or environmental toxins Social habits, including tobacco, alcohol, and caffeine use Chronic medical illnesses, including endocrinologic disturbances In utero DES exposure Physical Examination Examination of vagina and cervix Examination of uterus with attention to uterine size and signs of DES exposure Body habitus Signs of metabolic disease Diagnostic Tests Sonohysterography, HSG, or hysteroscopy Luteal phase endometrial biopsy Parental karyotypes LAC antibody ACA Thyrotropin Fasting insulin and glucose
Recurrent Pregnancy Loss
Aneuploidy
The risk of aneuploidy, or an abnormal number of chromosomes, increases with advancing maternal age. Aneuploidy occurs from maternal nondisjunction, paternal gonadal mosaicism, translocations, and inversions. Monosomies are almost always lethal, whereas some fetuses with trisomies survive to birth and beyond. Parental chromosomal abnormalities occur in 4% of couples with RPL, which is five times more frequently than in the general population. Of spontaneous abortions secondary to aneuploidy, 75% occur in the first 8 weeks of pregnancy. Chromosomal translocations are the most common structural abnormalities associated with RPL. Sixty percent of translocations are reciprocal, or balanced, with material exchanged between nonhomologous chromosomes. All genetic material is preserved, but when the abnormal chromosomes segregate into germ cells during meiosis, fetal aneuploidy can result (Fig. 16-1). Of translocations, 40% are robertsonian, in which two acrocentric chromo- 243 somes fuse and lose their short arms. Robertsonian translocations always result in fetal aneuploidy. Inversions occur when a chromosomal segment breaks and is reinserted in reverse order. Chromosomal inversions can result in phenotypically normal infants. Paracentric crossovers and recombinations are more likely to result in cytogenetically unbalanced embryos. Female translocation and inversion carriers are twice as likely as male carriers to produce affected offspring.
Single Gene Mutations
Many single gene mutations are associated with RPL, and undoubtedly many more as yet are unidentified. The true scope of single gene mutations is unknown. Mutations in “housekeeping genes” result in preimplantation pregnancy failure, whereas mutations in specific adhesion molecules can
Figure 16-1
Chromosome Chromosome A B
Parental balanced translocation between nonhomologous chromosomes can yield unbalanced offspring. Balanced translocation carrier
Unbalanced translocation trisomy chromosome B
Unbalanced translocation trisomy chromosome A
Normal
Balanced translocation carrier
Normal
Reproductive Endocrinology and Infertility
interfere with implantation. Women with glucose-6-phosphate dehydrogenase deficiency are twice as likely to have a spontaneous abortion. Other important single gene mutations occur in the factor V Leiden, methylene tetrahydrofolate reductase (MTHFR), prothrombin, and antithrombin genes. These are discussed in greater detail in the thrombophilias section.
Diagnosis and Treatment
244
Structural abnormalities are diagnosed by cytogenetic testing (karyotyping). A loss at 9 weeks of gestational age is most likely to be associated with an abnormal karyotype in the abortus, and the frequency of abnormalities decreases sharply after 16 weeks. Beyond this period, most spontaneous abortions are associated with maternal rather than genetic factors. After one karyotypically abnormal abortus, subsequent losses have a 70% risk of being chromosomally abnormal. Cytogenetic testing is expensive, but karyotyping of both parents should be included in the routine workup for couples that have experienced three or more first-trimester losses. Routine cytogenetic analysis of the abortus is not usually indicated, and the decision to do this analysis should be made on an individual basis. Some distraught couples can work through their grief more easily after knowing the cause of their loss. Still, cytogenetic testing is incapable of detecting many genetic etiologies of RPL. Fluorescent in situ hybridization facilitates analysis of tissue that cannot be cultured and has identified important roles of single gene mutations, Xinactivation, and imprinting (epigenetic chromosome modification) in the etiology of habitual spontaneous abortion. Fluorescent in situ hybridization is also very expensive and is still used primarily in the research setting. Development of new molecular techniques will continue to elucidate the genetic mechanisms of RPL. At-risk couples should be offered genetic counseling. A trained genetic counselor can advise couples best about their risk of abnormal pregnancy and can be an important source of psychological support. Preimplantation diagnosis is still under development, but allows couples to screen for karyotypically abnormal embryos. For preimplantation diagnosis, one or two cells are removed from the day 3 cleavage stage embryos for testing, and only normal embryos subsequently are transferred. Prenatal testing involves chorionic villus sampling or amniocentesis to detect fetal abnormalities. Elective abortion of severely affected fetuses is an option for some couples. Comprehensive psychological support is an important part of treatment and should not be overlooked. Box 16-2 summarizes the main points concerning genetic error and RPL.
UTERINE ANOMALIES Uterine anomalies affecting pregnancy have congenital and acquired etiologies. Congenital uterine abnormalities occur in 10% to 15% of women with RPL, but in only 3% of the general population and result from errors in müllerian development or from in utero diethylstilbestrol (DES)
Recurrent Pregnancy Loss
Box 16-2 ● ● ● ●
Summary of Genetics and Recurrent Pregnancy Loss
Parental chromosomal abnormalities occur in 4% of couples with RPL. Chromosomal translocations are the most common structural abnormalities associated with RPL. Cytogenetic testing (karyotyping) should be included in the workup for couples with RPL. Genetic counseling is an important treatment component in couples with known genetic abnormalities.
exposure. Acquired uterine abnormalities include intrauterine adhesions and leiomyomata. 245
Diagnosis of Uterine Anomalies
Transvaginal ultrasound and sonohysterography are noninvasive and inexpensive first studies for uterine abnormalities. Ultrasound alone is not as sensitive at diagnosing subtle defects in uterine architecture. Filling the uterus with saline increases sensitivity, but this is invasive. Ultrasound is especially useful for identifying noncommunicating or obstructed uterine horns. Hysterosalpingogram (HSG) is a common test for diagnosis of uterine anomalies. HSG assesses tubal patency and the internal architecture of the uterus. This test does not differentiate between septate and bicornuate uteri because an HSG does not elucidate the external uterine contour. In this case, an additional modality, such as sonohysterography, three-dimensional ultrasound, or magnetic resonance imaging (MRI), is required. A disadvantage of HSG is that it is invasive and involves radiation exposure. Three-dimensional ultrasound or MRI is noninvasive and valuable for diagnosis of uterine anomalies. The radiologist should be informed of the study’s purpose so that proper planes of section can be obtained. MRI is very expensive and cannot assess tubal patency.
Müllerian Development
Development of the female reproductive tract begins in week 7 when the embryonic müllerian (paramesonephric) ducts elongate and reach the urogenital sinus. By week 8, both ducts fuse into a single solid tube forming the primitive uterovaginal canal. Internal canalization forms a central lumen in each of the solid ducts. The septum is resorbed by week 20 forming the uterine lumen. Müllerian uterine anomalies occur when elongation, fusion, canalization, or septal resorption do not occur properly. The most common malformations associated with RPL are variations on the double uterus (bicornuate, septate, and didelphic). Septate and bicornuate uteri account for more than 50% of abnormalities. Figure 16-2 shows the various müllerian anomalies. Inadequate uterine vascularity is associated with müllerian anomalies. Eighty percent of women with müllerian defects have abnormal uterine artery flow compared with 10% of anatomically normal controls. Lateral placentation and poor perinatal outcome also have been correlated to müllerian
Reproductive Endocrinology and Infertility Figure 16-2 The American Society for Reproductive Medicine classification of müllerian anomalies. (From the American Society for Reproductive Medicine.)
I. Hypoplasis/Agenesis
*
a. vaginal *
c. fundal
b. cervical
d. tubal
e. combined
II. Unicornuate
246 a. communicating
b. non-communicating
c. no cavity
IV. Bicornuate
III. Didelphus
a. complete V. Septate
a. complete**
d. no horn
b. partial VI. Arcuate
b. partial VII. DES drug related
* Uterus may be normal or take a variety of abnormal forms. ** May have two distinct cervices
Recurrent Pregnancy Loss
defects. Uterine distortion and decreased intraluminal volume may restrict fetal growth and increase pressure on the lower uterine segment and cervix. Congenital anomalies are present in 30% of cases of cervical incompetence that contribute to midtrimester pregnancy losses.
Unicornuate Uterus
A unicornuate uterus results from agenesis or incomplete elongation of one müllerian duct. It is rare but has a poor prognosis and is associated with a 51% spontaneous abortion rate, a 15% preterm birth rate, and 40% overall fetal survival. Intrauterine growth restriction and malpresentation are common problems. There is no way to increase cavity size surgically. Some physicians recommend treatment with prophylactic cervical cerclage, but there are no good trials assessing outcome. (Some physicians elect to use a gestational carrier to reduce the risk of adverse pregnancy outcome.) It is necessary to look 247 for a rudimentary horn on the contralateral side and manage this as indicated. A complete workup should include renal ultrasound because 40% of women with a unicornuate uterus also have some degree of renal agenesis.
Uterus Didelphys
Uterus didelphys results from duplication of the vagina, cervix, and uterus in the absence of müllerian duct fusion. Each cavity has the same volume as a unicornuate uterus, but superior blood supply results in a smaller spontaneous abortion rate of 40%. Many women with uterus didelphys have normal reproductive outcome, however, so other etiologies should be examined before attributing RPL to a uterus didelphys. Careful examination of the fundus is required to differentiate a uterus didelphys from a septated uterus with cervical and vaginal duplication. If no other cause of RPL is identified, the uterus didelphys can be united by metroplasty, but surgery is of unproven benefit and is rarely performed for this abnormality. Metroplasty carries the risk of subsequent infertility, and the patient requires a cesarean section delivery.
Bicornuate Uterus
A bicornuate uterus consists of a single chamber for the vagina and cervix, with partial or complete separation of the uterine bodies. It results from incomplete fusion of the müllerian ducts at the uterine fundus. A bicornuate uterus is associated with a 30% spontaneous abortion rate and 60% overall fetal survival. Treatment can involve surgical unification by metroplasty, but this is rarely performed because there are no randomized controlled trials showing a benefit of surgical management. In cohort studies, the live birth rate increases to 75% after metroplasty, even in women with previous losses. Another reported treatment option is prophylactic cervical cerclage, which has success rates in cohort studies similar to those of metroplasty without the need for cesarean section. Cerclage must be placed before 20 weeks’ gestation to reduce the rate of intrauterine infection.
Septate Uterus
In a septate uterus, there is partial or complete failure of septal resorption in müllerian development. The septum is fibromuscular tissue and is poorly
Reproductive Endocrinology and Infertility
vascularized and does not generally support placentation; this contributes to an overall poor prognosis with spontaneous abortion rates of 85%. Treatment should be considered for women with RPL, fetal death, preterm delivery, or recurrent fetal malpresentation. Hysteroscopic incision of the septum with possible laparoscopic visualization of the uterus is the preferred treatment. In the hands of an experienced surgeon, the procedure has low morbidity and a high success rate. Postsurgical miscarriage rates are only 20% to 30%. Abdominal metroplasty is associated with higher morbidity and is generally not considered because of the benefits of a hysteroscopic approach. As with the bicornuate uterus repair, there are no randomized controlled trials that support a benefit of surgery.
248
Arcuate Uterus
An arcuate uterus has a slight fundal protrusion reminiscent of a very small septum. It is not associated with recurrent miscarriage or reproductive risk.
Diethylstilbestrol Exposure
DES is a synthetic estrogen that was used to treat RPL, preterm delivery, and other pregnancy complications starting in the 1940s. Its use was discontinued in 1971 when it was associated with vaginal clear cell adenocarcinoma. In addition, 70% of women exposed to DES in utero developed structural uterine abnormalities, and 44% have cervical anomalies. DES exposure is associated with a T-shaped uterus, widened lower uterine segment, irregular uterine margins, uterine constrictions, and uterine hypoplasia. The smaller endometrial surface area contributes to a spontaneous abortion rate of 24%. Cervical incompetence is increased, ectopic pregnancy is eight times more likely, and preterm labor is three times more likely than in the general population. Surgery generally cannot correct the malformations. Cervical cerclage should be considered for women with prior second-trimester losses.
Intrauterine Adhesions (Asherman’s Syndrome)
Asherman’s syndrome is characterized by acquired intrauterine adhesions, which can completely ablate the uterine cavity in severe cases. Adhesions develop when the endometrium is denuded, and the regenerative basal cells are destroyed by postabortal or postpartum curettage. The remaining endometrium is often inadequate to support placentation and is compromised by inflammation and fibrosis of the stroma and glands. An effort should be made to minimize damage to the endometrium because this population undergoes an increased number of dilation and curettage procedures. Symptoms include amenorrhea or irregular menses, infertility, and RPL. Asherman’s syndrome is diagnosed by multiple filling defects on HSG. There is an 80% spontaneous abortion rate before treatment. Treatment involves hysteroscopic lysis of adhesions, placement of a Foley catheter, and administration of estrogens. Postoperative spontaneous abortion rate is decreased to 15%. Success rates are based on cohort data and not randomized controlled trials. It also is possible to lyse the adhesions blindly without hysteroscopy, but this is not recommended because it can damage the endometrium further and may be suboptimal.
Recurrent Pregnancy Loss
Leiomyomata
Leiomyomata, also known as fibroids, are acquired benign tumors of the uterus and can be submucosal, intramural, subserosal, or pedunculated. Submucosal and intramural fibroids are associated with RPL and a 41% spontaneous abortion rate. Treatment involves resection of submucosal fibroids that distort the uterine cavity or occupy a large subendometrial area. Myomectomy for intramural fibroids may be performed if no other cause for RPL is identified. This procedure often is associated with high morbidity, including intra-abdominal adhesions, excessive blood loss, and the need for future cesarean section. The postoperative spontaneous abortion rate is decreased to 19% in representative cohort studies. Box 16-3 summarizes uterine anomaly issues.
ENDOCRINOPATHIES 249
Several endocrinologic conditions have been implicated in RPL, including luteal phase defect (LPD), polycystic ovary syndrome (PCOS), hyperandrogenism, increased gonadotropins, hyperprolactinemia, thyroid abnormalities, and diabetes mellitus. In some cases, it is possible to correct the endocrinopathy and improve pregnancy outcome.
Luteal Phase Defect
Ovarian progesterone is required for implantation and maintenance of early pregnancy. Some investigators believe that 20% to 25% of RPL results from progesterone deficiency during the luteal phase, termed LPD. No properly controlled trials have shown that LPD causes RPL. It is difficult to attribute losses after 8 weeks’ gestation to LPD because the placenta begins to synthesize progesterone, and ovarian progesterone is no longer required. In addition, many women with LPD are capable of conceiving and carrying to term. It is more likely that decreasing progesterone levels are a consequence of poor placental or fetal development and not the cause of pregnancy failure. In the past, LPD was diagnosed most commonly by out-of-phase endometrial biopsy specimens, where histologic dating lagged behind menstrual dating by at least 3 days. Diagnosis required two consecutive out-of-phase endometrial biopsy specimens because 30% of biopsy specimens from isolated cycles of normal women could be out-of-phase. There was significant interobserver variation when dating endometrial biopsy specimens. Other
Box 16-3 ● ● ● ● ●
Summary of Uterine Anomalies and Recurrent Pregnancy Loss
Uterine anomalies are diagnosed by sonohysterography, HSG, or MRI. The most common uterine malformations associated with RPL are variations on the double uterus. Inadequate uterine vascularity and decreased intraluminal volume may contribute to pregnancy loss in women with müllerian defects. DES exposure in utero is associated with structural uterine abnormalities, including T-shaped uterus. Acquired uterine anomalies include intrauterine adhesions and leiomyomata.
Reproductive Endocrinology and Infertility
clinicians diagnose LPD with midluteal progesterone levels less than 9 ng/mL, but this method is less accepted. Currently, the most accepted method for evoluating the luteal phase is by using urinary luteinizing hormone (LH) testing. If the length of time from the observed LH change to menses is ≥13 days, then the luteal phase is felt to be adequate. There are no convincing controlled clinical trials suggesting that progesterone supplementation effectively treats LPD or reduces miscarriages. Some physicians continue to advocate empiric progesterone supplementation for LPD because it is inexpensive with relatively few side effects. Although progesterone may not adversely affect a normal pregnancy, however, it may prolong abnormal pregnancies and ectopic pregnancies. Although progesterone is not a known teratogen, potential side effects must be considered when using any treatment during pregnancy, and medications of unproven benefit should be used cautiously. Clomiphene citrate is another treatment that has been used to treat LPD, with unproven success.
250
Polycystic Ovarian Syndrome
PCOS is a disorder characterized by acyclic production of estrogen via peripheral aromatization of circulating androstenedione. The clinical diagnosis is based on anovulatory infertility, hirsutism, obesity, acne, and amenorrhea or oligomenorrhea. PCOS occurs in 5% to 10% of reproductive-age women and is the most common cause of infertility. Elevated luteinizing hormone (LH) levels contribute to increased androgen production and enlarged polycystic ovaries. PCOS-associated hyperinsulinemia adversely affects the endometrium and preimplantation environment by reducing glycodelin and insulin-like growth factor I binding protein levels. Glycodelin inhibits the endometrial immune response against the embryo and is important for embryo survival. Insulin-like growth factor I binding protein facilitates adhesion at the maternal-fetal interface and is important for implantation. Elevated plasminogen activator inhibitor (PAI) levels also are associated with insulin resistance and occur in 52% of women with PCOS compared with 4% of women without PCOS. PAI inhibits fibrinolysis and may lead to thrombosis and clot formation in the placenta. All of these factors contribute to pregnancy difficulties in women with PCOS. PCOS is an independent risk factor for RPL and is associated with miscarriage rates of 30% to 50%. Diagnostic workup should include ovarian ultrasound, fasting insulin, testosterone, androstenedione, dehydroepiandrosterone sulfate, LH, folliclestimulating hormone, and PAI. Studies suggest that RPL in PCOS can be treated effectively with metformin, an insulin-sensitizing drug. Metformin decreases circulating androgens, minimizes the contribution of obesity to infertility, reduces hyperinsulinemic insulin resistance, decreases PAI activity, and improves ovulation. In one retrospective study, PCOS women treated with metformin had an 8.8% miscarriage rate compared with the 42% loss rate in untreated PCOS controls. Hyperandrogenism is associated with RPL, even in the absence of PCOS. Androgens may have an antagonistic effect on ovulation and estrogen priming of the endometrium. Diagnostic workup for women with signs and symptoms of hyperandrogenism should include testing for abnormalities in testosterone and dehydroepiandrosterone sulfate levels.
Recurrent Pregnancy Loss
Increased Luteinizing Hormone
Hyperprolactinemia
Increased LH is found in 33% of women with RPL and may contribute to premature luteinization. A 65% spontaneous abortion rate is associated with increased LH compared with a 12% loss rate in controls. Diagnostic workup should evaluate LH and follicle-stimulating hormone levels. Treatment with gonadotropin-releasing hormone agonists to suppress LH release has been shown to reduce loss rates in some studies. Menotropins (human menopausal gonadotropins) may increase fecundity in women with difficulty conceiving, but these pregnancies also may be predisposed to spontaneous abortion. Some investigators theorize that this predisposition to miscarriage may be due to the fertilization of suboptimal eggs that would have become atretic in a natural cycle.
Hyperprolactinemia affects the hypothalamic-pituitary-ovarian axis and 251 results in insufficient folliculogenesis and oocyte maturation. Even in the absence of ovarian or menstrual dysfunction, hyperprolactinemia has been associated with RPL. In observational studies, treatment with bromocriptine decreased the spontaneous abortion rate from 47.6% to 14.3%.
Thyroid
Overt hyperthyroidism and hypothyroidism have been associated with recurrent miscarriage, but correcting thyroid hormone levels results in normal outcome. Initial screening is by thyrotropin, with appropriate further evaluation based on the findings.
Diabetes Mellitus
Uncontrolled diabetes mellitus has been associated with a threefold increase in pregnancy loss. Well-controlled diabetes is not a risk factor for RPL, however. Diagnosis is by oral glucose tolerance screening or by glycosylated hemoglobin (hemoglobin A1c) levels.
Diagnosis and Treatment
A pertinent endocrinologic workup should be conducted on all women with RPL. Physicians should ensure that treatment choices are guided by welldesigned clinical trials, rather than historical practice. Box 16-4 summarizes issues related to endocrinopathies and RPL.
INFECTIONS Infection is a controversial cause of RPL. Although certain infections have been linked to spontaneous abortion, few are convincingly correlated to RPL. Bacterial vaginosis is associated with a fivefold increased risk of miscarriage in the first 20 weeks of gestation. Bacterial vaginosis is an alteration of the normal vaginal flora associated with loss of lactobacilli and overgrowth of anaerobic bacteria, including Gardnerella vaginalis, Mycoplasma hominis, and Ureaplasma urealyticum. Bacterial vaginosis is diagnosed clinically by a thin gray discharge with fishy odor, pH greater than 4.5, the presence of “clue
Reproductive Endocrinology and Infertility: Requisites
Box 16-4 ● ●
252
Summary of Endocrine Abnormalities and Recurrent Pregnancy Loss
Some investigators believe that 25% of RPL are due to LPDs, but no properly controlled trials have shown that LPD causes miscarriage. PCOS is associated with anovulatory infertility and RPL; studies suggest that metformin may reduce miscarriage rates in women with PCOS.
cells,” and bacteria-encrusted epithelial cells. The presence of bacterial vaginosis predicts early pregnancy loss in 36% of cases, and absence of bacterial vaginosis predicts normal delivery in 93% of cases. In another study, U. urealyticum was associated with a 44.4% spontaneous abortion rate before treatment with erythromycin and an 11.4% rate of spontaneous abortion after treatment. One study showed that primary infection with herpes simplex virus during pregnancy was associated with increased miscarriage, but other studies dispute this finding. Overall, it is agreed that Toxoplasma gondii, Chlamydia trachomatis, Treponema pallidum, Borrelia burgdorferi, Neisseria gonorrhea, Streptococcus agalactiae, Listeria monocytogenes, and cytomegalovirus are not associated with RPL. There is conflicting evidence regarding the role of infection in RPL, and additional research is required. Screening for and treating bacterial vaginosis in patients with RPL seems prudent. Some physicians advocate empiric antibiotic treatment with a tetracycline, assuming that infection is a possible cause of RPL. Practitioners should weigh the risk versus benefit of antibiotic treatment and endometrial culture. Box 16-5 summarizes issues related to infections and RPL.
THROMBOPHILIAS Increased thrombus formation at the maternal-fetal interface has been implicated in RPL. During pregnancy, changes in hemostasis favor thrombin formation and platelet activation, resulting in a hypercoagulable state. Figure 16-3 reviews the coagulation cascade. Thrombin formation is favored by increased levels of procoagulant factors VII, VIII, and X, beginning in week 12. With this procoagulant increase, there is no corresponding increase in natural anticoagulants. Protein S levels decrease by 50% to 60%. In addition, resistance to activated protein C develops during pregnancy, inhibiting fibrinolysis, which is required for placentation. A fourfold to fivefold increase in PAI also reduces fibrinolysis and predisposes to thrombosis. Platelet activation is favored by increased synthesis of thromboxane before 20 weeks. Coupled with decreased platelet sensitivity to the antiaggregatory
Box 16-5 ● ●
Summary of Infections and Recurrent Pregnancy Loss
Bacterial vaginosis, including infection with G. vaginalis, M. hominis, and U. urealyticum, has been associated with pregnancy loss. Empiric antibiotic treatment with doxycycline or erythromycin is frequently prescribed.
Recurrent Pregnancy Loss Figure 16-3 The coagulation cascade. (Adapted from Rai R, Regan L: Thrombophilia and adverse outcome. Semin Reprod Med 2000;18:370.)
Enhances fibrinolysis
Intrinsic pathway
Villa Va Thrombin
Inhibits
Activated protein C
Protein S cofactor
Thrombin
AT
Protein C Fibrinogen
Fibrin
AT
253 Thrombin
Endothelial cell
Thrombomodulin
effects of prostacyclins, these platelet mediator changes result in vasospasm and platelet aggregation, predisposing to placental infarction. Thrombophilic defects alone may not cause thrombosis, but they decrease the ability to cope with hypercoagulable states such as pregnancy. During pregnancy, there is an eightfold increased risk of thrombotic events associated with the inherited thrombophilias, and women with combined thrombophilic defects have an even poorer prognosis. Thrombophilic defects are unlikely to cause very early pregnancy loss because the maternal intervillous network does not form until gestational week 8, and many of the procoagulant changes do not begin until week 12. Many of the thrombophilic defects are associated, however, with losses before 20 weeks (miscarriage) and later in pregnancy (fetal death). The balance between coagulation and fibrinolysis maintains intact placental circulation. Microthrombi in placental vasculature lead to RPL, preeclampsia, and intrauterine growth restriction. Thrombosis of spiral arteries leads to uterine and placental insufficiencies and fetal loss. Histologic samples from lost pregnancies support these findings, showing increased fibrin deposition and clotting and suggesting an underlying cause of thrombosis.
Factor V Leiden Mutation and Activated Protein C Resistance
The factor V Leiden mutation (G1691A) renders factor V resistant to proteolysis and inactivation by activated protein C. Enhanced thrombin generation and increased clot formation result. The factor V Leiden mutation is present in 2% to 6% of the general population, but is probably underdiagnosed because most carriers are asymptomatic. Still, it is the most numerically important cause of venous thrombosis and familial thrombophilia. Women with the factor V Leiden mutation are predisposed to spontaneous abortion, placental infarction, severe preeclampsia, and intrauterine growth restriction. Nineteen percent of women with RPL are heterozygous and are
Reproductive Endocrinology and Infertility
at a 5-fold to 10-fold increased risk of venous thrombosis; 6% of women with RPL are homozygous and are at a 50-fold to 100-fold increased risk of thromboembolism. Activated protein C resistance results in increased thrombin formation because factor V is not proteolytically cleaved. Nine percent of women with RPL have acquired activated protein C resistance compared with 3.3% of controls.
Prothrombin (G20210A) Mutation
Factor II, or prothrombin, is converted to thrombin by the factor Va/Xa complex. A single base pair substitution at base 20210 gives rise to increased thrombin levels and arteriolar and venous thrombosis. The mutation is autosomal dominant, and carriers have a twofold increased risk of RPL. Two to three percent of the general population is heterozygous for the prothrombin (G20210A) mutation, whereas 8.8% of women with RPL are heterozygous. The mutation has been found in 6.7% of women with first-trimester miscarriages compared with 0.8% of normal controls, but has been implicated in early and late losses. Data are conflicting on the association of the prothrombin (G20210A) mutation and RPL, and further studies are needed.
Methylene Tetrahydrofolate Reductase (C677T) Mutation and Hyperhomocysteinemia
MTHFR allows homocysteine to be reconverted into methionine in the methionine salvage pathway. Decreased MTHFR activity results in accumulation of high homocysteine levels, which may cause vascular injury and early arteriosclerosis. Hyperhomocysteinemia has procoagulant effects by decreasing protein C activity and decreasing plasminogen activator. Reduced MTHFR activity and hyperhomocysteinemia may be evident only in the presence of folate deficiency, however, and adequate folate supplementation may prevent phenotypic expression of the mutation. Homozygosity and heterozygosity for the MTHFR (C677T) mutation are associated in some small studies with increased early fetal loss and twofold to threefold increased risk for early RPL. Conflicting data on the association between the MTHFR mutation and RPL necessitate further study.
Antithrombin Deficiency
Antithrombin binds to thrombin, inactivating thrombin and allowing it to be cleared, which also inhibits further thrombin formation. The autosomal dominant antithrombin III mutation is the most thrombogenic of the thrombophilias, but it is extremely rare. The rarity of this mutation makes it difficult to study in controlled trials. The trials that have been conducted show an associated 44% to 70% risk of thrombosis or fetal death in pregnancy and a fivefold increased risk of stillbirth. Antithrombin deficiency is believed to account for 12% of pregnancy-associated venous thromboembolic events. The exact relationship between the antithrombin III mutation and RPL must be investigated further.
Factor XII Deficiency
Factor XII deficiency results in defective fibrinolytic activation, disturbed hemostasis, and thromboembolism at the maternal-fetal interface. In one study, 15% of women with RPL were factor XII deficient (defined as 60%
254
Recurrent Pregnancy Loss
activity) compared with 0% of control women. Further research is necessary to define the exact role of factor XII deficiency in RPL.
Protein C and Protein S Deficiencies
Protein C and protein S deficiencies result from autosomal dominant mutations. The prevalence of protein C deficiency in the general population is about 1 in 500, whereas the prevalence of protein S deficiency is unknown. Both deficiencies are associated with a low but significant risk of thrombosis and fetal death in pregnancy. The risk of postpartum thrombosis is highest. The exact correlation to RPL requires further study.
Plasminogen Activator Inhibitor
PAI decreases fibrinolysis. Increased PAI levels have been found in 38% of women with RPL and PCOS. 255
Diagnosis and Treatment
It is debatable whether factor V Leiden, prothrombin (G20210A), MTHFR (C677T), antithrombin III, factor XII, PAIs, and protein C and protein S deficiencies should be included in the workup for RPL, owing to their relative rarity and the lack of evidence associated with treatment outcome. Ultimately, these thrombophilic disorders should be worked up only in a select population of women with personal or familial history of thrombosis or no other known cause of RPL. Diagnosis of the inherited thrombophilias is by polymerase chain reaction or by enzyme level detection. Specifically, the diagnosis of the factor V Leiden mutation is by polymerase chain reaction amplification of exon 10 in the factor V gene, and the MTHFR (C677T) mutation is diagnosed by polymerase chain reaction amplification of exon 2 and the intron of the MTHFR gene. The diagnosis of antithrombin III and protein C and protein S deficiencies is by enzyme assay. In one study, treatment of women with thrombophilic defects with lowmolecular-weight heparin increased the live birth rate from 20% to 75%. Other investigators advocate the use of heparin and aspirin. Good clinical trials measuring the outcome of anticoagulant therapy are largely lacking, however. More trials are necessary to establish specific treatment benefits and dosages. One known treatment for the MTHFR mutation is supplementation with vitamin B6 and folate, which has effectively suppressed phenotypic expression of hyperhomocysteinemia in some women. Future studies aimed at improving understanding of maternal intervillous blood flow, investigating the role of fetal thrombophilic defects in pregnancy outcome, and prospective trials with anticoagulant treatment are warranted. Box 16-6 summarizes issues related to thrombophilias and RPL.
IMMUNOLOGIC FACTORS There are many proposed immunologic mechanisms for RPL, including autoimmune etiologies (antiphospholipid syndrome [APS], other autoantibodies)
Reproductive Endocrinology and Infertility
Box 16-6 ● ● ●
●
Summary of Thrombophilias and Recurrent Pregnancy Loss
Pregnancy is a hypercoagulable state. Thrombosis of spiral arteries leads to placental insufficiency and RPL in women with thrombogenic defects. The clinician should test for factor V Leiden, prothrombin (G20210A), and MTHFR (C677T) mutations in women with a personal or family history of thrombosis and RPL. Future trials on anticoagulation therapy and pregnancy outcome are warranted.
and alloimmune etiologies. With the exception of APS, the immunologic etiologies of habitual abortion are poorly understood. 256
Antiphospholipid Syndrome
APS is an autoimmune disorder characterized by antiphospholipid antibodies and one or more clinical features, including RPL, unexplained fetal death, autoimmune thrombocytopenia, and thrombosis. The primary antiphospholipid antibodies are lupus anticoagulant (LAC) antibody and anticardiolipin antibody (ACA). These autoantibodies inhibit prostacyclins, which are potent vasodilators and inhibitors of platelet aggregation. Protein C activation also is inhibited, resulting in a procoagulant environment that favors thrombosis. Fetal death most likely occurs as a result of uteroplacental insufficiency from spiral arteriolar vasculopathy. In severe cases, decreased intervillous blood flow leads to placental infarction. APS is the cause of recurrent miscarriage in 5% to 10% of women and is most commonly associated with second-trimester loss. Seven percent of women with RPL are LAC antibody positive, and 19% are ACA positive, whereas only 2% of normal women have antiphospholipid antibodies. LAC antibody is found most commonly in women who do not meet the diagnostic criteria for systemic lupus erythematosus. LAC antibody is diagnosed by activated partial thromboplastin time, dilute Russell’s viper venom time, kaolin clotting time, or plasma clotting time. Abnormalities are confirmed by mixing the patient’s plasma with normal plasma, which does not correct the abnormality if inhibitor is present. Without treatment, LAC antibody is associated with an 80% spontaneous abortion rate. ACA is associated with a 38% fetal loss rate. ACA IgG and IgA are diagnosed on a continuum, but only medium-positive and high-positive titers (20 GPL units) are associated with RPL. High titers and previous history of fetal loss are additive risk factors influencing pregnancy outcome. It is important to diagnose APS because it is a treatable condition. Treatment for APS is aimed at antiplatelet, anticoagulant, or immunosuppressive activity. Heparin binds to antiphospholipid antibodies, preventing their harmful effects. The most accepted APS treatment is heparin and aspirin therapy for maximum anticoagulation. Combination therapy has a better outcome than either aspirin or heparin treatment alone. With optimal treatment, the spontaneous pregnancy loss rate is reduced to 15%. Treatment with prednisone and aspirin has a similar outcome as heparin and aspirin therapy. Glucocorticoids are discouraged, however, because they are associated with
Recurrent Pregnancy Loss
high maternal and fetal morbidity, including premature rupture of membranes and preeclampsia. Some physicians also advocate intravenous immunoglobulin (IVIG) immunotherapy, but there are no trials showing clinical or statistical benefit. There have been case reports of successful pregnancy with IVIG in heparin-resistant cases. Large clinical trials show, however, that addition of IVIG to heparin and aspirin therapy does not improve the number of live births, preeclampsia, fetal growth impairment, birth weight, or gestational age at delivery. The efficacy of IVIG treatment for APS is uncertain, and IVIG cannot be advocated at this time because of its high expense and lack of proven benefit.
Thyroid Autoantibodies
Thyroid autoantibodies (antithyroglobulin and antimicrosomal antibod- 257 ies) are associated with RPL, but the pathophysiology is poorly understood. One hypothesis is that thyroid autoantibodies are markers of abnormal T cell function or a generalized immune reaction against the fetal allograft. Another hypothesis is that thyroid autoantibodies are signs of mild hypothyroidism or decreased thyroid reserve. A third theory states that pregnancy loss results directly from thyroid peroxidase autoantibodies. Thyroid peroxidase autoantibody titers are higher at initial presentation in women who later miscarry. The presence of antithyroglobulin or antimicrosomal antibodies in early pregnancy, or just before pregnancy, is associated with a 17% risk of loss compared with 8% loss rates in normal controls. Despite this association, there is no benefit to testing routinely for thyroid autoantibodies because there is no recognized treatment, and their presence is not a modifiable risk factor.
Systemic Lupus Erythematosus
A diagnosis of systemic lupus erythematosus is associated with a 22% total pregnancy loss rate; 75% of losses secondary to systemic lupus erythematosus are in the second or third trimesters. The prognosis is significantly better for women with quiescent disease. Conception should be delayed until lupus is in remission.
Other Autoantibodies
Antinuclear antibodies are more common in women with RPL, but the presence or absence of antinuclear antibodies does not predict pregnancy outcome. In addition, there is no proven treatment for women who test positive for antinuclear antibody, so antinuclear antibodies should not be routinely tested in the RPL workup. Anti-β2 glycoprotein 1 is not independently associated with increased risk of pregnancy loss and does not predict adverse outcome. It should not be included in the routine diagnostic workup for RPL.
Alloimmunity
Successful gestation depends on an immunologic milieu that allows the mother to maintain the antigenically dissimilar fetal allograft in the uterus. Little is known, however, about the mechanisms that prevent immunologic
Reproductive Endocrinology and Infertility
258
rejection of the fetus in successful pregnancies. Some practitioners believe that HLA sharing between parents contributes to pregnancy loss, as the woman produces minimal antipaternal antibodies, which are required to produce blocking antibodies. This model is unlikely because HLA sharing does not preclude healthy pregnancy in most women, and there is no convincing statistical difference in the degree of HLA sharing between couples experiencing RPL and normal couples. The cytotoxic immune rejection theory states that leukocytic antibody activity increases in normal pregnancies, but not in women with RPL. This activity is probably a result of the number and duration of pregnancies and does not influence subsequent pregnancies. A third theory is that the maternal humoral response is necessary to prevent rejection of the fetal allograft. These maternal blocking antibodies are not universally present in normal pregnancies, however, and are not predictive of pregnancy outcome. Even in the absence of known alloimmune etiology, some physicians administer costly immunotherapy. One treatment is paternal leukocyte immunization to prevent paternally derived antigen expressed on embryonic tissue from resulting in fetal rejection. Well-designed trials have shown this therapy to be ineffective, however, at improving pregnancy outcome in women with recurrent miscarriage. IVIG also has been suggested as treatment for alloimmune causes of RPL. As discussed earlier, however, IVIG cannot be recommended because of lack of efficacy and high cost. APS remains the only known humoral cause of RPL, and it is effectively treated with heparin and aspirin anticoagulation therapy. Future research undoubtedly will elucidate additional immunologic mechanisms in RPL. Box 16-7 summarizes immunologic issues related to RPL.
LIFESTYLE AND ENVIRONMENTAL FACTORS Many couples experiencing RPL are concerned that environmental toxins may contribute to their reproductive difficulties. Popular media coverage often leads to exaggerated or inappropriate conclusions from research data. It is important for physicians to relate accurate and current information about the effects of lifestyle and the environment on pregnancy. Particular attention should be focused on modifiable risk factors, such as alcohol and tobacco use.
Box 16-7 ● ● ●
Summary of Immunology and Recurrent Pregnancy Loss
APS is the only known immunologic cause of RPL and is characterized by LAC antibody and ACA, thrombosis, and repeated miscarriage. The preferred treatment of APS involves heparin and aspirin therapy. Little is known about alloimmune mechanisms of RPL.
Recurrent Pregnancy Loss
Alcohol
Alcohol use in the first 8 weeks of gestation is associated with considerable risk of miscarriage. Drinking twice weekly is associated with a twofold increase in spontaneous abortion, and daily alcohol use is associated with a threefold increased risk of miscarriage. Alcohol should be avoided during pregnancy.
Tobacco
Smokers have 25% to 50% more spontaneous abortions than nonsmokers, and the risks are proportional to cigarettes smoked per day. Smoking more than 14 cigarettes per day is associated with a twofold increased risk of miscarriage. Tobacco should be avoided during pregnancy.
Caffeine
Drinking fewer than 1.5 cups of coffee each day has not been associ- 259 ated with increased pregnancy loss, but drinking more than 3 cups each day (300 mg of caffeine) is associated with a twofold increase in spontaneous miscarriages. The relationship between caffeine and miscarriage may not be causal, however, because women with viable pregnancies are more likely to experience nausea and reduce their caffeine intake. Women with nonviable pregnancies are more likely to defer curtailment of caffeine use, which may contribute to an overestimated relative risk. Still, it is recommended that women with a history of RPL limit their caffeine intake.
Radiation
Ionizing radiation is an abortifacient in sufficient doses (>5 cumulative rads). The average chest x-ray administers 8 mrads, and a barium enema delivers 800 mrads. Therapeutic radiation delivers 360 to 500 rads and almost always causes miscarriage.
Hyperthermia and Fever
Maternal hyperthermia resulting from fever or hot tub use is teratogenic and results in neural tube defects and spontaneous abortion. Hot tub and sauna use should be avoided during pregnancy.
Tap Water
High exposure to bromodichloromethane in tap water has been associated with a twofold increase in spontaneous abortions. In one California study, women who drank more than 6 glasses of tap water daily had a 10% to 50% increased risk of miscarriage. Other studies report conflicting evidence, however, and the exact risk of drinking tap water is unknown.
Other Factors
There is significant evidence that lead and mercury increase the risk of miscarriage. There is some evidence for the contribution of arsenic, formaldehyde, benzene, ethylene oxide, and nitrous oxide to pregnancy loss. Box 16-8 summarizes environmental and lifestyle issues related to RPL.
Reproductive Endocrinology and Infertility
Box 16-8 Summary of Lifestyle and Environmental Factors and Recurrent Pregnancy Loss Evidence suggests that frequent use of alcohol, tobacco, and caffeine contribute to spontaneous miscarriage.
CONCLUSION Many causes of RPL have been discussed in this chapter. Table 16-1 summarizes comprehensive diagnostic workups and treatments. It is unlikely that any one couple would require all of this testing. In 30% to 40% of couples, Table 16-1
260 Etiology, Diagnosis, and Treatment of Recurrent Pregnancy Loss
Etiology
Standard Diagnostic Tests
Supplemental Diagnostic Tests
Genetic error
Cytogenetic testing
Uterine anomalies
Sonohysterography
Endocrinopathies
Endometrial biopsy, progesterone
Infections
None
PCR of single gene Genetic mutation, counseling, clomiphene citrate prenatal challenge test testing, preimplantation genetic diagnosis Ultrasound, HSG, Surgical MRI correction, prophylactic cervical cerclage Androstenedione, Correction of testosterone, endocrinopathy DHEAS, prolactin, when possible LH, FSH, thyrotropin, fasting insulin U. urealyticum, Antibiotics G. vaginalis, M. hominis cultures; screen for bacterial vaginosis Antithrombin, Consider protein C, anticoagulation protein S, factor XII, PAI None Heparin and aspirin, prednisone and aspirin Test for lead, Avoid exposure mercury
Thrombophilias Factor V Leiden, prothrombin G20210A, MTHFR C677T Immunologic LAC antibody, ACA factors IgG, ACA IgM
Environment and lifestyle
Tobacco, alcohol, and caffeine use by history
Treatment
DHEAS, dehydroepiandrosterone sulfate; FSH, follicle-stimulating hormone; PCR, polymerase chain reaction.
Recurrent Pregnancy Loss
no etiology is determined after complete diagnostic workup. This situation can be frustrating and disheartening for affected couples. Informative and sympathetic counseling plays an essential role in this difficult situation. It is important to explain that couples experiencing RPL have live birth rates of 70% in subsequent pregnancies, even without treatment. This figure may provide comfort and hope to grieving couples. It is imperative to recognize that fear for future pregnancies is a prominent emotion, and the grieving process for lost pregnancies can last a lifetime. Some studies suggest that a “tender loving care” approach, including weekly ultrasound studies for assurance of fetal interval growth, improves subsequent pregnancy outcome. Regardless, adequate psychological support should be offered to all couples undergoing evaluation and treatment for RPL. Given the high emotional and financial costs of some existing therapies, proof of efficacy from well-designed randomized controlled trials should be 261 required. Patients undergoing experimental therapies should be aware of the risks and unproven nature before receiving treatment. There is a clear need for future clinical therapeutic trials that meet epidemiologic standards, including randomization, double-blindedness, and placebo control. Future studies should focus on women with unknown causes of RPL. Including women with two consecutive losses should be considered because the risk factors for subsequent losses seem to be similar, and this would increase sample sizes substantially.
SUMMARY OF KEY POINTS 1. 2.
3. 4. 5.
RPL is defined as three or more consecutive losses before 20 weeks’ gestation. RPL can have diverse etiologies, including genetic, structural uterine, endocrine, infectious, thrombophilic, immunologic, and environmental factors. An identifiable etiology is not found in 30% to 40% of RPL. Treatment decisions should be based on evidence from well-designed clinical trials. RPL is frustrating and frightening for couples, and appropriate psychological support is important.
SUGGESTED READINGS Clifford K, Rai R, Watson H, Regan L: An informative protocol for the investigating of recurrent miscarriage: preliminary experience of 500 consecutive cases. Hum Reprod 1994;9:1328-1332. Hill JA: Recurrent pregnancy loss. In: Creasy RK, Resnick (eds): Maternal-Fetal Medicine, 4th ed. Philadelpha: Saunders;1999. Kutteh WH: Recurrent pregnancy loss. In: Carr BR, Blackwell RE (eds): Textbook of Reproductive
Medicine, 2nd ed. Stamford, CT: Appleton & Lange; 1998:679-692. Ober C, Karrison T, Odem RR, et al: Mononuclear-cell immunisation in prevention of recurrent miscarriages: a randomised trial. Lancet 1999;354:365-369. Rai R, Regan L: Thrombophilia and adverse pregnancy outcome. Semin Reprod Med 2000;18:369-377. Stephenson MD: Frequency of factors associated with habitual abortion in 197 couples. Fertil Steril 1996;66:24-29.
Reproductive Endocrinology and Infertility Stray-Pederson B, Stray-Pederson S: Etiologic factors and subsequent reproductive performance in 195 couples with a prior history of habitual abortion. Am J Obstet Gynecol 1984;148: 140-146.
262 262
Warburton D, Kline J, Stein Z, Strobino B: Cytogenetic abnormalities in spontaneous abortion of recognized conceptions. In: porter IH (ed): Perinatal Genetics: Diagnosis and Treatment. New York: Academic Press; 1986;23-40.
17 ASSISTED REPRODUCTIVE TECHNOLOGIES Deborah L. Manzi-Smith 263
DEFINITIONS In vitro fertilization Intracytoplasmic sperm injection Assisted hatching Gamete intrafallopian transfer Embryo transfer Ovarian hyperstimulation syndrome
Fertilizing retrieved oocytes by insemination with sperm Injecting single sperm directly into ooplasm of oocyte Creating a defect in zona pellucida of cleaving embryo to enhance implantation Placing sperm and oocytes in a normal fallopian tube to achieve in vivo fertilization Atraumatically placing an embryo into uterine cavity to achieve pregnancy Complication of assisted reproductive technologies resulting in ovarian enlargement, increased vascular permeability, hemoconcentration, and ascites
Although many assisted reproductive technologies (ART) exist with a bewildering array of acronyms (Box 17-1), their goal is the same. ART procedures attempt to bring sperm and oocyte close together to increase the likelihood of fertilization, implantation, and delivery of a healthy infant. Initially, in vitro fertilization (IVF) was used only in patients with tubal factor infertility; however, in the 1980s, the application of IVF was broadened to include patients with male factor infertility, endometriosis, unexplained infertility, and immunologic infertility. The technology has improved significantly since the 1980s, and the rapid developments in the field suggest that these improvements will continue.
Reproductive Endocrinology and Infertility
Box 17-1
Acronyms for Assisted Reproductive Technologies
IVF—in vitro fertilization GIFT—gamete intrafallopian transfer ZIFT—zygote intrafallopian transfer ET—embryo transfer PGD—preimplantation genetic diagnosis ICSI—intracytoplasmic sperm injection AH—assisted hatching MESA—microsurgical epididymal sperm aspiration TESE—testicular sperm extraction
GENERAL PRINCIPLES 264
Oocytes obtained from ovarian follicles by aspiration are prepared and combined with sperm in a dish in the laboratory. Fertilization occurs outside the body with IVF (in vitro) or in the body (in vivo) with gamete intrafallopian transfer (GIFT). The outstanding effort of Edwards and Steptoe that produced the first IVF birth was achieved using a nonstimulated (natural) cycle with timing of the oocyte retrieval based on urinary luteinizing hormone (LH) levels. Nonstimulated cycles have been used to reduce costs, but pregnancy rates are only 10%. Most patients undergoing IVF procedures receive gonadotropins to increase the number of oocytes available for oocyte retrieval. A careful balance between producing numerous oocytes and preventing hyperstimulation is sought. Although multifollicular development can be achieved by using clomiphene citrate, most patients require injected preparations of follicle-stimulating hormone (FSH) to produce an adequate number of oocytes.
CONTROLLED OVARIAN HYPERSTIMULATION The process of creating an increased number of oocytes using medications is called controlled ovarian hyperstimulation. This stimulation is accomplished through the administration of medications such as clomiphene citrate, human menopausal gonadotropins (HMG), or follitropin (FSH). There are several formulations of HMG and FSH. Some formulations contain FSH and LH, whereas others contain FSH only (Table 17-1). Careful patient monitoring is required on a regular basis to prevent too many follicles from developing. Ultrasound of the ovaries and monitoring plasma estradiol levels are used to evaluate the effects of the superovulation medication and to help prevent overstimulation. The dose of medication is titrated almost daily to achieve the desired response. Most IVF cycles involve pretreatment with oral contraceptive pills and with a gonadotropin-releasing hormone agonist (GnRH) or midcycle treatment with a GnRH antagonist. Human chorionic gonadotropin is given when the lead follicles are 18 mm or greater in diameter. Human chorionic gonadotropin is usually given 34 to 38 hours before
Assisted Reproductive Technologies Table 17-1 Types, Gonadotropin Content, and Brand Names of Gonadotropin Preparations Used in the United States
Gonadotropin Content per Vial (IU) Type of Gonadotropin
FSH
LH
Brand Name
Human Derived HP FSH hFSH HMG
75 75 75
<0.1 <1 75
Bravelle Metrodin Pergonal, Repronex
Recombinants rFSHα rFSHβ
37.5–1200 50–600
None None
Gonal-f Follistim
hFSH, human follicle-stimulating hormone; HMG, human menopausal gonadotropin; HP FSH, highly purified follicle-stimulating hormone; rFSHα, recombinant follicle-stimulating hormone α; rFSHβ, recombinant follicle-stimulating hormone β.
the planned retrieval procedure. About 15% of cycles in the United States are cancelled before oocyte retrieval because the response to superovulation is excessive and the risk of ovarian hyperstimulation syndrome (OHSS) is substantial or because the response to ovarian stimulation is poor.
MEDICATIONS COMMONLY USED IN ASSISTED REPRODUCTIVE TECHNOLOGY PROCEDURES Oral Contraceptives
The use of oral contraceptive pills in ART stimulation protocol is a more recent innovation. Monophasic preparations of oral contraceptive pills have been used to allow greater flexibility in the schedule of cycle start dates. Oral contraceptive pills also are used for their known effect on ovarian cysts and to suppress spontaneous ovulation. Patients receiving oral contraceptive pills are less likely to have large ovarian or corpora lutea cysts at the initiation of the IVF cycle. These cysts may delay cycle initiation.
Human Menopausal Gonadotropins and Follitropin
The high degree of success with modern IVF would not be possible without the use of HMG or FSH. In 1954, pooled extracts of FSH from menopausal urine were noted to be clinically effective in stimulating oocyte production. The process of extracting FSH was described in 1961 with the first pregnancy from HMG occurring in 1962. There are several formulations of HMG available; now recombinant FSH also is available (see Table 17-1). Disagreement in the literature exists as to which is the better formulation to use. Some studies have shown better oocyte quality with FSH-only regimens compared with HMG or HMG/FSH combination regimens. Other studies showed no difference in oocyte quality between the regimens.
265
Reproductive Endocrinology and Infertility
GonadotropinReleasing Hormone Agonists
GnRH agonist has been used in IVF to induce a temporary hypogonadal state. The use of GnRH agonist has led to an improvement in stimulation protocols allowing for more synchronous development of follicles. The use of GnRH agonist also has almost eliminated the premature LH surge and effects of increasing progesterone on developing follicles. Before GnRH agonist was used in IVF cycles, there was a higher cancellation rate and higher proportion of postmature oocytes. GnRH agonist use has increased IVF pregnancy rates and has allowed flexible timing of the IVF cycle. GnRH agonist induces desensitization of the gonadotropic cells by decreasing the number of GnRH receptors on the cell membrane.
GonadotropinReleasing 266 Hormone Antagonists
GnRH antagonists (Cetrotide, Ganirelix) have been introduced into IVF protocols only more recently in the United States. These agents allow for greater flexibility in timing IVF cycle starts and effectively eliminate LH surges. GnRH antagonists typically are started after stimulation with FSH/HMG has begun. GnRH antagonists have minimal systemic side effects and have a higher binding affinity for the GnRH receptor than the native GnRH molecule. GnRH antagonists act by competitive blockade of the GnRH receptor and are characterized by an immediate suppression of pituitary gonadotropin release without inducing an initial stimulatory response. There is a short recovery phase of 2 to 4 days after GnRH antagonist use. The main application of GnRH antagonists is the suppression of LH surges during gonadotropin stimulation; however, GnRH antagonist use may be expanded for use in the treatment of fibroids, endometriosis, and female genital tract cancers.
ASSISTED REPRODUCTIVE TECHNOLOGY TECHNIQUES Oocyte Retrieval and Oocyte Identification
In the past, oocytes were collected using laparoscopic techniques, but now transvaginal follicle aspiration guided by ultrasound is the method of choice for oocyte retrieval. Transvaginal oocyte retrieval is typically performed using conscious sedation, although general anesthesia and spinal anesthesia have also been used. Most women are able to leave the office within 1 to 2 hours after the oocyte retrieval procedure. Oocyte retrieval is performed by aspirating each follicle in turn under ultrasound guidance, usually through a single vaginal needle puncture for each ovary. The follicular fluid (Fig. 17-1) collected is examined immediately under an operating microscope for the presence of a cumulus mass that contains an oocyte (Fig. 17-2). When the oocytes are collected, they are immediately placed in a culture medium containing the essential nutrients. Approximately 4 to 5 hours after retrieval, the oocytes are inseminated with sperm. A major discovery in ART was that sperm need not be added to the oocytes immediately after retrieval, and a delay of 4 to 6 hours improves fertilization rates. GIFT is another ART modality that can be used only in women with at least one patent tube. GIFT is a laparoscopic technique in which the transfer of gametes to the fallopian tube allows for in vivo fertilization. GIFT was
Assisted Reproductive Technologies Figure 17-1 Follicular fluid in test tube at oocyte retrieval.
267
first reported in 1984. By 1986, GIFT was commonly used throughout the United States. As with IVF cycles, GIFT uses controlled ovarian hyperstimulation followed by oocyte retrieval. GIFT can involve laparoscopic retrieval of oocytes or transvaginal ultrasound–guided retrieval. The fallopian tube is cannulated laparoscopically, and sperm and oocytes are injected into the distal fallopian tube. In the era of laparoscopic oocyte retrieval and poor embryo culture techniques, GIFT made good sense. Now, with simplification of IVF and improvement in culture conditions, GIFT is comparatively less effective and more invasive. It should be used in a very select population, specifically individuals whose religion or ethics proscribe in vitro fertilization.
Insemination of Oocytes
Routine Insemination Depending on the sperm quality, oocytes may be inseminated using “routine” fertilization (oocytes placed with sperm in a Petri dish) or through micromanipulation techniques, such as intracyctoplasmic sperm injection (ICSI). Sperm are prepared by washing and centrifugation. For routine fertilization, 50,000 to 100,000 motile sperm are placed in a Petri dish with an oocyte. Fertilization can be detected 12 to 20 hours after insemination by
Reproductive Endocrinology and Infertility Figure 17-2 Cumulus mass represents single oocyte.
268
the presence of two pronuclei found in the cytoplasm of the oocytes and the presence of two polar bodies in the perivitelline space (Fig. 17-3). Fertilization rates of greater than 60% of mature oocytes should be expected. Twentyfour hours after insemination, the pronuclear membranes dissolve allowing combination of the maternal and paternal chromatids (syngamy), which is followed by the first cleavage division to a two-cell embryo (Fig. 17-4).
Intracytoplasmic Sperm Injection The limited success with intrauterine inseminations for male factor infertility has led to numerous individuals pursuing ART in an attempt to achieve pregnancy. Initial experience with IVF without sperm injection techniques for male factor infertility was disappointing, with low fertilization and pregnancy rates. IVF has allowed access to the oocyte and the opportunity for IVF technicians to facilitate entry of sperm into the oocyte. The early techniques of facilitating sperm entry included partial zona dissection and subzonal insertion. One of the greatest advances in IVF success can be attributed to Van Steirteghem and coworkers in Belgium, who perfected the technique of ICSI. With ICSI, a single sperm is injected into a mature oocyte. The possibility of achieving pregnancy with only a single sperm launched a revolution in IVF. Sperm used for ICSI not only have been obtained from the ejaculate, but also in men with no sperm in the ejaculate by using microsurgical epididymal sperm aspiration or testicular biopsy (testicular sperm extraction). A few sperm also have been identified in men with Sertoli cell–only syndrome
Assisted Reproductive Technologies Figure 17-3 Zygote 12 to 20 hours postinsemination with two pronuclei represents successful fertilization.
269
and used for ICSI. Sperm precursors (spermatids, immotile sperm) have been used for ICSI, but fertilization rates using immature or immotile sperm have been lower than the rates using motile sperm. ICSI is the treatment of choice for severe oligospermia, microsurgical epididymal sperm aspiration or testicular sperm extraction derived sperm, or severe antisperm antibodies. There is a less than 5% chance of damage to the oocyte with ICSI in experienced laboratories. Since the introduction of ICSI, there has been concern about its safety. ICSI is an invasive procedure, which may bypass the “natural selection” mechanisms that sperm encounter during the course of natural conception. Additionally, small amounts of culture medium are injected into oocytes with the ICSI procedure, as are sperm components (i.e., acrosome) that normally do not enter the oocyte, with unknown effects. Data suggest that there is a slight increase in de novo sex chromosome aneuploidy (0.6% versus 0.2%) and structural autosomal abnormalities (0.4% versus 0.07%) with ICSI compared with the general neonatal population. There also are an increased number of inherited structural aberrations mostly from the infertile male partner. There seems to be no increased risk, however, for major and minor malformations in ICSI children compared with naturally
Reproductive Endocrinology and Infertility Figure 17-4 Two-cell embryo in culture.
270
conceived children, despite these chromosomal defects. Early studies that have evaluated development of children born through IVF with ICSI do not reveal significant problems.
In Vitro Culture of Embryos
An amazing discovery with IVF was that embryos are able to complete their development in vitro (Figs. 17-4 through 17-6). Tissue culture techniques for human embryos were largely borrowed from existing animal models. The media used to maintain the growth of embryos have changed dramatically since the late 1980s with the recognition that the metabolic requirements of a cleavage stage embryo that was only 24 hours old were significantly different than the requirements of a morula or blastocyst embryo. The incubator environment also is strictly controlled with respect to temperature, air quality, pH, and oxygen tension for optimal embryo development.
Embryo Transfer
Generally, embryos are transferred to the uterus on day 2, 3, or 5 after insemination, by which time the embryos have divided into two, four, or eight cells or the morula/blastocyst stage. Usually one to four embryos are transferred together in a tiny amount of embryo culture medium using a variety of soft plastic embryo transfer catheters. The number of embryos to transfer is based on the patient’s age, ovarian reserve, and prior history. Transabdominal ultrasound is often used to facilitate the transfer procedure and confirm placement of embryos in the uterine cavity. Embryos of good
Assisted Reproductive Technologies Figure 17-5 Four-cell embryo in culture.
271
morphologic grade in excess of those transferred can be cryopreserved for future use.
Luteal Phase Support
In natural cycles, the ovary produces progesterone after ovulation. There is evidence, however, that premature luteolysis may occur with some IVF regimens. Most IVF centers administer progesterone supplementation via intramuscular injections. Human chorionic gonadotropin also can be used for luteal support. Vaginal pessaries, gel-like formulations, suppositories, and oral micronized progesterone have been used for postretrieval progesterone supplementation, but there is evidence that these may not be as effective as progesterone in oil or human chorionic gonadotropin intramuscular injections.
Embryo Cryopreservation
Embryo cryopreservation provides couples with the option of freezing their unused embryos. The first pregnancy using cryopreserved embryos from an earlier IVF cycle was reported in 1984. Cryopreservation of embryos offers patients the opportunity to increase their chance of pregnancy after a single retrieval procedure. It is possible to cryopreserve embryos from the one-cell stage to the blastocyst stage. Cryopreservation reduces the number of HMG/FSH cycles and oocyte retrievals most patients would undergo. Approximately 75% of women younger than age 35 with good ovarian reserve have excess embryos to freeze compared with 20% of women older
Reproductive Endocrinology and Infertility Figure 17-6 Blastocyst in culture approximately 5 days after fertilization.
272
than 35. Pregnancies have resulted from embryos cryopreserved for many years. There is no known limit on the duration of storage for a cryopreserved embryo. There seems to be no increased risk of chromosomal abnormalities or spontaneous pregnancy loss in patients achieving pregnancy with cryopreserved embryos. Cryopreservation of embryos has contributed to the decrease in multiple pregnancy rates with IVF. Patients can be counseled that the freeze-thaw embryo survival rate is approximately 80%.
Assisted Hatching
Failure of implantation and conception might result from inability of the embryo at the blastocyst stage to escape from its zona pellucida. Assisted hatching involves the use of mechanical or chemical thinning of the zona pellucida surrounding the embryo before transfer. There is no clear evidence that assisted hatching has an impact on live birth rate when used in all IVF patients, but assisted hatching may be beneficial when used in select patients. Assisted hatching may increase pregnancy rates in women older than 38 years women with diminished ovarian reserve, women with poorquality embryos, women with previous failed IVF attempts, or women with a thick zona pellucida.
Assisted Reproductive Technologies
PREIMPLANTATION GENETIC DIAGNOSIS The detection of genetic disorders in human embryos has transformed the diagnosis of diseases from postimplantation to the preimplantation period. Preimplantation genetic diagnosis (PGD) is the genetic diagnosis of gametes and conceptuses before implantation in the uterus. The techniques used in PGD are possible only because of more recent developments in IVF coupled with revolutionary developments in molecular biology. Although the application of PGD has generated considerable controversy, the number of PGD cases continues to increase. PGD is a technically challenging procedure that requires an understanding of embryology and molecular biology. During IVF, oocytes and embryos are readily accessible, allowing a biopsy specimen to be taken from the oocyte or embryo. Many micromanipulation techniques applied to PGD originally 273 were developed for use in animal husbandry. Three major aspects of PGD have been applied successfully: sex determination, chromosomal analysis, and the detection of single-gene defects. These techniques are accomplished with the addition of micromanipulative procedures for oocyte or embryo biopsy, fluorescent in situ hybridization (FISH) for chromosomal analysis, or polymerase chain reaction (PCR). PGD is initiated with collection of genetic material, which must be accomplished without compromising embryo development (Box 17-2). The amount of genetic material that can be removed safely is limited, restricting the use of confirmational analysis. The complexity of PGD is compounded by the fact that the embryos must be implanted in a synchronized uterus. The entire procedure from the time of biopsy to implantation of the embryos in the uterus must be completed in a limited time. In general, embryos should be transferred within 48 hours of embryo biopsy. Despite its drawbacks, PGD is rapidly becoming an integral part of many IVF programs.
Biopsy Techniques
Polar body biopsy is performed before fertilization of the oocyte in an attempt to identify maternal genetic defects. The technique of the polar body biopsy is used for “preconception” genetic diagnosis. This technique can be used only if the female partner is the carrier of the genetic defect. The oocyte is arrested at the diplotene stage of meiosis until further resumption of meiosis occurs at the time of the LH surge. At the time of ovulation, the first meiotic division is completed, and the first polar body is extruded. This extruded polar body does not contribute to the subsequent development of the embryo; removal of the polar body is thought to impose minimal
Box 17-2 ● ● ●
Techniques for Obtaining Genetic Material
Polar body biopsy Blastomere biopsy Blastocyst trophectoderm biopsy
Reproductive Endocrinology and Infertility: Requisites
274
adverse effects on development after fertilization. Problems do exist with the use of the polar body. In the second meiotic division, the chromosomes containing normal and abnormal alleles from a heterozygous carrier segregate independently into the primary oocyte and polar body. If the polar body contains the abnormal allele, this would indicate that the oocyte contained the complementary normal allele. Conversely, if the polar body contains the normal allele, this would indicate that the primary oocyte contained the abnormal allele. The accuracy of this technique relies on the fact that homologous gene pairs do not cross over. Crossover occurs more commonly at the telomeric (distal) region of the chromosome than at the centromere. Location of the gene on the chromosome becomes important for accurate diagnosis. Timing also is important in polar body biopsy. The polar body should be retrieved within 4 to 6 hours after oocyte collection. Shortly after retrieval, the oocytes are treated with hyaluronidase to remove the cumulus cells to expose the polar body for ease of removal, after which ICSI is performed as a means of insemination. Conventional insemination techniques would increase the probability of polyspermia in oocytes that have had their cumulus cells removed. More than 5000 known genetic mutations are associated with specific inherited diseases for which polar body biopsy can be used. More than two dozen have been used for PGD. Despite its theoretical drawbacks, this technique has been used for preconception diagnosis in patients at risk for cystic fibrosis, sickle cell anemia, hemophilia, and α1-antitrypsin deficiency. There is general agreement that obviating disease by preventing fertilization of abnormal oocytes is justifiable. Public acceptance of PGD is higher for techniques that favor early intervention. Acceptance of techniques performed before fertilization is higher compared with techniques performed before implantation. Multicellular embryo biopsy is classified according to stage of embryo development. Blastomere biopsy samples cleavage stage blastomeres. Blastocyst trophectoderm biopsy involves the removal of numerous cells from the trophectoderm. Blastomere biopsy is best used to assess chromosomal number, multinucleation, or polyploidy. Blastocyst trophectoderm biopsy is best used for determining single gene defects and mosaicism. Embryo biopsy on day 3 of development is the most common method. Typically, when an embryo reaches the 6- to 12-cell stage, a single cell is removed. Despite the reduction in cell number, good pregnancy rates exist using this technique. The biopsy should be done as early as possible on day 3 before the development of tight gap junctions that occur at the start of cellular compaction. Blastocyst trophectoderm biopsy is associated with added advantages compared with biopsy at earlier stages. This technique, used extensively in animal science, allows for the removal of multiple cells. Blastocyst biopsy is a technically challenging procedure. This technique and blastomere biopsy, in contrast to polar body biopsy, can be used for male or female carriers of the genetic disease.
Assisted Reproductive Technologies
Genetic Analysis
After the material to be tested is obtained (i.e., polar body, embryonic cell, trophectoderm), several techniques are used to test the genetic material, including FISH and PCR. FISH is the preferred technique for detection of aneuploidy. The amount of genetic material obtained is limited, generally one polar body or one blastomere. The FISH procedure allows determination of specific chromosomal numbers by counting fluorescent signals in interphase nuclei in a single cell. The FISH technique is highly sensitive and has an acceptable accuracy for clinical use. PCR has revolutionized DNA analysis. The procedure involves the repeated amplification of DNA to obtain adequate genetic material for analysis. This technique makes it possible to detect single gene mutations in polar bodies or blastomeres. The list of disorders for which PGD-PCR techniques can be applied is growing rapidly. This technique is challenging because of inherent problems with the procedure, including control of 275 DNA contamination and the loss of genetic material. In clinical practice, cystic fibrosis and sickle cell anemia are the two genetic disorders that PCR most commonly identifies.
Other Techniques
Although not considered a preimplantation genetic diagnosis technique, another method of preconception gender selection is the use of flow cytometric separation of human spermatozoa (MicroSort). This technique can be used to decrease the likelihood of transmitting an X-linked disorder. It relies on the 2.8% difference in DNA content between X chromosome–bearing and Y chromosome–bearing spermatozoa, with the X chromosome being larger. There are more than 350 X-linked diseases in humans, including Duchenne muscular dystrophy, X-linked hydrocephalus, and hemophilia, for which this technique may be used. The use of the DNA flow cytometry separates the sperm sample into an X-enriched sample and Y-enriched sample. In trials of the MicroSort technique, 91% of the offspring were female using an X-enriched sample, and 76% of the offspring were male using a Y-enriched sample, significantly decreasing the likelihood of transmitting a genderlinked disorder. Combining the sperm separation techniques with IVF and subsequent preimplantation embryo testing increases the chance of a successful unaffected pregnancy.
Ethical Considerations
Although public support heavily favors PGD, some people do object to PGD even when it is used to prevent severely debilitating diseases. In public opinion polls, there is greater acceptance of polar body biopsy or sperm separation techniques (before fertilization or creation of embryos) than of embryo biopsy techniques when used to prevent diseases. Ethical concerns about PGD primarily stem from concerns that these techniques may be used for indications other than severe debilitating disease. As technology advances, it may be used to predict eye color, hair color, or other “desirable” physical characteristics that would not affect quality of life. Additionally, there is public concern that PGD would be used for gender selection. There are programs that use PGD for this purpose, despite statements discouraging its use by the
Reproductive Endocrinology and Infertility
American Society for Reproductive Medicine. When the technology is used for X-linked diseases, public support is high.
OOCYTE DONATION
276
Age is the main determinant of IVF outcome. Population-based data indicate a decline in fertility as an individual ages. In the United States, 10% of women 20 to 29 years old have an infertility problem compared with more than 50% of women older than age 40. The decline in fertility rates is evident in a classic study of the Hutterite population. The Hutterites are a religious sect in which contraception is strictly prohibited. There was a 7% infertility rate in women age 25 to 29 compared with 11% at age 30 to 34, 33% at age 35 to 39, and 87% at age 40 to 44. This study is an imperfect estimation of the effect of aging on reproductive potential, and it does not take into consideration other conditions that may impair fertility (i.e., decreased coital frequency, endometriosis, tubal disease). For many years, physicians have debated whether aging of the uterus or aging of the oocyte was primarily responsible for the age-related decline in fertility. Much of the early data in animal studies suggested that the uterus played a predominant role in limiting reproductive success, with markedly lower pregnancy rates in older animals receiving donor oocytes compared with matched, young recipients. Histologic assessment of the uterus and endometrium in humans reveals no consistent change with aging, however, when hormonal stimulation is controlled. Age-related changes in the endometrium seen in animals may be related to a change in hormonal function, which may affect implantation and lower pregnancy rates. The use of IVF and donor oocyte has provided a more direct means of assessing uterine aging. Young women undergoing IVF with their own oocytes have similar pregnancy rates as older women (>40 years old) using donated oocytes. This comparable success suggests that uterine aging does not play a role in humans in hormonally controlled cycles. There is no question that the aging of the oocytes is the primary factor contributing to a decline in pregnancy rates in older women. Although there is not always a consistent morphologic difference among mature oocytes and early embryos in older women compared with younger women, there is a clear difference in pregnancy rates. Data suggest that the oocytes of older women are more likely to show chromosomal abnormalities (aneuploidy), which could explain this decline in pregnancy and implantation rates. This age-dependent increase in aneuploidy has been shown in stimulated and unstimulated ovaries. Additionally, the percentage of chromosomally abnormal embryos diagnosed by FISH is approximately 70% in women of advanced reproductive age. Some IVF programs are performing PGD for aneuploidy diagnosis to help older women achieve pregnancy, its benefit is controversial. Because PGD requires the development of embryos to the blastocyst stage, this technique cannot be applied to most women of advanced reproductive age. There are significant age-related differences
Assisted Reproductive Technologies
in blastocyst formation (i.e., arrest at morula stage, diminished blastocyst expansion) as a woman ages; this coupled with lower oocyte yield tends to create too few embryos to use for PGD aneuploidy diagnosis in most women of advanced reproductive age. The principal impact of PGD in older women seems to be a reduction in spontaneous abortions, rather than improvement in pregnancy rate. Many women in their later reproductive years are able to conceive. The transition to a less fertile state is thought to be governed primarily by the rate at which a woman depletes her follicular reserves. At the time of birth females have a finite number of oocytes. There is a rapid decline in oocyte number from 20 weeks of gestation until birth. This decline in oocyte number continues after birth until menopause. It has been suggested that when the follicle reserve falls below a certain “available pool,” fertility is compromised. Further declines in the available pool lead to oligo-ovula- 277 tion, perimenopause, and eventually menopause. This threshold number of oocytes needed for normal reproduction has been documented in rats. Although a steady rate of decline of the available pool is seen in rats, in humans the loss of follicular reserves with advancing age is biexponential, with an accelerated decline starting around age 35. If this biexponential loss did not occur, and the initial rate of follicular atresia seen before age 35 continued, it is estimated that menopause would not be reached until age 70. The first human pregnancies after the use of donor oocytes were reported in 1983. These pregnancies were achieved by transcervical uterine lavage of oocyte donors 5 to 7 days after timed insemination with sperm from the recipient’s husband. The recovered embryos were transferred to the recipient. Presently, when a donor is selected, the donor and recipient undergo strict screening. The American Society of Reproductive Medicine (ASRM) has guidelines with regard to donor oocyte use. Box 17-3 presents the ASRM’s current indications for oocyte donor use. Donors typically undergo the same stimulation protocols and procedures as a couple having IVF treatment. The screenings listed in Box 17-4 are currently recommended by the ASRM and the Food and Drug Administration. Success with oocyte donation is high, with pregnancy rates of 75% per cycle at some IVF programs.
Box 17-3
Indications for Oocyte Donation
1. 2. 3. 4.
Hypergonadotropic hypogonadism Women of advanced reproductive age Diminished ovarian reserve Women who are known to be affected by or are the carrier of a significant genetic defect, or who have a family history of a condition and whose carrier status cannot be determined 5. Women with poor oocyte or embryo quality or multiple failures during prior attempts to conceive Adapted from ASRM guidelines for oocyte donation. Fertil Steril 2004;82(Suppl 1):S13-S15.
Reproductive Endocrinology and Infertility
Box 17-4
Recommended Screening During Oocyte Donor Cycles
Donor Screening Age 21-34 Medical history Family history Genetic screening Screen for risk factors Sexually transmitted disease exposure HIV exposure Transmissible spongiform encephalopathy exposure Organ transplant exposure VDRL Hepatitis B surface antigen Hepatitis C antibody Cervical cultures for Neisseria gonorrhoeae and Chlamydia trachomatis HIV 1 and 2 Blood type, Rh
278
Partner of Recipient Screening Medical history Semen analysis Blood type, Rh VDRL Hepatitis B surface antigen Hepatitis C antibody Cytomegalovirus IgG, IgM HIV 1 Genetic screening Psychological screening Recipient Screening Uterine evaluation Medical history Physical examination Blood type, Rh Rubella titer Varicella titer VDRL Hepatitis B surface antigen Hepatitis C antibody Cytomegalovirus IgG, IgM HIV 1 Genetic screening Psychological screening VDRL, Veneral Disease Research Laboratory Adapted from ASRM guidelines. Fertil Steril 2004;82(Suppl 1): for oocyte donation. S13-S15.
COMPLICATIONS OF ASSISTED REPRODUCTIVE TECHNOLOGIES Ovarian Hyperstimulation Syndrome
OHSS is a serious complication of IVF affecting approximately 5% to 10% of IVF cycles. In its most severe form, OHSS includes massive ovarian enlargement, hemoconcentration, ascites, and oligouria and can be complicated by renal failure, hypovolemic shock, thromboembolic events, and acute respi-
Assisted Reproductive Technologies
ratory distress syndrome. The intensity of OHSS is related to the degree of the patient’s response to stimulatory medications. OHSS was first reported in 1961 and is thought to be due to increase in capillary permeability of the ovarian vessels. Estrogens, the renin-angiotensin system, prostaglandins, vascular endothelial growth factor, and interleukins all have been reported as mediators of OHSS. OHSS can be classified as mild, moderate, or severe (Box 17-5) based on symptoms, ultrasound findings, and laboratory studies. Factors that increase a patient’s risk of developing OHSS are listed in Box 17-6. Mild OHSS is common among most IVF patients with an average to good response to stimulatory gonadotropins and has little clinical significance. Many cases of severe OHSS require a short period of hospitalization for stabilization (Box 17-7). Treatment options include albumin, aggressive intravenous hydration, heparin therapy, dopamine, paracentesis, and expectant management. 279 Box 17-5
Classification of Ovarian Hyperstimulation Syndrome
Mild OHSS Grade 1—Abdominal distention and discomfort Grade 2—Features of grade 1 plus nausea, vomiting, or diarrhea; ovaries enlarged 5-12 cm Moderate OHSS Grade 3—Features of mild OHSS plus ultrasound evidence of ascites Severe OHSS Grade 4—Moderate OHSS plus breathing difficulties; evidence of ascites or hydrothorax or both Grade 5—All of the above plus change in blood volume, increased blood viscosity owing to hemoconcentration, coagulation abnormalities, and diminished renal perfusion and function
Box 17-6 ● ● ● ● ● ● ●
High serum estradiol level Known high responder Luteal phase stimulation with human chorionic gonadotropin Numerous follicles Polycystic-appearing ovaries Polycystic ovary syndrome Pregnancy
Box 17-7 Syndrome ● ● ● ● ● ● ●
Risk Factors for Ovarian Hyperstimulation Syndrome
Criteria for Hospitalizing Patients with Ovarian Hyperstimulation
Severe abdominal pain requiring narcotics Coagulopathy Electrolyte imbalance Hematocrit >45% Hemorrhage Oliguria/anuria Respiratory distress
Reproductive Endocrinology and Infertility
Multiple Gestations
It was noted early in the practice of ART techniques that pregnancy rates increased as the number of embryos transferred to the uterus was increased. In 1996, the ASRM became concerned about the increasing number of multiple gestations among IVF couples. Multiple birth infants are at increased risk for preterm delivery, low birth weight, congenital malformations, neonatal death, and long-term disability. The argument for transferring fewer embryos has gained significant momentum. In the United States, no laws exist to limit the number of embryos transferred to date. Box 17-8 lists the ASRM guidelines regarding the number of embryos to implant.
PRESERVING FERTILITY FOR YOUNG WOMEN 280
Long-term survival rates for cancer have improved substantially because of the use of aggressive therapy. Many women receiving chemotherapy or radiation lose ovarian function, however. A technique to ensure successful cryopreservation of oocytes would benefit these young women who wish to retain their fertility potential. Two techniques have been used to help these women potentially retain fertility: cryopreservation of oocytes and cryopreservation of ovarian tissue. In contrast to the success of embryo freezing, which is considered routine, the cryopreservation of oocytes has been less successful. Only a few births have been achieved since this technique was first described in 1986. Survival of cryopreserved oocytes remains low, and more research is needed in this area. The low surface-volume ratio thwarts efficient replacement of cellular water with cryoprotectant, resulting in lethal crystallization. An alternative to cryopreservation of oocytes is cryopreservation of ovarian biopsy samples or ovarian slices. These ovarian sections may contain thousands of immature oocytes. Autografting of ovarian tissue has been attempted with limited success, although a single live birth has been reported. A significant theoretical risk of this technique is the possibility that Box 17-8
Number of Embryos to Transfer
1. In patients younger than age 35, no more than two embryos in the absence of extraordinary circumstances should be transferred. 2. For patients 35 to 37 years old having a more favorable prognosis, no more than two embryos should be transferred. All others in this age group should have no more than three embryos transferred. 3. For patients 38 to 40 years old, no more than four embryos should be transferred. 4. For patients older than age 40, no more than five embryos should be transferred. 5. Patients with two or more failed IVF attempts may have additional embryos transferred. 6. In donor oocyte cycles, the age of the donor should determine the number of embryos to transfer. Adapted from ASRM guidelines. Fertil Steril 2004;82(Suppl 1):S1-S2.
Assisted Reproductive Technologies
this biopsied tissue contains cancer, especially in patients with hematologic cancers, and reimplantation of this tissue may lead to recurrence or metastasis of the original tumors.
STEM CELLS AND THERAPEUTIC CLONING Much media attention has surrounded the use of embryonic stem cells for the treatment of degenerative diseases. Potential uses include restoration of function in patients with spinal cord injury or replacement of insulinproducing cells in patients with diabetes. Neurologic, musculoskeletal, hepatic, and cardiac cell lines have been developed with mouse embryos. The development of embryonic stem cell lines has been less successful in humans. 281
SUMMARY IVF is a rapidly expanding field with continued innovations improving pregnancy rates. Future goals include improvements in in vitro maturation of oocytes, oocyte freezing, and decreasing multiple pregnancy rates.
SUMMARY OF KEY POINTS 1. 2. 3. 4. 5.
Controlled ovarian hyperstimulation is crucial to increase the number of fertilizable oocytes. GnRH agonists or antagonists prevent premature luteinization in ART cycles. ICSI has dramatically improved success rates in male factor infertility. Oocyte donation normalizes success rates in women with compromised ovarian reserve. PGD is useful in preventing transfer of genetically abnormal embryos.
SUGGESTED READINGS Adams CE: Aging and reproduction in the female mammal with particular reference to the rabbit. J Reprod Fertil 1979;12(Suppl):1-16. Asch RH, Ellsworth LR, Balmaceda JP, et al: Pregnancy following translaparoscopic gamete intrafallopian transfer (GIFT). Lancet 1984;2:1034-1038. Balen A, Tan SL, MacDougall MJ, et al: Miscarriage rates following in vitro fertilization are increased in women with PCO and reduced by pituitary desensitization with Buserelin. Hum Reprod 1992;8:959-965. Blaha GC: Effect of age of the donor and recipient on the development of transferred golden hamster ova. Anat Rec 1964;150:413-416.
Buster JE, Bustillo M, Thorneycraft IH, et al: Nonsurgical transfer of in vivo fertilised donated ova to five infertile women: report of 2 pregnancies. Lancet 1983;2:223-228. Esteben-Altirrha J: Le Syndrome d’hyperstimulation massue des ovaries. Rev Fr Gyn Obstet 1961;56:555. Faddy MJ, Gosden RG, Crougeon A, et al: Accelerated disappearance of ovarian follicles in midlife: implications of forecasting menopause. Hum Reprod 1992;17:1342-1346. Golan A, Ronel R, Herman A, et al: Ovarian hyperstimulation syndrome: an updated review. Obstet Gynecol Surv 1989;44:430-440.
Reproductive Endocrinology and Infertility Granaroli L, Magli MC, Munne S, et al: Will implantation genetic diagnoses assist patients with a poor prognosis to achieve pregnancy. Hum Reprod 1997;12:1762-1767. Imthurn B, Macas E, Kosselli M, et al: Nuclear maturity and oocyte morphology after stimulation with highly purified follicle stimulating hormone compared to human menopausal gonadotropin. Hum Reprod 1996;11(11):2387. Klein J, Gauer M: Assessing fertility in women of advanced reproductive age. Am J Obstet Gynecol 2001;185:758-770. Macas E, Floersheim Y, Hotz E, et al: Abnormal chromosome arrangements in human oocytes. Hum Reprod 1990;5:703-707. Menken J, Trussell J, Larsen U: Age and infertility. Science 1986;233:1389-1394. 282 MicroSort. Available at: www.MicroSort.com. Accessed November 17, 2004. Munne S, Ahkani M, Tomken G, et al: Embryo morphology, development rates, and maternal age are correlated with chromosomal abnormalities. Fertil Steril 1995;64:382-391. National Summary and Fertility Clinic Reports: 2001 Assisted Reproductive Technology Success Rates. US Department of Health and Human Services; 2003. Navot D, Bergh PA, Laufer N: Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment. Fertil Steril 1992;58:249. Oktay K, Sonmezer M: Ovarian tissue banking for cancer patient’s fertility preservation, not just ovarian cryopreservation. Hum Reprod 2004;8:1924-1925. Palermo G, Joris H, Devroey P, Van Steirteghem AC: Pregnancies after ICSI of a single spermatozoa into an oocyte. Lancet 1992;340:17.
Plachot M, Vergu A, Montagut J, et al: Are clinical and biological IVF parameters correlated with chromosomal disorders in early life: a multicentric study. Hum Reprod 1988;3:627-635. Shenker JG, Weinstein D: Ovarian hyperstimulation syndrome: a current survey. Fertil Steril 1978;30:255. Sopelak VM, Butcher RL: Decreased amount of ovarian tissue and maternal age affect embryonic development in older rats. Biol Reprod 1982;27: 449-455. Speroff L, Glass RH, Kase NG: Clinical Gynecologic Endocrinology and Infertility, 6th ed. Philadelphia: Lippincott Williams & Wilkins; 1999. Stanger JD, Yovich JL: Reduced in vitro fertilization of human oocytes from patients with raised basal luteinizing hormone levels during the follicular phase. Br J Obstet Gynaecol 1985;92:385-393. Sterzl KK, Dallenbach C, Schneider V, et al: IVF: the degree of endometrial insufficiency varies with type of ovarian stimulation. Fertil Steril 1988;50: 457-520. Tietze C: Reproductive span and rate of reproduction among Hutterite women. Fertil Steril 1957;8:89-97. Trouson AO, Mohr LR, Wood C, Lecton JF: Effect of delayed insemination on IVF culture and transfer of human embryo. J Reprod Fertil 1982;64:285. Van Steirteghem AV, Bonduelle M, Devroey P, Liebaers I: Follow-up of children born after ICSI. Hum Reprod Update 2002;8:111-116. Volarcik K, Sheenan L, Goldfarb J, et al: The meiotic competence of in vitro matured human oocytes is influenced by donor age: evidence that folliculogenesis is compromised in the reproductively aged ovary. Hum Reprod 1998;13:154-160.
INDEX Note: Page numbers followed by b, f and t refer to boxes, figures and tables, respectively.
A Abortion, spontaneous recurrent. See Recurrent pregnancy loss. sporadic, 241 Acanthosis nigricans, 68 Acne, in polycystic ovarian syndrome, 67 Activated protein C resistance, recurrent pregnancy loss in, 254 Activin, in menstrual cycle, 21t, 25 Adrenal gland, in puberty, 35-36 Adrenal hyperplasia late-onset amenorrhea in, 54 versus polycystic ovarian syndrome, 68 male infertility in, 170, 176 Adrenal tumors, androgenproducing, 68 Adrenarche, 35 Adrenergic blockers, male infertility and, 172 Adrenocorticotropic hormone (ACTH) stimulation test, in polycystic ovarian syndrome, 69 Age bone resorption and, 110 diminished ovarian reserve and, 229-231, 230f, 231f female infertility and, 158, 230f maternal, chromosomal abnormalities and, 243 menopause and, 94, 94f myocardial infarction and, 100f
Albumin, 5, 5t Alcohol consumption in climacteric, 103 male infertility and, 171 recurrent pregnancy loss and, 259 Alendronate, for osteoporosis and fracture prevention, 122 Alloimmunity, recurrent pregnancy loss and, 257-258 Allopurinol, male infertility and, 172 Alopecia, in polycystic ovarian syndrome, 67 Alzheimer’s disease, in women, 99 Amastia, 45 Amenorrhea, 49-63 from chronic anovulation, 52-56 with estrogen absent, 51t, 55-56, 62, 62b with estrogen present, 50t-51t, 53-54, 61-62 classification of, 49-52, 50b, 50t-51t clinical evaluation of, 58-60, 58f, 59b-60b definition of, 49, 50t from female reproductive tract defects, 50t, 56-58, 57b, 57f, 62 hypothalamic, anovulation in, 194 laboratory tests in, 59-60, 59b-60b in polycystic ovarian syndrome, 53-54, 53b, 54b treatment of, 60-62, 61b, 62b
γ-Amino butyric acid (GABA), in puberty, 34 Anabolic agents 283 male infertility and, 171 for osteoporosis and fracture prevention, 124-125 Analgesics, for endometriosisassociated pain, 220, 222 Androgen receptor, 7 Androgen receptor antagonists, for hirsutism in polycystic ovarian syndrome, 74 Androgen resistance, complete, amenorrhea from, 57, 57b Androgens, 4, 7, 65. See also specific androgens, e.g., Testosterone. elevated. See Hyperandrogenism. in menstrual cycle, 23 in puberty, 35 in sexual response, 137-138 tumors producing, 68 weight gain and, 5 Androstanes, 3 Androstenedione, 4, 4f, 137 Anemia, sickle cell, male infertility and, 181 Aneuploidy detection of, 275 recurrent pregnancy loss from, 243, 243f Anovulation, 185-195 abnormal uterine bleeding from, 78-79, 82-83, 86, 89t amenorrhea from, 52-56 with estrogen absent, 51t, 55-56, 62, 62b
Index Anovulation (Continued) with estrogen present, 50t-51t, 53-54, 61-62 classification of, 186b evaluation of, 186 hypothalamic, 82 in hypothalamic amenorrhea, 194 infertility from, 156-157 physiology of, 186-188 in polycystic ovarian syndrome, 66, 186-193, 187f treatment of. See Ovulation induction. Anti-ß glycoprotein 1, recurrent 2 284 pregnancy loss and, 257 Antiandrogenic agents, for hirsutism in polycystic ovarian syndrome, 73-74 Antibiotics, male infertility and, 172 Anticardiolipin antibody, recurrent pregnancy loss and, 256 Anticoagulant therapy abnormal bleeding with, 81 for thrombophilias, 255 Antidepressants male infertility and, 172 tricyclic, for premature ejaculation, 144 Antihypertensive drug therapy, male infertility and, 172 Antimicrosomal antibodies, recurrent pregnancy loss and, 257 Antimüllerian hormone in menstrual cycle, 21t, 25 for ovarian reserve evaluation, 166-167 Antinuclear antibodies, recurrent pregnancy loss and, 257 Antiphospholipid syndrome, recurrent pregnancy loss in, 256-257 Antipsychotics, male infertility and, 172 Antiresorptive agents, for osteoporosis and fracture prevention, 121-124 Antisperm antibodies, infertility and, 158, 165, 176 Antithrombin deficiency, recurrent pregnancy loss in, 254
Antithyroglobulin antibodies, recurrent pregnancy loss and, 257 Antral follicles, 24, 230 count of, for ovarian reserve evaluation, 167, 234-235 Arachidonic acid, 9-10, 10f Arcuate uterus, 209, 246f, 248 Aromatase, 23, 35 Aromatase inhibitors for chronic anovulation, 192-193 for endometriosis, 224-225 Arousal phase, 133-134, 135, 135t, 136f, 138, 139 sexual dysfunction during, 142-144 Arsenic exposure, recurrent pregnancy loss and, 259 Asherman’s syndrome amenorrhea in, 58 infertility in, 201, 202f, 209 recurrent pregnancy loss in, 248 Aspirin, heparin plus for antiphospholipid syndrome, 256 for thrombophilias, 255 Assisted hatching (AH), 272 Assisted reproductive technologies (ART), 263-281 acronyms for, 264b assisted hatching in, 272 biopsy techniques in, 273-274, 273b complications of, 278-280 embryo cryopreservation in, 271-272 embryo transfer in, 270-271 for endometriosis, 226-227, 227t ethical considerations in, 275-276 genetic analysis in, 275 in vitro culture of embryo in, 270, 270f-272f luteal phase support in, 271 medications in, 265-266, 265t multiple gestations and, 280, 280b oocyte and ovarian tissue cryopreservation in, 238, 280-281
Assisted reproductive technologies (ART) (Continued) oocyte donation and, 276-277, 277b, 278b oocyte insemination in, 267-270, 268f, 269f oocyte retrieval and identification in, 266-267, 267f, 268f ovarian hyperstimulation in, 264-265, 265t ovarian hyperstimulation syndrome and, 193, 193b, 278-279, 279b preimplantation genetic diagnosis in, 273-276, 273b principles of, 264 stem cells and therapeutic cloning and, 281 techniques in, 266-272 Asthenozoospermia, 169 Azoospermia, 169, 179-181. See also Infertility, male.
B Bacterial vaginosis, recurrent pregnancy loss and, 251-252 Barium enema, in climacteric, 104t Bartholin’s glands, 131, 132f Benzene exposure, recurrent pregnancy loss and, 259 Beta blockers, male infertility and, 172 Bicornuate uterus, 200f, 207f, 209, 246f, 247 Biopsy in assisted reproductive technologies, 273-274, 273b endometrial in abnormal uterine bleeding, 86 out-of-phase, in luteal phase defect, 249-250 for ovulation confirmation, 161 for ovarian reserve evaluation, 236 Bisphosphonates, 106, 109, 121-123, 124
Index Black cohosh, 105 Bladder exstrophy, male infertility and, 181 Blastocyst trophectoderm biopsy, 274 Blastomere biopsy, 274 Bleeding menstrual heavy, 80, 81 normal, 31 postpartum, 12 uterine, abnormal. See Uterine bleeding, abnormal. Blood tests, in osteoporosis, 102 Body mass index in abnormal uterine bleeding, 80 calculation of, 68b in polycystic ovarian syndrome, 68 Body temperature chart, for ovulation confirmation, 160-161, 160b Bone mass, peak, 110 Bone mineral density bone strength and, 109-110 measurement of, 112-115, 113b, 113f, 114b, 114f, 115f screening recommendations for, 116, 117b Bone remodeling, 110 Bone remodeling markers, 118 Bone resorption, 110 Bone scan. See Dual-energy x-ray absorptiometry (DEXA) scan. Bone strength, 109-110 Bone turnover markers, 115 Brain lesions, precocious puberty and, 40, 40t, 41 Breast asymmetry of, 45 development of abnormal, 45 normal, 36, 37b, 37t premature, 44 hypertrophy of, 45 hypoplasia of, 45 Bromocriptine, for hyperprolactinemia, 176, 251
C Caffeine intake in climacteric, 103
Caffeine intake (Continued) recurrent pregnancy loss and, 259 Calcitonin, for osteoporosis and fracture prevention, 124 Calcium dietary sources of, 119, 120b intake of in climacteric, 103 for osteoporosis and fracture prevention, 119, 121 Calcium channel blockers, male infertility and, 172 Caloric intake, in climacteric, 103 Cancer endometrial, in polycystic ovarian syndrome, 74 ovarian, clomiphene citrate and, 191-192 testicular, infertility and, 169-170 Carboprost tromethamine, for postpartum hemorrhage, 12 Cardiovascular disease in climacteric, 100, 100f, 102, 102b risk of, in men versus women, 102, 102b Celiac sprue, 118 Central bone mineral density measurement, 112-113, 116 Central obesity, in polycystic ovarian syndrome, 68 Central precocious puberty, 39-40, 40t Cervical cerclage, for uterine anomalies, 247, 248 Cervical factor infertility, 206, 210 Cervical incompetence, 206 Cervical mucus hostile, infertility from, 157-158, 206 pre-ovulatory change in, 28 Cervical stenosis amenorrhea from, 58 infertility and, 210 Cervix agenesis of, amenorrhea from, 56
Cervix (Continued) examination of, in abnormal uterine bleeding, 80 functional evaluation of, 165 Chemotherapeutic agents, male infertility and, 171-172 Chlamydial salpingitis, 204 Cholesterol, 4f Chromosomal disorders male infertility in, 180-181 recurrent pregnancy loss in, 243, 243f Cimetidine, male infertility and, 172 Clear Plan Easy device, 161 285 Climacteric, 93-106 cardiovascular disease in, 100, 100f, 102, 102b clinical presentation in, 96-101 cognitive decline in, 100-101 connective tissue changes in, 99 definition of, 93 depression in, 97-98 diagnostic tests in, 101-102 health screening recommendations in, 104, 104t hormonal therapy in, 104-105 lifestyle interventions in, 103-104 menopause markers in, 101 onset and duration of, 93-95, 94f osteoporosis in, 99-100, 102, 110, 117, 118b pharmacotherapy in, 104-106 physiology of, 95-96, 95f sexual dysfunction in, 98-99 sleep disturbances in, 97 therapeutic interventions in, 103-106, 104t urogenital symptoms in, 98 vasomotor disturbances in, 96-97, 105 Clitoral erection, 133-134 Clitoris, 131, 132f Clitoromegaly, in polycystic ovarian syndrome, 67, 68 Clomiphene citrate adjuvants to, 192
Index Clomiphene citrate (Continued) for chronic anovulation, 71, 189-192, 190f, 191f and intrauterine insemination, for endometriosis, 226, 227t for male infertility, 176-177 ovarian cancer and, 191-192 side effects of, 190 Clomiphene citrate challenge test, 155, 166, 233-234, 234b Cloning, therapeutic, 281 Coagulation cascade, 252-253, 253f Coagulation disorders 286 abnormal uterine bleeding and, 81, 89t recurrent pregnancy loss and, 252-255, 253f, 256b Coelomic metaplasia theory of endometriosis, 214-215 Cognitive decline, in climacteric, 100-101 Colchicine, male infertility and, 172 Colonoscopy, in climacteric, 104t Computed tomography of spine, 112-113 Connective tissue changes, in climacteric, 99 Contraception, hormonal, 8, 81. See also Oral contraceptives. Contraceptive method change in, abnormal bleeding after, 82 history of, in abnormal uterine bleeding, 79-80 Corpora cavernosa, 130, 130f Corpora lutea cyst, persistence of, after ovulatory clomiphene citrate cycle, 190 Corpus luteum, 29, 30, 156 Corpus spongiosum, 130, 130f Corticosteroid-binding globulin, 5 Cowper’s gland, 130f, 131 Cryopreservation embryo, 271-272 ovarian tissue and oocyte, 238, 280-281 Cryptorchidism, male infertility and, 181 Cumulus oophorus, 24
Cushing’s syndrome amenorrhea in, 54 screening for, 68 Cyclic guanosine monophosphate (cGMP), in sexual response, 139 Cycling, male infertility and, 171 Cyclooxygenase-2 (COX-2) inhibitor, for dysmenorrhea, 12 Cyclooxygenase pathway, 10, 10f Cyproterone acetate, for hirsutism in polycystic ovarian syndrome, 74 Cystic fibrosis, male infertility and, 170, 181 Cytogenetic testing, in recurrent pregnancy loss, 244 Cytokines in menstrual cycle, 20, 21t-22t, 24-25 in pathogenesis of endometriosis, 216-217 Cytoplasm donation, for diminished ovarian reserve, 237-238 Cytotoxic immune rejection theory of recurrent pregnancy loss, 258
D Danazol, for endometriosis, 223-224 Dehydroepiandrosterone, 35 Dehydroepiandrosterone sulfate, 35, 68 Depression, in climacteric, 97-98 Desire, sexual, 135, 135t, 136-137, 136f Diabetes mellitus male infertility and, 170 in polycystic ovarian syndrome, 67, 69 recurrent pregnancy loss and, 251 Diethylstilbestrol infertility from, 200-201 recurrent pregnancy loss from, 248 Dieting, amenorrhea from, 55 Digital rectal examination, in male infertility, 173 Dihydrotestosterone, 7
Dilation and curettage amenorrhea after, 58 infertility after, 201 Dominant follicle, 20, 26-27, 230 Drugs male infertility from, 171-172, 173t osteoporosis from, 112b, 118 recreational and illicit, male infertility from, 171, 173t sexual dysfunction from, 139b Dual-energy x-ray absorptiometry (DEXA) scan, 102 bone mineral density measurements in, 112, 113-115, 113b, 113f, 114b, 114f, 115f for osteoporosis screening, 116, 117b Dyschezia, 213 Dyslipidemia, in polycystic ovarian syndrome, 70 Dysmenorrhea definition of, 213 in endometriosis, 217 primary, 11-12 Dyspareunia in climacteric, 98-99 definition of, 213 in endometriosis, 217 etiology and treatment of, 146-147 hypoactive sexual desire disorder related to, 141 Dysuria, in climacteric, 98
E Ectopic pregnancy, pelvic inflammatory disease and, 204 Ejaculation, 134 premature (rapid), 144-145, 171 retrograde, 176 Ejaculatory duct obstruction, 175 Embryo cryopreservation of, 271-272 in vitro culture of, 270, 270f272f transfer of, 270-271 Embryology of reproductive tract, 198-199, 200f
Index Embryonic rests theory of endometriosis, 215 Embryonic stem cells, 281 Emotional intimacy, sexual response and, 136-137, 136f Emotional issues, in erectile disorder, 143 Endocrinopathies female infertility and, 160 male infertility and, 170 recurrent pregnancy loss and, 249-251, 252b Endometrial ablation, for abnormal uterine bleeding, 87-88 Endometrial biopsy in abnormal uterine bleeding, 86 out-of-phase, in luteal phase defect, 249-250 for ovulation confirmation, 161 Endometrial polyp infertility and, 201 radiologic imaging of, 83, 85f treatment of, 87, 89t Endometriosis, 213-227 analgesics for, 220, 222 aromatase inhibitors for, 224-225 assisted reproductive technologies for, 226-227, 227t classification of, 220, 221f-222f clinical presentation in, 217-218, 217b coelomic metaplasia theory of, 214-215 composite theory of, 215 danazol for, 223-224 diagnosis of, 218-220, 219b, 219f embryonic rests theory of, 215 genetic factors in, 216 gonadotropin-releasing hormone agonists for, 224, 225b immune factors in, 216-217 implantation theory of, 213-214 induction theory of, 215 infertility from, 157, 217-218, 218b, 225-227, 226t, 227t
Endometriosis (Continued) laparoscopic evaluation of, 163 lesions that mimic, 219b lymphatic and vascular metastasis theories of, 215 in male, 215 medical treatment of, 220, 222-225, 223t oral contraceptives for, 222-223 pain in, 217 pathophysiology of, 213-217, 214f pleural, 215 progestins for, 223 surgical treatment of, 225-226, 226t Endometrium cancer of, 74 hyperplasia of, 74, 86 layers of, 18, 18b in luteal/secretory phase, 29, 30-31 in menstrual cycle, 19f in proliferative phase early, 18 late, 28 middle, 25-26, 27f re-epithelialization of, 31 sloughing of, theories of, 31 Environmental factors male infertility and, 170-171 recurrent pregnancy loss and, 258-259, 260b Enzyme assays, in thrombophilias, 255 Ephedrine, for retrograde ejaculation, 176 Epidermal growth factor, in menstrual cycle, 21t, 25 Epididymal sperm aspiration, 178-179, 178t Epididymovasostomy, 178 Epispadias, male infertility and, 181 Erectile disorder, 142-143, 171 Erection, psychogenic, 137 Erythromycin, male infertility and, 172 Estradiol, 4f, 6 basal, for ovarian reserve evaluation, 166, 235
Estradiol (Continued) in climacteric, 96 in menstrual cycle, 19, 19f, 23, 24, 27, 29, 30 in puberty, 35 Estranes, 3-4 Estriol, 4f, 6 Estrogen receptor-α, 6 Estrogen receptor-ß, 6 Estrogens assays for, 8, 8b in climacteric, 8-9 deficiency of, in climacteric, 96 effects of, 6, 7t for hormonal contraception, 8 287 for osteoporosis and fracture prevention, 123, 124 for ovarian failure, 61 in sexual response, 138 types of, 6 Estrone, 4f, 6 in climacteric, 96 Ethical considerations, in preimplantation genetic diagnosis, 275-276 Ethylene oxide exposure, recurrent pregnancy loss and, 259 Excitement, sexual, 133-134, 133f, 134f Exercise in climacteric, 103-104 for osteoporosis and fracture prevention, 120
F Factor V Leiden mutation, recurrent pregnancy loss in, 253-254 Factor XII deficiency, recurrent pregnancy loss in, 254-255 Fallopian tube, 133 abnormalities of diagnosis of, 208 infertility and, 157, 203-204, 205f, 210 agenesis of, 199 evaluation of, 162-164, 163f intraluminal disease of, 204, 205f, 210 Falls prevention of, 120 risk factors for, 111
Index Fecal occult blood testing (FOBT), in climacteric, 104t Fecundability, 213 Fecundity, 213 Female Alzheimer’s disease in, 99 cardiovascular disease risk in, 102, 102b definition of, 129 dyspareunia in, 98, 141, 146-147, 217 infertility in, 155-168. See also Infertility, female. reproductive tract of. See Reproductive tract. 288 sexual anatomy of, 131-133, 132f sexual response cycle of, 133135, 134f, 136-137, 136f vaginismus in, 147-148 Female orgasm disorder, 145-146 Female sexual arousal disorder, 143-144 Feminization, testicular, amenorrhea from, 57, 57b Ferriman-Gallwey scoring system for hirsutism, 68 Fertility. See Infertility. Fertility monitor, 161 Fertilization in vitro for endometriosis, 226-227, 227t procedure for, 237, 267-270, 268f, 269f normal, 156 Fever, male infertility and, 170 Fibroblast growth factor, in menstrual cycle, 21t Fibroids infertility and, 201-203, 203f, 209 radiologic imaging of, 83, 84f recurrent pregnancy loss and, 249 treatment of, 87, 89t, 209, 249 Filaria sanguinis-hominis infection, 46 Flexible sigmoidoscopy, in climacteric, 104t Flow cytometry, in preconception gender selection, 275
Fluorescence in situ hybridization (FISH), in preimplantation genetic diagnosis, 275 Flutamide, for hirsutism in polycystic ovarian syndrome, 73-74 Folate supplementation, for MTHFR mutation, 255 Follicle stimulating hormone (FSH) amenorrhea and, 59, 59b-60b in assisted reproductive technology procedures, 265 basal, for ovarian reserve evaluation, 165-166, 232-233 for chronic anovulation, 72 in climacteric, 94f, 95-96 formulations of, 264, 265t as menopause marker, 101 in menstrual cycle, 19f, 20, 23, 27-28 in ovarian failure, 52 in polycystic ovarian syndrome, 53, 66 in precocious puberty, 41 in puberty, 35 Follicular fluid, 24 Follicular/proliferative phase of menstrual cycle early, 18-24 late, 26-28 middle, 24-26, 27f Folliculogenesis, ovarian aging and, 229-231, 230f, 231f Follistatin, in menstrual cycle, 21t Foreskin, 130, 130f Formaldehyde exposure, recurrent pregnancy loss and, 259 45X/46XY karyotype, male infertility in, 180 47XXY karyotype, male infertility in, 180 Fracture, osteoporosisassociated, 110, 111, 112 bone mineral density and, 114, 115f prevention of, 119-120 Fragility fracture, 110, 112
G Galactorrhea, amenorrhea with, 56
Gamete intrafallopian transfer (GIFT), 266-267, 267f, 268f Gap junctions, 23 Gardnerella vaginalis, recurrent pregnancy loss and, 251-252 Gender myocardial infarction and, 100f preconception selection of, 275 sex versus, 129 Gender identity, 129 Gene mutation, single, recurrent pregnancy loss and, 243-244 Genetic counseling, in recurrent pregnancy loss, 244 Genetic diagnosis, preimplantation, 273-276, 273b Genetics endometriosis and, 216 male infertility and, 179-181 recurrent pregnancy loss and, 242-244, 243f, 245b Genitalia examination of, in abnormal uterine bleeding, 80 female, 131-133, 132f innervation of, 137 male, 130-131, 130f Genitourinary system in climacteric, 98 malformations of, male infertility and, 181 Genitourinary tuberculosis, male infertility and, 170 Gentamicin, male infertility and, 172 Germinal vesicles, 20, 230 Gestations, multiple, assisted reproductive technologies and, 280, 280b Gigantomastia, juvenile, 45 Glans, 130, 130f Glucocorticoids, adjuvant, for chronic anovulation, 192 Glucose, fasting, in climacteric, 104t Glucose tolerance test, 69, 70b Glycodelin, in polycystic ovarian syndrome, 250 Gonadal dysgenesis, 52
Index Gonadal ovarian failure. See Hypergonadotropic hypogonadism. Gonadotropin therapy adjuvant, for chronic anovulation, 192 in assisted reproductive technology procedures, 264-265, 265t for chronic anovulation, 62, 72, 193, 194 for hypogonadotropic hypogonadism, 176 and intrauterine insemination for diminished ovarian reserve, 237 for endometriosis, 226, 227t in polycystic ovarian syndrome, 72 severe ovarian hyperstimulation syndrome from, 193, 193b Gonadotropin-dependent folliculogenesis, 230 Gonadotropin-dependent precocious puberty, 39-40, 40t Gonadotropin-releasing hormone (GnRH) after ovulation induction in hypothalamic amenorrhea, 194 for chronic anovulation, 62 in menstrual cycle, 19-20, 19f in puberty, 34-35 Gonadotropin-releasing hormone agonists for abnormal uterine bleeding, 89-90 add-back therapy for use with, 224, 225b in assisted reproductive technology procedures, 266 for endometriosis, 224, 225b for precocious puberty, 43 for recurrent pregnancy loss, 251 Gonadotropin-releasing hormone antagonists, in assisted reproductive technology procedures, 266 Gonadotropin-releasing hormone pulse generator, 34-35
Gonadotropin-releasing hormone stimulation test, in precocious puberty, 41 Granulosa cell, 4, 23 luteinization of, 26-27 Growth factors in menstrual cycle, 20, 21t-22t, 24-25 in pathogenesis of endometriosis, 216 Growth hormone for precocious puberty, 43 in puberty, 36 Growth spurt, 37-38 Guanosine monophosphate, cyclic, in sexual response, 139 H Hamartoma, pituitary, precocious puberty and, 40 Hatching, assisted, 272 Health screening recommendations, in climacteric, 104, 104t Hemorrhage. See Bleeding. Heparin for antiphospholipid syndrome, 256 for thrombophilias, 255 Herpes simplex virus, recurrent pregnancy loss and, 252 Hip bone mineral density measurement of, 112, 116 fracture of, 110 Hip protectors, 120 Hirsutism, 5, 67, 68, 73-74 HLA (human leukocyte antigen) sharing, recurrent pregnancy loss and, 258 Homocysteinemia, recurrent pregnancy loss in, 254 Hormonal contraception, 8, 81. See also Oral contraceptives. Hormonal influences on sexual response cycle, 137-139 Hormonal responses, in puberty, 33-36 Hormonal status, history of, in abnormal uterine bleeding, 79-80 Hormone, steroid. See Steroid hormones.
Hormone response elements, 5 Hormone therapy, 8-9 abnormal bleeding with, 81 for abnormal uterine bleeding, 88-90 for chronic anovulation, 62 in climacteric, 8-9, 104-105 for osteoporosis and fracture prevention, 123 for ovarian failure, 61 Hot flashes, 96-97, 105 Hot tub use, maternal, recurrent pregnancy loss and, 259 Human chorionic gonadotropin adjuvant, for chronic 289 anovulation, 192 for chronic anovulation, 62, 72 definition of, 185 for hypogonadotropic hypogonadism, 176 in menstrual cycle, 30 before oocyte retrieval and identification, 264-265 in polycystic ovarian syndrome, 72 Human menopausal gonadotropin (HMG) adjuvant, for chronic anovulation, 192 in assisted reproductive technology procedures, 265 for chronic anovulation, 62, 72, 193, 194 definition of, 185 formulations of, 264, 265t in polycystic ovarian syndrome, 72 recurrent pregnancy loss and, 251 severe ovarian hyperstimulation syndrome from, 193, 193b Hydrosalpinx, 204, 205f, 210 17α-Hydroxyprogesterone, in congenital adrenal hyperplasia, 68 Hymen anatomy of, 131, 132f imperforate, amenorrhea from, 56 Hyperandrogenism
Index Hyperandrogenism (Continued) anovulation from, 66, 186-193, 187f. See also Polycystic ovarian syndrome. female infertility and, 160 in polycystic ovarian syndrome, 53, 67, 68, 69 Hypercoagulable state, pregnancy as, 252-253, 253f Hypergonadotropic hypogonadism, amenorrhea in, 50t, 52, 52b, 61, 61b Hyperhomocysteinemia, recurrent 290 pregnancy loss in, 254 Hyperinsulinemia, in polycystic ovary syndrome, 66-67, 186, 188, 250 Hyperparathyroidism, wrist DXA in, 116 Hyperprolactinemia abnormal uterine bleeding in, 83 amenorrhea in, 56, 56b female infertility in, 160 male infertility in, 176 in polycystic ovarian syndrome, 69 recurrent pregnancy loss in, 251 sexual response and, 138-139 Hyperthermia, maternal, recurrent pregnancy loss and, 259 Hyperthermic environment, male infertility and, 171 Hyperthyroidism abnormal uterine bleeding in, 82-83 amenorrhea in, 54 male infertility in, 170 osteoporosis in, 118 recurrent pregnancy loss in, 251 Hypoactive sexual desire disorder (HSDD), 141 Hypogonadism hypergonadotropic, amenorrhea in, 50t, 52, 52b, 61, 61b hypogonadotropic amenorrhea in, 51t, 54-56
Hypogonadism (Continued) male infertility in, 170, 176, 181 Hypothalamic disorders abnormal uterine bleeding in, 82 amenorrhea in, 51t, 54-55 Hypothalamic-pituitary-gonadal axis, male infertility and, 181 Hypothalamic-pituitary-ovarian axis in climacteric, 96 investigation of, 86 in puberty, 34-36 Hypothyroidism abnormal uterine bleeding in, 82-83 amenorrhea in, 54 male infertility in, 170 recurrent pregnancy loss in, 251 Hysterectomy for abnormal uterine bleeding, 88 for endometriosis, 226 Hysterosalpingography, 155 for fallopian tube evaluation, 162, 163f for infertility evaluation, 206, 208 of tubal disease, 204, 205f of uterine anomalies, 245 for uterine cavity evaluation, 164 Hysteroscopy for abnormal uterine bleeding, 87 for uterine anomalies, 248 for uterine cavity evaluation, 164
I Illicit drugs, male infertility from, 171, 173t Imipramine, for retrograde ejaculation, 176 Immotile-cilia syndrome, infertility and, 170 Immune factors in endometriosis, 216-217 in recurrent pregnancy loss, 255-258, 258b
Immunoglobulin, intravenous, for antiphospholipid syndrome, 257 Immunotherapy, in recurrent pregnancy loss, 258 Implantation theory of endometriosis, 213-214 In vitro culture of embryo, 270, 270f-272f In vitro fertilization (IVF) for endometriosis, 226-227, 227t procedure for, 237, 267-270, 268f, 269f Incontinence, urinary, in climacteric, 98 Induction theory of endometriosis, 215 Infections pelvic, infertility and, 197, 204 recurrent pregnancy loss and, 251-252, 252b urinary tract, in climacteric, 98 Infertility anatomic, 197-211 anatomy, physiology, and clinical presentation of, 198-206 diagnostic tests for, 206-208, 207f therapeutic interventions for, 208-210 cervical factor, 206, 210 definition of, 155 endometriosis-related, 217-218, 218b, 225-227, 226t, 227t female, 155-168 age and, 158, 230f causes of, 156-158, 157b cervical function evaluation in, 165 diminished ovarian reserve and, 229-239. See also Ovarian reserve, diminished. fallopian tube and peritoneal evaluation in, 162-164, 163f frequency of, 155 history in, 158-159, 158b
Index Infertility (Continued) ovarian reserve evaluation in, 165-167, 166b, 231-236, 232t ovulation and luteal phase evaluation in, 160-161, 160b physical examination in, 159-160 in polycystic ovarian syndrome, 67 uterine cavity evaluation in, 164-165 incidence of, 197 male, 169-182 drugs and medications contributing to, 171-172, 173t frequency of, 169 genetic considerations in, 179-181 history in, 169-172 laboratory evaluation in, 174-175, 174b, 175t pharmacologic treatment of, 175-177 physical examination in, 172-173 radiographic evaluation in, 175 surgical treatment of, 177-179, 178t pelvic inflammatory disease and, 197, 204 sexual dysfunction and, 149-150, 150t tubal, 203-204, 205f, 210 uterine factor, 158, 198-203 from acquired anomalies, 201-203, 203f anatomy and physiology of, 198-199, 200f from congenital anomalies, 199-200 diagnosis of, 208 from diethylstilbestrol, 200-201 treatment of, 208-209 Influenza vaccine, in climacteric, 104t Inguinal surgery infertility and, 170
Inguinal surgery (Continued) for varicocele, 177 Inguinal vas obstruction, radiographic evaluation of, 175 Inhibin, in folliculogenesis, 230-231 Inhibin A in climacteric, 95 in menstrual cycle, 19, 19f, 21t, 25, 28 Inhibin B basal, for ovarian reserve evaluation, 166, 236 in climacteric, 95 in menstrual cycle, 19f, 21t, 24, 25, 28 Insemination intrauterine for cervical stenosis, 210 clomiphene citrate and, for endometriosis, 226, 227t for diminished ovarian reserve, 237 oocyte intracytoplasmic, 176, 268-270 routine, 267-268, 268f, 269f Insulin, elevated, in polycystic ovary syndrome, 66-67, 250 Insulin resistance assessment of, 69, 70b in polycystic ovary syndrome, 67, 68 Insulin-like growth factor binding proteins, 25 Insulin-like growth factor-I, in menstrual cycle, 21t, 24, 25 Insulin-like growth factor-I binding protein, in polycystic ovarian syndrome, 250 Insulin-like growth factor-II, in menstrual cycle, 21t, 25 Insulin-sensitizing agents, for chronic anovulation, 188-189 Integrin, in endometriosis-related infertility, 218 Intercourse, pain during. See Dyspareunia. Intimacy, emotional, sexual response and, 136-137, 136f
Intracytoplasmic sperm injection (ICSI) for antisperm antibodies, 176 procedure for, 268-270 Intrauterine device, abnormal bleeding with, 81 Intrauterine insemination for cervical stenosis, 210 for diminished ovarian reserve, 237 for endometriosis, 226, 227t Intravenous immunoglobulin, for antiphospholipid syndrome, 257 Inversion, chromosomal, recurrent 291 pregnancy loss and, 243 Isoflavonoids, for osteoporosis and fracture prevention, 123
J Juvenile gigantomastia, 45
K Kallmann’s syndrome amenorrhea in, 55 male infertility in, 170, 181 Kaplan’s redefinition of sexual response cycle, 135, 135t Kartagener’s syndrome, male infertility in, 170, 181 Karyotyping, in recurrent pregnancy loss, 244 Klinefelter’s syndrome, male infertility in, 180
L Labia majora, 131, 132f Labia minora, 131, 132f Labial agglutination/fusion, amenorrhea from, 56 Labial hypertrophy, 45-46 Laparoscopic ovarian drilling, for polycystic ovarian syndrome, 73 Laparoscopic surgery, for endometriosis, 225-226, 226t Laparoscopic varicocelectomy, 177 Laparoscopy, for fallopian tube evaluation, 162-163 Laparotomy, for endometriosis, 225
Index Lead exposure, recurrent pregnancy loss and, 259 Leiomyomata infertility and, 201-203, 203f, 209 radiologic imaging of, 83, 84f recurrent pregnancy loss and, 249 treatment of, 87, 89t, 209, 249 Leptin, in puberty, 35 Letrozole, for endometriosis, 225 Leukocytic antibody activity, in recurrent pregnancy loss, 258 292 Leydig cells, 131 Libido, in climacteric, 99 Lifestyle male infertility and, 171 recurrent pregnancy loss and, 258-259, 260b Lifestyle interventions for chronic anovulation, 188 in climacteric, 103-104 Lipid disorders, in polycystic ovarian syndrome, 70 Lipoxygenase pathway, 10, 10f Low-molecular-weight heparin, for thrombophilias, 255 Lupus anticoagulant antibody, recurrent pregnancy loss and, 256 Lupus erythematosus, recurrent pregnancy loss in, 257 Luteal hormones, 156 Luteal phase defect in, 159 recurrent pregnancy loss and, 249-250 early, 29 evaluation of, 160-161, 160b middle to late, 30-31 Luteal phase support after ovulation induction in hypothalamic amenorrhea, 194 in assisted reproductive technologies, 271 Luteinizing hormone (LH) in climacteric, 96 in menstrual cycle, 19f, 20, 23, 26-27, 28, 29
Luteinizing hormone (LH) (Continued) midcycle surge of, detection of, 161 in polycystic ovarian syndrome, 53, 70 in precocious puberty, 41 in puberty, 35 recurrent pregnancy loss and, 251 Luteolysis, 30 Lymphatic metastasis theories of endometriosis, 215
M Macrophages, in pathogenesis of endometriosis, 216 Magnetic resonance imaging for infertility evaluation, 207f, 208 in precocious puberty, 41 of uterine anomalies, 245 Male cardiovascular disease risk in, 102, 102b definition of, 129 dyspareunia in, 146 endometriosis in, 215 infertility in, 169-182. See also Infertility, male. sexual anatomy of, 130-131, 130f sexual response cycle of, 133-135, 133f Male orgasm disorder, 145 Mammography, in climacteric, 104t Masters and Johnson’s sexual response cycle, 133-135, 133f, 134f Masturbation, directed, for female orgasm disorder, 146 Matrix metalloproteinases, in menstrual cycle, 30 Mayer-Rokitansky-Küster-Hauser syndrome, 199 McCune-Albright syndrome, precocious puberty in, 40, 42f Medications male infertility from, 171-172, 173t osteoporosis from, 112b, 118
Medications (Continued) sexual dysfunction from, 139b Medroxyprogesterone acetate, for endometriosis, 223 Megestrol acetate, for endometriosis, 223 Men. See Male. Menarche, normal onset of, 15, 38 Menopause. See also Climacteric; Perimenopause; Postmenopause. abnormal uterine bleeding after, 83, 89t definition of, 93 markers of, 101 sexual desire in, 138 Menorrhagia, 80, 81 Menstrual cycle age at onset of, 15, 38 in climacteric, 96 cytokines and growth factors in, 20, 21t-22t, 24-25 follicular/proliferative phase of early, 18-24 late, 26-28 middle, 24-26, 27f histologic change throughout, 26f history of, infertility and, 158-159 length of, 16-17, 16f, 17f luteal/secretory phase of early, 29 middle to late, 30-31 normal, 15-32, 16b, 19f, 78 ovulation and, 28-29 in polycystic ovarian syndrome, 67 two-cell ovarian physiology in, 23-24 Menstruation heavy bleeding during, 80, 81 normal, 31 pain during. See Dysmenorrhea. Mercury exposure, recurrent pregnancy loss and, 259 Mesalazine, male infertility and, 172 Mesonephric (wolffian) ducts, 198-199
Index Metalloproteinases, matrix, in menstrual cycle, 30 Metformin for chronic anovulation, 188-189 for polycystic ovarian syndrome, 72-73, 250 Methylene tetrahydrofolate reductase mutation, recurrent pregnancy loss in, 254 Metroplasty, for uterine anomalies, 247 Microsurgical epididymal sperm aspiration (MESA), 178, 178t, 264b Miscarriage recurrent. See Recurrent pregnancy loss. sporadic, 241 Misoprostol, for postpartum hemorrhage, 12 Mons pubis, 131, 132f Mottling, skin, in sexual response, 133 Müllerian agenesis, 199 amenorrhea from, 57-58, 57b Müllerian anomalies acquired, 201-203, 203f, 248-249 congenital anatomy and physiology of, 199, 200f infertility and, 199-200 recurrent pregnancy loss and, 245-248, 246f diagnosis of, 164-165, 245 from diethylstilbestrol, 200, 246f, 248 recurrent pregnancy loss and, 245-249, 246f, 249b treatment of, 208-209 Müllerian ducts, 198-199, 245 Müllerian inhibin substance. See Antimüllerian hormone. Multiple gestations, assisted reproductive technologies and, 280, 280b Muscular dystrophy, male infertility and, 181 Mycoplasma hominis, recurrent pregnancy loss and, 251-252
Myocardial infarction in climacteric, 100, 100f, 102, 102b incidence of, 100f
N Neomycin, male infertility and, 172 Neuropeptide Y, in puberty, 34 Night sweats, 96-97, 105 Nipple erection, 133 Nitric oxide, in sexual response, 139 Nitrous oxide exposure, recurrent pregnancy loss and, 259 Nonsteroidal antiinflammatory drugs for dysmenorrhea, 12 for endometriosis-associated pain, 220, 222 Norethindrone acetate, for endometriosis, 223 Nulliparity, menopause and, 94 Nutrition in climacteric, 103 puberty and, 34-35
O Obesity central, in polycystic ovarian syndrome, 68 in hyperandrogenism, 186 male infertility and, 171 Obstetric history infertility and, 159 recurrent pregnancy loss and, 241 Oligomenorrhea, 65, 67 Oligo-ovulation. See also Anovulation. abnormal bleeding from, 78-79, 82-83 in polycystic ovarian syndrome, 66 Oligozoospermia, 169, 176-177, 179-181. See also Infertility, male. Oocyte(s) cryopreservation of, 238, 280-281 fertilization of, 156 quantity of, age and, 231f
Oocyte donation, 237, 238f, 276-277, 277b, 278b Oocyte insemination intracytoplasmic, 176, 268-270 routine, 267-268, 268f, 269f Oocyte retrieval and identification human chorionic gonadotropin administration prior to, 264-265 procedure for, 266-267, 267f, 268f Oophorectomy, bilateral, for endometriosis, 226 Ooplasm donation, for diminished ovarian reserve, 237-238 293 Oral contraceptives for abnormal uterine bleeding, 88 in assisted reproductive technology procedures, 265 for chronic anovulation, 61-62 discontinuation of, abnormal bleeding after, 82 for endometriosis, 222-223 for hirsutism, 73 for polycystic ovarian syndrome, 71, 73 Orgasm, 133f, 134-135, 134f, 135t sexual dysfunction during, 144-146 Osteomalacia, 109, 116, 119 Osteopenia, 99, 109, 114, 114t Osteoporosis, 109-126 bone mineral density measurements in, 112-115, 113b, 113f, 114b, 114f, 115f bone turnover markers in, 115 classification of, 110 in climacteric, 99-100, 102, 110, 117, 118b clinical presentation in, 112 definition of, 109-110 diagnostic tests in, 112-115 evaluation for, 117, 118b fractures associated with, 110, 111, 112 bone mineral density and, 114, 115f prevention of, 119-120
Index Osteoporosis (Continued) high-turnover, 119 idiopathic, 110 low-turnover, 119 physiology of, 110-111, 111b, 111t, 112b prevention of, 119-126 primary, 110 screening for, 102, 116, 117b secondary, 110, 111b, 112b, 117-119 treatment of combination therapy for, 124 indications for, 120-121, 294 120b monitoring during, 125-126, 126b pharmacologic, 121-125 Ovarian aging, 229-231, 230f, 231f Ovarian biopsy, for ovarian reserve evaluation, 236 Ovarian cancer, clomiphene citrate and, 191-192 Ovarian cyst, persistent, 190 Ovarian drilling, laparoscopic, for polycystic ovarian syndrome, 73 Ovarian failure. See Anovulation; Hypergonadotropic hypogonadism; Menopause. Ovarian hormone production, in climacteric, 95-96, 95f Ovarian hyperstimulation, 264-265, 265t. See also Ovulation induction. Ovarian hyperstimulation syndrome, 193, 193b, 278-279, 279b Ovarian reserve diminished, 155, 229-239 age and, 229-231, 230f, 231f recurrent pregnancy loss and, 233 treatment of, 236-238, 237b evaluation of, 165-167, 166b, 231-236, 232t Ovarian tissue cryopreservation, 238, 280-281
Ovarian tumors amenorrhea in, 54 androgen-producing, 68 Ovarian volume, mean, measurement of, 235 Ovary(ies), 133 in follicular phase early, 18-20, 23 late, 26-28 middle, 24-25 in luteal/secretory phase, 29, 30 in menstrual cycle, 19f polycystic. See Polycystic ovarian syndrome. in puberty, 35 two-cell physiology of, 23-24 Ovulation, 28-29 deficiency of. See Anovulation. evaluation of, 160-161, 160b Ovulation induction aromatase inhibitors for, 192-193 in assisted reproductive technology procedures, 264-265, 265t clomiphene citrate for, 189-192, 190f, 191f in hypothalamic amenorrhea, 194 insulin-sensitizing agents for, 188-189 lifestyle alterations for, 188 ovarian hyperstimulation syndrome after, 193, 193b, 278-279, 279b in polycystic ovarian syndrome, 71-72, 73, 188-193 Ovulation prediction kit, 161 Ovulatory bleeding, 81-82 Oxytocin in menstrual cycle, 29 in sexual response, 139
P Pain in endometriosis, 217 during intercourse. See Dyspareunia. during menstruation. See Dysmenorrhea. Pain problems, as sexual dysfunction, 146-148
Pamidronate, for osteoporosis and fracture prevention, 122 Pap smear, in climacteric, 104t Paramesonephric (müllerian) ducts, 198-199, 245 Parathyroid hormone excess of, wrist DXA in, 116 recombinant, for osteoporosis and fracture prevention, 124-125 Paternal leukocytic immunization, in recurrent pregnancy loss, 258 Pelvic examination, in female infertility, 160 Pelvic inflammatory disease, infertility and, 197, 204 Pelvic organ prolapse, in climacteric, 98 Pelvic pain, in endometriosis, 217 Pelvic ultrasonography, in abnormal uterine bleeding, 83, 84f, 85f, 86 Penile pain, 146 Penis, 130, 130f Percutaneous epididymal sperm aspiration, 178-179, 178t Perhydrocyclopentaphenanthrene, 3-4, 4f Perimenopause abnormal bleeding in, 82 definition of, 93 early, 93 late, 93 onset and duration of, 94, 94f Peripheral bone mineral density measurement, 113, 116 Peripheral precocious puberty, 40, 41t Peritoneum, evaluation of, in female infertility, 162-164, 163f Peyronie’s disease, male dyspareunia in, 146 Phenylpropanolamine, for retrograde ejaculation, 176 Phosphodiesterase-5 inhibitors, 139 for erectile disorder, 142 Phytoestrogen preparations, 105 for osteoporosis and fracture prevention, 123
Index Pituitary disorders, amenorrhea in, 51t, 55-56 Pituitary gland postpartum necrosis of, 55-56 in puberty, 35 Pituitary hamartoma, precocious puberty and, 40 Pituitary tumors, male infertility and, 170 Plasminogen activator, in ovulation, 28 Plasminogen activator inhibitor (PAI) in polycystic ovarian syndrome, 250 in recurrent pregnancy loss, 255 Plateau, sexual, 133f, 134, 134f Platelet activation, in pregnancy, 252-253 Polar body biopsy, 273-274 Polycystic ovarian syndrome, 65-75 abnormal uterine bleeding in, 83 amenorrhea in, 53-54, 53b, 54b anovulation in, 66, 186-193 physiology of, 186-188, 187f treatment of, 188-193 clinical presentation in, 67-68 definition of, 65-66, 66t differential diagnosis in, 66t, 68-69 female infertility and, 160 hirsutism in, 67, 68, 73-74 laboratory tests in, 68-70, 69b, 70b physiology of, 66-67 recurrent pregnancy loss in, 249-250 treatment of, 61-62, 70-74 Polymerase chain reaction in preimplantation genetic diagnosis, 275 in thrombophilias, 255 Polyp, endometrial infertility and, 201 radiologic imaging of, 83, 85f treatment of, 87, 89t Postcoital test, 165, 206 Postmenopause
Postmenopause (Continued) abnormal uterine bleeding in, 83, 89t age and, 94, 94f bone resorption in, 110 definition of, 93 osteoporosis in, 99-100, 102, 110, 117, 118b Postpartum hemorrhage, 12 Preantral follicles, 230 Precocious puberty, 38-44 central (gonadotropindependent), 39-40, 40t definition of, 39 diagnosis of, 40-41, 42b in McCune-Albright syndrome, 40, 42f mixed, 43-44 peripheral (gonadotropinindependent), 40, 41t treatment of, 42-43, 43b Prednisone, osteoporosis from, 118 Pregnancy disorders related to, abnormal uterine bleeding in, 81 ectopic, pelvic inflammatory disease and, 204 hypercoagulation in, 252-253, 253f multiple, in assisted reproduction, 280, 280b Pregnancy loss recurrent. See Recurrent pregnancy loss. sporadic, 241 Pregnancy support, early, after ovulation induction in hypothalamic amenorrhea, 194 Pregnanes, 3 Preimplantation genetic diagnosis (PGD), 273-276, 273b Premature ejaculation, 144-145, 171 Prepuce, 130, 130f Primordial follicles, 20, 230 Primordial germ cells, 20 Progesterone, 4f, 6-7 for abnormal uterine bleeding, 88-89 assays for, 8, 8b
Progesterone (Continued) for chronic anovulation, 61 in climacteric, 8-9, 96 deficiency of, during luteal phase, 159, 249-250 for endometriosis, 223 for hormonal contraception, 8 in menstrual cycle, 19, 19f, 29, 30 for ovarian failure, 61 for polycystic ovarian syndrome, 71 serum, for ovulation confirmation, 161 295 in sexual response, 138 Progesterone receptor-A, 7 Progesterone receptor-B, 7 Progestin challenge, in amenorrhea, 55, 59, 59b Prolactin, elevated. See Hyperprolactinemia. Proliferative phase of menstrual cycle early, 18-24 late, 26-28 middle, 24-26, 27f Prostaglandin E1, for postpartum hemorrhage, 12 Prostaglandin E2, 11, 11b Prostaglandin F2α, 11, 11b dysmenorrhea and, 11-12 for postpartum hemorrhage, 12 Prostaglandin I2, 11, 11b Prostaglandin receptors, 10 Prostaglandins, 9-12 definition of, 3 physiology and clinical presentation of, 10-11, 11b production of, 9-10, 10f structure of, 10f therapeutic interventions related to, 11-12 Prostate, 130f, 131 examination of, in male infertility, 173 Prostheses, implantable, for erectile disorder, 142 Protein C or S deficiency, recurrent pregnancy loss in, 255
Index Prothrombin mutation, recurrent pregnancy loss in, 254 Prune belly syndrome, male infertility and, 181 Pruritus, vaginal, in climacteric, 98 Pseudoephedrine, for retrograde ejaculation, 176 Pseudopuberty, 40, 41t Psychogenic erection, 137 Pubarche normal, 36-37, 37b, 37t premature, 44 Puberty, 33-47 abnormal, 38-46 296 delayed, 45 hormonal responses in, 33-36 normal, 33-38 physical signs of, 36-38, 37b, 37t precocious, 38-44. See also Precocious puberty. timing of, 38 Pubic hair, development of normal, 36-37, 37b, 37t premature, 44
R Race, osteoporosis and, 112 Radiation, recurrent pregnancy loss and, 259 Raloxifene in climacteric, 105-106 for osteoporosis and fracture prevention, 124 Rape, sexual aversion disorder after, 141-142 Rapid ejaculation, 144-145, 171 Recreational drugs, male infertility from, 171, 173t Rectal examination, digital, in male infertility, 173 Recurrent pregnancy loss, 241-261 cervical incompetence and, 206 diminished ovarian reserve and, 233 endocrinopathies and, 249251, 252b genetics and, 242-244, 243f, 245b history, physical examination, and laboratory tests in, 242b
Recurrent pregnancy loss (Continued) immunologic factors in, 255-258, 258b infections and, 251-252, 252b lifestyle and environmental factors and, 258-259, 260b obstetric history and, 241 summary of, 260-261, 260t thrombophilia and, 252-255, 253f, 256b uterine anomalies and, 244-249, 246f, 249b Refractory period, after orgasm, 134, 135 Reproduction assisted. See Assisted reproductive technologies (ART). normal, 156 Reproductive failure. See Infertility. Reproductive tract anomalies of. See Müllerian anomalies. defects of amenorrhea from, 50t, 56-58, 57b, 57f, 62 evaluation of, 60, 60b embryology of, 198-199, 200f Resolution, sexual, 133f, 134f, 135 Retrograde ejaculation, 176 Retroperitoneal surgical approach for varicocele, 177 Rickets, 116 Risedronate, for osteoporosis and fracture prevention, 122 Robertsonian translocation male infertility and, 180 recurrent pregnancy loss and, 243
S Saline infusion sonography. See Sonohysterography. Salpingitis, chlamydial, 204 Salpingitis isthmica nodosa, 204, 205f Salpingo-oophorectomy, bilateral, for endometriosis, 226 Sampson’s theory of endometriosis, 213-214
Sauna use, maternal, recurrent pregnancy loss and, 259 Scrotum, 130, 130f, 131 examination of, in male infertility, 173 in hyperthermic environment, male infertility and, 171 repair of, for varicocele, 177 trauma to, infertility and, 170 Secretory phase of menstrual cycle early, 29 middle to late, 30-31 Selective estrogen receptor modifiers (SERMs). See also specific drugs, e.g., Clomiphene citrate. in climacteric, 105-106 for osteoporosis and fracture prevention, 124 Selective serotonin reuptake inhibitors male infertility and, 172 for premature ejaculation, 144 Semen abnormalities of, environmental toxins and, 170-171 analysis of, 174-175, 174b, 175t Seminal fluid, 131 Seminal vesicle, 130f, 131 examination of, in male infertility, 173 Septate uterus, 199, 200f, 209, 246f, 247-248 Serotonin reuptake inhibitors, male infertility and, 172 Severe ovarian hyperstimulation syndrome, 193, 193b Sex, versus gender, 129 Sex screening questions, 148-149, 148b, 149b Sex therapy specialists, 149b Sex-hormone–binding globulin (SHBG), 4-5, 5t Sexual activity desire for, 135, 135t, 136-137, 136f patient expectations about, 140 purpose of, 129 response cycle in. See Sexual response cycle.
Index Sexual anatomy female, 131-133, 132f male, 130-131, 130f Sexual aversion disorder (SAD), 141-142 Sexual dysfunction, 139-150 during arousal phase, 142-144 categories of, 140-141, 140t in climacteric, 98-99 during desire phase, 141-142 history taking in, 148-149, 148b, 149b infertility and, 149-150, 150t from medications, 139b during orgasm, 144-146 overview of, 139-141 pain problems as, 146-148 screening for, 148-149, 148b, 149b Sexual hair, development of normal, 36-37, 37b, 37t premature, 44 Sexual history, infertility and, 159 Sexual infantilism, in ovarian failure, 52 Sexual response cycle, 133-139 female, 133-135, 134f, 136-137, 136f hormonal influences on, 137-139 intimacy-based, 136-137, 136f Kaplan’s redefinition of, 135, 135t male, 133-135, 133f Masters and Johnson’s, 133-135, 133f, 134f neuronal influences on, 137 sexual dysfunction categories based on, 140, 140t Sexual trauma, sexual aversion disorder after, 141-142 Sexuality, 129-151 Sexually transmitted disease, male infertility and, 170 Sheehan’s syndrome, amenorrhea in, 55-56 Sickle cell anemia, male infertility and, 181 Sigmoidoscopy, flexible, in climacteric, 104t
Sims-Huhner test, 155 Skene’s glands, 131-132, 132f Skin changes of, in climacteric, 99 mottling of, in sexual response, 133 Sleep disturbances, in climacteric, 97 Smoking in climacteric, 103 male infertility and, 171 menopause and, 94 recurrent pregnancy loss and, 259 Sonohysterography in abnormal uterine bleeding, 83, 84f, 85f for fallopian tube evaluation, 163-164 of uterine anomalies, 245 for uterine cavity evaluation, 164 Sperm antibodies against, infertility and, 158, 176 environmental toxins and, 170-171 intracytoplasmic injection of for antisperm antibodies, 176 procedure for, 268-270 laboratory analysis of, 174-175, 174b, 175t retrieval of, 178-179, 178t Spermatic cord, 130-131, 130f Spina bifida, male infertility and, 181 Spine, bone mineral density measurement of, 112-113, 116 Spironolactone, for hirsutism in polycystic ovarian syndrome, 73 Statins, male infertility and, 172 Stem cells, embryonic, 281 Steroid hormones, 3-9. See also Androgens; Estrogens; Progesterone. anabolic, male infertility and, 171 assays for, 8, 8b classes of, 3
Steroid hormones (Continued) physiology and clinical presentation related to, 4-6, 5t structure of, 3-4, 4f therapeutic interventions related to, 8-9 Steroid receptors, 5 ß-Thalassemia, male infertility and, 181 Stratum basale, 18, 18b Stratum compactum, 18, 18b Stratum functionale, 18, 18b Stratum spongiosum, 18, 18b Strengthening exercise, for 297 osteoporosis and fracture prevention, 120 Stress abnormal uterine bleeding and, 82 amenorrhea and, 55 Sulfasalazine, male infertility and, 172 Superovulation. See Ovarian hyperstimulation. Suppositories, transurethral, for erectile disorder, 142 Synechiae, uterine amenorrhea in, 58 infertility in, 201, 202f, 209 recurrent pregnancy loss in, 248 Systemic lupus erythematosus, recurrent pregnancy loss in, 257
T Tamoxifen, for male infertility, 177 Tanner stages, 36-37, 37b Tap water consumption, recurrent pregnancy loss and, 259 Temperature charting, for ovulation confirmation, 160-161, 160b Teratozoospermia, 169 Teriparatide, for osteoporosis and fracture prevention, 124-125 Testicular cancer, infertility and, 169-170, 173 Testicular epididymal sperm aspiration, 178t, 179
Index Testicular epididymal sperm extraction, 178t, 179, 264b Testicular feminization, amenorrhea from, 57, 57b Testicular pain, 146 Testis, 130, 130f, 131 examination of, in male infertility, 173 Testosterone, 4, 4f, 7 assays for, 8, 8b in climacteric, 96 in sexual response, 137-138 supplementation of, male infertility and, 171 298 Tetanus-diphtheria booster, in climacteric, 104t Tetracycline, male infertility and, 172 Theca cell, 4, 23 Thelarche abnormal, 45 normal, 36, 37b, 37t premature, 44 Thoughts, interfering, in erectile disorder, 143 Thrombin formation, in pregnancy, 252 Thrombophilia, recurrent pregnancy loss and, 252-255, 253f, 256b Thromboxane, 11, 11b Thyroid autoantibodies, recurrent pregnancy loss and, 257 Thyroid disorders abnormal uterine bleeding in, 82-83 amenorrhea in, 54 male infertility in, 170 osteoporosis in, 118 recurrent pregnancy loss in, 251 Thyrotropin, elevated, in polycystic ovarian syndrome, 69 Transforming growth factor-α, in menstrual cycle, 22t, 25 Transforming growth factor-ß, in menstrual cycle, 21t Translocation, chromosomal male infertility and, 180 recurrent pregnancy loss and, 243
Transurethral suppositories, for erectile disorder, 142 Transverse vaginal septum, 56, 200f Trauma to scrotum, infertility and, 170 sexual, sexual aversion disorder after, 141-142 Tricyclic antidepressants, for premature ejaculation, 144 T-score, 109, 113-114, 113f Tubal factor infertility, 157, 203-204, 205f, 210 Tube, fallopian. See Fallopian tube. Tuberculosis, genitourinary, male infertility and, 170 Tumor necrosis factor-α, in menstrual cycle, 21t, 25 Tumors androgen-producing, 68 ovarian, amenorrhea in, 54 pituitary, male infertility and, 170 Tunica albuginea, 130, 130f
U Ultrasonography. See also Sonohysterography. for ovarian reserve evaluation, 167 in ovulatory clomiphene citrate cycle, 189-190, 190f, 191f pelvic, in abnormal uterine bleeding, 83, 84f, 85f, 86 in polycystic ovarian syndrome, 53, 54f three-dimensional, of uterine anomalies, 245 transrectal, in male infertility, 175 transvaginal in endometriosis, 218, 219f in polycystic ovarian syndrome, 70 of uterine anomalies, 245 Underwear, male, infertility and, 171 Unicornuate uterus, 199, 200f, 208-209, 246f, 247
Ureaplasma urealyticum, recurrent pregnancy loss and, 251-252 Urinary incontinence, in climacteric, 98 Urinary tract infection, in climacteric, 98 Urine tests, in osteoporosis, 102 Urogenital symptoms, in climacteric, 98 Usher’s syndrome, male infertility and, 181 Uterine artery embolization, for abnormal uterine bleeding, 87 Uterine bleeding, abnormal, 77-91 clinical presentation in, 79-80 diagnostic tests in, 83-85, 84f, 85f differential diagnosis in, 81-83 history in, 79-80 hormonal therapy for, 88-90 physical examination in, 80 physiology of, 77-79, 78b surgical therapy for, 86-88 treatment of, 86-90, 87b, 89b Uterine cavity, evaluation of, 164-165 Uterine fibroids infertility and, 201-203, 203f, 209 radiologic imaging of, 83, 84f recurrent pregnancy loss and, 249 treatment of, 87, 89t, 209, 249 Uterine polyp infertility and, 201 radiologic imaging of, 83, 85f treatment of, 87, 89t Uterine synechiae amenorrhea in, 58 infertility in, 201, 202f, 209 recurrent pregnancy loss in, 248 Uterus, 133 agenesis of, amenorrhea from, 56-57 anatomic abnormalities of abnormal bleeding from, 82, 89t
Index Uterus (Continued) acquired, 201-203, 203f anatomy and physiology of, 198-199, 200f congenital, 199-200, 245-248, 246f diagnosis of, 208, 245 from diethylstilbestrol, 200-201, 248 infertility from, 158, 198-203, 208-209 radiologic imaging of, 83, 84f, 85f recurrent pregnancy loss from, 244-249, 246f, 249b arcuate, 209, 246f, 248 bicornuate, 200f, 207f, 209, 246f, 247 embryology of, 198-199, 200f enlargement of, in sexual response, 134 with rudimentary horn, 209 septate, 199, 200f, 209, 246f, 247-248 unicornuate, 199, 200f, 208-209, 246f, 247 Uterus didelphys, 246f, 247
V Vacuum device therapy, for erectile disorder, 143 Vagina, 132-133, 132f agenesis of, amenorrhea from, 56-57 enlargement of, in sexual response, 134 examination of, in abnormal uterine bleeding, 80 lubrication of, in sexual response, 134 thinning and atrophy of, in climacteric, 98
Vaginal pruritus, in climacteric, 98 Vaginismus, etiology and treatment of, 147-148 Vaginosis, bacterial, recurrent pregnancy loss and, 251-252 Varicocele, infertility and, 173, 177 Varicocelectomy, laparoscopic, 177 Vas deferens, 130f, 131 Vascular endothelial growth factor in menstrual cycle, 21t, 25 in severe ovarian hyperstimulation syndrome, 193 Vascular metastasis theories of endometriosis, 215 Vasectomy reversal, 177-178 Vasomotor disturbances, in climacteric, 96-97, 105 Vasovasostomy, 177-178 Vertebral compression fracture, 110, 112, 118 Viremia, male infertility and, 170 Virilization inadequate, evaluation of, 172-173 in polycystic ovarian syndrome, 67, 68 Vitamin B6 supplementation, for MTHFR mutation, 255 Vitamin D deficiency of, 116, 117, 118, 125 dietary sources of, 119 intake of, for osteoporosis and fracture prevention, 119, 121 Voice deepening, in polycystic ovarian syndrome, 67, 68 Von Willebrand’s disease, 81 Vulva, 131, 132f
W Weight gain androgen level and, 5 in puberty, 37-38 Weight loss amenorrhea from, 55 for chronic anovulation, 188 for polycystic ovarian syndrome, 70-71 Weight-bearing exercise, for osteoporosis and fracture prevention, 120 Wolffian ducts, 198-199 Women. See Female. Wrist, DXA of, 116
X XX male syndrome, male infertility in, 181 XYY karyotype, male infertility in, 180
Y Y chromosome microdeletions, male infertility in, 180-181 Young’s syndrome, infertility and, 170, 181
Z Zoledronic acid, for osteoporosis and fracture prevention, 122 Z-score, 109, 114-115, 114f Zygote intrafallopian transfer (ZIFT), 264b
299
