Erectile Dysfunction

ERECTILE DYSFUNCTION EDITORS A. JARDIN - G. WAGNER - S. KHOURY F. GIULIANO - H. PADMA-NATHAN - R. ROSEN

1st International Consultation on Erectile Dysfunction - July 1- 3, 1999, Paris Co-Sponsored by World Health Organization (WHO) - International Society for Impotence Research Société Internationale d’Urologie

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FOREWORD

In the field of sexuality, the end of the second millennium was marked by: - a better understanding of sexual physiology, especially the physiology of erection, - the availability of easy to administer and effective treatments for erectile insufficiency, - recognition of the need for multidisciplinary collaboration to further our knowledge and to improve patient management. All of these elements naturally led the directors of the ICUD to organize a consultation on erectile dysfunction. This consultation was conducted according to the model of previous successful consultations in the fields of benign prostatic hyperplasia, prostatic cancer, incontinence, etc. The vast subject of erectile dysfunction was divided into 18 chapters, analysing all aspects and even included a chapter on FSD, due to the importance of the female in male sexuality, and to encourage research in the field of FSD, which is somewhat behind that of male sexual dysfunction. These 18 committees met on several occasions and each developed a text comprising recommendations which were discussed at the meeting held in Paris in July 1999. This book is the sum of all these texts and presents a summary of the recommendations developed by the Scientific Committee. This book therefore represents a unique body of knowledge and discussion, as it reflects the opinions of specialists from all continents. Like all books, it will become obsolete and will need to be updated by future consultations, but it nevertheless has a sound future. It was a great honour and a pleasure for me to be Chairman of this consultation. I would like to thank all those who, by their hard work, their very serious comments and their talent, contributed to the elaboration of the conclusions and recommendations presented in this book, which will certainly become rapidly indispensable to all those working in the field of sexual dysfunction.

A. Jardin

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Some of the members of the International Committees Paris - July 1 - 3, 1999

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EDITORS A. Jardin, France G. Wagner, Denmark S. Khoury, France F. Giuliano, France H. Padma-Nathan, USA R. Rosen, USA

MEMBERS OF THE COMMITTEES (Alphabetical order - Chairmen in bold print)

2 6 13 2 9 4 18 13 15 1 17 8 5 6 7 9 7 15 17 6 16 6 17 8 10

ALEXANDRE ANDERSSON ALTHOF BAY NIELSEN BECHER BEJIN BENNETT BENSON BONDIL BOYLE BRACKETT BROCK BRODERICK BURNETT BUVAT CARRIER CARSON CARTMILL CHARTIER-KASTLER CHEN CHOI CHRIST DENYS EARDLEY EVANS

L K-E S H. E A A.H G.S. P. P N G G.A. A.L. J S C. C R E K-K H.K. G P I C

France Sweden USA Denmark Argentina France USA USA France Italy USA Canada USA USA France Canada USA Australia France China Korea USA France UK U.K.

18 2 8 4 16 16 8 4 14 3 7 9 14 12 13 1 3 3 14 13 18 13 8 7 14

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FERGUSON D.M FITZPATRICK J FOURCROY J FUGL MEYER A GIAMI A GINGELL J.C. GIULIANO F GLINA S GOLDSTEIN I GONZALEZ CADAVID N GOOREN L GOVIER F GRAZIOTTIN A GUEGLIO G HAENSEL SM HATZICHRISTOU D HEATON J HEDLUND H HEIMAN J HENDRY B HIRSCH M. S. HULL E.M. HUTTER A.M. JAROW J JOHANNES C

USA Ireland USA Sweden France UK France Brazil USA USA NDL USA Italy Argentina NDL Greece Canada Norway USA UK USA USA USA USA USA

16 10 12 13 7 4 15 8 10 1 14 12 1 4 12 4 17 14 1 9 9 2 11 5 10 5 16 12 4 3 4 13 18 16 15 3

JOHNSTON JONAS JORDAN KIHARA KIM KIMOTO KNOLL KRANE KRISHNAMURTI LAUMAN LEVIN LEVINE LEWIS LO PICCOLO LUE LUKACS LUNDBERG MC KENNA MC KINLAY MC VARY MCMAHON MELCHIOR MELMAN MEULEMAN MONTAGUE MONTORSI MORALES MORELAND MULCAHY NEHRA O’LEARY OPSOMER PADMA-NATHAN PASINI PESCATORI PICKARD

B U G K Y.C. Y. D R S E R.J L R J T B. P.O. K J K C H. A E D F A R.B. J. J A M R.J. H W E. S. RS.

Canada Germany USA Japan Korea Japan USA USA India USA UK USA USA USA USA France Sweden USA USA USA Australia Germany USA NDL USA Italy Canada USA USA USA USA Belgium USA Switzerland Italy U.K.

9 12 7 12 6 18 11 3 16 10 16 11 2 5 3 17 10 15 3 6 5 8 16 11 5 16 7 8 9 17 4 10 10 16 18 12

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PORST H PRYOR J RAJFER J RALPH D RAMPIN O ROSEN R SACHS B SAENZ DE TEJADA I SAMKANGE C.A. SARRAMON J. P SCHMIDT A SEGRAVES T SHABSIGH R SHARLIP I SIMONSEN U SOENKSEN J SOHN M STACKL W STEERS W STIEF C TAN H.M TELOKEN C UGARTE F VAN DRIEL M.F. VARDI Y VELA RODRIGUEZ L VERMEULEN A VICKERS M VIRAG R VODUSEK D WAGNER G WESPES E WESSELLS H WILLIAMS G WYLLIE M. G YACHIA D

Germany UK USA U.K. France USA USA Spain Zimbabwe France S. Africa USA USA USA Denmark Denmark Germany Austria USA Germany Malaysia Brazil Mexico NDL Israel Spain Belgium USA France Slovenia Denmark Belgium USA U.K. U.K. Israël

MEMBERS OF THE COMMITTEES (by Committee) 1. EPIDEMIOLOGYAND NATURAL HISTORY AND RISK FACTORS INCLUDING IATROGENIC AND AGEING BOYLE P. Italy HATZICHRISTOU D. Greece LAUMAN E. USA LEWIS R. USA MC KINLAY J. USA

6. CURRENT RESEARCH AND FUTURE THERAPIES ANDERSSON K.E. Sweden BURNETT A.L. USA CHEN K-K R.China CHRIST G. USA RAMPIN O. France STIEF C. Germany

2. ECONOMICALASPECTS ALEXANDRE L. BAY NIELSEN H. FITZPATRICK J. MELCHIOR H. SHABSIGH R.

France Denmark Ireland Germany USA

3. PATHOPHYSIOLOGY GONZALEZ CADAVID N. HEATON J. HEDLUND H. NEHRA A. PICKARD R.S. SAENZ DE TEJADA I. SIMONSEN U. STEERS W.

USA Canada Norway USA U.K. Spain Denmark USA

7. ENDOCRINE AND METABOLIC ASPECTS INCLUDING TREATMENT BUVAT J. France CARSON C.C USA GOOREN L. NDL JAROW J. USA KIM Y.C. Korea RAJFER J. USA VERMEULEN A. Belgium 8. ORAL NON ENDOCRINE TREATMENT BROCK G. Canada EARDLEY I. UK FOURCROY J. USA GIULIANO F. France HUTTER A.M. USA KRANE R. USA TELOKEN C. Brazil VICKERS M. USA

4. SYMPTOM SCORE AND QUALITY OF LIFE BEJIN A. France FUGL MEYER A. Sweden GLINA S. Brazil KIMOTO Y. Japan LUKACS B. France MULCAHY J.J USA O’LEARY M. USA WAGNER G. Denmark

9. LOCAL PHARMACOLOGICALTREATMENT MODALITIES BECHER E. Argentina CARRIER S. Canada GOVIER F. USA MC VARy K. USA MCMAHON C. Australia PORST H. Germany VIRAG R. France

5. CLINICAL EVALUATION : PRACTICAL AND ETHICALASPECTS AND DOCTOR/ PATIENT DIALOGUE BRODERICK G. A. USA MEULEMAN E. NDL MONTORSI F. Italy SHARLIP I. USA TAN H.M. Malaysia VARDI Y. Israel

10. SURGICALTREATMENT AND MECHANICAL DEVICES EVANS C. U.K. JONAS U. Germany KRISHNAMURTI S. India MONTAGUE D. USA SARRAMON J. P. France SOHN M. Germany WESPES E. Belgium WESSELLS H. USA

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11. PSYCHOLOGICAL ISSUES IN DAGNOSIS AND TREATMENT LEVINE S.B. USA MELMAN A. USA SACHS B. USA SEGRAVES T. USA VAN DRIEL M.F. NDL

15. PRIAPISM BONDIL CARTMILL KNOLL PESCATORI STACKL

P. R. D. E.S. W.

France Australia USA Italy Austria

16. EDUCATION AND ETHICS AND SOCIOCULTURALASPECTS CHOI H.K. Korea GIAMI A. France GINGELL J.C. UK JOHNSTON B. Canada MORALES A. Canada PASINI W. Switzerland SAMKANTE C.A. Zimbabwe SCHMIDT A. S.Africa UGARTE F. Mexico VELA RODRIGUEZ L. Spain WILLIAMS G. U.K.

12. PEYRONIE’S DISEASE AND OTHER PENILE ABNORMALITIES GELBARD M. U.S.A. GUEGLIO G. Argentina JORDAN G. USA LEVINE L. USA LUE T. USA MORELAND R.B. USA PRYOR J. UK RALPH D. U.K. YACHIA D Israël 13. MALE ORGASMIC AND EJACULATORY DISORDERS ALTHOF S. USA BENSON G.S. USA HAENSEL SM NDL HENDRY B. UK HULL E. M. USA KIHARA K. Japan OPSOMER R.J. Belgium

17. CENTRAL NERVOUS SYSTEM DISORDERS AND ERECTILE EJCULATORY DYSFUNCTION BRACKETT N. USA CHARTIER-KASTLER E. France DENYS P. France LUNDBERG P.O. Sweden SOENKSEN J. Denmark VODUSEK D. Slovenia

14. FEMALE SEXUALDYSFUNCTION GOLDSTEIN I. USA GRAZIOTTIN A. Italy HEIMAN J. USA JOHANNES C. USA LAAN E. NDL LEVIN R.J. UK Mc KENNA K. USA

18. STANDARDS FOR CLINICALTRIAL : DESIGN AND ASSESSMENT-CRITERIA OF RESPONSE BENNETT A. H USA FERGUSON D.M USA HIRSCH M.S. USA PADMA-NATHAN H. USA ROSEN R. USA WYLLIE M. G U.K.

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Professor G. Wagner Honorary chairman of the Ist International Consultation on Erectile Dysfunction

Gorm Wagner has since he graduated from University of Copenhagen, Denmark and finished his internship in USA worked within reproductive and sexual medicine. Starting as guest investigator in George Corners Laboratory at Rockefeller University in New York with animal experiments followed by clinical training in gynecology and obstetrics at Copenhagen University Hospital. These were years with clinical research of induction of labour and studies of mechanisms of myometrial activity. During these years he worked closely with Anna-Riitta Fuchs, D. M. Sc. and they described the role of oxytocin in lactation and parturition with an early observation published in NATURE on the inhibitory effect of alcohol on the liberation of oxytocin. On a later study visit at Washington University, St. Louis, in the lab. of A.Csapo he continued the work with in vitro smooth muscle physiology now in relation to progesterone. This was followed by years in Copenhagen where he developed a rabbit model grafting small pieces of myometrium into a pre-inserted ear chamber and through electrodes and implantation of a radiotransmitter was able to map out the activity pattern during different reproductive phases, in the freely moving rabbit. This was a pioneering breakthrough in use of telemetry in biological studies. At this point he became assoc. professor at the Department of Medical Physiology, University of Copenhagen and began making teaching courses in reproductive physiology. After his first meeting with Bill Masters in St. Louis he got fascinated by the many intriguing and unsolved questions in genital physiology. With a group of colleagues from other disciplines he constructed a 35 hs long course in sexology for medical students and produced two educational films on the physiological responses to sexual stimulation in the laboratory. This period was followed by high

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activity in research of vaginal function in his lab. in close collaboration with the British physiologist Roy Levin and later with Bent Ottesen, who conducted studies of VIP and its activity in genitals of the female. But soon penile erection and erectile dysfunction came into focus. Description of a series of new investigations: dynamic cavernosography with stimulation, Xenon wash out, vibration test ect. were done in collaboration with Ebbehøj, Uhrenholdt and later Metz. A major step was taken when he and Brindley tried out the effect of atropine, propanolol, phenoxybenzamine and metyldopa on normal erection and thereby started the thinking of pharmacological intervention. With Richard Green he published the first monography on Impotence in 1981, studied the effect of tampons on vaginal milieu showing that oxygen could be one of the causes for development of Toxic Shock Syndrome and published anatomical studies of the penis. He gradually became involved in organisational work as a consultant to WHO, within the International Academy of Sex Research as president, the formation of International Society for Impotence Research (ISIR) and its president from 1988 to 1994. In 1989 he became founding co-editor-in-chief of the International J. Impotence Research (IJIR) and still serves the journal. Extensive international connections made him a valued speaker and educator and industry has made use of his deep knowledge of the field of erectile dysfunction. He has his Ph.D from San Francisco in sexology and co-authored a book on injection therapy with Helen Kaplan. Beside his academic endeavours he was an early activist in the fight against torture and part of the Danish Medical group who pushed this issue into the international political scene. Together with his wife Helle Larsen, Ph.D, an extensive work with torture victims and rehabilitation has been carried out internationally especially with sexually tortured persons. Recently he has started up a new clinical and experimental division of Sexual Physiology in collaboration with the Sexology Clinic at the University Hospital in Copenhagen. Although a citizen of the world he sticks to his roots and nourishes his creativity on his remote, peaceful farm in Jutland - breeding cattle.

ALAIN JARDIN SAAD KHOURY

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CONTENTS FOREWORD BY A. JARDIN

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PR G. WAGNER President of the Ist International Consultation on

Erectile Dysfunction

1 Epidemiology and Natural History of Erectile Dysfunction ; Risk Factors including Iatrogenic and Aging R. L EWIS, D. HATZICHRISTOU, E. LAUMANN, J. MCKINLAY

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2 Economical Aspects of Erectile Dysfunction R.SHABSIGH, L. ALEXANDRE,, H. BAY NIELSEN,, J. FITZPATRICK,, H. MELCHIOR

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3. Anatomy, Physiology and Pathophysiology of Erectile Function

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I. SAENZ DE TEJADA, N. GONZALES CADAVID, J. H EATON, H. H EDLUND, A. N EHRA, R.S. P ICKARD, U. S IMONSEN, W. STEERS

4 Symptom Score and Quality of Life

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G. WAGNER, A. BÉJIN, A. R. F UGL-MEYER, S. G LINA, Y. KIMOTO, C.S.B LUKACS, J. M ULCAHY, M. O’L EARY,

5 Clinical Evaluation and the Doctor-Patient Dialogue

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E. MEULEMAN, G.BRODERICK, F. MONTORSI, I.SHARLIP, H.MENG TAN, Y.VARDI

6 Current Research and Future Therapies

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K-E ANDERSSON, AL BURNETT, KK C HEN, GJ C HRIST, O R AMPIN, C STIEF

7 Endocrine and Metabolic Aspect including Treatment

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Y. C. KIM, J. BUVAT, C.C CARSON, L.J G OOREN, J. J AROW, J. RAJFER, A.VERMEULEN

8. Oral non endocrine treatment

241

R. KRANE, G. BROCK, I. EARDLEY, F. FOURCROY, A.GIULIANO, C.HUTTER, M.TELOKEN, M. VICKERS

9 Local Pharmacological Treatment Modalities R.Virag, E. BECHER, S. CARRIER, F. GOVIER, K. MC VARY, H.C. MCMAHON, H. P ORST

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305

10 Surgical Treatment and Mechanical Devices

355

U. JONAS, C. EVANS, S. K RISHNAMURTI, D. M ONTAGUE, J. P. SARRAMON, M. SOHN, E. W ESPES, H. W ESSELLS

11 Psychological Issues in Diagnosis and Treatment

405

A. MELMAN, S. LEVINE, B. SACHS, T. SEGRAVES, M.F. VAN DRIEL

12 Peyronie’s Disease

437

T.F. LUE, M.K. GELBARD, G.GUEGLIO, G.H. J ORDAN, L. A. L EVINE, R. MORELAND, J. P RYOR, D. R ALPH, D. YACHIA

13 Male Orgasmic and Ejaculatory Disorders

477

W.F. HENDRY, S.E. ALTHOF, G.S. B ENSON, S.M. H AENSEL, E.M. HULL, K. K IHARA , R.J. O PSOMER

14 Female Sexual Dysfunction

507

I.GOLDSTEIN, A. GRAZIOTTIN, J. R. HEIMAN, C. J OHANNES, E . L AAN, R. L. L EVIN, K. E. MCKENNA,

15 Priapism

557

W. STACKL, P. BONDIL, R. C ARTMILL, D. KNOLL, E.S. P ESCATORI

16 Socio-Cultural, Educational and Ethical Aspects of Erectile Dysfunction

573

A. MORALES, H. CHOI, A. GIAMI, C. G INGELL, B. J OHNSTON, W. PASINI, L. VELA-RODRIGUEZ, C. SAMKANGE, A. SCHMIDT, F. UGARTE, G. W ILLIAMS

17 Neurological Disorders: Erectile and Ejaculatory Dysfunction

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P.O. LUNDBERG, N.L. BRACKETT, P. DENYS, E. C HARTIER-KASTLER, J. SØNKSEN, D. B. V ODUSEK

18 Standards for Clinical Trials in Erectile Dysfunction: Research Designs and Outcomes Assessment

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R. ROSEN, A. BENNETT, D. F ERGUSON, M. H IRSCH, H. PADMA-NATHAN, M. W YLLIE.

Illustrated Atlas

679

D. HATZICHRISTOU

Recommendations of the 1st International Consultation on Erectile Dysfunction 709

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ERECTILE DYSFUNCTION EDITORS A. JARDIN - G. WAGNER - S. KHOURY F. GIULIANO - H. PADMA-NATHAN - R. ROSEN

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Committee 1

Epidemiology and Natural History of Erectile Dysfunction ; Risk Factors Including Iatrogenic and Aging

Chairman R. LEWIS

Members D. HATZICHRISTOU, E. LAUMANN, J. MCKINLAY

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CONTENTS

6. C ARDIOVASCULAR DISEASE AND HYPERTENSION

I. INTRODUCTION

7. M EDICATIONS AND RECREATIONAL DRUGS II. WORLDWIDE PREVALENCE OF ERECTILE DYSFUNCTION

8. S URGERY AND TRAUMA 9. THE EFFECT OF MODIFICATION OF RISK FACTORS

1. UNITED STATES AND OTHER NORTH AMERICAN STUDIES

V. CONCLUSIONS

2. EUROPEAN STUDIES 3. ASIAN STUDIES

VI. RECOMMENDATIONS

4. AUSTRALIAN STUDIES III. NATURAL HISTORY AND INCIDENCE STUDIES

APPENDIX A

APPENDIX B IV. RISK FACTORS APPENDIX C

1. G ENERAL RISK FACTORS 2. HORMONAL OR ENDOCRINE (INCLUDING “ANDROPAUSE”) 3. SMOKING OR OTHER TOBACCO USE 4. DIABETES MELLITUS 5. O THER CHRONIC DISEASE

APPENDIX D

REFERENCES

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Epidemiology and Natural History of Erectile Dysfunction ; Risk Factors Including Iatrogenic and Aging R. LEWIS D. HATZICHRISTOU, E. LAUMANN, J. MCKINLAY calculated in two ways – prevalence and inciden ce [3]. The former refers to the number of people who have the disorder at a given time and can be further characterized as current or lifetime prevalence. Prevalence rates, in fact, can be determined for any time duration but are commonly expressed as years or lifetime. Current prevalence reveals the percentage of people experiencing the disor der at the time of the assessment. Lifetime preva lence measures the percentage of people ever experiencing the disorder, even if they are no lon ger experiencing it. Incidence refers to the num ber of new cases of a disorder occurring in a spe cific population during a discrete period of time. These concepts are discussed in more detail in the introduction section of a critical review of empirical literature regarding incidence and prevalence of sexual dysfunction in men and women published in 1990 by Spector and Carey [3]. Twenty-three studies appearing over the fifty years prior to that publication are included in their report.

I. INTRODUCTION The 1993 National Institutes of Health (NIH) Consensus Conference on Impotence suggested erectile dysfunction as the appropriate term for this male sexual dysfunction rather than impotence [1]. The disorder is defined as the following: the inability to obtain and/or maintain penile erection sufficient for satisfactory sexual performance. Consistency and degree are important words missing in this definition. Adding these words provides a flexibility that has resulted in attempts to assign erectile dysfunction further into minor, moderate, and severe categories. However, by adding consistency, the duration of time for the disorder is mandatory, since there are instances of temporary failures that spontaneously resolve. Erectile dysfunction can be further classified as primary (life-long) or secondary. Thus, differences in definition affect the ability to compare different articles on epidemiology of erectile dysfunction. In fact, Boyle states in his recent chapter on the epidemiology of erectile dysfunction that the lack of a unifying definition is a fundamental problem for this disorder that requires resolution.[2]. He states further that it should be a priority to establish a system of classification after determination of the severity and ‘cause’ of erectile dysfunction. The two components of epidemiology, descriptive epidemiology (incidence and prevalence by per sons, place and time) and analytical epidemiolo gy (the search for disease risk that may serve to increase prospects for prevention) are the key components of this chapter [2].

Another consideration in developing this chapter is the source of the populations studied. Discussions of medical disease consist of people seen for the disorder in a hospital, clinical offices or those in community-based populations screened for the disorder by questionnaires or other methods. Both are potentially useful for different reasons but community studies are more popular recently for the definition of the potential number of patients who suffer from this disorder who might benefit from treatment. A community sample should be truly representative with social, cultural, and health status data available to validate the repre sentative nature of the group sampled. The frequency of the disorder generated from self reports

The occurrence rates of erectile dysfunction are

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is suspect and consequently will bias any epidemiological study that would investigate the etiology of the phenomenon [2]. To more clearly define the natural history of this disorder and to examine the effects of aging on erectile dysfunction, longitudinal studies as opposed to cross-sectional studies are needed. Longitudinal studies allow better definition of incidence of the disorder and facili tate sorting out confounding effects.

due to lack of awareness because the condition is asymptomatic or undiagnosed. Moreover, self reports vary in their ability to tap accurately the health condition of interest since these indicators may also capture alternate causes. There are only three population-based surveys of erectile dysfunction known in the literature, but only two of these use modern probability-based sampling strategies. Alfred Kinsey (1948) reported on erectile dysfunction based on his large and broadly selected sample, but he explicitly rejected the notion that randomly drawn samples could be drawn to study sensitive sexual phenomena and thus relied on volunteer samples from an ill-defined region of northern Indiana and the Chicago area plus additions [4]. It is well known that volunteer samples are biased in favor of those specially interested in the phenomena under investigation – in this case sexual behavior, and are therefore likely to overestimate the incidence and prevalence of various behaviors and conditions related to sexuality [5]. Estimates from Kinsey’s work can only be taken as suggestive and cannot reliably be used in systematic, over-time comparisons.

Studies of erectile dysfunction draw their sample populations in two fundamentally different ways. Each method has definite strengths and weaknesses that should be kept clearly in mind when assessing information in hand. The first method, clinical studies, recruits samples from patients who attend clinics because they have or suspect they have a particular health problem. Boyle has reviewed some of the data on erectile dysfunction from such sources [2]. Constituting the vast preponderance of available empirical studies on erectile dysfunction, such studies can reveal a great deal about the nature of erectile dysfunction in particular patients, even with concomitant disease processes like hypertension or diabetes. These studies offer the opportunity to collect carefully monitored physiological and biologically relevant tests, physical examinations and case histories that permit the exploration of complex etiologies and courses of dysfunction. One must realize, however, that these samples, drawn from the population at large in highly biased or selective ways, are difficult or impossible to gauge or evaluate. They can tell us little about the incidence or prevalence of the problem in the population at large.

The other two surveys are recent and use modern probability sampling techniques. The Massachu setts Male Aging Study (MMAS), consisting of 1,709 free-living, non-institutionalized men bet ween the ages of 40 and 70 living in the greater Boston area in 1987 to 1989 at base line, gathered extensive physiological measures, demographic information, and self-reported erectile functional status [6]. Because of the rigorous requirements for collecting blood samples from the respondents early in the morning, the length of time required, and the usual difficulties of recruiting male respondents, the sample completion rate is only 53%, raising some concerns about possible biases in participation. Another important feature of the MMAS is its longitudinal character, the followup sample succeeded in re-interviewing 1,290 persons some 8 years later, thus affording an opportunity to estimate incidence as well as prevalence rates. The National Health and Social Life Survey (NHSLS) is a national probability survey of 1,410 men and 1,749 women between the ages of 18 and 59 years living in households throughout the United States in 1992 [5,7]. It accounts for about 97% of the population in this age range – roughly 150 million Americans. It excludes people living in group quarters such as

The second method, probability-based surveys, recruits representative (cross-section) samples of well-defined populations at large. These samples are defined independently from the health condition of interest – that is, both healthy and afflicted persons are included in the sample in direct pro portion to their prevalence in that population universe. A central problem in these types of studies is the validity and reliability of identification of those who have the health condition and those who do not. The problem arises because the rich array of diagnostic techniques available in clinical studies are not practicable in most population surveys which forces reliance on self-reports. Self reports have a well-known biases of under-reporting due to concerns about social stigmatization or 22

barracks, college dormitories, and prisons as well as those who do not know English well enough to be interviewed. The sample completion rate was greater than 79%. While the central focus of the MMAS was on impotence among aging males, the NHSLS is principally directed to a broadranging inquiry into US sexual practices and beliefs among younger adults. Consequently, it collected only limited information on sexual dysfunction broadly defined and physical heath conditions. The two surveys complement one another rather nicely. The MMAS provides detailed opportunities to investigate the relevance of changing hormonal levels across ages on erectile functioning but with a limited capacity to generalize to the country as a whole. In contrast, the NHSLS has limited information on erectile dysfunction per se but has the capacity to place information in a much broader perspective of US demographics and sexual dysfunction. When the findings of these two studies overlap, they are remarkably consistent.

men who responded positively to the question of impotency estimated the percent of the erection achieved. Thirty-nine point eight percent had no erection at all, 26.1% had 1% to 50%, and 21.5% had 51% to 75% of a normal erection. Twelve point five percent were able to achieve 75% to 100% of a normal erection, but were unable to maintain their erection [9]. The Baltimore Longitudinal Study of Aging reported that, by the age of 55 years, impotence was present in 8% of healthy men. For 65, 75, and 80 year old men, the prevalence of impotence was 25%, 55%, and 75% respectively [10]. The MMAS study was the first cross-sectional, community-based, random-sample multidiscipli nary epidemiological survey on impotence and its physiological and psychosocial correlates in men. The design of the study, with four groups of intervening variables (sociodemographic and psychosocial characteristics, health status and lifestyle characteristics), permitted precise estimation of key parameters while controlling for potentially important confounders [6]. The ages of men studied in the MMAS study ranged from 40 years to 70 years of age. The MMAS sexual activity questionnaire included 9 items related to potency (Appendix A.) with 1,290 of the 1,709 male subjects (75%) providing a complete response. (See Table 1 for characteristics of the population studied.) In the MMAS study, the prevalence of impotence of all degrees was 52% (minimal at 17.2%, moderate at 25.2%, and complete at 9.6%) (Figure 1a). Extrapolating these numbers, it was estimated that about 18 million men are impotent in the United States. The MMAS instrument was linked to a direct assessment of potency by means of a separate calibration study in a subset of 303 men to categorize impotency as minimal, moderate, complete, or the participant as not impotent. [11] (Table 2). Between the ages of 40 and 70, the probability of complete impotence increased from 5.1% to 15% and moderate impo tence from 17% to 34%. Over the same age range, the probability of minimal impotence remained constant at about 17%. An estimated 60% of the men were not impotent at age 40 years, decreasing to 33% at age 70 (Figure 1b).

II. WORLDWIDE PREVALENCE OF ERECTILE DYSFUNCTION 1. UNITED STATES RICAN STUDIES

AND

OTHER NORTH AME-

Before the MMAS and NHSLS reports, the most extensive population-based source of normative data on male sexual behavior in the United States was the forty year old Kinsey report [4,8]. In Kinsey’s report, erectile dysfunction was reported in 42% of a sample of 5460 white and 177 black males and negatively correlated with age, that is the older the participant the higher the prevalence of erectile dysfunction. However, only 306 of the 15,781 men reported in this study were older than 55 years and only 4,108 were older than 25 years. In contrast, Spector and Carey’s review of articles published in the English language up to 1990, the prevalence of erectile difficulties in community studies was estimated to be between 3% and 9% [3]. In all such studies, prevalence increased with age. Another study of a community population 60 years or older in Michigan showed a prevalence of erectile dysfunction of 38.3% in married men and 51.2% in the other marital categories, 40.3% overall [9]. Eighty-eight percent of the 92 married

The recently published report by Laumann et al identified prevalence and predictors of erectile dysfunction along with other sexual dysfunction in 23

Table 1: Physical, medical and socio-demographic characteristics of 1,290 MMAS subjects included in study of impotence PHYSICAL MEASURES:* Age (yrs.) 53.8± 8.5 Ht. (inches) 69.1± 3.0 Wt. (pounds) 186.7± 31.5 Body mass index (kg/m 2) 27.5± 4.4 Serum cholesterol (mg/dl) 209±49 Physical activity (kcal/kg/day) 48.2±15.2 CIGARETTE SMOKING: Current smokers # 286 Cigarettes/day (smokers only)* 25.0± 15.1 Passive smoking at work # 475 Passive smoking at home # 366 MEDICAL CONDITIONS: # Diabetes: Not treated 36 Treated 52 Heart disease: Not treated 65 Treated 90 Hypertension: Not treated 176 Treated 200 Arthritis: Not treated 228 Treated 76 Allergy: Not treated 261 Treated 67 Ulcer: Not treated 98 Treated 31

MEDICATIONS: # Cardiac Antihypertensive Lipid-lowering Hypoglycemic agents Vasodilator Sympathetic SOCIO-DEMOGRAPHICS: # Married Have sexual partner‡ Living alone Employed Depressed Belonging to social groups Emotional support available RACE: # White Black Other EDUCATION: Below high school Completed high school Beyond high school Bachelor’s degree Graduate study or degree

(22) (38) (28)

(3) (4) (5) (7) (14) (16) (18) (6) (20) (5)

112 140 21 49 53 28

(9) (11) (2) (4) (4) (2)

1,082 1,290 112 1,061 120 706 1,196

(84) (100) (9) (82) (9) (55) (93)

1,240 28 22

(96) (2) (2)

125 205 377 174 409

(10) (16) (29) (13) (32)

*Mean « standard deviation # Number of patients (%) ‡ Criterion for inclusion in impotence substudy From: Feldman et al. J Urol 1994, 151: 54-61.

(8) (2)

Table 2: Self-rated impotence in calibration sample (303 subjects) related to sexual activity questions from MMAS Not Impotent

Minimally Impotent

Moderately Impotent

Completely Impotent

116

41

92

54

Sexual activity•

8

7

3

0

Full erection •

30

30

4

0

Awaken with erection •

10

10

3

0

No activity within last 6 mos. (%)*

2

7

20

61

Trouble getting erection (%)*

5

50

85

90

Trouble keeping erection(%)*

5

63

95

96

Satisfaction with frequency of activity (%)

65

46

15

17

Satisfaction with sex life#

1.6

3.0

4.1

4.6

Satisfaction with partner#

1.3

2.2

3.2

3.7

Partner satisfaction

1.5

2.6

3.5

4.1

No. subjects

•Median frequency/month *Among those reporting some sexual activity within last 6 months # Mean on scale from 1 (extremely satisfied) through 5 (extremely dissatisfied) From: Feldman et al. J Clin Epidem 1994: 47:457-467.

24

Figure 1 a: Prevalence of erectile dysfunction

Figure 1 b: Association between age and prevalence of erectile dysfunction

American men and women [7]. This report ana lyzes data on sexual dysfunction from the Natio nal Health and Social Life Survey (NHSLS) conducted in 1992 [5]. (Tables 3a-c and Appendix B) This is a national probability sample of 1410 men and 1749 women between the ages of 18 and 59 years living in households through the United States. In response to questions regarding trouble maintaining or achieving an erection, the following prevalence rates for age categories were reported: 7% for ages 18-29 years, 9% for 30-39 years, 11% for 40-49 years, and 18% for 50-59 years. While martial status affected preva-

lence rate (those married having a lower risk for erectile dysfunction), educational level did not affect the rate, although there was a slightly greater prevalence in those with an education level less than high school. The prevalence rate for erectile problems was less in Hispanics (5%) than White (10%), Black (13%), or other race or ethnic group (12%). (See Table 3c) Men who experience emotional or stress problems, urinary tract symptoms, and have poor health are more likely to have erectile dysfunction. Deterioration in economic position, indexed by falling household income, is associated with a higher prevalence of erectile difficul25

Table 3a: Prevalence of dysfunction items by demographic characteristics (Men)* PREDICTORS

LACKED INTEREST IN SEX Adjusted OR No. (%)

TOTAL

(95% CI)

1249

UNABLE TO ACHIEVE ORGASM Adjusted OR No. (%)

(95% CI)

1246

AGE 18-29

56 (14)

Referent

28 (7)

Referent

30-39

52 (13)

1.52 (0.95-2.42)‡

28 (7)

1.31 (0.71-2.40)

40-49

45 (15)

2.11 (1.23-3.64)#

26 (9)

1.79 (0.90-3.55)‡

50-59

30 (17)

2.95 (1.60-5.44)#

15 (9)

1.74 (0.79-3.83)

Married

77 (11)

Referent

49 (7)

Referent

Never married

71 (19)

2.75 (1.74-4.36)#

31 (8)

1.55 (0.86-2.79)

Divorced, separated, widowed

31 (18)

1.69 (1.05-2.73)#

15 (9)

1.29 (0.69-2.39)

Less than high school

30 (19)

Referent

18 (11)

Referent

High school graduate

42 (12)

0.61 (0.35-1.05)‡

25 (7)

0.62 (0.31-1.21)

Some college

65 (16)

0.88 (0.53-1.47)

32 (8)

0.68 (0.35-1.30)

College graduate

44 (14)

0.71 (0.40-1.24)

22 (7)

0.55 (0.27-1.12) ‡

White

134 (14)

Referent

68 (7)

Referent

Black

27 (19)

1.30 (0.67-1.90)

13 (9)

1.14 (0.57-2.26)

Hispanic

12 (13)

0.94 (0.47-1.86)

8 (9)

1.24 (0.54-2.83)

Other

10 (24)

2.02 (0.94-4.32)‡

8 (19)

2.83 (1.24-6.50) #

MARITALSTATUS

EDUCATION

RACE OR ETHNICITY

*Data from National Health and Social Life Survey. Estimated ratio of odds of reporting a given symptom for members of the specific group to odds for reference group. Derived from logistic regression models performed on respondents with at least 1 partner during the 12 month period prior to the survey. The model includes all predictor variables as well as controls for religious affiliation and residence in rural, suburban, or urban areas. Percentages are derived from respondents in each category, and the total number represents those who responded to the questions. OR indicates odds ratio; CI is confidence interval. (Laumann et al. JAMA 1999, 281(6):540) [7] # P≤ .05 ‡ P≤ .10

26

Table 3b: Prevalence of dysfunction items by demographic characteristics (Men)* PREDICTORS

TOTAL

CLIMAX TOO EARLY Adjusted OR No. (%) 1243

(95% CI)

SEX NOT PLEASURABLE Adjusted OR No. (%) 1246

(95% CI)

AGE 18-29

121 (30)

Referent

39 (10)

Referent

30-39

122 (32)

1.01 (0.72-1.42)

30 (8)

0.95 (0.54-1.69)

40-49

83 (28)

0.88 (0.60-1.30)

25 (9)

1.04 (0.54-2.01)

50-59

55 (31)

0.95 (0.61-1.49)

10 (6)

0.73 (0.31-1.69)

Married

214 (30)

Referent

41 (6)

Referent

Never married

111 (29)

0.95 (0.68-1.33)

40 (11)

1.80 (1.02-3.18)#

Divorced, separated, widowed

54 (32)

1.12 (0.77-1.62)

21 (13)

2.27 (1.27-4.04)

Less than high school

61 (38)

Referent

22 (14)

Referent

High school graduate

125 (35)

0.91 (0.61-1.35)

21 (6)

0.35 (0.17-0.68)#

Some college

106 (26)

0.58 (0.39-0.87)#

39 (9)

0.59 (0.32-1.08)‡

College graduate

87 (27)

0.65 (0.42-1.00)#

21 (6)

0.44 (0.22-0.88)#

White

290 (29)

Referent

70 (7)

Referent

Black

49 (34)

1.14 (0.75-1.72)

23 (16)

2.33 (1.29-4.20) #

Hispanic

25 (27)

0.78 (0.46-1.31)

7 (8)

0.95 (0.40-2.29)

Other

17 (40)

1.63 (0.86-3.09)

4 (9)

1.29 (0.44-3.82)

MARITALSTATUS

EDUCATION

RACE OR ETHNICITY

*Data from National Health and Social Life Survey. Estimated ratio of odds of reporting a given symptom for members of the specific group to odds for reference group. Derived from logistic regression models performed on respondents with at least 1 partner during the 12 month period prior to the survey. The model includes all predictor variables as well as controls for religious affiliation and residence in rural, suburban, or urban areas. Percentages are derived from respondents in each category, and the total number represents those who responded to the questions. OR indicates odds ratio; CI is confidence interval. (Laumann et al JAMA1999, 281 (6):540-541 [7]. #P≤.05 ‡ P≤ .10

27

Table 3c: Prevalence of dysfunction items by demographic characteristics (Men)* ANXIOUS ABOUT PERFORMANCE

PREDICTORS

No. (%)

TOTAL

1247

Adjusted OR

TROUBLE MAINTAINING OR ACHIEVING AN ERECTION Adjusted OR

(95% CI)

No. (%)

(95% CI)

1244

Age 18-29

77(19)

Referent

30 (7)

Referent

30-39

65 (17)

0.98 (0.65-1.48)

35 (9)

1.46 (0.84-2.57)

40-49

55 (19)

1.09 (0.68-1.75)

31 (11)

1.84 (0.97-3.47)‡

50-59

25 (14)

0.87 (0.49-1.54)

31 (18)

3.59 (1.84-7.00) #

Married

98 (14)

Referent

65 (9)

Referent

Never married

78 (21)

1.71 (1.14-2.56) #

37 (10)

1.73 (1.00-2.97) #

Divorced, separated, widowed

45 (26)

2.29 (1.51-3.48) #

24 (14)

1.61 (0.96-2.71)‡

Less than high school

37 (23)

Referent

21 (13)

Referent

High school graduate

65 (18)

0.68 (0.42-1.10)

32 (9)

0.64 (0.34-1.18)

Some college

77 (19)

0.70 (0.44-1.13)

43 (10)

0.76 (0.42-1.38)

College graduate

41 (13)

0.49 (0.28-0.83)#

31 (10)

0.66 (0.35-1.26)

White

173 (18)

Referent

98 (10)

Referent

Black

35 (24)

1.22 (0.76-1.95)

19 (13)

1.21 (0.67-2.17)

Hispanic

5 (5)

0.24 (0.09-0.61)#

5 (5)

0.53 (0.20-1.39)

Other

9 (21)

1.33 (0.61-2.90)

5 (12)

1.17 (0.44-3.12)

MARITALSTATUS

EDUCATION

RACE OR ETHNICITY

*Data from National Health and Social Life Survey. Estimated ratio of odds of reporting a given symptom for members of the specific group to odds for reference group. Derived from logistic regression models performed on respondents with at least 1 partner during the 12 month period prior to the survey. The model includes all predictor variables as well as controls for religious affiliation and residence in rural, suburban, or urban areas. Percentages are derived from respondents in each category, and the total number represents those who responded to the questions. OR indicates odds ratio; CI is confidence interval. (Laumann et al. JAMA1999, 281(6):541 [7] #P≤.05 ‡ P≤ .10

28

ties. Interestingly, men who were victims of adultchild contact and men who have sexually assaulted women were 3.3 times as likely to report erectile dysfunction. Men with erectile dysfunction experience diminished quality of life as measured by multiple indicators, including happiness, physical health status, and physical and emotional satisfaction with sexual partners.

For comparative purposes, it is worth knowing how the five other dysfunctions co-exist with erectile dysfunction. The respondent checked as many dysfunctions as applied to him. Thus, the conditional probability of having a particular dysfunction can be determined, given that the man also has an erectile dysfunction. Accounting for the prevalence of the other dysfunction in question allows the computation of the odds of having sexual dysfunction A and erectile dysfunction against the odds of having erectile dysfunction alone (Table 4).

Sexual dysfunction was indexed in the NHSLS according to 7 dichotomous response items, each measuring presence of critical symptoms or problems during the past 12 months. Response items included:

Table 4: Odds ratios of both sexual dysfunction A and erec tile dysfunction versus erectile dysfunction.

1) lack of desire for sex; 2) arousal difficulties (i.e. erection problems in men, lubrication difficulties in women);

Climax too early Lack of interest in sex

4.06 4.58

3) inability to achieve climax or ejaculation;

Experienced pain during sex

7.46

4) anxiety about sexual performance;

Sex not pleasurable Anxious about performance

7.69 10.53

5) climaxing or ejaculating too rapidly;

Unable to achieve orgasm

14.24

6) physical pain during intercourse; and

From Laumann et al 1999[7]

7) not finding sex pleasurable.

Jonler and colleagues used a self administered questionnaire for assessing potency during a free screening program of prostate cancer in three different locations in the United States - Madison, WI, New York, NY, and New Orleans, LA.[12] 1517 of 1680 men responded to the questionnaire (90.3%). Of the men responding, 70.4% were Caucasian, 24.9% African-American, 3.1% Hispanic, 1.2% Arabic and 0.4% reported as other races. One hundred twenty-nine (7.7%) of the responding men had not had any erections during the previous 12 months. The 1388 men who reported an erection in the previous 12 months were asked a second question requesting more detail of their ability to have erections during the past month. 12.4% of these had erections on less than one occasion in five. The percentage of this response increased with age with 10% of those age 50-59 having erections on less than one occasion in five to 40% of men age 70-79 with the same answer. Vice versa, 60% of men age 50-59 usually had erections with sexual stimulation while only 20% of men age 70-79 gave a similar response. Another 7.3% of the entire group reported inability to have an erection less than half of the time when sexually stimulated in any way. There was no demonstrable difference between ethnicity and response to the two questions regarding potency.

(The NHSLS measure of erectile dysfunction, because it asks the respondent to identify a pro blem of at least several months duration, seems roughly equivalent to the MMAS’ definition of complete impotence. For the men aged 40 to 59 in both samples, self-reported erectile dysfunction rates are roughly comparable). Table 3 outlines the prevalence of six male dysfunction items by demographic characteristic, including age, marital status, education, and race or ethnicity. The adjusted odds ratios in the table take into account all the demographic predictors plus controls for religious affiliation and residence in rural, suburban or urban areas. Note that, except for marital status and age, the other demographic characteristics are unrelated to the prevalence of erectile dysfunction. For comparative purposes, it is worth noting that there are differential distributions of the other sexual dysfunctions across demographic categories. It is also worth noting that while erectile dysfunction is clearly related to age, the crude prevalence of erectile dysfunction among 18 to 29 year olds stands at 7%. This is likely to be under-estimated because of the strong social concerns about stigmatization among the younger men. 29

questionnaire that included general data and questions regarding urinary incontinence and other urologic symptoms, including impotence [15]. The source of the population sample consisted of men born on odd dates every five years from 1912-1947. The response rate varied from a low of 69% for the birth cohort 1907 to a high of 80% for the birth cohort 1922. Overall response rate was 74.2%. There was an overall impotence prevalence rate of 7.6% ranging from 1.5% for age 45 yrs. to 17.8% for age 80 yrs. with a steady increase for each succeeding five years of age. There was also a linear decrease in sexual activity with increasing age with 76.1% reporting being sexually active for age 45 to 16.7% for age 80. Reported prevalence of regular sexual activity overall was 50.1%.

2. EUROPEAN STUDIES In a small sample of 109 men in a British survey (representing 25% of solicited population, predominately biased toward the better educated social classes) published in 1996, 32% reported some problem in obtaining an erection during foreplay with their partner [13]. Twenty per cent had some difficulty maintaining an erection long enough to have intercourse with their partner ( see Table 5). In 1993, a Danish study of 411 men aged 51 years, the prevalence of erectile dysfunction was determined by a questionnaire. One hundred of these same men were subsequently interviewed [14]. In the questionnaire, 16 (4%) of the 411 men reported having suffered from erectile dys function on more than a few occasions during the previous year. Another 61 (15%) reported only occasional erectile dysfunction. None of the 16 men had a subsequent interview. Although none of the 100 men interviewed reported suffe ring from erectile dysfunction on more than a few occasions during the previous year on the questionnaire, 7 reported erectile dysfunction on more than one occasion at the time of the inter view. At the time of the interview, another 16 reported impaired erection of other kinds, such as “too soft”, “too slowly erecting”, or “too fast decreasing”. In this survey, almost 40% of the men felt that they suffered from some sort of sexual dysfunction. However, only 7% considered the problem abnormal for their age, only 5% plan ned to consult a therapist and only 2% conside red their sexual problem to be part of a disease.

In 1999, Fugl-Meyer and Sjogren Fugl-Meyer presented data from a Swedish study on sexual disabilities in 2810 respondents aged 18 to 74 (1,475 who were men). This study used structured questionnaires and check-lists with structured face-toface interviews conducted by trained professional interviewers [16] (See Table 6). Of the 4,781 patients chosen to participate in the study 1,971 declined to participate or could not be located (approximately 100 of the 1,971) for a 41% dropout rate. Only 5% of the 1,288 men responding to questions regarding erectile function reported sexual disability (in the categories of quite often, nearly all the time, or all the time for erectile disability). Erectile disability was age dependent (Table 6). The authors reported that in the 5% of men with erectile disability, 69% felt that this was a problem for them and of those with this perception, 75% were not sexually satisfied. In the dis-

In 1997, in an epidemiological study in Goteberg, Sweden, 10,458 men were invited to respond to a Table 5: Erectile functioning (n = 93; missing data = 16) * PERCENTAGE TOTAL

PERCENTAGE TOTAL

Do you get an erection during

Can you keep an erection long enough

foreplay with your partner

to have intercourse with your partner

Never

0

Never

0

Occasionally

3

Occasionally

1

Half of the time

1

Half of the time

1

Most of the time

28

Most of the time

18

All of the time

68

All of the time

80

*From: Spector and Boyle. British J Med Psych, 1996, 59: 3510-3518. [3]

30

Table 6: Prevalence of erectile dysfunction in a nationally representative swedish population by Age-Cohorts* AGE COHORTS

RESPONDENTS N

ERECTILE DISABILITY %

18 – 24

251

3

25 – 34

331

2

35 – 49

435

2

50 – 65

339

7

66 – 74

119

24

* From: Fugl-Meyer and Sjogren Fugl-Meyer. Scandinavian Journal of Sexology 1999, 2:79-105. [16]

cussion section of this report, the authors present prevalence rates of 7.5% for erectile dysfunction in French men between the ages of 18 and 69. The French study, conducted by Giami, was reported to be in press. The authors also mention two other Scandinavian studies of erectile dysfunction, one from Finland and one from Denmark, with similar prevalence rates for erectile dysfunction.

eight of the practices recorded the number of the questionnaires distributed and of the 1697 distributed, 1100 were returned to the institute conducting the study for a response rate of 64.8%. The other 309 questionnaires were received from 24 participating doctors who did not record the number of questionnaires distributed. Prevalence data were similar in both sources of questionnaires. Of these 1409 returned questionnaires, 169 men opted not to participate in the study producing a participation rate of 88%. 39.4% of those returning the questionnaires reported erectile dysfunction in the following categories: 119 (9.6%) occasionally, 110 (8.9%) often, and 231 (18.6%) all the time with 30 men (2.3%) giving no indication of severity. Among the 707 men aged 40-69 the prevalence of erectile dysfunction was 33.9% (240 men) and 11.9% had complete impotence. The prevalence of erectile dysfunction increased with age from 2% in those 40-49 years of age to 44.9% in those in the 70-79 year age group. Only 11.6% of those reporting erectile dysfunction on this questionnaire had received treatment for the disorder. Hypertension, ischemic heart disease, peripheral vascular disease, and diabetes mellitus were frequently associated with erectile dysfunction.

Bejin evaluated questions regarding premature ejaculation and erectile dysfunction from analysis of a larger survey of sexual lifestyles conducted in France that had been reported in 1992. The original survey was applied to 20,055 people aged 18-69 years. The prevalence rate for erectile dysfunction reported “often” was 7%, for erectile dysfunction reported as “often”, “sometimes”, or “quite seldom” was 47%. In men age 18-24 years, 11% reported erectile dysfunction alone and 22% reported erectile dysfunction and premature ejaculation. For those men 60-69 years of age, similar rates reported were 27% and 41% respectively [17].

3. ASIAN STUDIES Shirai et al estimated the prevalence rate of erectile dysfunction to be 26% in Japan. This rate is based upon a compilation of data regarding the number of men affected with conditions associated with erectile dysfunction and the estimated prevalence of erectile dysfunction in these populations [18].

III. NATURAL HISTORY AND INCIDENCE STUDIES There is a paucity of data due to the lack of lon gitudinal studies. However, data has recently become available from the Massachusetts Male Aging Study [20]. Analyses were performed on 847 men without erectile dysfunction at baseline (1987-89) and with complete follow-up informa tion (1995-97) using a random, population-based survey. The baseline average age of the 847 men

4. AUSTRALIAN STUDIES Astudy to determine erectile dysfunction prevalence by a questionnaire distributed to consecutive adult male attendees at 62 general medical practices was conducted in the metropolitan Perth area [19]. The mean age of participants was 56.4 years in the 1240 men completing the questionnaire. Thirty-

31

was 52.2 years (range 40-69). The crude inciden ce rate for erectile dysfunction was 25.9 cases/1000 man-years (95% confidence interval [CI], 22.5-29.9). The annual incidence rate increased with each decade of age (CI of 95% for all): 12.4 cases/1000 (9.0-16.9), 29.8 cases/1000 (24.0-37.0), and 46.4 cases/1000 (36.9-58.4) respectively for men aged 40-49, 50-59, and 60-69. Age-adjusted risk of erectile dysfunction was higher for men with lower education, diabetes (50.7 cases/1000 man-years), treated heart disea se (58.3 cases/1000) and treated hypertension (42.5 cases/1000). [20] Applying the MMAS incidence estimates to the population of men aged 4069 at risk in Massachusetts resulted in an expected 17,718 new cases of erectile dysfunction annually. The corresponding estimate for U.S. white men in the same age range is 617,715 new cases annually. Using data from the MMAS, the likely worldwide increase in erectile dysfunction between 1995 and 2025 has been published [21].

and has a number of medical applications, such as evaluation of diagnostic systems [25,26,27] and generation of epidemiological estimates using symptom data [28,29]. Latent class analysis tests whether a latent variable, specified as a set of mutually exclusive classes, accounts for observed covariation among manifest, categorical variables. By accounting for observed covariation among dysfunctional items, LCA, in essence, attempts to improve on construct validity that is more problematic when using information from only one survey indicator. These categories, then, represent a typology of disorders for sexual dysfunction found in the US population, indicating both prevalence and types of symptoms. Only those respondents reporting at least 1 part ner in the prior 12 month period were included in the LCA. This procedure may limit the results because excluded respondents may have avoided sex because of sexual problems. However, this procedure was necessary to ensure that each respondent answered all the symptom items since only three items were asked of sexually active respondents. One hundred and thirty-nine men were excluded on this basis. The excluded men were more likely to be single and have lower levels of education. We expect that this will bias the estimates of prevalence of sexual dysfunction downward since sexually inactive men generally reported higher rates of symptoms. With respect to erection problems, 14% of the excluded men reported this problem in comparison to 10% prevalence among men included in the analysis.

The lone published estimate of the incidence of erectile dysfunction is based on data from a convenience sample of 3,250 men aged 26-83 (mean 51) seen at a preventive medicine clinic at least twice between 1987 and 1991 [22]. The incidence for erectile dysfunction after 6-48 months follow-up (median 22 months) was 12 cases/1000 man years and was age-related. Incidence rates were 2.4 cases/1000 man years among men less than 45 to 52.3 cases/1000 man years among men over the age of 65. This population was healthier, younger, and followed for less time than the MMAS study. Erectile dysfunction was measured differently in the two studies - this study by one question in a lengthy medical history questionnaire and the MMAS study by discriminate analysis of 13 questions and a single global question. Both measures were self-reported.

The results of the LCA allow for analyzing risk factors and quality-of-life concomitants in rela tion to categories of sexual dysfunction, rather than individual symptoms. These results indicate that the clustering of symptoms according to syndrome can be represented by 4 categories of men. Latent class analysis also estimates the size of each class as a proportion of the total sample, a result corresponding to sexual dysfunction category prevalence in the US population. Finally, LCA identifies symptoms for each class, indicating the likelihood that respondents in that class will exhibit a given symptom, thus providing researchers with information about what elements characterize each category. Although not equivalent to clinical diagnosis, this approach offers a statistical representation of sexual dysfunction.

IV. RISK FACTORS 1. G ENERAL RISK FACTORS A latent class analysis (LCA) of the NHSLS data was used to evaluate the syndromal clustering of individual sexual dysfunctions or symptoms. (See Appendix C). Latent class analysis is a statistical method used to group categorical data into latent classes [23,24] 32

A large proportion of men (70% prevalence) constitutes an unaffected population. The remaining three classes consist of premature ejaculation (21% prevalence), erectile dysfunction (5% prevalence), and low sexual desire (5% prevalence). The LCA procedure estimates 5% overall prevalence rate for erectile dysfunction, a figure that is lower than the 10% estimate using the single indicator. The difference, explained by the lower validity of the latter, is likely to include other causes of the indicator unrelated to erectile dysfunction. Tables 7 and 8 present multinomial logistic regressions on categories of sexual dysfunction. Adjusted Odds Ratios (OR) indicate the relative risk of experiencing a given category of sexual dysfunction versus reporting no problems for each risk factor, while controlling for other characteristics.

same sex activity are more than twice as likely to experience premature ejaculation and low sexual desire. Male victims of adult-child contact or forced sexual contact are 3 times as likely to experience erectile dysfunction and approximately twice as likely to experience premature ejaculation and low sexual desire than those who have not been victims of adult-child contact. Finally, men who have sexually assaulted women are 3 times as likely to report erectile dysfunction. Indeed, traumatic sexual acts continue to exert profound effects on sexual functioning, some effects lasting many years beyond the occurrence of the original event.

2. HORMONAL OR ENDOCRINE (INCLUDING “ANDROPAUSE”) Androgens influence the growth and develop ment of the male reproductive tract as well as secondary sexual characteristics [30]. Their effect on libido and sexual behavior is well esta blished but the effect of androgens on the erecti le mechanism remains unclear [31,32]. The controversy is mainly due to the lack of a large study on hormones in a healthy aging male population. Serum levels of testosterone, prolactin, FSH and LH at various ages of man have been frequently studied in the literature [33,34]. Spark et al found neuroendocrine dysfunction in 1% of impotent men, while Slag et al reported hypogonadism in 19%, hypothyroidism in 5%, hyperthyroidism in 1% and hyperprolactinemia in 4% of 188 impotent patients with mean age of 60 years [35,36].

Table 8 classifies risk factors into three sets: health and lifestyle, social status, and sexual experience. Regarding health and lifestyle risk factors, those who experience emotional or stress-related problems are more likely to experience sexual dysfunctions defined in each of the categories. Men with poor health have elevated risk for all three categories of sexual dysfunction. The presence of urinary tract symptoms appears to impact premature ejaculation and erectile dysfunction. However, having a history of a sexually transmitted infection, moderate to high alcohol consumption, and circumcision generally do not result in increased odds of experiencing sexual dysfunction.

The MMAS constitutes the largest male endocri ne database presently available. It includes reliable measurement of 17 hormones, a complete hormonal profile [6,32]. Interestingly, testostero ne – either free, albumin-bound, total or DHT, was not statistically significantly correlated with impotence. This may be explained by the fact that any decline in testosterone with age may be due in large part to ill health, rather than a natural physiologic phenomenon [6].

Social status variables, which measure an individual’s socioeconomic and normative position relative to other persons, assess how sociocultural position affects sexual function. Deterioration in economic position, indexed by falling household income, doubles the likelihood of erectile dysfunction but has no association with the other two categories of male dysfunction. Men with liberal attitudes about sex are approximately 1 1/3 times more likely to experience erectile dysfunction and 1 3/4 more likely to experience premature ejaculation.

No correlation with impotence was found for any of 17 hormones measured, including FSH, LH, prolactin, androtenedione, androstanediol and estrogens, with the exception of the adrenal androgen metabolite dehydroepiandrosterone sulfate (DHEAS) [6]. DHEAS levels of 0.5 mg/ml were associated with a high probability of complete impotence (16%), comparing to DHEAS

Finally, various aspects of sexual experience results in an increased risk of sexual dysfunction. Sexual history, indicated by having more than five lifetime partners and by masturbation practices, does not increase relative risk for men. Men reporting any 33

Table 7: Quality of life concomitants by latent classes of sexual dysfunction * SATISFACTION WITH PRIMARY PARTNER AND HAPPINESS LATENT CLASS

LOW PHYSICAL SATISFACTION

LOW EMOTIONAL SATISFACTION

LOW GENERAL HAPPINESS

(n=1218) Referent

(n=1219) Referent

(n=1238) Referent

Premature ejaculation Erectile dysfunction

0.79 (0.47-1.32) 4.38 (2.46-7.82)#

0.97 (0.63-1.48) 2.40 (1.33-4.33)#

1.28(0.75-2.18) 2.48 (1.22-5.05) #

Low desire

3.14 (1.74-5.69)#

1.57 (0.85-2.90)

2.61 (1.28-5.31) #

Men No problems

* Data from National Health and Social Life Survey and presented as adjusted odds ratio (95% confidence interval). Estimated ratio of odds of respondents of each latent class having negative concomitant outcomes. Derived from logistic regression models performed on respondents with at least 1 partner during the 12-month period prior to the survey. The dependent variables are the concomitant outcomes and the predictors variables, modeled simultaneously, includes latent classes as well as controls for age, marital status, education, race and ethnicity, religion, and place of residence. (Laumann et al. JAMA1999, 281(6):543 [7]). # P≤.05

Table 8: Latent classes of sexual dysfunction by risk factors (men)* ADJUSTED OR (95%CI) PREDICTORS Health and lifestyle (n=1202) Daily alcohol consumption STD ever Urinary tract symptom Poor to fair health Circumcised Emotional problems or stress SOCIAL STATUS (N=1232) HOUSEHOLD INCOME (1988-91) % CHANGE 1-20 increase 0-20 decrease > 20 decrease Liberal attitudes about sex Sexual experience (n=1039) ≥5 lifetime partners Sex frequency no more than once monthly Thinks about sex less than once weekly Masturbation at least once monthly Any same sex activity ever Partner had an abortion ever Sexually forced a woman ever Sexually harassed ever Sexually touched before puberty

PREMATURE EJACULATION

ERECTILE DYSFUNCTION

LOW DESIRE

0.79 (0.36-1.69) 1.10 (0.70-1.73) 1.67 (0.95-2.93)‡ 2.35 (1.40-3.95)# 0.87 (0.58-1.31 2.25 (1.58-3.20)

1.63 (0.61-4.34) 1.29 (0.64-2.59) 3.13 (1.48-6.63)# 2.82 (1.26-6.33) # 1.30 (0.63-2.70) 3.56 (2.00-6.34)#

2.24 (0.89-5.64)‡ 1.05 (0.51-2.15) 1.68 (0.71-3.97) 3.07 (1.38-6.81)# 1.64 (0.75-3.58) 3.20 (1.81-5.67) #

Referent 1.09 (0.74-1.61) 1.41 (0.87-2.29) 1.72 (1.17-2.53)#

Referent 1.49 (0.79-2.82) 2.11 (1.01-4.38) # 1.33 (0.72-2.46)

Referent 1.23 (0.65-2.34) 1.38 (0.62-3.07) 1.07 (0.57-2.00)

0.96 (0.64-1.45)

1.02 (0.50-2.05)

1.26 (0.61-2.60)

0.94 (0.58-1.52)

1.20 (0.55-2.63)

1.57 (0.79-3.12)

0.99 (0.49-2.02)

0.77 (0.25-2.42)

3.63 (1.57-8.40)#

1.09 (0.73-1.64) 2.11 (1.15-3.86)# 1.83 (1.15-2.90)# 1.74 (0.70-4.30) 1.43 (0.97-2.11)‡ 1.80 (1.12-2.90)#

0.66 (0.33-1.33) 0.72 (0.23-2.33) 0.63 (0.24-1.61) 3.52 (1.03-11.98) # 1.27 (0.66-2.47) 3.13 (1.49-6.59) #

1.72 (0.86-3.42) 2.51 (1.10-5.74)# 1.98 (0.92-4.23)‡ 0.49 (0.06-4.08) 1.31 (0.69-2.48) 2.23 (1.10-4.56)#

*Data from National Health and Social Life Survey. Estimated ratio of odds of membership in a given latent class for members of the specified group to odds for reference group in the default latent class of having no problems. Derived from multinomial logistic regression models performed on respondents with at least 1 partner during the 12-month period prior to the survey. Three models run separately for each sex (health and lifestyle, social status, and sexual experience). Predictor variables, in addition to those listed for health, lifestyle, and sexual history included age, marital status, education, race and ethnicity, religion, and place of residence. OR indicates odds ratios, CI is confidence interval and STD sexually transmitted disease. (Laumann et al. JAMA 1999, 281 (6):543 [7]. # P≤.05 ‡P≤ .10

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levels 5 and 10 mg/ml (6.5% and 3.4% respectively). Conversely, probabilities of complete impo tence increased as DHEAS levels decreased while the overall and moderate impotence proba bilities remained unchanged. Such patterns support the hypothesis that minimally impotent men may become complete impotence if their DHEAS levels decreased from 10 to 0.5 mg/ml. It should be noted that as the MMAS data were adjusted for age, the rapid decline of serum DHEAS concentration with age was not the cause of this finding. It is possible that the described pattern expresses the vascular health status of the sample. DHEAS levels have been proposed in the literature as a predictor for cardiovascular disease [37].

included in Table 9 [47]. Tenover cautions that most of this information has been reported only in Caucasian men with a paucity of data for other ethnic populations [46]. She also cautions that the magnitude of the decline in testosterone with aging is poorly documented and that there is also a lack of longitudinal population-based sampling. In response to the question of whether age exerts a negative impact on sexual function, Dr. Tenover reports that there is a mixed picture from the lite rature and that there may be a relationship bet ween declining testosterone and sexual activity and/or sexual desire but such a relationship with this decline and erectile dysfunction, is not wide ly supported [46]. It has recently been reported that hypo-testosteronemia may be more clearly related to other adverse effects of age in men such as osteoporosis, decreased body mass, lower red cell counts and hemoglobin, alterations in sexual response, mood, and cognitive functions and that these conditions may respond to testosterone supplementation.[48] However, the connection between hypo-testosteronemia and erectile dysfunction has not been confirmed [46,48].

Certainly, in most cases of hypogonadism both libido and sexual function are adversely affected. However, medical or surgical castration does not necessarily lead to the loss of erectile function. The adrenal glands in man may produce all the androgens that are necessary for corpora cavernosal function [38]. Rat models show much more androgen dependency for erectile activity [39]. Treating hypogonadal men with exogenous testosterone has been shown to increase both number of and degree of rigidity of nocturnal erection events [40]. Other authors show that testosterone treatment in normal eugonadotrophic men did not increase the frequency but did increase the rigidity of nocturnal erections suggesting an end organ effect [41]. The level of free testosterone may be more important than total serum testosterone levels in maintaining erections in the hypogonadal male [42]. Other studies have shown a differential androgen effect on erectile dysfunction in sexual situations and nocturnal erectile events but an independence of this effect on erotic visual sex stimulated erections [43-45]. Prolactin secreting tumors of the pituitary gland usually are associated with markedly decreased serum testosterone levels, but there are exceptions to this.

In a clinical review based on a Medline search of English language literature published between 1975 and 1992, Mulligan and Schmitt examined Table 9: Male reproductive hormone changes with normal aging Decreased testosterone production; decreased testosterone clearance • decrease in testicular Leydig cell numbers • decreased enzymes in metabolic pathways governing testosterone production • diminished testicular response to pituitary LH Decreased levels of serum total and free testosterone Increased sex hormone-binding globulin: Decreased “bioavailable testosterone” No change in serum levels of dihydrotestosterone Increased serum estradiol levels

Lisa Tenover recently addressed two important questions: whether many older men experience an age-associated decline in androgens and if this has a negative impact on their sexual func tion. To answer the first question, she summarized the recent literature which shows that there is a decline in androgen levels and production due to a number of factors [46]. In a later review article, Bhasin added other age-related changes which are

Small increase in serum gonadotropin (LH and FSH) levels Partial impairment of the hypothalamic GnRH pulse generator Decreased LH pulse amplitude Increased hypothalamic sensitivity to sex steroid feedback More asynchronous production of LH and testosterone Table generated from data from references [46 and 47]

35

the association between testosterone and erectile failure [49]. They were able to draw three conclusions:

4. D IABETES MELLITUS Erectile dysfunction has been reported to occur in at least 50% of men with diabetes mellitus, with the onset of the impotence occurring in an earlier age than those without diabetes mellitus [57,58]. Also the prevalence rate of erectile dysfunction is higher for each decade of diabetic men compared to non-diabetics [2]. Hatzichristou et al have reported that the prevalence of impotence in diabetics has been estimated between 35-75% in the literature [59]. Whitehead and Klyde reviewed a large amount of the reported associations between erectile dysfunction and diabetes mellitus present in the literature in a 1990 article on diabetes-related impotence in [58]. Their observations include the following: in greater than 50% of patients with impotence and diabetes, impotence is noted within ten years of the onset of diabetes. Impotence occurs at an earlier age in Type I insulin dependent diabetic patients (IDDM) compared to type II non-insulin dependent diabetic patients (NIDDM), although it probably occurs in equal frequency in the two types. Impotence may present as the first sign of diabetes in 12% of patients. Temporary impotence may be due to poorly controlled diabetes although this point is debatable. Impotence is present in almost all patients with diabetes who have manifestations of diabetic neuropathy such as bladder dysfunction or decreased testicular sensation. Diabetic macrovascular complications are reported as related to age, while duration of diabetes and degree of glycemic control affect microvascular complications. Lehman and Jacobs reported that 83% of the type I diabetics had vascular abnormalities compared to 57% of the type II diabetics [60]. In Boyle’s epidemiologic review chapter, he provides the following data [2]. Prevalence surveys in diabetics found rates of erectile dysfunction ranging from 35% to 59%. Erectile dysfunction in diabetic men had been reported to be associated with severe diabetic retinopathy, a history of peripheral neuropathy, cardiovascular disease, a higher glycosylated hemoglobin, use of antihypertensive drugs and a higher body mass index. In the MMAS report, the age-adjusted probability of complete impotence was three times higher in men who reported having treated diabetes than in those without diabetes [6].

- testosterone enhances sexual interest (libido, sexual thoughts and perceived sexual arousal) - testosterone led to increase frequency of sexual acts (the success rate for vaginal intercourse was not reported) - testosterone increased the frequency of sleeprelated erections but had little or no effect on fantasy or visually induced erections.

3. SMOKING OR OTHER TOBACCO USE The use of tobacco is clearly a risk factor for erectile dysfunction [50,51]. This risk has been substantiated in animal models [52,53]. Cigarette smoking is reported as an independent risk factor in the development of atherosclerotic lesions in the internal pudendal and common penile arteries of young impotent men [54]. In the MMAS group of patients, cigarette smoking exacerbated the risks of impotence associated with cardiovascu lar disease and medication [6]. Among subjects with treated heart disease the age-adjusted probability of complete impotence was 56% for current smokers, compared with 21% in current non-smokers. Among treated hypertensives, those who currently smoked had an elevated probability of complete impotence (20%), whereas the non-smokers (8.5%) were comparable to the general sample (9.4%). Smoking exacerbated drug effects on erectile dysfunction, which increased the age-adjusted probability of complete impotence in those taking cardiac medication (from 14% to 41%), antihypertensive medications (from 7.5% to 21%), and vasodilators (from 21% to 52%). However, in the MMAS study an overall effect of current smo king was not determined, with complete impoten ce present in 11% of smokers and 9.3% of nonsmokers. The probability of impotence demonstrated no dose dependency with current smoking or lifetime cigarette consumption among current smokers [6]. In a small group of patients, NPT measurements showed improvement in patients avoiding cigarettes for 24 hours [55]. Another report showed that smoking interfered with the erection response to intracavernosal pharmacological injection [56].

36

Each of the pathologic effects of diabetes melli tus on tissue, such as small arterial and arterio lar effects, neurologic demyelinization, and sinu soïds smooth muscle deterioration, have all been implicated as the etiologic factor likely associated with erectile difficulty. Metro and Broderick have reviewed these different areas of pathophysiology in erectile dysfunction in a recent report [61]. In that study, 105 diabetic men (79/105 NIDDM and 26/105 IDDM) underwent duplex Doppler evaluation of cavernosal arteries for the evaluation of erectile dysfunction. The authors reported the presence of coronary artery disease in IDDM patients was associated with lower peak systolic velocity than in those with NIDDM. However, the type of diabetes itself, smoking, or hypertension showed no difference in cavernosal artery peak systolic velocity between IDDM or NIDDM groups [61].

effects of diabetes on the corporal tissue, and by understanding these processes, clues to the pathophysiology of erectile dysfunction in the aging male may be forthcoming. Since this is such a prevalent disorder in the diabetic male, the National Institute of Health has recently announced a major research effort for the study of impotence in diabetics.

5. OTHER CHRONIC DISEASE Chronic neurologic disease correlated with a high risk for impotence include cerebrovascular accidents, temporal lobe epilepsy, multiple sclerosis, Arnold-Chiari syndrome, Guillain-Barre syndrome, autonomic neuropathy associated with AIDS or diabetes mellitus, Alzheimer’s disease, tumors, and infection [57]. Vardi and others reported a 38% coincidence of polyneuropathy and impotence in diabetics and a 10% coincidence rate in non-diabetics [65]. Sexual dysfunction is very common in Parkinson’s disease. The prevalence of erectile dysfunction is reported to be about 60% [66,67]. Multiple system atrophy, a syndrome that encompasses several conditions such as Shy-Drager syndrome, has also been associated with impotence in 96% of the cases; in 37% of them, erectile dysfunction was the first symptom [68].

de Tejada et al reported impaired autonomic nerve-mediated and endothelium-dependent relaxation of corporal smooth muscle in diabetic patients with maintenance of autonomic nervemediated contraction [62]. The longer the duration of diabetes, the less pronounced the neurogenic relaxation. No difference was seen between men who were treated and those not treated with insulin. Nor were there differences in those diabetics controlled for hypertension and smoking. Relaxation was normal in diabetics when induced by endothelium-independent vasodilators, sodium nitroprusside, and papaverine [62].

In a recent review article on urological condi tions associated with multiple sclerosis, the asso ciation with erectile dysfunction was discussed [69]. The following summary is largely drawn from that article. Some have reported a prevalen ce of erectile dysfunction in 40% of the males afflicted with the disease while others have repor ted it as high as 80% in patients suffering from multiple sclerosis [70,71]. Impotence onset is rarely seen early in the disease, generally occurring a decade after onset but has been reported 3.7 to 9 years after diagnosis [72,73]. There is approximately another five years from the time of the first symptoms of erectile dysfunction and seeking medical attention [70]. The effect of this disease on erectile dysfunction can be predominantly central (psychogenic) or the result of a neurological lesion of the spinal cord. Certain tests such as nocturnal tumescence monitoring (NPT) often do not clearly distinguish the two. [70] Some authors report that the sexual dysfunction parallels the disability while others report that the erectile problems are independent of the disability status

Sullivan et al demonstrated a significant increase in endothelin B (ETB) receptor binding sites on the rabbit corpus cavernosum six months after the induction of diabetes mellitus by alloxan [63]. They suggested that this could represent a pathophysiological pathway in diabetic erectile dysfunction (up regulation of smooth muscle constriction and initiation of cellular proliferation) or a compensatory response to impaired nitric oxide (NO) or prostacyclin (PGI2) release which has been reported in diabetic animal models [63]. Indeed, elevated plasma concentration of endothelin-1 in peripheral vein blood was significantly increased in non-diabetic and diabetic men with impotence compared to control men and also significantly higher in diabetic patients compared to non-diabetic patients [64]. There is much to be learned about the pathological

37

of the patient but is more closely related to bladder and pyramidal dysfunction [71,72-77].

density lipoproteins, arteriosclerosis, and per ipheral vascular disease are all cardiovascular factors that have high correlation with erectile dysfunction. Wabrek and Burchell reported that 64% of 131 males, aged 31-86 years, hospitalized for an acute myocardial infarction were impotent [81]. In 130 impotent men, the incidence of myocardial infarction was found to be 12% and 1.5% in patients with abnormal and normal penile hemodynamics respectively [10]. Heaton and his colleagues discuss some of the problems of assessing risk pre- and post- operatively in patients undergoing coronary artery bypass graft surgery [82]. In their introduction and discussion section, the authors remind us of psychological factors affecting erection in cardiac patients such as fear of angina, death with intercourse and fear of damaging chest wounds during intercourse in post operative bypass graft patients. Significant physiological effects such as high sympathetic drive seen in patients with congestive heart failure or significant coronary artery disease oppose the vasodilitation that is necessary for erection [82] .The authors appropriately call for prospective studies to clearly define risk factors for erectile dysfunction in the patient with cardiovascular disease [82].

Men suffering from depression have a greater risk for impotence possibly related to decreased testosterone levels [6,57]. Medications used to treat depression are also a risk factor for impotence as discussed below. In the MMAS, the psychological factors strongly associated with impotence include depression, low levels of dominance, and anger, either expressed outward or directed inward [6]. Chronic renal failure is associated with impoten ce in up to 40% of those affected [57]. Hyperprolactinemia, hypogonadism, hyperparathyroidism and zinc deficiency have been suggested as etiologic factors in the face of renal disease [57]. An excellent review of the hemodynamic pathophysiology in impotence associated with renal failure was prepared in 1994 by Kaufman and associates [78]. In patients with hepatic failure, there is an increased risk from impotence, particularly in alcoholic cirrhosis [57]. Chronic obstructive lung disease (perhaps associated with oxygen dependency for nitric oxide synthase) has been implicated as a risk for erec tile dysfunction [79]. In fact, three patients in this report were given home oxygen for resting or nocturnal hypoxemia and two had improvement of erectile function on therapy [79].

Several reports emphasize the association of hypertension with erectile dysfunction. Oaks and Moyer reported that 8-10% of untreated hypertensive patients were impotent at the time of diagnosis of the disease [83]. Muller et al found cavernosal artery insufficiency in 85% of 117 hypertensives tested [84].

Other diseases that may account for an increased risk for erectile dysfunction include Peyronie’s disease, other disease or injury leading to scarring or fibrosis of the tunica albuginea of the corpora, injury to the intracavernosal tissue (such as postpriapism seen with sickle cell disease and other states), chronic brucellosis, other infective or parasitic disease, and widower’s syndrome [57]. Scle roderma has been reported as a risk factor for erectile dysfunction and impotence has been reported in 12% to 60% of cases [80]. Impotence has been the presenting symptom of systemic scleroderma in 12% to 21% of the cases [80].

Treated heart disease (worse in smokers), treated hypertension (again, worse in smokers), and low serum levels of high density lipoproteins were significantly correlated with impotence in the MMAS report [6]. As discussed below, erectile dysfunction is frequently reported in association with drugs used to treat a variety of cardiovascular disorders. Wei et al found that a high level of total cholesterol and a low level of HDL are important risk factors for erectile dysfunction [22]. In the MMAS, the impotence probability pattern varied significantly with HDL-cholesterol, in a manner interactive with age [6]. The first pattern represents changes in younger men (aged 38-55 years) and

6. C ARDIOVASCULAR DISEASE AND HYPERTENSION Cerebrovascular accidents, coronary bypass sur gery, myocardial infarction, heart disease, hyper tension, hyperlipidemia, low serum levels of high

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the second in older men (aged 56-70 years). The probability of moderate impotence for the younger group increased from 6.7% to 25.5% when the HDL values decreased from 90 to 30 mg/dL. Considering that minimal impotence diminished from 27.7% at HDL levels of 90 mg/dL to 14.1% at HDL levels of 30 mg/dL, it was assumed that men with minimal impotence may increase to the moderate category. Values more than 90 mg/dL were associated with 0% probability of complete impotence. When the HDL values dropped to 30 mg/dL, the probability of complete impotence increased to 16.1%. These data, along with the finding that total serum cholesterol was not correlated with impotence probabilities, support HDL levels as a strong determinant of impotence.

tives than with calcium blocking agents, converting enzyme inhibitors or diuretics [85]. All antihypertensives lower blood pressure and this mechanism is probably the main reason that most are a risk to cause erectile dysfunction. However, reported decreases in libido with certain antihypertensives indicate that there may be a central effect as well from these medications. Based on Lundberg and Biriell’s commentary and the article by Meinhardt et al, it would appear that selective or non-selective beta-blocking agents are more likely to cause erectile dysfunction than other antihypertensives [85,86]. As suggested by Meinhardt et al, this side effect may result due to a change in the balance between alpha and beta sympathetic influence which results in insufficient antagonism of alpha-1 vasoconstriction [86]. Other authors have suggested that diuretics, particularly thiazide diuretics, are the most common cause of impotence from prescription drugs due to their common usage [57]. However, Prisant et al examined the short term usage of various antihypertensives in a media analysis of self-reported sexual dysfunction. There was no higher increase in erectile dysfunction from single agent use compared to those patients on a combination of a diuretic and a betablocker [87]. It seems reasonable to think that calcium re-entry blocking agents would be less likely to cause erectile dysfunction. However, commentary by Lundberg and Biriell shows that it is not uncommon for erectile dysfunction to be associated with this class of drugs as well, again probably due to the central lowering of blood pressure [85]. Reserpine, alphamethyldopa, and ACEantagonists may not only be a risk factor for erectile dysfunction because of their blood pressure lowering effect but also because of hormonal influences [57,86]. There may be some central effect of a few of these agents as well [57,85]. Every clinician who deals with erectile dysfunction has anecdotal data to suggest that changing the type of anti-hypertensive for the patient will often reverse erectile dysfunction. Calcium chan nel blockers and alpha adrenergic blockers may be theoretically the best alternative in attempting to reverse erectile dysfunction when associated with other anti-hypertensive agents.

Certainly, the presence of cardiovascular disease and its treatment is clearly a risk factor for erectile dysfunction. Similarly, impotence may be an indication of arterial disease in the coronary arteries although this has not been substantiated. More research into the relationship between disease in the cavernosal arteries and disease in the coronary arteries is highly recommended.

7. MEDICATIONS AND RECREATIONAL DRUGS Erectile dysfunction due to prescription medications is underreported. Slag et al reported a 25% incidence of drug-associated impotence in a medical outpatient population [36]. In the MMAS, a statistically significant correlation between impo tence and vasodilators, antihypertensives, car diac and hypoglycemic agents was noticed [6]. This topic has been discussed summarily by Lundberg and Biriell [85]. Meinhardt et al have reviewed the influence of medication on erectile dysfunction recently in some detail [86]. In Table 1 from that article, the authors list some 332 medications that are associated with erectile dysfunction. Major classes of prescription drugs com monly reported to be associated with erectile dys function are histamine-2 receptors antagonist, hormones, anticholinergics, and certain cyto toxic agents. Certainly, anti-hypertensive drugs appear to represent a major risk factor for erectile dys function. Lundberg and Biriell report that erectile dysfunction is more likely seen with alpha or alpha/beta blocking agents and guanidine deriva-

Patients on psychotropic drugs such as phenothiazine and butyrophenone tranquilizers, antidepressants including tricyclics, monamine oxidase

39

inhibitors, lithium, fluoxetine (Prozac) and other selective serotonin reuptake inhibitors (SSRI), benzodiazepines, and antipsychotics are definitely at greater risk of erectile dysfunction. An article published by Rosen and others in 1999 reviews sexual dysfunction problems associated with the SSRIs [88]. In that article, they report an incidence of erectile dysfunction with fluoxetine of 1.7%, with sertraline (100 mgm/day) of 2.5%, with paroxetine (30 mgm/day) of 6.4%. An antidepressant less likely to cause erectile dysfunction is trazodone, however, there is a risk for priapism. This agent could be considered as an alternate antidepressant drug when others produce the side effect of erectile dysfunction [86]. In general, it is sug gested that antipsychotics with strong alpha-1 receptor affinity properties be considered as sub stitutes for other prescription psychotropic drugs associated with erectile dysfunction.

Certain sports-related activities, such as bicycle riding, gymnastics involving bars or projections on gymnastic equipment, water ski and water jet ski accidents, as well as football-related trauma may cause site-specific blunt trauma to the perineum which could lead to erectile dysfunction [90]. Reports from the same institution have also recently been in the lay press suggesting that the current design of bicycle seats may be a source of chronic injury to the perineum and therefore a risk factor for erectile dysfunction. This has not been reported in peer reviewed scientific literature as yet. Surgery or trauma affecting any level of neuro logic control of erection or interfering with the arterial supply to the corpora cavernosal tissue are unquestionably risk factors for erectile dys function. This includes head trauma and brain surgery. Spinal cord injury, lumbar disc surgery, non-nerve sparing retroperitoneal lymph node dissection, and abdominal aneurysmectomy are all risk factors for erectile dysfunction [57]. Pelvic trauma and surgery (particularly radical bowel and genitourinary cancer surgery) are obvious potential risk factors for erectile dysfunction. The use of nerve-sparing surgery for radical genitourinary cancer has increased in order to lessen the high incidence of impotence previously reported from this type of surgery. The variability of the reports of successfully preserving sexual function with nerve-sparing techniques has been well discussed by Benet and Melman [57]. Radiation therapy for prostate malignancy is a risk factor for erectile dysfunction with delayed symptoms appearance compared to the immediate presentation of symptoms seen with surgery [91]. Both membranous urethral injury and surgical procedures designed to repair the strictures resulting from such injury are risk factors for erectile dysfunction. Transurethral surgery for benign prostatic hyperplasia (TURP) and stricture disease have been reported as minor risk factors for erectile dysfunction. However, an excellent prospective study done recently seriously questions equating retrograde ejaculation with erectile dysfunction [92].

Histamine-2-receptor antagonists have a high risk for erectile dysfunction, particularly cimeti dine [85]. More modern anti-ulcer drugs do not appear to present the same risk factor. Hormones and enzymes affecting hormones, including estrogens, progesterone, corticosteroids, cyproterone acetate, flutamide, finasteride, and gonadotropinreleasing hormone agonists, as well as non-hormonal drugs such as spironolactone and ketoconazole, lower testosterone and therefore have a significant risk factor for erectile dysfunction [57,86]. Digoxin may be associated with erectile dysfunction from a hormonal etiology, however, it has been suggested that the underlying mechanism for digoxin-associated impotence may be an inhibition of the Na+/K=-ATPase pump [57,86]. Life style related risk factors for erectile dysfunction include chronic alcoholism and chronic use of marijuana, codeine, meperidine, methadone, and heroin [57]. There was a recent case report when a chronic alcoholic suffering from Vitamin B1 deficiency had a reversal of his erectile dysfunction two weeks after receiving 25mg of oral thiamine daily [89].

8. S URGERY AND TRAUMA

DePalma recently reviewed the impact of vascular surgery on impotence [93]. Aortic and aortoinguinal bypass surgery are procedures that carry a risk for erectile dysfunction. Sixty percent of 23 men obtained spontaneous erections in the author’s own study [93].

Spinal cord injury patients obviously are at an increased risk for erectile dysfunction with psy chogenic induced erection possible in those with lower spinal cord injury and reflexogenic erec tion possible in those with upper cord injury. 40

disease risk factors and this study seems to demonstrate a similar benefit for developing erectile dysfunction. Given the limitations of this study, the findings highlight the need for future longitudinal studies of preventable risk factors. One important point of this study is that modi fiable risk factors may require earlier interven tion than middle age.

9. THE EFFECT OF MODIFICATION OF RISK FACTORS Using data from the reassessment of a portion of the population sampled in the original MMAS study, an attempt was made to assess the effect of modification of certain risk factors associated with erectile dysfunction [94]. Until then, spontaneous recovery seemed rare and occurred only in cases with resolution or dramatic improvement of associated medical or psychiatric diseases. After excluding men without erectile dysfunction, men treated for heart disease or diabetes, men with history of prostate cancer and those with incomplete data on risk factors, 593 men were identified for this study. These men, who were free of moderate or severe erectile dysfunction at baseline, were the basis of the analysis of the effect of modifying risk factors performed eight years later. Risk factors studied were cigarette smoking, alcohol use, obesity, and sedentary life style. The limitations of this study are that only two time points were studied and the small sample size within each category of risk factor change.

V. CONCLUSIONS There is a difference in the reporting of erectile dysfunction prevalence from the different regions of the world. These differences are explained by a number of different reasons. First, there is no standard adopted method for asking popu lations studied if and to what degree they have erectile dysfunction. Groups studied have ranged from patients seen in a clinical setting to random population studies. The population studies had varying degrees of success in the samples that used questionnaires or skilled questioning during face to face encounters. The perception of erecti le dysfunction depends on the surveyed popula tion’s understanding that their inability to obtain an erection is a sexual problem and if it interferes with their quality of life or satisfaction with their sex life. Two American studies, rigorously adhering to established epidemiologic standards, suggest that erectile dysfunction prevalence is higher than previously reported in other studies, particularly in the moderate and severe categories. Most studies have shown an increase in the prevalen ce of erectile dysfunction with aging. Epidemiologic studies establishing incidence rates are particularly lacking in the literature. Longitudinal stu dies were almost non-existent until the recently reported data from the Massachusetts Male Aging Study. Data from other regions of the world is sparse. This information could be impor tant in distinguishing cultural factors that may play a role in prevalence and incidence of erecti le dysfunction. The data could also be utilized for clarification of overlapping risk factors that may vary greatly among different regions of the world. Erectile dysfunction affects the quality of life for any patient. Other male sexual dysfunction problems, such as premature ejaculation, do not have the same impact on the person’s sex life and gene-

The majority of these men exhibited healthy behaviors at baseline and follow-up. Half of the smokers at baseline had quit and half of the heavy drinkers had reduced their alcohol consumption. Eighteen per cent of those obese at baseline had lost weight and 55% of those sedentary were less sedentary at follow-up. The results of this analysis showed that a change in smoking status or change in heavy drinking was not associated with decreased risk of erectile dysfunction. This analysis suggests that smoking cessation or a change in alcohol consumption in middle age do not significantly reduce the risk for erectile dysfunction. Men obese at baseline appeared to have a higher incidence of erectile dysfunction regardless of followup status. This suggests that by the fifth and sixth decade of life, the long-term pathophysiologic effects of obesity are difficult to reverse. Sedenta ry behavior status was associated with developing erectile dysfunction with the highest risk of dys function for those who remained sedentary. The lowest level of risk for erectile dysfunction, for all factors analyzed, was in those subjects who ini tiated physical activity after qualifying as seden tary at baseline. Increasing physical activity is effective for reversing other cardiovascular

41

ral quality of life. Men who suffer from erectile dysfunction, particularly if the condition is com plete or severe, are depressed by this condition. Relationships with sexual partners are disrupted and strained by this disorder. There are clearly identified risk factors for erecti le dysfunction but the interaction and interplay of one risk factor on another or clustering of risk factors must be confirmed by more rigorous stu dies. Particularly relevant is the emerging eviden ce that erectile dysfunction and cardiovascular disease are highly intertwined. Smoking or other tobacco use compounds other risk factors associated with erectile dysfunction. Modification of certain risk factors, such as consumption of alcohol or cigarette smoking, at a later age in life may not result in a change in the erectile dysfunction but may produce improvement in the erectile status of the individual if addressed at an earlier age. Chronic disease states, particularly diabetes mellitus, are clear risk factors for erectile dysfunction. Other chronic disease states may be independent risk factors for erectile dysfunction but an individual’s general disability may be a component of the associated erectile dysfunction rather than a direct risk effect. Certain medications are clearly associated with an increased prevalence of erectile dysfunction, particularly antihypertensives and psychotropics. The effect of testosterone levels is a controversial issue. Clearly established clinical hypogonadism is associated as a risk factor for erectile dysfunction but the idea of andropause, a condition of decreasing androgens with aging, is not an established cause of erectile dysfunction, but may play a role in fat deposition, loss of muscle and bone mass.

reviewed literature regarding the worldwide prevalence of ED is imperative. c. To establish the effect of a particular disease on erectile dysfunction, it is necessary to separate treated from untreated patients for analysis of populations affected with the given disease. d. There are certain social and cultural barriers hindering access to data for epidemilogic analysis and/or medical care that must be address to promote the relevance of erectile dysfunction as a medical condition worldwide. e. There is a pressing need to study the presence of erectile dysfunction as a sentinel event indicative of coronary artery disease. 2. M ETHODOLOGICAL RECOMMENDATIONS a. Future epidemiological studies should: • be community based and randomized • be of significant size • cover broad age groups (30 years to death) • be longitudinal whenever possible so that incidence data can be more clearly established which will allow elucidation of temporal relationships to diseases and other risk factors. b. Standardized questions for determination of erectile dysfunction should be developed, at least for epidemiologic surveys. ( See Appendix D) c. People who do not have access of health care systems should be included in epidemiologic surveys.

VI. RECOMMENDATIONS

d. There is an immediate need for international comparative studies.

1. S UBSTANTIVE RECOMMENDATIONS a. To clarify the comparison of epidemiologic studies of prevalence and incidence rates, there is an immediate need to standardize the definition of erectile dysfunction and to include an allowance for degree and/or persistence in that definition. b. A meta-analysis, performed by an established scientific body devoted to the study of erectile dysfunction, of published and peer-

42

APPENDIX A Sexual activity questions related to potency, from self-administered instrument included in MMAS. [6] 1. I N AN AVERAGE WEEK, HOW OFTEN DO YOU USUALLY HAVE SEXUAL INTERCOURSE OR ACTIVITY? (Enter number in box) 2. D URING AN AVERAGE 24-HOUR DAY, HOW OFTEN DO YOU

HAVE A FULL HARD ERECTION?

(Enter number in box) 3. DURING THE LAST 6 MONTHS HAVE YOU EVER HAD TROUBLE GETTING AN ERECTION BEFORE INTERCOURSE BEGINS? a. No b. Yes c. Have not had sexual intercourse within last 6 months 4. D URING THE LAST 6 MONTHS HAVE YOU EVER HAD TROUBLE KEEPING AN ERECTION ONCE INTERCOURSE HAS BEGUN? a. No b. Yes c. Have not had sexual intercourse within last 6 months 5. HOW FREQUENTLY DO YOU AWAKEN FROM SLEEP WITH A FULL ERECTION? a. Daily b. 2 or 3 times per week c. Once a week d. 2 or 3 times per month e. Once a month f. Less than once per month g. Not at all within the last 6 months 6. HOW SATISFIED ARE YOU WITH YOUR SEX LIFE? a. Extremely satisfied b. Somewhat satisfied c. Neither satisfied nor dissatisfied d. Somewhat dissatisfied e. Extremely dissatisfied 7. HOW SATISFIED ARE YOU WITH YOUR SEXUAL RELATIONSHIP WITH YOUR PRESENT PARTNER OR PARTNERS? a. Extremely satisfied b. Somewhat satisfied c. Neither satisfied nor dissatisfied d. Somewhat dissatisfied e. Extremely dissatisfied 8. HOW SATISFIED DO YOU THINK YOU PARTNER(S) a. Extremely satisfied b. Some satisfied c. Neither satisfied nor dissatisfied d. Somewhat dissatisfied e. Extremely dissatisfied

IS (ARE ) WITH YOUR SEXUAL RELATIONSHIP?

9. HAS THE FREQUENCY OF YOUR SEXUALACTIVITY a. as much as your desire? b. less than you desire? c. more than you desire?

WITH A PARTNER BEEN:

43

APPENDIX B Description Of Variables The variables used in the analysis of the NHSLS data were constructed using answers provided by respondents to the questions present in the Appendix. For further information about the questionnaire, Laumann et al. (1994). [5] DEMOGRAPHIC CHARACTERISTICS Age : We grouped age into 10 year intervals, except for the youngest group, which was expanded to include respondents below 20 years. Marital status : We grouped respondents who were, at the time of the survey, divorced, separated from their spouse or widowed. Education : “What was the highest grade or year of schooling you completed?” The possible answers include: 8 th grade or less, Some high school, Finished high school or equivalent, Vocational/trade/business school, Some college or 2 year degree, Finished college, 4 to 5 year degree, Master’s degree or equivalent, and Other advanced degree. We collapsed 8th grade or less with Some high school. Vocational/trade/business school was combined with Some college or 2 year degree and combined all respondents with at least a four year college degree. Race/ethnicity : Respondents who identified themselves as Hispanic were coded with this ethnicity rather than with a racial category. Asian/Pacific Islander and Alaskan Native/Native American and Other were grouped into a single category called Other. Religion : The primary components of our religious classification are as follows: Mainline Protestant consists of Methodists, Presbyterians, Lutherans, and Episcopalians. Conservative Protestant includes Baptists, Pentecostals, and a number of smaller denominations. Other includes Jews, Greek Orthodox, Muslims, Hindus, Eastern religions, and small Protestant groups and other religions. RISK FACTORS Drinks alcohol daily : “During the past 12 months, about how regularly did you drink alcoholic beverages?” Possible responses include Daily, Several times a week, Several times a month, Once a month or less, and Not at all. We contrasted those answering with Daily against all the other categories. STD ever : “There are several diseases or infections that are transmitted during sex. These are sometimes called venereal diseases or VD. We will be using the term sexually transmitted disease or STDs. As I read each STD, tell me whether you have ever been told by a doctor that you had it.” (Yes/No) If respondents answered Yes to any of the following diseases, they were coded as having an STD: gonorrhea, syphilis, herpes, chlamydia, genital warts, hepatitis, AIDS or HIV, pelvic inflammatory disease (women only), nongonococcal urethritis (men only), and any other STD. Urinary tract symptoms : “During the past 12 months, have you ever experienced any of the following symptoms:” (Yes/No) If the respondents answered yes to any of the following: painful or difficult urination, painful intercourse, lesions or sores in the genital area, intense chronic itching of genital area, and vaginal discharge (women only). Poor/Fair Health : “In general, would you say your health is. . .” Possible responses include Excellent, Good, Fair, and Poor. We created a dichotomous variable, grouping Fair with Poor and Excellent with Good. Circumcised – “Are you circumcised?” (Yes / No) Emotional problems/stress : This dichotomous variable was constructed from two questions. “(A) During the past 12 months, how much of the time have emotional problems interfered with your sexual activities? (B) During the past 12 months, how much of the time has stress or pressures in your life interfered with your sexual activities?” Possible answers for both questions include All of the time, Most of the time, Some of the time, A little of the time, and None of the time. If respondents answered, All of the time, Most of the time or Some of the time to either question, we indicated that the respondent suffered from emotional or stress related problems. Household income : “Compare your total household income from all sources in 1991 with your total household income four years ago (in 1988).” Possible answers include: Risen a lot (e.g. by 20% or more), Risen somewhat, Remained about the same, Fallen somewhat, Fallen a lot (e.g. by 20% or more). We grouped Risen a lot with Risen somewhat and Remained about the same with Fallen somewhat.

44

Liberal attitudes toward sex : Respondents were asked whether they Strongly agree, Agree, Disagree or Strongly Disagree with three statements. “(A) Any kind of sexual activity between adults is okay as long as both persons freely agree to it. (B) I would not have sex with someone unless I was in love with them. (C) My religious beliefs have shaped and guided my sexual behavior.” The responses of (A) were reversed and then (A), (B), and (C) were averaged. We then dichotomized the average response. 5 or more lifetime partners – See Laumman et al. (1994) [5.]for the variable Page 18. Sex frequency less than monthly : “ About how often did you have sex during the past 12 months?” Responses include Not at all, Once or twice, About once a month, Two or three times a month, About once a week, Two or three times a week and Four or more times a week. We dichotomized this variable by grouping Not at all and Once or twice with About once a month and then collapsed the remaining categories together. Thinks about sex less than weekly : “On the average, how often do you think about sex?” Possible answers include More than once a day, Everyday, Several times a week, Once a week, 2-3 times a month, Once a month, Every other month, 3-5 times a year, 1-2 times a year, and 0 times this year. We grouped Every other month, 3-5 times per year, 1-2 times per year, and 0 times this year together and then collapsed the remaining categories. Masturbation more than monthly : “On average, in the past 12 months, how often did you masturbate? “ Possible answers include More than once a day, Everyday, Several times a week, Once a week, 2-3 times a month, Once a month, Every other month, 3-5 times a year 1-2 times a year and 0 times this year. We grouped Every other month, 3-5 times a year, 1-2 times a year and 0 times this year together and then collapsed the remaining categories. Any same sex activity ever : For male respondents, if they answered Yes to any of the following questions “(A) Have you ever performed oral sex on a man? (B) Has a man ever performed oral sex on you? (C) Have you ever had anal intercourse with a man where you were the inserting partner? (D) Have you ever had anal intercourse with a man where you were the receiving partner? (E) Have you ever done anything else sexual with a man? “ (YES / NO) For female respondents, if they answered Yes to any of the following questions: “(A) Have you ever performed oral sex on a woman? (B) Has a woman ever performed oral sex on you? (C) Have your every done anything else sexual with another woman?” (YES / NO) Abortion ever : For women, “Have you ever had an abortion?” (YES / NO) For men, “Have you ever had a sexual partner who became pregnant by you and ended that pregnancy by abortion?“ (YES / NO) Sexually harassed ever : “Sometimes at work women (men) find themselves the object of sexual advances, propositions, or unwanted sexual discussions from co-workers or supervisors. The advances sometimes involve physical contact and sometimes just involve sexual conversations. Has this ever happened to you?” (YES / NO) Forced a woman ever : “Have you ever forced a woman to do something sexual that she did not want to do? “ (YES / NO) Forced by a man ever : “Have you ever been forced by a man to do something that you did not want to do? “ (YES / NO) Sexually touched before puberty : “Before your were (age of puberty, or if respondent doesn’t know 12 or 13 years old), did anyone touch you sexually? “ (YES / NO) QUALITY OF LIFE CONCOMITANTS Low physical satisfaction : “How physically pleasurable did you find your relationship with (PARTNER) to be? “ Possible answers include Extremely, Very, Moderately, Slightly, and Not at all. We dichotomized this variable by grouping Extremely and Very together and collapsing the remaining variables. Low emotional satisfaction : “How emotionally satisfying did you find your relationship with (PARTNER) to be? “ Possible answers include Extremely, Very, Moderately, Slightly and Not at all. We dichotomized this variable by grouping Extremely and Very together and collapsing the remaining variables. Low general happiness : “Generally, how happy have you been with your personal life during the past 12 months?” Possible answers include: Extremely happy, Very happy most of the time, Generally satisfied, pleased, Sometimes fairly unhappy, and Unhappy most of the time. We grouped Sometimes fairly unhappy and Unhappy most of the time and collapsed the remaining categories. HELP-SEEKING BEHAVIOR Seeking medical help : “Sometimes people have problems like this, they go to someone for help such as a doctor or a counselor of some sort. In the past 12 months, have you gone to any of the following people for help with the sexual problem(s) you have experienced: a private psychiatrist or psychologist, a psychiatrist or psychologist in a clinic, another type of private doctor, or another type of doctor in a clinic?” (YES / NO)

45

APPENDIX C Latent Class Analysis This appendix provides a brief overview of LCA, its application to NHSLS symptom data, and the results of our analysis. Our information regarding LCAis abridged and focuses on its applicability to sexual dysfunctions. For an indepth description of latent class model, see Rehm et al. (1995) [95] or McCuthcheon (1987). [24] THE LATENT CLASS MODEL The latent class model (LCM) is a statistical method that tests whether a set of mutually exclusive latent classes accounts for observed association in a cross-classification of manifest, categorical variables. A central assumption in the LCM is local independence. In short, this assumption means that a T-class solution should explain all the associations between manifest variables, making them statistically independent of one another. Let variables A, B,. . .,E denote observed, categorical variables that take values i, j, . . ., m, respectively, and let variable X denote a T-class latent variable. The general form of the latent class model states:

Where the left term indicated the probability that a randomly selected case will be located in the I, j, . . ., m cell for the t th latent class. The final term indicates the probability than an individual will be in class t of latent variable X. The remaining terms denote the probabilities than an individual in class t of latent variable X will be located at level i, j, …, m of variables A, B, …, E, respectively. A number of researchers have noted the utility of LCA in medical diagnosis. Applications of LCAhave focused on rater agreement on diagnostic criteria, validation of diagnostic indicators, and the generation of epidemiological estimated using symptom data. Table c1: Latent classes and conditional probabilities of sexual dysfunction WOMEN LATENT CLASS LC Probability Conditional probabilities of symptoms Lacked interest Unable to orgasm Pain during sex Sex not pleasurable Anxious about performance Trouble lubricating MEN LATENT CLASS LC probability Conditional probabilities of symptoms Lacked interest Unable to orgasm Climax too early Sex not pleasurable Anxious about performance Trouble maintaining erection

NO PROBLEMS

LOW DESIRE

AROUSAL DISORDER

SEXUAL PAIN

0.58

0.22

0.14

0.07

0.04 0.05 0.03 0.01 0.04 0.08

0.74 0.49 0.07 0.38 0.12 0.16

0.83 0.84 0.56 0.80 0.40 0.63

0.19 0.04 0.63 0.36 0.29 0.50

NO PROBLEMS

PREMATURE EJACULATION

0.70

0.21

0.05

0.05

0.04 0.00 0.16 0.00 0.03 0.01

0.16 0.10 0.68 0.17 0.49 0.24

0.64 0.71 0.60 0.51 0.75 0.97

1.00 0.37 0.38 0.41 0.31 0.00

ERECTILE DYSFUNCTION

LOW DESIRE

Source: National Health and Social Life Survey LCA excluded the climax too early item for women and the pain item for men in order to avoid sparse data problems.

46

RESULTS OF LCA Table C.1 shows latent class and conditional probabilities for the best fitting models and indicates the prevalence of a category of sexual dysfunction and the likelihood that a class member will exhibit a given symptom. The procedures used to generate our final latent class models consisted of three stages: (1) selection and cross-classification of manifest variables, (2) generation of best-fitting models, and (3) assignment of individual cases to latent classes. For both women and men, we used six manifest, dichotomous variables generating a corresponding crossclassification table with 26 = 64 cells. The mean frequency of women per cell is 23.2, and for men this figure is 19.7. For each sex, we excluded one symptom variable: orgasm too early for women and pain with sex for men. This is justified based on partly theoretical and partly empirical grounds. Both of these symptoms are the least prevalent for each respective gender and are not considered critical symptoms of sexual dysfunction. If we included these variables in our analysis, it would have dropped our mean frequency per cell counts to 11.6 for women and 9.8 for men. Using all seven symptoms caused a number of cells with a frequency of 0 which generated sparse data problems in our analysis. One important implication of this strategy is that women and men are not completely comparable since they match on only five of the six indicators. Next, we generated a series of models for women and men. Typically, goodness of fit tests utilize df calculations that are reclaimed when conditional probabilities are found to be zero or one. However, while this is a convenient strategy, it is not, strictly speaking, correct. Instead, we performed goodness of fit tests that did not reclaim df. As shown in Table C.2, the best fitting model for women was the four-class model. Although the five-class model misallocated fewer cases (2.6% versus 3.4%), it is not as parsimonious, so we decided to go with the four-class model. Table C 2: Fit statistics for latent class models of female dysfunction NUMBER OF LATENT CLASSES One-class model Two-class model Three-class model Four-class model Five-class model Four vs. Five

LIKELIHOODRATIO X 2

DF

P

VALUE

INDEX OF DISSIMILARITY

1256.44 145.79 92.23 45.76 34.89

50 43 36 29

0.000 0.000 0.128 0.208

0.079 0.059 0.034 0.026

10.87

7

0.144

0.008

The best fitting model for men was also a four-class solution. Here, the five-class solution did not have any advan tages over the four-class, and the latter was the most parsimonious model. Table B.3 shows these results.

Table C 3: Fit statistics for latent class models of male dysfunction NUMBER

OF LATENT

One-class model Two-class model Three-class model Four-class model Five-class model Four vs. Five

CLASSES

LIKELIHOODRATIO X 2

INDEX OF DF

77.36 114.17 76.42 42.09 31.53 10.57

50 43 36 29 7

P

VALUE

0.000 0.001 0.224 0.341 0.159

DISSIMILARITY

0.066 0.045 0.032 0.032 0.000

Finally, in assigning individual cases to the latent classes, the procedure correctly allocated 84.8% of the women and 87.1% of the men.

47

7.

LAUMANN EO, PAIK A, AND ROSEN R: Sexual Dysfuntion in the United States: Prevalence and Predictors. JAMA 1999, 281 (6):537-544.

8.

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9.

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APPENDIX D Global Question for Self-Rating of ED IMPOTENCE means being able to get and keep an erection that is rigid enough for satisfactory sexual activity. How would you describe yourself? (Circle one letter) A)

10. MORLEY JE: Impotence. Am J Med 1986, 80:897905.

B)

11. FELDMAN HA, GOLDSTEIN I, HATZICHRISTOU DG, KRANE RJ, MCKINLAY JB: Construction of a Surrogate Variable for Impotence in the Massachusetts Male Aging Study. J Clin Epidem 1994, 47:457-467.

C)

12. JONLER M, MOON T, BRANNAN W, STONE NN, HEISEY D AND BRUSKEWITZ RC: The Effect of Age, Ethnicity and Geographical Location on Impotence and Quality of Life. Brit J Urol 1995, 75:651-655.

D)

13. SPECTOR KR AND BOYLE M: The Prevalence and Perceived Aetiology of Male Sexual Problems : A NonClinical Sample. British J Med Psych 1996, 59:3510358.

NOT IMPOTENT: always able to get and keep an erection good enough for sexual intercourse

MINIMALLY IMPOTENT: usually able to get and keep an erection good enough for sexual intercourse MODERATELY IMPOTENT: sometimes able to get and keep an erection good enough for sexual intercourse COMPLETELY IMPOTENT: never able to get and keep an erection good enough for sexual intercourse

14. SOLSTAD K AND HERTOFT P: Frequency of Sexual Problems and Sexual Dysfunction in Middle-Aged Danish Men. Arch Sex Behavior 1993, 22(1):51-58.

Submitted by JB McKinlay

15. MALMSTEN UGH, MILSON I, MOLANDER U, NORLEN LJ: Urinary Incontinence and Lower Urinary Tract Symptoms: An Epidemiological Study of Men Aged 45 to 99 Years. J Urol 1997, 158:1733-1737.

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49

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52. JUNEMANN K-P, LUE TF, LUO J-N, BENOWITZ NL, ABOZEID M, TANAGHO EA: The Effect of Cigarette Smoking on Penile Erection. J Urol 1987, 138:438-441.

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53. XIE Y, GARBAN H, NG C, RAJFER J, GONZALEZCADAVID NF: A Fact of Long Term Passive Smoking on Erectile Function and Penile Nitric Oxide Synthase in the Rat. J Urol 1997, 157:1121-1126.

67. BROWN RG, JAHANSHASI WTJR, QUINN N, MARSDEN CD: Sexual Function in Patients with Parkinson’s Disease and their Partners. J Neurol Neurosurg Psych 1990, 53:480-486.

54. ROSEN MP, GREENFIELD AJ, WALKER TG, GRANT P, DUBROW J, BETTMAN MA, FRIED L, GOLDSTEIN I: Cigarette Smoking: An Independent Risk Factor for Athersclerosis in the HypogastricCavernous Arterial Bed of Men with Arteriogenic Impotence. J Urol 1991, 145:759-763.

68. BECK RO, BETTS CD, FOWLER CJ: Genitourinary Dysfunction in Multiple System Atrophy: Clinical Features and Treatment in 62 cases. J Urol 1994, 151:13361341. 69. LITWILLER SE, FROHMAN EM, ZIMMERN PE: Multiple Sclerosis and the Urologist. J Urol 1999, 161:743-757.

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57. BENETAE, MELMAN A: The Epidemiology of Erectile Dysfunction. Urol Clinic N Am 1995, 22:699-709. 58. WHITEHEAD ED, KLYDE BJ: Diabetes-Related Impotence in the Elderly. Clin Geriatric Med 1990, 6:771-795.

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74. GHEZZI A, MALVESTII GM, BALDINI S. ZAFFARONI M AND ZIBETTI A: Erectile Impotence in Multiple Sclerosis: A Neuro-Physiological study. J Neurol 1994, 242:123-126.

60. LEHMAN TPAND JACOBS JA: Etiology of Diabetic Impotence. Journal of Urology 1983,129:291-294. 61. METRO MJ, BRODERICK GA: Diabetes and Vascular Impotence: Does Insulin Dependence Decrease the Relative Severity? Int J Impotence Res 1999, 11:87-9.

75. VALLEROY MLAND KRAFT GH: Sexual Dysfunction in Multiple Sclerosis. Arch Phsy Med Rehab 1984, 65:125-128.

62. SAENZ DE TEJADA I, GOLDSTEIN I, AZODOI K, KRANE RJ, COHEN RA: Impaired Neurogenic and Endothelium-Medicated Relations of Penile Smooth Muscle from Diabetic Men with Impotence. New Eng J Med 1989, 320:1025-1030.

76. LUNDBERG PO: Sexual Dysfunction in Patients with Multiple Sclerosis. Sexuality Disability 1978, 1:218. 77. KIRKEBY HJ, POULSEN EU, PETERSON T, AND DORUP J: Erectile Dysfunction in Multiple Sclerosis. Neurology 1988, 38:1366-1371. 78. KAUFMAN JM, HATZICHRISTOU DG, MULHALL JP, EITCH WP, GOLDSTEIN I: Impotence and Chronic Renal Failure: A Study of the Hemodynamic Pathophysiology. J Urol 1994, 151:612-618.

63. SULLIVAN ME, DASHWOOD MR. THOMPSON CS, MUDDLE JR, MIKHAILIDIS DP, MORGAN RJ: Alterations in Endothelin B Receptor Sites in Cavernosal Tissue of Diabetic Rabbits: Potential Relevance to the Pathogenesis of Erectile Dysfunction. J Urol 1997, 158:1966-1972.

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64. FRANCAVILLA S, PROPERZI G, BELLINI C,

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80. NEHRA A, HALL SJ, BASILE G, BERTERO EB, MORELAND R, TOSELLI P, DE LAS MORENAS A, GOLDSTEIN I: Systemic Sclerosis and Impotence: A Clinicopathological Correlation. J Urol 1995, 153:11401146.

88. ROSEN RC, LANE RM, MENZAM: Effects of SSRIs on Sexual Function: A Critical Review. J Clin Psychopharm 1999, 19(1):67-84. 89. TJANDRA BS AND JANKNEGT RA: Neurogenic Impotence and Lower Urinary Tract Symptoms Due to Vitamin B1 Deficiency in Chronic Alcoholism. J Urol 1997, 157:954-955.

81. WABREK AJ AND BURCHELL RC: Male Sexual Dysfunction Associated with Coronary Artery Disease. Archives of Sexual Behavior 1990, 9:69-75.

90. MUNARRIZ RM, YAN RQ, NEHRAA, UDELSON D, GOLDSTEIN I: Blunt Trauma: The Pathophysiology of Hemodynamic Injury Leading to Erectile Dysfunction. J Urol 1995, 153:1831-1840.

82. HEATON JPW, EVANS H, ADAMS MA, SMITH K, MORALES A: Coronary Artery Graft Surgery and Its Impact on Erectile Dysfunction: A Preliminary Retrospective Study. Int J Imp Research 1996, 8:35-39.

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92. SODERDAHL DW, KNIGHT RW, HANSBERRY KL: Erectile Dysfunction Following Transurethral Resection of the Prostate. J Urol 1996, 156:1354-1356.

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93. DEPALMA RG: Vascular Surgery for Impotence: A Review. Int J Imp Research 1997, 9:61-66.

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87. PRISANT LM, WEIR MR, FRISHMAN WH, NEUTEL JM, DAVIDOV ME, LEWIN AJ: Self Reported Sexual Dysfunction in Men and Women Treated with Bisoprolol, Hydrochlorothiazide, Enalapril, Amlodipine, Placebo, or Bisoprol/ Hydrochlorothiazide. J Clin Hypertension 1999, 1:22-26.

95. REHM J, ARMINGER G, KOHLMEIER L: Using Follow-Up Data to Avoid Omitted Variable Bias: An Application to Cardiovascular Epidemiology. Stat in Med 1992, 11:1195. ______________________

51

52

Committee 2

Economical Aspects of Erectile Dysfunction

Chairman R. SHABSIGH

Members L. ALEXANDRE, H. BAY NIELSEN, J. FITZPATRICK, H. MELCHIOR

53

CONTENTS

V. THE EMERGING GUIDELINES FOR THE DIAGNOSTIC EVALUATION AND TREATMENT OF ED AND THEIR ECONOMIC SIGNIFICANCE

I. INTRODUCTION

II. THE ECONOMIC SIGNIFICANCE OF THE EPIDEMIOLOGY OF ED

VI. INCREASED EXPENDITURE OF THE INDUSTRY ON R&D IN ED III. THE IMPACT OF ED ON QUALITY OF LIFE AND RELATIONSHIP AND ITS ECONOMIC SIGNIFICANCE

VII. THE ACCUMULATIVE ECONOMIC IMPACT OF ED ON SOCIETY, PATIENTS, HEALTH CARE PROVIDERS, INSURANCE, INDUSTRY, ACADEMIA, ETC

IV. UTILIZATION OF HEALTH CARE SERVICES AND THERAPIES FOR ED

VIII. THE UNKNOWNS ABOUT THE ECONOMIC IMPACT OF ED

1. RECENT INCREASE IN THE UTILIZATION OF ED TREATMENTS

IX. CONCLUSIONS

2. IMPACT OF INTRODUCTION OF ORAL THERAPY 3. PENILE IMPLANTS

X. RECOMMENDATIONS

4. VACUUM CONSTRICTION DEVICES XI. ACKNOWLEDGEMENTS

5. ALTERNATIVE MEDICINE 6. REIMBURSEMENT

REFERENCES 7. ED MANAGEMENT COST IN THE UK

54

Economical Aspects of Erectile Dysfunction R.SHABSIGH, L. ALEXANDRE, H. BAY NIELSEN, J. FITZPATRICK, H. MELCHIOR macotherapy for erectile dysfunction including oral medications. The answer to this important question lies in the understanding of the epidemiological and medico-economic factors related to erectile dysfunction. Four facts have been repeatedly demonstrated: erectile dysfunction is highly prevalent; its incidence is age-related, it is a progressive condition, and it is currently significantly undertreated. The Massachusetts Male Aging Study (MMAS) suggests the number of men in the USA with erectile dysfunction to be 1020 million [1]. Inclusion of patients with partial erectile dysfunction may increase the estimate to 30 million [1]. Erectile dysfunction has been found to be associated with age [1-4]. Data on seeking medical help for erectile dysfunction reveals that erectile dysfunction is undertreated [5]. It is estimated approximately 15% of patients with erectile dysfunction might ultimately seek treatment annually. In one study, 50% of patients with erectile dysfunction refused evaluation and treatment [3]. This data underscores the fact that erectile dysfunction is undertreated.

I. INTRODUCTION A brief introduction into the general principles of economics is helpful. The study of the economics of a certain medical condition may be performed in different steps or levels. These steps include: descriptive economics, analytic economics and interventional economics. The first and most fundamental step is descriptive economics. At this level the condition under study, i.e. ED is defined. The definition is very important because it permits accurate identification of the human subjects, i.e. patients (or in some economic terms consumers). In addition to definition, the epidemiology of ED is an indispensable part of this level of the study of economics. Descriptive data are collected and summed. The next step is analytic economics, where data are analyzed for recognition of trends, correlations, predictors and other statistical indicators. This analysis usually leads to the understanding of consumer/market behavior and the identification of factors influencing such behavior. At this step models and hypotheses are created and theories may emerge. The most advanced step in the study of economics is planning an intervention and investigating the consumer/market response. This chapter on the economics of ED at the first international consultation on ED, is limited mostly to descriptive and to a lesser extent to analytic economics.

The data from the MMAS showed that ED was not only age related but also suggested that ED was a progressive condition (fig. 1). New data from a follow up study of the MMAS showed that in the USA approximately 921,000 new ED cases are expected annually [6]. The population growth compounded by the population aging will clearly result in acceleratingly increasing number of men with erectile dysfunction. The introduction of new oral medications and the intensified public awareness and education will result in a higher rate of seeking and utilizing treatment. The combined effects of population growth (fig. 2) and aging (fig. 3, 4) with the increased utilization of treatment will simply lead to a larger patient base. Such a larger patient base will naturally include all

II. THE ECONOMIC SIGNIFICANCE OF THE EPIDEMIOLOGY OF ED Health care providers, economic planners and the public are concerned about the economic impact of the development of efficacious and safe phar-

55

levels of severity of erectile dysfunction. Erectile dysfunction has evolved to follow a step-care health delivery model. Oral therapy has become the first line treatment. Intracavernous injection therapy and intraurethral therapy have become second line treatment and penile implants have become a third line treatment. Vacuum constriction devices can be used at any step of the process. Hormonal therapy and penile revascularization are indicated in a small number of patients with specific requirements. Sex therapy can be utilized alone in specific cases or as an adjunct in other cases.

that the improvement of symptoms of depression and the positive effect on quality of life of the successful treatment of ED, may ultimately result in a positive economic effect. Such hypothesis definitely justifies further socio-economic research.

IV. UTILIZATION OF HEALTH CARE SERVICES AND THERAPIES FOR ED 1. RECENT INCREASE IN THE UTILIZATION OF ED TREATMENTS: Comparing the number of prescriptions and the drug sales of 1995 with 1998 shows very clearly that the utilization of treatment increased dramatically in such a short time (fig. 7 and 8) [8]. During this short period the number of total prescription grew 650% and the ED drug sales grew 3,127%. This increase is an indisputable evidence that ED has been an undertreated medical condition with a big room for expansion in utilization of therapies. The growth in the utilization of drug therapy for ED was not only in the USA but similarly worldwide (fig. 9). Just in 1 year between 1997 and 1998, the world wide ED drug sales increased 187%. With the exception of Japan, all world regions experienced significant increases in the utilization of drug therapy for ED (fig. 10). These increases ranged from a low of 147% in Asia to 344% in the USA. The main driver for the growth in drug therapy has been the development and registration of new safe and efficacious drugs. Tracking the number of prescriptions (fig 11) and the drug sales (fig. 12) from 1995 to 1999 in the USA clearly shows that the introduction of new drugs increased the number of total prescriptions and new prescriptions, consequently increasing drug sales. Aside from major «blips» prescriptions are stable at approximately 300,000 new Rx/month and 800,000 total Rx/month. Drug sales are stable at approximately $ 55,000,000.

III. THE IMPACT OF ED ON QUALITY OF LIFE AND RELATIONSHIP AND ITS ECONOMIC SIGNIFICANCE The economic impact of a disease or a medical condition is not only limited to the cost of diagnosis and treatment. Medico-economic analysis has been used to determine other economic impact of a disease or a medical condition on society. Such impact may include lost time at work, decreased productivity, effect on partner, wife, family and coworkers. Erectile dysfunction has many correlates with known high economic impact such as atherosclerosis, myocardial infarction, hypertension and diabetes. However, it should be clear that it is not ED that causes these conditions, nor does it worsen them. Nevertheless, depression and relationship issues might well be negatively affected by ED and consequently have a negative economic impact. The MMAS has shown that ED was highly correlated with depression. Another study comparing patients presenting with ED alone, BPH alone and ED + BPH showed that the incidence of ED was twice as high in those with ED alone or ED + BPH as compared to BPH alone (fig. 5) [7]. A recently completed multicenter clinical trial on the treatment of ED in patients with ED and comorbid depressive symptoms (fig. 6) showed that improvement of erectile function in men with ED who responded to treatment was associated with a significant improvement in their symptoms of depression. Results from this study also showed that successful treatment of ED with sildenafil significantly improved 5 out of 8 general quality of life parameters. One could hypothize

2. IMPACT OF INTRODUCTION OF ORAL THERAPY The strongest impact was the introduction of oral therapy, i.e. sildenafil (Viagra). Indeed, between 1995 and 1998 there was a major shift toward oral therapy with this new drug (fig. 13-15). Currently, oral drugs make up the highest percentage of number of prescriptions as well as drug sales (fig. 16 and 17). In 1995, oral drug sales (Yohimbine) 56

Figure 1: MMAS Erectile dysfunction is highly prevalent, age-related and progressive.

Figure 2: Growth of the male population of the world

Figure 3: Increase in average male life expectancy of the world

Figure 4: Aging of the male population of the world

Figure 5: Erectile dysfunction is associated with increased incidence of depression

Figure 6: Successful treatment of ED improves comorbid depressive symptoms

57

Figure 7: Increased number of prescriptions for ED between 1995 and 1998 in USA

Figure 8: Increased ED drug sales between 1995 and 1998 in USA

Figure 9: Increased ED drug sales between 1997 and 1998 worldwide

Figure 10: Increased ED drug sales between 1997 and 1998 in the various regions of the world

Figure 11: Effect of introduction of new drugs on number of prescriptions for ED in USA

Figure 12: Effect of introduction of new drugs on ED drug sales USA

58

Figure 13: Change in type of ED treatment in the past 4 years in USA

Figure 14: Change in type of ED treatment in the past 4 years in USA

Figure 15: Change in type of ED treatment in the past 4 years in USA

Figure 16: Oral drugs make up the highest percentage of number of prescriptions and drug sales for ED in the USA

Figure 17: Oral drugs make up the highest percentage of number of prescriptions and drug sales for ED in the USA

59

constituted 68.7% of the total ED drug sales. In 1998, oral drug sales (mostly Viagra with some Yohimbine) constituted 82% of the total ED drug sales in the USA. This trend was also evident in other regions of the world (fig. 18-23).

(Viagra).

V. THE EMERGING GUIDELINES FOR THE DIAGNOSTIC EVALUATION AND TREATMENT OF ED AND THEIR ECONOMIC SIGNIFICANCE

3. PENILE IMPLANTS Although penile implants decreased in the past 4 years, this trend appears to have stabilized (fig. 24).

The introduction of oral therapy had a great impact on the practice of ED, changing the pattern of health care delivery from specialty to primary care. Consequently, this changed the diagnostic and therapeutic algorithm and resulted in development of practice guidelines. One of such practice guidelines is the process of care in the USA [10]. In addition, there are also guideline initiatives in Europe and other regions of the world. These guidelines will directly and indirectly affect the economics of ED.

4. VACUUM CONSTRICTION DEVICES Although vacuum devices decreased in the past 2 years, this trend appears to have stabilized (fig. 25).

5. ALTERNATIVE MEDICINE Use of alternative medicine for treatment of ED has been known for a long time all over the world. This may include herbs, acupuncture, etc. The economic impact of alternative medicine for ED is not known.

The introduction of oral drug therapy has resulted in a shift toward primary care at least in the initial management of ED. This is evident in the percentage of sildenafil (Viagra) prescriptions by prescriber (fig 29). The step-care model of health care delivery is becoming rapidly established in ED with the majority of initial management by primary care physicians and selective advanced management by specialists. The economic significance of such changes in health care delivery are obvious.

6. REIMBURSEMENT Reimbursement of drug cost by insurance is still in transition. Many insurance companies and even governmental agencies are passing through confusion as to what is reasonable in reimbursement of drug cost. Concern about uncontrollable high costs is always present. In the USA the majority of patients pay cash for ED oral drug therapy with Viagra (fig. 26).

7. ED MANAGEMENT COST IN THE UK

VI. INCREASED EXPENDITURE OF THE INDUSTRY ON R&D IN ED

An attempt at studying the annual cost of ED to the United Kingdom Society was recently undertaken [9]. In 1997/98 a total of 113,000 patients sought treatment in approximately 390,000 visits (fig. 27). The annual total National Health Service cost of managing ED was £43.9 million in 1997/98 (fig. 28). The burden was sensitive to the number of outpatient visits and to a lesser extent the number of prescriptions. The burden was insensitive to the number of GP visits. It must be qualified that the UK situation is unique and that this data was prior to the introduction of sildenafil

It is very evident that the pharmaceutical industry has dramatically increased its expenditure on research and development of drugs for the treatment of ED. This increase is driven by the fact that ED has been an undertreated condition and also by the fact that the first oral drug sildenafil (Viagra) has been very successful. The next few years are expected to witness the introduction of a number of new oral drugs. Exact numbers of the pharmaceutical R&D expenditure are not available at the

60

Figure 18: Change in type of ED treatment from 1997 to 1998 in the various regions of the world

Figure 19: Change in type of ED treatment in the past 4 years in the various regions of the world

Figure 20: Change in type of ED treatment in the past 4 years in the various regions of the world

Figure 21: Change in type of ED treatment in the past 4 years in the various regions of the world

Figure 22: Change in type of ED treatment in the past 4 years in the various regions of the world

Figure 23: Change in type of ED treatment in the past 4 years in the various regions of the world

61

Figure 24: Worldwide change in penile implants

Figure 25: Worldwide change in vacuum devices

Figure 26: Reimbursement for sildenafil (Viagra) in the USA

Figure 27: ED annual cost to UK society 1997/98

Figure 28: ED annual cost to UK society 1997/98 (cont)

Figure 29: Sildenafil (Viagra) prescriptions by prescriber

62

time of the preparation of this report.

ve symptoms and decreased quality of life associated with ED? What is the positive economic impact of improved depressive symptoms and improved quality of life and relationship with the successful treatment of ED? How justifiable, visà-vis affordable are future drug combinations?

VII. THE ACCUMULATIVE ECONOMIC IMPACT OF ED ON SOCIETY, PATIENTS, HEALTH CARE PROVIDERS, INSURANCE, INDUSTRY, ACADEMIA, ETC

IX. CONCLUSIONS Medico-economic analysts have taken a strong interest in the projections of the ED industry or market. One such analysis predicts that, within 4 years, the ED industry will grow more than 4 times reaching almost 5 billion dollars worldwide

Available limited data suggests that the economic impact of ED has increased significantly in the past 4 years. The reasons for this increase are: increase of patient base of this undertreated condition; introduction of new drug therapies; introduction of oral therapy; increased awareness and education. This increasing economic impact is expected to accelerate with the growth and aging of the male population of the world. There are still many unknown important issues in the economics of ED.

X. RECOMMENDATIONS Further extensive research is recommended to determine the various components of the economic impact of ED and its treatments on groups and society. Studies should be not only cross-sectional but also longitudinal because of the accumulative impact of ED and the unknown long term issues such as drop out rates. Cost-efficacy considerations may help in refining ED management algorithms. Drug combination and drug comparative studies might shed light not only on the efficacy and safety of therapy, but also might help in avoiding unnecessarily expensive and ineffective combinations. Reasonable insurance reimbursement guidelines need to be developed.

Figure 30: World wide projections of ED industry 1998 to 2002.

(fig 30) [11].

VIII. THE UNKNOWNS ABOUT THE ECONOMIC IMPACT OF ED There are known epidemiologic data about the prevalence and incidence of ED. However, there are many unknown factors that contribute to the inability to accurately measure or predict some of the aspects of the economic impact of ED. These include the following questions. How much will the rate of utilization of treatment increase with the introduction of new treatments? How long will patients use treatment? What will the long term drop out rate of the new oral therapies be? How many patients will progress in the treatment algorithm through the step-care model from the least invasive treatments to more invasive treatments? What is the negative economic impact of depressi-

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XI. ACKNOWLEDGEMENTS

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JOHANNES, C.B., ARAUJO, A.B., FELDMAN, H.A., et al: IJIR, 10: S55, 1998 abstract in supplement.

7.

SHABSIGH, R. KLEIN, L., SEIDMAN, S., KAPLAN, S.A., LERHOFF, B., & RITTER, J.: High incidence of depressive symptoms is associated with erectile dysfunction. Urol. 52: 848-852, 1998.

8.

IMS prescription tracking data 1999.

9.

Schwarz Pharma, data on file 1999.

S G COWEN: Therapeutic Categories Outlook 3/99.

The chairman of the committee on economical aspects of ED wishes to extend acknowledgement and appreciation to the following individuals, companies and institutions for their contribution to this chapter in form of data and/or advice: STEVE POMERANTZ Pfizer, Inc KENT SUMMERS Lilly Corporation AMBER FENSOM Schwarz Pharma

10. R. ROSEN, I. GOLDSTEIN, J. HEIMAN, S. KORENMAN, M. LAKIN, T. LUE, D.K. MONTAGUE, H. PADMA-NATHAN, R. SADOVSKY, R.T. SEGRAVES, R. SHABSIGH: The process of care model for evaluation and treatment of erectile dysfunction. IJIR, 11: 59-74, 1999.

LEON YAFFE DOUGLAS TRAPP

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Committee 3

Anatomy, Physiology and Pathophysiology of Erectile Function

Chairman I. SAENZ DE TEJADA

Members N. GONZALEZ CADAVID, J. HEATON, H. HEDLUND, A. NEHRA, R.S. P ICKARD, U. SIMONSEN, W. STEERS

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CONTENTS

A. ANATOMY

C. PATHOPHYSILOGY OF ERECTILE DYSFUNCTION

B. PHYSIOLOGIC REGULATION OF PENILE SMOOTH MUSCLE CONTRACTILITY

I. NEUROGENIC ERECTILE DYSFUNCTION 1. THE ETIOLOGIES OF NEuROGENIC ED CAN BE CLASSIFIED AS: 2. ERECTILE DYSFUNCTION IN SPINAL CORD INJURY 3. ERECTILE DYSFUNCTION AFTER RADICAL PELVIC SURGERY

I. PENILE SMOOTH MUSCLE CONTRACTION II. PENILE SMOOTH MUSCLE RELAXATION

II. VASCULAR ED

1. ROLE OF NITRIC OXIDE AND THE CGMP PATHWAY

1. ED IN ATHEROSCLEROSIS AND HYPERCHO-

2. THE CAMP PATHWAY

2. ED IN HYPERTENSION 3. PELVIC/PERINEAL TRAUMA 4. DIABETES

LESTEROLEMIA

3. RELAXATION THROUGH HYPERPOLARIZATION OF THE MUSCULAR CELL

III. ED IN END-STAGE RENAL DISEASE (ESRD)

III. REGULATION OF THE BALANCE BETWEEN THE DILATOR AND CONSTRICTOR MECHANISMS

IV. PRIMARY ERECTILE DYSFUNCTION

1. REGULATION OF THE ADRENERGIC ACTIVITY BY PROSTANOIDS 2. ADRENERGIC REGULATION NERVES 3. MOLECULAR OXYGEN OF PENILE ERECTION

AS A

OF

NANC

V. DRUG INDUCED IMPOTENCE

MODULATOR

REFERENCES

66

Anatomy, Physiology and Pathophysiology of Erectile Function I. SAENZ DE TEJADA N. GONZALEZ CADAVID, J. HEATON, H. HEDLUND, A. NEHRA, R.S. PICKARD, U. SIMONSEN, W. STEERS (~50%-45%) with endothelium, fibroblasts, and nerves [3-5,9]. The corpora are separated in the pendulous penis by an incomplete septum and proximally separate into two individual corpora, terminating in the paired crura which directly attach to the ischiopubic ramus. This latter structure is particularly susceptible to pelvic trauma1 [11] and x-radiation during wide beam therapy for prostate cancer (see iatrogenic causes of erectile dysfunction) [12]. Crural leakage can result in a dysfunctional veno-occlusive mechanism and erectile dysfunction [11].

A. ANATOMY The average length of the human male pendulous penis is 8.8 cm flaccid, 12.4 cm stretched and 12.9 cm erect with neither patient age nor size of the flaccid penis accurately predicting erectile length [1]. In another study, erect penile length varied from 10-20 cm with an erect thickness of 3-5 cm [2]. The penis is composed of three bodies of erectile tissue; the corpus spongiosum, encompassing the urethra and terminating in the glans penis; and the two corpora cavernosa which function as blood-filled capacitors; providing structure to the erect organ [3-5]. In this section we will discuss the anatomical composition of the three erectile tissues of the penis, the nerve and blood supply and the connective tissue and fascia which together make up the intact penis.

The tunica albuginea is a multilayered structure of inner circular and outer longitudinal layers of connective tissue encompassing the paired corpora cavernosa [13-15]. An incomplete septum separates the two corpora cavernosa and anchors into the circular inner layer of the tunica albuginea. In the distal pendulous penis, intracavernous pillars anchor the tunica across the corpora cavernosa at the two- and six-o’clock positions with minor struts branching off these pillars at the five- and seven-o’clock positions [15]. It has been demonstrated that tunical thickness varies from 1.5 to 3 mm thick depending on the circular position around the tunica [13-15]. The longitudinal outer layer which provides strength to the tunica albuginea is absent at the six-o’clock position where the corpus spongiosum fits in the indentation between the two corpora cavernosa [15]. It has been proposed that this design allows unrestricted expansion of the corpus spongiosum so that ejaculation is unimpeded during penile erection [15]. The longitudinal layer is also thinnest at the three- and nine-o’clock positions, consistent with the greatest number of traumatic penile fractures in those positions [14]. The tunica albuginea is composed of fibrillar (mainly type I but also type III) collagen in organized arrays interlaced with elastin fibers [15]. While collagen has a greater tensile strength

The corpora cavernosa are a unique vascular bed consisting of sinuses (the trabeculae) whose arterial blood supply arises from the resistance helicine arteries (figure 1); which in turn are fed from the deep penile cavernosal artery [3-5]. The trabeculae are drained by the subtunical venules that coalesce to form the emissary veins which in turn communicate with the cavernosal veins (figure 2). The penile arterial and venous supply are discussed in greater detail below. The lacunae have measured blood PO2 of 20-40 mmHg when the penis is in the flaccid state [6-8]. This venous-like flaccid blood PO2 increases upon erection with dilation of the helicine arteries to 90-100 mmHg, [6] and these changes in oxygen tension directly impact both the physiologic function and trabecular structure of the corpora cavernosa (see pathophysiology section) [9-10]. Histologically, the corpora are composed primarily of trabecular smooth muscle (40%-50%) and connective tissue

67

Figure 1: Scanning electron microscopic study of a cast of penile microcirculation. It shows an helicine artery opening directly into a lacunar space. Helicine arteries regulate the amount of blood entering into the lacunar spaces acting as resistance vessels. After the proper stimulus, the muscle surrounding the artery relaxes, increasing the blood flow and pressure delivered to the lacunar spaces. (Courtesy of Dr. Yoshiaki Banya).

Figure 2: Scanning electron microscopic study of the venous system of the corpus. A dense plexus of venules that drain the lacunar spaces can be seen beneath the tunica albuginea. This veins coalesce to form the emissary veins. (Courtesy of Dr. Yoshiaki Banya).

68

than steel, it is unyielding. In contrast, elastin can be stretched up to 150% of its length [15 ]. It is the elastin content that allows the compliance of the tunica albuginea and helps to determine stretched penile length [16]. Disorganization of the circular or longitudinal layers in the tunica as well as disruption of elastin or a decrease in elastin content can result in penile deformities during erection as well as erectile dysfunction. Further, damage to the tunica albuginea can result in site-specific leakage or undermining of the draining tunical venules [17].

logic studies implicate the parasympathetic nervous system as the primary effector of penile erection. The neurophysiology of erection is dealt with in greater detail elsewhere in this volume. Neural innervation of the penis may be divided into autonomic (parasympathetic and sympathetic) and somatic (sensory and motor) [3,5,18]. Parasympathetic preganglionic fibers originate from the second to fourth sacral vertebra and proceed to the pelvic or hypogastric plexus. This plexus serves as a relay station for preganglionic and postganglionic fibers to the penis. The cavernous nerve begins at the pelvic plexus and travels through the pelvic fascia to the prostatic capsule where it goes across the posterolateral aspect of the prostate. Distal to the membranous urethra, branches of the cavernous nerve penetrate the tunica albuginea of the corpus spongiosum. Other branches enter the crura of the corpora cavernosa along the pudendal artery and exiting cavernous veins. The remaining branches proceed down the dorsal nerve to innervate distal portions of the penis. Sympathetic preganglionic fibers arise preganglionic neurons from ninth thoracic and fourth lumbar vertebra. These neurons interface with sympathetic chain neurons at the level of the spinal cord and proceed downward to the superior hypogastric plexus. This plexus divides into the right and left hypogastric nerve. One of these branches then interfaces with the pelvic plexus. Sensory stimuli elicited in the glans, penile, and other perineal and inguinal areas are originated in sensory receptors whose nerve fibers converge to form the dorsal nerve of the penis. This nerve joins other pelvic nerves to become the internal pudendal nerve, ascending to the dorsal root of the second, third and fourth sacral vertebra. Motor innervation of the penis derives from the second, third and fourth sacral vertebra within the sacral nerves which lead to the pudendal nerve that reaches the bulbocavernous and ischiocavernous muscles. Contraction of the latter muscle is important in the rigid erection phase by constriction and compression of the corpora cavernosa while rhythmic contraction of the bulbocavernous muscle is important for the expelling of semen during ejaculation [3,5,18].

The corpus spongiosum has a similar histologic appearance to the corpus cavernosum in that it is a spongy erectile tissue, but this erectile tissue does not provide structure to the erection. The intraspongiosal pressures are one-third to one-half that of the corpora cavernosa; an advantage in that this lower pressure may prevent urethral blockage during ejaculation [5]. This may also be the reason for the absence of longitudinal tunical fibers in the sixo’clock position of the tunica albuginea, such that the urethra is not restricted during ejaculation [15]. Three sets of peripheral nerves have a role in erectile function: thoracolumbar sympathetic, sacral parasympathetic, and sacral somatic (figure 3). The pelvic plexus (occasionally referred to as the inferior hypogastric plexus in humans) found in the pelvic fascia on either side of the lower genitourinary tract and the rectum is also a very important site for the integration of autonomic input to the penis via the cavernous nerves (see below). The efferent limb originates in the parasympathetic center in the sacral cord, which contributes fibers to the pelvic nerve that enters the cavernosal tissue as the cavernous nerves. Careful attention to preserving these nerve tracts has gained importance in radical pelvic cancer surgery in the potent patient. In the brain, several regions modulate the psychogenic component of erection, including the thalamic nuclei, the rhinencephalon, and the limbic structures, with integration of these various areas occurring in the preoptic anterior hypothalamic area [18]. Input from the brain involves descending spinal pathways and is relayed through both lumbar sympathetic and sacral parasympathetic outflows to the penis. Anti-erectile sympathetic efferent pathways arise in paravertebral sympathetic chain ganglia and course to the penis primarily through hypogastric and pudendal nerves. Physio-

The arterial blood supply of the penis is primarily via the hypogastric artery [3-5].The internal pudendal artery branches off the hypogastric artery and proceeds through Alcock’s canal becoming the common penile artery (figure 4). However, 69

Figure 3: The pelvic plexus

Figure 4

70

accessory internal pudendal arteries arising from the obturator or other pelvic arteries are not uncommon. The internal pudendal artery splits into the bulbourethral, dorsal, and cavernosal arteries. The bulbourethral artery supplies the urethra and the glans while the cavernosal arteries enter the corpora cavernosa at a point where the two crura converge. As the cavernosal arteries proceed proximally, they lie in the middle of the corporal bodies. The cavernosal arteries give rise to the helicine resistance arteries which in turn feed the individual trabeculae. The paired dorsal penile arteries proceed down the penis in the eleven and one-o’clock positions along with the dorsal nerves and supply superficial structures in the penis as well as potentially supplying the corpora cavernosa via circumflex arteries. Thus the dorsal penile artery can supply the cavernous tissue with multiple branches along the shaft of the penis as a normal variant. There can also be rich anastomotic networks of vessels between the arteries of the pelvic area, and one side may also supply both corporeal spaces as a normal variant.

glans and many of the circumflex vessels anastomosis with small tributaries from the spongiosum. The deep dorsal vein in the infrapubic region (where it can also receive tributaries from the prepubic fat) usually consists of one trunk that drains into the pelvic preprostatic venous plexus or the internal pudendal veins. The deep penile drainage system consists of the cavernosal and/or crural veins that drain the deeper cavernous tissue. The cavernosal veins are in fact extensions of emissary veins from the infrapubic cavernous tissue that drain directly into the pelvic plexus or the deep dorsal vein in the deep infrapubic area. The crural veins are direct emissary veins from the antero- to posterolateral surface of the crura of the cavernous tissue that usually drains into the internal pudendal veins or the pelvic plexus. The penile skin is continuous with that of the abdominal wall and covers the glans penis as the prepuce to reattach at the coronal sulcus [4]. The underlying Colles’fascia is continuous with Scarpa’s fascia of the lower abdominal wall. The deep layer of penile fascia, Buck’s fascia, covers both corpora cavernosa and the corpus spongiosum in separate fascial compartments. This fascia layer has a dense connective tissue structure and is attached proximally to the perineal membrane and distally to the coronal sulcus where it fuses with the corpora cavernosa. Buck’s fascia gives rise to the suspensory ligament of the penis which attaches to the pubic symphysis. Colles’ fascia also gives rise to the fundiform ligament which, superior to the suspensory ligament, attaches to the public symphysis as well. Both of these ligaments are important in maintaining penile position during erection. The bulbocavernosal and ischiocavernosal muscles are inferior to Colles’ fascia but superior to Buck’s fascia.

The venous drainage system of the penis occurs on three levels: superficial, intermediate, and deep [3-5]. The superficial venous system, which lies above Buck's fascia and primarily drains the penile skin, can also have anastomotic connections to the deep dorsal vein. This superficial system drains into the femoral vein via the saphenous and the external pudendal veins. The intermediate system consists of the deep dorsal and circumflex veins. The trabeculae of the corpora cavernosa drain into a system of sub-tunical venules that coalesce on the outer surface of the cavernous tissue just beneath the tunica albuginea of the corpus cavernosum [3-5]. These venules form a number of veins transversing the tunica albuginea called emissary veins which usually drain into the circumflex veins on the outer surface of the tunica albuginea. The circumflex veins in turn drain into the deep dorsal vein of the penis shaft between the dorsal arteries usually lying just laterally adjacent, all beneath Buck's fascia. Occasionally, the deep dorsal vein consists of more than one trunk on the most distal shaft of the penis, and occasionally the deep dorsal vein receives direct emissary veins from the cavernous tissue in the dorsal midline. The deep dorsal vein near the glans penis is also initially constituted by numerous trunks from the

Lymphatic draining of the penile skin and prepuce proceeds towards the presymphyseal plexus where it divides right and left joining the lymphatics from scrotum and perineum [4]. Here they travel along with the external pudendal blood vessels to junction with the superficial inguinal lymph nodes. The lymphatics of the penile glans and urethra drain via the deep inguinal and presymphyseal lymph nodes and occasionally drain into the external iliac lymph nodes [4].

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extracellular calcium entry for the maintenance of the contractile tone.

B. PHYSIOLOGIC REGULATION OF PENILE SMOOTH MUSCLE CONTRACTILITY

Adrenergic stimulation causes vasoconstriction of the penile arteries and contraction of the trabecular muscle which results, respectively, in the reduction of the arterial inflow and in the collapse of the lacunar spaces. The contraction of the trabecular muscle causes decompression of the drainage venules from the cavernous bodies, allowing the venous drainage of the lacunar spaces [23-25]. Even though the role of the adrenergic neuroeffector system as mediator of detumescence of the erect penis has been demonstrated, its role in the maintenance of penile flaccidity is not clearly defined. An important argument against an ? adrenergic mechanism in the maintenance of the flaccidity of the penis is the observation that the intracavernosal injection an ? -adrenergic receptor blocker, in the absence of other stimuli, does not cause an erection. However, ? -adrenergic blockers are effective in prolonging the duration of an already established erection.

The state the contractile tone of penile smooth muscle (arterial and trabecular) determines the hemodynamic events that induce erection or maintain penile flaccidity (figure 5). The contractile activity of the penile muscle (arterial and trabecular) is regulated by several factors: adequate levels of agonists (neurotransmitters, hormones, and endothelium-derived substances), adequate expression of receptors, integrity of the transduction mechanisms, calcium homeostasis, interaction between contractile proteins, and effective intercellular communication among smooth muscle cells (gap-junctions) [19].

I. PENILE SMOOTH MUSCLE CONTRACTION

The peptide endothelin and some eicosanoids (PGF2 ? , thromboxane A2) are candidates for participation in the maintenance of penile flaccidity. Endothelin-1 is a member of a family of three peptides, discovered in 1988 [26]. This peptide is a potent constrictor synthesized by the lacunar endothelium and, possibly, by the trabecular muscle itself [27,28]. Its presence and constrictor activity in human cavernous tissue suggests the participation of this peptide in the regulation of trabecular smooth muscle contractility. It has been also demonstrated that endothelin potentiates the constrictor effects of catecholamines on trabecular smooth muscle [29]. Two receptors for endothelin, ETA and ETB, mediate the biological effects of endothelin in vascular tissue. ETA is the principal mediator of the contraction in response to endothelin while ETB prevails in endothelium, mediating a endotheliumdependent vasodilator response. The mechanism of intracellular transduction for both receptors is the activation of the metabolism of inositol-phosphate, with release of intracellular calcium and activation of protein kinase C (PKC).

The contraction of smooth muscle depends on the rise, relatively rapid, of the intracellular concentration of free calcium. This concentration must be maintained above baseline level for the maintenance of the contractile tone. Several mechanisms are activated favoring entry of calcium from the extracelular compartment and/or the release of calcium accumulated in intracellular organelles; mainly the sarcoplasmic reticulum [20].

•ALPHA-ADRENERGIC MECHANISMS Locally, the detumescence of the erect penis is mediated by adrenergic nerve terminals whose neurotransmitter, norepinephrine, activates adrenergic receptors. Contraction of human penile arteries and trabecular smooth muscle is largely mediated by ? 1 adrenergic receptors [20,21]. The ? 1d and ? 1a subtypes are the ones expressed with higher density in the trabecular muscle [22]. The ? -adrenergic receptors can also be stimulated by circulating catecholamines (norepinephrine as well as epinephrine) (figure 6). Contraction mediated by ? 2-receptors depends on the entry of calcium from the extracellular compartment while the activation of ? 1 receptors provokes the release of intracellular calcium, initially, with subsequent

Several constrictor prostanoids, including PGH2, PGF2 ? and thromboxane A 2 (TXA2) are synthesized by the human cavernous tissue. In vitro studies have demonstrated that prostanoids are res-

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Figure 5: Schematic representation of the structures involved in penile erection. In flaccidity (top) constrictor tone is predo minant, producing a low flow and low pressure state in lacunar spaces. Penile erection (bottom) requires the vasodilatation of cavernosal and helicine arteries and the relaxation of trabecular smooth muscle, expanding the lacunar spaces and tunica albuginea. This fact produces an elongation of subtunical venules, reducing their diameter and increasing the resistance to outflow (veno-occlusive mechanism).

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Figure 6: Schematic representation of the regulation of contractile tone of penile smooth muscle by adrenergic mechanisms. NE, norepinephrine; NO, nitric oxide; 1, -adrenergic receptor type 1; 2, -adrenergic receptor type 2; 2, -adrenergic receptor type 2.

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ponsible for the tone and the spontaneous activity of isolated trabecular muscle [30]. Also it has been observed "in vitro" that constrictor prostaglandins, simultaneously released with nitric oxide, attenuate the dilator effect of this substance [31]. The correlation of these in vitro findings with the physiological regulation in vivo is not yet established.

isoforms of NOS have been identified in the cavernous body, the presence or the possible physiological role of the inducible form, in this tissue, is yet to be determined. Unlike many other regulatory substances, such as the classic neurotransmitters (acetylcholine, noradrenaline) or growth factors, nitric oxide does not have a specific receptor on the cellular membrane. Nitric oxide crosses the plasma membrane of the cells targeting the enzyme guanylate cyclase, producing a conformational change in the molecule that increases its activity. Activated guanylate cyclase catalizes the conversion of guanosine-5"triphosphate (GTP) to 3', 5' cyclic guanosine monophosphate (cGMP) (figure 8). The accumulation of cGMP sets in motion a cascade of events at the intracellular level which induce a loss of contractile tone. These include: hyperpolarization, closure of voltage activated calcium channels, sequestration of calcium by intracellular organells, decrease in intracellular calcium and, probably, changes in the affinity of the contractile apparatus for calcium (figure 9). Many are the experiments that demonstrate, both in vivo and in vitro, an essential role for nitric oxide in the erection of the penis [6, 35-45]

II. PENILE SMOOTH MUSCLE RELAXATION Dilation of the penile arteries (cavernous artery and helicine arteries), is the first event in the development of erection. Its consequence is the increase of blood flow and pressure into the lacunar spaces. Following arterial dilation, the trabecular muscle relaxes increasing the compliance of the lacunar spaces to its expansion facilitating the accumulation of blood. The relaxation of the muscle depends on endocrine (circulating substances), paracrine mechanisms (neurogenic and endothelial) as well as, possibly, on autocrine mechanisms (release of vasodilator substances generated in the muscle) (figure 7).

1. ROLE OF NITRIC OXIDE AND THE CGMP PATHWAY

2. THE CAMP PATHWAY

Nitric oxide (NO) is a free radical (the molecule has an electron in excess), therefore it is a highly reactive and chemically unstable molecule. It is now known that this molecule is synthesized in different types of cells in mammals and that it is a modulator of several biological activities including: endothelium-dependent dilation of blood vessels, inhibition of platelet-aggregation, macrophage cytotoxic activity, and also has a role as a neurotransmitter in the peripheral and central nervous system [32]. The constitutive forms of nitric oxide synthase (NOS), located in nerves (nNOS) and endothelium (eNOS), use the amino acid arginine and molecular oxygen to produce nitric oxide and the amino acid citrulline [33,34]. This reaction requires a series of co-factors, among them NADPH, tetrahydrobiopterin and calcium-activated calmodulin. The inducible form of this enzyme, whose expression in cells occurs after the stimulation with cytokines, does not require calcium activated calmodulin as cofactor [33,34]. While the constitutive

Vasoactive intestinal peptide (VIP), in the autonomic nerves, prostaglandin E (PGE1 and PGE2), synthesized by the smooth muscle, and neural or circulating catecholamines (norepinephrine and epineprine), stimulate specific receptors coupled to Gs proteins with stimulation of the adenylate cyclase, that catalyzes the formation of cAMP (figure 7). This is an efficient route for the relaxation of the smooth muscle of the penis, as demonstrated by the erectogenic effect of intracavernosal PGE1 administered for the treatment of impotence. It is probable that the coordinated activation of both pathways, cGMP and cAMP, participate in the physiology of erection. During the 80's great attention was given to VIP as the possible mediator of erection. This proposal was based on the observation of nerve fibers that contained VIP in cavernous tissue and that exogenous VIP was a potent relaxant of the smooth muscle of the penis [46-48]. Furthermore, the intracavernosal administration of VIP caused tumescence and rigid erection in some individuals [49].

75

Figure 7: Schematic representation of the processes leading to penile smooth muscle relaxation. E, epinephrine; EP-R, pros tanoid receptor type E; Na+-pump, Na+/K+-ATPase; NE, norepinephrine; NO, nitric oxide; PGE, prostaglandin E; VIP, vasoactive intestinal peptide; VIP-R, VIPreceptor; 2-AR, -adrenergic receptor type 2.

Figure 8: Schematic representation of nitric oxide generation and action pathway in penile smooth muscle and the processes involved in its regulation. NO, nitric oxide; NOS, NO synthase; O2, superoxide anion; PDE5, phosphodiesterase type 5, 2-AR, -adrenergic receptor type 2.

76

nels, hyperpolarizing the cell. This effect on K+channels can be provoked by the cAMP-dependent protein kinase (PKA), by the cGMP-dependent protein kinase (PKG) or by cGMP itself. The activation of potassium channels (of the "maxiK+" type) by the action of the PGE1, an effect mediated by cAMP, has been demonstrated [54]. It has also been demonstrated that relaxation of penile arteries is inhibited, in part, upon blocking of calcium-dependent K+-channels [38]. Hyperpolarization causes the closure of voltage-dependent calcium channels, therefore reducing the calcium entry from the extracellular compartment, with decrease in the concentration of intracellular free calcium and subsequent relaxation of the muscle.

The discovery of the role of nitric oxide diverted the interest from VIP to the new molecule. Recently, the co-localization of VIP and nNOS in nerves within the corpus cavernosum has been reported [50]. This has revived once more the concept of co-transmission in this tissue and the interest in VIP. The two molecules, VIP and NO, would induce relaxation in the muscle by two different, and potentially synergistic, pathways. Selective release of neurotransmitters depending on the stimulation frequency has been demonstrated. Thus, for example, nitric oxide would be released at low frequencies, while the largest release of VIP would occur with high frequencies. The precise physiological role of this modulation in the release of neurotransmitters in erection is not known. VIP receptors in the cavernous body are coupled to Gs proteins that stimulate the catalytic activity of adenylate cyclase with formation of cAMP (figure 10). Prostaglandin E1 and E2 are the most abundant prostanoids synthesized by the smooth muscle of the penis. It is not known if the endogenous prostanoids participate in the regulation of penile smooth muscle contractility, although preliminary evidence supports such a role for PGE. The receptor (s) that mediates trabecular relaxation to PGE is designated as the EP receptor. The specific subtype, of the four that exist in the EP family, has not been determined. The EP2 and EP4 subtypes are the most likely candidates, since they are coupled to Gs proteins which stimulate adenylate cyclase. Finally, the stimulation by catecholamines of ? adrenergic receptors causes relaxation of arterial and trabecular smooth muscle. The ? 2 subtype is probably the most important receptor mediating these effects [51-53]. Adrenaline has a high affinity for this receptor, whose stimulation counteracts in part the constrictor effects, mediated by ? -adrenergic receptors, of this catecholamine. There is evidence in the vascular system that the expression of ? 2-adrenergic receptors decreases with age, giving way progressively in the erectile tissue to the constrictor mechanisms (? -adrenergic) which would prevail.

Independent of this mechanism, provoked by the action of the cyclic nucleotides, it has been proposed that, in arteries, nitric oxide can directly stimulate the opening of potassium channels as well as the sodium-potassium ATPase (the sodium pump). This last mechanism has been demonstrated in the trabecular muscle [55]. The sodiumpotassium ATPase pump is electrogenic due to the fact that it extracts three positive charges from the cell while introducing only two. Therefore, the cell hyperpolarizes initiating the same mechanisms of closure of calcium channels decribed after the activation of K+-channels. This process represents, therefore, a mechanism for relaxation that does not depend on cyclic nucleotides.

III. REGULATION OF THE BALANCE BETWEEN THE DILATOR AND CONSTRICTOR MECHANISMS • Cholinergic nerves Erection is initiated by a sacral parasympathetic nerve input, the preganglionic neurotransmitter of which is acetylcholine. Because of this fact, it was initially assumed that post-ganglionic cholinergic nerves were the direct mediators of penile smooth muscle relaxation. As it has already been explained, it is now known that the relaxation of the smooth muscle is mediated by one or more nonadrenergic, noncholinergic (NANC) neurotransmitters.

3. RELAXATION THROUGH HYPERPOLARIZATION OF THE MUSCULAR CELL One of the mechanisms by which the cyclic nucleotides induce relaxation of the smooth muscle is through the opening of potassium chan-

Nevertheless, cholinergic nerves are present in the cavernous body and seem to have a modulator role

77

Figure 9: Schematic representation of the mechanisms involved in penile smooth muscle relaxation by the cGMP pathway. GC, guanylate cyclase; IP3, inositol triphosphate; PKA, protein kinase A; PKG, protein kinase G; PLB, phospholipase B; PLC, phospholipase C; NO, nitric oxide.

Figure 10: Schematic representation of the mechanisms involved in penile smooth muscle relaxation by the cAMP pathway. AC, adenylate cyclase; EP-R, type E prostanoid receptor; Gs, stimulating G-protein; IP3, inositol triphosphate; PGE, prosta glandin E; PKA, protein kinase A; PKG, protein kinase G; -R, -adrenergic receptor.

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on the other neuroeffector systems. Adrenergic nerves receive inhibitory interneuronal cholinergic modulation. The interaction of acetylcholine with muscarinic receptors in the adrenergic nerves reduces their release of noradrenaline [21,56]. This prejunctional regulation, therefore, would favor erection through the decrease of constrictor adrenergic tone. Cholinergic nerves also seem to modulate NANC nerves but, in this case, they facilitate or potentiate the vasodilator response mediated by these nerves [56]. The specific underlying mechanism of this facilitation remains unidentified. In summary, cholinergic activity in the cavernous body would have a modulatory role facilitating erection, on the one hand reducing constrictor tone (adrenergic) and on the other facilitating NANCmediated relaxation.

by the increase in adrenergic activity would have two components: one direct, constrictor, on the smooth muscle, mediated by ? 1 and ? 2 receptors and other one indirect, in which the vasodilator effect of nitrergic nerves is inhibited by a prejunctional, ? 2 adrenergic-mediated mechanism.

3. MOLECULAR OXYGEN OF PENILE ERECTION

The precise physiological role of the endogenous prostanoids has not been clearly established. Prostacyclin is produced by the endothelium and participates, probably together with the nitric oxide, in the regulation of homeostasis between the trabecular wall and the blood. Prostaglandins E (E1 and E2) are the most abundant prostanoids synthesized by the cavernous muscle. In addition to their role as a relaxants of trabecular muscle, previously mentioned, and that of regulators of the collagen synthesis [57], PGE also modulates adrenergic nerves through a prejunctional mechanism. It has been demonstrated in human cavernous tissue that PGE1 inhibits the release of noradrenaline by adrenergic nerves [58]. Prostaglandins E, therefore, promote erection by their direct relaxant effect on the muscle and by their indirect effect of reduction of adrenergic tone. Certain prostanoids, such as PGD2, have the opposite effect, since they facilitate the release of noradrenaline by adrenergic nerves [58]. OF

MODULATOR

The partial oxygen pressure (PO2) in the blood of the cavernous body during the flaccid state is similar to that of venous blood (~ 35 mmHg). However, during the erection, due to the increase in arterial blood entering the lacunar spaces, the PO2 increases to approximately 100 mmHg (i.e. the corpora cavernosa are arterialized) [7]. Molecular oxygen is a substrate, together with L-arginine, for the synthesis of nitric oxide mediated by NOS. In corpus cavernosum tissue, it has been demonstrated that the synthesis of nitric oxide is directly regulated by the oxygen concentration [7]. At the low oxygen concentrations that are measured in the cavernous body in the flaccid penis, the synthesis of nitric oxide is profoundly inhibited, blocking, therefore, endothelium and neurogenic relaxation of the trabecular muscle. This would help in the maintenence of penile flaccidity since it facilitates constrictor tone by supressing relaxation.

1. REGULATION OF THE ADRENERGIC ACTIVITY BY PROSTANOIDS

2. ADRENERGIC REGULATION NERVES

AS A

After arterial vasodilatation, the oxygen concentration in the cavernous bodies rises providing sufficient substrate (O2) so that nitric oxide is synthesized. It has been estimated, after "in vitro" studies, that the minimal concentration of oxygen in the cavernous bodies necessary to reach a full activity of the nitric oxide synthase is between 50 and 60 mmHg. Inferior concentrations would induce a partial synthesis of nitric oxide with, subsequent, partial relaxation of the trabecular muscle. In a similar way to the nitric oxide synthase, the prostaglandin H synthase (the ciclooxygenase) is also a oxygenase and uses oxygen as substrate for the synthesis of prostanoids. It has been demonstrated that the oxygen concentration to which the cavernous bodies are exposed regulates the synthesis of prostanoids [60]. In the case of the PGE, the relaxing prostaglandin of the trabecular muscle, physiological variations in the oxygen concentration will condition its endogenous production: inhibited in flaccidity and stimulated in erection.

NANC

In intracavernosal arteries from experimental animals, prejunctional regulation of NANC nerves by ? 2 adrenergic receptors has been demonstrated. The activation of these adrenergic receptors inhibits vasodilation induced by nitrergic nerves [59]. This regulation suggests that termination of the erection

79

The synthesis of the vasoconstrictor, endothelin, is also subject to modulation by the oxygen concentration. In this case low oxygen concentrations (Venous) promote its synthesis and high levels (arterial) inhibit it.

one includes iatrogenic causes and mixed ED, the prevalence of neurogenic ED is probably much higher. While the presence of a neurologic disorder or neuropathy does not exclude other causes, confirming that ED is neurogenic in origin can be challenging.

This capacity of the molecular oxygen for regulating the synthesis of endogenous vasoactive substances, make of it an important modulator of the erectile activity of the penis.

1. THE ETIOLOGIES OF NEuROGENIC ED CAN BE CLASSIFIED AS: • Peripheral (peripheral ED) • Spinal (sacral-peripheral ED, suprasacral-central ED) • Supraspinal (central ED) Peripheral ED can be secondary to the disruption of sensory nerves that bring local information to the brain and contribute the afferent arm of reflex erection, or to the disruption of autonomic nerves which mediate arterial dilation and trabecular smooth muscle relaxation (See tables 1, 2, 3). ED from central origin can occur from lack of excitation or increased inhibition of central autonomic pathways.

C. PATHOPHYSILOGY OF ERECTILE DYSFUNCTION Normal erectile function requires the involvement and coordination of multiple regulatory systems and is thus subject to the influence of psychological, hormonal, neurological, vascular and cavernosal factors. An alteration in any of these factors may be sufficient to cause ED, but in many cases a combination of several factors is involved.

I. NEUROGENIC ERECTILE DYSFUNCTION

2. ERECTILE DYSFUNCTION INJURY

IN

SPINAL CORD

Men with spinal cord injury have several associated sexual dysfunctions including alterations in ejaculation, orgasm and erectile function. Patients are frequently young and face a life long perspective of difficulties in their sexual and reproductive capacities. The degree of completeness and the level of the lesion determines the erectile function of the patient [74]. In general patients with lesions above the sacral parasympathetic center maintain reflexogenic erection. In these patients minimal

Erection can be initiated in the brain (central erection) and/or follow genital stimulation (reflex erection). The combination of both is probably involved in sexual activity. Events that disrupt central neural networks or the peripheral nerves involved in sexual function can cause ED. This form of ED has been termed “neurogenic impotence”. It has been estimated that 10 to 19% of ED is of neurogenic origin [61,62]. If

Table 1: Peripheral ED LOCAL ETIOLOGIES SURGERY

TRAUMA

PELVIC PATHOLOGY

PERIPHERAL NEUROPATHIES TOXINS

M ETABOLIC DISORDERS

INFECTIOUS DISEASES

? ?Organic compounds

? ?Diabetes mellitus

? ?Leprosy

? ?Heavy metals

? ?Alcoholism

? ?HIV

? ?Peptide neurotoxins

? ?Uremia

? ?Viral infections

? ?Hypothyrodism (References 18,61,63-66)

80

OTHERS ? ?Systemic lupus erythematosus ? ?Hematochromatosis

Recovery of erectile function after radical pelvic surgery can be slow over the course of 12 to 18 months. Early treatment (with self intracavernosal administration of vasoactive agents) of these patients has been shown to improve the probability of recovering erectile function. It is believed that the pharmacologically-induced erections prevent the structural tissue changes associated with the prolonged ischemia associated in turn with infrequent or no erections during the nerve recovery process.

Table 2 : Spinal ED ?

Multiple sclerosis

?

Spinal cord injury

?

Tumor

?

Syringomyelia

?

Transverse myelitis

?

Arachnoiditis

?

Disk disease

?

Myelodysplasia

(References 67-74) Table 3 : Brain ED

II. VASCULAR ED

?

Tumor

?

Stroke

?

Encephalitis

?

Parkinson's disease

?

Various dementias

?

Olivopontocerebellar degeneration (Shy-Drager syndrome)

?

Epilepsy (temporal lobe)

Alterations in the flow of blood to and from the penis are thought to be the most frequent causes of ED. Penile arterial vasodilation and relaxation of the trabecular smooth muscle initiate erection. This allows filling of the sinusoids and entrapment of pressurized blood in the corpora cavernosa. These are the primary hemodynamic events that initiate and maintain penile erection. An increase in intracavernous pressure of 50-90 mm Hg, depending on the geometry and penile tissue factors, is required for erection with sufficient rigidity for vaginal intromission. Proximal arterial stenosis and an increase in penile vascular arterial resistance can lead to organic ED. A higher prevalence of ED is observed in patients with cardiovascular risk factors, such as hyperlipidemia, hypertension, smoking and diabetes. The prevalence of ED is increased with the accumulation of cardiovascular risk factors, as occurs in cardiovascular disease. Indeed, ED can be a symptom of vascular disease. The association of impotence with vascular disease is well-documented in the literature. Prolonged illness has been thought to account for a great portion of the decline in sexual function with aging. Alterations in corpus cavernosal arterial inflow (CAI) and corporal veno-occlusive dysfunction (CVOD) are thought to be the two most frequent causes of organic erectile dysfunction. Both CAI and CVOD have been reported in patients with hypertension, myocardial infarction, cerebrovascular accidents, peripheral vascular disease and following coronary arterial bypass surgery. Wabrek reported ED in 64% of the 131 males aged 31-86 years hospitalized for acute myocardial infarction [80].

(References 61,75,76)

tactile stimulation can trigger erection, albeit of short duration requiring continuous stimulation to maintain erection [74]. If the lesion is incomplete patients can receive input from psychogenic erection and maintain erectile function. Patients with significant lesions affecting the sacral parasympathetic center do not have reflex erections and have severe erectile dysfunction [74].

3. ERECTILE DYSFUNCTION PELVIC SURGERY

AFTER

RADICAL

The mechanism of erectile dysfunction after radical prostatectomy or cystoprostatectomy is usually neurologic but can also be vascular (due to disruption of anomalous pudendal arteries that course the anterior aspect of the prostate) [77]. The neurologic lesion occurs in the pelvic plexus or in the cavernosal nerves located in the postero-lateral aspect of the prostate. The incidence of erectile dysfunction after radical bladder or prostate surgery was, in the past in the vicinity of 100 %, but has improved with the introduction of nerve-sparing procedures. Maintenance of erectile capacity with these techniques varies between 35% and 68% depending on the surgical technique, the clinical and pathological staging of the tumor and the age of the patient [78,79]. 81

Several studies have correlated a prevalence of ED with an increasing number of vascular risk factors [81]. Shabsigh et al. reported that smoking, diabetes, and hypertension are risk factors for vasculogenic ED, and abnormal penile vascular findings increased significantly as the number of risk factors increased with ED. Virag et al. investigated distribution of four main arterial risk factors of diabetes, cigarette smoking, hypertension, and hyperlipidemia. A physiologic cause was reported in 80%, with 53% reported to be in the arterial atherosclerotic group and 34% secondary to hypercholesterolemia. The study concluded that hypertension, smoking, diabetes, and hyperlipidemia were all significantly more common in this cohort than in the general population. In summary, the major factors for vasculogenic ED are diabetes mellitus, hypertension, hypercholesterolemia, peripheral vascular disease, smoking, and coronary arterial disease.

[83]. The cause for erectile dysfunction in these patients can probably be ascribed to the presence of a flow limiting stenosis caused by atherosclerotic lesions in the penile large arteries. The atherosclerotic lesions extend to the cavernous arteries in men with erectile dysfunction [84, 85,86]. Atherosclerotic disease is associated with a reduced blood flow to the corpora cavernosa during erection. In a rabbit model where proximal atherosclerotic lesions were induced by ballon-deendothelizatioin of the iliac arteries and by feeding a cholesterolrich diet, this was followed by vasculogenic erectile dysfunction [87]. The erectile dysfunction in these animals can probably be ascribed to both a limited iliac blood flow and corporal venoocclusive dysfunction due to a decreased expandability of the trabecular smooth muscle [88,89]. The authors have later in the same animal model demonstrated that the chronic ischaemia provoked by the proximal iliac stenosis is also associated with functional changes in the distal part of the penile vasculature such as decreased NOS activity, reduced endothelium-dependent and neurogenic NO-mediated relaxation in cavernosal tissue [90,91] (figure 11). The changes were not altered by L-arginine supplementation. NO inhibits endothelial eicosanoid and superoxide production [92]. This observation may explain that in the rabbit model the impaired NO formation is also associated with increased production of contractile thromboxane and prostaglandin formation and potentiation of neurogenic contractions of the cavernosal smooth muscle [90,91]. Indomethacin partially restored the functional changes of the NO/cGMP-pathway. In the latter studies the reduced NOS activity in these rabbits can probably be explained either by decreased NOS expression or reduced enzyme activity. The above-mentioned studies, although extensive, are concerned with the combined effect of hypercholesterolemia and ischaemia and do not allow for distinction of the influence of chronic ischaemia alone on the erectile tissue. Moreover in the cholesterol-fed rabbit model the plasma cholesterol is extremely high (925 mg/dl or 20-25 mmol/l), [90] and it also increases liver weight [93,94] probably leading to an altered metabolization of the steroid hormones and hence expression of NOS in erectile tissue.

Cavernosal arterial insufficiency (CAI) and CVOD are the main factors resulting in vasculogenic ED in diabetic patients. The incidence of impotence is noted at earlier ages in diabetics than in the general population. The prevalence of impotence in diabetes has been estimated at 35%-50%, and in some reports the percentage was as high as 75%. Deterioration of sexual function was the first symptom in 12% of diabetics. The incidence of impotence in diabetes has been found to be agedependent: 15% at 30 years and 55% at 3460 years. Other investigators have reported that at ages 20-29, 9% of diabetics complained of ED, and up to 50% of patients with diabetes were impotent within 10 years of their diagnosis. While there was no statistical correlation between the duration of diabetes and ED, Rubin also reported that 45% of men with diabetes of more than five years developed impotence and diabetes in conjunction with hypertension increasing the incidence to 80% [82].

1. ED IN ATHEROSCLEROSIS AND HYPERCHOLESTEROLEMIA

Originally arterial disease and impotence were linked by the French surgeon Leriche, who in 1940 noted that a majority of patients with occlusive arterial disorders at the bifurcation of the aorta into the two major arterial trunks of the common iliac arteries suffered from failure in erectile capacity

In summary, atherosclerotic lesions in the penile

82

Figure 11 : Pathophysiology of erectile dysfunction in vascular disease.

large arteries are flow limiting and the disease can extend to the cavernosal arteries. The chronic ischaemia is associated with alterations of both endothelial and neuronal NO/cGMP-pathways and structural changes of the corpus cavernosum.

[100,101]. The cholesterol-fed rabbit ultrastructural studies of corpus cavernosum have also revealed an early atherosclerotic process in the cavernosal sinusoids [102]. In contrast to the endothelial NO/cGMP-pathway, the neuronal vasodilation does not appear to be affected in hypercholesterolemic rabbits [90]. The selective affection of the endothelial NO/cGMP-pathway in hypercholesterolemia could be ascribed to an increased superoxide production of NOS inhibitors such as LNMMA and ADMA. L-arginine supplementation reverses the impairment of the endotheliumdependent relaxations [90], and this observation supports the suggestion that endothelial dysfunction is due to an increased endogenous production of NOS inhibitors. Further studies are needed to clarify whether hypercholesterolemia has induced structural and functional changes in the distal part of the penile vascular bed in patients with erectile dysfunction.

Besides the changes induced in the penile vascular bed by atherosclerotic lesions in the large or conductive arteries, hypercholesterolemia appears to have an effect "per se" on the vasculature. Oxidized low density lipoproteins (ox-LDL) inhibit the endothelium-dependent NO-mediated relaxations in rabbit large arteries [95], but this does not appear to be the case in small systemic arteries [93,94] or the trabecular smooth muscle [96]. In the latter study the lipoproteins did not interfere with the NO/cGMP-pathway, but ox-LDL induced contractions [96], and these contractions are probably mediated through increases in intracellular inositol phosphate and calcium [97]. In contrast, chronic hypercholesterolemia reduces endothelium-dependent relaxations in the corpus cavernosum [98,99]. It has earlier been found that endothelium-dependent relaxation was impaired only in systemic arteries with atherosclerotic lesions

Lipid-lowering therapy in hypercholesterolemic patients improves endothelium-dependent vasodilatation measured in the forearm of hypercholesterolemic patients probably due to an increased bio-

83

availability of NO [103]. This underlines the fact that the dysfunction of the endothelial NO/cGMPpathway in hypercholesterolemia is reversible. However, it remains to be elucidated whether this is also the case for penile vasculature.

tor for the subsequent development of persistent ED. The pathophysiology of traumatic erectile impairment is multifactorial. Both psychogenic and hemodynamic factors have been reported with incidence of 4% and up to 80%, respectively. A retrospective nine-year review revealed CVOD prevalence in 62% and cavernosal arterial insufficiency in 70% of patients. Another study reported 52% incidence of ED in patients who self-reported potency prior to the trauma. It has been proposed that the traumatic CVOD occurs as a consequence of focal trauma-induced changes in corporeal tissue compliance [11].

2. ED IN HYPERTENSION Hypertension is a major risk factor associated with atherosclerotic disease, stroke and myocardial infarction, and antipypertensive treatment reduces both morbidity and mortality [104]. The genesis of hypertension is unknown in the majority (95%) of hypertensive subjects. The disease is characterized by an increased peripheral vascular resistance [105]. Several studies have reported an increased vasoconstrictor and decreased endotheliumdependent vasodilation in spontaneously hypertensive rats [106]. It remains controversial whether essential hypertension is characterized by impaired endothelium-dependent vasodilation to specific agonists in vivo [107]. Several mechanisms have been suggested for this impairment: 1) a reduced endothelial synthesis of NO due to either a disturbed signal-transduction pathway and /or a reduced activity of NO synthase, 2) an accelerated NO degradation within the vessel wall [107], or

4. DIABETES Diabetes mellitus (DM) is a common chronic disease throughout the world with a prevalence of 0.5-2%. It is characterized by hyperglycaemia secondary to lack of insulin (Type I, insulin dependent DM), or insulin insensitivity (Type II, noninsulin dependent DM) which leads to pathological changes in a number of cellular and organ systems. There is good epidemiological evidence of a causal link between diabetes and erectile dysfunction (ED) [111]. The prevalence of ED is three times higher in diabetic men (28% versus 9.6%) [112], occurs at an earlier age and increases with disease duration, being approximately 15% at age 30 rising to 55% at 60 years [113,114]. Erectile dysfunction amongst men with diabetes is more frequent in those with co-existing neuropathy but the relationship with vascular disease is less clear. The prevalence of coronary arterial disease (20%) and peripheral vascular disease (5%) amongst men with diabetes is far higher than in the general population; both common associated physical health risk factors for ED. Impotence however appears to be equally common amongst diabetics with and without evidence of atheromatous vascular disease.

3) alterations in the vessel architecture resulting in an overall reduced dilatory capacity of the small arteries [108]. However, in studies on isolated human small arteries, the endothelium-dependent relaxation induced by acetylcholine appears to be conserved [109,110]. Therefore, the increased peripheral vascular resistance in hypertensive patients can probably be ascribed either to plasma factors inhibiting the NO/cGMP-pathway or to structural changes in the small arteries reflected as an increased wall/lumen ratio [105] (figure 11). In addition to structural changes in the small arteries, hypertension is a risk factor for atherosclerosis and such lesions in large arteries may explain the increased incidence of sexual dysfunction in untreated hypertension. However, there is an obvious lack of studies addressing these questions in the erectile tissue from animal models of hypertension and in hypertensive patients.

Diabetes mellitus may cause ED through a number of pathophysiological changes affecting psychological function, CNS function, androgen secretion, peripheral nerve activity, endothelial cell function and smooth muscle contractility [115]. In a particular individual the problem may be due to one or a combination of these possible factors. This section will examine the evidence for a relationship between diabetes and penile haemodynamic, endothelial and smooth muscle dysfunction.

3. PELVIC/PERINEAL TRAUMA Blunt trauma to the pelvic or perineal region of the corpora cavernosa has been considered a risk fac-

84

a) Experimental materials

• Functional studies: Men with diabetes show a reduction in the number and rigidity of nocturnal erections experienced during sleep [117]. Although this suggests an organic aetiology the test has many pitfalls; it has low predictive value and will not discriminate between vascular and neurological causes. Early diagnostic studies prior to the use of vasoactive agents relied upon the ratio of penile (measured by Doppler probe) over brachial blood pressure as an index of penile arterial insufficiency. Significantly lower values were found in diabetics compared with both potent and impotent men without diabetes suggesting penile arterial insufficiency [118]. However results showed considerable overlap as the method measured dorsal penile arterial pressure only and were conducted in the flaccid state, making the results of limited value. Reported use of artificial pharmacological erection as a test of intact penile vasculature is limited to several uncontrolled case series. In one study 40% of diabetic men with ED achieved full rigidity following intracavernosal papaverine (25 mg) compared to 70% in an unselected group of non-diabetic men with ED [119]. Studies using duplex ultrasonography following intracavernosal injection of vasoactive agents have found a high prevalence of penile arterial insufficiency amongst diabetics with ED ranging from 75 - 100%[120]. None of these studies found any differences between men with Type I or Type II DM. In general it can be said that atheromatous disease is more common in diabetic men and such disease within the penile arterial tree is associated with ED.

Due to the multifactorial aetiology of ED in DM it is difficult to isolate haemodynamic factors from other changes, particularly peripheral neuropathy. Data have been obtained from results of vascular investigation of penile blood flow in impotent men with diabetes, responses of isolated human cavernosal tissue and histological studies. Indirect evidence is provided from isolated forearm blood flow studies and experiments using other endothelial tissue or cellular preparations. The use of animal models such as streptozotocininduced diabetic rats and alloxan-induced diabetic rabbits help the design of experiments focused on particular aspects of the problem, but extrapolation to the human condition is problematic. In addition these animal models tend not to develop long term atheromatous damage, commonly seen in the human disease, because of their limited life span. A substantial body of work looking at the cause of vascular disease in diabetics is focused on changes in endothelial cell function, in particular the nitric oxide (NO)-cyclic GMP (cGMP) signal transduction pathway. Although not primarily concerned with penile erection, it seems reasonable to assume that results obtained from other vascular smooth muscle preparations will be applicable to endothelial cell - smooth muscle interaction within the corpora cavernosa. b) Haemodynamic changes Penile erection depends upon a greatly increased blood flow into the corpora cavernosa, which is in turn dependent upon perfusion pressure, relaxation of the supplying arterial tree and relaxation of cavernosal smooth muscle. Disturbances of these mechanisms can be clinically detected by anatomical studies such as angiography or functional studies such as duplex ultrasonography. •Anatomical imaging: Large vessel atheromatous disease is 40 times more prevalent amongst men with diabetes compared to non-diabetics and is more commonly associated with ED. The only angiographic study primarily concerned with diabetic patients found that stenoses of the internal pudendal and, to a lesser extent, internal iliac vessels were more severe in men with ED in both diabetics and non-diabetics [116]. Other less well characterized studies suggest a greater degree of atheroma occurring at a younger age in men with diabetes.

c) The effect of diabetes on cavernosal tissue • Structural changes: One study using electron microscopy has shown ultrastructural changes in cavernosal tissue from diabetic men compared with controls [121](figure 11). These include reduction in smooth muscle content, increased collagen deposition, thickening of the basal lamina and loss of endothelial cells. Although these changes were most marked in tissue from men with diabetes they were also seen in those with other non-diabetic causes. • Functional changes: A number of studies testing the response of isolated preparations of human cavernosal tissue to contractile and relaxant agents have found differences in tissue responses from diabetic and non-diabetic men 85

The contractile responses to ? -adrenergic agonist were similar in tissue from diabetic and non-diabetic men with impotence [123]. Recording of responses to endothelin-1, an endogenous contractile agent, revealed no change in smooth muscle responsiveness between potent men and those with ED irrespective of whether diabetes was present, suggesting that endothelin is unlikely to have a role in diabetic impotence [29]. A closer examination of the kinetics of cavernosal smooth muscle contraction suggested that tissue responsiveness to ? -adrenergic agonist was higher in men with Type I diabetes, but unchanged in Type II, this however remains to be confirmed by other studies [128]. Overall there is limited evidence suggesting that smooth muscle contractility to adrenergic stimulation may be impaired in cavernosal tissue from men with diabetes.

[122-125]. These experiments generally measure relaxant responses in tissue strips pre-contracted with ? -adrenergic agonists. The studies have consistently found a reduction in the response following stimulation of the relaxant innervation which is predominately mediated by the NO cGMP pathway. In addition relaxant responses evoked by acetyl choline which are dependent upon release of NO from the endothelium were impaired [122-124] (figure 11). In comparison to control tissue from potent men, specimens from diabetic men showed a similar impairment in relaxant responses to those from non-diabetics with severe arterial disease or veno-occlusive dysfunction, suggesting a common aetiology [123]. Relaxation evoked by nitrovasodilators such as sodium nitroprusside were similar in tissue from diabetic men with impotence, to those with nondiabetic impotence and controls, suggesting that the cellular events following NO release are not impaired [122,123]. Relaxation following PGE1, which is mediated through cAMP was significantly impaired compared to control tissue in one reported study [125]. One study has looked directly at NO formation following relaxant nerve stimulation in tissue from impotent men with and without diabetes compared to controls [126]. Neurogenic NO formation was significantly impaired amongst men with diabetes and vascular impotence compared to those with non-vascular impotence and controls. This was mirrored by reduced magnitude of the relaxant response. Subsequent cGMP formation was also reduced, although differences were less clear. These studies suggest a specific impairment in NO synthesis or release which appears common to diabetic and non-diabetic men with clinical evidence of vasculogenic impotence. Direct smooth muscle relaxation with various pharmacological agonists appears unimpaired. A possible aetiology to explain these findings is the presence of elevated levels of advanced glycosylation end products (AGEs) in diabetics which act as oxidative free radicals and quench NO as it is released, thus preventing its relaxant action on smooth muscle. One study has found increased levels of AGEs in the cavernosal tissue of impotent men with diabetes compared to a non-diabetic impotent control group [127]. The researchers went on to speculate that AGEs may increase the expression of inducible type II NOS (iNOS) which in turn down-regulates eNOS.

All such studies using human tissue report a heterogeneous group of impotent men, generally with severe erectile dysfunction. In addition sample size, particularly in potent control groups, is small, hampering firm conclusions on the data presented. It does appear that physiological pathways of relaxation of corpus cavernosum are impaired in impotent men with diabetes and that the main area of dysfunction appears to be at the level of NO synthesis and release rather than the transduction pathway within the smooth muscle cell. •Animal models: In the streptozocin-induced diabetic rat incubation of cavernosal tissue with low concentrations of sodium nitroprusside (a NO donor) resulted in higher levels of cGMP than healthy controls [129]. Similarly, incubation with PGE1 produced higher levels of cAMP in the diabetic group suggesting an intact or upregulated distal signalling mechanism. Other studies have described reduced response to receptor-mediated stimulation of endothelial nitric oxide synthase (eNOS), suggesting down-regulation of the NOgenerating mechanism. An alternative pathway of relaxation involving the release of the prostanoid, prostacyclin was also found to be impaired amongst aged diabetic rats1[130]. Increased eNOS binding found in one study suggested increased NOS production in diabetic rats [131]. This was confirmed by another study which found higher NOS levels in diabetic rat penises and not in pelvic ganglia, suggesting a tissue-specific effect [132]. The cavernosal tissue appeared intact 86

in these studies with no demonstrable histological or ultrastructural abnormality. Further studies showed that the increase in neuronal NOS (nNOS) levels in diabetic rats can return to normal following insulin therapy or treatment with free radical scavengers [133]. In addition such therapy increased expression of eNOS. Against these findings, a recent study found a significant decrease in nNOS in similar streptozocin-induced diabetic rats and could also find no induction of growth factor expression [134].

smooth muscle itself appears unaffected. This is in agreement with the findings in human tissue described above and suggests a defect in the formation or release of NO rather than in the signal transduction pathway within the smooth muscle cell. A possible pathological mechanism for these events is the NO-quenching action of elevated levels of AGEs. d) Generalized endothelial dysfunction in diabetes •Introduction: Endothelial cells form a permissive layer that regulates the flow of nutrients and the action of bioactive molecules circulating in the blood upon the underlying tissue, particularly vascular smooth muscle. This is achieved by a wide range of membrane-bound receptors and junctional proteins. The endothelium also secretes vasoactive molecules that regulate blood flow in a paracrine fashion through induction of changes in vascular smooth muscle tone. Knowledge of endothelial physiology and pathophysiology in diabetes is chiefly derived from experimental data from in vivo measurements of blood flow in human subjects and laboratory animals together with cell biological studies using endothelial cell cultures from a variety of animal and human tissues. The main clinical marker for endothelial dysfunction in diabetics is the presence of microalbuminuria indicating the presence of renal microangiopathy. This occurs in approximately 50% of diabetics, the reason why the remainder are protected is unknown.

In the alloxan-induced diabetic rabbit cGMP production in response to direct stimulation by sodium nitroprusside was unaffected [135]. However other findings in this study suggested a defect in the receptor-activated formation of prostacyclin, perhaps as a result of reduced phosphokinase C activity that has also been found in other endothelial cell preparations in laboratory animals rendered diabetic. In addition the formation of cAMP by PGE1 which would normally result in smooth muscle relaxation was impaired in the diabetic rabbit model. Increased smooth muscle tone may result from the increase in endothelin-B receptors found in one study of diabetic rabbits [136]. In the presence of high bathing sugar solutions, mimicking the hyperglycaemic state, responses of rabbit corpus cavernosus to acetyl choline were impaired. This effect was reversed by both indomethocin and superoxide dismutase suggesting the involvement of prostaglandins and free oxygen radicals [137]. There was no change to the response evoked by nitrovasodilators in this study, suggesting a mechanism through reduced activity of eNOS. In another study using alloxan-induced diabetic rabbits the relaxant response to SNP was again unaffected but neurogenic and relaxation was impaired and remained so despite insulin treatment [138]. In contrast the impairment in acetyl choline-induced relaxation via eNOS was reversed by treatment with either insulin or L-arginine.

•Vasoregulation: Nitric oxide is released from endothelial cells through the action of type III NO synthase (eNOS) located within the cellular membrane. The enzyme is activated by the binding of various agonists such as thrombin, adenosine 5’diphosphate, bradykinin, substance P and acetyl choline to specific membrane receptors and also by gene amplification stimulated by sheer stress. The released NO relaxes underlying vascular smooth muscle and may also be involved in enhancing endothelial repair following injury. The endothelium also secretes endothelium-derived hyperpolarising factor (EDHF) which enhances muscarinic receptor-mediated smooth muscle relaxation. The other major vasoactive molecule expressed by the endothelium is the potent vasoconstrictive agent, endothelin-1. This is formed by gene transcription stimulated by hypoxia, sheer

Data from animal studies is far from complete, but despite conflicting results, some tentative conclusions can be drawn which can then be fitted into the prevailing view of the aetiology of generalized diabetic vascular pathophysiology. There appears to be a consistent finding of impaired endogenous NO-evoked relaxation from both neural and endothelial sources. The contractility of cavernosal 87

stress and ischaemia. Endothelin acts through Gprotein coupled ET-A receptor activation which elevates plasma calcium and hence causes contraction. The eicosanoid, prostacyclin (PGI2) is also produced by the endothelium and acts as a paracrine signalling molecule, inducing vascular smooth muscle relaxation through the IP receptor. It is mainly implicated in the regulation of vascular tone in areas of injury or disease.

sodilators and some physiological agonists is blunted, whilst infusion of muscarinic agonists produces similar degrees of increased blood flow to control. One study has suggested that in well controlled diabetics vasoactivity appears normal. In experimental animals blood flow responses appear to be enhanced in the early stages of the disease with decreased responses becoming prevalent with increasing disease duration. Isolated reports also suggest increased endothelin levels in patients with NIDDM which may act to indirectly reduce dilator response.

The following section describing our present knowledge of the effects of diabetes on endothelial cell physiology uses a number of recent specialist reviews to which the reader is referred for more information and references of original experimental work [139-144].

• Enhancement of oxygen free radical production in diabetes: A body of evidence exists detailing various mechanisms by which levels of oxygen free radicals may be elevated in diabetes which quench released NO thereby reducing the vasodilator response. The most important appears to be the formation of advanced glycosylated end products (AGEs). These molecules formed from crosslinked products of glucose and lysine or arginine residues on various proteins and are produced in approximately four-fold greater quantities in hyperglycaemic states. They may also have a further role in endothelial cell dysfunction by increasing inflammatory cell activity. Elevated PKC levels may also induce the formation of excess free oxidative radicals. Increased sorbitol production in the diabetic state encourages hydrogen peroxide formation which again enhances quenching of NO causing oxidative stress injury. • Summary: Diabetes causes generalised endothelial cell dysfunction which results in increased prevalence of vascular disease in both type I and type II diabetics. Particular important effects are reduced activity of eNOS, diminished effect of released NO and the presence of oxidative free radicals including AGEs.

• Effect of diabetes on endothelial cell turnover: Exposure to hyperglycaemia induces increased expression of collagen, decreased proliferation and increased programmed cell death (apoptosis). This has an adverse effect on repair mechanisms, enhancing the progressive damage associated with atherosclerotic injury. Expression of the cytokine TNF-? is also increased resulting in further endothelial cell destruction. • Effect of diabetes on nitric oxide synthase: Insulin is thought to enhance NOS activity by increasing transport of L-arginine into the cell and furnishing greater quantities of the essential cofactor NADPH. These effects are reversed in the insulin lack or insulin resistance of diabetes. This enhancement of NOS activity also occurs following exposure to adenosine, a potent circulating vasodilator. Some work has suggested a decreased responsiveness of endothelial cells to adenosine in gestational diabetes. The ratio of reductase co-factors NADH/NAD+ is increased in diabetes. This reduces the levels of NADPH, an essential co-factor for NOS and increases the levels of calciumelevating second messengers such as diacylglycerol (DAG) and protein kinase C (PKC) thus increasing smooth muscle contractility.

III. ED IN END-STAGE RENAL DISEASE (ESRD)

• Effect of diabetes on nitric oxide-mediated endothelium-dependent vasodilatation:

Thirty-eight to 80% of patients with ESRD have decreased sexual activity with complete impotence in 20-60% of patients [145].

A number of human studies using arm vein plethysmography have demonstrated fairly consistent findings. Basal levels of NO-mediated endothelium-dependent vasodilation appear similar to normal controls. The response to exogenous nitrova-

The pathophysiology of ED in these patients can be multifactorial, including: endocrinologic, neuropathic, vascular and iatrogenic. 88

Vascular disease and ESRD are commonly associated. It is recognized that some patients with ESRD can develop accelerated atherosclerosis and, usually, have associated vascular risk factors also identified as risk factors for the development of erectile dysfunction, i.e. diabetes mellitus, hypertension and hyperlipidemia [86].

cent with veno-occlusive dysfunction [148]. Primary ED can be subdivided up into three basic categories 1) malformations of the erectile apparatus including the corpora cavernosa, 2) endocrinologic disorders which result in ED and

In addition to arterial disease impotent men with ESRD have a high prevalence of corporo-venoocclusive disease [86].

3) trauma to the crus and/or penis sustained in early childhood or puberty. Case reports of congenital malformations of the corpus cavernosum penis resulting in primary ED are rare [149-151]. In the first report, two cases seen as adults were described where the congenital defect was identified as a problem in compliance secondary to corporal fibrosis [149]. Diagnosis was initiated by Doppler ultrasonography, and both patients were treated by penile prosthesis insertion [149]. In the second report, a 33-year-old man was described with a similar congenital defect characterized by isolated cavernous bodies, veno-occlusive dysfunction, and hypoplastic cavernous arteries [150]. The most recent report of two young men also describes a patient similar to the previous reports with separation of the corporal bodies and complaining of veno-occlusive dysfunction [151]. Interestingly, the other patient had a partial aplasia of the distal corpora cavernosa which was corrected surgically [151]. While there remain to be reported genetic links to ED in humans, a single gene mutation in mice has been described which is linked to ED [152]. Regardless of the fact that the bulk of patients reporting ED suffer primarily from nongenetic causes (e.g., vascular risk factors, depression, trauma), [112,153155] further research is required to identify genetic causes of human ED. The importance of testosterone for penile development prepubertally as well as during puberty is well recognized [156,157]. However, the role of androgens in penile erection is currently unclear [158]. It should be noted that one class of primary ED patients is those with secondary endocrinologic complaints [159-162]. For these patients, the reader is referred to the section on “Endocrinologic ED.” The final group of patients which may complain of primary ED are those patients who have sustained penile or crural trauma early in life, resulting in subsequent dysfunction. Management of similar patients has been described [11]. If the patient is

Further mechanisms proposed that can alter the vascular response of the penis would be the accumulation of naturally occurring analogs of L-arginine (eg. L-NMMA) that inhibit NOS and peripheral hypoxia associated with anemia. As mentioned before, oxygen is a substrate for NO synthesis and its reduced concentration can limit the activity of NOS and thus the production of NO. The association of neuropathy and ESRD also exists. Peripheral neuropathies in ESRD can be secondary to uremia, associated to diabetes mellitus or may be secondary to hyperparathiroidism [146]. Endocrinologic alterations are common in men with ESRD. Elevations of FSH, LH and prolactin are well recognized in these patients. In addition it is common to observe low levels of total and free testosteronee [146,147]. Finally, men with ESRD frequently need medication for the disease or associated diseases that can interfere with erectile function (see section on drug induced erectile dysfunction). Some of these medications include anti-hypertensives, digoxin, clofibrate and antidepressants [144-146].

IV. PRIMARY ERECTILE DYSFUNCTION Primary erectile dysfunction (ED) is defined as “absence of full sustained erections since early childhood or puberty” [148]. In a study of 67 patients, it was found that there were organic causes of ED in 85 percent (57/67) [148]. Of these patients, there were overlapping etiologies of disease with 18 percent with neurologic disease, 52 percent with arteriogenic disease and 52 per89

young and healthy and the defect appears to be arterial in origin, penile revascularization collaterals of the internal pudendal artery may be a valid surgical option. Otherwise, treatment entails the insertion of a penile prosthesis.

link should be treated seriously even if a causal basis is not immediately apparent. e) Impact 1. Drug effects offer one of the few windows of opportunity for prevention in treating men with erectile dysfunction (ED). 2. A careful assessment of the medical program of a patient is a prerequisite to further treatment of ED. 3. All drugs with possible or definite negative impacts on EF should be changed if possible to less noxious drugs.

V. DRUG INDUCED IMPOTENCE Many classes of drugs can induce ED. In some cases the association of a specific drug with ED is well established through appropriately controlled studies, but in many others the evidence is anecdotal and based on case reports.

PUBLISHED EVIDENCE OF EFFECTS

THEORETICAL BASIS FOR DRUG-INDUCED ERECTILE DYSFUNCTION

1. ANTIHYPERTENSIVES a) Diuretics The negative impact of diuretics on EF, particularly thiazide diuretics, has been suggested and reported for years. In truth, men taking antihypertensive medications have hypertension, which is a form of vascular disease. In addition, penile erections are dependent on normal functioning vasculature. There are no studies in normal men where the primary outcome variable was erectile status and the drug on trial was hydrochlorthiazide. Therefore in practice, the reports for all antihypertensives have to be taken in the context of at least the revealed hypertension, if not the unrevealed vascular and supposed cardiac disease. Some studies have shown no discernable effect beyond that of treated hypertension [163]. In others, thiazides have contributed to a great extent to the high rate of non-compliance with antihypertensive regimes – and ED has been a major complaint causing drop-outs [164]. More recently an excellent study of mildly hypertensive men found a significant association between men with ED and hydrochlorthiazide therapy [165].

a) Drugs 1. change the hormonal milieu 2. specifically antagonize any of the key pathways 3. induce hemodynamic instability b) Timing 1. the proposed drug effect must occur within the known time of action of the drug 2. the off-setting of drug effect may be critical in inducing an erectolytic effect (for example twice-a-day antihypertensives used once a day) 3. the effect of a drug on erectile function (EF) has to take into account the usual domestic schedule (sex at night) in comparison to the time of administration. Most trials for instance administer drugs in the morning. It is therefore possible to take a highly erectolytic drug with a T1/2 of 2 hours in the morning and not report any adverse sexual effects where the same drug administered 2 hours before sex would have profound effects.

b) Beta adrenoceptor blockers

c) Dose 1. Drugs may have different receptor binding capacities at different concentrations. 2. Small doses of a drug (e.g., clonidine) may have profoundly different effects when compared with large doses.

There is much real and anecdotal evidence to suggest a profound effect of beta-adrenoceptor blockers on EF [166,167]. There are reports that challenge this assertion [163]. However, what seems clear is that there may be variation in the adverse event profile among the available agents [168,169,170]. Also, in binding studies on human erectile tissue, it was demonstrated, that the alpha adrenoceptors dominate over the beta adrenocep-

d) Idiosyncratic effects 1. In treating patients, any occurrence of an adverse event with a reasonable basis for a temporal

90

tors in a 10:1 relation [51]. These experimental results indicate a low functional role of the beta adrenoceptors in the penile erectile process. The mechanism underlying beta-blockers induced ED is presently unknown.

2. PSYCHOTROPICS a) Antipsychotics Sexual side-effects during antipsychotic treatment have been estimated in a high number of psychiatric patients [180]. Erectile dysfunction, alterations of ejaculation and reduced libido are known sexual difficulties related to these compounds, conspicuously so during thioridazine therapy [180]. Theoretically, the induced sexual dysfunction (SD) in patients on antipsychotics is the result of anticholinergic effects and alpha-adrenergic antagonism. Several antipsychotic drugs cause increased release of prolactin following blocking of the dopamine release [181]. Thioridazine has associated effects on serum testosterone, which is reduced, but haloperidol has not.

c) Alpha adrenoceptor agents Alpha antagonists are known to provide no problem [164] or to have a positive impact on EF [171]. Prazosin has been reported to induce priapism [172]. Alpha adrenoceptor agonists are used therapeutically to treat priapism (epinephrine, etc) and are intrinsically vasoconstrictive and erectolytic [173]. Other alpha adrenoceptor agonists, such as neo-synephrine, ephedrine etc, are commonly found in decongestants and even the moderate potency of most of the current agents is enough to impose a degree of penile vasoconstriction [174]. Clonidine, an alpha 2 adrenoceptor agonist, deserves special mention because of its predominently central action [175]. Hydralazine, alphamethyldopa and reserpine have also been associated with ED. d) Calcium channel blockers The general consensus is that calcium channel blockers have little impact on EF, but may intefere with the ejaculation mechanism [176]. e) Angiotensin-converting enzyme-inhibitors The report on erectile impact for the Treatment of Mild Hypertension Study (TOMHS) is a key piece of evidence in the evaluation of antihypertensive therapy and ED, where five antihypertensive agents of different drug families were compared on their effects on sexual function. In brief, the incidence of erectile problems was “lowest in the doxazosin group but was not significantly different from the placebo group“. Incidence for acebutolol, amlodipine, and enalapril groups was similar to that in the placebo group“ [177] while thiazide diuretics did have a negative impact on erectile function. In most cases, ED did not require withdrawal of medication. The study was not designed to assess true pharmacological impact because the design was for equipressor doses not for sex at fully stable equipressor moments.

b) Antidepressants There are two main groups of antidepressants, the tricyclic antidepressants and the monoamine oxidase (MAO) inhibitors, both of which interfere with sexual function. The tricyclics are sedative and have anticholinergic and antihistaminic actions. However, the clinical documentation of side-effects during antidepressant therapy is based on small series of controlled studies [182]. Ejaculation and orgasmic dysfunction are reported to be of main concern for these compounds. Different chemical configuration of the tricyclics explains modified and differentiated effects between the compounds, which inhibit the reuptake of the centrally working neurotransmitters, noradrenaline and serotonin [183]. The MAO inhibitors are more frequently linked to sexual dysfunction (SD) but are rarely used today. Delayed ejaculation and abscence of or reduced orgasm are the most commonly reported sideeffects of the selective serotonin reuptake inhibitors (SSRI) [184,185]. Fluoxamine was described to have a low incidence of ED. c) Anxiolytics The benzodiazepines do not normally interfere with the penile erectile mechanism. Improved sexual performance has been described at lower doses but at higher doses, these anxiolytics will have a sedative effect with impaired sexual function [186].

f) Potassium channel openers Use of these drugs has not been associated with ED. Intracavernosal administration of potassium channel openers has been reported to have erectogenic effects [178,179].

The main conclusion on the effects on sexual function of psychotropics is that in general these agents 91

cause sedation and central nervous depression [187]. The mental condition of the individual patient is also a factor of main concern. Interpretation of data on sexual dysfunction must always be related to methodological considerations [188].

ne and bleomycin (CVB) in patients with metastatic germ-cell cancer. He found that most patients had a peripheral sensory neuropathy with a central conductive defect. In approximately 30% of the patients,cholinergic nerve dysfunction was observed. Azoospermia was documented in one third of the patients but only a few reported ED.

3. MISCELLANEOUS COMPOUNDS

Naturally, in the total perspective of SD in patients during therapy of diagnosed malignancy, it may be difficult to separate, if the selected treatment or the disease is the main cause of the erectile failure. In most cases, a combined effect of the two is a more rational explanation.

a) Hormonal agents The normal penile erectile process depends on an intact hypothalamic-pituitary-gonadal system [189]. Any agent suppressing pathways of this system will have the risk of inducing ED. Generally, it is accepted to treat impotent hypogonadic men with androgen administration [189,190,191]. Androgen substitution to impotent male subjects with mild hypogonadism showed improved sexual function in men with low levels of serum free testosterone but not in men with normal levels [192, 193]. Recently, in a placebo-controlled study Schiavi et al (1997) [194] reported, that ejaculatory frequency was higher and sexual desire improved in healthy men with ED following testosterone substitution. Interestingly, even if the sexual capacity increased in these eugonadal men during testosterone administration compared to placebo, there was no effect on the penile erectile function.

c) Digoxin

In men with endocrine therapy for prostatic malignancy, all antiandrogen therapy dramatically decreased sexual activity [195]. By using pure anti-androgens or 5 alpha-reductase inhibitors in patients with prostatic malignancy, sexual function may be preserved to a greater extent [195,196, 197]. In treatment of benign prostatic obstruction with finasteride, the erectile capacity has been reported as being intact in most patients [198].

Neri et al (1987) [201] investigated sexual function after long-term administration of digoxin. They found a correlation between SD and a reduced plasma level of testosterone. Correspondingly, the plasma level of estrogens were raised. The interference by digoxin on EF may be explained by the similarity in chemical structure to sex steroids. Another possible mechanism has been suggested by Gupta et al (1998) [55,202]. In an experimental study on isolated human corpus cavernosum, they found that digoxin concentration-dependently inhibited sodium pump activity and counteracted the relaxant effect induced by acetylcholine and by electrical field stimulation. In this study, they also reported that therapeutic concentrations of digoxin diminished penile rigidity compared to placebo during visual sexual stimulation. In conclusion, the authors suggested that digoxin promoted contraction of corpus cavernosum tissue by inhibition of sodium / potassium adenosine triphosphate causing impaired nitric oxide relaxation.

b) Antineoplastics

d) Histamine-H2-receptor antagonists

From clinical experience in practice, it is known that during anti cancer therapy patients are reported to have reduced sexual function. Also, it is confirmed in extended series of cancer treatment with specific antineoplastics that libido is reduced with impaired erectile function [199]. However, there is limited documentation in the literature on objective effects on EF by different antineoplastic compounds.

The histamine-H2-receptor antagonist cimetidine has been used world-wide by several million people over the last 20 years [203,204]. The safety record of the drug is impressing but a small number of different adverse events have been reported including SD [172,203,205,206]. Ranitidine is another histamine-H2-receptor antagonist with lesser incidence of adverse events than those reported for cimetidine [172,205]. Cimetidine is described to have potential for inhibiting acetylcholinesterase activity and will cause ganglionic blockade at high doses. The effect on sexual func-

Hansen (1992) [200] reports on the long-term effects after treatment with cisplatinum, vinblasti-

92

tion by cimetidine may be two fold. The ganglionic blocking effect at peripheral sites has only been suggested at supratherapeutic doses [205]. Also, cimetidine has been found to have antiandrogenic actions with incresed prolactin levels [207]. Ranitidine has been reported to induce SD but with lower incidence compared to cimetidine.

tence. Smoking was described to induce early atherosclerotic lesions in the internal pudendal artery. In 1987, Juenemann et al [215] showed in an acute dog model that smoking caused vasoconstriction, decreased penile arterial inflow and venous leakage with a reduced intracavernosal pressure during pelvic nerve electrical stimulation. Similar observations have been reported in humans [216].

e) Hypolipidaemic agents Clofibrate is a hypolipidaemic agent, which has been reported to induce SD by interfering with the androgen metabolism [172,207]. Recently, a high incidence of SD was observed in a population of men with primary hyperlipidaemia [208]. The authors concluded that ED was a frequent disorder in hyperlipidaemic patients but as the results revealed a higher number of impotent men on active hypolipidaemic treatment, SD was seen as a possible side-effect of the drug. In a controlled study, a slow releasing nicotinate, pentaerythriol tetranicotinate, was given to hyperlipaemic impotent patients [209]. The results indicated that patients on active treatment had improved sexual function compared to the pretreatment period and to the control group.

b) Alcohol In chronic alcoholism SD appears to be a common problem [217]. Acute alcohol intake will in moderate and high doses have a central sedative effect but in small doses libido may be raised [218]. Impaired sexual function in chronic alcoholics may be related to insufficient liver capacity, testicular damage and polynephropathy [219]. Several studies have focused attention on SD in chronic alcoholics with normal liver function compared to subjects with liver damage [220,221,222,223]. It was emphasized, that in men with liver damage an increased prevalence for SD was observed. However, cirrhotic alcoholics reported a higher incidence of SD than age-matched men with non-alcoholic liver disease [221].

4. OTHER DRUGS

c) Narcotics

It has been reported that carbonic anhydrase inhibitors used in glaucoma therapy decreased libido with SD [210,211,212]. Sexual function was restored after discontinuation or by giving supplental sodium bicarbonate [207]. The exact mechanism of this side-effect may be explained as a result of the malaise and depression found in some patients on carbonic anhydrase inhibition [211,212]. The antimycotic drug ketoconazole has been found to cause SD by inhibition of testosterone biosynthesis [186,213]. In a placebo-controled study, the effects by ketoconazole were compared to another antimycotic agent, terbinafine [213]. Terbinafine showed no influence on the pituitarygonadal axis in normal young men compared to ketoconazole and placebo.

Cocaine is regarded as an aphrodisiac and its use is often combined with alcohol abuse. The compound is suggested to have potent dopamine agonist properties as described for opioids [186]. However, chronic use of cocaine, heroine and metadone increase the incidence of ED [211, 224,225]. Interestingly, Hanbury et al (1977) [226] found that street heroin addicts with altered sexual function had a higher risk of developing persistent SD on metadone therapy.

6. IN WOMEN In women, SD has not been rated of the same priority as in men. Until now, drug-induced SD is women has not been of specific clinical interest. Consequently, SD in women is not fully explored and relevant clinical documentation is missing. However, encouragingly there are studies in which female SD has been studied and related to treatment with antihypertensives [163,177,181] and antipsychotics [180,181,184].

5. SUBSTANCE OF ABUSE a) Nicotine (cigarette smoking) Cigarette smoking was reported by Rosen el al (1991) [214] to be an independent risk factor for artheriosclerosis in men with arteriogenic impo-

93

The results available indicate that drug-induced SD in women is of lesser magnitude than in men. Nevertheless, most studies point out that reduced vaginal lubrication and delayed or impaired orgasm are the manifestations of drug-induced sexual disfunction in women [163,181,227].

R.J., UDELSON, D., SAENZ DE TEJADA, I. AND MORELAND, R.B. Mechanisms of venous leakage: a prospective clinicopathological correlation of corporeal function and structure. J. Urol. 156:1320-1329, 1996. 10.

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HSU, G.-L., BROCK, G.B., MARTINEZ-PIÑEIRO, L., NUNES, L., VON HEYDEN, B. LUE, T.F. AND TANGAHO, E.A. Anatomy and strength of the tunica albuginea: its relevance to penile prosthesis extrusion. J. Urol. 151: 1205-1208, 1994.

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UDELSON, D., NEHRA, A., HATZICHRISTOU, D., AZADZOI, A., MORELAND, R.B., KRANE, R.J., SAENZ DE TEJADA, I. AND GOLDSTEIN, I. Engineering analysis of penile hemodynamic and structural dynamic relationships: Part I.- Clinical implications of penile tissue mechanical properties. Int. J. Impotence Res., 10: 15-24, 1998.

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GASIOR, B.L., LEVINE, F.J., HOWANNESIAN, A., KRANE, R.J. AND GOLDSTEIN, I. Plaque-associated corporal veno-occlusive dysfunction in idiopathic Peyronie’s disease: a pharmacocavernosometric and pharmacocavernosographic study. World J. Urol. 8: 90-97, 1990.

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CHUANG, A.T. AND STEERS, W.D., “Neurophysiology of penile erection.” in Textbook of Erectile Dysfunction, CARSON, C.C. KIRBY, R. AND GOLDSTEIN, I., editors, (ISIS Medical Media, Oxford, 1999), pp59-72.

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7. IN THE ELDERLY Drug-induced geriatric SD if of main concern for different reasons. Firstly, the normal aging process is counteract the sexual physiology. Secondly, the risk of adverse events in ageing men and women on treatment with antihypertensives, cardiovascular agents and antipsychotics are heavily increased compared to their younger counterparts [228].

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167. WEISS RJ, Effects of antihypertensive agents on sexual function. Am Fam Physician 1991 Dec;44(6):2075-82.

184. ROSEN RC, LANE RM, MENZA M. Effects of SSRIs on sexual function: a critical review. J Clin Psychopharmacol 1999;19:67-85.

168. STOKES GS, MENNIE BA, GELLATLY R, HILL A. On the combination of alpha- and beta-adrenoceptor blockade in hypertension. Clin Pharmacol Ther 1983 Nov;34(5):576-82.

185. WALDINGER MD, OLIVER B. Selective serotonin reuptake inhibitor-induced sexual dysfunction: clinical and research considerations. Int Clin Psychopharmacol 1998;13 Supple 6:S27-33.

169. BURRIS JF, GOLDSTEIN J, ZAGER PG, SUTTON

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TRAISH AM, GOLDSTEIN I. A possible mechanism for alteration of human erectile function by Digoxin: inhibition of corpus cavernosum sodium/potassium adenosine triphosphatase activity. J Urol1998;159:15291536.

186. BROCK GB, LUE T. Drug-induced male sexual dysfunction. Drug Saf 1993;8:414-26. 187. GITLIN MJ. Psychotropic medications and their effects on sexual function: diagnosis, biology, and treatment approaches. J Clin Psychiatry 1994;55:406-13.

203. PIPER DW. A comparative overview of the adverse effects of antinulcer drugs. Drug saf 1995;12:120-38.

188. DEMYTTENAERE K, DE FRUGT J, SIENAERT P. Psychotropics and sexuality. Int Clin Psychopharmacol 1998;13 Suppl 6:S35-41.

204. GLEDHILL T. Cimetidine 6 years later: a review. Can J Surg 1983;26:312-5.

189. SCHIAVI RC, WHITE D. Androgens and male sexual function: a review of human studies. J Sex Marital Ther 1976;2:214.

205. GWEE MCE, CHEAH LS. Actions of cimetidin and ranitidine at some cholinergic sites:implications in toxicology and anesthesia. Life Sci 1986;39:383-88.

190. JOHN H. Testosterone and impotence - when is androgen substitution advisable? Ther Umsch 1998;55:372-6 (in German).

206. ZIMMERMANN TW. Problems associated with medical treatment of peptic ulcer disease. Am J Med 1984;77(5B):51-6.

191. TOSTAIN J, LEGON C, LUDOT T, CASTRO R, LI GR. Treatment of erectile disorders with androgen: When? How? Prog Urol 1997;7:314-9 (in French).

207. WEIN AJ, VAN ARSDALEN KN. Drug-induced male sexual dysfunction. Urol Clin North Am 1988;15:23-31.

192. CARANI C, ZINI D, BALDINI A, DELLA CASA L, GHIZZANI A, MARRAMA P. Effects of androgen treatment in impotent men with normal and low levels of free testosterone. Arch Sex Behav 1990;19:223-34.

208. Bruckert E, Giral P, Heshmati HM, Turpin G. Men treated with hypolipidaemic drugs complain more frequently of erectile dysfunction. J Clin Pharm Ther 1996;21:89-94.

193. GODEC CJ, BATES H, LABROSSE K. Testosterone receptors in corpora cavernosa of penis. Urology 1985;26:237-9.

209. HWANG TI, YANG CR. The clinical effect of slow releasing nicotinate on hyperlipemic impotent patients. Chung Hua I Hsueh Tsa Chih (Tapei) 1993;52:253-7 (in Chinese).

194. SCHIAVI RC, WHITE D, MANDELI J, LEVINE AC. Effect of testosterone administration on sexual behaviour and mood in men with erectile dysfunction. Arch Sex Behav 1997;26:231-41.

210. EPSTEIN RJ, ALLEN RC, LUNDE MW. Organic impotence associated with carbonic anhydrase inhibitor therapy for glaucoma. Ann Ophtalmol 1987;19:48-50. 211. SEGRAVES RT, MADSEN R, CARTER CS, ET AL. ERECTILE DYSFUNCTION ASSOCIATED WITH PHARMACOLOGICAL AGENTS. IN SEGRAVES RT, SCHOENBERG HW (eds): Diagnosis and Treatment of Erectile Disturbances, New York: Plenum, 1985, pp 23-63.

195. SCHROEDER FH. Endocrine therapy: where do we stand and where are we going? Cancer Surv 1991;11:177-94. 196. LUNGLMAYR G. Efficacy and tolerability of Casodex in patients with advanced prostate cancer. International Casodex Study Group. Anticancer Drugs 1995;6:50813.

212. WALLACE TR, FRAUNFELDER FT, PETURSSON GJ, EPSTEIN DL. Decreased libido - a side effect of carbonic anhydrase inhibitor. Ann Ophtalmol 1979;11:1563-6.

197. MIGLIARI R, MUSCAS G, USAI E. Effect of Casodex on sleep-related erections in patients with advanced prostate cancer. J Urol, 148:338-41, 1992.

213. NASHAN D, KNUTH UA, WEIDINGER G, NIESCHLAG E. The antimycotic drug terbinafine in contrast to ketoconazole lacks acute effects on the pituitary-testicular function of healthy men: a placebo-controlled double-blind trial. Acta Endocrinol (Copenh) 1989;120:677-81.

198. EKMAN P. A risk-benefit assessment of treatment with finasteride in benign prostatic hyperplasia. Drug Saf 1998;18:161-70. 199. BALDUCCI L, PHILIPS DM, GEARHART JG, LITTLE DP, BOWIE C, et al. Sexual complications of cancer treatment. Am Fam physician 1988;37:159-72.

214. ROSEN MP, GREENFIELD AJ, WALKER TG, GRANT P, DUBROW J, BETTMANN MA, FRIED LE, GOLDSTEIN I. Cigarette smoking: an independent risk factor for atherosclerosis in the hypogastric-cavernous arterial bed of men with arteriogenic impotence. J Urol 1991;145:759-63.

200. HANSEN SW. Late-effects after treatment for germ-cell cancer with cisplatin, vinblastine, and bleomycin. Dan Med Bull 1992;39:391-9. 201. NERI A, ZUKERMAN Z, AYGEN M, LIDOR Y, KAUFMAN H. The effect of long-term administration of digoxin on plasma androgens and sexual dysfunction. J Sex Marital Ther 1987;13:58-63.

215. JUENEMANN K-P, LUE TF, LUO JA, BENOWITZ NL, ABOZEID M, et al. Effects of cigarette smoking on penile erection. J Urol 1987;138:438-441.

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arteries in response to cigarette smoking. Urology 1990;36:99. 217. SCHIAVI RC. Chronic alcoholism and male sexual dysfunction. J Sex Marital Ther 1990;16:23-33.

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219. ABEL EL. A review of alcohols effects on sex and reproduction. Drugs and Alcohol Depend 1980;5:321-2. 220. GUMUS B, YIGITOGLU MR, LEKILI M, UYANIK BS, MUEZZINOGLU, BUYUKSU C. Effect of longterm alcohol abuse on male sexual function and serum gonadal hormone levels. Int Urol Nephrol 1998;30:7559.

226. HANBURY R, COHEN M, STIMMEL B. Adequacy of sexual performance in men maintained on methadone. Am J Drug Alcohol Abuse 1977;4:13-20. 227. SHEN WW, SATA LS. Inhibited female orgasm resulting from psychotropic drugs. A clinical review. J Reprod Med 1983;28:497-99.

221. BANNISTER P, OAKES J, SHERIDAN P, LOSOWSKY MS. Sex hormone changes in chronic liver disease: a matched study of alcoholic versus non-alcoholic liver disease. Q J Med 1987;63:305-13.

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Committee 4

Symptom Score and Quality of Life

Chairman G. WAGNER

Members A. BÉJIN, A. R. F UGL-MEYER, S. GLINA, Y. KIMOTO, C.S.B LUKACS, J. M ULCAHY, M. O’L EARY,

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CONTENTS

I. SYMPTOM SCORE

III. CONCLUSION

II. QUALITY OF LIFE

REFERENCES

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Symptom Score and Quality of Life G WAGNER, A. BÉJIN, A. R. F UGL-MEYER, S. G LINA, Y. KIMOTO, C.S.B L UKACS, J. M ULCAHY, M. O’LEARY,

Sexual health is the integration of the somatic, emotional, intellectual, and social aspects of sexual being, in ways that are positively enri ching, and that enhance personality, communi cation and love (WHO, 1974). This chapter falls in two closely connected, but separate parts. These are symptom evaluation of the severity of erectile dysfunction (ED) using questionnaires or checklists and evaluation of the quality of (sexual) life. The main topics addressed are:

if his partner(s) to his knowledge has little or no sexual disabilities. In the case of ED; anatomical, endocrinological, neurological or vascular disorders may constitute bodily sexual impairments that may cause loss of erectile function. A loss which per se may result in sexual disability. Hence, and following the recent suggestions of the WHO[1] ED may refer both to an impairment and to a disability. This is shown in figure 1 (right half of diagram). Both erectile impairment and psychosexual maladaptation may cause ED which, in turn may cause erectile problems. In this context it must be emphasised that ED is not synonymous with having erectile problems. In a recent epidemiological investigation it has, thus, been demonstrated that among sexually active men who at least quite often during the preceding year had experienced ED, 69% stated that the ED was a problem for them [2]. Among those who stated that the ED was a problem 75 % reported low level of overall satisfaction with sexual life. However, erectile dysfunction has become a widely accepted term in English language and will be used in this chapter.

What information can be adequately obtained by checklists/questionnaires? Why use questionnaires or checklists in the evaluation of ED and quality of life? Which instrument(s) can be recommended for the use in clinical practice, particularly by those who are not specially trained urologists or sexologists?

I. SYMPTOM SCORE Some conceptual considerations: A sexually wellbeing man has adequate function (at the anatomical and physiological organ-levels, cf WHO,[1]) that allow him to act in order to fulfil his sexual aspirations. Through reaching these aspirations, or believing that he can reach them, he can reach satisfaction with his sexual life if he has no or litt le sexual impairments such as decreased desire (we shall here avoid to use the psycho-analytical term libido as it denotes something over and above desire), ED, ejaculatory disabilities (premature or retarded ejaculation and orgasmic disability). And

The distinctions between erectile impairment, erectile disability (dysfunction) and erectile problems are necessary for reaching an adequatebased differential diagnosis as a starting point for therapeutic interventions. In other words, in order to obtain valid guidelines for treatment, ED must be seen within the framework of each individual’s somatic, psychological and social adaptation and ED will often, but far from obligatorily, lead to experienced erectile problems that for the majority will result in low level of sexual satisfaction.

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Figure 1: A model for case-analysis

What information on ED can or should be obtai ned by questionnaires or checklists, whether or not in the form of aggregated sum-scores? Given the conceptual model outlined above, it appears that neither somatic sexual impairment per se nor, at reasonable depths, psychological and social factors (including partner’s sexual disabilities that may or may not cause or contribute to ED) can be sufficiently analysed by reasonably brief and simple questionnaires or checklists. A good case history, preferably taken from both partners, together with, if indicated, an adequate physical examination including proper laboratory investi gations are the necessary ingredients for the choice of treatment strategy in ED. On the other hand it appears that questionnaires can be important, both for initial focusing of ED as an introduction to the case history and also as a simple means for following up treatment effects. Other advantages are that subject self-administered indexes are “private,” and when properly psychometrically validated, are both reliable and reproducible. When choosing what to include in a battery of statements/questions whether or not using aggregated scores, it is of paramount importance to observe

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that conceptual lucidity must prevail. Thus, the following “domains” of overall sexual function, while highly intercorrelated, need to be considered individually and separately, particularly in scoring scenarios. • Physical impairments and psychological maladaptation • Erectile dysfunction • Erectile problems • Sexual satisfaction • Overall life satisfaction/quality of life should rigidly be kept apart. Another constructional main issue that influences the choice of what to measure is the width of the measuring instrument. The construct may in its simpliest form solely focus on ED per se. It may include diseases/injuries, abuse, etcetera, that directly - or in most cases, indirectly – have an impact on the individual’s capacity to achieve an erection. The instrument may further, address other sexual disabilities such as decreased or low desire and interest, occurrence of premature and retarded ejaculation, inability to reach orgasm and also dyspareunia.

Moreover it may be considered relevant to incorporate items addressing erectile capacity during masturbation and also to include one or more items on the occurrence of nocturnal penile tumescence. Other aspects that can be encompassed by the instrument could be whether the ED is lifelong (primary or secondary, situational only with present partner) and also to which extent present partner (if the patient has a partner) is sexually attractive for him (hence addressing the question of partner related vs general level of desire). The patient’s sexual identity, orientation and occurrence of paraphilias could also be included. Besides the sheer complexity of such a checklist/questionnaire, cultural (including patient’s own attitudes and taboos) and legal factors seem to prohibit the inclusion of several or all of these items. Even partner’s (if any) sexual impairments, Komma disabilities/problems, as experienced by the patient might be included. The rationale for including this kind of items would be that female sexual disabilities have a profound influence on their male partner (and vice versa). For instance, female excitatory and orgasmic impairments (dysfunctions)/disabilities often (in about 35-50%) are experienced as problems for their male partners and among these men only about 20% feel that their sexual life is satisfactory [3]. In summary much can be measured. We, however, prefer to recommend that ED symptom score should include only items that focus the ED per se. The committee feels that additional domains from various instruments may be helpful in describing the overall condition of sexual function, but for the purposes of describing erection, the symptom score should focus on that alone. The duration of an individual’s dysfunction has been handled differently in different indexes. A general principle is to use a time frame that allows a sufficient “window” to adequately ascertain the subject’s true state, but not so long as to be affected by his ability to recall. A duration of 3 months (or more) seems adequate. Why use ED symptom scores?: Firstly, well validated, reliable, repeatable and standardised symptom scores may provide a simple means for the medical and sexological practioner to quantitatively and semi-qualitatively gain an impression of the patient’s perception of

the magnitude of his ED. Thus, the committee’s basic consideration is that a narrow and brief (few items) checklist should be recommended for general use in clinical practice. This does not preclude a modular system by which increasing complexity can be introduced. Increasing levels of complexity are probably inevitable when dealing with clinical trials, in depth epidemiological investigations and when it comes to more specialised treatment of complicated cases of ED. Which set of questions/statements should then be recommended? There are several batteries to be found that address sexual disabilities, emotions and problems. Most of them appear to mix different components such as ED per se, its possible somatic and psychological etiologies – the component that in the conceptual model given above is characterised as impair ment/maladaptation, the extent to which the ED causes problems – the statement component in the case analysis model, which indicates to which extent the ED causes what by Michalos [4] has been labelled an aspirations/achievement gap and the perceived quality of sexual life. Some such instruments are those described Derogatis and Melisarotis [5] and more recently by O’Leary et al [6] and Rosen et al [7]. Turner et al [8] used a sexologically oriented nonspecific checklist to measure sexual desire, arousal, orgasm and satisfaction when assessing treatment effects with the use of vacuum devices and intracavernous injections. Recently Althof et al [9] described yet another instrument that wholly addressed ED in a prospective treatment related way. These authors devised a questionnaire that included 11 items on how treatment itself and its effects are perceived by the patient and his partner. This inventory is as such truly outcome-oriented. In an epidemiological investigation Feldman et al [10] stated that: ”Impotence is best defined by the individual’s assessment of his own situation in simple terms of minimal, moderate or complete impotence as presented to a physician for treatment”. These authors used a 4-graded ordinal scale: no/minimal/moderate/complete impotence to characterise degree of ED. In some contrast Spector and Carey [11] emphasised that meticulous descriptions are necessary in order to make possible reasonably (epidemiological) comparative analyses. In an epidemiological investigation 107

performed in Scandinavia [2]another simple (statement) scale was used: «it happens that the man’s penis does not become rigid or gets flaccid during intercourse». Has this happened in your sexual life during the last 12 months? Answering alternatives were: never/hardly ever/quite rarely/quite often/ nearly all the time/ all the time. In a recent investigation of sexual dysfunction in the USA Laumann et al [12]formulated their one item on male arousal using a “mixed” question that encompassed both ED as such and trouble caused by ED. Whereas these three types of - nearly nominal ordinal scales may be adequate in broad surveys and may be useful for analyses that aim to investigate their relationship with other components such as etiology or problems, they are most definitely much too simple for use in clinical practice.

ted into ten (now 30) different languages. A factor analysis of the 15 IIEF-items has been found to 5 questions that focus on erectile ability but this factor also to a considerable degree is influenced by a confidence and by a general intercourse satisfaction item. Lately an abbreviation of the IEEF-15, termed IEEF-5, has been described [16] and widely distributed. This inventory includes items 2, 3, 5, 7 and 15 from factor 1 in the IEEF-15. It does not solely focus ED per se as one of the 5 items addresses confidence and another satisfaction. The abbreviated inventory has been validated. One major advantage of the BMFSI and the IIEF15 inventories is that they do not exclusively concentrate on erection during penetrative intercourse. Thus none of the 3 ED-related items of the BMFSI do so. Furthermore, item 1 in the IEEF-15 is phrased: How often were you (during the last 6 months) able to get an erection during sexual activity? Item 2 does not, either, necessarily focus intercourse as it is phrased: When you had erection (during the last 6 months) with sexual stimulation, how often were your erections hard enough for penetration?

Which items are, at the moment, conceptually clear enough for use as denominators of ED? To our knowledge there is at present no globally accepted item (or series of items) for such use. During the 1990:ies two symptom score assessment batteries have been proposed. Both are based upon the widely acknowledged contention (see for instance [10, 13] that sexual abilities are best assessed by ”subjective” self reports. One of these two instruments called the BMSFI was described by O’Leary et al [6] the other the IIEF-15 introduced by Rosen et al [7]. The validity and test- retest reliability are good for both instruments. This, in particular, pertains to that part of the IIEF-15 that focuses ED. The IIEF-15 has, in subsequent publications by Cappelleri et al [14, 15]been shown to possess excellent properties concerning convergent, divergent, and discriminant validity and also clearly acceptable sensitivity and specificity.

It may be concluded that there to our knowledge is no available conceptually lucid ED symptom score. There are, however, widely used and partially validated items. Upon this background and as a preliminary step the five items given in table I are recommended for scoring quantity and quality of achievement and maintenance of erection following the definition of the NIH [17]. All these items are taken nearly verbatim from the IEEF 15 and none of them transgress the rigid conceptual framework for acceptance established by us above. (Table 1)

There are, though some major mutual drawbacks for these two instruments. Thus, both of them mix ED per se with other conceptual categories such as confidence (in maintaining erection) and sexual satisfaction. They, moreover, provide information on a wider aspect of sexual performance than ED. It should also be observed that both instruments have largely been developed on the basis of selfreports of men who have more or less pronounced impotence. Hence, so far, they have not been epidemiologically validated. On the other hand, the IIEF-15 questionnaire was statistically validated in more than 1000 men with ED (and about 100 without ED!) in a cross-cultural study [7], transla-

An important issue to address is whether or not these five items can be cumulated into one score. Evidently a sum-score may be easy to apply; in particular if different cut-offs into for example severe, moderate, mild and no erectile dysfunction: However, the 5 items each having 5 answering alternatives offer no less than about 3000 different combinations or ”profiles” and it would, just knowing the total score, be impossible to deduct which type(s) of erectile dysfunction a particular man has (i.e. lack of capacity to achieve and/or maintain an erection) as well as the severity of the ED. In this context it should be emphasised that although sexual erection achievement and 108

Table 1: ED intensity scale

ED INTENSITY SCALE Each question has several responses. Put in the empty box the number of the response that best describes your own situation. Please be sure that you select one and only one response for each question. PATIENT NAME :

DOB :

ID :

DATE OFASSESSEMENT :

Almost never A few times Sometimes or never (much less than (about half half the time) the time)

Most times Almost always (much more than or always half the time)

1. H OW OFTEN WERE YOU ABLE TO GET AN ERECTION DURING SEXUAL ACTIVITY?

2. WHEN YOU HAD ERECTIONS WITH SEXUAL STIMULATION, HOW OFTEN WERE YOUR ERECTIONS HARD ENOUGH FOR PENETRATION (ENTERING YOUR PARTNER )? 3. WHEN YOU ATTEMPTED INTERCOURSE, HOW OFTEN WERE YOUABLE TO PENETRATE (ENTER) YOUR PARTNER?

1

2

3

4

5

1

2

3

4

5

1

2

3

4

5

1

2

3

4. DURING SEXUAL INTER COURSE, HOW OFTEN WERE YOU ABLE TO MAINTAIN YOUR ERECTION AFTER YOU HAD PENETRATED (ENTERED) YOUR PARTNER?

4

5

Extremely difficult

Very difficult

Difficult

Slightly difficult

1

2

3

4

Not difficult

5. DURING SEXUAL INTER COURSE, HOW DIFFICULT WAS IT TO MAINTAIN YOUR ERECTION TO COMPLETION OF INTERCOURSE ?

5

ED Intensity Score : • Instructions for Possible Scoring: Add the scores for each item 1-5 (total possible score =25). ED Severity Classification: Total score 5-10 (severe); 11-15 (moderate); 16-20 (mild); 21-25 (normal). Note: The above questions should only be completed by individuals who have been sexually active and have attempted sexual intercourse in the past 3 months. For sexually inactive individuals, the questionnaire may be answered for the last period of time (3 months or longer) during which the individual was sexually active.

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maintenance may be closely associated they are basically two different categories of ED and it is arguable whether nominal data can be added to each other. Moreover, in many cases ED is accompanied or precipitated by premature ejaculation [18]; a combination which may be overlooked by the clinician if only using a sum-score. If the main application of the suggested 5-items is to initiate and facilitate for the clinician a dialogue with the patient in order to focus on a precise differential diagnosis an aggregated score appears to be somewhat insufficient. On the other hand, many clinicians may want to have overall score at hand in order primarily to obtain a general impression of the effect of one or more treatment modalities. For this purpose a cumulated score may be well worth using and post-hoc analyses may evidence whether such a score is not only statistically valid, but in fact is an adequately useable clinical indicator. It is, thus, at the moment not unambiguously clear whether the five ED-items can be aggregated. The committee, though, recommends that at least those clinicians that are well acquainted with the different aspects of ED use the set of items both as separate entities and in aggregation.

“something many people talk about but nobody very clearly knows what is and what to do about” and Bowling [20] has seconded that opinion by stating that QoL is a vague, multidimensional concept, which theoretically incorporates all aspects of an individual’s life. This is further underlined by the definition offered by the WHO [21]: “QoLis defined as an individual’s perception of their position in life in the context of the culture and value systems in which they live in relation to their goals, expectations, standards and concerns. It is a broad ranging concept affected in a complex way by the person’s physical health, psychological state, level of independence, social relationships and their relationships to salient features of their environment”. The concept has as a caricature been characterised thusly: “QoL is like love. Everybody knows what it is, but who would trust anybody else’s definition?” What information on QoL/life satisfaction can be obtained? From a philosophical perspective Musshenga [22] identified three different, but interrelated, concepts. QoLcan be seen as the dcgree of normal functioning as a member of the biological species homo sapiens. QoL can also denote degree of satisfaction derived from an individual’s life. Thirdly, QoL can be seen as the level of human development. In medical research the two first of these concepts are increasingly used.

II. QUALITY OF LIFE Some conceptual considerations. All assessment questions and inventories must be ontologically well-anchored. The dimensionality of each item and scores must be well defined. When dealing with measurements of Quality of Life (QoL) it is highly relevant to clearly define if the assessment has it’s background in generally or medically accepted normality (ie: is based upon a Gaussian distribution) or if the single individual’s experienced QoL is the central issue. From the methodological point of view validity, reliability and repeatability is as important for assessment of QoL as for symptom scores. It is also highly relevant to ascertain whether items or instruments are monoor pluriculturally oriented.

The degree of normal biological function may from the medical but even the psychological point of view erroneously be interpreted as the level of quality of life. This type of medicalized objectivism (a professional on-looker judges somebody else) does not take into account the individual’s experienced goal-achievements. We shall, therefore, disregard such judgements as irrelevant to the conceptual model given above. The second definition above, characterising QoL as degree of life satisfaction appears relevant. Here we deal with two different categories; namely health related satisfaction and general satisfaction. While health related QoL/life satisfaction might be adequate to measure within a certain specified area, this type of assessments has drawbacks as it is biased in two ways. First of all comparisons with health (in a narrow, pathology-specific sense as well as in a broad general health-related context) does not allow for comparisons with people who assess

During later years QoL and life satisfaction have been increasingly emphasized as indicators of the impact of pathological conditions and of the effect of therapeutic endeavours. Quality of life is, however, an ambiguous concept. More than 20 years ago Campbell et al [19] stated that QoL is 110

themselves as being at good health. Secondly, people who are not at good health appear to assess their QoL as relatively lower when they answer a health-related QoL-question than they do if the questionnaire is not so. On the other hand, clinical practitioners often feel a need for specialized health-related “subjective” assessment of health related QoL. Within this area a series of instruments exist. The pro tempore most used general instruments are the SF-36 [23, 24] the Nottingham Health Profile [25, 26] and the Sickness Impact Profile [27]. These are broad ranging questionnaires or checklists that only to a very limited extent, if at all, address sexual life. They may therefore not be sensitive enough to detect subtle differences in ED-subjects.

It contains one overall item (satisfaction with life as a whole) and 10 domain specific items. The latter are included (factor analysis) in a very robust factor pattern among which sexual life, partner relationship and family life form one. Besides the instrument having very good internal consistency, all items (6-graded scale) have good test-retest reliability and a high degree of specificity and sensitivity. For instance, in a sample of ED-men (n:413) satisfaction with sexual life was particularly low, but men with psychogenic ED were also significantly less satisfied with partner relationship and family life than were a reference group [32]. Successful treatment that restored the erectile ability resulted in “normalization” of level of sexual satisfaction. This instrument is now widely used and has been translated into more than 10 different languages. In a recent statistical analysis (to be published) it has been shown that in the general population sample (cf above) an aggregated score incorporating the four items: Satisfaction with life as a whole, with sexual life, with partner relationship and with family life is valid. Even this aggregation is, however, from the differential diagnostic point of view, unspecific.

Concerning health-related QoL the most simple item is that employed in the IPSS [28] namely: “If you were to spend the rest of your life with your urinary condition the way it is now, how would you feel about that?” The 5-graded scale now being: very satisfied/rather satisfied/mixed equal ly satisfied and dissatisfied/rather dissatisfied /very dissatisfied.. A considerably more elaborate ED-related instrument is the 19 items inventory described by Wagner et al [29]. Each item has a four-graded response scale and taken together the items are suggested to characterize masculinity, emotional reactions to ED and overall life satisfaction (but none of the items addresses QoL explicitly). This scoring system has been applied in two, rather small samples of men with ED. It has excellent internal consistency and test-retest reliability.

Which items should be included to provide ade quate information, primarily for general practitio ners, on the impact of ED? Bearing in mind that the instrument should be brief and easy to administer and, furthermore that the instrument should provide information as to the impact of ED on quality of life, so that a decision could be made whether and to which extent therapeutic interventions are indicated, the following items appear adequate indicators of quality of life in relation to ED:

About a decade ago Fugl-Meyer et al [30] introduced a life satisfaction inventory, which has later been expanded slightly. It has now been validated in a nationally representative Swedish population sample aged 18-74 (1475 men and 1335 women).

1. The ED impact (bother) item given in table 2: A 5-graded scale is believed adequate, for characterizing the degree of distress or bother caused

Table 2: ED impact scale

ED IMPACT SCALE VERY

RATHER

DISSATISFIED DISSATISFIED

MIXED, ABOUT

RATHER

EQUALLY SATISFIED

SATISFIED

VERY SATISFIED

AND DISSATISFIED

IF YOU WERE TO SPEND THE REST OF YOUR LIFE WITH YOUR ERECTILE CONDITION THE WAY IT IS NOW, HOW WOULD YOU FEEL ABOUT THAT?

1

2

3

111

4

5

2. Four life satisfaction items (table 3): Satisfaction with sexual life, partner relationship (if the patient has a partner), family life and with life as a whole, using the test-re-test reliable 6-graded scale.

Whereas clinicians may prefer to use aggregated scores the committee recommends cautiousness in such use. Aggregated scores may be statistically valid, but they may provide in sufficiently detailed information as they mix different categories of ED or of quality of life. On the other hand, the 10 items can be used as an “ED-profile”.

III. CONCLUSION

The committee emphasizes that both the ED intensity score inventory and the two QoL-inventories aim to provide the general practitioner with guidelines that can not only save time but primarily can be an aid or a prelude to taking an adequate case history. The committee, again, wishes to stress that a good case history, if indicated leading to further biological and psychological investigations, is a sine qua non for adequate treatment of ED.

The committee has reached the conclusion that a brief, by and large validated, robust, sensitive, specific and test-retest reliable set of totally 10 items can be recommended. Among these, 5 items characterise ED per se, one characterises prospectively judged, quality of sexual life (“bother”), one characterises overall quality of sexual life, two items concern quality of other intimate aspects of life (partnership and family) and, finally, one item addresses overall quality of life.

Finally, the committee believes that this instrument is applicable for establishing evidence based follow-up.

Table 3: Life satisfaction score

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17. NIH Consensus Development Panel on Impotence. Impotence. JAMA. 270:83-90, 1993.

REFERENCES 1.

World Health Organization (WHO). International Classification of Functioning and Disability (ICIDH-2). Beta-2 Draft, Geneva July, 1999.

2.

FUGL-MEYER AR, FUGL-MEYER KS. Sexual Disabilities, Problems and Satisfaction in 18-24-Year-Old Swedes. Scand J Sexol 2:79-105, 1999.

3.

FUGL-MEYER KS. Erectile Problems – The Perspective of the Female. Scand J Urol and Nephrol 32:12, 1998.

4.

MICHALOS AC.Satisfaction and Happiness. Soc Indic Res 8:385-422, 1980.

5.

DEROGATIS LR, MELISARATOS N. The DSFI: A Multidimensional Measure of Sexual Functioning. J Sex Marital Ther, 1979.

6.

O’LEARY MP, Et al. A Brief Male Sexual Function Inventory for Urology. Urology. 46:697-706, 1995.

7.

ROSEN RC, et al. The International Index of Erectile Function (IIEF): A Multidimensional Scale for Assessment of Erectile Dysfunction. Urology 49:822-830, 1997.

8.

TURNER LA et al. Twelve-month Comparison of Two Treatments for Erectile Dysfunction: Self-injection versus External Vaccuum Devices. Urology 39:822-830, 1992.

9.

ALTHOF SE et al. EDITS: Development of Questionnaires for Evaluating Satisfaction with Treatments for Erectile Dysfunction. Urology 53:793-799, 1999.

18. BEJIN, A.Epidémiologie de l’éjaculation prématurée et de son cumul avec la dysfonction érectile. Andrologie 9:211-225, 1999. 19. CAMPBELL et al. The Quality of American Life: Perceptions, Evaluations and Satisfactions. Russel Sage Foundation, New York, 1976. 20. BOWLING A. Measuring Disease. Open University Press. Buckingham, 1995. 21. WHO QoL Group. Measuring Quality of Life. The Development of the World Health Quality of Life Instrument (WHO QoL), Geneva, 1995. 22. MUSSHENGA AW. The Relation Between Concepts of Quality-of-Life, Health and Happiness. J Med and Philosof 22:11-28, 1997. 23. WARE J et al. The MOS 36-item Short-Form Health Survey (SF-36):I. Conceptual Framework and Item Selection. Medical Care 30:473-483, 1992. 24. MCHORNEY CA et al. The MOS 36-item Short-Form Health Survey (SF-36):II. Psychometric and Clincal tests of Validity in Measuring Physical and Mental Health Constructs. Medical Care 31:247-263, 1993. 25. MCEWEN J, MCKENNASP. Nottingham Health Profile. In: Spilker B (ed) Quality of Life and Pharmacoeconomics in Clinical Trials, Second edition. LippincottRaven Publishers. Philadelphia, 1996. 26. LUKKARINEN H AND HENTINEN M.Assessment of Quality of Life with the Nottingham Health Profile Among Patients with Coronary Heart Disease. J Advanced Nursing. J Advanced Nursing 26:73-84, 1997.

10. FELDMAN et al. Impotence and its Medical and Psychosocial Correlates: Results of the Massachusetts Male Aging Study. J Urol 151:54-61, 1994. 11.

27. BERGNER Met al. The Sickness Impact Profile: Development and Final Revision of a Health Status Measure. Medical Care. 19:787-806, 1981.

SPECTOR IP , CAREYMP. Incidence and Prevalence of the Sexual Dysfunctions: A Critical Review of the Empirical Literature Arch Sex Behav 19:389-408, 1990.

28. BARRY, MJ et al. The American Urological Association Symptom Index for Benign Prostatic Hyperplasia. J Urol 148:1549, 1992.

12. LAUMAN EO et al. Sexual Dysfunction in the United States: Prevalence and Predictors. JAMA 281:537-544, 1999.

29. WAGNER TH et al. Cross-cultural Development of a Quality of Life Measure for Men with Erectile Difficulties. Qual Life Res 5:443-449, 1996.

13. ANDERSON BL, BROFFIT B. Is there a Reliable and Valid Self-report Measure of Sexual Function? Arch Sex Behav 17:509-525, 1988.

30. FUGL-MEYER AR et al. Happiness and Domain-Specific Life Satisfaction in Adult northern Swedes. Clincal Rehabilitation 5:25.33, 1991.

14. CAPPELLERI JC et al..???Some Developments on the (incomplete!).

31. FUGL-MEYER AR et al. On Life Satisfaction in Male Erectile Dysfunction. Int J Impotence Res. 9:141-148, 1997.

15. CAPPELLERI JC et al. Diagnostic Evaluation of the Erectile Function Domain of the International Index of Erectile Function. Urology 54:346-351, 1999 16. ROSEN RC et al. Development and Evaluation of the IIEF 5 as a Diagnostic Tool for Erectile Dysfunction. Int J Imp Res. 11:319-326, 1999.

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Committee 5

Clinical Evaluation and the Doctor-Patient Dialogue

Chairman E. MEULEMAN

Members G.BRODERICK, H.MENG TAN, F. MONTORSI, I.SHARLIP, Y.VARDI

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CONTENTS 2. PENILE PHARMACO DUPLEX ULTRASOUND (PPDU) [68] 3. PPDU EXAMINING PROTOCOL 4. PPDU ASSESSMENT OF THE PENILE INFLOW TRACT 5. PPDU ASSESSMENT OF THE VENOOCCLUSIVE MECHANISM 6. PPDU IN STAGING OF PEYRONIE'S DISEASE 7. DYNAMIC INFUSION PHARMACO-CAVERNOSOMETRY AND CAVERNOSOGRAPHY (DICC) 8. DICC UNDER CONTROLLED COMPLETE SMOOTH MUSCLE RELAXATION 9. PENILE ARTERIOGRAPHY [87, 88,89] 10. CT- AND MR IMAGING 11. NUCLEAR IMAGING

INTRODUCTION

A. INITIAL ASSESSMENT OF A PATIENT WITH ED I. HISTORY 1. M EDICAL HISTORY 2. SEXUAL HISTORY [4] 3. P SYCHOSOCIAL HISTORY II. PHYSICAL EXAMINATION III. DIAGNOSTIC TESTS 1. RECOMMENDED DIAGNOSTIC TESTS 2. O PTIONAL DIAGNOSTIC TESTS 3. S PECIALIZED DIAGNOSTIC TESTS

III. PSYCHOPHYSIOLOGICAL TESTS

IV. PATIENT EDUCATION 1. NOCTURNAL PENILE TUMESCENCE / RIGIDITY TESTING (NPT) 2. VISUAL EROTIC STIMULATION (VES)

V. TREATMENT VI. SPECIALIST CONSULTATION AND REFERRAL

IV. NEUROLOGICAL TESTING [105, 106]

B. SPECIALIZED EVALUATION

1. BASIC PRECEPTS IN NEUROPHYSIOLOGICAL TESTING 2. TESTING OF THE EFFERENT (MOTOR) PATHWAYS 3. TESTING OF THE AFFERENT (SENSORY) PATHWAYS 4. AUTONOMIC TESTS

I. ENDOCRINE EVALUATION 1. TOTAL TESTOSTERONE 2. Free TESTOSTERONE [23] 3. LUTEINIZING HORMONE (LH) AND FOLLICLE STIMULATING HORMONE (FSH) 4. PROLACTIN (PRL) 5. THYROXINE 6. THYROID STIMULATING HORMONE (TSH)

V. PSYCHOLOGICAL OR PSYCHIATRIC EVALUATION

VI. SUMMARY STATEMENT

II. VASCULAR DIAGNOSTICS 1. IN OFFICE PENILE INJECTION PHARMACO-

REFERENCES

TESTING

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Clinical Evaluation and the Doctor-Patient Dialogue E. MEULEMAN, G.BRODERICK, H.MENG TAN,, F. MONTORSI, I.SHARLIP, Y.VARDI

psychosocial history, a physical examination and diagnostic testing. Additionally, diagnostic tests are recommended with a proven value in specific patient profiles. Their utility is left to the clinical judgement of the treating physician.

INTRODUCTION The recent proliferation of laboratory and clinical research concerning erectile function and erectile dysfunction (ED) and the resulting emergence of effective oral treatment has greatly increased the number of patients seeking medical help for ED. ED-care has shifted from the specialist to the primary care physician. Consequently, the basic approach to the management of ED has become multidisciplinary and goal-directed [1].

The rationale for testing and the potential impact of a positive test should be explained to the patient. Upon completion, the physician should be able to characterize the problem, to propose the treatment-options and to assess the need for additional testing and specialist consultation. Patient and (partner’s) need, expectations and priorities are important elements in this assessment.

The aim of the committee was to serve three purposes. The first is to help the primary care physician who does not have much experience in manageing patients with ED (Initial assessment). The second is to define the indications for referral to a specialist. The third is to outline the optional components of a specialised evaluation.

I. HISTORY It is very important for the physician to create a therapeutic alliance with the patient. Although not always possible on the first visit, every effort should be made to involve the patient’s partner in the process. Cultural and social preferences as well as individual patient needs and preferences may influence the partner ’s availability.

A. INITIAL ASSESSMENT OF A PATIENT WITH ED The cornerstone of clinical assessment for all men with ED is the initial evaluation. This work-up should be performed by a physician knowledgeable in male sexual function and dysfunction, and with sensitivity toward cultural, ethnic and religious factors. Although a patient with ED may be referred to a non-physician for psychosexual therapy, the medical (pharmacological) and surgical therapies for ED require the involvement of a physician (a). Basic knowledge of anatomy and physiology of male sexuality is essential. In special situations, a multidisciplinary approach may be required. The initial evaluation of the patient with ED should consist of a comprehensive medical, sexual and

FLOW CHART FOR THE INITIAL EVALUATION History • Medical • Sexual • Psychosocial Physical Examination Diagnostic Tests Patient Education Treatment ↔ Specialist consultation (a) It was the opinion of some of the delegates at the meeting of the first consultation on Erectile Dysfunction in Paris, July first 1999, that the initial work-up may be done by a specialized nurse under the supervision and responsibility of a physician.

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1. M EDICAL HISTORY

RISK-FACTORS FOR ORGANIC ED

The goal of the medical history is to differentiate between psychogenic and organic ED and to identify risk factors for organic ED. For the first purpose the Leiden Impotence screening Test (LIST) may be helpful [2].

• Ageing • Hypertension • Atherosclerosis • Diabetes mellitus • Smoking • Depression • Pelvic/perineal/penile trauma or surgery • Neurological illness • Endocrinopathy • Prescription and recreational drugs

THE KEY-ELEMENTS OF THE LEIDEN IMPOTENCE SCREENING TEST

Characteristic Organic • Onset Gradual • Circumstances Global • Course Constant • Non-coital erection Poor • Psychosexual problem Secondary • Partner problemSecondary • Anxiety and fear Secondary

Psychogenic Acute Situational Varying

2. SEXUAL HISTORY [4]

Rigid

BASIC-ELEMENTS IN THE SEXUAL HISTORY • • • • •

Long history At onset Primary

For the latter purpose the medical history should focus on risk factors for organic ED. In this context, it is appropriate to make inquiries into the patient’s lifestyle. Does the patient have any high-risk habits such as smoking, excessive alcohol consumption or drug-abuse? Referral to a specialist may be appropriate at this point to assist the patient in controlling his abusive habits. Often ED is a first symptom of cardiovascular disease or chronic illness. An example is that 16% of patients presenting with ED have previously undiagnosed coronary artery disease [3]. Or, over 35% of all male patients with diabetes mellitus suffer from some degree of ED [125]. The patient’s prescription drugs must be carefully identified, because they may be an important causal factor. The most important of these are antihypertensives, antidepressants and tranquillisers [126]. The use of certain drugs can be a contraindication to some forms of ED-treatment (e.g. nitrates in the case of sildenafil).

Nature of the problem Psychosocial context Chronology of the problem Severity of the problem Definition of patient’s needs and expectations

The goal of the sexual history is to define the nature, chronology, psychosexual context and severity of the problem. To obtain an accurate sexual history it is necessary for the doctor and patient to discuss matters privately. Many men and women find it difficult to talk about their sexual problems. The physician should put the patient at ease by listening carefully and by creating an atmosphere of privacy, security and confidentiality. It is also of importance for the physician to be «open» to the patient’s problems and to speak in terms which the patient uses and understands. In the initial consultation, the physician should let the patient do most of the talking in order to acquire a clear idea of what the problem is and what the patient wants. Any questions that the physician asks during this phase should have an open-ended character. Validated sexual-function questionnaires may be used to assist in obtaining the sexual history. Sex questionnaires are a valuable option to the sexual history; they may help the physician to initiate or structure the interview but are not a substitute for

Depression is often associated with ED. Depressed mood is a common reaction to marital or sexual difficulties and primary depression is often associated with ED. Treatment of depression may result in improved sexual function and mood [127].

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the patient - physician dialogue. In clinical practice, the substitution of a questionnaire for ‘the patient - physician dialogue’ may result in a failure to diagnose the etiology of ED (organic versus psychological), and may not address the specific religious, cultural, educational and economic factors of the individual patient. Primarily, sex questionnaires are research tools, which provide efficacy endpoints in drug studies. To date, the ‘international index of erectile function (IIEF)’ [5], the ‘erectile dysfunction inventory of treatment satisfaction (EDITS)’ [6], and the ‘brief male sexual function inventory for urology’ [7] are frequently used for this purpose. To acquire a clear understanding of the various aspects of the patient’s sexual activity, the sexological mini-anamnesis may be used. [8] This history, which is based on the sexual response cycle defined by Masters & Johnson [9], enables the physician to obtain in a simple manner a global picture of the nature and extent of the problem. To acquire a deeper understanding of ED this list can be supplemented by a few specific questions. Physicians manageing patients with sexual dysfunction should be thoroughly familiar with the sexual response cycle. Many patients who ask for help with a sexual problem have little difficulty answering the questions on the sexological minianamnesis. SEXUAL RESPONSE CYCLE ACCORDING TO MASTERS & JOHNSON 1. Desire 2. Excitement 3. Plateau 4. Orgasm 5. Resolution Problems with erection arise, in particular, in phases 2 and 3, where interaction with the envi ronment and the partner plays an important role a) Desire The assessment of sexual desire is somewhat easier in men than in women, because desire is manifested in men as the urge to initiate lovemaking. However, the patient may misinterpret a reduced level of desire (libido) as ED. Sexual response for many men is synonymous with obtaining an erection, but also, of course, sexual response has an experiential compo-

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nent. The main difficulties are 1) to decide whether loss of sexual desire preceded or is a result of ED, and 2) to distinguish between loss of desire and concern about sexual performance, which can become a preoccupation. Loss of desire following ED is an understandable response to the genital failure. But loss of sexual desire, which clearly preceded other dysfunction, may have organic causes, such as hormonal deficiency, which need to be identified. The pathogenesis of decreased sexual desire is often complex and heterogeneous. Its elucidation may require much more careful history taking than is necessary with other types of sexual problems. A man’s attitude to his general health may be important because concern about sexual function is sometimes part of a general hypochondriacal pattern. Concerns about body image are sometimes important. b) Excitement In assessing the excitement phase, it is important to establish whether full erection can occur in any situation or at any stage during lovemaking. c) Orgasm and ejaculation Orgasmic disturbances, such as premature ejaculation, are common and must be clearly distinguished from erectile disturbances. Premature ejaculation is sometimes mistaken for an erectile problem because of the rapid loss of erection that follows it. Adult-onset premature ejaculation is often associated with erectile failure, as a result of the performance anxiety caused by the erectile problem. Also, with erectile impairment, the time taken to elicit an erection may be prolonged, whereas that required to produce ejaculation is not. This can give the impression of premature ejaculation. Absent or delayed ejaculation also requires careful description. Does the problem occur only in the presence of the partner; e.g. is the patient able to ejaculate normally when masturbating on his own? Or is it only a problem intravaginally, i.e. can he ejaculate outside the vagina during love play with his partner? d) Pain Pain experienced by one of the partners during lovemaking (e.g. as a result of balanitis or postmenopausal changes in the female) can also have an inhibiting effect on sexuality. The degree of satisfaction can be reduced even though there are no serious problems with erectile function.

SEXOLOGICAL MINI-ANAMNESIS • I understand that, at present, things are not going quite right sexually. I want to ask you a few questions so I can get a clear idea of your pro blem. Can you tell me again what is not going quite right in your sexual relationship? • Have you noticed any changes in the level of your sexual desire? • Have you noticed any changes recently in the pleasure you get from sex? • Do you get turned on sexually as easily as you used to? • Have you noticed any changes in the way your penis gets hard? • What are your nighttime/early morning erections like? • Is intercourse still satisfying? Do you occasio nally come too soon? • Do you experience any pain when inserting your penis into the vagina or during sexual inter course? • Do you usually have a satisfying orgasm? • How long have you had these problems? Are they always present under all circumstances when you want to have sex, or are you occasionally free from them? • Does your partner also have a sexual problem, as a result of illness or old age perhaps, which she doesn’t want to talk about? • Do you or does your partner suffer from any ill nesses which you think your sexual problems are responsible for? • How are you coping with these problems? Are you, or your partner or both of you weighed down by them? • Finally, can you tell me something about the things which, in your opinion, are going well in your sex life? • Is there anything else you would like to ask me about your sexuality?

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THE COMMITTEE’S SAMPLE SEXUAL HISTORY QUESTIONS CHRONOLOGY - Could you describe your sexual problem? - When was the last time you had a satisfactory erection? - How was your sexual function prior to this time? - Was the onset of your dysfunction gradual or sud den? - When was the last time you had satisfactory pene tration? - What portion of sexual attempts is satisfactory to you? - Is your partner satisfied with your sexual func tion? - If we can restore your erections what would be your average frequency of sex each month? SEVERITY / QUANTIFY - Do you have morning or night time erections? - How strong are the erections you get with mastur bation? - On a scale of 1 to 10 how would you rate the stiff ness of those erections, ten being normal? - With sexual stimulation can you initiate an erec tion? - With sexual stimulation can you maintain an erec tion? - Do you lose erection before penetration, or before climax? - Do you have to concentrate to maintain an erec tion? - Do you lose the erection if you don’t have conti nuous direct stimulation to the penis? - Is there a significant bend in your penis? - Do you have pain with erection? SEVERITY / QUALIFY THE IMPACT ON THE PATIENT / PARTNER - How strong is your desire for sex, now and in the past? - Is your erectile problem partner or situational specific? - Is your partner able to become aroused when you have sex together? - What has been your partner’s reaction to your sexual difficulties? - Do you have difficulty reaching orgasm? - Do you have problems with ejaculating too soon or not at all?

body habitus (secondary sexual characteristics), an assessment of the cardiovascular, neurological and genital system focusing on penile, testicular and rectal exam. The physical examination may corroborate aspects of the medical history and may occasionally reveal unsuspected physical findings (e.g. decreased peripheral pulses, penile plaques, atrophic testes, and suspicion of prostate cancer.

3. PSYCHOSOCIAL HISTORY A psychosocial assessment is valuable in every patient. Given the interpersonal context of sexual problems, the physician should carefully assess past and present partner relationships. Sexual dysfunction may affect the patient’s self-esteem and coping ability, as well as his social and occupational performance. The physician should not assume that every patient is involved in a monogamous heterosexual relationship. For that reason, it is advisable to begin with the «Are you sexually active at the moment» or «do you have a regular sex partner?» and then ask «Is that a hetero- or homosexual relationship?» The early stages in the development of a problem are often of crucial significance to treatment. Were there particular times of change in the sexual relationship? If so, what was going on in the patient’s life at those times? In addition, questions should be asked about other important elements of the patient’s life, including other relationships, work, financial security and family life. Does overload or stress play a part, either at work or in his private life? ELEMENTS OF THE

PHYSICAL EXAMINATION • Complete genital exam (digital rectal) • Gynaecomastia • Body hair, fat distribution • BP, heart rate, peripheral pulses, edema • Vibratory sensation, BCR • Lower extremity strength and coordination

III. DIAGNOSTIC TESTS The physician must tailor the laboratory work-up based on patient complaints and risk factors outlined by the history and take into consideration the cost and availability of testing resources.

PSYCHOSOCIAL HISTORY

• ageing • lifestyle factors • current psychological state • symptoms of depression • altered self esteem • coping skills • past and present partner relationships • sexual practices • job and social position satisfaction • history of sexual trauma / abuse • educational attainment

The diagnostic tests used in the assessment of the patient with ED may be stratified as:

1. RECOMMENDED DIAGNOSTIC TESTS A test of proven value in the evaluation of patients with ED, use of which is recommended during initial evaluation. These tests include the following: a) A fasting glucose or glycosylated hemoglobin (HbA1C) and lipid profile - if not available within the previous 12 months - to rule out diabetes mellitus and hyperlipidemia both of which are significant risk factors for ED. b) A morning testosterone assay to assess the hypothalamic-pituitary-gonadal axis. Although controversy exists as to the relative value of the various testosterone assays (total, free or bioavailable), consensus exists that at least one of these assays should be performed. It may be argued that testosterone testing is statistically associated with a low positive yield. In a group of men with hypogonadism, testosterone replacement represents a potentially reversible form of ED.

II. PHYSICAL EXAMINATION Although in general, a physical examination does not identify the cause of ED, a focused physical examination should be performed on every patient with ED. The physical examination should include a general screening for medical risk factors that are associated with ED (co-morbidity) such as,

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2. OPTIONAL DIAGNOSTIC TESTS

V. TREATMENT

A test of proven value in the evaluation of specific patient profiles, with use left to the clinical judgement of the treating physician.

Following the completion of the diagnostic evaluation, all treatment options should be discussed with the patient (and his partner) and treatment choices should be made.

OPTIONAL DIAGNOSTIC TESTS - Prolactin, free and total testosterone, LH - Thyroid stimulating hormone (TSH) - CBC - Urinalysis (dip or microscopic) - PSA

VI. SPECIALIST CONSULTATION AND REFERRAL With the advent of effective oral treatment and the subsequent popularization of ED, new categories of physicians are involved in the initial evaluation and treatment of ED. Only in a minority of patients, referral to a specialist is necessary. Traditionally, the urologist is the specialist in the evaluation and treatment of men with ED.

3. SPECIALIZED DIAGNOSTIC TESTS A test of value in selected patients. Should be considered only in a specialized setting (see section B).

IV. PATIENT EDUCATION

A wide range of diagnostic tests is available. These can be used to separate somatically determined from purely psychogenic ED or to tailor specific vascular surgery in patients with arterial disease or venoocclusive dysfunction. In the majority of ED patients, the diagnostic evaluation has little impact on the therapeutic options. Diagnostic categorization is particularly worthwhile for those patients in whom a reversible form of ED is suspected.

The rational selection of therapy by patients is only possible following appropriate education. Patient education is also important in fostering a therapeutic relationship, facilitating patient-physician communication and enhancing patient compliance. When all the information from the history, physical examination and the supplementary diagnostic tests have been collected, it is time to actually formulate the complaint. Generally, the information obtained from the initial evaluation is sufficient to direct the majority of patients toward therapy.

INDICATIONS FOR SPECIALIST REFERRAL • Patient’s request • Treatment failure • Peyronie’s disease • Primary ED • History of pelvic/perineal trauma • Cases requiring vascular or neurosurgical intervention • Complicated endocrinopathy • Complicated psychiatric or psychosexual disorder • Complex relationship problems

Not everyone who presents with an erection problem is a candidate for treatment. With older patients, it is advisable to explain that the rigidity of erection decreases with age, as also does the extent to which the penis stands upright. The frequency of sexual activity also decreases. The refractory period after orgasm, in which the penis can not become rigid, increases from several minutes in a young man to hours or even days in older men. Many men find that the pleasure of the orgasm becomes less intense as they get older. Finally, the patient’s female partner may also experience changes in sexuality, complicating the couple’s sexual dysfunction

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QUESTIONS AND ANSWERS IN DIAGNOSIS OF ENDOCRINE CAUSES OF ED

B. SPECIALIZED EVALUATION

• Which test should be used for screening of androgen deficiency, total or free testostero ne? Ideally, free if cost is not a factor. • Should any test at all be done for the initial eva luation of the standard patient with ED? Yes, at least total Testosterone. If cost is a factor, only in men > 50 years. Otherwise you may miss 40% of patients with androgen deficiency [128].

Some of these tests are illustrated in the Atlas section p. 679

OPTIONS FOR TESTING IN A SPECIALIZED EVALUATION

• Endocrine evaluation • Vascular evaluation In office penile injection pharmacotest Penile pharmaco Doppler Ultrasound (PPDU) Dynamic infusion pharmaco-cavernosometry and cavernosography (DICC) Penile arteriography CT - and MR-Imageing Nuclear imageing • Psychophysiological tests • Nocturnal Penile Tumescence/rigidity Testing • Visual Erotic Stimulation (VES) • Neurophysiological evaluation

Because steroid hormone binding globulin (SHBG) is known to be decreased in hypothyroidism, obesity and acromegaly, and increased in hyperthyroidism and oestrogen therapy, it is necessary to measure the free biologically active testosterone in these conditions, when total testosterone can be misleading (d). If testosterone is low, a repeat test is advised. If the second test reveals again a low serum testosterone, a full hormonal evaluation consisting of LH, Prolactin, FSH, and TSH is recommended. If the patient has a history of decreased libido and/or the physical examination reveals gynaecomastia or testicular atrophy, a full endocrinological evaluation is advised. The blood samples should be taken between 8 and 10 am because of a diurnal peak in the morning. If the prolactin level is raised, a repeat test should be done with the patient completely rested and blood sample taken in the morning after awakening. Secondary causes of hyperprolactinemia should be looked for. Persistent, unexplained hyperprolactinemia should warrant a CT- or a gadolinium enhanced MRI-scan of the head to exclude a pituitary tumour. ED and inhibition of sexual drive also may be associated with thyroid disorder, both hypothyroidism and hyperthyroidism. However, the mechanism of how thyroid disorders affect male sexual function is still uncertain. It is not known whether dysthyroidism causes ED or whether dysthyroidism and ED are associated by occurrence in similar populations. Therefore evaluation of thyroid should be considered only in a specialised setting.

I. ENDOCRINE EVALUATION Although endocrinopathy is a rare cause of male erectile dysfunction, ED can be the presenting symptom of several endocrine disorders. Hypogo nadism and hyperprolactinemia account for the majority of these cases [10]. In the literature the prevalence of hypogonadism in men with ED ranges from 4.3 to 19.3% [11]. The rate of hyperprolactinemia ranges from 1% to 5% [12,13,14]. The prevalence of thyroid disorders is less than 1% [15]. Despite the low diagnostic and therapeutic [16] yield and the persisting controversy as to the relative value of the various testosterone assays (total, free or bioavailable) it is considered important to include a routine total testosterone in the evaluation to detect subtle hormonal changes in men with ED so as not to miss hypogonadism or a partial androgen deficiency syndrome in the ageing male [17] (PADAM) (c) or associated serious medical conditions, such as pituitary tumours, which are treatable [18, 19, 20,21].

(b) Only 55 percent of men with ED and primary hypogonadism and 17 percent of men with ED and secondary hypogonadism respond to androgen replacement therapy [129]. (c) The clinical manifestations of androgen deficiency in the ageing male are :Depression, diminished libido, ED, fatigue, infertility, muscle weakness and osteoporosis. (d) When SHBG is increased, the non-SHBG bound testosterone fraction, which constitutes the bioavailable testosterone may be decreased, despite normal level of total testosterone.

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3. LUTEINIZING HORMONE (LH) AND FOLLICLE STIMULATING HORMONE (FSH)

SECONDARY CAUSES FOR HYPERPROLACTINEMIA IN THE MALE

• LH and FSH are gonadotrophins, synthesised in the pituitary gland. • LH and FSH increase testicular testosterone and spermatogenesis respectively. • Metabolic clearance rate of LH is considerably greater than that of FSH. • FSH is a more sensitive reflection of the serum gonadotropin level than LH, because FSH is raised before LH and LH is rapidly metabolised. • Asingle measurement of circulating LH may be as much as 50% above or below the mean level. • Circulating levels of both LH and FSH are increased in ageing.

• Coitus • Hypothyroidism • Stress • Chronic renal failure • Exercise • Severe liver disease • Sleep • Drugs [22] Protirelin, fenfluramine, thyrotropin-releasing hormone, estrogens, antipsychotic agents, methyldopa, opiates, opioids, metoclopramide, reserpine and amoxapine DESCRIPTION OF THE AVAILABLE HORMONAL TESTS

4. PROLACTIN (PRL) • Synthesised and secreted by the anterior pituitary gland. • Serum prolactin increases during sleep, peak in the early morning and decline immediately after awakening. Basal concentration varies considerably. • The hypothalamic peptides, thyrotropin releasing hormone (TRH) and vasoactive intestinal peptide (VIP) stimulate release of PRL from the pituitary.

1. TOTAL TESTOSTERONE • Secreted episodically from testicular Leydig cells in response to luteinizing hormone (LH) pulses. • Diurnal pattern with a peak level in the early morning and a nadir in the evening. • 98% of testosterone is bound to plasma proteins; majority of the binding is to albumin 40% and globulin 57%. Only 2% of total testosterone are free. Bioavailable testosterone consists of both free and albumin-bound testosterone. • Total testosterone level decreases with age.

• The hypothalamus exerts tonic inhibitory control over prolactin release, mainly through the prolactin - inhibiting factor dopamine.

2. Free TESTOSTERONE [23]

• Prolactin levels in human blood are elevated with oestrogen, antipsychotic, antidepressant, some tranquillising drugs and stress and decreased by L-dopa and ergot derivatives.

• Consists of only 2% of total. Biologically active. • Exert effects in target cell where it is converted to more potent dehydrotestosterone by 5 alphareductase. • Level affected by estrogens [24], thyroid hormone and cirrhosis (decrease free testosterone) and androgen, growth hormone, glucocorticoids and obesity (increase free testosterone level). • Very much more expensive to measure free testosterone than total testosterone. • Testosterone replacement improved sexual functions only in men with low free fraction but NOT in subjects with a normal free fraction [25]. • Free testosterone level lowers significantly with ageing. • Prevalence of partial androgen deficiency in ageing males (PADAM) may be as high as 50% if free testosterone level is used.

5. THYROXINE • The L-isomer is the active iodine compound existing normally in the thyroid gland. • May need to measure T3 for certain cases of thyroid disorders.

6. THYROID STIMULATING HORMONE (TSH) • Produced by the anterior lobe of the pituitary gland. • Stimulates the growth and function of the thyroid gland. • Used in diagnostic test to differentiate primary and secondary hypothyroidism. 124

• For scientific and clinical reasons to define the cause of ED in groups of patients with a chronic disease, such as diabetes mellitus or renal failure [39, 40, 41]. • For medicolegal reasons.

II. VASCULAR DIAGNOSTICS Organic factors in ED may be classified as neurogenic, myogenic, endocrine arteriogenic and venoocclusive [26]. The latter two are the causes of the clinical entity known as vascular ED. Risk factor assessments suggest that ED is most often of a vascular etiology [27]. However, because combinations of etiologies are common, the term vascular ED does not rule out the presence of contributing psychological or neurological factors. The two principal causes of arteriogenic ED are atherosclerotic vascular disease [28, 29] and traumatic arterial occlusion, following blunt pelvic or perineal trauma. The most common comorbidities for ED due to atherosclerotic vascular disease are cigarette smoking, diabetes, hypertension and hypercholesterolemia. Venoocclusion is a hydraulic process related to volume and pressure changes mediated by variations of the tone of the cavernous smooth muscle cells. Venooclusive dysfunction of the cavernous body may have several causes [30], such as 1) neurogenic changes; 2) altered intercellular communication [31,32]; 3a) heightened contractility of corporeal smooth muscle, secondary to increased reactivity to alpha1adrenoceptor activation with age and disease [33]; 3b) impaired relaxation of corporeal smooth muscle [34]; and 4) parenchymal changes at the level of extracellular matrix or of the corporeal smooth muscle cells [35, 36, 37]. Several tests are available for evaluating the penile vascular inflow and venooclusion. These include pharmacotesting, enhanced pharmacotesting such as in pharmaco penile duplex ultrasonography (PPDU) [38], cavernosometry and selective penile angiography.

The basic indications for vascular testing are either to select patients for penile vascular surgery or to test for the proper dose of drug for intracavernous injection therapy. An adequate test for the latter is the pharmacotest in the office, or eventually a trial of auto-injection therapy at home. One should realise, however, that an adequate erectile response does not rule out obstruction of the penile inflow tract and that an inadequate erectile response may be due to anxiety [42 , 43, 44]. To select patients for specific surgical treatments such as penile revascularization or veno-restrictive surgery, PPDU may be used as the first-line test to discriminate between hemodynamic abnormalities in the penile inflow tract and venoocclusive system. If abnormal, more invasive tests such as dynamic cavernosometry or penile angiography may be required [45]. Today, it is recognised that the best candidates for revascularization are younger men with isolated lesions in the pudendal artery, the common penile artery, or both, due to pelvic or perineal trauma [46]. The best candidates for venorestrictive surgery are men with anatomic abnormalities such as ectopic veins exiting the cavernous corpora or abnormal communications between the cavernosum and glans/spongiosum. These men may have a history of primary ED, congenital penile abnormalities, urethral surgery, or blunt trauma to the erect penis [47].

INDICATIONS FOR VASCULAR TESTING • To select patients for penile vascular surgery • To establishing the proper dose of drug for intra cavernous injection therapy • To allow the patient to experience the degree of rigidity he still may get after a maximal pharma cological stimulus

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In the era of effective oral medication, a reason for a pharmacotest in the office is to allow the patient to experience the maximal degree of rigidity he still may get after maximal pharmacological stimulation. This is clinically important because it will allow the patient to compare the responses to the oral agent and the intracavernous injection. Thus, men failing on oral medication who have experienced an effective response to an injection may recall this a more advantageous therapy and wish to try it at home when oral medication fails. There are several methods to enhance the erectile response to an intracavernous pharmacological challenge: genital self-stimulation [48], vibratory stimulation [49, 50] visual erotic stimulation

[51,52] and the application of a penoscrotal tourniquet [53].

The most feared complication of pharmacotesting is prolonged erection. The group most prone to prolonged erection are younger patients with nonvascular ED and a better baseline erectile function [61]. There is no consensus as to the best intracavernous agent or dosage for pharmacotesting. The ideal agent offers a maximal erectogenic effect and a minimal chance of prolonged erection [62,63]. A variety of agents and dosage regimens have been studied: papaverine 60 mg, papaverine 60 mg / phentolamine 1 mg, papaverine 30 mg / phentolamine 1 mg, papaverine 45 /phentolamine 2.5, PGEI 10 µg, 20 µg and 30 µg [64]. To date, a challenge of 10 µg of PGEI, combined with genital stimulation and/or visual erotic stimulation [65] (VES), is considered to be the best possible initial challenge [66]. It is noteworthy that Montorsi et al advocate that «visual erotic stimulation (VES) and manual self-stimulation of the genitalia should always be associated with a pharmacotest in order to maximise the relaxation of corporeal smooth muscle and subsequently to obtain the greatest erectile response [67]. In case the best quality erection is not obtained 20 minutes after this challenge, a second and eventually third injection at the same dosage (re-dosing) is advised.

Furthermore, it may be important for scientific and clinical reasons to define the cause of ED in groups of patients with a chronic disease, such as diabetes mellitus or renal failure [54, 55, 56].

1. IN OFFICE PENILE INJECTION PHARMACOTESTING

The demonstration that vasoactive injections can produce penile erection revolutionised the diagnosis and treatment of ED [57]. Intracavernous vasoactive injectables provide a direct test of end organ vascular integrity, and the first aetiology specific pharmacotherapy (vasoactive medicine for a penile vascular problem). Pharmacotesting is the intracavernous injection of a vasoactive medication and rating of the subsequent erection quality by visual inspection and palpation [58]. Several numeric scales have been proposed for rating erectile rigidity; the simplest scale assesses the erection with three qualifiers: 1) inadequate for penetration; 2) adequate for penetration; and 3) unbending rigidity of at least 20 minutes duration.

2. PENILE PHARMACO DUPLEX ULTRASOUND (PPDU) [68]

The office pharmacotest is the most commonly used diagnostic procedure for erectile dysfunction. It is, despite its lack of specificity, cost-effective, simple, minimally invasive, and performed without special monitoring [59]. A positive response (normal erectile rigidity of sustained duration of at least 20 minutes) implies the patient does not have significant venooclussive or arterial pathology. Recent correlation with PPDU confirms that a positive pharmacological erection test is indicative of normal venoocclusion but may occur with borderline arterial function [60].

All too often the response to pharmacotesting is suboptimal. This situation leaves the physician questioning: «does my patient have venous leakage, arterial insufficiency, high anxiety or was the pharmacological challenge too low?» PPDU provides a more objective, minimally invasive evaluation of penile hemodynamics following a pharmacotest [69]. The accuracy of PPDU has been tested through comparison to visual rating of erection following penile injection, cavernosometry-ography and pharmaco-penile angiography [70]. Since its introduction by Lue (1985) [71] duplex Doppler penile sonography has proven to be an accurate and reproducible technique for evaluating erectile dysfunction. With the initial grey scale imaging of duplex sonography, study quality was highly dependent on the skill of the examiner. Vessel localisation within the corporal tissue was difficult and dorsal vessel imaging all but impossible. The addition of colour has facilitated consistent detection of dorsal, cavernous and urethral vessels. PPDU permits the rapid acquisition and measure-

PHARMACOTESTING • Pharmacotesting consists of an intracavernous injection of a vasoactive agent and rating of the subsequent erection quality by visual inspection and palpation • A positive response rules out significant vascular pathology.

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ment of small vessels in low flow states. High frequency linear array transducers (5 to 10 MHz) provide the best images of the penis. The most recent development in non-invasive penile diagnostics, 3dimensional power Doppler ultrasonography, facilitates the study of morphology and functionality of the cavernous microcirculation in full detail [72 ,73, 74]. PPDU uses the imageing principles of pulsed Doppler: a pulse of ultrasound is emitted from the transducer, reflected back and received. When the returning echo has a different frequency than the emitted frequency a Doppler shift has occurred; ultrasound reflecting back off a moving object (penile blood) causes a Doppler Shift. Doppler frequency shift depends on several factors: frequency of the transducer, velocity of the moving object (penile blood), speed of sound through the medium (penile tissue) and angle between the Doppler beam and direction of blood flow. The blood flowing in a vessel, which is approaching the transducer, will produce echoes with a higher frequency than was emitted; blood flowing away produces a lower frequency. As blood flow velocities increase Doppler shift increases. The Doppler shift is displayed on grey scale as spectrum (waveform) or in PPDU as two dimensional colour image. In PPDU the colour display has an angle dependence just like the grey scale spectrum of the Doppler shift. If the vessel runs parallel to the skin surface, ultrasound scanning lines are perpendicular (90’ Doppler angle). This will yield no Doppler shift and no colour within the vessel. To correct this problem of physics, linear array transducers use phasing to steer the scan lines at a more appropriate angle or an angled stand-off wedge on the end of the transducer to provide a non-perpendicular Doppler angle. It should be noted that PPDU merely allows for a qualitative and not for a quantitative assessment of penile blood flow, because blood flow velocities and not blood flow are measured.

see ultrasound views of your penile vessels; some of these run on the surface of the penis and two are central arteries providing the pressure to your erection. When the Doppler is activated the sound you hear will be blood flowing into your penis with each heartbeat.’ The corporal bodies should be scanned in the transverse plane from base to tip to demonstrate normal anatomy (paired cavernous and dorsal arteries). The echo texture should be homogeneous, fibrotic processes are relatively hyperechoic in comparison. The penile vessels and flow velocities are assessed in the sagittal plane (parallel to the long axis of the penis). Vessels may be scanned from a dorsal, ventral or lateral aspect of the penile shaft. Lateral scanning will demonstrate both cavernous vessels in the same image, with the hyper echoic septum in between both arteries. Cavernous to cavernous collaterals are best imaged in the sagittal projection.

4. PPDU ASSESSMENT OF THE PENILE INFLOW TRACT The parameters used to infer the integrity of the penile inflow tract are cavernous peak systolic velocity (PSV), acceleration time (time from the start of systolic velocity to the maximum value), and acceleration [75] (peak flow velocity over acceleration time) [76]. Because penile erection is a dynamic event, with a maximal challenge of the cavernous inflow tract in the early phase of erection (tumescence), multiple blood flow velocities should be measured between 1 to 10 minutes after injection [77, 78]. Delayed responses are typical in smokers and both the hypertensive and the anxious patient. PPDU ASSESSMENT OF PENILE INFLOW TRACT • Parameters: Peak Systolic blood flow Velocity (PSV) and Acceleration Time. • A PSV < 25cm/s and/or an acceleration time >122ms are indicative for severe penile arterial insufficiency. • PSV > 25 cm/sec but < 30 cm/s suggests mild arterial insufficiency • To assess the penile inflow tract, the blood flow velocities should be measured between 1 and 10 minutes following pharmacostimulation • Cavernous blood flow velocities decrease with age. A functional venoocclusive mechanism may compensate for decreased inflow across a wide range of velocities

3. PPDU E XAMINING PROTOCOL The examination should be performed in a warm darkened room. A warm secure setting is essential to reduce anxiety and thus sympathetic cavernous smooth muscle tone. The patient should be assured that the examination setting is private and secure. The patient should be supine; he need only disrobe from the waist down. His attention should be directed at the video monitor with periodic explanation of images displayed: ‘you are going to 127

In the series from the University of California San Francisco, normal subjects had a mean PSV of 34.8 cm/sec [130, 131]. In the Baylor University study normal volunteers had mean PSV of 40 cm/s [132]. Normal volunteers in the Harvard Medical School study [133] had mean PSV of 47 cm/s. Each of these groups concurs that a peak systolic velocity < 25 cm/sec suggests severe penile arterial insufficiency. In the Mayo Clinic series PSV < 25 cm/sec had a sensitivity of 100% and specificity of 95% in selection of patients with abnormal penile angiography.A PSV of 35 cm/sec or more is consistently associated normal penile arteriograms. The Mayo Clinic group recommends that in patients with bilateral peak systolic velocities > 30 cm/s, arteriography should not be performed [134].

PPDU ASSESSMENT OF THE VENOOCCLUSIVE MECHANISM

The diagnosis 'venoocclusive dysfunction' should be considered when PSV > 30 cm/s, and EDV > 3 - 5 cm/sec or RI < 0.9. , associated with erectile rigidity rated as inadequate. In a Mayo Clinic study an EDV of > 3cm/s measured 15-20 minutes after intracavernous pharmacological stimulation yielded a specificity of 94% and sensitivity of 69% for detection of venoocclusive dysfunction when compared with pharmacocavernosometry. In an Australian series, investigators found RI calculations 15 minutes after intracavernous pharmacological stimulation correlated well with cavernosometry [135]. In Japan, investigators found RI > 0.9 was associated with normal dynamic infusion cavernosometry in 90% and RI < 0.75 was associated with venous leakage in 95% of patients [136]. Based on these data, the diagnosis 'venoocclusive dysfunction' should be considered when PSV > 30 cm/s, and EDV > 3 - 5 cm/sec or RI < 0.9, associated with erectile rigidity rated as inadequate.

Penile blood flow velocities decrease with age[79]. This does not necessarily imply that erectile function decreases proportionally, because, a functional venoocclusive mechanism may compensate for decreased inflow across a wide range of velocities. Thus, the dynamics of venoocclusion is the more critical factor in the ageing erectile response.

5. PPDU ASSESSMENT OF THE VENOOCCLUSIVE MECHANISM

It is important to note that the deep dorsal vessels are not subjected to changing intracorporeal pressure during erection. Therefore, a well-sustained rigidity is associated with persistent antegrade diastolic flow in the dorsal arteries. Moreover, deep dorsal vein flow is not reduced or shut off during erection and therefore blood flow in the deep dorsal vein should not be interpreted as evidence of venoocclusive dysfunction

Parameters to assess the venooclussive function are end diastolic flow velocity (EDV) and resistance index (RI) [80 , 81]. Clinically, EDV and RI correlate with erectile response, since both are descriptions of penile rigidity/intracavernous pressure. The formula for RI = PSV - EDV / PSV. The value of RI depends on the resistance to arterial inflow, and in the context of corporeal physiology this is a function of changing intracorporeal pressure during the various phases of erection. As penile pressure equals or exceeds diastolic systemic pressure, diastolic flow in the corpora will approach zero and the value for RI approaches 1.0. In full rigidity diastolic flow in the cavernous arteries may reverse (momentarily be retrograde) in which case the calculated RI will be > 1.0. During tumescence or with a partial erection diastolic antegrade flow persists and the value for RI remains < 1.0.

6. PPDU IN STAGING OF PEYRONIE'S DISEASE Indications for performing PPDU in Peyronie's disease include patients with a severe angulation in whom corrective surgery is considered or men who claim complete loss of erection and request placement of a penile prosthesis. Potentially the most useful preoperative staging information, is the demonstration of collaterals from the dorsal vascular bundle. Dorsal artery

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collaterals piercing down through the tunica to anastomose with the ipsilateral cavernous artery may be in proximity to plaques. Operative mobilisation of the neurovascular bundle for plaque excision in these cases would of necessity sacrifice the dorsal contribution to cavernous inflow. The tunica albuginea is normally hyper- echoic compared to the corpora proper. As the corporal bodies distend with blood the cavernous sinusoids become more hypo-echoic increasing the contrast between the tunica and corpora. Penile plaques are hyper-echoic thickenings of the tunica albuginea. The typical dorsal plaque underlies the dorsal vasculature. Denser plaques cast an acoustical shadow and are well visualised in either the transverse or sagittal plains. If the plaque casts an acoustic shadow like a renal stone, then calcification should be suspected and plain radiographs taken. Although most plaques localise to the proximal and middle third of the pendulous shaft, distal plaques even at the level of the corona may cause curvature. Circumferential narrowing of the corporal bodies by plaque sonographically results in an hour glass shape to the erection; the patient complains of 'hinging' with erection.

INDICATIONS FOR DICC In patients who are suspected to have a site-speci fic leak and in whom vascular surgery is conside red a treatment option • Congenital • Peyronie's disease with poor rigidity • History of penile fracture • Perineal / pelvic trauma history DICC is only performed when vascular surgery is considered a treatment option [82]. A correct diagnosis and the demonstration of venous leakage require complete smooth muscle relaxation. Failure to achieve complete pharmacological corporal smooth muscle relaxation is an inherent source of error in DICC testing. A method that enables DICC under conditions of known corporeal smooth muscle relaxation increased its reliability for clinical practice [83,84,85].

8. DICC UNDER CONTROLLED COMPLETE SMOOTH MUSCLE RELAXATION Two 21-gauge needles are inserted into the midpendulous shaft (dorsolateral); injection of vasoactive agent is made and equilibrium pressure measured at ten minutes. An intracavernous pressure of 80-90 mm Hg associated with rigidity is a normal response with no significant venoocclusive dysfunction. Infusion of heparinized saline is the next step; the flows to maintain the intracavernosal pressures at respectively 30, 60, 90,120,and 150 mm Hg are measured. Complete smooth muscle relaxation is characterised by a linear relationship between the flows to maintain and intracavernosal pressures. If this linear relationship is not obtained, the patient is re-dosed with a vasoactive agent. At 150 mm Hg, flow of saline is stopped and intracavernosal pressure fall over 30 second is recorded. Maintenance flow rate (MFR) is considered [86] as the most important criterion of venoocclusive function. It is the flow to maintain the intracavernous pressure at 150 mm Hg. In a state of complete smooth muscle relaxation, normal flow rates to maintain intracavernous pressure at a pressure of 150 mm Hg is 3 ml/min or less. The Pressure Decay, fall of intracavernous pressure over 30 seconds from 150 mm Hg should be less than 45 mm Hg.

For medicolegal reasons it also may be important to measure penile length and diameter during PPDU, as every operation on the penile shaft is associated with some risk of shortening. Often the patient's perception of postoperative shortening of his penis exceeds the reality and it is useful to document the pre- and postoperative penile measurements.

7. D YNAMIC INFUSION PHARMACO-CAVERNOSOMETRY AND CAVERNOSOGRAPHY (DICC) Insufficient corporal venoocclusion is implicated in up to 50% of patients complaining of ED who have vascular testing. DICC is invasive requiring two needles to remain in the penis one for heparinized saline / radiographic contrast infusion and one for pressure recording. DICC is reserved for the rare patient who might have a site-specific venous leak, e.g. Peyronie's disease with poor rigidity, history of penile fracture, perineal / pelvic trauma history.

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10. CT- AND MR IMAGING

DICC RECOMMENDATIONS

Computer Tomography and Magnetic Resonance Imageing are sophisticated imageing techniques, which visualize pelvic and genital anatomy. They may be used in specialized settings of pelvic, perineal or penile trauma or Peyronie's disease. These imageing techniques provide no insights into cavernosal hemo-dynamics.

• A correct diagnosis of venoocclusive dysfunction requires complete cavernous smooth muscle relaxation. • Failure to achieve complete smooth muscle relaxation is an inherent source of error in DICC testing. If cavernosometry performed in a proven state of complete smooth muscle relaxation, suggests that significant venoocclusive dysfunction is present, the anatomic site of leakage can be demonstrated by intracavernous infusion of contrast (cavernosography) at an intracavernosal pressure of 90 mm Hg. Please note that establishing a diagnosis of isola ted venous insufficiency requires demonstration of intact normal arterial inflow. A method of functional evaluation of the cavernous artery at the time of cavernosometry is by measuring its occlusion pressure. Cavernous artery systolic occlusion pressure (CASOP) is obtained during the third phase of DICC, following complete smooth muscle relaxation after one or several intracavernous vasoactive injections. The CASOP is demonstrated by saline infusion and monitoring cavernous arterial pulsatile flow with Doppler. The intracavernous pressure at which arterial pulsations reappear after suppression by saline infusion (suppression by high intracavernous pressure) is the CASOP. Normal CASOP varies by < 35 mm Hg with the brachial artery systolic pressure.

9. PENILE ARTERIOGRAPHY [87, 88,89] Penile arteriography is the radiographic imaging of the internal pudendal arteries and their outflow tracts. It set the initial standards for diagnosis of vascular ED. Accurate penile arteriography requires pharmacologically stimulated erection since the vessels of the flaccid shaft are contracted and tortuous and consequently hard to visualize. Arteriography provides the best anatomic information about the origin of the common penile arteries, but as a screening test it is too invasive and nonspecific for the assessment cavernosal hemodynamics. It is generally reserved for young men with a history of pelvic / perineal trauma who may be candidates for operative revascularization [90].

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11. NUCLEAR IMAGEING Radioisotopic penography assesses the rate of washout of a radioisotope from the penis following pharmacotesting or visual erotic stimulation [91, 92, 93, 94,95]. This test remains experimental without standardization of isotopes or parameters of penile blood flow. It provides dynamic but not anatomic information.

III. PSYCHOPHYSIOLOGICAL TESTS 1. NOCTURNAL PENILE TUMESCENCE / RIGIDITY TESTING (NPT) NPT or sleep related erection is a recurring cycle of erections associated with rapid eye movement during sleep [96]. Sleep erections are androgendependent and thus usually impaired in hypogonadal men. Registration of nocturnal penile tumescence (NPT) is useful for separating psychological and organic cases [97]. Its main advantage is that it is relatively free from psychologically mediated effects. The documented presence of a full erection indicates that the neurovascular axis is functionally intact and that the cause of the ED is most likely psychogenic. Although this assumption seems overall plausible, doubts have been raised about it. Anxiety and depression can at times influence the content of the dream state, negatively affecting spontaneous nocturnal erections. In addition, sleep disturbances such as apnoea or motor agitation can also induce erroneous recordings. Dysfunction at the level of the cortex and spine may still permit nocturnal tumescence while causing an ED in the awake state. Moreover, normal NPT may also occur in patients with a mild vascular problem who often loose an erection during pelvic thrusts. Finally, NPT evaluation has proved to be age-dependent [98] and quite costly, as it is ideally done in a specially equipped sleep center [99,100].

NPT is tested over at least 2 nights, to eliminate the 'first night effect'. To be accurate, it must include measurements not only of penile circumference but also of penile rigidity. The Rigiscan® device, providing real-time recordings of tumescence and rigidity, used in the sleep laboratory is regarded as the optimal standard of NPT recording [101]. However, because the Rigiscan® measures radial rigidity (compressibility) in stead of axial rigidity (buckling force) the validity of the rigidity measurements have been questioned. Allen et al reports that, when Rigiscan® base and tip radial rigidity exceeds 60% of maximum, correlation with axial rigidity is poor. In this range, the Rigiscan® fails to discriminate axial rigidities between 450 and 900 g of buckling force. As an axial rigidity of more than 550 g is necessary for vaginal penetration, the Rigiscan® may not be able to detect subtle abnormalities in erectile function [102]. Hatzichristou et al demonstrated in a study in healthy volunteers that NPT with at least 1 erectile episode of tip penile rigidity greater than 60% and 10 minutes in duration might be associated with potency [103].

tory, visual, olfactory, and imaginative stimuli, are mediated by sympathetic pathways. Reflexogenic erections, elicited by tactile stimulation at the genital level, are mediated by a spinal reflex arc consisting of afferent somatic and efferent parasympathetic nerve fibres. Therefore, the neurological factor in ED may include central and peripheral neural structures [107 ,108]. The ideal neurophysiological assessment will objectively and quantitatively evaluate the functional status of all parts of this neurological network. In the last two decades, a series of tests has been developed, each of which reflects a specific part of the network. The medical history and physical examination provide the basis for these tests. Test can be classified as those detecting somatic efferent (motor) pathways, afferent (sensory) pathways, reflexes and autonomic responses. Wise use of these tests, should consider the relations between each specific test and the neural function it detects. NEUROLOGICAL TESTING Motor • Bulbocavernosus EMG • Magnetic stimulation • Reflex latency testing

2. VISUAL EROTIC STIMULATION (VES) A full erectile response to VES makes a psychogenic cause of ED likely. Although this theory seems reasonable, the clinical value of VES is questionable. Unlike NPT, response to VES, although possibly closest to normal sexual response, is strongly susceptible to psychological factors, such as erotic excitement inhibition, and maybe normal in states of endocrine abnormality. Degree and latency of erectile responses to VES in eugonadal, sexually non-dysfunctional men correlates with endogenous testosterone levels. Moreover, the response to VES is negatively correlated with age, limiting its value in older man. To date, the most important application of VES is to investigate the erectogenic or antierectogenic effect of drugs, in clinical pharmacological studies [104].

Sensory • Nerve conduction velocity • Evoked potentials • Biothesiometry • Thermal threshold testing • Reflex latency testing Autonomic • Cardiovascular reflex tests • CcEMG • Sympathetic skin response In general however, a goal-directed approach to ED does not tend to neurophysiological testing because history and a physical examination alone are likely to reveal clinical signs of neuropathy. Neurophysiological testing is recommended in research protocols or liability procedures after trauma or surgical interventions and it should be specifically tailored for the individual patient - No routine work-up should be used. Patients suspec-

IV. NEUROLOGICAL TESTING [105, 106] Penile erection is elicited by two different neurophysiolocal mechanisms and mediated by somatic and autonomic pathways. Psychogenic erections, initiated in supraspinal centres in response to audi131

ted of having CNS lesions should be studied by magnetic stimulation and somatosensory evoked potentials. In patients with a history of neuropathy tests of the peripheral system such as nerve conduction, EMG and thermal testing in the lower limbs are relevant. Patients with a history suggestive of low spine or pelvic disorder should be studied by EMG of the sphincter muscles, bulbocavernosus reflex, dorsal nerve conduction and magnetic stimulation of the genitalia.

2. TESTING OF THE EFFERENT (MOTOR) PATHWAYS a) Electromyography of the musculus bulboca vernosus (bulbocavernosus EMG) This test can identify damage to the sacral 2-4 motor roots and the pudendal efferents .It samples large myelinated fibres. The test is well known and extensively used. It is clinically relevant in ED associated with lesions to the low backbone, with nerve root damage. Indications: conditions that affect the continuity of the pudendal nerve such as lumbar disc disorders, pelvic anatomical lesions, pelvic surgery etc.

1. B ASIC PRECEPTS IN NEUROPHYSIOLOGICAL TESTING In clinical practice, the somatic nerves are evaluated by testing nerve conduction velocities and evoked potentials. These tests have well-known reproducibility, validity and range of confounding factors. Autonomic function tests are less reliable, because they simultaneously measure a chain of events or reactions involving receptors, small fibers, and target organs. Confounding factors such as medication, caffeine, temperature, hypo- and hypervolemia, mental mood, and receptor or target organ dysfunction may influence each individual component. Additionally, the complex interaction between central and peripheral sympathetic and parasympathetic nerve systems, as in the pelvic plexus, makes autonomic testing difficult. Moreover, efferent autonomic function tests involve the evaluation of vasomotor and sudomotor fibres and target organs, which may not be equally affected by neuropathy. Toxic metabolic events, especially cause length- dependent neuropathy, because long fibres are more prone to metabolic damage than short fibres [109]. Finally, current autonomic tests are not well standardised. therefore reproducibility, validity and comparability of test results between laboratories are difficult. Thus, autonomic testing is difficult and must be tailored to the specific small fibres or target organ to be tested, with elimination or standardisation of confounding factors. If these conditions are fulfilled, a normal test result rules out neuropathy, while an abnormal test result does not necessarily imply neuropathy. In ED, tests must be focused on vasomotor parasympathetic and sympathetic fibres with vascular and trabecular smooth muscles as target organs.

Reference values: No activity at rest. Units have less than 10ms of duration, and normally, full recruitment can be obtained. b) Magnetic stimulation With this test the conduction velocity in the central and peripheral efferent pathways of the bulbocavernosus muscle can be measured. The test is limited to large myelinated fibres and their central connections. The clinical value of the test is not clear, since it is not yet validated. More data are needed in order to evaluate the role of this test in neurogenic ED. Reference values: In 18 normal males, cortex to bulbocavernosus muscle latencies of 28.8 ms during rest and of 22.5 ms during contraction have been found. c) Bulbocavernosus reflex (BCR) Traditionally, the measurement of the BCR latency time has been used as first line test in the neurophysiological evaluation of erectile and lower urinary tract dysfunction [110]. BCR attempts to determine the integrity of the neural reflex arc S2S4. The afferent and efferent arm of the reflex consists of the pudendal nerve and its distal sensory branch, the dorsal penile nerve. A prolonged BCR latency or the absence of the BCR is a sign of neurological dysfunction. The test is relevant for patients with lesions in the lower spinal cord (cauda) and pelvis. Pathology of the roots or pudendal nerves is likely to result in prolonged or absent response. The use of BCR in patients with suspected neuropathy, and in patients with no evidence of neurological disease is discouraged, because of its low sensitivity.

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Reference values: In a study in 39 potent males a mean BCR of 34.6 ms was found. Bemelmans et al found a normal range of 20 - 40 ms [111].

reflect indirectly the function of the penile efferent (motoric) nerve fibres. Thus, the rationale of performing this test is that evidence of impaired thermal sensation might suggest similar impairment of the autonomic motoric innervation of the cavernous body. However, more data are needed regarding its clinical application.

3. TESTING OF THE AFFERENT (SENSORY) PATHWAYS a) Dorsal nerve conduction velocity

e) Bulbocavernosus reflex (BCR)

This is a test for the large myelinated dorsal penile sensory fibres, which can be valuable in the evaluation of neuropathy, for example in patients with diabetes mellitus. Sensitivity and specificity of this test have not been established yet.

4. AUTONOMIC TESTS a) Cardiovascular reflex tests In 1982, Campese first related abnormal cardiovascular reflexes with ED. Cardiovascular reflex tests assess variations in heart rate and blood pressure in response to various stimuli such as forced breathing, standing up or tilting, Valsalva's manoeuvre, sustained isometric handgrip, mental arrhythmic task, or cold pressure [116]. Heart rate variations reflect parasympathetic function, while blood pressure variations reflect sympathetic function. Loss of variation is indicative for autonomic neuropathy, presuming absence of confounding factors such as cardiac arrhythmia, nicotine, or caffeine use before testing, medication (especially antihypertensives), hypo, or hypervolemia, and dysfunction of baroreceptors or target organs [117].

Reference values: Mean normal velocity of 27.4 ms, and mean amplitude 12 µV was found. When the penile shaft was stretched with a weight of 1 pound, velocity decreased to 33 ms. b) Somatosensory evoked potentials (SEPs) Latencies of SEPs are a measure for the conduction velocity along the sensory pathways from the genital region to the sensory cerebral cortex. Reference values [111]: (mean + 2sd) (50 healthy males, mean age 54 years, range 29-62): Tibial evoked potential (TEP): 35-46ms, Pudendal Evoked Potential (PEP). c) Biothesiometry [112] Biothesiometry and thermal threshold testing may be used to measure the integrity of sensory pathways quantitatively [113]. Biothesiometry is designed to measure the perception threshold of large sensory fibres to various amplitudes of vibratory stimulation [114]. Although extensively used, solid data regarding its sensitivity and specificity is lacking.

b) Corpus cavernosum EMG (ccEMG) This is a relatively new technique, in which needle or surface electrodes record the electrical activity of the corpora cavernosa [118 , 119, 120, 121, 122]. Basic questions regarding the signal recorded, and how to interpret it, are still unresolved. Thus, despite some clinical use this test must be regarded as experimental.

d) Thermal threshold testing In this test a temperature surge is offered as a stimulus to the patient [115]. The afferent pathway consists of small nerve fibres - warmth conduction by unmyelinated C-fibres with conduction velocities of 0.5 - 2.0 m/s, cold conduction by A8 fibres with conduction velocities of 6 - 30 m/s. The test thus yields objective data on the conductance of small sensory nerve fibres and therefore may

c) Sympathetic skin response: Measures a sudomotor related potential, which is evoked in response to sympathetic activation [123,124]. The potential can be recorded from the penis, assessing the sympathetic innervation of this organ. However, basic questions regarding the technique are still unresolved, and its clinical usefulness is limited.

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V. PSYCHOLOGICAL OR PSYCHIATRIC EVALUATION

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FOSTER R, MULCAHY J, CALLAGHAN J, CRABTREE R, BRASHEAR D. Role of serum prolactin determination in the evaluation of the impotent patient. Urology 1990;36:499-501.

14

APKUNONU BE, MUTGI AB, FEDERMAN DJ, YORK J, WOLDENBERG LS. Routine prolactin mea surement is not necessary in the initial evaluation of male impotence. J gen Intern Med 1994;9:336.

15

WORTSMAN J, ROSNER W, DUFAU MC. Abnormal testicular function in men with primary hypogonadism. Am J med 1987;82(2):207-212.

16

JOHN H. testosterone and impotence. When is androgen substitution advisable ? Ther Umsch 1998 ; 55 (6) : 372-376.

17

TENOVER L. Testosterone and the ageing male. J Androl 1997;18:103-106.

18

BUVAT J, LEMAIRE A. Endocrine screening in 1.022 men with erectile dysfunction: Clinical significance and cost-effective strategy. J Urol 1997;158:1764-1767.

19

KROPMAN RF, VERDIJK RM, LYCKLAMAA NIJEHOLT AAB, ROELFSEMA F. Routine endocrine screening in impotence: significance and cost-effectiveness. Int J impotence Res 1991;3:87.

20

MAATMAN TJ, MONTAGUE DK. Routine endocrine screening in impotence. Urology 1986;27:499.

See chapter 11

VI. SUMMARY STATEMENT The number of patients seeking medical help for ED has greatly increased and the care for these patients has shifted from the urologist to the primary care physician and other specialists in the field of sexual medicine. Consequently, the basic approach to the management of ED has become multidisciplinary and goal-directed. Key-elements in the initial evaluation are the medical and sexual history and the identification of indications for referral to a specialist.

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Committee 6

Current Research and Future Therapies

Chairman K-E ANDERSSON

Members A.L. B URNETT, K.K. CHEN, G.J. CHRIST, O. RAMPIN, C. STIEF

139

CONTENTS VI. THERAPEUTIC ASPECTS : GENE THERAPY & MOLECULAR BIOLOGY: THE PROMISE OF MOLECULAR SURGERY

I. INTRODUCTION II. MODELS OF ERECTION. BEHAVIORALAND PHYSIOLOGICAL MEASURES IN CONSCIOUS ANIMALS

1. WHAT IS MOLECULAR BIOLOGY? 2. GENETIC PREDISPOSITION TO ERECTILE FAILURE 3. GENETIC/MOLECULAR ALTERATIONS ATTRIBUTABLE TO, OR wHICH ACCOMPANY, ERECTILE FAILURE 4. DIFFERENTIALLY EXPRESSED TRANSCRIPT IN CULTURED CORPORAL SMOOTH MUSCLE CELLS FROM DIABETIC PATIENTS 5. AGE-RELATED DECLINE IN CONNEXIN43 (CX43) MRNA EXPRESSION IN HUMAN CORPORAL TISSUE STRIPS 6. MOLECULAR MECHANISMS OF CORPORAL FIBROSIS 7. I DENTIFICATION OF SMOOTH MUSCLE SPECIFIC GENES 8. SOMATIC GENE THERAPY FOR THE TREATMENT OF ERECTILE DYSFUNCTION 9. THE EVOLUTION OF CARDIOVASCULAR GENE THERAPY 10. RATIONALE FOR GENE THERAPY AS A TREATMENT OF ERECTILE DYSFUNCTION 11. BRIEF REVIEW OF CURRENT GENE THERAPY APPROACHES

1. CONTEXTS 2. P ERIPHERAL MECHANISMS UNDERLYING PENILE ERECTION RECORDED IN CONSCIOUS ANIMALS 3. CORRELATIONS WITH CHANGES IN BRAIN NEUROTRANSMISSION 4. C ONSEQUENCES OF THE LESION OF SELECTIVE BRAIN NUCLEI: 5. EXPLORATION OF PERIPHERAL AND CENTRAL NEURAL PATHWAYS IN ANESTHETIZED ANIMALS 6. IN VITRO PREPARATIONS AND THE STUDY OF MEDIATORS, RECEPTORS, ION CHANNELS AND SECOND MESSENGERS. 7. N EURAL CONTROL III. TRANSMITTERS AND RECEPTORS 1. CENTRAL NEUROMEDIATION 2. PERIPHERAL NEUROMEDIATION IV. SIGNAL TRANSDUCTION 1. THE SYNCYTIAL TISSUE TRIAD : THE MECHANISTIC BASIS FOR THE LOCAL COORDINATION OF PENILE ERECTION. 2. THE FLOW OF INFORMATION AND THE DIVERSITY OF SIGNAL TRANSDUCTION 3. I ONIC DISTRIBUTION ACROSS THE CORPORAL SMOOTH MUSCLE CELL MEMBRANE 4. K+ CHANNELS IDENTIFIED IN HUMAN CORPORAL SMOOTH MUSCLE

VII. THERAPEUTIC ASPECTS : PHARMACOLOGICAL BASIS FOR CURRENT AND FUTURE THERAPIES 1. DRUGS

FOR

INTRACAVERNOUS ADMINIS-

TRATION

2. DRUGS

FOR

NON-INTRACAVERNOUS ADMI-

NISTRATION

V. SMOOTH MUSCLE FUNCTION

VIII. RECOMMENDATIONS

1. ELECTROMECHANICAL COUPLING 2. PHARMACOMECHANICAL COUPLING 3. RELAXATION

REFERENCES 140

Current Research and Future Therapies K-E ANDERSSON, A.L. BURNETT, K.K. C HEN, G.J. C HRIST, O. R AMPIN, C. S TIEF

Perspective 1: Today’s challenge is to search for central brain and spinal nuclei, neurotransmit ters, receptors and second messengers involved in the control of penile erection. Another aim is to find out whether one or several peripheral pathways exist between the brain and the penis. This latter aspect gains importance when one considers the impact of peripheral nerves lesions or spinal cord injury on penile erection in patients.

I. INTRODUCTION The introduction of intracavernous injection of papaverine as a treatment of erectile dysfunction [1] has stimulated a wide research interest in the mechanisms of penile erection. Recent progress concerning both the central [2, 3, 4, 5, 6] and peripheral [4, 7, 8] control mechanisms of penile erection has made it possible to define several new targets for pharmacological treatment of the disorder.

1. CONTEXTS

In this review, models of erection as well as the physiological basis for erectile function and dysfunction are discussed, as are current and future therapeutic aspects on erectile dysfunction.

a) Erections in copula Erections in copula are difficult to number and measure under direct behavioral observation. Therefore data have been inferred either from models in which penile erection was allowed in a copulation-related context, but intromissions were prevented so as to directly observe the penis, [9], or has been inferred from the motor pattern that accompany penile insertion [10]. Finally techniques for recording the response of the erectile tissue or the activity of the perineal striated muscles have been used. A concern regarding the measure of penile erection in copula has emerged in several instances from the difficulty to separate between mechanisms that regulate sexual behavior, the latter including penile erection as one of its several outputs, and those more directly related to penile erection itself.

II. MODELS OF ERECTION. BEHAVIORALAND PHYSIOLOGICAL MEASURES IN CONSCIOUS ANIMALS In mammals, penile erection occurs in several different natural contexts, e.g., during copulation, as a reflex response to stimulation of the genital area, in the presence of an estrous female (contact with the female is not required), and during sleep. In an attempt to better understand the mechanisms underlying such responses, pharmacological manipulations of neural and endocrine pathways have been used to elicit penile erection. Lesions or electrical stimulation of central brain nuclei have also been performed. Extensive analysis of the variety of contexts that elicit penile erections led to the concept that erections were governed by a variety of neural and endocrine mechanisms, depending upon the sources of information that elicited them.

b) Reflexive erections In conscious dogs and rats, manual stimulation or tonic retraction of the penile sheath elicits episodes of penile erection that are easily observed [11]. In rats, an appreciable characteristic of these erections is that they are grouped into clusters, and the number and frequency of clusters and of reflexive erections are easily measured. Further-

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more reflexive erections are independent from social interaction with the female. Spinalization releases reflexive erections from supraspinal influences, making the model appropriate to study the spinal control of penile erection.

preoptic-anterior hypothalamic region, the paraventricular nucleus, the medial forebrain bundle, and the mamillary bodies [24, 25, 26, 27] and during cortical spreading depression in rats [28, 29].

2. P ERIPHERAL MECHANISMS UNDERLYING PENILE ERECTION RECORDED IN CONSCIOUS ANIMALS

c) Noncontact erections A new model has been established in conscious rats. Noncontact erections (NCE) occur in male rats in response to the presence of estrous females [12]. The model has been proposed as a tool to understand the psychogenic erections displayed by humans. Because volatile odors from the estrous females have been shown to be the necessary and sufficient stimulus for this response [13], noncontact erections are very likely due to integration of peripheral information by supraspinal structures.

The activity of the two peripheral tissues involved either directly (the penile smooth muscles) or indirectly (the perineal striated muscles) in penile erection have been recorded in unanesthetized animals, in a variety of erectile contexts.

d) Erections induced by pharmacological or elec trical stimulation in conscious animals A variety of drugs that interact with brain neurotransmission have been delivered either peripherally (sc, ip, im, iv) or into the cerebral ventricles, or into some specific brain nuclei, and episodes of penile erection reported in solitary male rats or monkeys [14, 15]. The mixed D1 and D2 or D2 receptor agonists, apomorphine, amantadine, N-npropyl-norapomorphine, LY 171555, LY 163502, bromocryptine, lisuride, the mixed dopaminergic and 5-HT1A receptor agonist, RDS-127, the cholinergic receptor agonist, pilocarpine, the serotonin uptake inhibitor, fenfluramine, and the 5HT2C receptor agonist, m-chlorophenylpiperazine (mCPP), were identified as proerectile drugs [16, 17, 18, 19, 20, 21, 22, 23]. As well, apomorphine, LY 171555, glutamate, oxytocin (OT) and NO donors elicited episodes of penile erection when delivered in the hypothalamic paraventricular nucleus of conscious rats [14]. In contrast opioid peptides had inhibitory effects. From these experiments, two hypothalamic nuclei were put in front: the medial preoptic area [15], and the paraventricular nucleus [14]. Dopamine and nitric oxide seem to play a major regulatory role in these two structures. Furthermore, oxytocin is a main proerectile neurotransmitter in the paraventricular nucleus.

By recording intracavernous or intraspongiosus pressure during copulation or reflexive erections in goats, bulls, dogs, stallions and rats, experiments demonstrated that erection was characterized mainly by a two-step increase in penile pressure, the first leading to a plateau reaching systolic levels, the second represented by suprasystolic peaks. The plateau increase lasted several seconds to minutes. By recording the electromyographic activity of the perineal striated muscles, i.e. the ischiocavernosus (IC) and bulbospongiosus (BS) muscles, it was demonstrated that suprasystolic peaks, whose duration was shorter than plateaus, were paralleled by an intense activity of the IC and BS muscles. Anesthesia of the IC or BS muscles abolished the suprasystolic peaks respectively in the corpus cavernosum and corpus spongiosum, and in rats excision of the IC or BS respectively abolished intense corpus cavernosum and glans erections. Plateaus of pressure were not recorded in rats during copulation, suggesting in this species a particular mechanism supported by a coordination of autonomic and somatic pathways to the penis and perineal muscles [30, 31, 32, 33, 34, 35, 36].

3. CORRELATIONS WITH CHANGES NEUROTRANSMISSION

IN

BRAIN

The limits of the pharmacological experiments reported hereabove reside in the use of exogenous compounds, either agonists or antagonists. A means through which the biological support of these studies may be better determined is to measure the natural release of endogenous neuromediators or their related metabolites in brain nuclei during penile erection. Recently an increase in

In conscious animals, penile erection has been reported in response to electrical stimulation of brain nuclei, including the gyrus rectus, the septo-

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nitric oxide production was demonstrated in the hypothalamic paraventricular nucleus during noncontact erections and copulation [37].

measure. Another outstanding basic mechanism of penile erection, the increased blood flow in the penile arteries, became measurable by using techniques issued from cardiovascular explorations, e.g., Doppler techniques. Finally, since the erectile tissue represents a bulk of smooth muscle fibers, the electromyographic activity of this tissue has been recorded and proposed as a tool to measure the response of smooth muscle to a variety of manipulations.

4. C ONSEQUENCES OF THE LESION OF SELECTIVE BRAIN NUCLEI: Evidence for supraspinal inhibitory pathways. Penile erection occurred as one of the consequences of large lesions of the limbic structures (amygdala, insular cortex) in cats as well as lesion of the locus coeruleus in rats [38]. In rats and dogs, lesioning the spinal cord at the middle thoracic level, or (in rats) pharmacological or electrolytic lesions of serotoninergic systems projecting to the spinal cord, facilitated reflexive erections [39, 40, 41, 42].

b) Stimulation applied on peripheral efferent pathways

Contribution of other nuclei to penile erection. In rats, noncontact erections were abolished by medial amygdala lesions and were severely affected by lesion of the paraventricular nucleus, nucleus accumbens and bed nucleus of the stria terminalis [43, 44, 45, 46]. In contrast, medial preoptic area (MPOA) lesions had no effect on such responses [45].

5. EXPLORATION OF PERIPHERAL AND CENTRAL NEURAL PATHWAYS IN ANESTHETIZED ANIMALS a) Measuring penile erection in anesthetized ani mals A variety of methods have been used to qualify and quantify erection, this variety reflecting the historical evolution of the concepts of the basic mechanisms of erection, and the techniques available at the same time. As early as the end of the nineteenth century, penile erection has been estimated through the number of blood droplets leaking from the sectioned penis, thereby pointing out the importance of blood flow changes through the penile tissue during penile erection. More recently, the changes in the volume of the penis comprising corpus cavernosum and corpus spongiosum have been measured by using penile plethysmography, bringing a reliable quantification to the common observation of increased volume of the organ. By the 1980-ies, recording of intracavernous or intraspongiosus pressure rises in response to peripheral nerve stimulation or drug injections became a standard of penile erection

Electrical stimulation applied on the sacral parasympathetic pathways (lumbosacral spinal cord, sacral ventral roots, pelvic nerve and plexus, cavernous nerve) elicited penile erection in either dogs, cats, rabbits, rats, mice and humans. In some of these species, because the additive stimulation of the lumbosacral paravertebral sympathetic chain elicited subsidence of erection, an effect suppressed by sectioning the pudendal nerves, it was inferred from these studies that the sympathetic antierectile pathways ran in these nerves. To date, the role of the hypogastric nerve in erection remains controversial. Depending on the animal species studied, and the model used (peripheral nerves intact or lesioned, spinal cord intact or lesioned), there has been demonstration of a proerectile role of at least some fibers running in the hypogastric nerve in some intact anesthetized animals, and a compensatory proerectile role following interruption of the pelvic nerve in rats [47]. By stimulating the motor pudendal nerve, i.e., eliciting contraction of the IC and BS muscles, on an erect penis, an additional rigidity and suprasystolic penile pressure rises were recorded. It was therefore suggested that under physiological conditions, both autonomic pathways to the smooth muscle of the erectile tissue, and somatic pathways to the muscles and sphincters of the perineum contributed to penile erection. The spinal cord, at the origin of these pathways, represents the coordinating center of these activities. By injecting contrast medium in the internal pudendal artery of anesthetized male goats, then eliciting penile erection via electrical stimulation of parasympathetic pathways, an interruption of the flow of contrast medium in the penis was recorded, suggesting that compression of the arte-

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rial supply to the penis and its venous outflow occurred [48]. In dogs and monkeys, a 10 fold increase in arterial inflow to the penis was recorded that was resistant to anticholinergic agents [49, 50]. In the same species, stimulation of the cavernous nerve elicited a transient arterial blood flow increase in the internal pudendal artery that preceded the sustained increase in intracavernous pressure [51, 52]. Increased blood flow to the penis also elicited a local increase in oxygen tension [53].

68]. The pressure rises recorded shared the characteristics of pressure rises elicited by the activation of the sacral parasympathetic outflow, and in some instances were eliminated by pelvic nerve section. The contribution of the sympathetic outflow, recruited by the same central stimulation, has also been coined out. e) Pharmacological studies The stimulation of neural pathways helped identifying those nerves or brain nuclei that contributed in some way to penile erection. Many of these experiments combined a pharmacological approach. Drugs that could block or mimick the effects of neural stimulation have been tested. It was soon recognized that antierectile effects were due to noradrenaline (NA) release by sympathetic nerve endings in the corpus cavernosum. In contrast, blocking postganglionic cholinergic transmission with atropine had few or no effects on electrically induced erections, suggesting that proerectile pathways peripherally released a non-adrenergic, non-cholinergic transmitter. Further experiments tested the role of calcitonin gene-related peptide (CGRP), substance P (SP), vasoactive intestinal polypeptide (VIP), adenosine triphosphate (ATP) and nitric oxide (NO) [7, 69]. In parallel, morphological studies demonstrated the presence of these compounds or enzymes required for their synthesis in nerve terminals running in the erectile tissue. CGRP, SP, VIP, ACh and NO (synthase), all present in nerve terminals, displayed proerectile effects, i.e. were responsible for a change in penile pressure when either injected intracavernously or intra-arterially, or released upon nerve stimulation. Transmitter release has no consequence per se if the target cell does not bear the appropriate receptor. Furthermore, binding of the transmitter to its receptor activates a cascade of intracellular events, in some instances leading to second messenger synthesis. Modulation of the penile response to either intracavernous injection of proerectile drugs or electrical stimulation of nerves by specifically targeting receptors or affecting second messengers has been a tremendous growing field in a recent past. The use of α-AR (adrenoceptor) antagonists (phentolamine), activators of cAMP synthesis (prostaglandin E1 ; PGE 1 and non specific (papaverine) or selective (sildenafil) inhibitors of phosphodiesterases illustrates the clinical developments of these pharmacological approaches.

c) Stimulation applied on peripheral afferent pathways The dorsal nerve of the penis conveys sensory information from the glans penis and the preputial skin to the spinal cord. In rats, it joins more proximally the sensory branch of the pudendal nerve, the latter also conveying sensory information from the perigenital area. In anesthetized rats, stimulation of the dorsal penile nerve or of the sensory pudendal nerve elicited reflex responses of the cavernous and motor pudendal nerves [54, 55]. It also elicited rises in penile pessure, and activity of the bulbospongiosus muscles, both responses being more reliable in spinalized animals [54, 56, 57]. In the spinal cord, neurones of the dorsal horn, dorsal grey commissure, and intermediolateral cell column, mainly at the lumbosacral levels, are activated by such stimulation [58, 59, 60]. Primary afferents from the dorsal penile nerve project only in the dorsal horn and dorsal grey commissure, suggesting intraspinal relayed pathways between sensory afferents and autonomic and somatic efferent pathways. In contrast, this central projection extends largely to very rostral levels of the spinal cord, suggesting a possible regulatory role of genital afferents on many autonomic and somatic outflows [61]. Stimulation of penile sensory fibers elicits responses in the medullary reticular formation, and hypothalamic nuclei such as the medial preoptic area and paraventricular nucleus [62, 63, 64]. d) Stimulation applied to central brain nuclei A limited number of data are available on the exploration of brain nuclei in anesthetized animals. In rats, stimulation of the paraventricular nucleus and the medial preoptic area of the hypothalamus, and of the hippocampus, elicited episodes of penile pressure rises, either during or after application of the stimulation [65, 66, 67,

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f) Tracing peripheral and central neural path ways controlling penile erection Some synthetic molecules or exogenous enzymes can be captured by nerve terminals and transported along the axons to the neural soma. By using this qualitative technique, several studies have identified the location of neurones that innervate the corpus cavernosum, and the motoneurones that innervate the IC and BS muscles. This technique allows the use of immunohistochemistry to reveal the neuromediators present in these neurones. In rats, postganglionic neurones that innervate the corpus cavernosum are present in the major pelvic ganglion, the cavernous nerve and the paravertebral sympathetic chain. In this species, the pudendal motoneurones that innervate the IC and BS muscles are present in the dorsomedial and dorsolateral nuclei of the L5-L6 spinal cord [70, 71]. A limit to conventional tracing techniques is that tracers don’t cross synapses. Therefore only direct links between a neurone and its target tissue are evidenced. Hence the presence of preganglionic sympathetic neurones in the intermediolateral cell column and dorsal grey commissure of the T12-L2 spinal cord, as well as the location of parasympathetic preganglionic neurones in the sacral parasympathetic nucleus of the L6-S1 spinal cord have not been demonstrated from retrograde labelling from the corpus cavernosum, but have been inferred from dye injection in the pelvic or hypogastric nerves, the major pelvic ganglion or the lumbar sympathetic chain. This obstacle was recently eliminated by the use of neurotropic viruses (mainly herpes-like viruses, e.g. pseudorabies virus) in neuronal tracing. Those viruses are selectively captured by nerve terminals, replicate in the neural soma of first order neurones, and cross the synaptic cleft to reach the soma of second order neurones, where they again replicate [72, 73]. Pseudorabies viruses were injected either in the corpus cavernosum or the ischiocavernosus or bulbospongiosus muscles. Neurones transsynaptically labelled by the virus were identified in the spinal cord and supraspinal nuclei that send projections either directly or through relayed pathways onto autono mic and somatic spinal neurones that control erection [74, 75]. Main characteristics of these studies were:

lumbar sympathetic and the lumbosacral parasympathetic levels, those neurones likely contributing to integration of peripheral and supraspinal information, 2) constant labelling of neurones in the raphe nuclei, the source of the serotoninergic innervation to the spinal cord; 3) labelling of neurones in hypothalamic nuclei, mainly the medial preoptic area and paraventricular nucleus.

6. IN VITRO PREPARATIONS AND THE STUDY OF MEDIATORS, RECEPTORS, ION CHANNELS AND SECOND MESSENGERS. In vitro preparations of retractor penis, penile arteries and veins, and corpus cavernosum have been widely used as a tool to understand the local effects of agents supposed to play a role in penile erection. A basal tension is applied either mechanically and/or pharmacologically to these preparations of penile tissue, the latter containing smooth muscle cells, nerve terminals and endothelial cells. Electrical field stimulation (that elicits release of neurotransmitters by nerve terminals) or drugs (that act on receptors present on either kind of cells or nerve terminals) are then further applied to the preparation. Changes in the tone of the preparation evidences contractant or relaxant properties of endogenous or exogenous compounds. Contractile effects of NA released by nerve endings of the sympathetic nervous system through α1- and α2- ARs have been shown, whereas stimulation of β-ARs elicited relaxant effects. Contractile effects of peptides on corpus cavernosum smooth muscle fibers have been demonstrated for e.g., endothelin-1, released by endothelial cells and acting at endothelin receptors. Acetylcholine, released by parasympathetic nerves, had contracting effects on isolated smooth muscle cells of the corpus cavernosum. Because antagonists to cholinergic and adrenergic transmissions did not prevent relaxation induced by electrical field stimulation, relaxation of the penile tissue and artery was associated with the release of a non adrenergic non cholinergic agent [76, 77, 78]. The close similarity between the relaxant effects of nerve stimulation and those elicited by an endothelium derived relaxing factor was demonstrated. Nitric oxide (NO) release and

1) the presence of many neurones in the dorsal grey commissure in and between the thoraco-

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cGMP formation were demonstrated upon electrical stimulation of isolated strips of rabbit corpus cavernosum [79]. NO could also be released spontaneously in this preparation, as well as in response to acetylcholine. Both the endothelium and nerve terminals can release NO [80, 81, 82, 83, 84, 85]. A reevaluation of neuromediators present in parasympathetic nerve endings (NO synthase, VIP, acetylcholine) suggests that NO is the main mediator of penile erection. Acetylcholine can inhibit NA release by sympathetic nerve endings and facilitate NO release by endothelial cells. Finally, VIP, whose role in the local mechanisms of penile erection has been extensively investigated during the 1980-ies, may play a role in proerectile mechanisms occurring at a longer latency and displaying a longer effect (e.g., vascular tone and adaptation of penile arteries). Recent experiments have used quantitative and qualitative analysis to evaluate the presence and physiological relevance of synthase (NOS), in the corpus cavernosum. Demonstration of the presence of several NOS isoforms in the penis was obtained combining measurement of the enzyme specific activity, immunohistochemistry, protein analysis with Western blot and mRNA analysis with Northern blot. A variety of experiments converge to evidence the presence of nNOS (neuronal NOS) in the rat penis [86]. Today’s directions are the search for other NOS isoforms in the penis of other animal species. There are also studies using animal models that mimic diseases known to elicit erectile dysfunction in humans (diabetes, hypercholesterolemia, hypertension, atherosclerosis) or natural alteration of erection (ageing). In some of these models, an alteration of the NOS functions has been demonstrated [87, 88, 89]. Perspectives 2: The above cited experiments point out the need of appropriate models for the study of erectile dysfunction, the need to develop animal models of erectile dysfunction [90] and the need for correlating datas collected in studies using animal models of erectile dysfunction with clinical studies evaluating erectile dysfunction in humans.

nating within the penis, originate or mediate the neurophysiologic events required for an erectile response. Intuitively, the brain originates erotic thoughts whereas neuronal circuits from the spinal cord to the genitalia process tactile sensations peripherally. The neural control of penile erections involves the integration of diverse neurochemical mechanisms at both peripheral and central nervous system levels (Figure. 1)

Figure 1: The neural control of penile erections involves the integration of several mechanisms at both peripheral and central nervous system levels.

a) Central regulation The central nervous system (CNS) is involved at least in the initiation of penile erection, either through spinal mechanisms by local stimulation, or through supraspinal stimulation in the brain. However, due to the complexity in the CNS, the loci in the brain, neuronal circuits and pathways, and neurotransmitters (or neuromodulators) involved in the control of penile erection are relatively little investigated, and, as compared with peripheral neural mechanisms, knowledge is limited. b) Loci in CNS involved in regulation of penile erection Current status. The medial preoptic area (MPOA) [91, 92, 93, 94], paraventricular nucleus of hypothalamus (PVN) [95, 96, 97, 98] and hippocampus [95, 99] have been reported to be the brain loci, which elicit penile erection when stimulated. There is a linkage between hippocampus and PVN [98, 100]. Removal of the temporal lobes bilaterally, including the amygdala, uncus and the most part of the hippocampus, results in hypersexuality in monkeys and humans [101, 102]. This suggests

7. N EURAL CONTROL Penile erection is a complex hemodynamic function that occurs principally under regulatory control of the nervous system. Multiple levels of the neuroaxis, from the brain to the nerves termi-

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that the temporal lobes may exert an inhibitory effect on penile erection.

2) neurotropic virus as a tracer, such as pseudorabies [118, 119] to investigate the network of neurons, and 3) c-fos labelling by immunohistochemical study [120, 121] to find the distribution of neurons after sexual stimulation.

Nucleus paragigantocellularis (NPG) in the medulla has also been considered to exert a descending inhibition of penile erection. Lesions of the NPG enhance male copulatory behavior and alter ex copula penile reflexes [103, 104, 105]. Future research. An important aim of future research is to investigate more brain loci, which upon stimulation elicit or inhibit penile erection. Amygdala, ventral tegmental field, and locus coeruleus may be the potential targets for investigation. Electrical stimulation or lesioning, and chemical stimulation with L-glutamate to the neuronal body (not to fibers passing by are suitable methods for these future studies.

III. TRANSMITTERS AND RECEPTORS 1. CENTRAL NEUROMEDIATION The central mechanisms influencing the erectile response involve spinal and supraspinal pathways. While the central neurotransmission of penile erections has remained complex, progress continues to be made to identify effectors involved in this function. Much of the knowledge gained in this area relates to morphological and pharmacological studies in experimental animal models (e.g., rodents, primates) in which neurochemical perturbations can be achieved and responses monitored in a reasonably meaningful way. However, it has been wisely stated that results of these investigations must be carefully interpreted, because these studies may encompass a range of types and modes of elicitation of sexual function, species differences, drug dependent effects, and multiple central nervous system drug sites of action [2]. Monoamines (e.g., 5-hydroxytryptamine, dopamine, and norepinephrine), amino acids, neuropeptides (e.g., oxytocin, ACTH and opioids), acetylcholine and recently NO have been considered to interact in the central mechanisms of penile erection.

c) Neuronal circuits and neural pathways Current status. The subnucleus parvocellularis of PVN may through the descending oxytocinergic pathways to the lumbosacral spinal cord mediate apomorphine-induced penile erection [106, 100]. A direct descending projection from the PVN to the spinal nucleus of the bulbocavernosus and the dorsolateral intermediolateral nucleus in lumbosacral region of the spinal cord has also been reported [107, 108]. Axons from motoneurons of both the above mentioned two neural nuclei innervate bulbospongiosus and ischiocavernosus muscles, which are essential for penile erection [109, 110]. Besides a direct projection to the sympathetic preganglionic neurons in the spinal cord, PVN neurons also project to the dorsolateral funiculus indirectly through the reticular formation in the pons and medulla [111, 112, 113, 114, 115]. Neurons in PVN also send fibers to the parasympathetic preganglionic neurons in the lumbosacral cord [111, 112, 113]. The efferent fibers in MPOA project to the midbrain through the medial forebrain bundle [116]. As mentioned above, there exists a hippocampal-PVN pathway in the neuronal circuitry for the regulation of penile erection [98]. Future research. To identify the neural pathways, several methods mentioned above may be used: 1) retrograde injection of tracer, such as horse radish peroxidase, wheat germ agglutinin [117] into peripheral sites to find the innervating neurons, or anterograde injection of tracer into the surroundings of neuronal cell body to identify the neurons,

a) 5-Hydroxytryptamine A large proportion of the studies investigating the central regulation of sexual behavior have focused on the serotonergic system. 5-hydroxytryptamine (5-HT; serotonin) has been most strongly implicated in the spinal pharmacology of erectile function with participation in both sympathetic and parasympathetic outflow mechanisms. Experimental paradigms in animals have indicated that 5-HT pathways exert a general inhibitory effect on male sexual behavior [122], although these pathways may be inhibitory or facilitatory depending upon the action of the chemical at different 5-HT receptors located in the central nervous system [3]. 147

5-HT-positive nerve terminals are present throughout the central nervous system and influence multiple neurological levels of control of sexual behavior. 5-HT-containing neurons exist in the medullary raphe nuclei and ventral medulla reticular formation, including the rostral nucleus paragigantocellularis, as well as the lumbosacral spinal cord in association with mainly somatic and possibly autonomic outflow projections to the pelvis [105, 123, 124, 125, 126].

NOS inhibitors given by intracerebrovascular administration prevent 5-HT 1C-receptor mediated erectile responses [131]. Thus, 5-HT appears to serve various functions in male sexual function and likely acts as a major modulator of the central neuroregulatory control of penile erections. b) Dopamine The dopaminergic system has also been intensely investigated as a likely major effector in the central neuromediation of penile erection. The involvement of dopamine in the control of penile erection followed the original discovery that low, but not high, doses of the classical dopamine agonist apomorphine, administered systemically to male rats, induces penile erection [132]. Yawning and seminal emission were also observed to accompany penile erections following dopamine administration. These observations were subsequently extended to investigations involving the low dose systemic administration of other dopamine agonists such as piribedil, lisuride and quinelorane in rats and other animals [4]. The conclusion that the erectile response was associated with the stimulation of central dopamine receptors followed the observation that the apomorphine effects were attenuated with the application of centrally, but not peripherally, acting dopamine receptor antagonists. Two main types of dopamine receptors, D1 and D2, are associated with erectile function centrally with the latter perceived to predominate in this effect.

Sexual activity is enhanced with the decreased amount of 5-HT in the brain, occurring experimentally with the inhibition of serotonin synthesis with parachlorophenylalanine administration, destruction of 5-HT-containing axons by intracranial administration of 5,7-dihydroxytryptamine or electrolytic destruction of the dorsal raphe nucleus [127, 128]. Conversely, sexual activity is attenuated following the intracerebroventricular or intrathecal administration of 5-HT and drugs that increase central release or synthesis of 5-HT [22, 129, 130]. Despite this general understanding, conflicting reports of 5-HT agonists either enhancing or depressing sexual function were recognized and then attributed to the action of multiple 5HT receptors. In accordance with the selective use of 5-HT receptor agonists and antagonists, components of male copulatory behavior were found to be displayed variably. The sum of multiple studies suggests that 5-HT2 and 5-HT1A receptors mediate inhibitory effects on penile erection whereas 5HT1C receptors mediate facilitatory effects on this function.

Dopaminergic neurons comprise an incertohypothalamic system with projections to the medial preoptic area and paraventricular nucleus [133]. The injection of apomorphine into these central nuclei has facilitatory effects on sexual behavior. In the medial preoptic area, use of selective receptor agonists has established that low levels of dopaminergic stimulation, via D1 receptor in particular, facilitates erections [134]. In the paraventricular nucleus, similar pharmacological experiments have established that D2 rather than D1 receptors primarily facilitate erections [135]. The mechanism of erection following paraventricular D2 receptor stimulation apparently involves oxytocinergic neurotransmission. Dopaminergic neurons impinge on oxytocinergic cell bodies in the paraventricular nucleus [136, 137] and apomorphine-induced penile erection is prevented dose-

The predominant role of 5-HT in the central neuromediation of erectile function appears to be associated with inhibitory control of spinal sexual reflexes involving the brain stem level [105]. Intrathecal injection of 5-HT in the spinalized anesthetized male rat blocked the appearance of the coitus reflex suggesting that endogenous 5-HT may act in the descending input to the lumbar spinal cord that inhibits sexual reflexes [105]. A similar procedure in other experiments also inhibited ejaculation as well as penile intromission in rats, suggesting an alternative role of 5-HT in the transmission of sensory feedback information necessary for sexual responses [130]. A role for 5-HT in the supraspinal neurotransmission of penile erection has been suggested, since

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lated. In rats administered clonidine, an α2-AR agonist, by direct injection into the medial preoptic area, male sexual behavior was suppressed [149]. The suppression is inhibited by pretreatment with selective α2-AR antagonists [150], consistent with established facilitatory effects of these agents on erectile responses in rats [150]. However, while several α2-AR antagonists most notably yohimbine have been shown to increase sexual responses in rats, the relatively poor therapeutic efficacy of yohimbine in clinical use among men with erectile dysfunction [151], casts doubt on the significance of central noradrenergic mechanisms in erectile function.

dependently by oxytocin receptor antagonists [138, 139] or by electrolytic lesions of the paraventricular nucleus that deplete central oxytocin content [140, 141]. Conversely, injection of oxytocin into the paraventricular nucleus induces erections that are not attenuated by dopamine receptor blockade, suggesting that dopaminergic neurons activate oxytocinergic neurons in the paraventricular nucleus and that released oxytocin then accounts for the erectile response (see Oxytocin section). Dopaminergic neurons have also been identified as traveling from the caudal hypothalamus within the diencephalospinal dopamine pathway to innervate the lumbosacral spinal cord [142, 143]. The implication is that dopamine may participate in the central nervous system regulation of autonomic and somatic components that produce penile reflexes. Indeed, low but not high dose systemically administered dopaminergic agonists enhance spinally-mediated penile reflexes ex copula [144] with a similar response observed following their local injection into the medial preoptic area or into the paraventricular nucleus [134, 145]. Conversely, dopaminergic antagonists injected into the medial preoptic area decrease the number of penile reflexes [146]. The perception that the dopaminergic effect on penile reflexes converges on lumbar spinal cord dopamine receptors has been reinforced with the finding that injections of apomorphine into the lumbosacral subarachnoid space impairs penile reflexes [147, 148]. The responses appear to be D1 receptor-dependent although an interaction between D1 and D2 receptors remains possible. Thus, a seeming role for the dopaminergic system in the control of spinal penile reflexes as much as in the incertohypothalamic basis of penile erection must also be recognized.

d) Excitatory amino acids Excitatory amino acids (eg., glutamic acid, aspartic acid) appear to exert a role in penile erection in the activation of central oxytocinergic neurotransmission of the response (see Oxytocin section). The injection of N-methyl-D-aspartic acid (NMDA), a selective agonist of the excitatory amino acid NMDA receptor subtype, into the paraventricular nucleus of rats induces penile erection, which is prevented by the intracerebroventricular administration of an oxytocin antagonist [152]. The NO synthase signal transduction pathway is considered to mediate the effect since the administration of NOS inhibitors into the paraventricular nucleus and intracerebroventricularly blocks the NMDA effect [153, 154]. Further support is provided by findings that NMDA injected into the paraventricular nucleus also leads to the increased concentration of NO metabolites in this region of the hypothalamus [155]. The mechanism for NOS activation would conceivably involve increased calcium influx through previously described calcium channel-coupled NMDAreceptors [156]. However, the ineffectiveness of omega-conotoxin injected into the paraventricular nucleus in blocking erections induced by NMDA conotoxin injected in this nucleus indicates that omega-conotoxin sensitive N-type calcium channels are not responsible for this mediation [157].

c) Noradrenaline Evidence for noradrenergic effects in the central neuromediation of penile erection is sparse. However, the current data suggest that increased noradrenergic activity stimulates, whereas decreased noradrenergic activity inhibits, sexual function [122]. Insights have almost exclusively drawn from experimental work involving the administration of agents that interact through α-AR pathways. Furthermore, accurate conclusions may only draw from work that suggests that central adrenergic receptors have been selectively stimu-

e) Gamma-amino butyric acid Cumulative data resulting from investigations on the role of gamma-aminobutyric acid (GABA) in penile erection indicate that this neurotransmitter may function as an inhibitory modulator in the autonomic and somatic reflex pathways involved

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in penile erection [3]. In male rats, high concentrations of GABA have been measured in the medial preoptic area of the hypothalamus [158], and GABAergic fibers and receptor sites have been localized to the sacral parasympathetic nucleus and bulbocavernosus motor nucleus [159, 160]. The injection of GABAA agonists into the medial preoptic area decreases [161], whereas the injection of GABAA antagonists into this region increases, copulatory behavior of male rats [162]. Systemic administration or intrathecal injection at the lumbosacral level of the GABAB receptor agonist baclofen decreased the frequency of erections in male rats [122].

oxytocinergic receptor coupling with calcium channels through a pertussis toxin-sensitive G protein [170, 171]. The oxytocinergic system may also be influenced by the NO synthase signal transduction pathway since inhibitors of this pathway prevent penile erection and yawning in rats induced by oxytocin, dopamine, and NMDA stimulation [172, 173]. Recent studies have explored the physiologic basis for central oxytocin release. Dorsal penile nerve electrical stimulation in rats, presumed to represent physiological tactile stimulation during copulation, elicits neurohypophyseal recordings from oxytocinergic neurons [174].

f) Oxytocin

g) ACTH and related peptides

Oxytocin is believed to be another spinal effector of penile erection released from hypothalamic supraoptic and paraventricular nuclei that project to spinal centers influencing this function. Plasma oxytocin concentrations are known to be elevated in humans following sexual stimulation [163, 164]. When injected into the lateral cerebral ventricle, the paraventricular nucleus, or hippocampus in laboratory animals, oxytocin is found to be a potent inducer of penile erection [165, 166, 167]. Oxytocin receptors are believed to mediate erections since the erectile response is blocked by the administration of oxytocin antagonists and by electrolytic lesion of the paraventricular nucleus [138, 168]. Immunoreactive oxytocin-containing spinal neurons associating with sacral preganglionic neurons confirmed by retrograde labelling supports the role of oxytocin in the autonomic spinal circuitry that mediates penile erection [126].

Peptides derived from the common 31 kDa precursor pro-opiomelanocortin, including adrenocorticotropic hormone (ACTH) and alpha-melanocyte stimulating hormone (alpha-MSH) [175, 176], have been associated with erectile responses since it was early shown that ACTH induced penile erection along with the ”stretching-yawning syndrome” following its injection into the lateral ventricles of several laboratory animals [177, 178]. Confirmation of the sites of action of ACTHMSH peptides in central neurotransmission has been hindered by the failure to identify specific binding sites (receptors) for these peptides in the central nervous system. ACTH appears to exert its effects through the hypothalamus and via calcium channel mediation since the intracerebroventricular injection of the N-type calcium channel inhibitor omega-conotoxin prevents the ACTH effect [170]. However, the failure of both lesions of the paraventricular nucleus [168] and injections of omega-conotoxin into this same nucleus [179] to alter erection induction by ACTH, combined with evidence that excitatory amino acids do not affect ACTH effects [180], have suggested that an alternative hypothalamic site or mechanism of action is responsible for ACTH-induction of erection other than that involving dopamine or oxytocin action in the paraventricular nucleus [181].

Oxytocin appears to exert an autoactivation mechanism involving the stimulation of oxytocinergic receptors located in the cell bodies of the same oxytocinergic neurons in the paraventricular nucleus [165, 166]. In support of this view, immunoreactive cell bodies of oxytocinergic synapses have been found to impinge upon the cell bodies of oxytocinergic neurons in both hypothalamic supraoptic and paraventricular nuclei [169]. Several central neurotransmitters may also converge upon the oxytocinergic system as activators (e.g., dopamine) or inhibitors (e.g., opioid peptides) of its transmission. Evidence supports calcium as a second messenger mediating oxytocin-induced penile erection in the paraventricular nucleus and

h) Opioid peptides Endogenous opioid peptides have long been assumed to be involved in the regulation of male sexual responses, since sexual dysfunction has been observed clinically in men chronically using

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opiates [182, 183] and copulatory behavior in male rats is depressed experimentally with the systemic administration of morphine or other opioids [184, 185]. β-Endorphin injection into the cerebral ventricles or medial preoptic area of the hypothalamus of male rats attenuates copulatory behavior [184, 186]. Morphine, injected systemically or into the paraventricular nucleus of male rats, prevents penile erection induced by intracerebroventricular administration of oxytocin or subcutaneous dopamine [187], or NMDAinjected into the paraventricular nucleus [167]. However, similar application of a selective agonist of the kappa opioid receptor does not alter apomorphine- or oxytocin-induced erectile responses [188]. This evidence and the demonstration that the opiate antagonist naloxone administered systemically abolishes the central morphine preventative effect on erections in rats have supported the belief that µ receptors in the paraventricular nucleus account for the morphine effect [188]. NO metabolite concentrations that are increased in the paraventricular nucleus following apomorphine, oxytocin, or NMDA local administration become reduced following morphine administration also into the paraventricular nucleus, indicating that the morphine effect depresses a NO-mediated erection induction mechanism at this level [167, 188]. Current data support the hypothesis that opioid µ receptor stimulation centrally prevents penile erection by inhibiting mechanisms that converge upon central oxytocinergic neurotransmission of this function.

effect of NOS inhibitors was not observed when these compounds were injected concomitantly with L-arginine, the substrate for NO. The paraventricular nucleus has been implicated as a prime site for NO action mediating an oxytocinergic mechanism for penile erection [173]. This brain nucleus was earlier identified to contain one of the highest concentrations of NOS in the brain [191]. Nitroglycerin, an NO donor, induces penile erection in the rat with injection into the paraventricular nucleus [192]. The medial preoptic area is also purported to liberate NO with sexual activity in rats, given direct measurement of its release with copulatory behavior and its lack of production following NOS inhibitor local administration, which decreased copulatory behavior [193]. Interestingly, since guanylate cyclase inhibitors (e.g., methylene blue) injected into the paraventricular nucleus fail to prevent drug-induced penile erection, and 8-bromo-cGMP injected into the paraventricular nucleus fails to elicit erections, it has been proposed that the mechanism of NO action is unassociated with the activation of guanylate cyclase [131]. The additional finding that the NO scavenger hemoglobin does not prevent penile erection in spite of its ability to block NO production in the paraventricular nucleus suggested that NO acts as an intracellular rather than an intercellular modulator of erectile responses involving the paraventricular nucleus [131]. NO may additionally mediate the actions of ACTH and 5HT1C agonists, which elicit erections when injected into the intracerebroventricular system according to mechanisms unrelated to oxytocinergic neurotransmission [131].

i) Acetylcholine The role of acetylcholine at central levels in the regulation of penile erection is mostly inferred from limited neuropharmacologic studies involving primarily locally administered muscarinic and nicotinic receptor antagonists and lesioning studies in the brain [20, 189]. These studies have suggested that acetylcholine operating seemingly at the hippocampus may have a regulatory role in erectile function.

2. PERIPHERAL NEUROMEDIATION The different structures of the penis receive sympathetic, parasympathetic, somatic, and sensory innervation. The distribution of autonomic nerves within the corpora cavernosa has been studied by several investigators [2, 3, 4], but the density of nerves and the quantitative relations between the number of nerve terminals and the number of smooth muscle cells have not been established. The nerves contain different transmitters and the nerve populations have been categorized as adrenergic, cholinergic, and non-adrenergic, non-cholinergic (NANC). The latter nerves may contain

j) Nitric oxide The role of NO in the central neuromediation of penile erection followed observations that the injection of NOS inhibitors into the intracerebroventricular nucleus or the paraventricular nucleus of the hypothalamus prevented penile erectile responses induced by dopamine agonists, oxytocin, and NMDA in rats 154, 172, 190]. The inhibitory 151

that of β-ARs [196]; the number of α−AR binding sites per cell was estimated to 650,000 [197]. Not only the number of receptors is of importance. Androgens may regulate the α-AR responsiveness of cavernous smooth muscle. Compared to normal rats, castrated animals showed an enhanced reactivity to α1-AR stimulation [198].

not only neuropeptides, but also transmitters and transmitter/modulator generating enzymes, such as NO synthase (NOS) and heme oxygenases (HO). NANC transmitters/modulators may be found in adrenergic and cholinergic nerves [194], which should make it more meaningful to define nerve populations based on their transmitter content. Thus, it seems that one important population of nerves in the corpora cavernosa contain not only acetylcholine, but also NOS, VIP, and neuropeptide Y [195].

Both α1-and α2-ARs have been demonstrated in human corpus cavernosum tissue [4, 199, 200], but available information supports the view of a functional predominance of α1-ARs. This may be the case also in the penile vasculature, although a contribution of α2-ARs to the contraction induced by NA and electrical stimulation of nerves cannot be excluded (see below). In horse penile resistance arteries, NA activated predominantly α1-ARs, whereas postjunctional α2-ARs seemed to play a minor role [201].

The nerves and vasculature of the penis produce and release transmitters and modulators, producing contraction or relaxation (Figure 2). These transmitters/ modulators interact in their control of the contractile state of the corpus cavernosum smooth muscle. In addition they may also have other important functions, some of which are discussed below. a) Contraction-mediating transmitters and recep tors 1. NORADRENALINE AND α-ADRENOCEPTORS Penile arteries, cavernosal smooth muscle, and the principal penile veins receive adrenergic innervation, and it is generally accepted that the penis is kept in the flaccid state mainly via a tonic activity in these nerves through release of NA (Figure 3). NA stimulates α-ARs in the penile vasculature contracting the helicine vessels, and in the corpus cavernosum, contracting the trabecular smooth muscle [4]. NA stimulates not only α-, but also βARs. However, in the human corpus cavernosum, receptor binding studies have revealed that the density of α-ARs is almost 10 times higher than

An important question is whether or not one of the α1-AR subtypes is more important than the others for the contractile effects of NA. The subtypes of α1-AR with high affinity for prazosin [202], currently designated as α1A, α1Band α1D (the cloned counterparts are termed α1a α1b and α1d) have been demonstrated in human corporal tissue. In a preliminary communication, Price [203] reported that in human corporal tissue, mRNAs for α1a, α1b and, α1d (current terminology) could be identified, the α1a- and α1d-ARs predominating. This was confirmed by other investigators [204, 205]. However, it is known that the levels of mRNA expression do not always parallel the expression of a functional receptor protein. Traish [200] characterized the functional α1-AR proteins in human corpus cavernosum tissue, using receptor binding

Figure 2: The nerves and vasculature of the penis produce and release transmitters and modulators, producing contraction or relaxation. These transmitters/ modulators interact in their control of the contractile state of the corpus cavernosum smooth muscle.

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support previous data [4] suggesting the occurrence of postjunctional α2-ARs in the human corpus cavernosum. However, whether or not these α2ARs are of importance for the contractile regulation of tone in corpus cavernosum smooth muscle is still unclear. Prejunctional α2-ARs have been shown to modulate stimulus-evoked release of NA from nerves in the human corpus cavernosum, stimulation inhibiting the release of the amine [208]. However, stimulation of prejunctional α2-ARs in horse penile resistance arteries was shown also to inhibit NANC-transmitter release [209]. This might be one of the mechanisms by which NA maintains detumescence. 2. ENDOTHELINS AND ENDOTHELIN RECEPTORS Endothelins (ETs) have been demonstrated in penile erectile tissues and suggested to contribute to the maintenance of corporal smooth muscle tone [4]. Three distinct ET peptides have been demonstrated: ET-1, ET-2, and ET-3, all widely distributed in the body. Two types of ET receptors have been cloned and expressed: the ETA receptor which is stimulated by ETs with the rank order potency ET-1 = ET-2 > ET-3, and the ETB receptor for which the rank order is ET-1 = ET-2 = ET3. ET-receptors are G-protein-coupled; they may use various transduction systems in mediating their actions [210].

Figure 3: The penis is kept in the flaccid state mainly via a tonic activity in adrenergic nerves through release of nora drenaline (NA). Endothelin-1 may increase the sensitivity to released NA, but may also by a direct action contribute to the maintenance of tone in vascular and corporal smooth muscle. The role of contraction-mediating prostanoids is unclear.

and isometric tension experiments. Their results demonstrated the presence of α1A-, α1B-, and α1D-ARs, and they suggested that the NA-induced contraction in this tissue is mediated by two or possibly three receptor subtypes.

Saenz de Tejada et al [211] showed that cultured endothelial cells from the human corpus cavernosum, but not non-endothelial cells, expressed ET-1 mRNA. In the endothelium of human cavernous tissue, intense ET-like immunoreactivity was observed; immunoreactivity was observed also in the cavernous smooth muscle [211]. Binding sites for ET-1 were demonstrated by autoradiography in the vasculature and cavernous tissue [212, 213]. Both ET A and ET B receptors have been found in human corporal smooth muscle membranes, and it cannot be excluded that both receptor subtypes are functional [214]. In rat corpus cavernosum ET-1 and ETA receptor binding sites were primarily localized to the endothelium lining the cavernosal lacunar spaces [215].

There is increasing evidence that an additional α1AR subtype with low affinity for prazosin (α1L), which is not yet fully characterized, may occur in, for example, vascular smooth muscle [206]. The possibility that the α1L-AR subtype may be of importance in penile erectile tissues was recently suggested [207]. Whether or not antagonists, selectively acting at any of the α1-AR subtypes, would offer any advantages over presently used drugs (phentolamine, moxisylyte) in the treatment of erectile dysfunction, remains to be established. Traish et al. [199] demonstrated expression of mRNA for α1A-, α1B-, and α1C-ARs in whole human corpus cavernosum tissue. Radioligand binding studies with a highly selective ligand for α2-ARs revealed specific α2-AR binding sites, and functional experiments showed that the selective α2-AR agonist, UK 14,304, induced concentration-dependent contractions of isolated strips of corpus cavernosum smooth muscle. These results

ET-1 potently induces slowly developing, longlasting contractions in different penile smooth muscles: corpus cavernosum, cavernous artery, deep dorsal vein, and penile circumflex veins [4] Contractions can be evoked in human corpus

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cavernosus tissue also by ET-2 and ET-3, although these peptides have a lower potency than ET-1 [211]. In bovine retractor penis muscle and penile artery, the contraction induced by ET-1 was mediated primarily by ETA-receptors [216]. The contractions induced by ET-1 may be dependent on both transmembrane calcium flux (through voltage-dependent and/or receptor-operated calcium channels) and on the mobilization of inositol trisphosphate (IP3-) sensitive intracellular calcium stores [212, 217]. ET-1 may function not only as a long-term regulator of corporal smooth muscle tone, but also as modulator of the contractile effect of other agents, e.g., NA [212, 214, 218], or as a modulator of cellular proliferation and phenotypic expression [219].

angiotensin II [222]. In vitro, angiotensin II contracted canine corpus cavernosum smooth muscle, an effect that was increased by NOS inhibition [223]. Intracavernosal injection of angiotensin II caused contraction and terminated spontaneous erections in anesthetized dogs, whereas administration of losartan, selectively blocking angiotensin II receptors (type AT1), resulted in smooth muscle relaxation and erection [222]. Also in the rabbit corpus cavernosum, results were obtained suggesting involvement of the reninangiotensin system in the regulation of corpus cavernosum smooth muscle tone, and that the angiotensin II receptor subtype AT1 is important for mediation of the response [224]. Whether or not angiotensin II is an important regulator of tone in penile erectile tissues, is unclear. Studies using angiotensin II receptor antagonists, for example losartan, designed to elucidate this question, would be of interest.

Ari et al [220] found that in the pithed rat, intravenously injected ET-1 had a vasodilator action (increase in corporal pressure) at low, but a vasoconstrictor action at high doses. ET-3 had mainly vasodilator effects. They suggested that the vasodilator actions were mediated by activation of ETB receptors on the endothelium and local release of NO, since these actions were inhibited by LNAME. Parkkisenniemi & Klinge [216] suggested that the ETB receptors that could be demonstrated on the bovine retractor penis muscle, at least partly were located on the inhibitory nerves that mediate relaxation via activation of the L-arginine/NO/cGMP pathway.

b) Relaxation-mediating transmitters and receptors 1. ACETYLCHOLINE AND CHOLINERGIC RECEPTORS The importance of parasympathetic nerves for producing penile erection has been well established [7]. Penile tissues from humans and several animal species are rich in nerves staining for acetylcholine (ACh) esterase [239]. From these nerves, ACh can be released by transmural electrical field stimulation. Human corpus cavernosum contains a high density of muscarinic receptors, and Costa et al [197] calculated the number of binding sites on isolated corpus cavernosum smooth muscle cells to be 45, 000, which was about 15 times less than the number of α-ARs. In these cells, carbachol consistently produced contraction. This means that relaxation induced by ACh can be obtained either by inhibition of release of a contractant factor, e.g., NA, and/or is produced by the release of a relaxation-producing factor, e.g., NO (Figure 4). Four muscarinic receptor subtypes (m1-m4) were shown to be expressed in human corpus cavernosum tissue [225]; the receptor on smooth muscle was suggested to be of the M2 subtype [225, 226], whereas that on the endothelium was of the M 3 subtype [225].

Even if much available in vitro information suggests that ETs may be of importance for erectile physiology and pathophysiology, the role of the peptides in vivo is unclear. Christ et al [214] found no detectable age- or diabetes-related changes in contractile effects in human corpus cavernosum tissue. On the other hand, ET-1 and ETA receptor binding was found to be increased in diabetic rat cavernosal tissue [215]. Francavilla et al [221] found no differences in plasma concentrations of ET-1 in diabetic and non-diabetic patients with erectile dysfunction, and the concentrations of ET-1 in cavernous body blood were no different following intracavernous injection of PGE1. Further studies are needed to define the role of ETs in erectile function and dysfunction. 3. ANGIOTENSIN AND ANGIOTENSIN RECEPTORS

It is important to stress that parasympathetic acti vity is not equivalent with the actions of ACh; other transmitters may be released from choli -

Human corpus cavernosum was found to produce and secrete physiologically relevant amounts of

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ned for both endothelial NOS (eNOS) and NADPH diaphorase. However, the endothelium of cavernous sinuses did not contain eNOS and did not stain for NADPH-diaphorase. This is in contrast to findings in both normal mice and in mice with targeted deletion of nNOS [232]. In both types, eNOS was present in the endothelium of the penile vasculature and in sinusoidal endothelium within the corpora cavernosa. These observations are important for several reasons. Species differences in the mechanisms of penile erection have to be considered when evaluating results from different animal models, and for example the rat has been extensively used as model for NO action in penile erection. Some of the results obtained may not be valid for other species, including humans, where there is functional [4] evidence for the occurrence of eNOS in the endothelium of the sinusoids.

Figure 4 : Relaxation induced by stimulation of cholinergic nerves can be obtained either by acetylcholine (ACh) inhi bition of release of contractant factors, e.g., noradrenaline (NA), and/or by the release of relaxation-producing factors, e.g., nitric oxide (NO) and vasoactive intestinal polypeptide (VIP). Prostanoids may act both prejunctionally (decrea sing the release of NA) and postjunctionally in producing smooth muscle relaxation.

Mice lacking nNOS [234] have erections, show normal mating behaviour, and respond with erection to electrical stimulation of the cavernous nerves [232]. Surprisingly, isolated corporal tissue from both wild type and nNOS-deleted animals showed similar responses to electrical stimulation [232]. It was suggested that eNOS is essential for erection, not only in nNOS deleted, but also in normal mice. The importance of eNOS was stressed by Bloch et al. [235]. They demonstrated that eNOS is expressed in cavernosal smooth muscle and they suggested that eNOS could be a main source of NO alongside with nNOS. However, it was shown that mice carrying a mutation in the nNOS gene are still able to express an alternatively spliced mRNA of nNOS, which could be the source of NO in nNOS mutant mice [236]. Since NO is produced, and the guanylyl/cGMP/cGKI pathway apparently is intact in the CC of these animals, they are not suitable to test whether or not the NO/cGMP pathway is a prerequisite for normal penile erection.

nergic nerves [194]. Parasympathetic activity may produce penile tumescence and erection by inhibiting the release of NAthrough stimulation of muscarinic receptors on adrenergic nerve terminals [227], and/or by releasing NO and e.g., vasodilating peptides from nerves and endothelium. 2. NITRIC OXIDE AND /CGMP PATHWAY

THE GUANYLATE CYCLASE

An important role for NO in the relaxation of corpus cavernosum smooth muscle and vasculature is widely accepted [4, 228]. In vitro, several investigators have shown that both ACh- and neuronally mediated relaxation in animal and human corpus cavernosum (cc) involves release of NO, or a NOlike substance [4]. Both the endothelium and/or the nerves innervating the corpus cavernosum (CC) may be the source of the NO, and thus, more than one isoform of NOS can be involved. There seems to be no doubt about the presence of NOS in the cavernous nerves and their terminal endings within the CC, and in the branches of the dorsal penile nerves and nerve plexuses in the adventitia of the deep cavernous arteries [228, 229, 230, 231, 232, 233]. In the rat, Dail et al [233] found that all smooth muscle regions of the penis were richly innervated by nerves containing neuronal NOS (nNOS), and that the endothelium of vessels stai-

cGMP signals via three different receptors in eukaryotic cells, including ion channels, phosphodiesterases, and protein kinases. At present, however, the molecular targets which are activated by cGMP and finally execute the relaxation of penile smooth muscle are not known. Two different cGMP-dependent protein kinases (cGK I and II) have been identified in mammals. Inactivation of cGKI in mice abolished both NO/cGMP-depen-

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dent relaxation of vascular and intestinal smooth muscle and inhibition of platelet aggregation, causing hypertension, intestinal dysmotility and abnormal hemostasis [237].

VIP receptors (types 1 and 2), linked via stimulatory G-proteins to adenylyl cyclase, are considered to mediate the actions of the peptide [249]. The importance of the different subtypes of VIP in penile tissues have not been clarified. VIP related peptides, e.g., pituitary adenylyl cyclase-activating peptide (PACAP), which has been found to be colocalized with VIP in penile nerves [241], seem to act through one of the VIP receptors.

cGKI-deficient (cGKI-/-) mice (see above) show a very low ability to reproduce. CC tissue from these mice has an inability or markedly reduced ability to relax in response to neuronally or endothelially released, or exogenously administered NO [238]. The expression of cGKI in penile tissue fom cGKI+/+ mice, as revealed by immunohistochemistry, was confined to the smooth muscle of the walls of the central and helicine arteries, and to the smooth muscle of the trabecular septa surrounding the cavernous spaces. This is in line with its presumed role in the erectile events. The total innervation (PGP immunoreactivity) and distribu tion of nerve populations containing transmitters or transmitter-forming enzymes (vesicular acetylcholine transporter: VAChT: VIP, tyrosine hydroxylase : TH, NOS) believed to be important in the regulation of tone in CC tissue [4], were similar in normal and cGKI-null mice. Analysis of the NO/cGMP-induced relaxation clearly showed that cGKI is the major mediator of the cGMP signaling cascade in CC tissue. Its absence cannot be compensated by the cAMP signaling cascade that relaxes normal and cGKI-null penile erectile tissue to a similar extent. Taken together, these findings suggest that activation of cGKI is a key step in the signal cascade leading to penile erection.

The stimulatory effect of VIP on adenylyl cyclase leads to an increase in cAMP, which in turn activates cAMP-dependent protein kinase. However, VIP may increase not only cAMP, but also cGMP concentrations in various smooth muscles [250]. On the other hand, this does not seem to be the case in corporal tissue from humans [241], or rat and rabbits [251], where VIP increased cAMP concentrations without affecting the cGMP levels. In experimental diabetes in rats, Maher et al [252] found that the VIPcontent of the major pelvic ganglion and penis was markedly increased, whereas intracavernous injection of VIP, which caused erection in control rats, had no effect in diabetic animals. Since forskolin, which directly activates adenylyl cyclase, induced erection in both controls and diabetic rats, it was concluded that there was a defect at the level of the VIP receptor or of the associated G-protein. This is in contrast to previous findings in diabetic rats, showing that VIPstimulated cAMP generation was significantly increased [251]. They are also in contrast to observations in human diabetes [253, 254] showing that in patients with impotence, there was a marked reduction of VIP-like immunoreactivity in nerves associated with the cavernous smooth muscle. However, the latter observation has not been confirmed by other investigators [255].

3. VASOACTIVE INTESTINAL POLYPEPTIDE (VIP) AND VIP RECEPTORS The penis of humans as well as animals is richly supplied with nerves containing VIP [239]. The majority of these nerves also contain immunoreactivity to NOS, and colocalization of NOS and VIP within nerves innervating the penis of both animals and humans has been demonstrated by many investigators [240, 241, 242, 243, 244, 245, 246, 247]. It seems that most of these NO- and VIP-containing neurons are cholinergic, since they also contain VAChT [238], which is a specific marker for cholinergic neurons [248]. However, Tamura et al [243] reported that in the human penis, NOS could be found also in nerves containing TH, suggesting that NO can be generated by adrenergic nerves. As pointed out by the investigators, the physiological significance of such a localization is presently unclear and the finding has to be confirmed.

Undeniably, VIP has an inhibitory and relaxationproducing effect on strips of human corpus cavernosum tissue and cavernosal vessels in vitro, but it has been difficult to convincingly show that VIP released from nerves is responsible for relaxation of penile smooth muscle in vitro or in vivo [4]. VIP-antiserum [256] and chymotrypsin [257] reduced or abolished the relaxant effect of exogenous VIP on isolated human corpus cavernosum tissue, but had no effect on relaxation induced by electrical stimulation of nerves. Kim et al [258] reported that in rabbit corpus cavernosum, a VIP156

antagonist inhibited electrically-induced contractions, suggesting that the peptide was released from nerves during stimulation. They concluded that VIP appeared to contribute to NANC-mediated corpus cavernosum relaxation, and that its mechanism of relaxation was dependent on prostanoids and involved the generation of NO. This is in contrast to the conclusion drawn by Hayashida et al [259], who found no evidence for a role of VIP in the regulation of tone in the canine corpus cavernosum.

cavernosum tissue has the ability to synthetize various prostanoids [269, 270], and has also the ability to locally metabolize them. The production of prostanoids can be modulated by oxygen tension and suppressed by hypoxia [271, 272]. There are five primary active prostanoid metabolites: PGD2, PGE2, PGF2α, PGI2, and TXA2, and it has been proposed that there are five major groups of receptors, corresponding to these metabolites, that mediate their effects, namely DP, EP, FP, IP, and TP receptors [273, 274]. cDNAs encoding representatives of each of these groups of receptors have been cloned, including several subtypes of EP receptors. The prostanoid receptors are G-protein-coupled receptors with differing transduction systems [273].

As mentioned previously, many penile nerves contain both NO and VIP and ACh, and the possible interactions between these agents should be of particular interest. The effects of NO and the NO donor linsidomine (SIN-1) were studied on human isolated cavernous artery and corpus cavernosum [260]. A non-synergistic, independent relaxant effect in both types of preparation was observed. Suh et al [261] investigated the effect of VIP and VIP combined with ACh given intracavernously in rats. They found that VIP and ACh, individually or in combination, did not produce full erection, and concluded that neither VIP, nor, ACh were likely to be principal transmitters.

Penile tissues may contain most of these groups of receptors. However, their role in penile physiology is still far from established. Prostanoids may be involved in contraction of erectile tissues via PGF2α and thromboxane A2, stimulating TX and FPreceptors and initiating phosphoinositide turnover, as well as in relaxation via PGE1 and PGE 2, stimulating EP receptors (EP2/EP4) and initiating an increase in the intracellular concentration of cAMP. Prostanoids may also be involved in inhibition of platelet aggregation and white cell adhesion, and recent data suggest that prostanoids and transforming growth factor-β1 (TGF-β1) may have a role in modulation of collagen synthesis and in the regulation of fibrosis of the corpus cavernosum [275].

Not only NOS, but also other peptides, seem to be co-localized with VIP. Peptide histidine methionine (PHM), which is derived from the same precursor as VIP [262, 263, 264, 265], and the VIP-related PACAP and helospectin [241, 264, 265, 266], have been found to be colocalized with VIP. Even if Hedlund et al [241] demonstrated some of these peptides to be effective relaxants of human CC preparations, a role for them as neurotransmitters and/or neuromodulators has yet to be demonstrated.

5. OTHER AGENTS Adrenomedullin is a recently discovered vasodilator peptide isolated from human phaeochromocytoma cells [276]. It consists of 52 amino acids and has structural similarities to calcitonin-gene-related peptide (CGRP). Adrenomedullin has been suggested to serve as a circulating hormone regulating systemic arterial pressure [276]. Champion et al. [277, 278, 279] showed that adrenomedullin, injected intracavernously in cats caused an increase in intracavernous pressure and in penile length. The increase in intracavernous pressure reached at a dose of 1 nM adrenomedullin amounted to 75 % of that induced by a triple drug combination of papaverine, phentolamine and PGE1, or with the response to CGRP at a 10 times lower dose [278]. The erectile responses to adrenomedullin or

Thus, whether or not VIP has a role as a neurotransmitter or modulator of neurotransmission in the penis has not been established. Even if its physiological role in penile erection and in erectile dysfunction remains to be settled, VIP receptors in the penis are an interesting therapeutic target. Particularly, the combination of VIP and phentolamine seems to be effective in the treatment of erectile dysfunction [267, 268]. 4. PROSTANOIDS AND PROSTANOID RECEPTORS Prostaglandins (PGs) and thromboxanes are locally acting hormones derived from arachidonic acid by the action of cyclooxygenases. Human corpus

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CGRP were unaffected by NO-synthase inhibition with L-NAME, or by KATP channel inhibition with glibenclamide, suggesting that NO or KATP channels were not involved in the response. Since CGRP responses were reduced by the CGRPantagonist CGRP (8-37) at doses having no effects on the adrenomedullin response, it was suggested that the peptides acted on different receptors. In the highest doses used, both adrenomedullin and CGRP (and the control triple combination) reduced blood pressure. These results with CGRP are in agreement with clinical experiences and support the suggestion by Stief et al. [280] that CGRPmay be useful in the treatment in erectile dysfunction. In patients, intracavernosal injection of CGRP induced dose-related increases in penile arterial inflow, cavernous smooth muscle relaxation, cavernous outflow occlusion, and in erectile responses. The combination of CGRPand PGE1 may even be more effective than PGE1 alone [281, 282].

IV. SIGNAL TRANSDUCTION 1. THE S YNCYTIAL TISSUE TRIAD: THE MECHANISTIC BASIS FOR THE LOCAL COORDINATION OF PENILE ERECTION. Coordination of activity among the corporal smooth muscle cells is an important prerequisite to normal erectile function. The autonomic nervous system plays an important role in this process by supplying a heterogeneous neural input to the penis. The density, distribution and roles of the various neuroeffector pathways are not completely understood, and in fact, may vary significantly between individuals, as well as over time within the same individual. For example, the activity of the autonomic nervous system differs dramatically during erection, detumescence and flaccidity. As such, it is increasingly clear that the role of the autonomic nervous system in normal penile function must be coordinated with the phenotype and activity of the constituent corporal and arterial myocytes. That is, the firing rate of the autonomic nervous system, myocyte excitability and signal transduction processes, and the extent of cell-tocell communication between corporal smooth muscle cells must be carefully integrated to ensure normal erectile function.

Nociceptin is a 17 aminoacid peptide that shares structural homology with the dynorphine family of peptides. It differs from other opioid peptides by not having the NH2-terminal residue which is essentail for activity at µ, δ, and κ opiod receptors [283]. The drug is an endogenous ligand for the orphan opioid receptor that has been identified in several species: the human clone is called ORL1. Its function is not established; it may be involved in hyperalgesia or analgesia [283].

This integrative mechanism for the coordination of tissue responses is referred to as the “Syncytial Tissue Triad”, and furthermore, the principles that govern its operation hold the key to understanding the initiation and spread of stimuli among corporal myocytes and its relationship to erectile physiology and dysfunction. Simply put, the principles that govern the coordination of corporal smooth muscle responses exist at three levels:

Champion et al. [277] compared the erectile responses to intracavernously given nociceptin with those of a triple drug combination (see above), VIP, adrenomedullin, and an NO-donor in cats. Nociceptin in doses of 0.3 - 3 nM elicited doserelated increases in intracavernous pressure and penile length comparable to that of the triple drug combination, but the duration of the response was shorter. These data on previously unknown receptors in penile erectile tissues that on stimulation can induce erectile responses are exciting, and show that the complex mechanisms involved in penile erec tion are far from clarified.

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1) The Signal: Direct activation of a fraction of the corporal smooth muscle cells by 1st messengers; i.e., neurotransmitters, neurohumors or hormones, etc. 2) Signal Spread: Electrotonic current spread and intercellular diffusion of relevant second messenger molecules/ions via gap junctions; and

3) Signal Transduction: Intracellular signal transduction within corporal smooth muscle cells mediated by activation of transducer G-proteins, i.e., 2nd and 3rd messengers etc. The inter-relationships that occur at these three distinct levels are depicted in Figure 5. At the first level, innervation and the mechanisms of action of neurotransmission are still areas of rapidly expanding knowledge. This is true also for the second and third levels, where the variety of electrotonic and chemical transduction mechanisms (2nd messengers, etc.) extant in the corpora, as well as the mechanistic basis for the rapid intercellular spread of these signals, respectively, are areas that are just beginning to be understood and more fully explored.

gic, cholinergic, etc.), transducers (i.e., G proteins) and effectors (i.e., enzymes and ion channels), and therefore, heterogeneous pathways may be activated. Nonetheless, the three biochemical pathways that have been most well documented and characterized are outlined in Figure 6, which depicts how information received from 1st messengers is translated into alterations in cellular biochemical activity, and finally, integrated over the entire tissue to affect erectile capacity. However, as illustrated, it is clear that despite the plethora of bifurcating signal transduction pathways that are present and physiologically relevant in corporal smooth muscle, the actions of most, if not all of the pathways, on corporal smooth muscle tone, are exerted, at least in part, via their respective effects on the ion channels present in corporal smooth muscle.

Recent experimental and theoretical studies support the supposition that the presence of the “Syn cytial Tissue Triad” in the human penis confers a great deal of plasticity, flexibility and adaptability to erectile function [284, 285, 286]. The presence of such multiple, overlapping and apparently redundant mechanisms for coordination of erectile capacity is consistent with the proximal importance of penile erection to the survival of the species, as well as the emotional well being of men and their sexual partners. The supposition is advanced that understanding autonomic neural control of corporal smooth muscle tone needs to add a new component, that is, the syncytial nature of corporal smooth muscle. These concepts, and the evidence for their existence, are highlighted in the context of new therapeutic approaches to the treatment of erectile dysfunction (i.e., gene therapy) that take advantage of their presence.

2. THE FLOW OF INFORMATION AND DIVERSITY OF SIGNAL TRANSDUCTION

3. I ONIC DISTRIBUTION ACROSS THE CORPORAL SMOOTH MUSCLE CELL MEMBRANE Critical to the understanding of ion channel function is the distribution of the relevant ions across the cell membrane. The distribution of ions across the corporal smooth muscle cell, in conjunction with resting membrane potential of the corporal smooth muscle cell, ultimately determines the direction of ion flow during the opening of any given ion channel. These ionic gradients are maintained by a series of active membrane ion pumps and co-transporters, and are absolutely critical to the normal function of the corporal smooth muscle cell. Ionic movements associated with the opening of various ion channels are discussed below in the context of the individual ion channels thus far characterized in human corporal smooth muscle.

THE

4. K+ CHANNELS IDENTIFIED IN HUMAN CORPORAL SMOOTH MUSCLE

The intrinsic variability/diversity that is built into the regulation of corporal smooth muscle contraction is a primary factor in understanding erectile physiology, as well as the etiology and, ultimately, the improved therapy of erectile dysfunction. The exact nature of this diversity is reflected by the relative contribution(s) of the numerous distinct signal transduction pathway(s) present in these cells (Figure 6). It is conceivable that corporal myocytes from different individuals and under different conditions (i.e., age- or disease-related changes) may have/express different complements of membrane receptors (i.e., serotonergic, adrener-

To date, at least four distinct K+ currents have been described in human corporal smooth muscle. These are: 1. A calcium-sensitive maxi-K (i.e., KCa), channel. 2. A metabolically-regulated K channel (i.e., KATP). 3. A delayed rectifier K channel (i.e., KDR) and 4. An “A” type K current. The first two of these K channel subtypes are the most well characterized, and probably, the most physiologically relevant.

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Figure 5: Schematic depiction of the expected impact of molecular biology on the understanding, diagnosis and treatment of erec tile dysfunction. The Molecular Biology Quandrangle depicts the four major arenas in which the application of molecular techno logies will result in a significant accumulation of new knowledge. This knowledge will play a criti cal role in the development of novel and more selective oral and gene-based therapies for erectile dysfunction.

Figure 6: Signal transduction pathway(s) present in penile vascular and corporal smooth muscle cells, mediating contraction and relaxation. Prostaglandin E1 (PGE1) acts through stimulation of adenylyl cyclase, increasing the concentration of cyclic AMP(cAMP), which via protein kinase A (PKA) decreases the intracellular Ca2+ concentration and thereby produces relaxa tion. Nitric oxide stimulates guanylyl cyclase, increasing the intracellular concentration of cyclic GMP(cGMP), which via pro tein kinase G (PKG) decreases the intracellular Ca2+ concentration with consequent relaxation of the smooth muscle cell.

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The distribution of K + across the corporal smooth muscle cell membrane ensures that the opening of K channels will lead to efflux of K+ from the smooth muscle cell, down their electrochemical gradient. The movement of positive charge out of the cell results in cellular hyperpolarization, or a decrease in membrane potential. The main implication of K channels to erectile physiology/dysfunction is that their presence provides an important hyperpolarizing mechanism for modulating corporal smooth muscle tone and penile erection, via their effects on transmembrane Ca2+-flux through voltage-dependent Ca channels.

nel, have documented the presence of the KATPchannel protein [287]. Consistent with these observations, several studies have documented that K channel modulators, putative activators of the K ATP channel subtype, elicit a concentrationdependent relaxation of isolated human corporal smooth muscle. Very recent experiments on freshly isolated corporal smooth muscle cells have documented the presence of two distinct ATP-sensitive K+ currents in cultured and freshly dissociated human corporal smooth muscle cells [290]. The two K ATP channel subtypes had conductance values of ≈20 and ≈60 pS, respectively [290]. Consistent with observations at the single channel level, whole cell patch clamp studies documented a significant, glibenclamide-sensitive, increase in the whole cell outward K+ currents in the presence of the K channel modulator levcromakalim [290]. These data, ranging from the molecular, through the cellular and whole tissue levels, clearly document the presence and physiological relevance of the KATP channel subtype(s) to the modulation of human corporal smooth muscle tone.

a) The K Ca channel The calcium-sensitive K channel has been well characterized in human corporal smooth muscle. Briefly, KCa channel mRNA and protein have been detected on both freshly isolated human corporal tissues and cultured corporal smooth muscle cells [287]. Consistent with such observations, the single channel conductance (≈180 pS), whole cell outward currents and voltage and calcium-sensitivity of the KCa channel are remarkably similar when comparing data collected with patch clamp techniques on freshly isolated corporal smooth muscle myocytes versus similar experiments on short term explant cultured corporal smooth muscle cells [288, 289].

c) The L-type, voltage-dependent calcium chan nel As illustrated in Figure 7, the distribution of calcium ions across the corporal smooth muscle cell membrane ensures that opening of calcium channels will lead to influx of calcium ions into the corporal smooth muscle cell down their electrochemical gradient. The movement of positive charge into the smooth muscle cell has the opposite effect of the movement of K+ out of the cell, and therefore, will lead to an increase in membrane potential, or depolarization. Several studies have documented the importance of continuous transmembrane calcium flux through L-type voltage-dependent calcium channels to the sustained contraction of human corporal smooth muscle [291, 292, 293, 294, 295]. There is only one published report of inward Ca2+ currents in corporal smooth muscle using direct patch clamp methods [296]. However, much of the most compelling mechanistic data concerning the role of calcium channels in modulating human corporal smooth muscle tone have been established using digital imaging microscopy of Fura-2 loaded cultured corporal smooth muscle cells. These studies have provided strong evidence for the presence and physiological relevance of

Not surprisingly, the KCa channel appears to be an important convergence point in modulating the degree of corporal smooth muscle contraction. That is, the activity of this channel is increased quite dramatically following cellular activation of either the cAMP pathway (8-Br-cAMP, PGE1 [289], or the cGMP pathway (nitroglycerin or 8Br-cGMP; Christ et al., unpublished observations). As such, it seems clear that the two most physiologically relevant endogenous second messenger pathways act to modulate corporal smooth muscle tone (i.e., elicit relaxation), at least in part, via activation of the KCa channel subtype. The resulting hyperpolarization, in turn, is coupled to decreased transmembrane calcium flux through Ltype voltage-dependent calcium channels (see below), and ultimately, smooth muscle relaxation. b) The metabolically-regulated K ATP channel Western blots on isolated tissue strips, and immunocytochemistry of cultured corporal smooth muscle cells, using antibodies to the KATP chan161

Figure 7: Signal transduction in corporal smooth muscle is more a network event than the simple activation of a physiologi cal cascade or pathway in individual myocytes. IP3 = inositoltrisphosphate; cGMP = cyclic AMP; cAMP= cyclic GMP

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transmembrane calcium flux through the L-type voltage-dependent calcium channel in response to cellular activation with endothelin-1 (ET A/B receptor subtype) and phenylephrine (α1-adrenergic receptor subtype [297, 298, 299].

muscle cell membrane would result in increased activity of this Cl- channel. The ensuing depolarization of the corporal smooth muscle cell, would result in increased transmembrane Ca2+ flux due to activation of L-type voltage-dependent calcium channels, and concomitant elevations in corporal smooth muscle tone/contractility to oppose the imposed external force. Also, even if the stretchsensitive Cl- channels are present in low abundance in vivo, the presence of the intercellular pathway provided by the gap junction network present in the human corpora (see below), would still ensure that effects of alterations in Cl- channel function on some fraction of the corporal myocytes would be transmitted to neighboring myocytes. Thus, it is not unreasonable to assume that activation of stretch-sensitive Cl- channels may well contribute to global changes in corporal smooth muscle cell tone.

d) Chloride channels in human corporal smooth muscle. The contribution of chloride channels/currents to the modulation of human corporal smooth muscle tone is less well understood than that of the other ion channels. However, it seems clear that the distribution of the chloride ions across the corporal smooth muscle cell membrane ensures that the opening of chloride channels will result in the efflux of Cl- from the smooth muscle cell. Moving negative charge out of the cell will result in depolarization, or an increase in the membrane potential, presumably leading to increased cellular excitability (i.e., contractility). Further complicating study of these ion channels is that their presence during patch clamp experiments on cultured myocytes is relatively rare (i.e., ≈ 5% of cells actually have any detectable chloride current [297, 300]. The precise reason for this fact is uncertain, but it seems unlikely that their rarity in membrane patches is an artifact of the cell culture conditions per se, as there seems to be a similar infrequency of their appearance on freshly isolated corporal myocytes (Wang et al., unpublished observations). Although rigorous analysis of Cl- channels is hindered by the lack of truly selective channel blockers, there is still strong evidence for the presence of at least two subtypes of Cl- channels on corporal myocytes. The first of these is a large conductance (i.e., 350 pS) [297], calcium-sensitive, chloride channel. The second detectable Cl- channel subtype is a lower conductance (i.e., ≈ 150 pS), stretch-sensitive chloride channel. The calciumsensitive Cl- channel has a very small open probability, making assessment of its potential physiological significance a difficult task. However, as recently discussed [300], the stretch-sensitive Clchannel may well provide an important servomechanism for length maintenance of the corporal smooth muscle cell in the face of differential hydrostatic gradients, or additionally, during the rapid corporal pressure changes that occur during alterations in the flow of blood to and from the penis during normal penile erection and detumescence. For example, it is conceivable that increased stretch or deformation of the corporal smooth

e) The importance of intercellular communica tion through gap junctions. Signal transduction in corporal smooth muscle is more a network event than the simple activation of a physiological cascade or pathway in individual myocytes (Figure 7). Therein lies the true importance of the contribution of gap junctions to the modulation of corporal smooth muscle tone, and thus, erectile capacity. A logical extension of this observation is that the presence of intercellular communication through gap junctions provides the corpora with a significant “safety factor” or capacity for plasticity/adaptability of erectile responses. Thus, regardless of the precise mechanistic components operant in the corporal myocytes, intercellular communication through gap junctions plays an important role in ensuring coordinated smooth muscle responses among them. Despite the identification of more than a dozen mammalian connexins, connexin43 is the predominant gap junction protein found in corporal myocytes [301, 302, 303, 304, 305]. Thus, the following discussion pertains exclusively to connexin43. Briefly, gap junctions represent aggregates of intercellular channels where each channel is formed by the union, across the extracellular space, of two hemichannels or connexons, one contributed by each cell of an adjacent pair (Figure 8). Rafts of these individual channels (i.e., hundreds to thousands) aligned in adjacent cell membranes form the structural basis for the gap 163

theoretical studies of junctional communication have predicted that down regulation of intercellular communication is much more likely to be physiologically relevant than up regulation of intercellular communication [306]. In conclusion, the presence of connexin43-derived gap junction channels in corporal myocytes, ensures that there are many distinct combinations of the individual components of the “Syncytial Tissue Triad” which are sufficient to ensure coordinated smooth muscle function, and thus, the maintenance of erectile capacity. The converse of this statement is that erectile dysfunction would have to manifest at multiple levels in order to overcome the extant safety factor provided by the presence of the intercellular pathway. In vivo support for these experimental and theoretical suppositions derives from the well documented clinical fact that organic erectile dysfunction is indeed multifaceted. Further evidence for these concepts is provided by recents studies in a well documented rat model in vivo, where the verity of these ideas has been exquisitely tested and verified [308, 309]; see gene therapy section for details).

Figure 8 : Gap junctions represent aggregates of intercellu lar channels where each channel is formed by the union, across the extracellular space, of two hemichannels or connexons, one contributed by each cell of an adjacent pair. IP3 = inositoltrisphosphate; cGMP = cyclic AMP; cAMP = cyclic GMP

V. SMOOTH MUSCLE FUNCTION

junctional plaques frequently, but not always, observed between smooth muscle myocytes. The functional correlate of these structures is that corporal smooth muscle cells function as a network (Figure 6).

1. ELECTROMECHANICAL COUPLING In electromechanical coupling, changes in the sarcoplasmic Ca 2+ concentration, and thereby in the contractile state of the smooth muscle cell, are caused by changes in the membrane potential. Action potentials or long-lasting changes in the resting membrane depolarize the membrane potential, thus opening voltage-gated L-type Ca 2+ channels [310]. Thus, Ca2+ enters the sarcoplasm driven by the concentration gradient and triggers contraction.

Consistent with their proximal role in coordinating responses among the diverse array of corporal smooth muscle cells, recent publications have shown that connexin43-derived gap junction channels have characteristically long open times (0.5-5 s) and high open probabilities (≈ 85%), coupled with modest voltage sensitivity [302, 304]. In addition, while subconducting states of the connexin43 main state clearly do exist, the dwell time(s) is too short to be of any physiological significance, and therefore, the ≈100 pS main state accounts for virtually all of the relevant unitary activity of these channels [305]. Moreover, all of the major modulators of corporal smooth muscle tone are of the size (i.e., ≈1000 kD), or have already been shown to be gap junction permeant [295, 297, 306, 307]. As such, it is not surprising that

Changes in the membrane potential may also be induced by membrane channels other than Ca2+channels. Opening of K+channels (see above) can produce hyperpolarization of the cell membrane. This hyperpolarization inactivates the L-type calcium channels, resulting in a decreased Ca2+ influx and subsequent smooth muscle relaxation.

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resulting in Ca 2+ entry to the sarcoplasm down its concentration gradient. A rather modest increase in the level of free sarcoplasmic Ca2+ by a factor 35 to 550-700 nM then triggers myosin phosphorylation (see below) and subsequent smooth-muscle contraction.

2. PHARMACOMECHANICAL COUPLING a) Contraction Pharmacomechanical coupling describes the regulation of the sarcoplasmic Ca2+ concentration without changing the membrane potential. The major mechanisms of pharmacomechanical coupling-induced smooth-muscle contractions are the release of inositol 1,4,5-trisphosphate (IP3) and the regulation of Ca2+ sensitivity (see below). Furthermore, specific agonists may activate either Ltype calcium channels at a constant membrane potential or receptor-operated, nonspecific ion channels, resulting in an increase in intracellular levels of free Ca2+ and subsequent smooth-muscle contraction. With regard to the physiologically important phosphatidylinositol cascade, many agonists (e.g., α1-AR agonists, ACh, angiotensin, vasopressin) bind to specific membrane-bound receptors that are coupled to phosphoinositidespecific phospholipase C via guanosine triphosphate (GTP)-binding proteins. Phospholipase C then hydrolyzes phosphatidylinositol 4,5-biphosphate (PIP2) to 1,2-diacylglycerol (DG; this activates protein kinase C) and IP3. The water-soluble IP3 binds to its specific receptor [311, 312] on the membrane of the sarcoplasmic reticulum (intracellular compartment for Ca2+ storage), thereby opening this Ca2+ channel. Since the Ca2+ concentration in the sarcoplasmic reticulum is about 1 mM, Ca2+ is thus driven into the sarcoplasm by the concentration gradient, triggering smoothmuscle contraction. This increase in sarcoplasmic Ca2+ concentration may activate a distinct Ca2+ release channel of the sarcoplasmic reticulum (i.e., the ryanodine receptor-operated channel), leading to a further increase in the Ca2+ concentration of the sarcoplasm (muscle [313, 314].

In the smooth muscle cell Ca 2+ binds to calmodulin, which is in contrast to striated muscles, where Ca2+i binds to the thin-filament-associated protein troponin [314, 315]. The Ca-calmodulin complex activates myosin light-chain kinase (MLCK) by association with the catalytic subunit of the enzyme (Figure 9). The active MLCK catalyzes the phosphorylation of the regulatory light-chain subunits of myosin (MCL 20). Phosphorylated MCL20 activates myosin adenosine triphosphate (ATPase), thus triggering cycling of the myosin heads (cross-bridges) along the actin filaments, resulting in contraction of the smooth muscle. A decrease in the intracellular level of Ca2+ induces a dissociation of the Ca-calmodulin MLCK complex, resulting in dephosphorylation of the MLC20 by myosin light-chain phosphatese and in relaxation of the smooth muscle [313, 314]. A specific long-lasting state of contraction with reduced cycling frequency and low energy (ATP) consumption is termed a latch state. The mechanism of this high-force and low-energy-consumption state is not known.

b) Myosin phosphorylation and contraction As in striated muscle, the amount of intracellular free Ca2+ is the key to regulation of smoothmuscle tone. In the resting state, the level of sarcoplasmic free Ca2+ amounts to about ≈ 100 nM, whereas in the extracellular fluid the level of Ca2+ is in the range of 1.5-2 mM. This 10,000-fold gradient is maintained by the cell-membrane Ca2+ pump and the Na+/Ca2+ exchanger. Neuronal or hormonal stimulation can open Ca2+ channels,

Figure 9 : The Ca2+-calmodulin complex (Ca . CaM) acti vates myosin light-chain kinase (MLCK) by association with the catalytic subunit of the enzyme. Phosphorylated myosin (myosin – P) reacts with actin to form activated actomyosin (actomyosin – P), which produces contraction. Phosphorylated myosin (myosin – P) can be inactivated by myosin light-chain phosphatase (MLCP), which leads to relaxation.

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c) Regulation of Ca 2+ sensitivity and Ca2+-inde pendent contraction In smooth muscle, the force/Ca2+ ratio is variable and depends partly on specific activation mechanisms. For example, α-AR agonists induce a higher force/Ca2+ ratio than does a depolarizationinduced (i.e., KCl) increase in intracellular Ca2+, suggesting a “Ca-sensitizing“ effect of agonists. Furthermore, it has been shown that at a constant sarcoplasmic Ca2+ level, decrease of force (”Cadesensitization”) can be observed. The effect of Ca-sensitizing agonists are mediated by guanosine triphosphate (GTP)-binding proteins that generate protein kinase C or arachidonic acid as second messengers [310, 314]. These inhibit the myosin light-chain phosphatase (MLCP), thus increasing MLC 20 phosphorylation by basal-level activity of MLCK. The resulting myosin phosphorylation and subsequent smooth-muscle contraction therefore occurs without a change in sarcoplasmic Ca2+ concentration.

second-messenger system. Via specific receptors, β-AR agonists activate membrane-bound adenylate cyclase, which generates cAMP. cAMP then activates protein kinase A (PKA or cAK) and, to a lesser extent, protein kinase G (PKG or cGK). Atrial natriuretic factor (ANF) acts via the membrane-bound guanylate cyclase, whereas NO stimulates the soluble form of guanylate cyclase; both generate cGMP, which activates PKG and, to a lesser extent, PKA. Activated PKA and PKG phosphorylate phospholamban, a protein that normally inhibits the Ca 2+ pump within the membrane of the sarcoplasmic reticulum. The Ca2+ pump is then activated and, consequently, the level of free cytoplasmic Ca2+ is reduced, resulting in smooth-muscle relaxation. Similarly, the protein kinases activate the cell-membrane Ca2+ pump, leading to a decreased sarcoplasmic Ca 2+ concentration and to subsequent relaxation [313, 314]. As described above, cAMP and cGMP are synthetized from the corresponding nucleoside triphosphates by their respective membrane-bound or soluble adenylate or guanylate cyclases. cAMP and cGMP are inactivated by phosphodiesterases (PDEs) by hydrolytic cleavage of the 3’-ribosephosphate bond. Presently, more than 9 different families of PDE are known, which differ in their specificity for cAMP and cGMP, cofactor requirements and kinetic properties [319, 320, 321]. Each family can again be divided into subfamilies. Because of their central role in smooth-muscle tone regulation and the considerable variation of PDE isoenzymes with respect to species and tissues PDEs have become an attractive target for drug development. PDE 2, PDE 3, PDE 4, PDE 5 and several other isoenzymes have been identified in human cavernous tissue [322, 323, 325, 326, 327]. Functionally, PDE 3 and PDE 5 seem to be the most important [328, 329].

Ca-desensitization occurs in vivo in the presence of a sarcoplasmic Ca2+ concentration higher than that required for the activation of the MLCK (its affinity for the Ca-calmodulin complex is lower). This high concentration of Ca2+ activates the Cacalmodulin-dependent protein kinase II, which then reduces the affinity of MLCK for Ca-calmodulin by phosphorylation of a specific site [316]. The resulting decrease in the activity of MLCK leads to an increase in myosin dephosphorylation by basal-level activity of MLCPand to subsequent smooth-muscle relaxation. Ca2+-independent contractions have been observed. Thus, phorbol-ester-induced contractions are not accompanied by changes in the level of sarcoplasmic free Ca2+ or in myosin phosphorylation [317, 318]. Ca2+-independent contractions are probably mediated via receptor-operated membrane-bound GTP proteins that activate Ca2+-independent protein kinase C (I-PKC). The subsequent proteins responsible for further mediation of the contractile response have not yet been elucidated.

The identification of PDE families has been paralleled by the synthesis of selective or partially selective inhibitors. Sildenafil is a highly selective inhibitor of PDE type 5 [330, 331]. It enhances NO-mediated relaxation of rabbit and human corpus cavernosum in vitro, [326, 328, 329, 332, 333] and increases dose-dependently the intracavernous pressure in anesthetized dogs [334]. Sildenafil increases the intracellular concentrations of cyclic GMP[333, 335]. The effect of sildenafil may thus be due to an amplification of the endogenous

3. RELAXATION Pharmacomechanical coupling mechanisms of smooth-muscle relaxation are mediated via the intracellular cyclic nucleotide/ protein kinase/

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NO-cyclic GMP pathway. This seems to involve a novel cellular signal transduction pathway in which force is dissociated from myosin light chain phosphorylation [333].

simultaneously in four major arenas as displayed in the schematic Figure 5. The four arenas will be referred to as the Molecular Biology Quadrangle, and together they will serve as the foundation/cornerstone for the genetic analysis and therapy of erectile dysfunction. That is, the application of molecular technologies to the field of erectile physiology/dysfunction will permit the following:

VI. THERAPEUTIC ASPECTS : GENE THERAPY & MOLECULAR BIOLOGY: THE PROMISE OF MOLECULAR SURGERY

1) Evaluation of the possibility that there may be a genetic predisposition to erectile failure.

1. WHAT IS MOLECULAR BIOLOGY? The term “molecular biology” seems to have been first used by Warren Weaver in his 1938 address to the Rockefeller Foundation, where he stated: “Among the studies to which the Foundation is giving support is a relatively new field, which may be called molecular biology...” [336]. Since that seminal description, developments in many distinct scientific and clinical disciplines have been tremendously impacted by the ever burgeoning field of “molecular biology”. In the most broadly conceived definition “molecular biology” includes the study of the structure and function of biolo gically important macromolecules; ranging from proteins to RNA and DNA. This rather broad conceptualization explains why “molecular biology” exists at the interface of crystallography, biophysics, biochemistry, biology and genetics. In fact, many sophisticated techniques have been developed as tools to assist in the more efficient study of “molecular biology”. Some relevant examples include the recent commercialization and popularization of techniques, such as Northern, Western and Southern blots, and the polymerase chain reaction. The widespread availability of this technology has moved “molecular biology” to the forefront of scientific thought and development. Along the way many subdisciplines of “molecular biology” have evolved. For the purposes of this discussion the terms molecular bio logy, molecular genetics, and all related terms will be used interchangeably. Molecular biology, erectile physiology, and the treatment of erectile dysfunction The contribution of molecular technologies to the improved understanding, treatment and diagnosis of erectile dysfunction is expected to proceed

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2) Evaluation of the possibility that there may be genes or sets of genes/gene products whose expression or function are themselves altered by erectile dysfunction. 3) Evaluation of the possibility that there may be a smooth muscle specific distribution of genes or sets of genes/gene products that would allow one to selectively modulate smooth muscle tone in the penis, independent of other peripheral tissues. 4) Evaluation of the possibility that there may be genes or sets of genes/gene products whose expression or function can be stably and reproducibly altered so that erectile potency can be effectively restored in the absence of the necessity for any other form of treatment; i.e., somatic gene therapy. Each of these four arenas will be considered briefly below.

2. GENETIC PREDISPOSITION TO ERECTILE FAILURE Technologies exist for detecting mutations in, or altered expression of, any gene(s)/gene product(s) that might predispose one to erectile failure. However, given the multifactorial, age-related nature of erectile dysfunction, and the frequent overlap between erectile dysfunction and, for example, the presence of diabetes and/or vascular disease (i.e., hypertension), it may take some time to sort out a precise correlation between genetic alterations and erectile dysfunction. Currently, with the exception of Peyronie’s disease, which seems to have a truly relevant gene-based component (i.e., chromosomal instability), there is no compelling evidence either for, or against, the presence of a significant genetic component to the most common forms of organic erectile failure. This will certainly be an area of much interest in the future, and as with most other human diseases,

it would not be surprising to find a significant genetic contribution to at least some aspects of erectile dysfunction.

5. AGE-RELATED DECLINE IN CONNEXIN43 (CX43) MRNA EXPRESSION IN HUMAN CORPORAL TISSUE STRIPS

3. GENETIC/MOLECULAR ALTERATIONS ATTRIBUTABLE TO, OR wHICH ACCOMPANY, ERECTILE FAILURE

A series of recent publications has documented the central role played by intercellular communication through gap junctions in ensuring normal penile erection [301, 302, 303, 304, 306]. Briefly, by virtue of their presence in, and ubiquitous distribution among, corporal smooth muscle cells, these aqueous intercellular channels help ensure the coordinated relaxation and contraction responses among corporal smooth muscle cells, that are an absolute prerequisite to penile erection and detumescence. Thus, molecular studies examined the expression of the connexin43 transcript, to evaluate the hypothesis that altered intercellular communication may account for some aspects of the agerelated decline in erectile capacity [339]. A significant, age-related (patient age ranged between 2789 years), a ≈ 3-fold decline in the expression of the gap junction Cx43 transcript was detected in frozen tissues excised from patients with organic erectile dysfunction due to a diverse array of etiologies. It is important to emphasize that this relatively modest decline occurred over virtually the entire adult human life span. As such, this observation clearly indicates the relative plasticity of intercellular communication through gap junctions, although it certainly does rule out the possibility that in any given patient, alterations in Cx43 mRNA levels may well contribute to the etiology of erectile dysfunction.

The other side of the coin, with respect to the aforementioned discussion, is whether or not the presence of organic disease and the ensuing erectile dysfunction is correlated with detectable alterations in the expression or function of a gene(s) or gene product(s). That is, does advancing age, or the presence of organic disease per se, result in or produce any consistent alteration(s) in the expression or function of a gene(s) or gene pro duct(s) that facilitates, or is associated with, erec tile failure ?. Not surprisingly [337], much of the information collected to date has been obtained on animal models of the human disease. These findings, and their similarities and differences with respect to the human condition are the subject of recent reviews, and will not be further discussed here. As such, the data described below concerns only findings on the molecular physiology and pathophysiology of human corporal tissue.

4. DIFFERENTIALLY EXPRESSED TRANSCRIPT IN CULTURED CORPORAL SMOOTH MUSCLE CELLS FROM DIABETIC PATIENTS Because diabetic patients account for approximately half of all patients with erectile dysfunction, one recent study utilized differential display technologies to examine the possibility of diabetesrelated alterations in molecular aspects of human corporal smooth muscle cells. In this preliminary study, a differentially expressed gene product was detected in corporal tissue excised from diabetic patients [338]. That is, differential display techniques revealed that a transcript expressed in tissue derived from a patient with impotence secondary to a radical prostatectomy (i.e., nominally neuronal in origin and free from organic disease) was greatly reduced or absent in corporal tissue from 3 diabetic patients. While no significant homology was found between this transcript and sequences deposited in GenBank, this was the first evidence supporting the supposition that genetic alterations may attend the manifestations of erectile dysfunction in some patients.

6. MOLECULAR MECHANISMS FIBROSIS

OF

CORPORAL

Immunostaining and densitometry techniques have shown evidence for decreased smooth muscle cell content in corporal tissue excised from impotent men [340, 341], and thus, recent efforts have been undertaken to understand the molecular mechanisms that might account for such apparent structural alterations [275, 342]. In trying to evaluate the putative mechanistic basis for corporal fibrosis and ensuing erectile failure, recent investigations have centered around evaluating the relationship between collagen synthesis/deposition and their relationship to transforming growth factor β1 (TGF-β1) mRNA and TGF-β1 membrane receptor levels. The rationale is analogous to that established as the etiologic basis for fibrosis in 168

other human disease states (e.g., hepatic cirrhosis or pulmonary interstitial fibrosis), in which increased TGF-β1 levels have been documented to contribute to increased extracellular matrix via enhanced collagen deposition. In fact, molecular studies conducted on cultured human corporal smooth muscle cells have clearly established that there may be an important reciprocal relationship between the levels of, for example, prostaglandin E1, NO and oxygen tension on the one and, and TGF-β1-induced increases in collagen synthesis/ deposition on the other. Corresponding molecular studies conducted on human corporal tissue biopsies, however, found no evidence for a physiologically relevant differential expression of either TGF-β1 mRNA or TGF-β1 membrane receptor levels in tissues excised from patients with a wide range of organic etiologies, but which had significant differences in the extent of corporal fibrosis. Nonetheless, even when, as in this case the hypothesized in vitro mechanism does not appear to contribute to the in situ molecular/genetic alterations, such studies still provide an important foundation for identifying and evaluating the contribution of relevant molecular mechanisms to the etiology of corporal fibrosis and the pathogenesis of erectile dysfunction.

cess of sildenafil, a much better characterization of smooth muscle specific genes/gene products is required. More specifically, consider the fact that many of the documented side effects of sildenafil (gastrointestinal distress, visual effects, facial flushing, hypotension, etc.,) result from the fact that the PDE 5 enzyme, the molecular target of sildenafil, is found not only in the smooth muscle cells of the penis, but also smooth muscle cells in other peripheral organs. Thus, the development of more efficacious oral therapies with fewer systemic side effects is dependent on the identification of even more specific/selective molecular targets. The later, in turn, awaits more precise details concerning the distribution, relative stoichiometry, and moreover, function, of genes or sets of genes/gene products that are critical to the regulation of smooth muscle cell tone/phenotype in physiologically diverse smooth muscle tissues. The technologies for making such comparisons already exist, and must now be applied to this important medical problem.

8. SOMATIC GENE THERAPY FOR THE TREATMENT OF ERECTILE DYSFUNCTION What specifically is gene therapy? The idea of genetic therapy for human disease derives largely from the application of molecular techniques to clinical medicine [343, 344, 345, 346, 347]. Historically, and not surprisingly, genetic therapies have been utilized to correct diseases/disorders that have an underlying genetic component. In this scenario, the introduction of foreign genetic information into human cells either restores or supplements defective functions, or conversely, functionally antagonizes the effects of expression of a mutant genetic phenotype. Thus, the term gene therapy has been coined to describe the genetic modification of a population of cells, and is the term that will be used throughout this report.

In summary then, while the number of molecular studies in human corporal tissue are still relatively few, this is clearly a promising area of research with significant clinical potential. Many important details concerning the physiological, pharmacological and pathophysiological regulation of corporal smooth muscle tone have been gleaned in the past few years, and it is only a matter of time before the rather robust techniques of molecular biology begun to identify the most relevant molecular alterations that contribute to the etiology of erectile dysfunction. Certainly, a more precise identification of the relevant molecular/genetic alterations associated with erectile failure is a clear prerequisite to the improved diagnosis and treatment of erectile dysfunction.

Somatic gene therapy, in particular, refers to the genetic modification of differentiated cells, as opposed to modifying more pluripotent (less differentiated) germ line cells. In fact, it is now possible for one to selectively express foreign genes in specific target cells, and thus alter, in a measurable fashion, a desired cellular response. A detailed description of all the methodologies involved in gene therapy is well beyond the scope of this report, suffice it to say that the identification, iso-

7. I DENTIFICATION OF SMOOTH MUSCLE SPECIFIC GENES The application of molecular technologies will also be critical to the development of novel oral and gene-based treatments for erectile dysfunction. For example, to really improve upon the suc-

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lation, sequencing, synthesis, cloning and expression of exogenous genes can now be accomplished in relatively short order, and with great accuracy and fidelity. The goal of this section of the report is to highlight how these strategies will impact the treatment of erectile dysfunction, and furthermore, to outline several recent applications of such technologies to the genetic therapy of erectile dysfunction. Before so doing, a brief review of the evolution of gene therapy for the treatment of systemic cardiovascular disease provides a nice encapsulation of the strategies, limitations and overall goals of any form of somatic gene therapy. A brief description is thus given below.

9. THE EVOLUTION GENE THERAPY

OF

given the relatively short time frame over which these techniques have been utilized. Notwithstanding the overall promise of gene therapy, at least three significant obstacles to clinical success still remain, and they are: 1) The specificity of gene transfer/incorporation into one tissue or cell type, as opposed to others. 2) The efficiency and stability of gene incorporation after cellular uptake/invasion. That is, what percentage of cells needs to be transfected, and for how long? 3) Finding appropriate vectors so that the first two conditions can be met without producing other undesirable side effects, such as insertional mutagenesis (i.e., as might be expected with retroviruses (e.g., Rous Sarcoma Virus (RSV)), or immunogenic reactions, that is, as might be expected from utilizing non-integrating, even non- replicating viral vectors such as the adenovirus [343, 344, 345, 351, 355].

CARDIOVASCULAR

Exploration of the potential utility of gene therapy to the treatment of cardiovascular disease dates back to the beginning of this decade [348]. The original intent was to utilize somatic gene therapy to ameliorate the symptoms of cardiovascular disorders such as atherosclerosis, vasculitis and restenosis after balloon angioplasty [348, 349, 350, 351]. Since these seminal investigations, the techniques for gene transfer into muscle cells have continued to be developed and improved upon, with the dual purpose of providing insights into myocyte gene regulation (see above), as well as providing novel therapeutic strategies for the treatment of cardiovascular diseases. In fact, experimental studies have elucidated some global boundary conditions that govern the efficiency and persistence of gene transfer into muscle cells, and moreover, have indicated that muscle may be unique in its ability to incorporate and express naked DNA [344]. The efficiency of transfection can vary widely depending on the muscle cell type and the particular vector used, but has been reported to range from values as low as 0.01% in cardiac myocytes following a single injection of naked DNA [352, 353] to as high as 80% in vascular wall cells using more aggressive strategies such as adenovirus mediated gene transfer techniques [354]. Following cellular incorporation of the vector/DNA, the DNA is thought to remain extrachromosomal (i.e., episomal), with persistence of exogenous DNAin vascular wall cells reported for up to 5 months post transfection [348]. Such results are quite exciting and encouraging,

10. RATIONALE FOR GENE THERAPY AS A TREATMENT OF ERECTILE DYSFUNCTION In this regard, the anticipated successful utilization of genetic therapy for the treatment of erectile dysfunction is based on the results of recent clinical, experimental and theoretical studies, all of which indicate that the coordination/homeostasis of corporal tissue responses exists at the intersection of: 1. the activity of peripheral neural pathways, 2. the subsequent activation of bifurcating intracellular signal transduction pathways, and 3. the spread of such locally restricted neural signals throughout the corpora via intercellular communication through gap junctions and/or regenerative electrical events (i.e., action potentials) [284, 286, 306, 307, 309]. This triumvirate of requisite mechanisms for the coordination of tissue responses has been referred to as the “syncytial tissue triad”, and serves as the foundation for integrative tissue physiology in many other peripheral organ systems composed primarily of smooth muscle cells. This in mind, the salient evidence supporting the supposition that genetic modification of only a small fraction of the corporal smooth muscle cells will be sufficient for the restoration of normal tissue function is summarized below, and the overall strategy behind the therapy is conceptualized in Figures 10 - 12.

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Figure 10: Nonviral vector technology using “naked DNA”. As illustrated in the lower panel, a plasmid, in this case the commercially avai lable pcDNA plasmid (Invitrogen) is a circular double stranded eukaryotic DNA that can be used to obtain high-level, stable and nonreplica tive expression of the gene of interest in many mammalian cell types. Specifically, using appro priate restriction enzymes, one can “cut” the pcDNA vector between regions 1 & 2 (note that the cross-hatched, darkened red area is actually a blow-up of an underlying region which contains the region encoding the T7-Sp6 promo ter, which flank the inserted sequence of interest. Thus, this region is not on the same scale as the rest of the molecule). As such, regions 1 & 2 demarcate the initiation and termination regions for replication of the inserted DNAsequence. As shown in this example, a linear double stranded DNA sequence that encodes the pore forming region of the human maxi-K channel (hSlo) is routinely inserted. The top panel emphasizes that the gene of interest in this study, the hSlo cDNA, is nearly the same size as the vector itself.

Figure 11: Schematic depiction of the proposed use and putative corresponding sequence of events involved in gene therapy for erectile dysfunction. As illustrated, a tourniquet could be placed at the base of the penis to restrict the outflow of blood from the cavernous spaces. Aneedle injection of the “naked” DNAinto the penis would then result in diffusion of the DNAin the penis, and uptake into the corporal smooth muscle cells by an as yet undetermined mechanism. The use of “naked” DNAas illustrated in Figure 10, results in a nonintegrating or episomal DNA. The DNA then finds its way to the nucleus where it is able to take advantage of the existing nuclear machinery to synthesize mRNA encoding the maxi-K channel protein. The mRNA exits the nucleus, and protein is synthesized in the cytosol resulting in the incorporation of a functional maxi-K channel in the cell mem brane Clearly, as outlined in the text, other genes, that encode different proteins, can also be used.

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Figure 12: The putative mechanistic basis for the observed in vivo efficacy of gene therapy with the maxi-K channel. As illustra ted, K+ channels and gap junctions are ubiquitously distributed throughout the corpora. The result is that the corporal smooth muscle network behaves as an electrical syncytium. The main physiological implication is that not all of the cells need to be direct ly activated by an endogenous neural or humoral signal. In this scenario, intracellular second messenger signals (i.e., ions and other small molecules such as Ca2+, K+, cAMP, cGMP) can quickly spread and equilibrate throughout the smooth muscle cell network, without the necessity for direct activation of each smooth muscle cell. In fact, during erection, that is, syncytial relaxa tion of the corporal smooth muscle cells, it is believed that waves of hyperpolarization spread throughout the corpora. It is with respect to this latter phenomenon that gene therapy with the maxi-K channel is thought to work. As illustrated in the upper panel, K+ currents are equilibrated throughout the corporal smooth muscle network at some basal level, which, as illustrated in the bot tom panel, can be augmented by the over expression of the maxi-K channel on some fraction of the total cellular network (in this example, the cells labeled A, B & C). In the example illustrated here, augmented K channel activity, due to over expression of the maxi-K channel, essentially “drives” the rest of the tissue. Certainly, as reviewed in the text, other genetic strategies can also take advantage the syncytial nature of the corporal smooth muscle cell network.

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There are three major isoforms of the nitric oxide synthase (NOS) enzyme [358]. Two of these are constitutive (the neuronal (nNOS or NOS 1) and endothelial (eNOS or NOS 3) isoforms), and one of these is inducible (iNOS or NOS 2). Two recently published abstracts [359, 360] examined the ability of gene therapy with iNOS to enhance erectile capacity in a rat model. The utilization of iNOS is based on the rationale that, in contrast to the constitutive NOS isoforms, iNOS could provide “on demand” increases in NO levels. Thus, nerve-stimulated intracavernous pressure response (ICP) responses were evaluated in the rat in vivo as well as in vitro. In one series of in vitro studies [360] it was shown that cultured myoblasts transfected with iNOS elaborated NO into culture medium. In another series of in vivo studies [359], iNOS was expressed in adenovirus, and then either the iNOS/adenoviral vector itself, or transformed myoblasts containing the adenoviral/iNOS construct were directly injected into the rat penis. iNOS gene expression in the rat penis was found to be time-dependent, being maximal at day 4, with lower levels at days 2 and 7. The maximal nerve-stimulated ICPresponse was elevated 2-fold as expected. However, of major significance was the observations that the basal, or resting, ICP was also 10-fold greater in those animals containing the iNOS transgene. The former is encouraging, but the latter would be an extremely undesirable side effect. Nonetheless, these initial studies document that physiologically relevant amounts of iNOS can be delivered either directly packaged with adenovirus (and presumably subsequently incorporated in corporal smooth muscle cells), or indirectly via a shuttle vector/cell type (i.e., the myoblast cells), and then injected into the penis.

11. BRIEF REVIEW OF CURRENT GENE THERAPY APPROACHES Below 5 distinct reports of possible gene-based strategies for the treatment of erectile dysfunction are briefly described. Note that all of these reports represent preclinical studies. a) Gene therapy utilizing ex vivo-transformed endothelial cells injected intracorporally. Endothelial cells are an important source of vasomodulators (e.g., NO, prostacyclins and prostaglandins, etc.), thereby influencing the tone, and perhaps the phenotype, of the underlying corporal smooth muscle cells. As such, altered endothelial cell function is thought to contribute to the etiology of erectile dysfunction in some patients. In this regard, two recent abstracts [356, 357] evaluated the possibility of utilizing genetically modified endothelial cells for the treatment of erectile dysfunction. That is, this proposed utilization of gene therapy would involve genetic modification of the endothelial cells ex vivo, and then the endothelial cells would be injected into the penis. In these preliminary studies, the investigators harvested microvascular endothelial cells from the rat epididymal fat pad, fluorescently labeled them, and subsequently injected the endothelial cells back into the rat corpus cavernosum. Viable, fluorescently labeled endothelial cells were identified within the corporal sinusoids, adjacent to corporal smooth muscle bundles at 48 hours post-injection. Labeled endothelial cells were present for up to two weeks after transplantation. Such observations indicate that it is conceivable that one could harvest microvascular endothelial cells, genetically manipulate them, and place them back in the penis with the expectation that they would remain viable. While much more work clearly needs to be done, these seminal studies provide “proof of principle” that isogeneic (self) transplantation of genetically modified endothelial cells might assist with the restoration of the normal balance between the effects of local relaxing and constricting factors on the degree of tone in the underlying smooth muscle cells.

c) Gene therapy with rat penile iNOS (i.e., RPi NOS).

b) Gene therapy with intracorporal injection of inducible nitric oxide synthase (iNOS)/adeno viral constructs or intracorporal injection of myoblasts transformed with iNOS/adenoviral constructs.

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Garban et al [361], also in the rat model, described in great detail another elegant strategy, which is also designed to take advantage of the prominent role played by NO in erectile function. These studies utilized the rat penile iNOS gene that the authors cloned themselves. The goal was to determine if gene therapy could restore the age-related decline in the intracavernous pressure response (ICP) observed in 20 month old rats, when compared to 5 month old rats. To this end, 10 µg of the rat penile iNOS cDNA (i.e., RPiNOS / pcDNA;

i.e., “naked” DNA) was injected intracorporally in a 100 µl volume. Transcript and protein for RPiNOS were both detected following the intracavernous injection of RPiNOS/pcDNA, and moreover, a significant enhancement in the cavernous nerve stimulated intracavernous pressure response (ICP) was noted for up to 10 days post injection of the RPiNOS/pcDNA construct. By 21 days, however, the effects were no longer significant. Clearly these studies provide further evidence for potential utility of a gene therapy strategy for the treatment of human erectile dysfunction.

in older animals [309]. That is, hSlo cDNA/ pc DNA transfection was sustained for at least 2 months, but perhaps as long as 4 months in vivo, and was associated with measurable and physiologically relevant alterations in the mean amplitude of the cavernous nerve-stimulated intracavernous pressure response (ICP); an objective index of erectile capacity. However, since more than 50% of impotent men are diabetic, a second series of studies was more recently conducted to determine if KCa gene therapy would also be sufficient to prevent the decline in erectile capacity that is known to be associated with streptozotocin (STZ)induced experimental diabetes in rats [364]. Thus, 47 rats were made diabetic by a single subcutaneous injection of STZ (35 mg/kg). Two months after the diabetic state was established (when significant neuropathy is known to occur) [365], all animals received a single intracorporal injection of naked pcDNA/hSlo cDNA (again, 100 ∝g in 200 ∝l final volume).

d) Gene therapy with the hSlo/pcDNA encoding the human calcium-sensitive potassium (K) channel subtype. Christ et al [309] applied the principles of integrative tissue physiology [284, 285, 286] to test the hypothesis that low efficiency gene transfer is an attractive therapeutic option for correcting diminished erectile capacity. The specific rationale for the approach was as follows. Heightened contractility and/or impaired relaxation of the corporal smooth muscle is a primary cause of erectile dysfunction in many impotent men [4, 303, 362]. Therefore, any therapy that increases either the “driving” force for relaxation (i.e., the gene therapy techniques designed to enhance NO signals, as described above), or the “sensitivity” of the smooth muscle cells to vasorelaxants, would be expected to improve erectile capacity. Recent publications have documented that potassium (K) channels are important modulators of human corporal smooth muscle tone and erectile capacity, by virtue of their ability to modulate corporal smooth muscle membrane potential, transmembrane calcium flux, and therefore, the free intracellular calcium concentration [288, 290, 296, 297, 303]. Thus, the initial gene therapy approach was designed around one of the most prominent K currents present in human corporal smooth muscle cells, that is, the calcium-sensitive, maxi-K channel [288, 290]. Consistent with the important role of K channels as mediators/modulators of the effects of a vast array of physiologically relevant vasomodulators, it was documented that a single bolus intracavernous injection of naked hSlo cDNA (which encodes the pore forming subunit of the large conductance calcium-sensitive maxi-K channel, KCa) [363] was sufficient to prevent the age-related decline in erectile capacity normally observed

The ICP response to cavernous nerve stimulation was studied 1-2 months later, and the results for several levels of current stimulation clearly indicated that the presence of the hSlo transcript was sufficient to restore the nerve-stimulated ICP response to levels that were statistically significantly greater than STZ-diabetic animals that did not receive an hSlo injection, but indistinguishable from age-matched control animals. Taken together with previously published work, these studies clearly document that KCa gene therapy can restore both the age-related [309] and the STZ-induced [364] decline in erectile capacity observed in rats in vivo, and the putative mechanistic basis for this effect is depicted in the schematic diagram shown in Figure 12. Such observations provide further support for the possibility that a similar genetic strategy will be useful in treating men with erectile dysfunction due to diverse organic causes. e) Gene therapy with vascular endothelial grow th factor (VEGF). Another recent study [366] seeks to take advantage of the fact that erectile dysfunction is often associated with alterations in the flow of blood to or from the penis, and moreover, that problems with vascular perfusion to the erectile tissue of the penis may be a proximal cause. Several endogenous growth factors are known to regulate/induce

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angiogensis/vasculogenesis, that is, the formation and growth of new blood vessels. Vascular endo thelial derived growth factor (VEGF) is among the most potent of the known angiogenic/vasculogenic factors, and thus, was chosen as the initial molecular target for these studies. Since VEGF therapies in laboratory animals and/or humans with peripheral vascular disease have been shown to produce measurable increases in tissue vascularity, the investigators sought to identify the VEGF transcript(s) present in the adult rat and human penis, as a prelude to the identification of the best therapeutic agent. Thus, penile tissue was obtained from adult rats, as well as human patients undergoing penile prosthesis implantation.

disease and cystic fibrosis. First, preclinical studies have illustrated that the intracavernous injection and cellular incorporation of naked DNA [309, 359, 361, 364], leads to the subsequent expression of transcript, and finally, of functional protein in vivo. Since physiologically relevant alterations in erectile capacity have been documented following such genetic strategies, these exciting data would nominally obviate the necessity for utilizing an adenoviral or retroviral vector for the treatment of erectile dysfunction. In turn then, the use of “naked” DNA would have the additional benefit of minimizing the two most prominent side effects of gene therapy, that is, insertional mutagenesis and immune responses [367].

Analysis of the VEGF transcript isoforms was performed using reverse-transcriptase polymerase chain reaction (i.e., RT-PCR). In short, four previously described VEGF isoforms were detected in both rat and human corporal tissue. Again, the identification of the relevant and predominant human VEGF isoforms is the first step toward genetic manipulation of VEGF in the penis as a therapy for erectile dysfunction related to compromised vascular perfusion. The proposed advantage of such a therapy, is related to the fact that all currently available forms of therapy for erectile dysfunction treat the symptoms of erectile failure and not the cause. That is, current therapeutic options are available “on demand”, and thus, represent largely palliative, and not curative, therapies. If validated in an appropriate animal model, and moreover, in clinical trials, this would indeed represent a significant advance in the treatment of human erectile dysfunction in that subset of patients in whom vascular disease is a proximal etiologic factor in their disease.

The fact that a tourniquet can be placed around the base of the penis for several minutes, under the low blood flow conditions of flaccidity, will ensure the maximum possible restriction of the intracorporally injected naked DNA within the penis; minimizing the presence of naked DNAin the systemic circulation and other peripheral tissues. Furthermore, the presence of intercellular communication through gap junctions ensures that only a fraction of the total corporal smooth muscle cell population needs to be genetically modified in order to affect rather global changes in erectile function; as such, the efficiency of cellular transfection is not likely to be an important limitation. Lastly, preliminary preclinical observations in the rat model in vivo have indicated that the expression of the gene of interest can last for up to four months [309]. That is, three intracavernous injections of the hSlo cDNA per year may be sufficient to restore erectile potency in men, in the absence of a need for any other form of therapy. Such a therapeutic strategy stands in stark contrast to the currently tolerated 34 intracavernous injections per week that some men are willing to endure. Unequivocally then, if the specificity, physiology and duration of the effect of gene transfection are similarly robust in man, gene therapy would represent a major advance in the treatment of erectile dysfunction. Based on the encouraging preclinical data reviewed herein, the future of gene therapy for the treatment of human erectile dysfunction seems bright indeed.

f) Summary and conclusions concerning gene therapy for the treatment of erectile dysfunction. In short, the field of gene therapy for erectile dysfunction is still in its infancy. Clearly, divergent genetic strategies are plausible. To summarize, there are several reasons for suspecting that utilization of a relevant molecular target(s) will lead to a genetic therapy of erectile dysfunction that will be inherently more successful than gene based strategies for the treatment of diseases such as cancer, systemic cardiovascular

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block receptors for 5-hydroxytryptamine (5-HT, serotonin) and cause release of histamine from mast cells. Phentolamine also seems to have another action, possibly involving NOS activation [377]. Since phentolamine non-selectively blocks α-ARs, it can be expected that by blocking prejunctional α2-ARs, it would increase the NA release from adrenergic nerves, thus counteracting its own post-junctional α1-AR blocking actions. Whether or not such an action contributes to the limited efficacy of intracavernosally administered phentolamine to produce erection, is not known.

VII. THERAPEUTIC ASPECTS : PHARMACOLOGICAL BASIS FOR CURRENT AND FUTURE THERAPIES 1. DRUGS

FOR

INTRACAVERNOUS ADMINIS-

TRATION

Among the many drugs and/or drug combinations tested [368, 369, 370, 371], only three, used alone or in combination, have become widely clinically accepted and administered on a long-term basis, namely papaverine, phentolamine, and prostaglandin PGE1 (alprostadil). The experimental and clinical experiences with several other agents, used for treatment and discussed below, are limited.

In dogs, phentolamine like papaverine decreased the resistance to arterial inflow to the penis. However, papaverine, but not phentolamine, increased the resistance to venous outflow [375]. Lack of effect on venous outflow by intracavernous phentolamine has also been demonstrated in man [378].

a) Papaverine Papaverine is often classified as a phosphodiesterase inhibitor, but the drug has a very complex mode of action and may be regarded as a «multilevel acting drug» [373]. Which of its several possible mechanisms of action is the one that predominates at the high concentrations that can be expected when the drug is injected intracavernously is difficult to establish. In vitro, it has been shown that papaverine relaxes the penile arteries, the cavernous sinusoids, and the penile veins [374]. In dogs, Juenemann et al. [375] demonstrated that papaverine had a dual hemodynamic effect, decreasing the resistance to arterial inflow and increasing the resistance to venous outflow. The latter effect, which has been demonstrated also in man [376], may be related to activation by papaverine of the veno-occlusive mechanism.

There is a general lack of information about the pharmacokinetics of phentolamine. The drug has a reduced efficacy when given orally, probably due to extensive first-pass metabolism. A discrepancy between the plasma half-life (30 min) and effect duration (2.5-4 h) has been demonstrated [379]; whether this can be attributed to active metabolites is not known. When the drug is given intracavernosally, the serum concentration of phentolamine will reach a maximum within 20-30 minutes, and then rapidly decline to undetectable levels [380]. The most common side effects of phentolamine after intravenous administration are orthostatic hypotension and tachycardia. Cardiac arrhytmias and myocardial infarction have been reported, but these are very rare events. Theoretically, such effects may be encountered also after intracorporal administration, but so far this does not seem to be the case. Since a single intracavernous phentolamine injection does not result in a satisfactory erectile response in most cases, the drug is widely used in combination with papaverine [368, 381], or with VIP [382].

Since a main mechanisms of action of papaverine is non-selective PDE inhibition, and the main PDE activities in the human CC appears to be PDE3 and PDE 5, PDE inhibitors with actions on these isoenzymes, but which lack the ”non-specific” side effects of papaverine would be an interesting alternative. b)

2. THYMOXAMINE

-Adrenoceptor antagonists

Thymoxamine (moxisylyte) has a competitive and relatively selective blocking action on α1-ARs. In addition, it may have antihistaminic actions. Little is known about its pharmacokinetics, but after systemic administration, it has an effect duration of 3-

1. PHENTOLAMINE Beside being a competitive α-AR antagonist with similar affinity for α1- and α2-ARs, which is its main mechanism of action, phentolamine can also

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4 h. Moxisylyte is a prodrug, rapidly transformed into an active metabolite in plasma (deacetylmoxisylyte or DAM). Elimination of the active metabolite occurs by N-demethylation, sulpho- and glucuroconjugation. The N-demethylated metabolite is sulphoconjugated only. Urine is the main route of excretion [383]. In vitro, moxisylyte relaxed NA-contracted human corpus cavernosum preparations [384], but was less potent than prazosin and phentolamine.

effects and clinical use have recently been reviewed [371, 372]. PGE1 is metabolized in penile tissue to PHE0 [393], which is biologically active, and may contribute to the effect of PGE1 [394]. PGE1 may act partly by inhibiting the release of NA [395], but the main action of PGE1 and PGE0 is probably to increase the intracellular concentrations of cAMP in the corpus cavernosum smooth muscle cells through EPreceptor stimulation [394, 396, 397, 398].

Moxisylyte was shown to produce erection when injected intracavernosally [385], and in a doubleblind crossover study Buvat et al. [386] showed it to be more active than saline, but less active than papaverine. Buvat et al. [386] reported on the experiences of intracavernous injections of moxisylyte in 170 patients with impotence, and pointed out that the drug did not produce, but facilitated, erection by inducing prolonged tumescence. They also stressed that the main advantage of the drug was its safety. Only 2 out of the 170 patients injected had prolonged erections. Buvat et al. [387], comparing papaverine and moxisylyte, also found that moxisylyte had less tendency to produce corporal fibrosis than papaverine (1.3% vs 32%). The positive safety aspects were underlined by Arvis et al. [388], who reported no serious side effects among 104 men followed for 11 months and performing 7507 self-adminstrations.

PGE1 is known to have a variety of pharmacological effects. For instance, it produces systemic vasodilatation, prevents platelet aggregation, and stimulates intestinal activity. Administered systemically, the drug has been used clinically to a limited extent. Little is known about its pharmacokinetics, but it has a short duration of action and is extensively metabolized. As much as 70% may be metabolized in one pass through the lungs [399], which may partly explain why it seldom causes circulatory side effects when injected intracavernosally Palmer et al [396] found that forskolin, which directly stimulates adenylate cyclase, was a potent stimulant of intracellular cAMP formation in cultured human corporal smooth muscle cells. Threshold forskolin doses were found to significantly increase the production of cAMP by PGE1, which suggested a possible synergistic effect. Traish et al [394]confirmed this synergistic effects of forskolin and PGE1 in cultured human corpus cavernosum cells. They also demonstrated that the augmentation of the forskolin-induced cAMP generation by PGE1 and PGE0 was mediated by EP receptors and attributable to interactions at the adenylyl cyclase and G-protein levels.

In a comparative study between moxisylyte and PGE1, Buvat et al. [389] showed that PGE1 was significantly more effective than moxisylyte (71% vs 50% responders), especially in patients with arteriogenic dysfunction (96% vs 46%). However, moxisylyte was significantly better tolerated than PGE1, causing fewer prolonged erections and fewer painful reactions.

Both forskolin and PGE1 elicited concentrationdependent increases in the magnitude and duration of intracorporal pressure in dogs without systemic effects [398] and Mulhall et al [400] reported that intracorporal administration of forskolin to patients with erectile dysfunction and not responding to triple-drug therapy, responded when forskolin was added. These results suggest that it is possible to enhance the relaxant corporal effects of PGE1, and may be other vasodilators, by forskolin and analogues [401], and it cannot be excluded that this may provide new strategies for pharmacologic treatment of erectile dysfunction.

As a facilitating drug, moxisylyte may be a reasonable alternative for treatment of erectile dysfunction. An interesting development is nitrosylated moxisylyte, which may act as as combined NO-donor and α1-AR antagonist [390]. Clinical studies experiences are so far lacking. c) Prostaglandin E 1 (alprostadil) PGE1, injected intracavernously or administered intraurethrally, is currently one of the most widely used drugs for treatment of erectile dysfunction [371, 372, 391, 392], and several aspects of its 177

d) Other drugs

tachycardia and flushing [409, 410]. However, the plasma half-life of the peptide is short, which may contribute to the fact that systemic side effects are rare when it is administered intracavernosally.

1. VASOACTIVE INTESTINAL POLYPEPTIDE (VIP) A role for VIP as neurotransmitter and/or neuromodulator in the penis has been postulated by several investigators, but its importance for penile erection has not been established [4, 402]. However, the inability of VIP to produce erection when injected intracavernosally in potent [403] or impotent men [404, 405, 406], indicates that it cannot be the main NANC mediator for relaxation of penile erectile tissues.

It seems that VIP administered intracavernously together with phentolamine may be an alternative to the more established treatments with papaverine/phentolamine or PGE 1, but more experience is needed to give a fair evaluation of the advantages and disadvantages of this combination. 2. CALCITONIN GENE-RELATED PEPTIDE (CGRP) Stief et al. [411] demonstrated CGRP in nerves of the human corpus cavernosum, and suggested its use in erectile dysfunction. In human blood vessels from various regions, CGRP is known to be a potent vasodilator. Its effect may be dependent or independent of the vascular endothelium [412, 413]. The peptide relaxed the bovine penile artery by a direct action on the smooth muscle cells [414], which suggests that it may have important effects on the penile vasculature.

VIP has been shown to produce a wide range of effects. It is a potent vasodilator, inhibits contractile activity in many types of smooth muscle, stimulates cardiac contractility, and many exocrine secretions. It stimulates adenylate cyclase and the formation of cyclic AMP. Wagner and Gerstenberg [403] found that even in high doses (60 ug), VIPwas unable to induce erection on intracavernous injection in potent men. On the other hand, when used in conjunction with visual or vibratory stimulation, intracavernous VIP facilitated normal erection. Kiely et al. [405] injected VIP, papaverine, and combinations of these drugs with phentolamine intracorporally in twelve men with impotence of varying etiology. They confirmed that VIP alone is poor at inducing human penile erections. However, in combination with papaverine, VIP produced penile rigidity similar to that obtained with papaverine and phentolamine. Gerstenberg et al. [407] administered VIP together with phentolamine intracavernously to 52 patients with erectile failure. Forty percent of the patients had previously received treatment with papaverine, alone or with papaverine together with phentolamine. After sexual stimulation, all patients obtained erection sufficient for penetration. Those patients previously treated with papaverine or papaverine/phentolamine stated that the action of the VIP combination was more like the normal coital cycle. No patient developed priapism, corporal fibrosis, or any other serious complication [407]. McMahon [408] performed a pilot study in 20 men with erectile dysfunction of various etiology using a VIP/phentolamine combination. Sixteen of the patients responded favorably, and side effects were few.

It is reasonable to assume that drugs acting via NO may be useful for treatment of erectile dysfunction. Linsidomine, the active metabolite of the antianginal drug molsidomine, is believed to act by non-enzymatic liberation of NO [417, 418], which by stimulating soluble guanylate cyclase increases the content of cyclic GMP in the smooth muscle cells and produces relaxation. Linsidomine also inhibits platelet aggregation [419], and in some countries it is registered for treatment of coronary vasospasm and coronary angiography. The drug was reported to have a plasma half-life of approximately 1-2 h [418, 420].

VIPgiven intravenously can produce hypotension,

Linsidomine was found to effectively relax prepa-

In patients, intracavernosal injection of CGRP induced dose-related increases in penile arterial inflow, cavernous smooth muscle relaxation, cavernous outflow occlusion, and in erectile responses. The combination of CGRP and PGE1 may be more effective than PGE 1 alone [415, 416]. It cannot be excluded that CGRP, alone as a facilitating drug, or in combination with with other drugs as an initiator of erection, can be useful for therapeutic purposes, but to assess its potential, more experience is needed. 3. LINSIDOMINE CHLORHYDRATE (SIN-1)

178

rations of rabbit and human corpus cavernosum contracted by NA or endothelin-1 in a concentration-dependent way [212, 213]. In preliminary studies, Stief et al. [421, 422], and Truss et al. [423] studied the effect of linsidomine injected intracor porally in impotent patients and found that the drug induced an erectile response by increasing the arterial inflow and relaxing cavernous smooth muscle. There were no systemic or local side effects, and no patient had a prolonged erection. These promising results have not been confirmed by other investigators [424, 425]. Placebo-controlled, randomized clinical trials must be performed to ascertain whether linsidomine is a useful therapeutic alternative to existing drugs available for intracorporal injection.

Owen et al. [430] performed a placebo-controlled, double-blind study on the effect of nitroglycerin ointment applied on the penis of 26 impotent patients with a diagnosis of organic, psychogenic, or mixed-type impotence. Nitroglycerin increased, relative to placebo, penile circumference significantly in 18 out of 26 patients, and in 7 out of 20 patients it increased blood flow in the cavernous arteries. Hypotension and headache was observed in one patient. In a double-blind, randomized, placebo-controlled trial, Claes and Bart [431] treated 26 impotent men with nitroglycerin patches. They observed a positive response to nitroglycerin with return to satisfactory sexual function in 12 (46%) patients, and some erectile improvement in 9 (35%). Only one patient of the 26 reported restoration of potency with placebo patches. Twelve of the patients reported mild to moderate headache during nitroglycerin treatment.

Another NO donor, sodium nitroprusside (SNP), have been given intracorporally for treatment of erectile dysfunction, but has been shown not to be effective [426, 427], and caused profound hypotension. These rather discouraging results with donors of NO do not rule out that drugs acting through the L-arginine/ NO/ guanylate cyclase/ cGMP pathway can be effective for treatment of erectile dysfunction (see below).

2. DRUGS

FOR

The effects of nitroglycerin plaster applied to the penis were also investigated in 10 impotent patients by Meyhoff et al. [432]. They found that when tested in the laboratory, all patients achieved an erectile response. When the plaster was selfadministered, potency was restored in 4, semirigidity insufficient for intercourse was seen in 2, tumescence in 3 and no effect in 1. Seven patients complained of headache. A sufficent erectile response to the same nitroglycerin plaster was found in 5 out of 17 patients with spinal cord injury [433].

NON-INTRACAVERNOUS ADMI-

NISTRATION

There is a generally a high placebo response (4050%) to non-intracavernously administered drugs. Therefore, placebo-controlled trials and valid instruments to measure response are mandatory to adequately assess effects.

Comparing transdermal nitroglycerin and intracavernous injection of papaverine in 28 patients with spinal cord lesions and erectile dysfunction, Renganathan et al. [434] found that 61% responded to nitroglycerin and 93% to papaverine. Nine patients had complications with papaverine, while the only side effect of transdermal nitroglycerine was mild headache (21%).

a) Organic nitrates Nitroglycerin and other organic nitrates are believed to cause smooth muscle relaxation by stimulating soluble guanylate cyclase via enzymatic liberation of NO [417]. Both nitroglycerin and isosor bide nitrate were found to relax isolated strips of human corpus cavernosum [428].

Even if the efficacy of transdermal nitroglycerin is limited, and headache seems to be a common side effect, it may be an effective treatment in selected patients.

Transdermal administration of nitroglycerin is well established in the treatment of angina pectoris. The observation that topical application of nitroglycerin to the penis may lead to erection adequate for sexual intercourse [429], has stimulated several investigations on the efficacy of this potential mode of treatment of erectile dysfunction.

b) Phosphodiesterase inhibitors The L-arginine/NO/guanylate cyclase/cGMP pathway seems to be the most important for penile erection in some species (see above), and recent results with sildenafil, a selective inhibitor of the cGMP-

179

specific phosphodiesterase (PDE 5), found in the human corpus cavernosum [323, 331] further support the view that this may be the case also in humans [331]. Sildenalfil is 4000 more selective for PDE 5 than for PDE 3, 70 times more selective for PDE 5 than PDE 4, but only 10 times more selective for PDE 5 than for PDE 6 [329]. Sildenafil is rapidly absorbed after oral adminstration (bioavailability 41%) and has a plasma half-life of 3-5 h.

However, the frequency of intercourse or ability to perform in men that had no erection prior to drug therapy was not addressed. The most common side effect was penile pain, experienced by 9.1% to 18.3% of the patients receiving alprostadil. There were no episodes of priapism. In another doubleblind, placebo-controlled study on 1511 men with chronic erectile dysfunction from various organic causes, 64.9% had intercourse successfully when taking transurethral alprostadil compared to 18.6% on placebo [392]. Again the most common side effect was mild penile pain (10.8%).

A large number of placebo-controlled, randomized, double-blind trials have shown that sildenafil can improve erections in men with erectile dysfunction, regardless of whether the cause is due to psychogenic, organic, or mixed factors [435]. Since PDE 5 is not restricted to the penis, but can be found in other tissues as well, side effects such as nasal congestions, dyspepsia, headache, facial and chest flushing, and diarrhea may develop. Dominating in the safety discussions have been possible cardiovascular and visual side effects. An absolute contraindication to sildenafil is the use of nitrates and several, but not all, of the deaths associated with sildenafil use have been attributed to concomitant use of nitrates. However, based on experiences so far, sildenafil must be considered a safe drug [435, 436, 437].

Despite early encouraging results, some suggest the true efficacy is nearer to 30-40% and the quality of erection deteriorates over time. Penile pain remains a problem in many patients. For men finding intracavernous injections problematic, the ease of intraurethral administration is an option. However, optimism should be tempered in those with severe dysfunction and who have failed intracavernous therapy. d) K+ Channel openers Several K+channel openers (pinacidil, cromakalim, lemakalim, and nicorandil) have been shown to be effective in causing relaxation of isolated cavernous tissue from both animals and man, and to produce erection when injected intracavernosally in monkeys and humans [440, 441]. However, only minoxidil, an arteriolar vasodilatator used as an antihypertensive agents in patients with severe hypertension, seems to have been tried in man. Minoxidil is a prodrug, not active in vitro, but is metabolized in the liver to the active molecule, minoxidil N-O sulfate [442]. It has been shown that minoxidil sulfate has the properties of a K+ channel opener. Minoxidil is well absorbed, both from the gastrointestinal tract and transdermally, but its biotransformation to the active metabolite has not been evaluated in man. The drug has a halflife in plasma of 3 to 4 hours, but the duration of its vascular effects is 24 hours or even longer.

Sildenafil appears to be one of the most promising orally active agents for treatment of erectile dysfunction. The high response rate and good tolerance makes it an attractive first alternative to patients who would previously have been considered candidates for injection therapy. Other selective PDE 5 inhibitors are in clinical development (e.g.IC351, [438], but data are not yet available for evaluation. c) Prostaglandin E1 Vasoactive agents can be administered topically to the urethral mucosa and can apparently be absorbed into the corpus spongiosum and transferred to the corpora cavernosa. PGE1 (alprostadil) and a PGE1/prazosin combination were demonstrated to produce erections in a majority of patients with chronic, organic erectile dysfunction [439]. In a prospective, multicenter, double-blind, placebocontrolled study on 68 patients with long-standing erectile dysfunction of primarily organic origin [391], transurethrally administered alprostadil produced full enlargement of the penis in 75,4%, and 63.6% of the patients reported intercourse.

In a double-blind trial, minoxidil was given to 33 patients with neurogenic and/or arterial impotence, and compared with placebo (lubricating gel) and nitroglycerin (2.5 g 10% ointment). Minoxidil was applied on the glans penis as 1 ml of a 2% solution. Minoxidil was superior to both placebo and nitroglycerin in increasing penile rigidity, and it was suggested that the drug might be considered 180

for long-term treatment of organic impotence [443].

intravenous infusion of yohimbine had no erectogenic effects. This does not exclude that orally administered yohimbine may be effective (see below). In a randomized, double-blind, placebocontrolled study, Montorsi et al. [449] found that combination treatment with yohimbine and trazodone was more effective than placebo for the treatment of psychogenic impotence. Jacobsen [450] found in a pilot study that eight out of nine patients with impotence associated with antidepressive treatment with the serotonin reuptake blocker, fluoxetine, responded favorably to oral yohimbine. A potentiation of yohimbine effects by the opioid receptor antagonist naltrexone has been demonstrated [451].

The main side effects of the drug, when used in the treatment of hypertension, are fluid and salt retention, cardiovascular effects secondary to baroreflex activation, and hypertrichosis. Side effects have so far not been reported when the drug is used for treatment of erectile dysfunction, but the experiences are limited. The principle of K+ channel openening is interesting, and the preliminary experiences with minoxidil seem promising, but further controlled clinical trials are needed to confirm and assess the efficacy and side effects of the drug in patients with erectile dysfunction. e)

The effects of yohimbine have been investigated in controlled trials on patients with organic [452], psychogenic [453] , and mixed [454, 455] etiology to their impotence. In organically impotent patients, marginal effect of the drug demonstrated, i.e., 43% responded (complete or partial response) to yohimbine and 28% to placebo (difference n.s.) [452]. In studies of the same design in patients with psychogenic impotence, similar figures were obtained, although this time the difference between active treatment and placebo was significant [452, 453]. Positive responses in patients with impotence of mixed etiologies were reported in approximately 1/3 of the cases [454, 455].

- Adrenoceptor antagonists

1. PHENTOLAMINE Early studies with oral phentolamine showed some success in patients with non-specific erectile insufficiency [444, 445], Zorgniotti [445] considered non-intracavernous, ”on demand” administration of phentolamine a promising approach for treatment of impotence. Becker et al. [446] performed a double-blind placebo-controlled trial with oral phentolamine 20, 40, and 60 mg in patients with erectile dysfunction and a high likelihood of organogenic etiology, and found the drug to be of benefit. There were no serious complications, but some circulatory side effects were seen after 60 mg.

A cross-over, double blind study on 62 patients with impotence, where the efficacy of yohimbine ointment administered locally on the penis was compared with that of placebo, suggested positive results in a subgroup of patients [456], but in the total material no significant effects were found.

Whether or not phentolamine is a competitive alternative to other oral treatments of erectile dysfunction has to be demonstrated in comparative clinical trials.

High dose yohimbine (36 mg per day) was found to have no positive effect in a prospective, randomized, controlled double-blind, cross-over study of 29 patients with mixed-type erectile dysfunction [457]. Another double-blind, placebo-controlled study of 86 patients without clearly detectable organic or psychologic causes [458], revealed that yohimbine was significantly more effective than placebo (71 vs 45%) in terms of response rate.

2. YOHIMBINE In man, yohimbine has for a long time been considered as an aphrodisiac. Yohimbine is a relative selective antagonist of α2-ARs, and even if other actions have been demonstrated [447], these can be demonstrated only in concentrations that most probably cannot be obtained in man. The site of action of yohimbine is most probably not peripheral, since the predominant subtype of α-adrenoceptos in penile erectile tissue is of α1-type [7], and since intracavernosal injection of another, more potent, α2-AR antagonist, idazoxan, did not produce penile erection in man [385]. In normal healthy volunteers, Danjou et al. [448] found that

The plasma half-life of yohimbine was found to be 0.6 h [459], whereas the plasma NA-increasing effects of the drug lasted for 12 h [460]. This discrepancy may be explained by the presence of an active metabolite [459]. The side effects reported included increases in heart rate and blood pressu181

re, but also orthostatic hypotension, anxiety, agitation, and manic reactions have been described [461, 462, 463].

libido or frequency of sexual intercourse, but early morning erections increased significantly. It cannot be excluded that increased inhibition by opioid peptides may be a factor contributing to non-organic erectile failure, and that naltrexone therapy in these cases may be a useful therapeutic agent. However, well-controlled studies confirming this are lacking.

It cannot be excluded that orally administered yohimbine can have a beneficial effect in some patients with erectile dysfunction. The conflicting results available may be attributed to differences in drug design, patient selection and definitions of positive response. However, generally, available results of treatment are not impressive.

g) Dopamine receptor agonists It is well established that dopaminergic mechanisms may be involved in the regulation of male sexual behavior in animals [122, 470]. Apomorphine, a dopamine receptor agonist which stimulates both dopamine D1 and D2 receptors, has been shown to induce penile erection in rats [471, 472] as well as in normal [473] and impotent [474, 475] men. L-dopa may also stimulate erection in patients with Parkinson´s disease [476]. It has been suggested that dopamine D2 receptor stimulation may induce penile erection in rats, while activation of D1 receptors have the opposite effect [477]. In rhesus monkeys, quinelorane, a dopamine D2 receptor agonist produced penile erection [478], favoring the view that D2 receptor stimulation is important for this response. This may be the case also in man [475]. However, clinical trials with quinelorane were discontinued prematurely before its efficacy could be assessed.

f) Opioid receptor antagonists In man, it is well known that chronic injection of opioids can lead to impotence [464, 465]. It has also been suggested that endogenous opioids can be involved in sexual dysfunction, and that opioid antagonists would be effective as a treatment [466]. Intravenous naloxone, which is a pure antagonist at opioid receptors, was found to have no effect on arousal in normal subjects [467]. Naltrexone has effects similar to those of naloxone, but can be given orally, and has a higher potency and a longer duration of action (24-72 h) than naloxone. It is well absorbed from the gastrointestinal tract, but is subject to an extensive first-pass metabolism, metabolized in the liver and recycled by enterohepatic circulation. The major metabolite of naltrexone, 6-ß-naltrexone, also possesses opioid receptor antagonist activity and probably contributes to the effects of naltrexone. The plasma halflife of naltrexone is about 4 h and that of 6-ß-naltrexone 13 h.

1. INJECTED APOMORPHINE Lal et al. [473] showed in a placebo-controlled, double-blind study on healthy volunteers, that apomorphine, injected subcutaneously (0.25-0.75 mg), was able to induce erection. This was confirmed by Danjou et al. [448], showing that apomorphine induced erection and potentiated the erection induced by visual erotic stimulation. There was no increase in libido, which was in agreement with previous observations [479]. In 28 patients with impotence, Lal et al. [475] found that 17 responded with erection after subcutaneous apomorphine (0.25-1.0 g); no erection developed after placebo. Segraves et al. [480] also administered apomorphine subcutaneously (0.25-1.0 g) to 12 men with psychogenic impotence in a doubleblind and placebo-controlled study. They found a dose-related increase in maximal penile circumference. An erection exceeding 1 cm was obtained in 11 of the 12 patients. It cannot be excluded that a subgroup of impotent

In an open pilot study, Goldstein [468] found that naltrexone (25-50 mg/day) restored erectile function in 6 out of 7 men with «idiopathic» erectile dysfunction. Fabbri et al. [466] compared in a single-blind randomised study naltrexone to placebo in 30 men with idiopathic erectile impotence. It was found that sexual performance was improved in 11 out of the 15 naltrexone-treated patients, whereas placebo had no significant effects. Libido was not affected and there were no side effects. In general, the adverse effects of naltrexone are transient and mild, but hepatocellular injury may be produced with high doses. In a randomized, placebo-controlled, double-blind pilot study of 20 patients with idiopathic, non-vascular, non-neurogenic erectile dysfunction, van Ahlen et al. [469] found no significant effect on 182

patients may have an impairment of central dopaminergic functions, and that the principle of dopamine receptor stimulation may be used not only diagnostically, but also therapeutically. The therapeutic potential of apomorphine, however, seems to be limited mainly because of frequently occurring side effects. High doses (i.e., up to 5-6 mg in adult patients) may cause respiratory depression, and in the low dose range (0.25-0.75 mg) where effects on penile erection can be demonstrated, emesis, yawning, drowsiness, transient nausea, lacrimation, flushing, and dizziness [473, 480] may occur. Even if Lal et al. [474] observed that non-responders, but not responders, experienced side effects, agents other than apomorphine representing the principle of dopamine stimulation, may be useful.

te induces erection in rats and selectively increases the spontaneous firing rate of the cavernous nerves [486]. The mode of action of trazodone in depression is not fully understood; it has a marked sedative action. Trazodone has a serum half-life of about 6 h and is extensively metabolized. Blanco and Azadzoi [487] showed that trazodone and its major metabolite had an α−AR blocking effect in isolated human cavernous tissue. Later investigations confirmed that trazodone, in concentrations obtained in blood after intake of clinically relevant doses, had an inhibitory effect on isolated corpus cavernosum preparations contracted by NA or electrical stimulation [488]. However, the active metabolite, m-CCP, seemed to have no significant peripheral effects. Orally administered trazodone has been associated with priapism in potent men [489], and with increased nocturnal erectile activity in healthy volunteers [488]. When injected intracavernosally to patients with impotence, trazodone caused tumescence, but not full erection [489]. Intracavernosal trazodone acted as an α-AR antagonist, but was not as effective as papaverine or a combination of papaverine and phentolamine [489]. Positive clinical experience with the drug has been reported [490]. However, In a double-blind, placebo controlled trial, on 69 patients with different etiology of their erectile dysfunction, no effect of trazodone (150 mg/d) could be demonstrated [491].

2. ORAL APOMORPHINE Heaton and coworkers [481] reported that apomorphine, absorbed through the oral mucusa will act as an erectogenic agent. In twelve impotent patients with no documentable organic disease, but with proven erectile potential, 3 or 4 mg apomorphine in a sublingual controlled release form produced significantly durable erections in 67% without adverse effects. These results have been largely confirmed in a randomized, double-blind study including 520 patients [482]. Doses of 2, 4, 5 and 6 mg were investigated, with optimum effects (best effect and less side effects) obtained with 4 mg (apomorphine 58.1% vs placebo 36.6%). The occurrence of nausea (not severe) with 4 mg was 21.4 %.

The potential of trazodone in the treatment of penile erectile dysfunction has not been fully explored. The drug may be an alternative in some anxious or depressed men.

Similar results were obtained in two randomized double-blind studies including 977 patients with hypertension [483].

i) Future aspects Even if intracavernous treatment of erectile dysfunction has made great progress since the introduction of papaverine and phenoxybenzamine, there is still room for improvement. Local, noninjection administration may be developed to an effective on demand therapy for inducing erection. Oral treatment with apomorphine, and particularly with sildenafil, is promising, and these drugs may be important in the strategy of future treatment of erectile dysfunction. One could look forward to a rational approach to erectile disorders based on the proposed etiology of dysfunction. Following failure of one or more oral agents, intraurethral or intracavernous drug treatment could be tried.

These results suggest that sublingual apomorphine has a potential to be an effective agent for patients with erectile dysfunction. h) Trazodone Trazodone is an «atypical» antidepressive agent, which has been shown to selectively inhibit central 5-HT uptake. It increases the turnover of brain dopamine, but does not prevent the peripheral reuptake of NA [484]. In addition, trazodone has been demonstrated to block receptors for 5-HT and dopamine, whereas its major metabolite, mchlorophenylpiperazine (m-CCP), has agonist activity at 5-HT2C receptors [485]. This metaboli183

VIII. RECOMMENDATIONS

REFERENCES

1. MODELS OF ERECTION AND NEURAL CONTROL a) Rat is a suitable model. However, mice models are needed for molecular biology purposes. b) Behavioral assessments should be further persued. c) The anatomical interrelationships and interactions among the different brain nuclei that modulate erectile capacity and sexual function should be further explored. d) New and reliable animal models of erectile dysfunction should be developed. 2. TRANSMITTERS AND RECEPTORS a) The potential of new neuronal and non-neuronal transmitters/modulators (e.g., MSH, adrenomedullin, angiotensin II, nociceptin) should be further investigated. b) The interactions among the established neurotransmitters/modulators need to be further investigated, centrally and peripherally. 3. SIGNAL TRANSDUCTION a) The signal pathways for different transmitters/modulators should be studied in detail. Distribution and roles of e.g., receptors, cyclases, phosphodiesterases and protein kinases need further study. 4. SMOOTH MUSCLE FUNCTION a) Excitation-contraction coupling, cell to cell transmission of activation, ion channels, and changes in contractile proteins with erectile dysfunction should be further studied. 5. THERAPEUTIC ASPECTS I: GENE THERAPY & MOLECULAR BIOLOGY a) Strategies to prevent cavernosal degeneration and/or restore cavernosal function need to be investigated. b) The potential of intracavernosal somatic gene therapy should be further explored. 6. THERAPEUTIC ASPECTS II: PHARMACOLOGICAL BASIS FOR FUTURE THERAPIES Based on findings in basic experimental research, new molecular targets for drug treatments should be defined and explored.

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204

Committee 7

Endocrine and Metabolic Aspect Including Treatment

Chairman Y. C. K IM

Members J. BUVAT, C.C. CARSON, L.J GOOREN, J. JAROW, J. RAJFER, A. V ERMEULEN

205

CONTENTS

A. PATHOPHYSIOLOGY

C. TREATMENT

I .HYPOGONADISM IN PATIENTS WITH ERECTILE DYSFUNCTION

I. TESTOSTERONE EFFECTS ON THE BODILY SYSTEMS IN MALE

II. HYPOGONADISM IN AGING MALE AND ITS PREVALENCE

II. TESTOSTERONE TREATMENT IN PATIENT WITH ERECTILE DYSFUNCTION

III. DIABETES MELLITUS IV. HYPERCHOLESTEROLEMIA

III. AVAILABLE PREPARATION OF TESTOSTERONE

V. OBESITY, RENAL DISEASE AND THYROID DISEASE

IV. COMPLICATION OF TESTOSTERONE SUPPLEMENTATION V. CLINICAL RECOMMENDATIONS FOR TESTOSTERONE SUPPLEMENTATION

VI. HYPERPROLACTINEMIA

B. CLINICAL MANIFESTATIONS AND DIAGNOSIS OF HYPOGONADISM

VI. RECOMMENDATIONS

APPENDIX

I. SYMPTOMS OF HYPOGONADISM II. DIAGNOSIS OF HYPOGONADISM

206

Endocrine and Metabolic Aspect Including Treatment YOUNG CHAN KIM J. BUVAT C.C CARSON, L.J G OOREN, J. J AROW, J. R AJFER, A.VERMEULEN

Free testosterone (FT) or at least non Sex Hormone Binding Globulin (SHBG)-bound testosterone (bioavailable testosterone) are considered as the only fractions of serum testosterone available to the target cells. Buvat et al [19] assessed the prevalence of the decreases of both fractions in over 400 impotent patients according to their age. Free testosterone was decreased in 22.6% before the age of 50 and in 37.1% after age 50. Non SHBGbound testosterone was reduced in 3.9% before and in 24.4% after age 50. Korenman et al [20] also reported on a substantial prevalence of low levels of non SHBG-bound testosterone in the older men with impotence.

A. PATHOPHYSIOLOGY I . HYPOGONADISM IN PATIENTS WITH ERECTILE DYSFUNCTION The association between hypogonadism and erectile dysfunction (ED) has not been clearly clarified. There appears to be a direct relationship between serum androgen levels and libido but the association with sexual function is less clear. It is well known that libido can have a significant impact as a ‘conditioner’ for sexual function, and thus androgens may play an important role in both libido and the pathophysiology of erectile dysfunction.

Pirke et al[5] found, however, no difference between their groups of impotent patients and controls as regards the mean value of serum free testosterone. Moreover, in the studies of Korenman et al[20], the decrease in the levels of non SHBG-bound testosterone was not different whether the older men were impotent or not. On the other hand Buvat-Herbaut et al [7] found a significant decrease in the mean value of both free and non SHBG-bound testosterones in impotent patients compared with age-matched controls. Therefore, there are inconsistent results with dif ferences in the levels of bioavailable testosterone between normal and erectile dysfunction patients.

1. PREVALENCE OF HYPOGONADISM IN THE PATIENTS REFERRED FOR ERECTILE DYSFUNCTION

Total testosterone is usually normal in these patients. Its average value does not differ from that of men with normal erectile function [1-5] or is only slightly decreased [6-11]. In 7 series totaling 2722 patients referred for impotence, 2.1 to 21% of them according to the series (making a total of 227, thus in average 8.3%) were found to have a serum total testosterone lower than 300 ng/dl [12-18]. The prevalence of the low testosterone levels increases with age. For example in a series of 1022 unselected impotent patients, 9% of those over 50 years old had a serum testosterone < 300 ng/dl, including 2,6% < 200 ng/dl, compared to respectively 4 and 0.8% of those less than 50 years [18].

2. TESTOSTERONE AND SEXUAL INTEREST Androgens are clearly required for sexual inter est in men. In hypogonadal men supplemented with androgens, cessation of supplementation results in a progressive decline of sexual interest,

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sexual fantasies and arousal, starting after 2 or 3 weeks after withdrawal. Surgical or drug-induced castration following the administration of LHRHagonists [21,22] or antagonists [23], result in the same effects. Sexual interest and arousal return to the previous level about 2 weeks after reintroduction of androgens or cessation of anti-LHRH or anti-androgen therapy. These observations sug gest that the effect of testosterone upon sexual function in man is centrally mediated through libido.

dal men, suggesting that erectile response to VES may also be influenced by androgen sensitive mechanisms [24]. Lange et al [28] also found a borderline significant relationship between the erectile response to AVSS and the serum testosterone level. All together, these studies support the fact that the psychogenic erections are only part ly androgen-dependant, although the level of evidence is lower than that of the studies having established the androgen-dependence of the nocturnal erections, due to a less rigorous methodology.

3. TESTOSTERONE AND ERECTIONS

4. TESTOSTERONE, EJACULATION AND ORGASM

Relationships are more complex. Spontaneous erections, either nocturnal or morning, are clear ly androgen-dependant. Nocturnal Penile Tumescence and Rigidity (NPTR) monitoring using a Rigiscan device shows a significant reduction in frequency, amplitude and rigidity of the erections in men with marked hypogonadism while they are not reduced in moderate decrease of serum testosterone [24,25]. In the former case, NPTR significantly increases upon administration of androgens. Nocturnal erections are highly, significantly correlated with the serum testosterone level, and constitute the most sensitive clinical criterion of well-balanced androgen production. However nocturnal erections may require up to 6 to 12 months of androgen supplementation to regain complete normality [26]. Nocturnal erections are also highly correlated with sexual interest. Studies in paraphilic men [25] or sexual aggressors [27] treated with anti-androgens report a significant decrease of erections parallel with that of sexual interest. Psychogenic erections, i.e. induced by visual sti muli or fantasies, are only partly androgendependant. In young hypogonadal men, several studies reported complete erectile response to a strong audio-visual sexual stimulation (AVSS) as induced with erotic movies despite cessation of androgen supplementation, without increase of the response after restarting androgens. However several other studies conclude to some partial dependence on androgens The penile rigidity induced by visual erotic stimulation (VES) did not differ between hypogonadal men and controls. However, in terms of both duration and maximum level of rigidity, there was a significant increase following androgen replacement in the hypogona-

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Castration or removal of androgen supplementa tion results in delayed ejaculation and a reduc tion of the ejaculated volume. Subsequently ejaculation and orgasm disappear in many cases. They return to normal on androgen replacement[29, 30].

5. RELATIONSHIP BETWEEN SERUM LEVEL OF TESTOSTERONE AND ERECTILE FUNCTION a) The threshold value of serum testosterone in relation to erectile functions Research indicates the following levels of testosterone as minimum values for erectile functions; Levels below which sexual behaviour is impaired but there are normal night erections (i.e. 350 ng/dl) and there are still lower threshold values below which night erections are also impaired (i.e. 150 ng/dl) [31]. Others have suggested a level of 200 ng/dl as threshold for sleep related erection[32]. It appears that the plasma testosterone levels requi red for normal libido and sexual activity are rather low. b) Upper limit of the effects of testosterone upon male sexual function It is generally believed that the effects of testosterone on sexual function are maximal as soon as plasma level gets close to the lower limit of the normal adult range, and that no additional effect would occur following further increase over this limit. In controlled studies, the effects of testosterone injections upon sexual function definitely correlate with the serum testosterone level only up to a certain level. Salminies et al [33] suggested that between 200 and 450 ng/dl effect is maximal. No marked increase in sexual interest or activity

occurred over this limit. Buena et al[34] did not observe changes in sexual function when the serum testosterone levels of normal men were pharmacologically changed by means of testosterone injections following pituitary desensitization with a LHRH-agonist. Indeed, after suppressing testosterone levels with GnRH analogues, which resulted in a marked decrease in frequency of sexual desire and activity, androgen replacement at a dose maintaining testosterone levels approximately half the basal levels, was found to be appropriate for sustaining normal libido and sexual activity [23].

a) Brain centers In rodents, the neurons of anterior hypothala mus , and more specifically of the median preop tic area (mPOA) have the capacity of accumula ting isotopically labeled sex steroids as evidenced by auto-historadiographic studies. These neurons play an essential role in male sexual behavior (sexual performance) since these are stimulated when the corresponding neurons are electrically stimulated and abolished when they are destroyed[39]. The appetitive elements of sexual behavior (sexual motivation) would be under control of other neuronal systems, also able to accumulate sex steroids (amygdala, lateral septum ,ventral striatum) [39], although other data suggests that mPOA is also involved in these appetitive aspects[40]. According to Clark[41], steroids would act on both motivational and consummatory aspects of sexual behavior by modulating a central alpha 2 adrenergic tone permanently inhibiting it. Steroids would also act through their impact on different peptidergic systems colocalized with the adrenergic transmission, especially neuropeptide Y, somatostatin and angiotensin which all strongly inhibit the copulatory behavior. Less data is available in humans. However androgen receptors have been detected in the human temporal cortex [42].

Other data, however, support the probability of a stimulating effect of increases of the serum testosterone level from values exceeding 4 ng/ml. Different methodological flaws could explain the discordant results of these studies, including: small number of patients in certain series, limited information resulting from only single testosterone determinations. Several studies also reported a significant increase in sexual interest and arousal following injection of large doses of androgens to eugonadal males [35,36], including males referred for lack of sexual interest [37], though in all these studies this effect was too modest to lead to an increase in sexual activity. In eugonadal men, amplitude and duration of NPTR proved to be modestly but significantly increased following injection of large doses of testosterone esters [24]. Lastly, Buvat et al [38] observed a borderline significant improvement in satisfying sexual intercourse by increasing the circulating level of testosterone with injections of chorionic gonadotropins in eugonadal males referred for erectile dysfunction or low sexual interest.

b) Peripheral control (spinal cord centers and pelvic autonomous nervous system)

This body of data thus supports a highly signifi cant relationship between the serum testosterone level and sexual interest and activity up to a cer tain limit, probably individually different, but with values not exceeding 200 to 450 ng/dl. Beyond this level, a weaker relationship may exist, but the most extensive studies[36,37] suggest no therapeutic effect of androgen administration in eugonadal men can be expected.

6. SITE OF ACTION OF TESTOSTERONE; CENTRAL AND/OR LOCAL Testosterone seems to act centrally and at local level, at least in animals (Figure 1). 209

In spinal animals, postural reactions to sexual stimulation are facilitated by testosterone [30,43]. Certain spinal motor neurons accumulate andro gens [44]. The major pelvic ganglion, which is an important intermediary of the autonomic innervation to the penis, is also a target for androgens [45]. Testosterone stimulates the tyroxine hydroxylase and choline acetyl-transferase activities in its neurons [46]. Recent animal model data sug gests that androgens may have a direct effect upon the penis [47,48]. Reilly and colleagues demonstrate that castration obliterates the penile erectile response to pelvic ganglionic stimulation via both nitric oxide and non-nitric oxide dependent pathways in a rat model [49,50]. They reported that androgen mediated the erectile response by stimulating the expression of the neuronal isoform of nitric (NO) and by alternative pathway, including one that is independent of NO but involves the synthesis of cyclic GMP.

Figure 1: Sites of action of testosterone: Testosterone appears to act centrally and at local level.

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II. HYPOGONADISM IN AGING MALE AND ITS PREVALENCE Recent studies have shown an increased preva lence of erectile dysfunction in the aged where hypogonadism is more frequent than in young men. It has increased awareness to hypogona dism itself in the aging male, regardless of their status of sexual function, because of the numerous benefits of testosterone on the whole bodily systems, such as body composition and sense of well-being.

1. PADAM(PARTIAL ANDROGEN DEFICIENCY OF THE AGING MALE) Unlike women, there is no sharp decline or break off point in serum sex steroid levels. In contrast, cross-sectional studies have documented a gradual age-related decline in serum testosterone concentrations in healthy adult men [51]. Furthermore, the occurrence of an age associated gradual decline in bioactive testosterone levels is now generally accepted, being now confirmed by lon gitudinal data [52,53]. Highest plasma levels are observed in the age group 20-30 yrs, levels starting to decrease around age 35 yrs and at age 75yrs, mean free testosterone (FT) levels are only 50% (0.22 nMol/l) of levels at age 25yrs (0.45 nMol/l) [54]. It is not clear how to define “hypogonadism” in aging men. Should hypogonadism be defined based upon the criterion of normal levels of young men, older men, or as a specific decrease from levels measured earlier in life? For instance, a halving of serum testosterone within the normal range from 800 ng/dl to 400 ng/dl (both are within the normal range) may represent a physiologically significant decline in androgen levels for that individual and may respond to androgen replacement therapy. In the absence of longitudinal data it is impossible to state with certainty whether or not this is the case. The exact prevalence of hypogo nadism amongst aged men is not known and is dependent upon the definition of hypogonadism that is utilized. One definition that has been utilized is to select the population with the lowest quintile of serum testosterone and the highest quintile of gonadotropins. Using this definition,

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the prevalence of hypogonadism in the Massachusetts Male Aging Study is 4% amongst men aged 40 to 70 years old [51]. The prevalence of hypogonadism amongst men over 55 years increases to 20% when hypogonadism is defined as having a serum testosterone concentration below the normal range of serum testosterone for healthy young adult men. The major part of serum testosterone is tightly bound to SHBG produced by the liver. The serum testosterone fractions that are free or loosely bound to albumin are considered to be bioavailable to target organs. Cross-sectional and longitudinal studies have also demonstrated a significant increase in SHBG concentrations in aging male. Thus, not only does total testosterone decline but a higher percentage of the remaining testosterone is tightly bound to SHBG, further reducing the amount of bioavailable testosterone. The prevalence of testosterone deficiency amongst older men increases dramatically if hypogonadism is defined by the amount of bioavailable testosterone in the serum and has been estimated by some authors to be as high as 50%[51]. In an investigation of 300 healthy men applying a definition of hypogonadism as a morning level of testosterone below the lower limit of normal (12 nmol/L), Vermeulen and Kaufman [55] reported that none of the men aged 20-40 years had testosterone levels within the hypogonadal range, but 7% of those aged 40-60 year, 21% of those aged 60-80 years and 35% of those over the age had hypogonadism. The elderly men who meet these criteria might be good candidates for testosterone supplementation, and expect improvement of age-related symptoms. There exists, however, at any age a wide interin dividual variation in free testosterone (FT) levels,and, while at age 75 yrs, 20 % have FT levels which even for young male would be in the highest quartile (> 0.6 nMol/l or 17 ng/dl), at least 25 % have levels below the normal limit for young adults (0.2 nMol/l or 6 ng/dl) and, hence, can be considered to be hypogonadal [56]. The important large interindividual variability of androgen levels in healthy men is attributable to genetic, socioeconomic and environmental factors. Meikle et al [57] attributes about 30 % of the variability to genetic factors. Circadian and ultradian pulsatile variations in androgen levels also play a role in the variability of the measured values. Among the more personal factors, obesity, probably via the

induced hyperpinsulinemia and low SHBG levels, is accompanied by decreased testosterone levels and in morbid obesity even decreased FT level [58] whereas several studies suggest that a vegetarian diet is accompanied by lower FT levels. Smokers on the other hand have higher FT levels than non smokers. Physical or psychological stress are generally accompanied by decreased testosterone levels. It should be mentioned moreover that most acute or chronic illnesses such as myocardial infarction, acute infectious diseases, diabetes mellitus, chronic rheumatoid arthritis, renal, hepatic or pulmonary insufficiency, respectively, are accompanied by decreased testosterone levels.

abnormalities in the hypothalamo-pituitary axis [55,65], showing an increased SHBG level was a primary event leading to low levels of bioavailable testosterone in older men. Therefore, it appears that, the hypogonadism present in elderly men is multifactorial.

3. RELATIONSHIP OF HYPOGONADISM WITH IMPOTENCE IN THE AGING MALE Male hypogonadism is defined by decreased androgen effect which is most commonly due to impaired testicular secretion of testosterone but may also be due to decreased bioavailability of circulating androgens through an increase in serum binding proteins. Normal serum androgen levels are critical for the maintenance of normal bone and muscle mass, erythropoiesis, cognition, and libido. As stated previously, studies have shown an increased prevalence of erectile dysfunction in the aged [66]. This finding is also associated with age-related sexual changes which include reduced libido, delays in achieving erection and orgasm, and prolonged latency time [67-70]. Current evidence documents an age - related decrease in serum androgen levels which is associated with an age - related decrease in sexual function. Pfeiffer and associates documented an inverse relationship between age and coital frequency and sexual interest [71]. These observations correspond with a well described decline in serum androgen levels with age [51,53,67,72]. However, it is unclear whether or not there is a causal relationship between these two phenomena. Yet there is a paucity of data on the human male sexual response with age and its relationship with hypogonadism. Korenman and associates addressed this issue in a cohort controlled study of 267 men with erectile dysfunction and 107 controls equally divided amongst potent young and older men [65]. They observed an increased prevalence of hypogonadism amongst older men as compared to young controls. However, when corrected for age, there was no association between hypogonadism and erectile dysfunction in the older population. In other words, both hypogonadism and erectile dysfunction are common conditions in the aging male but they may not be causally related.

This androgen deficiency in elderly men is generally moderate and some authors suggest to use the term: Partial Androgen Deficiency of the Aging Male, or PADAM. More importantly, it should be realized that the normal testosterone levels for our aging males are defined on the basis of data obtained in young men. It is, however, not certain that the same criteria can be used for our elderly men. Indeed the tissular sensitivity to androgens may be different in young and elderly men , whereas it might moreover vary between the different tissues. There is, for example, good evidence that the hypothalamo-pituitary system of the elderly is more sensitive to sex hormone feed back [59-61], whereas the decrease of the androgen receptor concentration in the corpora cavernosa or pubic skin suggests a decreased sensitivity at this level [62,63]. Unfortunately, a more reliable parameter of androgen action is not available and, hence, the required testosterone concentration in elderly males remains questionable.

2. ETIOLOGY OF AGE-RELATED HYPOGONADISM The cause of hypogonadism amongst aging men is unclear. The preponderance of evidence points towards a primary Leydig cell defect. Quantitative histological studies in man demonstrate decreased number and volume of Leydig cells [55]. Zir kin and colleagues [64] observed similar findings in a Brown-Norway aging rat model where both spermatogenesis and steroidogenesis decrease in an age-dependent manner similar to that observed in the human condition. The primary defect in these aged rats is Leydig cell dysfunction. In contrast, several human studies have demonstrated

Currently available evidence suggests that endo crine factors do not play a substantial role in the age-associated increased prevalence of erectile

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dysfunction observed in man. Many other causes of erectile dysfunction increase with age. The predominant etiological factor of erectile dys function in older men appears to be atheroscle rotic vascular disease. The diminution of libido associated with age most likely has an endocrinologic basis, yet androgen replacement therapy may not be sufficient to restore normal sexual function in aging men due to the presence of other etiologic factors (ie, atherosclerosis).

III. DIABETES MELLITUS Diabetes mellitus has been the most common cause of erectile dysfunction(ED) seen in men throughout the world. As many as 28% of men presenting with ED have diabetes mellitus as the principal cause of their erectile dysfunction. Most often, ED develops during the course of diabetes with 50% of diabetic men being impotent after 10 years of diabetes [73]. Occasionally, however, ED is the first symptom of diabetes and is its presenting symptom. Although the severity of diabetes has been suggested as a predictor of ED, there appears to be little difference in the likelihood of ED in patients treated with oral hypoglycemics or those who require insulin. Age, duration of diabetes and other diabetic complications, however, appear to predict ED in most diabetic patients. Because ED in younger diabetics is most commonly caused by microangiopathy, retinopathy and other complications of diabetes are the most accurate predictors of the development of ED in diabetic patients. While glycosylated hemoglobin has been suggested as a predictor of the association of ED and diabetes, other factors, such as alcohol intake, age and anti-hypertensive medications are more accurate predictors [74-76].

corpora cavernosa [81]. These changes may progress to involve larger myelinated fibers with the classic peripheral sensory abnormalities associated with peripheral neuropathy. The use of corpus cavernosum electromyography, while controversial, may provide some evidence for early peripheral neuropathy affecting diabetic men [82]. Diabetic men are also at high risk for associated conditions that increase risk for ED. These include hypercholesterolemia, hypercoagulability, hypertension, and cardiac disease [83-86]. Each of these conditions increases the risk of microvascular and major vessel vascular disease inhibiting endothelial, smooth muscle function, and vascular flow [87-89]. Because diabetes is the most common single cause of ED, all men who present with newly diagnosed ED should be evaluated for undiagnosed dia betes [73]. A strong family history of diabetes or history of associated symptoms of diabetes should be elicited. Laboratory studies should include random blood sugar and a glycosylated hemoglobin to identify diabetes and to assess control if diabetes has been previously diagnosed [77]. Since diabetes is associated with a risk of hypogonadism, a serum testosterone should also be evaluated routinely. Initial improvements in diabetic control should be initiated to optimize treatment outcomes. While few patients will realize restored erections from diabetes control alone, improvement in overall health status may improve patients sexual response and response to other treatment. A goal-oriented approach to patients with erectile dysfunction caused by diabetes is essential. Treatment with the most conservative method for restoration of erections will provide the best clinical outcome. Experimental treatment with aldose reductase inhibiting medications for patients with significant peripheral neuropathy have demonstrated some improvement in erectile dysfunction as well as restoration of peripheral nerve function. A number of these agents continue in clinical studies but have not yet been approved for clinical use. Most available treatment modalities for impotence, such as oral medications, intracavernosal injections, vaccum erection device and prosthetic surgery can be applied to the treatment of diabetic impotent patients.

The pathophysiology of erectile dysfunction in diabetics is dependent upon neuropathy, microangiopathy and generalized vascular disease [77]. Specifically, animal studies have provided evidence that diabetes produces endothelial cell dysfunction that leads to smooth muscle dysfunction in the microvascular beds in the penis producing ED. A number of animal studies have confirmed this association [78-80]. Diabetic changes are not isolated to microvascular abnormalities, but also include significant peripheral neuropathy in the

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IV. HYPERCHOLESTEROLEMIA Atherosclerosis is a significant risk factor for erectile dysfunction. It has been estimated that atherosclerotic vascular disease is an associated risk factor for as many as half of all men over 50 with ED[90]. Because the penis is a high flow system during erectile function, ED may be an early sign of atherosclerotic disease, which subsequently may appear as cardiac disease or peripheral vascular disease. Thus, systemic conditions such as atherosclerosis, myocardial infarction, hypertension, peripheral vascular disease, may be precursors or sequelae of erectile dysfunction in the aging male. Hypercholesterolemia as well as hypertriglyceridemia are clearly important risk factors for atherosclerosis [91]. These risk factors are enhanced by the presence of other risk factors such as smoking [92]. There is little question that hypercholesterolemia is associated with ischemic heart disease and increased incidence of vascu lar dysfunction and heart disease with increasing age. In the multiple risk factor intervention trial (MRFIT), men were investigated with elevated cholesterols for risk of ischemic heart disease [93]. Hypercholesterolemia, hyperlipidemia and other risk factors for vascular disease are closely asso ciated with erectile dysfunction. These risk fac tors from hypercholesterolemia are associated with both atherosclerosis in the hypogastric cavernous arterial bed as well as endothelial and smooth muscle dysfunction in the corpus caver nosum. Studies reporting an association of corporal venous leakage and veno-occlusive dysfunction are the clinical end result of this smooth muscle dysfunction. Animal studies have clearly documented the impairment of endothelium dependent vascular relaxation in a variety of animal models and vascular environments. Studies by Kim et al demonstrated that cavernosal hyperlipidemia produces not only endothelial changes but also smooth muscle dysfunction and structural destruction of endothelial cells in the corpus cavernosum [94]. These same authors documented reversal of these changes with the addition of LArginine, the nitric oxide precursor [95]. Thorne and colleagues [96] have used L-Arginine clinically to improve nitric oxide production in smooth muscle relaxation in patients with clinical atheros-

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clerosis. It appears that high cholesterol produces not only endothelial cell dysfunction but smooth muscle dysfunction and a net decrease in production and effectiveness of the neurotransmitter nitric oxide. In animal modes, these effects can be ameliorated by reversal of serum cholesterol levels, addition of dietary L-Arginine to increase nitric oxide precursor, and addition of antioxidants such as vitamin C and vitamin E [97-100]. Treatment of erectile dysfunction associated with hypercholesterolemia begins with dietary counseling to restore normal weight and decrease intake of saturated fat and cholesterol [101]. Drug therapy, in addition to lifestyle changes such as diet, increased physical activity, and smoking cessation; however, many patients require drug therapy to normalize cholesterol and lipid levels [102]. Agents such as nicotinic acid, cholestyramine and HMG-CoA reductase inhibitors (vastatins) block the rate limiting step in cholesterol synthesis and increase LDLcatabolism, thus lowering LDL cholesterol levels. While these agents have not been studied in large trials of patients with erectile dysfunction, they have been widely and carefully studied in patients with atherosclerotic and cholesterol related cardiac disease with substantial improvement or stabilization of cardiac disease. The combination of a low cholesterol diet, lipid lowering agents other than clofibrate, and perhaps, the addition of dietary L-Arginine, vitamin C, or other anti-oxidants may improve erectile dysfunction in these patients [103].

V. OBESITY, RENAL DISEASE AND THYROID DISEASE 1. OBESITY Obese men who are otherwise healthy have been found to have low serum testosterone levels with a progressive fall in serum testoste rone [104]. Despite this low serum testosterone, obese men might not display clinical evidences of hypogonadism [105]. They have normal libido, potency, testicular size and spermatogenesis. This paradox is partially explained by the fin ding that most obese men have normal free tes tosterone (non-protein bound) levels. This is due to a decrease in the sex hormone binding globu-

lin (SHBG) which reduces the protein-bound testosterone. There are some men with marked obesity (> 250% of ideal body weight) that has subnormal free testosterone levels. Obese men have elevated estradiol and estrone levels [106]. The high estrogen levels may reflect the ability of the adipose tissue to convert androgens to estrogens. When these obese men lose weight and their adipose tissue, the abnormal androgen and estrogen levels revert to normal [107]. Serum gonadotropins are normal in obese men.

rapy. If exogenous testosterone fails to improve the dysfunction that is usually what occurs in this setting [118], then a vasculopathy and/or neuropathy as the etiology of the dysfunction should be addressed.

3. THYROID DISEASE

2. R ENAL DISEASE Chronic renal failure impairs sexual function in about 50% of the men[108] and hemodialysis does not seem to improve it. Men with renal fai lure have elevations of LH and FSH and some decrease in serum testosterone, hormone levels that are characteristic of a primary testicular dysfunction [109,110]. This is supported by the observation that hCG stimulation testing in these patients fails to elevate serum testosterone levels [111]. Elevated prolactin levels may also be seen in men with chronic renal failure [112,113], although the impact of this endocrinopathy in the dysfunction seen in these patients is unclear. However, renal failure patients may also have accelerated changes in their vascular system and an autonomic neuropathy, two non-endo crine causes of erectile dysfunction. Vascular testing demonstrate cavernous artery occlusive disease in 78% and corporeal veno-occlusive dysfunction in 90% of patients with chronic renal failure [114]. In addition, these patients have a lot of psychological issues regarding their disease and the many medications they have to take for hypertension etc. that may affect sexual function [115]. In some patients, renal transplantation may reverse the low serum testosterone levels seen pretransplant and improve sexual function in about 80% of patients [116]. Dialysis rarely improves the sexual dysfunction [117]. If potency does not improve posttransplantation, the etiology of the dysfunction is most likely non-endocrine such as an abnormal vascular supply to the penis. Therefore, in patients with chronic renal failure, a lowered serum testosterone level may be the cause of the sexual dysfunction and these patients may be candidates for exogenous androgen the-

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Thyroxin can affect the male reproductive system. Increased thyroid hormone secretion has been associated with an increase in total testosterone but with normal unbound testosterone. This is due to the increase in the sex hormone binding globulin (SHBG) or as it is occasionally referred to as testosterone-estrogen binding globulin (TEBG) associated with hyperthyroidism. The increase in SHBG causes a relative decrease in the free testosterone levels which cause an elevation of serum LH (negative feedback) and further increase in serum testosterone and by peripheral conversion, an increase in serum estradiol. As a result of the increase in circulating estrogens, these men with hyperthyroidism may complain or present with gynecomastia, spider angiomas and a decrease in libido [119]. The libido does not respond to exogenous testosterone that may also make the gynecomastia worse. Treatment of the thyrotoxicosis reverses the symptoms and signs of the disorder. In hypothyroidism, LH and FSH are usually elevated, which is consistent with testicular resistance to gonadotropins. Serum testosterone and SHBG are usually decreased. Free testosterone has been reported to be either increased, decreased or normal. Potency is usually normal in hypothyroidism but erectile dysfunction and decrease in libido were reported in some men. If hypothyroid men complain of impotence, replacement with thyroxin rarely improves the potency [120].

VI. HYPERPROLACTINEMIA Hyperprolactinemia is a common endocrine cause of erectile dysfunction. Men with hyper prolactinemia tend to have reduced libido and have erectile dysfunction. Some of men with hyperprolactinemia have galactorrhea, which is important physical sign for this abnormality. Serum gonadotropins and testosterone are

usually decreased in men with hyperprolactinemia. Hyperprolactinemia can decrease gonadotropins [121] by inhibition of GnRH secretion, and larger nonfunctioning tumors cause hypogonadism by direct damage to the gonadotrophs. The abnormalities of testosterone metabolism have been reported in hyperprolactinemia[ 122]. Other mechanisms which are proposed to be responsible for diminishing erectile activity in hyperprolactinemia are direct suppression of the libido center or decreased relaxation of the corpus cavernosum through mechanisms that are independent of testosterone action [123].

B. CLINICAL MANIFESTATIONS AND DIAGNOSIS OF HYPOGONADISM

I. SYMPTOMS OF HYPOGONADISM 1. HYPOGONADISM IN THE RELATIVELY YOUNGER MEN The clinical manifestations of hypogonadism depends on the time of onset of hypogonadism. Prepubertal androgen deficiency is associated with small- sized testes and/or phallus, abnormality of secondary sex characteristcs, abnormal skeletal proportions with long legs, and infertility (Figure 2). Hypogonadism, which occur after puberty, often accompanies sexual dysfunction( i.e. decreased libido and increased erectile dysfunction), the changed body hair patterns, decreases in bone and muscle mass, and a loss of aggressive behaviour (Figure 3).

Men with acquired hypogonadotropic hypogonadism (i.e. pituitary tumor) commonly complain of decreased erectile function. Signs of this type of tumor include decreased facial hair, decreased muscle strength, central obesity, premature facial wrinkling and abnormal visual fields, the result of a mass lesion causing hypogonadism. These tumors commonly secrete prolactin and high serum prolactin levels can interfere with the reproductive axis at many levels. Prolactin also interferes with brain neurotransmission and may impair libido.

2. AGING AND HYPOGONADISM IN THE AGED MEN

Treatment of these pituitary tumors, if small (microadenomas), usually respond to dopamine agonist therapy. With large tumors (macroadenomas), the LH and FSH deficiency are not always restored to normal upon the dopamine agonist treatment even if the prolactin levels return to normal. In addition, prolactin may also have adverse effects on sexual function in men separate from that of testosterone suppression since treatment of these patients with exogenous testosterone does not always reverse erectile dysfunction until the prolactin levels have been returned to normal levels [124]. If medical therapy fails to control the effects of the tumor, transphenoidal adenectomy may be indicated. Depression and anxiety are common in men with pituitary secreting hyperprolactinomas independent of the lowered testosterone levels and may play a role in the decreased libido seen in these men [125].

Many of the clinical features, accompanying the aging proces in men, are reminescent of the symptomatology of hypogonadism: decrease of libido and sexual activity, decrease of signs of virilism such as decreased sexual pilosity or beard growth, decrease in muscle mass and strength, lack of energy, ostopenia, decrease of cognitive functions, irritability, excessive sweating with, occasionnally hot flushes, decrease of the feeling of general well-being (Table 1). Hence, it is tempting to attribute, at least part of these symptoms to an age associated decrease in testosterone levels. a) Sexual functions Coital frequency declines rapidly with age from, according to Masters, a mean maximal coital frequency of about 4 times a week at age 25 yrs, to once a week at age 50, 3 times a month at age 70 yrs and 1.7 times a month between age 75 and 79 yrs [127]. Moreover ED increases dramatically with age: rare before age 30 yrs, it is observed in 8

Besides an ademona, hyperprolactinemia may also be caused by certain drugs and is seen in some patients with chronic renal failure [126].

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Figure 2: Clinical manifestations of prepubertal androgen deficiency:

Figure 3: Clinical manifestations of postpubertal hypogonadism:

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determinant of free testosterone(FT) levels, gluteal fat and lean body mass affect the FT levels very little.

Table 1: Clinical manifestations which may be associated with hypogonadism in the aging male PSYCHOLOGICAL Lack of mental energy

The ratio of subcutaneous over visceral fat decreases significantly with age and this independently of body mass index. These data suggest that elderly men, similar to hypogonadal men, accumulate visceral fat preferentially. This fat accumulation is the major cause of insulin resis tance and the atherogenic lipid profile, this sug gests that obesity in elderly men is a more impor tant health hazard than in young men. It is probable that the atherogenic effect of androgen deficiency is largely mediated via this fat accumulation. Androgen substitution decreases abdominal fat mass and increases the insulin sensitivity [132,133]. As obesity is a cause of decreased free and total testosterone levels, it could be hypothesized that the decrease in testosterone levels in aging males is the consequence of the increase in fat mass. Multiple regression analysis showed however, that age and fat mass are independent determinants of free and total testosterone levels. Age is also accompanied by an important decrease of muscle mass and there exists a highly significant correlation between muscle mass and FT levels, which persits after correction for age; moreover testosterone supplementation increases muscle mass [133].

Decreased of cognitive functions Decrease of the feeling of general well-being. Irritability Inablity of concentration Depressive symptoms Nervousness PHYSICAL Generalized weakness Lack of physical energy Decrease in muscle mass and strength Ostopenia Gynecomastia Decreased body hair Abdominal obesity VASOMOTOR Excessive sweating Occasional hot flushes Insomnia Palpitation SEXUAL Decrease in sexual activity Loss of libido Erectile dysfunction

It is evident, however, that the changes in body composition in elderly men are not uniquely the consequence of the decreased FT levels but that other factors such as the somatopause and the decrease in physical activity are important codeterminants of these changes.

Lengthening of refractory period Less-well defined quality of orgasm Poor intensity of ejaculation Decrease in volume of ejaculate

Bone mass decreases with age in both males and females even if osteoporosis manifests itself at a later age in men than in women. There exists a negative correlation between bone mass and tes tosterone levels [134]. Senile hypogonadism is a risk factor for hip fractures, although instability, secondary to the reduction in muscle mass and strength, plays the major role.

% subjects age 50 yrs, 20 % at age 65 yrs, 40 % at age 70 yrs and ± 60 % in men over 70yrs old [128,129]. This might however be related to the aging process itself, as the hormonal differences lost their significance after correction for age. b) Body composition and others Aging is accompanied by a decrease of lean body mass (LBM) and an important increase in fat mass [130,131] and, although aging itself is an important determinant of body composition, plasma testosterone levels are negatively correlated to fat mass, independently of age. Moreover, it has been shown that the abdominal fat mass is the major

Aging is accompanied by a decrease in cognitive functions and androgen substitution improves spatial abilities and mathematical reasoning[135]. As far as memory is concerned, the age associated impairment is evident, but the role, if any, of sex hormones in the loss of memory is questionable.

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II. DIAGNOSIS OF HYPOGONADISM 1. THE HYPOTHALAMIC-PITUITARYGONADAL (HPG) AXIS An understanding of the HPG axis is essential for the proper hormonal evaluations and treatment of androgen in the male (Figure 4).

2. DIAGNOSIS OF HYPOGONADISM While hormonal status is usually evaluated by measurements of serum hormone levels, determi nation of total testosterone has been regarded as a universally accepted diagnostic method of serum hormonal level to date. However, there are increasing evidences that the serum concentration of total testosterone may not be an accurate marker for the levels that exert their action on target organs. Androgen deficiency can be better demonstrated by measuring bioavailable testosterone, i.e. free and albumin-bound fractions of circulating testosterone. Therefore, measuring total testosterone in aging men may not be adequate to determine whether they have testosterone deficiency because levels of circulating SHBG increase with age [136] and that measurement of bioavailable or free fractions of testosterone is needed to correctly diagnose hypogonadism in men over age 50. However, this approach may not be adequate in terms of cost effective diagnostic paradigm, and has not been used in a large populations of normal aging males as well as impotent men. To make accurate diagnosis of hypogonadism, dia gnostic criteria using bioavailable testosterone should be established in the future especially in the aging male. It has been suggested that measurement of testosterone is reserved to the patients with positive physical findings of hypogonadal symptoms. However, determination of total testosterone is strongly recommended for all patients with erectile dysfunction as the first line endocrine evaluation because libido which is the principal symptom of hypogonadism may be a nonspecific finding, and physical examinations is usually normal in postpubertal hypogonadism.

When patients have low or borderline testostero ne level, repeat measurement of testosterone is generally recommended because there is evidence that a substantial number of impotent patients found to have a low serum testosterone level at a first determination had a normal level when the test was repeated [15]. At this time, measurement of bioavailable fraction of serum testosterone, LH, and prolactin can be done to verify whether there is low testosterone and what its causes might be. Total testosterone and SHBG can be checked for evaluation of bioavailable testostero ne levels [137]. It should be realized that direct measurement of free testosterone by RIA using an testosterone analogue may give falsely low free testosterone levels[138], whereas the free androgen index (100T/SHBG) is relatively unreliable [139]. Measuring gonadotropin is necessary to avoid missing many states of compensated testicular failure in which the serum testosterone level is usually normal [140,141]. One more reason for measuring gonadotropin is to detect secondary hypogonadism, which requires specific diagnosis and treatment. It should be realized that in hypogonadism of the elderly males, plasma LH levels are often not increased. Single determination of LH is preferable in terms of cost effective approach. However, it has been suggested that measurement of both gonadotropins including FSH can be helpful in certain clinical situations. In the secondary hypogonadism where the serum LH and FSH levels are low or normal with concomitant low level of serum testosterone, the evaluation for identifying a cause of secondary hypogonadism should be mandatory including serum iron study, thyroid function tests, and an evaluation for pituitary macroadenoma.(Figure 5. Algorithm) The routine use of prolactin is less well defined because isolated hyperprolactinemia is rare and most patients with hyperprolactinemia have abnormally low testosterone levels. Patients who present the symptoms of hyperprolactinemia such as decreased libido and headache with depressed testosterone levels, are suggestive of prolactin abnormality.

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Figure 4: Hormonal control of testosterone secretion: The hypothalamic-pituitary-gonadal (HPG) axis consists of a closedloop feedback control mechanism. The hypothalamus is a pulse generator for the cyclic secretion of pituitary and gonadal hor mones. The portal vascular system provides a direct communication for pulsatile delivery of hypothalamic hormone to the pituitary gland, avoiding the systemic circulation delete. The function of GnRH is to stimulate the secretion of LH and FSH from the anterior pituitary. LH stimulate testosterone secretion while FSH stimulate Sertoli cell function with production of inhibin. Testosterone is a strong regulator of its own production through negative feedback mechanism on the HPG axis and inhibin is important in the feedback regulation of FSH.

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HISTORY AND PHYSICAL EXAMINATION

NORMAL

APPROPRIATE ENDOCRINE TESTING

POSITIVE FINDINGS

TESTOSTERONE PROLACTIN THYROID STUDY CORTISOL

TOTAL TESTOSTERONE

OTHER TESTS FOR IMPOTENCE

NORMAL

ABNORMAL OR BORDERLINE NORMAL

REPEAT TOTAL TESTOSTERONE,

NORMAL TESTOSTERONE

SHBG, LH, AND

PROLACTIN

LH ELEVATION

TESTOSTERONE TREATMENT

PROLACTIN

EVALUATION FOR

ELEVATION

HYPERPROLACTINEMIA

LH DECREASE OR NORMAL

TESTS FOR IDENTIFYING NO ENDOCRINE DISORDER

ETIOLOGIES OF SECONDARY HYPOGONADISM

(I.E. IRON STUDY, THYROID FUNCTION TESTS, G NRH S TIMULATION TEST)

ENDOCRINE RELATED DISORDER

SPECIFIC TREATMENT Figure 5: Basic diagnostic algorithm for hormonal evaluation in men

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C. TREATMENT

I. TESTOSTERONE EFFECTS ON THE BODILY SYSTEMS IN MALE Hypogonadism in men is associated with decrea sed bone mineral density and decreased muscle mass and androgen replacement certainly ame liorates these symptoms. Apart from its evident effects on libido, testosterone improves also cognitive functioning of men, notably of spatial abilities. Both testosterone levels and bone mineral density decline with aging. Indices of bone mass have been and plasma testosterone levels have been found to be positively correlated. Hypogonadism is a risk factor in hip fracture in aging men. The first data on the effects of androgen administration to aging men on bone mass are certainly encouraging [142]. The cause of the decrease in muscle mass and strength in elder men is probably multifactorial, with a decrease in physical activity and a decrease in growth hormone as contributing factors. The first studies of the effects of androgens on muscle mass and/or strength are encouraging particularly since the administration of androgens may also decrease fat mass. There is male predominance in cardiovascular morbidity/mortality compared to premenopausal women which is generally attributed to the effects of androgens on lipid metabolism as one of the risk factors in cardiovascular disease. But it has been found that men suffering from cardiovascu lar disease have lower-than-normal androgen levels. The explanation could possibly lie in the so-called syndrome X, the association that has been found between visceral obesity, hyperlipidemia, hypertension and cardiovascular disease and non-insulin dependent diabetes mellitus. Men with a large degree of visceral obesity tend to have low androgen levels. So, in reality, it could rather be the lowered androgen status, which explains the higher cardiovascular disease / mortality rate in middle aged men [143]. There are some reports now that androgen administration indeed decreases visceral obesity [144]. Prescribing androgens to aging men is considered a responsible decision by most physicians. Most

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experts agree that in cases of evident hypogonadism in the aging male, testosterone replacement is as much warranted as in younger men. In all likelihood not only libido will improve but also bone mineral density and muscle mass therewith helping the locomotion of the aging male. Side effects are acceptable [145]. So far there is no solid evidence that there is a relationship bet ween circulating androgens and prostate disease [146]. This notwithstanding, androgen administration to men above 50 years requires careful monitoring of the prostate. Nevertheless, epidemiological studies show that hypogonadal men are at higher risk of cardiovascular incidents than normal men and there exists generally an inverse correlation between testosterone levels and the atherogenic lipid profile, atheromatosis [147,148] or the degree of coronary artery stenosis [149], whereas androgens supple mentation within the physiological range, nor malizes the lipid profile, probably via increasing insulin sensitivity and decreases Lp(a) levels [150], a well known risk factor for atheromathosis. Notwithstanding the apparently favorable effects on the lipid profile and atherogenesis, the testosteronemia is not correlated with the risk of cardiovascular mortality [151,152], suggesting that besides the effects on the lipid profile, testosterone has direct unfavorable effects on the blood vessels [153,154]. Moreover, testosterone has complex effects on both coagulation and fibrinolysis. It is, finally, evident, that supraphysiological levels of testosterone, non aromatizable anabolic steroids or alpha alkylated androgens are clearly atherogenic and often cause cardiovascular accidents [155].

II. TESTOSTERONE TREATMENT IN IMPOTENT PATIENT 1. MECHANISM OF HYPOGONADISM IN THE PATIENTS REFERRED FOR IMPOTENCE In 155 impotent patients with total serum testosterone < 300 ng/dl coming from 5 different studies [12-14,16,18], serum LH was low or normal in 98 (hypogonadotropic hypogonadism) and it was elevated in 57 (peripheral hypogonadism). The most frequent identified causes were Leydig cell failure, and, in a minority of the cases, hyperpro-

lactinemia or hemochromatosis. In many cases no organic cause was found. For example in the 8 cases with markedly decreased serum LH (< 2.5 mIU/ml) of Buvat and Lemaire [18], 3 times the hypogonadism resulted from a pituitary adenoma, but in the 5 other cases it seemed to result from a functional hypothalamic abnormality. Such cases, in whom clomifene citrate was able to increase serum testosterone to normal, have also been reported by Guay et al [156]. They could result from psychosomatic mechanisms like stress and depression that are often present in impotent patients and can induce a mild hypogonadotropic hypogonadism [157,158]. The reduction in sexual activity could also play a role in the decreased testosterone levels of the impotent patients since several studies have observed an increase in testosterone secretion following sexual activity in men [159-162]. Lastly the variability of serum testosterone could be responsible for some false hypogonadism. Indeed 6 of the 22 impotent patients of Maatman and Montague [15] who were found a low serum testosterone level at a first determination had a normal level when the test was repeated. The same was observed by Buvat and Lemaire in 39 of their 98 cases, thus in 35% of the cases of these 2 series.

also physical capacity. Also they may experience various symptoms related to hypogonadism; such as nervousness, depression, impaired memory, inability to concentrate, easy fatigability, insomnia, hot flashes, periodic sweating, reduction of muscle mass and power, aching bones, and sexual dysfunction. Treatment of hypogonadism in the aging male has a special clinical value. In addi tion to sexual function, testosterone treatment produce numerous beneficial effects on whole body systems including body composition and sense of well being. Therefore, physicians are encouraged to prescribe testosterone preparations in the older patients with hypogonadism. 1) Elderly men with clearly decreased plasma tes tosterone levels:

2. C ANDIDATES FOR TESTOSTERONE TREATMENT a) Relatively young patients with erectile dys function Impotent patients either with low level of testos terone or borderline normal level can be candi dates for the testosterone treatment. With respect to exact serum level of testosterone, there is a problem with establishing a universal lower limit for normal serum testosterone. Serum testosterone levels vary based upon time of day that the sample is obtained, method of preparation of the sample and the antibody utilized in the RIA assay. These variations make it impossible to accurately establish a universal lower limit for normal testosterone level.

Age-related decreases in androgen level vary widely between the individuals. The favorable effects of hormonal replacement therapy can be expected in men with clearly decreased serum level of testosterone [163]. The reported proportion of the population who are considered hypogonadal differs between several studies and depends on how the term hypogonadism is defined. The proportion of the patients who fit these criteria was intensively discussed on chapter A-II. “Hypogonadism in aging male and its prevalence ”. The criteria of the serum levels of testosterone for hypogonadism in the aging male might be different from the reference values of young men. Empirical criteria of hypogonadism in which testosterone supplementation might produce beneficial effects in the aged men would be higher than that of young men. 2) Elderly men with symptoms that are associated with hypogonadism, but normal testosterone levels and those with marginally lowered testos terone levels: Testosterone supplementation might be considered in these situations, although this has been debated. The rationale supporting its use in such patients is as follows:

b) Elderly men with hypogonadism

• Elderly men with symptoms but plasma testos terone levels in the normal range:

High prevalence of hypogonadism and sexual dysfunction is observed in men over age of 50. Impotent patients with hypogonadism may experience a decline in not only sexual function but

Frequently, men are encountered who do not meet the criteria for diagnosis of hypogonadism by plasma testosterone determinations, but who respond to testosterone treatment with improve-

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ments in physiological and biochemical parameters. The reasons for this have not yet been fully elucidated, but the explanation may be similar to that for men with marginally lowered plasma testosterone levels (see below).

those with normal testosterone levels, and what effects in target tissues are achieved by increasing plasma testosterone levels in older men with mild degrees of androgen insensitivity.

3. EFFECTS OF TESTOSTERONE ON SEXUAL FUNCTION

• Elderly men with marginally lowered plasma testosterone levels:

a) Effects of testosterone treatment on the sexual function of the patients with hypogonadism primarily referred for hypogonadism who are usually relatively young:

There is increasing evidence that men in this category respond to testosterone treatment [164]. The rationale for supporting hormonal treatment in these men is that the plasma level of testosterone does not reflect the intensity of androgenic effects in target tissues. Moreover, despite plasma testosterone being in the normal range, its effects in target tissues may not be adequate. In such situations, it is possible that testosterone treatment may produce desirable effects, the rationale for which includes the following: ➦ Classical parameters such as the plasma testos terone level do not always accurately detect hypogonadism. Therefore, a man with a total testosterone level in the normal range may still be considered to have hypogonadism in terms of androgen actions in the target tissues. ➦ Since the definition of hypogonadism is not well established, clinicians may miss the proportion of the population in whom testosterone treatment may be of benefit. There is increasing evidence that testosterone supplementation in aging men has a great chance of improving age-related symptoms, especially in the hypogonadal state, and this may be particularly relevant to men with borderline biochemical abnormalities [165]. ➦ There is evidence in animal studies that the sensitivity to androgens may be affected, decreasing the effect of testosterone in target tissues [166,167].

Many studies with a control group receiving a placebo have shown that in such men testosterone constantly and significantly increases sexual interest and arousal, the frequency of sexual acts, and nocturnal and morning erections [24,25,33,168-172]. Conversely no study was able to objectively demonstrate an improvement of coital erections, a concept that is methodologically more difficult to prove. The effect of testosterone on sexual function appear to be clearer in the patients with more severe hypogonadism. b) Effects of testosterone treatment in impotent patients with hypogonadism primarily referred for impotence: These effects are markedly less clear-cut and constant than in the young patients primarily referred for hypogonadism. On the other hand very few controlled studies were done in hypogonadal men referred for impotence. 1) Marked hypogonadism Six studies reported on the results of androgen therapy in men referred for impotence and in whom serum testosterone was found consistently < 300 ng/dl or 11.5 nmol/l [14,16,18,173-175]. Several modalities of androgen therapy had been used, including injections of testosterone esters or in one study of chorionic gonadotropins (which stimulate testosterone secretion by the Leydig cells) when serum LH was not elevated [18], and oral administration of testosterone undecanoate or in one study of methyl-testosterone [173]. No study was placebo controlled. The total number of treated patients was 162. Only 60 of the 162 (37%) had definite erections (Table 2). Sexual interest was improved in some additional cases without simultaneous improvement of erections. For example, 5 of the 23 patients of Morales et al [175] had improved libido in addition to the 10 improved in both the erections and the sexual

From these observations, it might be proposed that even though plasma level of testosterone is not in the abnormal range, hypogonadism may still exist. In view of all these situations in which the plasma level of testosterone may not accurately reflect androgen actions in the body, it is evident that elderly men with testosterone levels in the normal range could be carefully considered for hormone supplementation. Questions that need to be answered in such cases are whether exogenous testosterone produces down-regulation of androgen receptors in 224

Table 2: Positive effect of androgen therapy in 162 men referred for erectile dysfunction AUTHORS

NO. SUBJECTS

TYPE OFANDROGEN

NO. OF SUBJECTS IMPROVED (%)

Keogh et al

22

T pellets

11 (50%)

Kropman et al Morales et al (1994)

15 27

NA Methyltestosterone

2 (13%) 2 (7%)

Morales et al (1997)

23

T Undecanoate

14 (61%)

Rakic et al Buvat and Lemaire

31 44

T propionate HCG, T Undecanoate

15 (48%) 16 (36%)

Total

162

60 (37%)

T: Testosterone HCG : Human Chorionic Gonadotropin

interest. Guay et al [176] also reported a placebocontrolled trial of clomifene citrate in 17 patients with impotence and functional hypogonadotropic hypogonadism. They found that nocturnal penile tumescence and rigidity testing, as well as the number of intercourse and the sexual satisfaction index significantly increased on clomifene compared to placebo in the younger subgroup. 2) Mild hypogonadism: Nankin et al [177] found that testosterone cypio nate had significant, although modest, effects on the sexual function of impotent men with serum testosterone levels within the range of 300 to 400 ng/dl. Conversely, using chorionic gonadotropins, or testosterone undecanoate when the serum LH level was high, Buvat et al [19] were able to definitely improve the erectile function of only 1 out of 21 impotent men with decreased free testosterone and normal total serum testosterone and 2 of 19 impotent men with decreased non SHBG-bound testosterone. Reason for this low effectiveness of testosterone treatment in the impotent men with mild hypogo nadism: Young hypogonadal men where testosterone treatment produce significant effects on sexual function, are rarely referred for impotence since their hypogonadism was diagnosed and treated from puberty. The lesser correlation between testosterone and sexual behavior in the often older patients referred for erectile dysfunction could result from the fact that sexual behavior progressively becomes less dependant on hormones in men, like in animals, in proportion to time of exposure to androgens and to previous sexual experience.

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Moreover, in some men with erectile impotence, low testosterone could be more a consequence of impotence rather than its cause. As previously discussed, low testosterone could result from reduction in sexual activity, stress and depression, all of which can inhibit testosterone secretion [158]. Lastly low testosterone is often only one of several consequences of aging, supported by the high rate of associated other organic abnormalities in the series of 60 impotent patients with hypogonadism thoroughly investigated by Buvat and Lemaire [18]: 25 (41,6%) could be classified as vasculogenic according to significant arterial abnormalities in 17, a pattern of veno-occlusive dysfunction at pharmaco-cavernosometry in 8, while 4 had in addition significant neurological abnormalities. Such multifactorial cases were also reported by Kropman et al [16]. 3) Effects of testosterone treatment in the impotent patients with normal testosterone levels: Although testosterone treatment has been widely used for decades in eugonadal impotent men, very few studies have compared its effects to those of a placebo according to double-blind designs. Benkert et al [178] did not find any superiority of testosterone undecanoate over placebo in such impotent men. However, serum testosterone could have not been really increased because of the feedback control, operational in these men. Conversely, Buvat et al[38] found a borderline significant superiority of injections of chorionic gonadotropins (2 x 5000 IU per week) over placebo in increasing the number of satisfying intercourse of eugonadal males with erectile impotence or low sexual desire. In addition, Carani et al [24] observed a modest but

significant increase in the extent and duration of the nocturnal penile rigidity of eugonadal impotent men following injection of supraphysiological doses of testosterone enanthate. O’Carroll and Bancroft [37] also reported on a significant but modest increase in sexual interest following testosterone treatment in males with low sexual interest and erectile dysfunction, but this improvement did not result in an increase in the number of sexual intercourse. In a single blind study comparing injections of high doses of testosterone with a placebo in normal young males, Anderson et al [36] also observed a significant increase in sexual interest and arousal without subsequent increase in the number of intercourse. Lastly Moss et al [179] reported on a significant increase in the number of sexual intercourse and orgasms, and in the sexual satisfaction, in male anabolic steroid abusers compared with other athletes not using steroids. These data are consistent with a modest stimula tory effect of increasing the serum testosterone level with testosterone injections upon sexual interest of the eugonadal men, including those with low sexual interest and perhaps erectile dysfunction. But this effect is too small to have a therapeutic interest, especially in erectile dysfunction

III. AVAILABLE PREPARATION OF TESTOSTERONE

1) mimic diurnal patterns of endogenous hormone secretion, 2) produce physiologic levels of not only testosterone but also its metabolites of dihydrotestosterone (DHT) and estradiol (E2), 3) should be well tolerated, comfortable, convenient and cost effective. Agents available currently include oral, sublingual, implantable testosterone pellets, intramuscular, and transdermal agents (Table 3). Table 3 : Available testosterone preparations PREPARATION

USUAL DOSAGE

ORAL Methyl Testosterone Fluoxymesterone

10 –15 mg daily 5 mg 1-4 times daily

Testosterone undecanoate

120-240 mg daily

PARENTERAL Testosterone cypionate Testosterone enanthate

200 mg Q 2 wk 200 mg Q 2 wk

TRANSDERMAL Androderm

1 - 2 patch daily

Testoderm TTS Testoderm (Scrotal)

1 patch daily 1 patch daily

Oral agents for testosterone replacement are clearly convenient and comfortably used. Oral testosterone, however, is rapidly absorbed from the GI tract and circulated through the portal blood [181]. Because of this portal circulation and rapid hepatic metabolism, only a small volume of testostero ne is circulated and only serum testosterone metabolites are raised. Most importantly, these agents have been reported to produce significant long-term hepatic toxicity. Oral testosterone does not reproduce the circadian pattern of testosterone production of the testes nor does it achieve normal physiologic levels of dihydrotestosterone or estradiol. As to oral preparations, only testosteroneundecanote is orally active, due to its partial absorption via the lymph, thus escaping first pass hepatic inactivation. Testosterone undecanoate is available in areas other than the US [175]. The usual dose is 120-240 mg/d dived over 2 of 3 doses. Absorption and plasma levels achieved are rather variable but others reported that it restores

Testosterone has been used to forestall the effects of aging in middle-age men for many years. Brown-Sequard reported in 1889 that a self-administered watery testicular extract improved his work capacity and overall vigor. Testosterone, however, was not isolated as a substance until the mid-1930’s, but since that time attempts have been made to physiologically replace testosterone and raise testosterone levels to normal using exogenous testosterone and its metabolites. These agents are also used in excessively high doses to improve athletic performance and strength [180]. Because androgen replacement therapy is necessarily of long duration and testosterone’s serum halflife is short, pharmacologic preparations have been developed to provide sustained testosterone blood levels and prolong androgenic activity. The ideal testosterone replacement agent should:

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serum testosterone levels and improves libido in hypogonadal men. Plasma estradiol levels also rise to physiologic levels with oral testosterone undecanoate treatment [175]. The most effective of these oral agents are the 17 alpha alkylated testosterones such as methyl testosterone. These may be administered either orally or bucally. Because of their high cost, minimal potency, and risk of hepatotoxicity, these kinds of oral androgens should not be used for androgen replacement in hypogonadal men.

tosterone levels in the eugonadal range for approximately 3 weeks. 400 mg doses, while obtaining higher peak values, will not maintain eugonadal levels beyond the 3 week limit. These agents in hypogonadal men produce an improvement in libido, sexual function, potency, energy level, and mood if these abnormalities are caused by androgen depletion. Reports of increased sexual aggressiveness and overall aggressive behavior during peak levels of injectable testosterone levels have been reported [182]. Careful counseling about these mood and behavioral changes in patients undergoing injectable testosterone therapy are essential. These adverse effects are, however, rare and testosterone enanthate is the most widely used agent for exogenous testosterone replacement in the US. It is cost effective and convenient.

Parenteral preparations for intramuscular testosterone replacement are clearly effective in increasing serum testosterone levels, but produce significant elevations in serum testosterone levels immediately after administration and a very low nadir before repeat injection. Intramuscular androgens do not provide the normal circadian pattern of testosterone and the injections are somewhat uncomfortable [182]. Similarly, while restoring serum DHT levels, estradiol levels may be excessive in patients with high testosterone levels after injection. Intramuscular 17 beta hydroxyl esters of testosterone are widely used. These esters of testosterone lack inherent androgenic activity and must be hydrolyzed to testosterone before they become active. Parenteral testosterone is usually administered in an oil-based vehicle such has cottonseed or sesame oil. The 17 beta hydroxyl esters of testosterone include the short acting testosterone propionate, and longer acting testosterone enanthate and cypionate. Because of the short activity of testosterone propionate, it is impractical to use as it must be injected every second day to maintain serum testosterone levels. In hypogonadal men, however, testosterone enanthate and cypionate may be administered every 2-3 weeks to maintain normal average testosterone levels. There are, however, surges in testosterone from 12 days following administration with supraphysiologic serum levels as high as 1400 ng/dl which then decline over 14-21 days reaching a nadir in approximately 21 days. Because of these significant peaks and valleys in serum testosterone, patients may have mood swings and significant changes in sexual function. Long acting parenteral testosterone may be administered in 200, 300, or 400 mg every 2-4 weeks. 200 mg injections maintain normal testosterone levels for approximately two weeks while 300 mg levels will maintain tes-

However, there is good evidence that injectable testosterone preparations induce plasma levels of testosterone, which are supraphysiological, and may be a cause of important side effects such as an atherogenic lipid profile, insulin resistance, polycythemia, sleep apnea, fluid retention, hypertension. Furthermore, supraphysiologic testoste rone levels with testosterone result in aromatiza tion to estradiol or its esters which may produce gynecomastia or erectile dysfunction. These side effects are most pronounced with supraphysiologic doses in eugonadal men taking androgen supplements. Hence it is important when administering testosterone to avoid even transient supraphysiological levels. As a result of these concerns, transdermal patches and oral undecanoate form of testosterone, notwithstanding their high cost, will probably become the treatment of choice because they avoid supra-physiologic levels and restore the normal diurnal testosterone pattern. They have, moreover, the advantage that, when side effects occur, the patches can be immediately removed. Transdermal testosterone is the newest approved replacement modality and is currently available as a scrotal or non-scrotal patch [172, 183]. Transdermal administration utilizes unmodified testosterone and is an alternative to intramuscular or oral medications. These transdermal patch systems provide normal testosterone levels with diurnal variations in a physiologic fashion when the patches are applied prior to bedtime. Peak testos-

227

terones are achieved in the early morning with a nadir prior to bedtime. While the scrotal patch (Testoderm®) requires scrotal shaving weekly and increases DHT levels beyond the normal range, normal physiologic serum testosterone ranges can be obtained. The non-scrotal transdermal patch (Androderm®), however, also maintains a diurnal serum concentration curve with normal testosterone levels and normal estradiol and dihydrotestosterone levels. Because the testosterone levels do not increase beyond normal as with intramuscular testosterone, the mood and aggressiveness occasionally occurring with intramuscular testosterone should not be seen with transdermal preparations. While long-term studies are still unavailable on these issues, a smoother more natural serum testosterone level can be obtained with these preparations. Clearly, transdermal systems are of higher cost and in some patients inappropriate because of compliance and motivation. Clinical studies with transdermal preparations have, however, demonstrated improved sexual function, libido, and nocturnal penile tumescence (NPT) response, with normal hematocrit, lipid, and PSA levels. Local side effects of dermatitis make these agents inappropriate for some men.

will focus only on the adult male treated with parenteral or transdermal testosterone and not with any oral androgen preparations. Testosterone therapy in adult men can cause an increase in red blood cell production, stimulate prostate growth, exacerbate sleep apnea, alter hepatic function and induce gynecomastia and acne.

1. LIPID PROFILE There is no strong supporting data that the major serum cholesterol profiles are adversely affected by exogenous androgen treatment [51,184]. This is most likely mediated through the androgen effects upon serum lipoproteins but other factors such as vascular reactivity may also play a role. There is limited long term data in man but all available data demonstrate little or no adverse effect of androgen replacement upon serum cholesterol levels in aged men. All studies reported to date demonstrate either no change or even a decrease in both total cholesterol and low-density lipoproteins. However, androgens was reported to be associated with decreases in HDL cholesterol and apolipoprotein A-I levels and reduced LDL cholesterol and apolipoprotein B levels

Administration of testosterone by long acting implantable tablets has been investigated in Europe [180]. These subcutaneous capsules are fused pellets of unmodified testosterone and can be implanted every 4-6 months. Because these pellets require percutaneous trochar or minor surgical administration, they are infrequently used. Further development of these pellets to decrease invasiveness of administration may lead to their use for long term therapy.

2. ERYTHROPOIESIS Androgens are known to stimulate an increase in the hematocrit and hemoglobin levels [185] due to stimulation of erythropoietin production [186]. The increase in erythropoiesis in these aged patients may be exacerbated by sleep apnea and an elevated body mass which may necessitate changes in the way the testosterone is administered. It can be minimized by using lower and more frequent dosing, such as with transdermal preparations. Polycythemia may increase blood viscosity and lead to diminished cerebral blood flow with the possibility of a cerebrovascular event [187]. Some patients may even require phlebotomy to reduce the erythrocytosis [188].

IV. COMPLICATION OF TESTOSTERONE SUPPLEMENTATION The risks of this therapy depends on the age and medical condition of the patient and the type of testosterone preparation used. Not all androgens are metabolized the same and each may have dif ferent side effects. For example, testosterone can be metabolized to estrogen whereas other preparations of DHT that do not have this capability will not have any feminizing effects. This summary

228

3. SLEEP APNEA Sleep apnea can be exacerbated by exogenous testosterone therapy [189] and, with the additional possibility of erythropoiesis, decreased cerebral blood flow may result. The mechanism of this disordered breathing could be an increased sensitivity to hypoxia.

4. PROSTATE Both benign prostatic hyperplasia and prostate cancer are highly prevalent diseases in older men. The prostate is dependent upon androgens for normal growth and function. Prostate volume decreases with castration and is restored by androgen replacement. In addition, castration has a temporary palliative effect upon prostate cancer. The limited studies performed to date have not demonstrated any significant adverse effect of androgen replacement therapy upon the pros tates of older men. However, there may be possibilities that androgens play a role in promoting prostatic growth and, therefore, the treatment of the aging male with exogenous androgens remains a concern vis a vis the development of BPH and prostate cancer. The presence of a clinical prosta tic carcinoma is an aboslute contraindication for androgen supplementation and should be exclu ded by rectal examination and PSA measure ment, eventually complemented by rectal echo graphy. While there are two studies in the literature that demonstrate an increase in PSA with androgen therapy [164,190], there are about a dozen or so studies that do not demonstrate any increase in PSA. However, caution must be exercised in the aging male and a baseline elevation in PSA or elevation in PSA following therapy may indicate an underlying malignancy that needs to be eva luated [191,192].

5. HEPATOTOXICITY Liver damage and occasionally hepatomas have been associated with the use of oral 17 alphaalkylated androgens but not parenteral or transdermal preparations [193]. The main effect on hepatic function occurs at the site of the transport of metabolites from the hepatocyte to the bile. Underlying hepatic disease may reduce the metabolism of estrogens formed from parenteral androgens and lead to gynecomastia. The elevation in the liver enzymes are reversible once the androgens are stopped [194].

tered. Since estrogens are formed from testosterone peripherally in the adipose tissue, it is metabolized in the liver. A normally functioning liver is capable of metabolizing the estrogen unless there is preexisting liver damage. Therefore, the presence of gynecomastia in an adult following testosterone supplementation may be an indicator of underlying hepatic disease [195].

7. ACNE The development of acne with exogenous testosterone therapy is reversible once the testosterone injections are stopped [194].

V. CLINICAL RECOMMENDATIONS FOR TESTOSTERONE SUPPLEMENTATION The discussion will focuses mainly on hypogona dism in aging male as guidelines for impotent patients are similar to those of aging male.

1. PROPOSED CANDIDATE FOR SUPPLEMENTATION It is evident that men with subnormal or borderline normal testosterone levels are candidates for androgen substitution. Among the clinical signs, decrease in muscle mass and strength, decrease in bone mass and increased abdominal fat mass are most easily identified, whereas clinical symptoms such as decrease in libido, memory loss or decrease in general well being are more difficult to objectivate. The final decision whether to treat or not will depend upon the balance between expected benefits and possible serious side effects. If testosterone therapy is clearly indicated, it can be given to enhance the quality of life of patients, even if they are of advanced age [141].

2. EXPECTED OUTCOME Recent studies have shown that testosterone supplementation in aging men provides beneficial effects on bone density and bone turnover, muscle mass and strength, and body composition, as well as possibly enhancing their sense of well being, energy level, sexual function and libido [51,196].

6. GYNECOMASTIA While common in children after testosterone supplementation, gynecomastia is rare in adults unless extremely large doses of testosterone are adminis -

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Even though older men may have successful erections, their sexual desire, mood and general behavior may be impaired, and these aspects of sexual function can be expected to improve with testosterone supplementation. Furthermore, the intensity of orgasms and ejaculations might also be expected to improve [165].

b) Plasma hormone determinations Total testosterone has been regarded as accepted single determinant of serum hormonal level. When patients are found to have a testosterone level which is low or at the lower borderline of normal range, repeat testosterone measurement is generally recommended. At this time measurement of bioavailable fraction of serum testosterone, LH, and prolactin can be done to clarify the level of screening testosterone. In secondary hypogonadism where the serum LH level is low or normal with concomitant low level of serum testosterone, further the evaluation for identifying a cause of hypogonadism is required.

3. GOAL OF TESTOSTERONE SUPPLEMENTATION

The goal of testosterone supplementation in the aging male is less well defined, but may be summarized as follows:

• Elderly men should benefit from the disappearance of symptoms related to hypogonadism with hormonal supplementation.

c) Prostate evaluation It is generally accepted that the most effective method for early detection of prostatic cancer is the combination of prostate-specific antigen (PSA) determination and digital rectal examination (DRE) [199]. However, in a study in which ultrasound-guided prostate needle biopsy was performed in 77 patients with low total or free testosterone levels but normal PSA levels (4 ng/ml or less) and DRE results, prostatic cancer was identified in 14% of the entire group and 29% of those older than 60 years [200]. Thus, the possible presence of prostatic cancer should still be borne in mind despite normal PSA and DRE findings. Furthermore, there is a possibility that exogenous androgen administration may aggravate the preexisting prostate cancer. Therefore, it has been recommended that TRUS (with or without biopsy of the prostate) is performed before starting hormonal therapy in the men over the age of 60. Since screening TRUS is unreliable, and random biopsy unproven, this practice cannot be enthusiastically embraced. Further information on prostatic assessment and hormonal treatment of men with low testosterone levels is required d) Other recommended tests Questionnaires are available for evaluating subjective symptom score for hypogonadism, the patient’s sense of well-being and sexual function in the aging male. In addition, physicians may measure the waist-hip ratio for the evaluation of body composition. Lipid profile including triglyceride, high density lipoprotein cholesterol (HDL-C), total cholesterol and liver function tests could be recommended to monitor risk to patients.

• Serum levels of testosterone and its metabolites, such as DHT and estradiol, should increase with exogenous testosterone supplementation. There is some debate over the target level of testosterone during supplementation. Weksler [197] advocates a serum level of between 240 and 460 ng/dl as a reasonable target, whereas others [198] have suggested the desired level is between 400 and 900 ng/dl.

• The hormonal deficiency in the aging male is partial, and most men maintain their secretory capacity to some extent. Ideal supplementation with exogenous testosterone will maintain preexisting testosterone secretion, and not suppress the hypothalamic-pituitary-gonadal axis. In the case of secondary hypogonadism caused by hypothalamic or pituitary dysfunction, the underlying disease should be treated before initiating hormonal supplementation.

4. ASSESSMENT AND DIAGNOSTIC TESTS a) Medical history, physical examination and blood tests A full medical history looking for the presence of diabetes mellitus, hypertension, smoking, endocrine disorders, heart disease, sleep-related apnea, and other medications should be undertaken when testosterone supplementation is considered. The physical examination and tests conducted prior to initiating testosterone therapy should include measurement of body weight, pulse rate, blood pressure, complete blood cell count, urine analysis, and blood chemistry analysis. The physical manifestations related androgen deficiency also should be assessed. 230

discontinuation of treatment. Any increase of PSA with more than 0.75 ng/ml in two consecutive controls requires further exploration, whereas an increase of the hematocrite over 50 % or unfavorable changes in the lipid profile requires a reduction of the substitutive dose or discontinuation of treatment. It is evident that androgen substitution should be continued lifelong, unless side effects appear or the patient is no longer concerned by the signs and symptoms of hypogonadism

5. F OLLOW-UP Periodic follow-up during supplementation is mandatory to detect adverse reaction related to treatment as early as possible. However, the interval of appropriate follow-up is not well defined. In his paper describing 10 years’ experience with administration of oral testosterone undecanoate, Gooren [201] followed his patients at 3-monthly intervals during the first year of treatment. After that, follow-up was performed every 6 months for the following 3 years. Other protocols[165] include a follow-up interval of 6 months for the first 2 years after initiating treatment. The first follow-up should take place within 3 months after initiating treatment, to evaluate whether the testosterone level is rising to the desired level, whether the patient has developed any adverse effects (e.g. elevation of PSAand acne), how the patient feels about testosterone supplementation, and how symptoms have improved with supplementation. At this time, physicians can measure serum PSA and testosterone levels, perform a physical examination including DRE, and ask the patient to fill out questionnaires, if required. Subsequent follow up will take place every 6 months for next 2 years to continuous monitoring of clinical symptoms and adverse effects of treatment. Laboratory tests consist of urinalysis and complete blood cell counts, as well as DRE and PSA for prostate evaluation. In addition, physicians may assess the patient’s liver function, blood glucose level and serum lipid profile. It is suggested that at least for 1. 5 to 2 years monitoring is needed to assess PSA Velocity (PSAV), a highly specific marker for the presence of prostate cancer, and that three PSA measurements might be optimal during this period to minimize shortterm within-individual variability between measurement[202]. Considering that occult prostate cancer can be missed in men with normal DRE findings and normal PSA levels, physicians should do everything possible to detect preclinical carcinoma of prostate. In this regard, measurement of PSAmust be recommended at 6 months interval of treatment, especially in men over the age of 40. After this period, annual follow up is recommended. When supplementation ceases less than 6 months after initiation of testosterone treatment, measurement of PSA is recommended even after

VI. RECOMMENDATIONS I. PATHOPHYSIOLOGY OF HYPOGONADISM The association between hypogonadism and erectile dysfunction is not clearly defined. There is a direct relationship between serum androgen levels and libido, but the association of androgens and erectile function is more complex. Nocturnal erections have been related to testosterone levels in several studies. On the other hand, erections induced by visual stimuli or fantasies, are only partly androgen-dependant. In addition to libido and erectile function, testosterone increases the ejaculate volume. The threshold value of serum testosterone in relation to sexual activity appears to be rather low. It is generally believed that the effects of testosterone on sexual function are adequate at the lower limits of the normal adult range. Serum testosterone levels decline with age. Similarly, prevalence of erectile dysfunction increases with age. Only those aged men with hypogonadism will potentially benefit from testosterone therapy. Metabolic conditions such as diabetes mellitus, hypercholesterolemia, obesity, renal and thyroid disease, and hyperprolactinemia may be prominent factors in sexual dysfunction.

II. SYMPTOMS OF HYPOGONADISM Clinical menifestations of hypogonadism differ according to the time of onset in life. Common symptoms and signs of hypogonadism include: asthenia,decrease of libido, sexual activity, reduced ejaculate volume, decrease in muscle mass and strength, osteopenia, decrease of cognitive functions, decrease of the feeling of general well-being.

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terone preparations are available. Testosterone replacement therapy should restore serum testosterone levels to normal. Close monitoring during the treatment should be mandatory to avoid potential complications of testosterone treatment. Monitoring should include: regular digital rectal examination, PSA, and Hb/Hct determinations especially in older man.

III. DIAGNOSIS OF HYPOGONADISM The most widely used biochemical parameter for the diagnosis of hypogonadism is a single morning total serum testosterone. However, there increasing evidence that androgen deficiency can be better demonstrated by measuring bioavailable testosterone, i.e. free and albumin-bound fractions of circulating testosterone. Therefore, it is essential that diagnostic criteria for bioavailable testosterone be established to improve the accuracy of the diagnosis of hypogonadism especially in the aging male. A morning baseline total testosterone should be measured. When the level of total serum testosterone is low or borderline, repeat measurement of total testosterone should be performed with assessment of bioavailable testosterone. SHBG, LH, and prolactin levels are determined to evaluate bioavailable testosterone, and status of hypothalamic-pituitary-gonadal axis. Criteria for routine measurement of prolactin are less well defined.

APPENDIX PRACTICAL CLINICAL RECOMMENDATIONS ON TESTOSTERONE SUPPLEMENTATION I. EVALUATION OF PATIENTS 1. Only men with low or borderline normal serum testosterone are suitable candidates for testosterone supplementation. 2. Careful history and physical examination should be performed before beginning testosterone replacement therapy. 3. The etiology of hypogonadism should be determined in all patients. 4. The patients following conditions are contraindicated from testosterone supplementation: a) Breast cancer and prostate cancer b) Polycythemia c) Severe cardiac insufficiency 5. Patients with the following conditions can be treated with testosterone replacement therapy and careful monitoring: Sleep apnea, low urinary tract symptoms (LUTS), hyperlipidemia, unsatisfactorily treated hyperprolactinemia. 6. A morning baseline total testosterone should be measured. When the level of total serum testosterone is low or borderline, repeat measurement of total testosterone should be performed with bioavailable testosterone. SHBG, LH, and prolactin

IV. TREATMENT Patients with either low or borderline normal levels are candidates for the testosterone replacement therapy as plasma level of testosterone does not necessarily reflect the intensity of androgenic effects in target tissues in men and patients with borderline testosterone values may benefit from this intervention. While many other etiologies of erectile dysfunction may play a role in the older patient, when erectile dysfunction, is accompanied by hypogonadism, testosterone replacement therapy is indicated. Androgens, also, have considerable effects not only on sexual function, but also on bone mass, muscle mass and strength and certain cognitive brain functions in men. Testosterone replacement therapy is contraindicated in men with prostate cancer, breast cancer, polycythemia, and severe cardiac insufficiency. Patients with the following conditions can be treated with testosterone replacement therapy and careful monitoring: sleep apnea, low urinary tract smyptoms (LUTS), hyperlipidemia, unsatisfactorily treated hyperprolactinemia. Parenteral testosterone esters, oral undecanoate form of testosterone, and transdermal testos-

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levels are determined to evaluate bioavailable testosterone and for status of hypothalamic-pituitary-gonadal axis. 7. Regular monitoring of patients with testosterone replacement therapy should include: digital rectal examination, PSA, Hb/Hct especially in older men. II. TESTOSTERONE PREPARATIONS 1. Parenteral testosterone esters, oral undecanoate form of testosterone, and transdermal testosterone preparations are available. 2. Testosterone replacement therapy should restore serum testosterone levels. III. RECOMMENDED FOLLOW-UP PROTOCOL 1. FIRST 1-3 MONTHS The first follow-up should evaluate the testosterone level, and whether any adverse effects, as well as the hypogonadal symptoms. At this time, physicians can measure serum testosterone levels, PSA and perform DRE.

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Committee 8

Oral Non-Endocrine Treatment

Chairman R. KRANE

Members G. BROCK, I. EARDLEY, J. FOURCROY, F. GIULIANO, A. H UTTER, C. TELOKEN, M. VICKERS

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CONTENTS

A. CENTRALLY ACTING DRUGS

NO DONORS

I. APOMORPHINE

L-ARGININE/YOHIMBINE

II. MELANOTAN II

D. POTENTIAL COMBINATION THERAPIES

B. CENTRALLY AND/OR PERIPHERALLY ACTING DRUGS

E. CONCLUSION I. TRAZODONE II. PHENTOLAMINE

REFERENCES

III. YOHIMBINE

ANNEX I C. PERIPHERALLY ACTING DRUGS

ANNEX II

PDE INHIBITORS ANNEX III I. SILDENAFIL

ANNEX IV

II. IC 351

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Oral Non-Endocrine Treatment R. KRANE, G. BROCK, I. E ARDLEY, J. F OURCROY, F. GIULIANO, A. H UTTER, C. T ELOKEN, M. V ICKERS

rapid growth in basic scientific investigation related to the pathophysiology of erectile dysfunction that began in the early 1980’s and led to the finding that NO is the primary neurotransmitter required for the initiation of an erection. A review of our present knowledge of erectile physiology appears elsewhere in the text. Sildenafil and the other drugs reviewed in this chapter are products of this knowledge. A variety of neurotransmitters (both central and peripheral) have been elucidated and include VIP, NO, dopamine, serotonin (5-HT), oxytocin, ATP, norepinephrine and acetylcholine to name a few. Substances that can enhance or block these neurotransmitters may promote erectile initiation centrally or corporal smooth muscle relaxation peripherally. Centrally apomorphine, trazodone and melanotan-II have been used and studied in the treatment of ED. Peripherally sildenafil and other PDE-5 inhibitors, trazodone, phentolamine, yohimbine and arginine have also been shown to have erectogenic capabilities. These and other newer and more recently introduced drugs will be critically reviewed. We have chosen to discuss melanotan II in this chapter even though it has to date been administered subcutaneously for the treatment of ED. The reader should be aware that most of the placebo-controlled studies of oral agents have used the results of questionnaires (e.g. the IIEF) as the means of determining outcomes and benefits of the agent being tested. An improvement in one’s erection may not always translate to reproducible ability to perform sexual relations with an adequately rigid erection.

INTRODUCTION Although many oral remedies have been utilized for the treatment of erectile dysfunction, the approval by the U.S. Food and Drug Administration of sildenafil (Viagra®) marked the beginning of a new and exciting era in the treatment of this disorder. From the moment that sildenafil became commercially available, it became clear that not only would ED treatment be forever changed but also society’s ability to discuss sexual matters and disorders would never be the same. Almost daily in a newspaper, magazine or on television Viagra made news. Who would have thought that a Republican nominee for the Presidency of the United States would become a spokesman for erectile dysfunction? In addition to its cultural effects, Sildenafil has changed the way ED is treated. Clearly it has become the first line of therapy for ED. It has also for the most part, changed the focus of the primary ED doctor from the urologist to the primary care physician. It has also brought into question the role of the psychologist/sex therapist. If a patient fails Sildenafil treatment should he have a diagnostic evaluation or should he simply be considered to have an organic etiology and move on to the next therapy available? These and other related issues must be answered as a new therapeutic algorithm develops. In addition, unlike previous oral agents for ED, Sildenafil’s development is directly related to the

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Apomorphine can be administered via mucosal membranes and other possible routes are intranasal, sublingual, and rectal. Intranasal administration is quite effective, but the dose needed to achieve the same effect can be up to 10 times that of subcutaneous apomorphine. The latency of onset was substantially longer.

A. CENTRALLY ACTING DRUGS

I. APOMORPHINE

Unmodified parenteral administration of apomorphine has disadvantages in human use for erectile dysfunction when compared with its application in the management of Parkinson’s disease. Unmodified apomorphine given orally or sublingually may be effective in producing erections, but is associated with unacceptable side effects.

1. INTRODUCTION Apomorphine is an aporphine (not an opiate) that acts as a dopaminergic agonist. Although synthesized from morphine, there is little pharmacological similarity with morphine, and apomorphine has not been shown to result in narcotic addiction [1].

Apomorphine has now been specifically formulated in a tablet for sublingual administration that has been demonstrated to maintain its erectogenic effects while minimizing the side effects associated with other routes of administration.

2. PHARMACOLOGY Apomorphine was the first dopamine receptor agonist to be synthesized and has the most complete pharmacological profile compared with other dopamine agonists. Apomorphine has a high affinity for D2, D3, and D4 receptors and is unique in its affinity for D1 receptors [2]. It elicits effects similar to those of levodopa. Apomorphine was first synthesized via acid-catalyzed skeletal rearrangement of morphine, with the levo-rotating product, (-)apomorphine, retaining little structural similarity to the narcotic analgesic. Throughout the latter 19th century, concurrent clinical and animal studies led to further use of apomorphine as an antispasmodic and for the treatment of specific movement disorders and epilepsy. In the 19th century it was used for its behavioral effects in domestic animals and was approved in veterinary medicine for induction of vomiting. In the first half of the 20th century, apomorphine was used as a sedative for psychiatric disturbances and as behavior-altering agent for alcoholics and addicts.

Apomorphine sublingual is the first drug for ED that acts as a central initiator. It is effective centrally at nanogram concentrations. Since apomorphine acts in the brain, the signals generated follow the natural pathways and generate an erection indistinguishable from a physiological erection. The action on the cerebral nuclei is highly specific and sensitive, and there is little discernible direct action on cells outside the central nervous system at the doses used.

3. ANIMAL STUDIES Central dopaminergic transmission is involved in the control of penile erection. The incerto-hypothalamic dopaminergic pathway reaches the medial preoptic area (MPoA) and the paraventricular nucleus (PVN) of the hypothalamus. The proerectile role of these two nuclei has been determined in animal models [6]. Therefore there exists a strong link between central dopaminergic transmission, the PVN and penile erection. Animal data strongly suggest that dopaminergic mechanisms are involved with the erectile responses. and these have been associated with activity on nuclei in the supraoptic region of the hypothalamus. The characteristics of apomorphine activity as an erectogenic agent have been well defined in animal models. In rats it causes a stereotypical behavior of erections in concert with yawning.

In the 1960s, it was established that apomorphine is structurally similar to dopamine and it was found to be a useful drug in the management of refractory on-off oscillations in Parkinson’s disease. Since then it has been documented to have potent activity at D1 and D2 dopamine receptor sites. It is not known to share the addictive potential of morphine. Its actions are thought to be mediated post-synaptically. Apomorphine has been demonstrated to produce an arousal response manifested by yawning and penile erection in animals and man [3, 4, 5].

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In rats, apomorphine administered intraperitoneally causes episodes of penile erection. Following subcutaneous apomorphine in rats, erections are accompanied by intracavernosal pressure increases, occurring as a plateau of 47.9 ± 3.9 mmHg, lasting 34.0 ± 4.0s, with 11.2 ±1.5 peaks lasting 0.20 ± 0.03s and reaching 194.5 ± 22.4 mmHg [3].

patients) may cause respiratory depression and, in the low-dose range (0.25-0.75 mg), where effects on penile erection can be demonstrated, emesis, yawning, drowsiness, transient nausea, lacrimation, flushing, and dizziness may occur [11]. b) Oral apomorphine Apomorphine has poor bio-availability in oral form (approximately 10% of the subcutaneous dose) but has been shown to be absorbed through mucous membranes. Apomorphine is rapidly cleared because of its high lipid solubility, large volume of distribution, and rapid metabolism.

Episodes of penile erection are also elicited by micro-injection of apomorphine to the paraventricular nucleus of the hypothalamus in the rat [4]. In monkeys, in a placebo-controlled study, apomorphine facilitated erections in males in the presence of receptive females, but did not facilitate erections in the absence of females.

Heaton et al. [12] described a study in which apomorphine was formulated in a proprietary slowrelease tablet form. It was hoped that the slow release form (onset of action was 30 minutes) would provide an erectile response without the previously described side effects, especially nausea and drowsiness. It was administered sublingually to a selected population of patients with no documentable organic causes of erectile dysfunction, but with proven erectile potential (psychogenic ED). Initially it was felt that since the drug worked centrally it required normal peripheral neurovascular integrity if it were to be erectogenic, hence the initial trial on patients with psychogenic ED. Twelve patients were given either placebo, 3 mg or 4 mg of apomorphine sublingually and underwent real-time Rigiscan measurements in a single-blind dose escalation study. Eight of the 12 patients (67%) had durable erections without side effects at a dose of 3 and 4 mg. Erectile activity was seen during both sexually neutral and erotic visual stimulation to a significantly greater extent than with placebo. About 70-80% of the erection obtained while watching erotic stimulation could be obtained while watching sexually neutral videos. There were no side effects seen during the trial. An on demand home trial was continued by 7 of the 8 responders and found to be successful.

Experimental results provide neuroanatomical evidence that apomorphine, at a dose which selectively induces erections, causes specific and selective expression of c-fos in several brain structures which are recognized to play a crucial role in the integration of autonomic, vascular and endocrine regulation of penile erection [7]

4. HUMAN STUDIES a) Injected apomorphine Lal et al [5] showed, in a placebo-controlled, double-blind study on healthy volunteers that apomorphine, injected subcutaneously (0.25-0.75 mg), was able to induce erection. This was confirmed by Danjou et al [8], showing that apomorphine induced erection and potentiated the erection induced by visual erotic stimulation. There was no increase in libido, which was in agreement with previous observations. In 28 patients with impotence, Lal found that 17 responded with erection after subcutaneous apomorphine [9]. Segraves et al. [10] also administered apomorphine subcutaneously (0.25-1.0 mg) to 12 men (eight with psychogenic impotence) in a double-blind and placebo-controlled study. They found a dose-related increase in maximal penile circumference. An erection was obtained in 11 of the 12 patients, while 8 of the 12 developed nausea as a side effect.

The efficacy of Apomorphine SL tablets for the treatment of male erectile dysfunction was determined by Rigiscan testing. The mean value of every Rigiscan parameter (tip rigidity and tumescence and base rigidity and tumescence) was higher for both the 6 mg and the 4 mg doses of apomorphine than for placebo [12]. All differences

The therapeutic potential of apomorphine, however, seems to be limited due to frequently occurring side-effects. High doses (up to 5-6 mg in adult

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were statistically significant for the 6 mg dose, with mean values vs. placebo of 52.5% vs. 40.1% for maximum base rigidity (p=.013), 43.1% vs. 26.7% for maximum tip rigidity (p=.004), 10.9 cm vs. 10.3 cm for maximum base tumescence (p=.018), 9.4 cm vs. 8.7 cm for maximum tip tumescence (p=.001), and 4.8 minutes vs. 1.7 minutes for duration above 55 % base rigidity (p=.014). Differences for the 4 mg dose vs. placebo were significant for both maximum base rigidity (50.7% vs. 41.0%, p=.037) and maximum tip rigidity (45.8 % vs. 32.3% p=.024) [12].

and 60.9% for 6mg vs. 29.3% for placebo (p<0.001) (Figure 2). The commonest adverse event was nausea (mostly mild to moderate) seen in 2.9%, 21.4%, 32.8% and 34.5% of patients taking 2, 4, 5 and 6 mg, respectively. Only 2.6% of the 6 mg group and 0.8 % of the 5 mg group experienced severe nausea (no severe nausea at lower doses). Vasovagal episodes have been reported in less than 1% of patients apparently in relation to age or presence of hypertension. The median time to erection for all dosing regimens ranged from 1522 minutes. [14] (Table 1).

In the first Phase III study using the sublingual preparation 457 [13] men with ED and no major organic component were randomized into 3 arms each being a separate crossover comparing either 2 mg, 4 mg or 6 mg of apomorphine to placebo. The primary endpoint was the number of attempts resulting in an erection firm enough for sexual intercourse.

The efficacy and safety of apomorphine in patients with hypertension and ED has been studied. A review of two multicenter, double-blind studies involving 977 patients randomized to 2mg, 4mg, 5mg and 6mg of apomorphine vs. placebo revealed that 236 (24 %) were hypertensive.

The percentage of attempts that resulted in a firm enough erection for each group was: 45.8% for 2 mg vs. 32.2% for placebo (p<0.001); 52% for 4 mg vs. 35% for placebo (p<0.001) and 59.6% for 6 mg vs. 34.2% for placebo (p<0.001) (Figure 1). Mostly mild to moderate nausea (only 2.7% of the 6mg group had severe nausea) was the most common adverse event seen in 39%, 19.5%, and 2.1% in the 6mg, 4mg and 2mg groups, respectively (up to 4.9% in the placebo group) [13].

The primary endpoint for these studies was the percentage of attempts resulting in an erection firm enough for intercourse. For the patients with hypertension, the percentage of attempts resulting in erections firm enough for intercourse was significantly higher for apomorphine SL dosing than for placebo: 42.0% vs. 32.4% for 2 mg compared to placebo (p=.013), 51.2% vs. 27.8% for 4 mg compared to placebo (p<.001), 46.4% vs. 30.0% for 5 mg compared to placebo (p=.017), and 63.2% vs. 33.1% for 6 mg compared to placebo (p<.001) (Figure 3).

Padma-Nathan et al. randomized 520 patients with ED (median age 54) into four arms each being a separate crossover arm comparing either 2 mg, 4 mg, 5 mg or 6 mg of apomorphine sublingually to placebo [14]. The primary endpoint for the study was the percentage of attempts that resulted in an erection firm enough for intercourse. Secondary endpoints included successful intercourse rate (according to patient and partner), time to erection and IIEF responses.

The commonest adverse event reported for these patients was nausea with 15.0%, 20.0%, and 29.4% of patients reporting related nausea when taking 4, 5, and 6 mg apomorphine SL, respectively, versus up to 1.6% while on placebo (no nausea was seen with 2 mg dosing) [15]. c) Conclusion Apomorphine will act as an erectogenic agent when absorbed through the oral mucosa.

The percentage of attempts resulting in an erection firm enough for intercourse was significantly higher for each of the four apomorphine SL dose than for placebo:

The preparation of apomorphine in a sublingual form is effective in inducing erections under laboratory conditions and is also effective in home use. The commonest adverse effect is nausea and is dose-dependent [16].

44.1% for 2 mg vs. 38.0% for placebo (p=0.013); 58.1% for 4 mg vs. 36.6% for placebo (p<.001); 52.8% for 5mg vs. 28.9% for placebo (p<0.001)

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Table 1: Average percentage* of administrations resulting in adverse events 2 MG GROUP

4 MG GROUP

5 MG GROUP

6 MG GROUP

ADVERSE EVENT

APO SL N=127

PBO N=130

APO SL N=117

PBO N=117

APO SL N=128

PBO N=118

APO SL N=116

PBO N=106

Nausea Dizziness

0.5 0.3

0.1 1.0

11.7 7.5

0.8 0.2

16.0 6.8

1.0 0.6

16.6 6.7

0.3 0.2

Sweating Somnolence

0.2 0.3

0 0.9

5.7 5.9

0 0.3

6.0 5.6

0 0.2

7.4 6.0

0.1 0.9

Yawning

0.3

0

3.4

0.1

5.8

0.2

4.7

0

Vomiting Hot flushes

0.1 0.9

0 0.3

2.6 0.7

0 0.1

5.0 2.3

0 0.5

2.4 3.0

0 0.1

Asthenia

0.3

0

1.3

0

2.1

0.2

4.8

0

Padma-Nathan H. et al J.Urol, 161: 214S, 1999 [14]

Padma-Nathan H. et al J. Urol, 159: 214S, 1998 [13]

Figure 1: Attempts resulting in an erection firm enough for intercourse

Padma-Nathan H. et al J. Urol, 161: 214S, 1999 [14]

Figure 2: Attempts resulting in an erection firm enough for intercourse

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Lewis. R et al J. Urol, 161:214s, 1999 [15]

Figure 3: Attempts resulting in an erection firm enough for intercourse

The SYS is usually seen 15-60 minutes after injection of ACTH or MSH into the lateral ventricle and lasts with erections for 2-5 hours. Copulatory movements and usually ejaculation accompany these erections. Castrated animals will not show any sexual effect from these injections.

II. MELANOTAN II 1. BACKGROUND Melanotan II is a non-selective melanocortin receptor agonist. Melanotan II is a synthetic cyclic heptapeptide, which contains the 4-10 melanocortin receptor binding region common to Alpha-MSH and ACTH, but with a lactam bridge and several amino acid substitutions. This cyclic peptide was synthesized by solid phase chemistry [1]. The injection of ACTH or MSH peptides into the cerebrospinal fluid of mammals induces a dramatic change in behavior, characterized mainly by repeated stretching and yawning movements (stretching yawning syndrome (SYS)) and by recurrent episodes of erection and ejaculation [2]. Sexual response to ACTH and alpha MSH has been observed in rats, rabbits, cats, dogs and in squirrel monkeys. Antagonists to both oxytocin and dopamine do not block this reaction to ACTH and alpha MSH, nor does pretreatment with MSG, which depletes ACTH and MSH from the hypothalamus. It is likely that dopamine, oxytocin and ACTH act in the hypothalamus in a sequence to induce sexual behavioral responses [3]. The exact area in which ACTH and alpha MSH act is not known, but it is felt to be downstream from the paraventricular nucleus where dopamine agonists such as apomorphine work [3].

Melanotan II is an analog of alpha MSH. In 1992 it initially underwent a phase I pilot study with the intention of developing this drug to increase skin pigmentation without being exposed to ultraviolet light, because of its direct effect on melanocytes. In 1996, a phase I single-blind placebo-controlled study administered subcutaneous injections to normal males daily for two weeks to study its effect on erectile dysfunction [4]. In addition to increased pigmentation in 2 of the 3 males, all males showed the stretch yawning syndrome combined with spontaneous intermittent erections, which lasted 1-5 hours, and increased as the dose of melanotan II increased. Melanotan II has been known to darken the skin color of animals for several months until the color returns to normal. As mentioned before the spontaneous erections that occurred were dose-dependent. This marked the first time that this type of drug caused erections when not given directly into the CNS. It is still felt that this effect is mediated through receptors in the brain, as melanotan II does cross the blood brain barrier.

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A randomized double-blind placebo-controlled crossover study in 10 patients with psychogenic erectile dysfunction was performed [5]. Patients were determined to have psychogenic erectile dysfunction on history, physical exam and NPT monitoring.

2. C HEMICAL PROPERTIES MT-II is a cyclic heptapeptide synthetically modeled from melanotropin derivatives. The drug (a white powder) is reconstituted in 0.9% NaCl solution for injection and concentrations of 5 mg per ml. • Chemical name: Ac-Nle-c Asp-His-D-Phe-ArgTrp-Lys -NH2 • Molecular formula:C50H69N15O9 • Molecular weight:1024.2 Appearance: white powder Administered subcutaneously

Patients were required to have at least one nocturnal erection for at least 10 consecutive minutes with 70% tip rigidity. Patients with known causes of organic erectile dysfunction or vascular risk factors were excluded from the study. Patients received 4 injections of MT-II (0.025-0.157 mg/kg) or saline placebo subcutaneously with 24hour washout periods between injections. Rigiscan data were obtained for six hours following injection. The patients were followed for one hour for acute toxic responses and then sent home on Rigiscan monitoring for the additional five hours which was to be free of any sexual stimulation. At home during the five hours of Rigiscan study, a questionnaire was completed which recorded subjectively the number and duration of erectile events as well as penile pain and other side effects. Following placebo injection, erectile activity as well as rigidity were minimal to non-existent. At the 0.025 mg/kg dose, there was an increase in both circumferential change as well as penile rigidity, which increased even further when 0.133 mg/kg was injected subcutaneously. Of 10 men in the study 8 reported subjective erections during the 6-hour period, which were confirmed by Rigiscan study.

3. PRECLINICAL STUDIES a) Toxicology studies MT-II has been shown to be relatively non-toxic. Mice tolerated a high dose of 56 mg/kg by subcutaneous injection with no toxicity or mortality during a 90-day observation period. Rats treated with 0.5 mg/kg/day of MT-II orally or subcutaneously for 30 days showed no change in mortality, food intake, weight gain or behavior. There were no serum chemistry changes and, except for a lower platelet count in female rats, there were no hematological abnormalities. MT-II did not demonstrate any mutagenic potential. In the repeated dose study, all rats were sacrificed after 30 days and organs were analyzed for gross or histopathologic changes which were not evident. b) Pharmacokinetics The oral bio-availability of MT-II is unknown. It is apparently cleared by the kidney. The estimated half-life for the initial phase is 8 hours.

There was no episode of ejaculation or painful erection. The time to erectile onset in the 8 respondents ranged from 15-270 minutes (mean 127.5 minutes). There was a marked statistical difference between the injected group and the placebo group in terms of total duration of erectile activity, tip rigidity duration, tip tumescence activity, base rigidity duration and base tumescence activity. Transient side effects were reported in all patients and in 5 of 10 placebo-treated patients. Adverse events largely involved nausea, yawning and decreased appetite. Fourteen of the twenty injections of MT-II produced stretching and yawning.

c) Clinical studies In 1996 a double-blind placebo-controlled phase I study was conducted in three subjects to evaluate the ability of this drug to cause skin tanning which was in fact observed in the MT-II group [4]. Subcutaneous injections of MT-II or saline were administered daily for 2 weeks for a total of 10 injections per subject. The starting dose of MT-II was 0.01 mg/kg and the increments of escalation were 0.005 mg/kg. Two subjects were escalated to 0.03 mg/kg and 1 subject was escalated to 0.025 mg/kg. All subjects developed intermittent spontaneous erections at 1-5 hours after dosing. Two of the subjects showed increased skin pigmentation.

In 1998 a similar study using MT-II was performed in men with organic erectile dysfunction [6]. Ten subjects based on history, physical exam, and NPT testing were felt to have organic dysfunction

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and were entered into the study. The pre-trial NPT revealed a mean of 0.5 erectile events per night lasting a mean of 6 minutes (0-18) with a mean maximum rigidity of 36%. Pre-treatment mean values for questions 3 and 4 of the IIEF were 0.77 and 0.22 respectively.

B. CENTRALLY AND/OR PERIPHERALLY ACTING DRUGS

A double-blind placebo-controlled crossover study design was used. MT-II and the dosage of 0.025 mg/kg and a vehicle were administered twice by subcutaneous injection. Injections were separated by at least 48 hours. Rigiscan monitoring, a questionnaire and visual analog score of penile rigidity were used to quantify erectile responses.

I. TRAZODONE 1. INTRODUCTION Trazodone hydrochloride was introduced as an antidepressant in 1982. Soon after its launch, anecdotal reports of associated priapism began to appear in the literature [1,2] and these were soon followed by occasional cases of successful use of trazodone in men with erectile dysfunction [3,4].

The results showed that 9 of 10 subjects reported Rigiscan and subjective evidence of erections with MT-II versus only 1 patient in the placebo group. The mean values for rigidity were 4.37 in the MTII group versus 0.47 in the placebo group. The subjective reported duration of erection in the MTII group was 64.1 minutes.

2. BASIC SCIENCE a) Pharmacology Trazodone is a triazolopyridine derived oral antidepressant agent. It has a number of pharmacological actions including alpha-adrenoceptor blocking actions, 5-HT receptor blocking actions and dopaminergic blocking actions [5]. One of its major metabolites, mCPP ((-)-m-Chlorophenylpiperazine), is a central 5-HT agonist [6] and an alpha-adrenoceptor blocking agent.

There was a statistical difference in the level of sexual desire between the groups with a higher score in the MT-II group. Nausea, stretching and yawning and flushing occurred more frequently in the MT-II group with 4 of 19 injections resulting in severe nausea and 1 subject vomited. d) Conclusion

b) Mode of action There are two main theories concerning the mode of action of trazodone. • Peripheral -adrenoceptor antagonist Trazodone is an α-adrenoceptor antagonist. In vitro studies [7] demonstrated an ability to impair cavernosal contractions induced by noradrenaline suggesting a local action for the drug within the penis. However, in another study, intracavernosal injection of trazodone only produced tumescence rather than a full erection [8], suggesting that other mechanisms were also active. c) Central actions on the serotonin (5-HT) system Trazodone is a central blocker of 5-HT receptors, with a preferential affinity for 5-HT2 over 5-HT1 receptors. It has been demonstrated in animal experiments that 5-HT is intimately involved in sexual activity [9], and it has been suggested that trazodone produces its effects on sexual function by anti-5HT mechanisms; m-CPP may also have a

This drug, which mimics the activity of ACTH and alpha MSH when injected into the lateral ventricle, appears to be able to cause spontaneous erectile activity after subcutaneous injection in patients with psychogenic as well as organic erectile dysfunction. At present, our knowledge is based on clinical data involving studies of very few patients. The drug must now be tested in a larger group of patients who are older (both previous studies were done in relatively young patients) with both organic and psychogenic erectile dysfunction. The outcome for this next study should be the ability to perform sexually with an adequate erection. It should also be remembered that some of these patients would have an increase in skin pigmentation, which they may not desire. If this drug is consistently effective in patients with organic dysfunction, further studies would be necessary to determine its exact site of activity.

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role in this respect. In animals mCPP, which stimulates 5-HT-2C receptors, increased giving in the cavernous nerve and elicits use in intracavernous pressure through the activation of the spinal sacral parasympathetic outflow to the penis [10]. mCPP is still active in spinalized rats suggesting an action at the spinal cord. 5-HT-2C receptors have recently been described on spinal neurons controlling penile erection in the rat [11]. Furthermore evidence for a specific role of mCPP on 5HT-2C in the proerectile responses of conscious rats has been provided [10]. d) Laboratory data and animal studies

Table 1: Results of a randomized trial comparing Trazado ne, Ketanserin, Mianserin and Placebo in the treatment of psychogenic ED [12];

Trazodone has been shown to have a relaxant effect upon cavernous smooth muscle [7] while intracavernosal injection of either trazodone or mCPP produces penile tumescence in rabbits [8].

Cure Moderate response No response

TRAZODONE KETANSERIN MIANSERIN PLACEBO N=23 N=21 N=19 N-22 Response 15 rate (65.2%)

4 (19.1%)

6 (31.6%)

3 (13.6%)

Table 2: Results of a controlled trial comparing Trazodone, Testosterone and hypnosis in the treatment of psychogenic ED [13] TRAZODONE TESTOSTERONE HYPNOSIS CONTROL N=21 N=20 N=20 N=18

In normal men who were administered trazodone nocturnal penile tumescence studies demonstrated increased erectile activity compared with trimiprimine and placebo [7].

8

8

12

0

6 7

4 8

4 4

1 11

There was no statistical advantage for any of the treatments. Meinhardt et al. enrolled 69 men with both psychogenic and organic ED [14]. Patients were randomized to receive either 150mg trazodone per day or placebo for 4 weeks after a 2-week run-in period. The mean age was 54-55 years and 11 patients failed to complete the study. The main end point was a global question concerning the patient’s opinion of whether the medication had worked well. Only 4/26 of the trazodone group felt that the medication worked well, compared with 5/32 of the placebo group.

3. CLINICAL DATA a) Efficacy Anecdotal reports initially suggested that trazodone might be effective in men with erectile dysfunction [3,4]. In the first published placebo-controlled trial, 100 men with psychogenic ED, all of whom responded to intracavernosal 60mg Papaverine were randomized into 4 groups taking either trazodone 50mg tid, ketanserin 20mg bid (5-HT2 antagonist), mianserin 10mg tid (anti 5HT1 and 5HT2) or placebo for 30 days [12]. The mean age of the patients was 47 years. Success was defined as 3 or more successful intercourses within the 30 days. 15 men were ultimately excluded from the analysis for varying reasons. Positive responders are enumerated in Table 1. A subsequent trial randomized 79 men with psychogenic ED to receive either 120mg testosterone undecanoate daily (n=20) or 150mg trazodone daily (n=21) or to undergo hypnosis (n=20) [13]. The final 18 men acted as controls. The mean ages of the patient groups were 34-40 years. Cure was defined as a man who was happy and who had no sexual problems on questioning, while a moderate result was considered to be a man who was improved but who still had some failures. The results are shown in Table 2.

A more recent double-blind placebo-controlled crossover study randomized 51 patients to either 50 mg of trazodone or placebo at bedtime for 3 months and then, after a washout period, patients crossed over to the other group. There were no statistically significant differences in respect to improved erections or improved sex drive between any of the groups [15]. b) Safety A number of adverse events have been reported including priapism, sedation, xerostomia, blurred vision [9], sedation [13], dizziness, drowsiness, headache and nausea [14]. The numbers in the trials were too small to allow definitive assessments of the frequency of these side effects, although sedation seems to be the commonest.

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c) Indications 1. DOSING

c) Intracavernosal -adrenoceptor blockade Both α1 and α2 receptors are found within both the cavernosal smooth muscle and on the arteriolar smooth muscle of the penis [10]. Noradrenergic stimulation leads to contraction of both sets of smooth muscles and α1/α2 adrenoceptor blockade results in cavernosal smooth muscle relaxation and arteriolar dilatation [11]. It has been demonstrated that phentolamine displaces α1 and α2 agonists from cavernosal smooth muscle in both man and in rabbits, and in vitro organ bath experiments have confirmed that it inhibits both α1 and α2 mediated cavernosal contraction [12].

The usual dosage is 150mg per day in divided doses. 2. P OTENTIAL SYNERGIES One trial explored the value of combination therapy with yohimbine [16]. In a placebo-controlled crossover study, 63 men with psychogenic ED received placebo or 15mg yohimbine per day and 50mg trazodone per day. Each treatment period lasted 8 weeks. The trial demonstrated an advantage for combination treatment with 39 men (62%) achieving a good response (p<0.01), which was subsequently sustained for up to 6 months in 31 men.

d) Direct intracavernosal relaxant effects A second local effect of phentolamine within the penis has been proposed [12]. Phentolamine was found to decrease the endothelin and potassium induced contraction of cavernous smooth muscle. Since these agents cause contraction by non-adrenergic mechanisms, it has been postulated that phentolamine has other actions in addition to its aadrenoceptor blocking actions. Since the effect of phentolamine on cavernosal relaxation was reduced by a nitric oxide synthase (NOS) inhibitor (LNAME) and since it was also reduced by de-epithelialisation, it has been postulated that this additional mechanism of action is exerted via α receptor on the endothelium which leads to activation of NOS.

d) Conclusion The clinical trials have failed to consistently demonstrate efficacy for this medication in the treatment of men with ED. Available data are lacking concerning the use of this drug for ED

II. PHENTOLAMINE 1. INTRODUCTION Phentolamine has been used as an adrenoceptor antagonist for around 40 years. Outside the realm of andrology, its chief use is in the treatment of pheochromocytoma-induced hypertension. Since the 1980s it has been used as an intracavernosal agent, usually in combination with Papaverine and prostaglandin El [1,2]. When injected alone it has usually shown less than modest erectile responses. Following a number of pilot studies with oral formulations of the drug [3,4] for the treatment of erectile dysfunction it has recently entered Phase II/III clinical trials for this condition [5,6,7,8].

e) Central -adrenoceptor blockade It is interesting that intracavernosal injection of phentolamine alone does not lead to a full and rigid erection [13]. This might suggest that phentolamine has extra-cavernosal actions. It is also known that centrally acting α2 adrenoceptor blocking agents such as yohimbine have some benefit in erectile dysfunction [14]. Since it seems likely that phentolamine crosses the blood-brain barrier, it is therefore possible that phentolamine has additional central α2 adrenoceptor antagonistic actions, which are valuable in the treatment of erectile dysfunction.

2. BASIC SCIENCE a) Pharmacology Phentolamine is an α1 and α2 adrenoceptor bloc king agent [9]. It also has other actions including blockade of 5HT receptors and blockade of potassium channels.

There exist both morphological and pharmacological evidence to support a role for noradrenaline in the neural control of penile erection at the brain and spinal cord level [15]. Nevertheless, the αadrenoceptor subtypes mediating this regulation remain essentially unknown. From available pharmacological data, the general view is that central

b) Mechanism of action Phentolamine currently thought to act via three main mechanisms. 252

activation of α1 adrenoceptors and inhibition of α2 adrenoceptors facilitates sexual functions. More studies are mandatory to define the exact mechanism of action of phentolamine within the central nervous system.

Area under the curve

33.3 ng/hr/ml

f) Laboratory data and animal studies

Cmax(peak concentration)

19.3 ng/ml

There are no reported or published data relating to animal studies with this formulation. Organ bath and other in vitro data relating to the compound are discussed above.

T 1/2 (Half-life)

2.14 hr

Tmax (time to peak concentration)

0.69 hr

Table 3: Pharmacokinetic data for orally administered Phen tolamine

ORAL 40 MG PHENTOLAMINE

bo [6]. Following a single-blind placebo phase, 4 men reported successful erections and were excluded. Success was defined as an erection adequate to achieve vaginal penetration. The success rates are shown in Table 5. Again, the results for phentolamine were not significantly better than those achieved with placebo.

g) Pharmacokinetic data The Cmax, Tmax and T1/2 following an oral dose of phentolamine mesylate are shown in Table 3. If a level of 10ng/ml is considered adequate for a pharmacological effect in the penis, then the onset of clinical activity would be less then 20 minutes and would last for just under 2 hours.

b) Phase III trials The largest reported trials to date have been undertaken in men with mild to moderate erectile dysfunction [7,8]. Two protocols were used. In one, 459 men were randomized to receive phentolamine 40mg, 80mg or placebo and were asked to attempt sexual intercourse at least 4 times in 4 weeks [7]. 424 men completed the study. Mean ages of the patient groups were 57-59 years. End points included the change in the IIEF, the ability to achieve vaginal penetration and the ability to achieve erection sufficient for penetration and ejaculation in at least 75% of attempts. The results are outlined in Table 6. An analysis of the individual domain scores of the IIEF again demonstrated an advantage for phentolamine over placebo (Table 7). All changes were statistically significant other than those noted in the table as NS. The other protocol randomized 312 men to receive both placebo and 40mg phentolamine in a crossover fashion [8]. Again the mean ages were 58-59 years. The results of the trial are shown in Table 8. The latter 2 parameters (shaded) are quoted in the abstract but are not fully defined.

3. CLINICAL DATA a) Pilot studies An initial placebo-controlled crossover trial in 16 men with ED suggested a modest benefit for oral phentolamine 50mg over placebo, with 11/16 responding to phentolamine and 3/16 responding to placebo [3]. This formulation of the drug was subsequently withdrawn. A further pilot study using phentolamine mesylate 50mg in 3 centers suggested that there was a 42.3% rate of full spontaneous erections in men with ED [4]. Phase II studies in Germany were reported in 1996 [5,6]. In one large placebo-controlled multicentre study, using phentolamine mesylate, 230 men with organic ED were recruited [5]. The age of the patients was not stated. All were given 3 doses of placebo and any man who obtained an erection with any of the doses was excluded from the subsequent trial. 177 men who entered the second phase were randomized to receive 3 doses of phentolamine (20mg, 40mg, 60mg) or placebo. Success was defined as at least one successful attempt at sexual intercourse. The results are outlined in Table 4. There was no statistically significant advantage for phentolamine over placebo. In a smaller, single center study, 44 men with recent onset (less than 3 years) ED and a probable organic etiology were randomized to receive phentolamine mesylate (20mg, 40mg, 60mg) or place-

c) Safety data Only limited safety data are currently available for this formulation of the drug. The basic side effects profile, from the parallel group and cross-over studies outlined above [7,8], is shown in Table 9. 253

Table 4: Phase II studies of oral Phentolamine in 177 men with ED [5] 20 MG

PLACEBO

Success rate in men <50 yr. Success rate in men > 50 yr.

42% 28%

40 MG

60

MG

PHENTOLAMINE

PHENTOLAMINE

PHENTOLAMINE

36% 17%

27% 50%

50% 40%

Table 5: A single centre placebo-controlled study of oral phentolamine in men with organic ED [6]. PLACEBO

Successful patients Successful doses

20 MG

40

60 MG

MG

PHENTOLAMINE

PHENTOLAMINE

PHENTOLAMINE

N=10

N=10

N=10

N=10

2 13.4%

3 20%

5 30%

4 36.7%

Table 6: Phase III trial of oral Phentolamine in the treatment of men with mild to moderate ED [7]. Men were randomized to receive either placebo or phentolamine 40 mg or 80 mg PLACEBO N=139

PHENTOLAMINE 40 MG N=139

PHENTOLAMINE 80 MG N=146

Mean change in IIEF from baseline

+ 2.39

+ 5.65 p<0.0001

+ 6.66 p<0.0001

Shift in domain score of IIEF

15%

40% p<0.0001

53% p>0.001

Ability to achieve penetration in at least 75% of cases Ability to achieve ejaculation in at least 75% of cases Overall satisfaction

38%

51% p=0.012 29% p=0.005 33%

53% p=0.005 29% p=0.006 40%

16% 10%

Table 7: Phase III trials of oral Phentolamine in the treatment of men with mild to moderate ED [7]. Results of the indivi dual domain scores of the IIEF. PLACEBO

PHENTOLAMINE 40 MG

PHENTOLAMINE 80 MG

Frequency of penetration Frequency of maintaining erections

- 0.3 NS -0.2 NS

0.3 0.4

0.6 0.8

Orgasmic function Sexual desire

-0.1 NS 0.1 NS

0.8 0.3 NS

1.0 0.3 NS

Intercourse satisfaction Overall satisfaction

-0.4 NS 0.2 NS

0.8 1.3

1.2 1.5

Table 8 : A phase III placebo-controlled crossover trial of phentolamine and placebo in men with mild to moderate ED [8] PLACEBO

PHENTOLAMINE 40 MG

Ability to achieve penetration in at least 75% of attempts

48%

55% p=0.004

Ability to achieve ejaculation in at least 75% of attempts

26%

37% p<0.001

Improved erectile function

26%

36% p=0.0149

Overall responders

24%

35% p=0.0013

254

Table 9 : Side effects of oral Phentolamine [7, 8 ] PLACEBO

PHENTOLAMINE 40 MG

PHENTOLAMINE 80 MG

Rhinitis

3.8%

7.7%

20.9%

Headache Dizziness

1.7% 0.2%

3.1% 2.0%

4.5% 7.0%

Tachycardia Nausea

0.6% 0%

1.5% 0.7%

7.0% 3.5%

Hypotension Hypertension

0% 0.2%

0.2% 0%

2.0% 2.0%

It seems that most side effects are dose-related, and that the drug is generally well tolerated at these doses with this formulation.

4. CONCLUSION Phentolamine is an alpha-adrenergic blocking agent with both central and peripheral activity. In placebo-controlled studies, it has been found to have modest efficacy in patients with mild to moderate ED. Adverse events profile dizziness, nasal stuffiness and tachycardia which is generally well tolerated at the 40 mg dose.

Phentolamine is a mixed alpha-l and alpha-2 receptor antagonist, which is used clinically to treat hypertension caused by pheochromocytoma. It is therefore theoretically capable of inducing hypotension. In the clinical trials outlined above, a number of patients were taking concomitant medications including antihypertensive agents (placebo: 32%, phentolamine 40mg: 25%, phentolamine 80mg: 28% in the parallel group study), but there were no reported interactions.

III. YOHIMBINE 1. PHARMACOLOGY

d) Indications Presented or published phase II clinical trial data only relate to mild or moderate ED, and further data are awaited in men with more severe ED.

Yohimbine is an indolalquinolonic alkaloid found in the bark of the Pausinstalia yohimbe tree and the root of Rauwolfia. It is a selective competitive antagonist for α2 adrenergic receptors [1].

e) Dosing and storage

2. ANIMAL STUDIES

Phentolamine mesylate is a white dry odorless, crystalline powder. At present it seems likely that the tablet will be available in 40mg and 80mg doses.

a) Mode of Action 1. DIRECT Yohimbine partially antagonized norepinephrineinduced contractions in bull retractor penis, although its action is 1000 times weaker than that of phenoxybenzamine [2]. The injection of yohimbine into the penis of dogs did not induce tumescence or rigidity [3]. 2. INDIRECT The medial preoptic area has been implicated in the control of sexual arousal in males [4]. The medial preoptic area receives noradrenergic innervation from the α1 and α2 cell groups of the brain-stem [5]. α2 receptors have been identified in the medial preoptic area and other hypothalamic areas [6]. Yohimbine facilitates norepinephrine release from the rat hypothalami in vitro [7,8,9]. Yohimbine

f) Potential synergies Because of the differing mechanisms of action, it seems possible that phentolamine will be useful in combination with a wide range of other treatments for ED, including sildenafil, apomorphine, intraurethral therapy and intracavernosal therapy. At present this is largely hypothetical with few studies exploring combination therapy. However, one recent study has, suggested that an adrenoceptor blockade might potentiate intracavernosal therapy, although on this occasion doxazosin, an alpha-l adrenoceptor blocking agent, was used [15]. 255

increases 3-methoxy-4-hydroxyphenylethyleneglycol sulphate norepinephrine metabolite [10]. There was no statistically significant difference in mean norepinephrine content between control and yohimbine treated rabbit corpus cavernosum, and control and yohimbine treated corpus cavernosum human [11]. Strips of the rabbit main pulmonary artery, precontracted with noradrenaline, were exposed to yohimbine, which enhanced the smooth muscle contraction induced by transmural sympathetic nerve stimulation [12]. b) Animal evidence for positive effect of yohimbi ne on sexual function In male rats, yohimbine induced copulatory activity in sexually inactive males and increased mounting after penile desensitization, a test which specifically measures sexual motivation [13]. Yohimbine induced copulatory activity in sexually inactive male rats up to 91 days after castration [14]. Yohimbine improved age-related deficits in sexual behavior of rats [15]. In male rats, yohimbine drastically decreased the ejaculation latency and the intercopulatory and post-ejaculatory intervals [16]. Yohimbine increased sexual motivation in rats with lithium chloride-induced inhibition of copulatory behavior [17]. The study of Lang demonstrated differences in the behavioral effects of yohimbine in several species. Yohimbine was excitatory when given to dogs and rats. In contrast, it produced behavioral depression in cats [18] and did not increase sexual motivation in primates. Early maternal and social deprivation markedly affects the behavioral response of adult nonhuman primates (macaque monkeys) to oral yohimbine [19].

3. H UMAN STUDIES a) Mode of Action 1. DIRECT Tolazoline (α2 adrenergic antagonist) inhibited noradrenaline-induced contraction of human corpora cavernosa smooth muscle cells [20]. Yohimbine partially antagonized norepinephrine-induced contractions of human CC in an in vitro muscle bath [11]. The inhibition of norepinephrine-induced contractions of strips from human corpus cavernosum by phentolamine is more intense than

256

that induced by moxisylyte, which in turn is more intense than that induced by yohimbine [21]. 2. INDIRECT ACTION VIA NOREPINEPHRINE OR

NORE-

PINEPHRINE METABOLITES

Yohimbine increases the levels of norepinephrine in cerebrospinal fluid [22]. In addition, Yohimbine, when compared to placebo, caused a significant increase in plasma MHPG concentrations (3methoxy-4-hydroxyphenylethyleneglycol) an index of brain norepinephrine turnover, 2, 3 and 4 hours following administration [23]. Yohimbine causes dose-dependent increases in plasma NE due to an increased rate of appearance of NE in plasma and not reduced clearance from plasma [24]. Yohimbine has an absorption half-life of 0.17 h ± 0.1 1 h and an elimination half-life of 0.60 ± 0.26 h. It does not have a distinct second compartment [25]. Hypertensive patients who were given 22 mg of oral yohimbine experienced a mean BP increase of 5 mm Hg, a 66% increase in plasma norepinephrine and a 25% increase in plasma dihydroxyphenylglyco1 (neuronal metabolite of NE) [26]. However, patients who received Yohimbine (l2 mg po qd) did not have any significant change in plasma noradrenaline after 15 days of treatment [27]. b) Physiological effects of yohimbine in humans Yohimbine 0.30 mg/kg iv did not modify penile diameter (without stimulation) and did not affect the physiological response to erotic stimuli [28]. Furthermore, there was no change in the penile brachial index with yohimbine during a doubleblind clinical trial [3]. Vogt et al. found no significant difference in NPT recordings with yohimbine during a double-blind clinical trial [29]. In addition, yohimbine (0.30 mg kg iv) did not induce erection and did not potentiate erection induced by visual stimulation [28]. Cherney et al. reported no change in sexual drive or sexual function with the administration of yohimbine 30 mg po [23]. In another study, there were no statistically significant changes in subjective response (sexual desire, best erection during sexual contacts, frequency of sexual contacts, sexual satisfaction) during the administration of yohimbine 30 mg po. In fact the values of the latter three parameters were identical in the yohimbine and placebo groups [29].

c) Clinical Trials

tile function in patients with psychogenic ED has not been demonstrated.

For close to 75 years, yohimbine has been considered to be an aphrodisiac. As seen above, some animal experiments demonstrated yohimbine to increase arousal and sexual motivation in rats. Early clinical investigators reported in uncontrolled studies up to 75-80% good to excellent results in the treatment of impotent patients [30]. More recent controlled studies have not been very promising regardless of the subset of the impotent population studied. Yohimbine is usually prescribed at a dose of 5.4 mg tid. A review of the relevant clinical trials in various etiological categories follows.

2. NO OBVIOUS CAUSE ED Vogt [29] studied patients in this group. His study combined questionable methodology with unacceptable statistical methods. The group included 86 men who were selected out of 309 men with ED. Outcomes were based on improvement, not on functional rigidity. Statistical significance was achieved by a secondary exploration of a combination of two negative initial statistical analyses. 3. MIXED (ORGANIC AND PSYCHOGENIC) ED In two [3, 34] of the four studies of patients with mixed ED, there was no significant difference between yohimbine and placebo. A third study [35], found a significant difference between yohimbine and placebo only for patients with psychogenic ED. This appeared to be a very small clinical effect. We are not informed as to how many patients had erections, which were good enough for intercourse, after taking the placebo or yohimbine. In the fourth study [36], yohimbine increased the number of men reporting good erections. There was a statistically significant difference between the favorable response to placebo and yohimbine. Missing data points after 12 weeks however seriously compromised the study. It is probable that these data would have had a negative impact on the yohimbine response rate.

1. PSYCHOGENIC ERECTILE DYSFUNCTION Two [31,32] of the three clinical trials with patients with psychogenic erectile dysfunction demonstrated a statistically significant difference in complete recovery of erectile function between yohimbine and placebo. However, the Reid trial [31] used methodology (partial crossover) which biased the study toward yohimbine. Additionally, the group of patients who crossed over from placebo to yohimbine did not show a significant change in response to therapy after the changeover. Only 21% of the crossover group reported some improvement in sexual functioning over pretreatment levels. 16 % of this group had responded favorably to placebo in the first phase of this study. The Turchi trial [32] demonstrated a significant difference in successes only in the group of patients with mild complaints such as inconsistently incomplete erections or loss of erections during intercourse. It is not clear how many of the successes had complete recovery with yohimbine or placebo. Additionally, we are not informed of the methods used to analyze the data. The third trial [33] found no significant difference in response between yohimbine and placebo based on the daily logs, NPT, VSS and Global Assessment.

• Summary statement: The majority of studies have failed to demonstrate that yohimbine facilitates functional penile rigidify in patients with mixed ED. The one study which suggests this possibility has flaws in methodology. 4. O RGANIC ED Three studies [37,38,39] did not demonstrate a significant difference between the effect of yohimbine and placebo on the erectile capacity of patients with organic ED (Table 10).

• Summary Statement: The efficacy of yohimbine to restore normal erec-

257

Table 10 : Yohimbine trials - randomized, double-blind, placebo-controlled trials STUDY-YEAR

NUMBER OF ETIOLOGY STUDY PATIENTS DESIGN

DOSE

COURSE

QUESTIONNAIRE TEST

OBJECTIVE TEST

STATISTICAL ANALYSIS

Rowland-1997

11

psych

crossover

15 mg 30mg

2 weeks 2 weeks

NS

NS

ANOVA

Turchi-1992

19

psych

crossover

1 gm

30 days

Significant1

NA

Biostatistics software

Reid-1987

48

psych

partial crossover

18 mg

10 weeks

Significant 2

NA

Chi-square test

Vogt-1997

83

no obvious no cause crossover

30 mg

8 weeks

NS3

NS

Fisher’s Exact

Kunelius-1997

27

mixed

36 mg

25 days

NS

NS

Mann-Whitney

NA

Chi-square test with Yates correction

crossover

Riley-1989

61

mixed

crossover

16.2 mg 8 weeks

Significant4

Sonda-1990

33

mixed

crossover

16.2 mg 4 weeks

NS

NS

Chi-square test

Mann-1996

30

mixed

no crossover 15 mg

7 weeks

Significant5

NS

ANCOVA

Teloken-1998

22

organic

sequential

100 mg

30 days

NS

NA

Chi-square test with Yates correction

Susset-1989

74

organic

partial crossover

22-42 mg 30 days

?6

NA

t test

Morales-1987

100

organic

partial crossover

18 mg

NSD

NA

Chi-square test

10 weeks

1. A significant difference was only noted in patients with mild complaints, such as inconsistently incomplete erections or loss of erections during coitus. 2. This partial cross-over has a bias toward yohimbine. The small size (<5) of some of the cells makes the statistical analysis questionable. 3. Significance is achieved in only one area of analysis and only through questionable methodology. 4. The data is incomplete after 12 weeks and it is possible that the missing data would significantly alter the statistical analysis. 5. Yohimbine had a very small and not therapeuti cally significant effect in patients with psychogenic ED. 6. The difference in response to yohimbine and placebo is unclear.

Central to our current theories of the physiology of erection is the role played by nitric oxide (NO). As shown in Figure 1 a, in the normally functioning man, NO released from cavernous nerves and from the endothelial surfaces within the penis during periods of sexual excitement activates the enzyme guanylate cyclase causing an increase in cGMP levels. Through subsequent activation of ion channels, elevated levels of cGMP induce calcium efflux and smooth muscle relaxation that results in increased penile blood flow and tumescence. The surrounding non-elastic tunica albuginea stretched by the increased penile blood volume limits the length and girth enhancement producing a rigid fully erect phallus. cGMP levels remain elevated only briefly as catalysis by PDE5 rapidly leads to degradation of cGMP within the penis. In disease states, such as diabetes, renal failure, or spinal cord injury, impaired NO stimulated cGMP induced Ca++ efflux is seen, resulting in reduced penile rigidity.

C. PERIPHERALLY ACTING DRUGS PDE INHIBITORS I. SILDENAFIL 1. REVIEW OF SILDENAFIL Viagra® (sildenafil citrate), a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), initially designated as compound UK 92,480 by Pfizer research, was studied in the late 1980s as an anti-anginal drug. An unexpected side-effect of the early clinical investigations was improved erectile function among the men studied. This serendipitous finding has transformed the field of erectile dysfunction (ED) therapy.

258

In brief, sildenafil potentiates the physiological erectile response through inhibition of PDE5, allowing higher local concentrations of cGMP within the corpus cavernosum. Although sildenafil has no direct action on the corpus cavernosum smooth muscle it enhances the biologic response to sexual stimulation of the cGMP pathway second messenger system through inhibition of PDE5 enzyme activity (Figure 1 a and b) [1-3].

cGMP-specific PDE5. Investigations have recently revealed that isozymes of cyclic-3’,5’-nucleotide PDE are a critically important component of the cyclic-3’,5’-adenosine monophosphate (cAMP) and to the cGMP signalling pathways. This superfamily of cyclic-3’,5’-PDE isozymes consists of at least 11 gene families (types): PDE1 to PDE11. Many PDE families are diverse and can consist of several subtypes and isoform-splice variants. PDE isozymes differ in molecular structure, catalytic properties, intracellular regulation, location, and sensitivity to selective inhibitors. They have selective sensitivities to cAMP and cGMP [5-7].

On March 27, 1998, the Food and Drug Administration approved sildenafil, the first oral pill to treat ED, a dysfunction that affects millions of men worldwide. Unlike previously approved treatments for impotence, sildenafil does not directly cause penile erections, but affects the response to sexual stimulation. The submission for approval included 21 clinical trials and over 40 pharmacokinetic and metabolism studies [4].

b) Other selective cGMP PDE inhibitors: Zaprinast, developed as an anti-allergy agent, was one of the first type 5 PDE inhibitors to be reported. It is a weak antagonist and poorly selective [8]. Excitement over sildenafil has led other pharmaceutical companies to investigate similar compounds.

a) Basic science data Sildenafil is a member of a class of PDE inhibitors (Table 1). It is a highly selective inhibitor of

c) Potency Sildenafil is an orally active inhibitor of type 5 cGMP-specific phosphodiesterase and is a more potent phosphodiesterase type 5 inhibitor than other known inhibitors with the following selectivities over the other PDE enzymes (>80 fold for PDE1, >1,0000 fold for PDE 2, PDE 3, and PDE4). Sildenafil is only about 10-fold as potent for PDE5 compared to the PDE6 isozyme found in the retina.

Sildenafil citrate - Viagra , UK-92,480 Viagra is manufactured by Pfizer Pharmaceuticals, New York, NY. Structural formula

d) Metabolism (Figure 2) There are 5 primary metabolic pathways of sildenafil that include 1) demethylation at the N-methyl piperazine, 2) N-methyl pyrazole moieties, 3) oxidation of the piperazine ring, 1-[3-(6,7-dihydro-1-methy]-7-oxo-3-propyl-

4) loss of a two carbon piperazine ring and

1 H - p y r a z o l [ 4 . 3 - d ] p y r i m i d i n - 5 - y l ) - 4 - e t h o x yphenyl] sulfonyl]-4-methylpiperazine citrate

5) aliphatic hydroxylation. The major circulating metabolite results from N-desmethylation of sildenafil; this compound is itself further metabolized. This metabolite has approximately 50% of the potency of the parent drug with plasma concentrations of approximately 40% of those seen for sildenafil. The metabolites account for about 20% of the pharmacologic effects of sildenafil.

- molecular weight of 666.7 - a white to off-white crystalline power with a solubility of 3.5 mg/ml in water - formulated as a blue, film-coated roundeddiamond-shaped tablet of 25 mg, 50 mg and 100 mg

259

Table 1: Families of Phosphodiesterase Inhibitors SUBSTRATE SPECIFICITY

SUBTYPES OF PHOSPHODIESTERASE (PDE INHIBITORS) TYPE OF TISSUE SPECIFICITY COMPARATIVE ACTIVITY#

PDE 1

cAMP+ cGMP

PDE 2

cAMP+ cGMP

Cardiac ventricle cells calcium/calmodulin-dependent Human corpora cavernosa

PDE 3

cAMP

80 55,000

Smooth muscle, platelets and cardiac tissue (milrinone inhibits)

PDE 4

cAMP

Human skeletal muscle brain and lung lymphocytes (rolipram inhibits)

PDE 5

cGMP

Predominant enzyme of human corpus cavernosum

PDE 6

cGMP

Rod specific cGMPis a key enzyme of the phototransduction cascade.

30,000 15,000

1 10

# adapted from Boolell et al 1996

The P450 system, and in particular CYP3A4 and CYP2C9, is responsible for the metabolism of sildenafil. Sildenafil is cleared predominantly by the CYP3A4 (major) and CYP2C9 (minor) hepatic microsomal isoenzymes. Drugs that can cause an increase in sildenafil serum concentrations by inhibiting the CYP3A4 system include protease inhibitors (ritonavir, indinavir, saquinavir), cimetidine, erythromycin, and ketoconazole (Table 2). A list of drugs that inhibit CYP3A4 is included in the ACC/AHA Expert Consensus Document, 1999 [8]. However sildenafil itself has no inhibitory effects on the P450 system and hence does not interfere with the metabolism of drugs that rely on this system for their catabolism.

Table 2: P450 Hepatic metabolism INHIBITORS CYP3A4

Erythromycin Ketoconazole Itraconazole Cimetidine Ritonavir Saquinavir

CYP2C9

Tolbutamide Warfarin*

*no evidence that this inhibition alters sildenafil concen trations

for penile smooth muscle relaxation and erection. Stimulation of penile autonomic innervation releases NO which activates guanylate cylase and enhances levels of cGMP. Elevated levels of cGMP in penile smooth muscle are normally hydrolyzed by PDE5. Inhibiting the cGMP breakdown catalyzed by PDE5 amplifies the neuronal NO/cGMP pathway essential for relaxation of human corpus cavernosum. The final erection results from relaxation of smooth muscle controlling inflow of blood to the corpus cavernosum. PDE5 has no direct effect on cavernosal tissue (Figure 2 b). The guanylate cyclase system affects vascular dilatation which may be associated with lowering of blood pressure. In addition, the guanylate cyclase system is involved in controlling platelet aggregation; in vitro PDE5 inhibition with sildenafil has

The terminal half-life of both sildenafil and its metabolites is 4 hours. Maximum observed plasma concentrations are reached within 30 to 120 minutes with a median of 60 minutes following oral dosing in the fasted state. This absorption is reduced after a high fat meal. There is no significant interaction with alcohol. e) Mechanism of action Penile erection is dependent on NO and its second messenger cGMP. cGMP is the ubiquitous second messenger for G-protein coupled receptors activated by endogenous substances such as NO and atrial natriuretic peptide (Figure 2 b). Intracellular levels of cGMP are controlled by activation of nucleotide cyclases and breakdown by PDEs. Neuronal NO is believed to be the main pathway 260

Figure 1 a: Physiology of penile erection

Figure 1 b: The mechanism of action of sildenafil in penile erection

261

Figure 2a: Metabolism of sildenafil

Figure 2 b: Second messenger cGMP pathway

262

been shown to result in inhibition of platelet aggregation in the presence of the NO donor sodium nitroprusside; however sildenafil shows no direct effects on bleeding time when taken either alone or with aspirin [4].

There was no effect on sperm motility or morphology after single 100 mg oral doses of sildenafil in healthy volunteers [4] No effects of sildenafil on spermatogenesis have been demonstrated [4].

2. CLINICAL DATA

f) Recommended doses:

The clinical data for submission to FDA included several thousand men. Over 1000 subjects participated in fixed-dose, placebo-controlled studies for 6 months. Placebo-controlled titration studies of 1 to 6 months involved another 1500 subjects. Open-label studies contributed around 1000 subject-years of exposure to sildenafil.

Sildenafil is available in 25, 50, and 100 mg doses. For most patients the recommended starting dose is 50 mg to be taken as needed approximately 1 hour before planned sexual activity. g) Review of animal experimentation carcinoge nesis, mutagenesis, and effects on fertility Sildenafil was not carcinogenic when administered to rats for 24 months, at a dose resulting in total systemic drug exposure to unbound sildenafil and major metabolite corresponding to 29 and 42 times, for male and female rats, respectively, the exposures observed in human males given the maximum recommended human dose of 100 mg. Sildenafil was not carcinogenic when administered to mice for 18 to 21 months at dosages up to the total maximum tolerated dose of 10 mg/kg/day. Sildenafil was negative in the in vitro bacterial and Chinese hamster ovary cell assay to detect mutagenicity and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity. There was no impairment of fertility in rats given sildenafil up to 60 mg/kg/day for 36 days to females and 102 days to males, a dose corresponding to more than 25 times the human male dose.

The men in the clinical trials, including both the dose-response and dose-escalation studies, ranged from 20 to 87 years of age with a mean between 57 and 60 (Tables 3, 4). Ninty-four percent of the subjects in the clinical studies were Caucasian. Sildenafil was evaluated primarily at doses of 25 mg, 50 mg, and 100 mg in 21 randomized, doubleblind placebo-controlled trials of up to 6 months in duration. Efficacy trial results were analyzed in terms of entry criteria, objective and subjective means of efficacy assessment, adverse reactions and complications. In 8 double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic ED, sildenafil resulted in improved erections as assessed by an objective measurement of hardness and duration of erections using RigiScan®. Most studies assessed the efficacy of sildenafil approximately 60 minutes post-dose.

Table 3: Subjects in clinical trials.

PHASE II/III

SILDENAFIL ONLY

PLACEBO

TOTAL

Single Dose

98

-

98

PRN

2600

769

3369

Multiple-daily

305

-

305

Table 4: Subjects in placebo-controlled and open-label controlled studies Age (years)

Total

18-28

28-38

38-48

48-58

58-68

68-78

78-88

88+

PBO

10

124

351

930

1373

993

152

2

3935

OL

2

33

154

545

790

595

79

1

2199

263

The inclusion criteria were men age >18 with ED of more than 6 months duration and in a heterosexual relationship for >6 months.

Other measurements included in the clinical trials were latency, rigidity, frequency, and duration of erections with RigiScan monitoring.

The exclusion criteria included those with blood pressure outside the 90/50 to 170/100 mm Hg range. Patients could be entered once their blood pressure was controlled. There was a 4-week, treatment-free run-in period during which baseline sexual performance data were collected.

Partner satisfaction was not evaluated in all studies, but when it was evaluated it looked at partner’s satisfaction with treatment, and overrall satisfaction with treatment; partners were also asked to evaluate the quality of the erection. In the clinical trials, men were included with the following concomitant conditions: hypertension, ischemic heart disease, hyperlipidemia, history of radical prostatectomy, spinal cord injury, and diabetes mellitus.

The primary measurement of efficacy was a scientifically developed and validated sexual function questionnaire, the International Index of Erectile Function (IIEF), administered during a 4-week treatment-free run-in period, at baseline, at followup visits and at the end of double-blind, placebocontrolled at home treatment [10].

a) Efficacy in diabetic men: A specific diabetic-only protocol reported by Rendell et al [13] entered 268 patients who were evaluated for safety and efficacy.

The IIEF was developed as a simple scale to be used in the multi-national assessment of erectile function. The IIEF is a 15-item self-report questionnaire that received initial testing for feasibility and face validity in a clinical population and has been translated and linguistically validated into most major languages and dialects. The entire IIEF is included in Annex II.

Subgroup analysis from these trials lasting between 6 and 26 months demonstrated improved erectile function in 59% of patients on active drug compared with 15% receiving placebo. Approximately 20% of the men were type 1 and 80% type 2 diabetics. Doses between 25 and 100 mg of sildenafil were tested. After 12 weeks of study (n=136) IIEF question 3 and 4 scores were 3.2 vs 2.0 and 2.9 vs 1.6 for sildenafil versus placebo, respectively.

Two of the IIEF questions served as primary study endpoints Question 3: Over the past 4 weeks when you attempted sexual intercourse, how often were you able to penetrate (enter) your partner?

The global efficacy question demonstrated an improvement in 57% of diabetic men receiving sildenafil compared with 10% of those receiving placebo (Figure 3) [13,14].

Question 4: Over the past 4 weeks during sexual intercourse, how often were you able to maintain your erection after you had penetrated (entered) your partner. The categorical responses for all 15 questions were (0) - no attempted intercourse (1) - never or almost never (2) - a few times (3) - sometimes (4) - most times (5) - almost always or always Improvement in erections in hypertensive patients and diabetic patients are noted in Figures 3 and 4 [11-13].

Figure 3: Improvement in erections in diabetic patients.

264

b) Efficacy in psychogenic ed or men without identifiable organic causes:

pretreatment reported improved function with sildenafil [16]. In the largest sildenafil study on spinal cord injured men, 111 of 143 (78%) reported improvement in erections at doses between 25 and 100 mg over a 6-week study period [17]. This study also reported improvements in quality of life in both SCI men and their partners [18].

These studies were performed early in the clinical trial program and resulted in a clear dose-response relationship of sildenafil to erectile function improvement. At doses between 10 and 100 mg, 65-93% of patients reported improved quality of erections. In these early trials, 87% of patients had doses titrated up to 50 or 100 mg of sildenafil. With active drug, patients described having erections firm enough for penetration 1.52 times per week compared to 0.64 for placebo [15].

d) Efficacy in post-radical prostatectomy men: Men post-radical prostatecomy were included across trials and had a reported 43% improvement versus 15% (Figure 4) [19,20].

c) Efficacy in spinal cord injured men:

In summary, treatment with sildenafil was well tolerated and the studies demonstrated statistically and clinically significant improvement in erections when compared to placebo in all clinical trials. Studies in special populations, e.g., hypertension, depression, diabetes mellitus, spinal cord injuries and post radical prostatectomy patients also demonstrated significant improvement in erections.

An early pilot study evaluated 12 men over a brief 4-week period. Patients were selected based on reporting some residual erectile function after traumatic spinal cord injury. In this cohort of men with incomplete injuries, 9 of 12 reported that 50 mg of sildenafil improved their erections compared to 1 of 14 on placebo. Interestingly, 16 of 25 men without evidence of residual erectile function

Figure 4: Improvement in erections post radical prostatectomy - Viagra product monograph.

265

Concomitant medical conditions in men with ED are important to consider because of the possible adverse effects involved in sexual activity [see Appendix I]. Tables 5 a and b show the associated factors and medications applying to the men with ED involved in the sildenafil trials.

3. SPECIAL CONSIDERATIONS a) Cardiovascular disease: In the clinical studies there were no relevant ECG changes noted in normal male volunteers. There were transient decreases in blood pressure with sildenafil that were not associated with mean changes in heart rate. Although such effects are of little consequence to most patients, caution is advised in patients who may not be able to tolerate such changes (e.g. patients with aortic stenosis, hypertrophic obstructive cardiomyopathy, and patients with severely impaired autonomic dysfunction). In healthy volunteers with single oral administered doses of 100 mg there was a mean maximum decrease of 8.5 mm Hg for systolic and 5.5 mm Hg for diastolic blood pressure (see sildenafil label annex IV). The decreases in blood pressure were most notable approximately 1 to 2 hours after dosing and returned to normal within 8 hours. These blood pressure changes were not considered to be dose or plasma level related.

A subgroup analysis of men on antihypertensive agents were compared to men not on antihypertensive drugs. The hypertension-treated group reported sildenafil response at 70% compared to the age-matched group without hypertension treatment at 72%. Placebo-controlled reported response rates were 21% and 27%, respectively (Figure 5) [11]. Conti et al. [21] noted that patients with erectile dysfunction and ischemic heart disease who were not taking nitrate therapy tolerated sildenafil. See also Jackson et al, 1999 [22] for further discussion of hemodynamic changes in men with stable ischemic heart disease. Table 5 b: Concomitant medications in clinical trial patients.

Table 5 a: Predisposing factors for ED in clinical trial patients

ACE inhibitors

283

10%

Hypertension

656

24%

Ca Channel Blockers

266

10%

Diabetes mellitus

432

16%

Cardiovascular disease

376

14%

Beta Blockers Diuretics

123 112

5% 4%

Hyperlipidemia

389

14%

Insulin Oral anti-diabetic drugs

137 260

5% 10%

Spinal cord injury

175

6%

Depression

132

5%

Analgesics Drugs for hyperlipidemia

490 249

18% 9%

Radical prostatectomy 1

10

4%

Ulcer-healing drugs Antidepressant drugs

140 104

5% 4%

Regulatory submission database, placebo-controlled studies SILDENAFILN=2722, PLACEBO N=1552

Regulatory submission data base, placebo-controlled studies SILDENAFIL N=2722, PLACEBO N=1552

Figure 5: Improvement in erections in hypertensive patients

266

b) Effects on Color Discrimination : There may be a transient dose-related impairment of blue/green color discrimination. This is reported in less than 3% of patients and the effects on blue-green color discrimination have been shown to occur usually 1 to 2 hours post-dosing during peak plasma levels of the drug [4]. These pharmacological changes are consistent with the inhibition of PDE6 which is involved in retinal phototransduction and is the reason for the FAA recommending that pilots should not fly within 6 hours of using sildenafil. Sildenafil has no effects on visual acuity or intraocular pressure [4].

Table 6: Treatment-related adverse events and discontinua tion from treatment. PLACEBO (N=181) N

%

SILDENAFIL 50mg 100mg 200mg (N=189) (N=190) (N=191) N

%

N

%

N

%

Headache Flushing

7 (4) 7 (4)

34 (18) 37 (20)

58 (31) 37 (20)

63 (33) 33 (17)

Dyspepsia

2 (1)

11 (6)

38 (20)

35 (18)

Abnormal vision Discontinued treatment

0 (0)

3 (2)

28 (15)

80 (42)

9 (5)

5 (3)

4 (2)

9 (5)

Adapted from Morales [23] – Amsterdam meeting presentation 1998

c) Use in Special Populations

dicated to use sildenafil because of the risk of developing potentially life-threatening hypotension. As a PDE5 inhibitor sildenafil potentiates the hypotensive effects of cGMP generated by nitrates. The combination of sildenafil with organic nitrates can produce profound hypotension.

• Geriatric population A clinical study demonstrated that men older than 65 years had a significantly reduced apparent clearance of sildenafil after a single 50 mg dose. There was a 4% decrease in drug clearance for each age decade increase. • Hepatic impairment Clinical trials demonstrated that chronic stable hepatic cirrhosis altered the pharmacokinetics of sildenafil. In cirrhotic patients there was a 46% lower drug clearance leading to an 85% increase in drug exposure.

Data describing a safe interval between sildenafil and nitrates is not available, however patients should be warned prior to use of any nitroglycerin product that a 24-hour minimal time interval is likely required to allow for complete elimination of sildenafil in most men [9].

• Renal impairment Men with severe renal impairment, i.e. creatinine clearance <30mL/min, had significantly altered metabolism of sildenafil. The increased exposure to the active drug was attributed to a reduction in oral clearance. Men with lesser degrees of renal impairment metabolized the drug normally.

b) Precautions The labeled warnings which imply caution is required when sildenafil is administered to patients who were not studied in clinical trials at the time of review and approval.

Since higher plasma concentrations may increase both the efficacy and incidence of adverse effects, consideration should be given to starting patients who are older than 65 years, or with hepatic or severe renal impairment at a dose of 25 mg and increasing the dose as indicated [4].

- patients who have suffered a myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months - patients with resting hypotension (BP<90/50) or hypertension (BP>170/110) - patients with cardiac failure or coronary artery disease causing unstable angina

4. SAFETY PROFILE The safety profile of sildenafil is illustrated by both Table 6 and the sildenafil label (Annex IV). It should be noted that few patients discontinued treatment; the discontinuation rate was not significantly different from placebo in clinical trials (2.5% vs 2.3%) [4].

- patients with retinitis pigmentosa (a few of these patients have genetic disorders of retinal PDEs).

a) Contraindications

c) Post-Approval Safety Surveillance and Sponta neous Cardiac Reports

Patients requiring a complicated antihypertensive regime may also need to be cautioned when using sildenafil, as clinical data confirming safety in this population is limited [9].

Patients undergoing any short or long-acting nitra te drug therapy or nitric oxide donors are contrain267

Almost immediately following the FDAapproval of

sildenafil in the United States, reports of treatment associated cardiovascular adverse events began to appear in the lay press and were subsequently posted on an FDA website. The reports of sildenafillinked cardiovascular events generated great concern among patients and physicians, however their clinical significance remain undetermined. While some of the cases listed were clearly unrelated to drug intake (drowning and homicide) or based on heresay and unsupported statements alone, other reports were concerning about a possible increased cardiovascular risk among sildenafil users. The last update on this website was performed in November 1998. An initial revised label for sildenafil in November 1998 added the exclusion criteria from the phase 3 studies and reports of priapism in most marketing experience, not seen among the preapproval studies. A more recent labeling change occurred in November 1999 and included information on protease inhibitors and recent hemodynamic data (See label Table) [22]. For more detailed information the reader is referred to the product monograph (Annex IV).

As for all drugs, the manufacturer the FDA and regulators wolrldwide continue to monitor all spontaneous adverse reports in order to maintain the safe use.

5. SUMMARY Since the approval of sildenafil the clinical safety and efficacy of sildenafil has been studied in numerous trials that have includ patients with ED due to organic, non-organic, and mixed etiologies. Over the past 4 years sildenafil has undergone numerous multicenter placebo-controlled trials demonstrating efficacy, as shown in Table 8. Recently, individual center experiences with sildenafil from general urology practices have been published [34,35] that support the efficacy and safety data from the pre-approval submission. Improvement in ability to achieve and maintain a rigid erection (Questions 3 and 4 of the IIEF) show significant improvement. A 65-85% positive response is seen in most studies describing general improvement in quality of erections. Sildenafil appears to be an effective and well tolerated oral therapy for the treatment of ED across a broad spectrum of etiologies. The clinical data bank upon which this PDE type 5 inhibitor has achieved approval in 101 countries world-wide is impressive in scope and consistency. The interaction with nitroglycerin compounds and safety in subpopulations with ischemic heart disease, angina, and those who wish to use other erectogenic agents in a concomitant fashion remains to be elucidated in future studies. The use of this first oral therapy should not preclude the appropriate evaluation of the causes of sexual dysfunction. Satisfactory sexual function is an important part of a couple’s healthy relationship and ongoing quality of life.

In the interval since approval (March 1998), a vast clinical experience has been achieved which permits a more refined evaluation of the issue of cardiovascular impact and safety associated with sexual activity as its relates specifically to sildenafil use. Recently, pooled data from 53 studies (30 doubleblind and 23 placebo-controlled) trials involving an exposure of 6884 patient years for sildenafil was compared to those patients receiving placebo (543 patient years) has been reported (Table 7). Incidence rates of myocardial infarction and death per 100 patient years demonstrated no increase in the treatment arms compared to placebo [23]. Table 7: Incidence of serious adverse events

Myocardial Infarction*

Death*

Placebo (543)

1.11 (0.41-2.40)

0.74 (0.20-1.89)

Sildenafil DB (964)

1.45 (0.79-2.44)

0.83 (0.36-1.64)

Sildenafil OL (5920)

0.69 (0.50-0.94)

0.35 (0.22-0.54)

Sildenafil Total (6884)

0.80 (0.60-1.04)

0.42 (0.28-0.61)

*Data are mean incidence per 100 patient years (95% confidence interval) Adapted from Mittleman MM, Glasser DB, Orazem J, Collins M: Incidence of Myocardial infarction and death in 53 clinical trials of Viagra® (sildenafil citrate). J Am Col Cardiol 35(Suppl.A):302,2000.

268

Table 8: Table of sildenafil in clinical trials SILDENAFILIN ERECTILE DYSFUNCTION TREATMENT PERIOD IN WEEKS

SIL DOSE

REFERENCE Cuzin,1997 [25]

24

25 - 100 mg

Derry,1998 [16] Eardley,1996 [26] Goldstein,1998 [27]

Hodges,1997 [28]

4 4 24

12

NUMBER PATIENT/POPULATION RESULTS PATIENTS STUDIED DOSAGE %

OF

50 mg 25 - 75 mg 25 - 100 mg

25 - 100 mg

205

organic - 29% non organic - 32%

SIL PL

79 27

27

mixed - 36% organic - 100%

SIL

75

42

spinal cord injury non organic --100%

PL SIL

7 92

PL

27

organic - 78% non organic - 9%

25 mg 50 mg

56 77

mixed - 13%

100 mg PL SIL -

84 25 81

PL

18

532

111

organic - 40% non organic - 39% mixed - 8%

Holmgren,1998 [17]

6

50, 100 mg -

178

organic-100 % spinal SIL cord injury PL

76 NR

Lue,1997 [29]

8

5 - 100 mg

416

organic - 73%

5 mg

48

non organic - 9% mixed - 25%

25 mg 50 mg

61 73

100 mg PL

78 28

organic - 58% non organic - 17%

50 mg 100 mg

72 80

mixed - 25

200 mg PL

79 21

organic - 49% non organic - 7%

50 mg 100 mg

72 80

mixed - 44

200 mg PL SIL

79 21 84

PL

24

Morales,1998 [30]

Morales,1998 [30]

Montorsi, 1999 [31]

12

12

12

50 - 200 mg

50 - 200 mg

25, 50, 100mg

497

254

515

organic -29% non organic - 24% mixed - 46%

Montorsi,1998 [32]

Olsson,1996 [33]

12

4

25 - 100 mg

10 - 50 mg

514

351

organic - 43%

25 mg

67

non organic - 32% mixed - 25%

50 mg 100 mg

78 86

non organic - 58%

PL 10 mg

24 65

25 mg 50 mg

79 88

PL SIL

39 74

PL

19

mixed - 42%

Padma-Nathan,

44

25 - 100 mg

329

1998 [34] Rendell,1998 [12]

organic - 59% non organic - 15% mixed - 26%

12

50. 100 mg

Legends: SIL: sildenafil; PL: Placebo; NR: dose not recorded

269

268

organic-96% diabetic SIL mixed - 4% PL

57 10

3. CLINICAL STUDIES

II. IC-351

The effect on erectile function of IC-351 has been assessed in a Phase II study measuring Rigiscan response to visual sexual stimulation [1].

1. INTRODUCTION IC-351 is a selective orally available PDE-5 inhibitor. As discussed in the section on Sildenafil, phosphodiesterases (PDE’s) facilitate the hydrolysis of secondary messengers (c-AMPand c-GMP). Therefore PDE inhibitors would block cyclic nucleotides thereby increasing normal cellular signals by increasing secondary messenger concentrations.

44 patients with mild to moderate erectile dysfunction for at least 6 months duration, ages 21-60 were entered into a double-blind, placebo-controlled, single crossover study. Each patient therefore underwent 2 sessions, one with placebo and one with 100 mg of IC-351 given prior to Rigiscan monitoring of response to VSS. In addition the patient evaluated the best erection by a 5-point scale. Response to IC-351 was reported as the difference in Rigiscan values obtained during a previous placebo run-in phase. The increase in > 55% rigidity at the penile base was 1.43 ± 6.34 minutes for placebo and 9.43 ± 12.66 minutes for IC-351 (p<0.001).

PDE inhibitors will only work after appropriate stimulation has been forthcoming. To date 10 types of human cyclic nucleotide PDE’s have been identified. PDE-5 is the PDE specific for both cGMP and the human corpus cavernosum.

2. FEATURES IC-351

The mean increased area under the Rigiscan curve at the base was 179 +/- 558.7 for placebo and 723.8 ± 830 for IC351 (p<0.001). Similar effects were seen at the penile tip. The patient’s change in his erectile assessment was 0.5 for placebo and 1.6 for IC-351 (p<0.001). There were no significant adverse events, EKG or vital sign changes during the study.

IC-351 is a longer acting PDE-5 inhibitor than sildenafil and therefore may be effective over a much longer period of time. This property may be both a positive and negative element. Obviously if IC-351 remains active over many hours it preserves the ability to be spontaneous to a greater degree than a shorter acting PDE-5 inhibitor. However prolonged PDE-5 inhibition may cause more and prolonged side effects not seen with shorter acting agents.

The most common side effects were headache, back pain and dyspepsia. Two other larger placebo-controlled, double-blind multicenter safety and efficacy studies in mild to moderate ED have been performed to date with IC351. 300 patients at 19 sites undergoing a daily dose study were randomized to either 4 different doses of IC351 or placebo (5 groups) daily for 3 weeks.

Another potential specific improvement over sildenafil is the relatively poor inhibitory properties of IC-351 towards PDE-6 (found in the retina) in contrast with sildenafil. While sildenafil is only 10 times more potent against PDE-5 than PDE-6, IC351 is approximately 800 times more potent. Thus one would expect little in the way of visual adverse events with the use of IC-351 (see Table 1).

The study endpoints were change in IIEF responses (especially questions 3 and 4) as well as personal diaries. In another study, 175 patients underwent an on-demand study and were randomized to the same 5 groups. Patients were permitted to take up to 14 pills in a 21-day period.

Table 1: IC351 Selectivity PDE

IC50 (nM)

Human PDE 5

0.9 ± 0.12

Human PDE 6

730 ± 120

The endpoints in this study were similar to those of the daily dose study. Unfortunately the results of these studies are not yet available for analysis.

Data provided by ICOS/Lilly

270

supplements in concentrations of 13.2 g/L and 23.2 g/L. Patients have taken 10 g of arginine per day over prolonged periods without adverse effects. Arginine is absorbed in the gut and reaches peak levels in about 2 hours. Radio-labelled Larginine studies have shown that approximately 1% of dietary L-arginine is excreted as labeled nitrate in the urine.

NO DONORS L-ARGININE/YOHIMBINE 1. INTRODUCTION AND COMBINATION RATIONALE

The combination of drugs that can produce direct smooth muscle relaxation along with blocking aadrenergic contraction has proven beneficial in treating erectile dysfunction in man. Alpha blocking agents have been shown clinically to potentiate the effects of direct vasodilators in the area of intracorporal pharmacotherapy with the combination of Papaverine and/or prostaglandin E-1 (both smooth muscle relaxants) with phentolamine. It has recently been shown that the ability of yohim bine to relax endothelin contracted corporal muscle strips was significantly enhanced by nitrosylated yohimbine [1].

3. CLINICAL STUDIES: L-ARGININE ALONE Intravenous arginine infusion (30 g over 60 minutes) has been successfully used to produce NO-dependent vasodilatation in cases of severe limb ischemia [2]. Femoral artery blood flow was significantly improved by 8%, while urine levels of NO3- and c-GMP increased by 39.5% and 84.9%, respectively. These effects were not seen with infusion of placebo. In another study, patients with congestive heart failure were treated with oral arginine, 5.6-12.6 grams or placebo daily for 6 weeks [3]. L-arginine significantly improved forearm blood flow in response to exercise, increased distances achieved during a 6-minute walk, improved arterial compliance and decreased circulating endothelin levels as compared to placebo in these patients. In 1994 Zorgniotti [4] treated 20 impotent men with 2800 mg of L-arginine vs. a placebo daily for 2 weeks. The placebo was given first. Patients older than 65 years or with significant vascular risk factors were excluded. Six of the 15 patients who completed the study responded positively to L-arginine treatment. None of the placebo group responded. The responders were younger and had better penile arterial pressures than the nonresponders. In 1999 Chen et al. randomized 50 patients with organic ED to 5 g of L-arginine per day and placebo. Patients responded to the O’Leary sexual questionnaire, recorded sexual diaries and underwent penile duplex ultrasonography. In addition, serum levels of nitrites and nitrates were determined pre- and post-therapy. 31% of the treated group and 11% of the placebo group reported subjective improvement of their erections. There was no difference between these groups or between responders and non-responders in terms of objective results of duplex ultrasonography (i.e. peak

This action was further potentiated by Zaprinast, a selective PDE-5 inhibitor. There was also a concentration-dependent increase of tissue c-GMP seen with nitrosylated yohimbine but not with yohimbine alone. These observations demonstrate that nitosylated a-blockers act as NO donors as well as an alpha blocking agents. In addition it has been shown that intracavernosal injections in the rabbit of nitrosylated yohimbine produced higher intracavernosal pressures for longer duration than the injection of yohimbine alone. The enhancement of yohimbine corporal smooth muscle relaxation by nitrosylation formed the rationale for combining yohimbine with L-arginine, a NO precursor, for the treatment of erectile dysfunction.

2. P HARMACOLOGY Yohimbine has previously been presented in this chapter. Arginine is an endogenous amino acid, which plays an essential role in protein synthesis. In addition it is a precursor of NO in the equation: arginine + O2 = NO + citrulline in the presence of NOS. Arginine is available in the United States as a non-prescription food supplement sold in 700 mg tablets. It is also available in liquid nutritional

271

systolic velocity, end-diastolic velocity or resistive index). Urinary and serum nitrate and nitrite levels were statistically increased in the L-arginine treated group. Initial levels of these metabolites were significantly lower in responders than in nonresponders. No side effects were noted [5]

E. POTENTIAL COMBINATION THERAPIES ERECTILE INITIATORS - apomorphine - melanotan II PERIPHERAL SMOOTH MUSCLE RELAXANTS: - PDE-5 inhibitors - alpha blocking agents - NO precursors

4. CLINICAL STUDIES: L-ARGININE AND YOHIMBINE Recently, two studies in men with mild to moderate erectile dysfunction have been performed using the combination of L-arginine and yohimbine. Padma-Nathan [6] performed a double-blind, crossover study between L-arginine (6 g) and yohimbine (6 g) (A/Y) vs. Yohimbine and placebo (Y/P) on 20 patients. Initially patients were tested with placebo/placebo (P/P) in a single-blind fashion prior to randomization. Doppler ultrasound of the cavernosal arteries was performed in intervals between 60 and 105 minutes following the 3 combinations in 3 separate visits. Mean peak systolic velocities at 60 minutes were 13.47, 10.6 and 6.44 for A/Y, Y/P and P/P, respectively. The results seen with the drug combination (A/Y) were statistically significant compared to placebo (P/P). This was not true for yohimbine alone (Y/P vs. P/P) In another study, Barre [7] et al used the same three groups (A/Y, Y/P, P/P) to treat 48 patients with ED on demand in the home setting. Efficacy was assessed by the IIEF. In this study, the erectile function domain response statistically improved in men in the A/Y group as compared to the P/P group (p=0.004) and showed a trend to improvement as compared to the Y/P group (p=0.096). The global sexual satisfaction score was statistically improved in the A/Y group as compared to the Y/Pgroup (p=0.047) and P/P group (p=0.022).

Combination therapy may involve any number of agents until a desired effect is obtained or side effects become intolerable. It would seem plausible that the erectile response of an initiator should be enhanced by the addition of a peripherally acting corporal smooth muscle relaxant. Drugs that act on the CNS would be expected to ultimately stimulate NO release in an enhanced manner by facilitating sacral parasympathetic nerves. They presumably work by delivering more NO than the normal physiological response. Therefore patients who fail peripherally acting agents should theoretically have increased corporal smooth muscle relaxation by combining a peripherally with a centrally acting drug. Two recent papers addressed this issue of central and peripheral synergy. Heaton studied the impact of severe stress induced by adrenergic stimulation on erections induced by apomorphine alone, sildenafil alone or a combination. Andersson et al. [1] recorded intracavernosal pressures in the awake rat after subcutaneous apomorphine injection. The intracavernosal pressure increases following apomorphine injection was prolonged (from 37 to 62 s) and increased (area under the curve: from 67 to 142) by an intravenous injection of sildenafil. Brien et al. [2] demonstrated that in the rat the rate of apomorphine induced erections in the presence of hyperadrenergic “stress” (produced by ip. methoxamine) was improved after intraperitoneal administration of sildenafil.

5. CONCLUSION It should be noted that in many countries both Yohimbine and L-arginine are available as over the counter drugs (i.e. no prescription needed). The adverse effects of this combination were minimal. It would appear that larger Phase III studies are required to determine the efficacy of these drugs for the treatment of milder forms of ED.

As with combination therapy used for intracavernosal pharmacotherapy, synergies exist between peripherally acting agents. Thus combined therapy with two or three of the peripheral agents would seem likely to successfully treat a larger percenta-

272

ge of ED patients than using one agent alone. As the addition of phentolamine (blocks smooth muscle contraction) enhanced the results of Papaverine (promotes smooth muscle relaxation) intracavernosal injections alone, so may the addition of oral phentolamine add to the performance of a PDE-5 inhibitor. Combination therapy with yohimbine and L-arginine attempts clinically to prove this principle.

expected in many cases to act synergistically as their modes of action usually differ. With the expected FDA approval of more of these agents, we can therefore expect a wide array of potential combination therapies. If this becomes the case one can expect that the primary care physician will continue to orchestrate ED treatment with a wider array of therapeutic possibilities. The urologist who had been the primary physician for the treatment of ED prior to successful oral drug therapy will most likely in the future see less and less early ED and more and more organic disease. The questions raised in the introduction of this chapter regarding the role of the psychologist and the new diagnostic algorithm will certainly need to be addressed. Another byproduct of better and improved medicines and combination therapies may well be patients seeking treatment with earlier disease.

FUTURE COMBINATION THERAPIES ORAL DRUGS:

SITE OFACTION

Apomorphine and sildenafil

central and peripheral

Apomorphine and phentolamine

central andperipheral

Apomorphine, sildenafil and phentolamine

central and peripheral

Sildenafil and phentolamine

central and peripheral

In the future newer drugs will assuredly be developed to treat ED. An endothelin antagonist and a protein G inhibitor are just beginning clinical trials. More specific and longer acting PDE-5 inhibitors are also undergoing clinical trials.

This will be much the same as the experience with the advent of oral agents for benign prostatic hyperplasia when patients with mild symptoms who would not have sought treatment when only surgical therapy was available began taking oral agents. This may initially increase the number of new patients for ED therapy but eventually a steady state will be reached with a larger proportion of patients with earlier vascular disease which will be more amenable to oral medicines.

Within several years it would be expected that 3 or 4 drugs will be FDA approved and clinically available for ED treatment. Basic science investigations have shown that the natural history in most agerelated (vasculogenic) ED begins with mild arterial insufficiency and progresses to more severe arterial damage and secondary corporal collagen replacement and venous leak. It would be interesting if oral treatment (which as mentioned above will begin at the stage of mild arterial disease) will be able to alter the natural history of the disease by promoting erections and thereby bringing oxygen rich blood to the corporal muscle. This may forestall collagen replacement of the corporal smooth muscle despite progressive worsening of the arterial insufficiency and allow oral agents to work for a longer period of the patient’s life.

Again the urologist will be seeing patients with more advanced ED who have failed oral drugs.

REFERENCES APOMORPHINE 1.

2.

F. CONCLUSION

3.

This chapter has attempted to critically review the oral agents (with the addition of melanotan II) presently available for the treatment of ED. These drugs can be classified with respect to their pharmacologic action in several ways. They can be

4.

273

MCGUIRE EJ, BLOOM D, CATALONA WJ, LIPSHULTZ LI, Advances in Urology, 9: 1996, MosbyYear Book, Inc. MORALES et al. The pharmacological basis of sexual therapeutics in: Erectile Dysfunction, Andersson, K-E and Steers, W. eds. Martin Dunitz, London,1998 GIULIANO F, BERNABE J, RAMPIN O, BENOIT G, JARDIN A. Intracavernous pressure monitoring of psychogenic and Apomorphine induced erections in the rat. Int.J. Impot. Res., 8, 3 1996. CHEN KUANG-KUO, CHAN J, CHAN S AND CHANG L. Elicitation of penile erection after administration of Apomorphine to paraventricular nucleus of hypothalamus in the rat. Int.J. Impot. Res. 8, 3 1996.

5.

LAL S, ACKMAN D, THAVUNDAYIL JX, et al (1984). Effect of apomorphine, a dopamine receptor agonist, on penile tumescence in normal subjects. Prog Neuropsychopharmacol Biol Psychiatry 8:695-9.

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DROLET G, ADAMS M, HEATON J, Evidence for the central sites of action of Apomorphine-induced erections. Int.J. Impot. Res., 8: 3 ,1996.

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Mc KENNA K.E. Central control fo penile erection.Int.Int.J. Impot. Res., 10, Suppl.1, s25-s34, 1998.

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DANJOU P, ALEXANDRE L, WAROT D, LACOMBLEZ L, AND PUECH AJ: Assessment of erectogenic properties of apomorphine and yohimbine in man. Br J Clin Pharmacol 26: 733-739, 1988.

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LAL S, TESFAYE Y, AND THAVUNDAYIL JX, et al. Apomorphine: clinical studies on erectile impotence and yawning. Prog Neuropsychopharmacol Biol Psychiatry 13:329-39,1989. SEGRAVES RT, BARI M, SERGRAVES K, AND SPIRNAK P: Effect of apomorphine on penile tumescence in men with psychogenic impotence. J Urol 145: 1174-1175, 1991. LAL S, LARYEA E, THAVUNDAYIL JX, NAIR NP, NEGRETE J, ACKMAN D, BLUNDELL P, AND GARDINER RJ: Apomorphine-induced penile tumescence in impotence patients-preliminary findings. Prog Neuropsychopharmacol Biol Psychiatry 11:235-242, 1987. HEATON JPW, MORALES A, ADAMS MA, JOHNSTON B, EL-RASHIDYR, Recovery of erectile function by the oral administration of apomorphine. Urology 45:200-6,1995. PADMA-NATHAN, H, FROMM S, RUFF D, ROSEN R, MCMURRAY J,. Efficacy and safety of apomorphine sl vs. placebo for male erectile dysfunction (MED). J. Urol 159:241S,1998. PADMA-NATHAN H, AUERBACH S, LEWIS R, LEWAND M. Efficacy and safety of apomorphine sl vs. placebo for male erectile dysfunction. J. Urol 161: 214S, 1999. LEWIS R, AGRE K, FROMM S, AND RUFF D. Efficacy of apomorphine sl vs. Placebo for erectile dysfunction in patients with hypertension. J. Urol 161: 214S,1999.

10.

11.

12.

13.

14.

15.

adrenocorticotropin connection. Ann NY Acad Sci 1988;515:330-337. 4.

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YOHIMBINE

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SILDENAFIL

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278

ANNEXES I - IV

ANNEX I RISK FACTORS FOR CARDIOVASCULAR DISEASE MEDICAL CONDITIONS ASSOCIATED WITH ED

ANNEX II INTERNATIONAL INDEX OF ERECTILE FUNCTION QUESTIONNAIRE

ANNEX III USE OF SILDENAFIL (VIAGRA) IN PATIENTS WITH CARDIOVASCULAR DISEASE (ACC/AHA CONSENSUS)

ANNEX IV VIAGRA® (SIDENAFIL CITRATE) LABEL (Revised June 1999)

279

ANNEX I

Risk Factors for Cardiovascular Disease Family history of CHD <55 years old Current smoking Hypertension >140/90 mmHg or on antihypertensive medication HDLCholesterol <35 mg/dL Diabetes mellitus Lack of exercise Adapted from:Wilson PWF, Culleton BF: Epidemiology of cardiovascular disease in the United States. Am J Kidney Dis, 32, S56-S65, 1998.

Medical conditions associated with ED CANADA

FRANCE

GERMANY

ITALY

SPAIN

UK

Heart disease

52%

45%

32%

39%

36%

19%

High blood pressure

33%

33%

62%

24%

21%

30%

Diabetes

36%

13%

20%

20%

20%

6%

Depression

13%

15%

13%

23%

10%

13%

Severe stress

17%

20%

13%

11%

10%

13%

Adapted from: Truica T, Sweeney M: Concomitant medical conditions in men with erectile dysfunction from six countries:results of the men’s health survey. Abstract of the First World congress on the Aging Male, 1998.

280

ANNEX II INTERNATIONAL INDEX OF ERECTILE FUNCTION QUESTIONNAIRE Please answer the following questions as honestly and clearly as possible. In answering these questions the following definitions apply: ❑ Sexual activity included intercourse, caressing, foreplay and masturbation. ❑ Sexual intercourse is defined as vaginal penetration of the partner (you entered your partner) ❑ Sexual stimulation includes situations like foreplay with a partner, looking at erotic pictures, etc ❑ Ejaculation is defined as the ejection of semen from the penis (or the feeling of this) Please answer the following questions for the past -------weeks by checking one box per question. 1. HOW OFTEN WERE YOU ABLE TO GET AN ERECTION DURING SEXUALACTIVITY ? ❑ No sexual activity ❑ Almost never/never ❑ A few times (much less than half the time) ❑ Sometimes (about half the time) ❑ Most times (much more than half the time) ❑ Almost always/always 2. WHEN YOU HAD ERECTIONS WITH SEXUAL STIMULATION, HOW OFTEN WERE YOUR ERECTIONS HARD ENOUGH FOR PENETRATION? ❑ No sexual activity ❑ Almost never/never ❑ A few times (much less than half the time) ❑ Sometimes (about half the time) ❑ Most times (much more than half the time) ❑ Almost always/always 3. WHEN YOU ATTEMPTED SEXUAL INTERCOURSE, HOW OFTEN WERE YOU ABLE TO PENETRATE (ENTER) YOUR PARTNER? ❑ Did not attempt intercourse ❑ Almost never/never ❑ A few times (much less than half the time) ❑ Sometimes (about half the time) ❑ Most times (much more than half the time) ❑ Almost always/always

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4. D URING SEXUAL INTERCOURSE, HOW OFTEN WERE YOU ABLE TO MAINTAIN YOUR ERECTION AFTER YOU HAD PENETRATED ( ENTERED) YOUR PARTNER? ❑ Did not attempt intercourse ❑ Almost never/never ❑ A few times (much less than half the time) ❑ Sometimes (about half the time) ❑ Most times (much more than half the time) ❑ Almost always/always 5. DURING SEXUAL INTERCOURSE, HOW DIFFICULT WAS IT TO MAINTAIN YOUR ERECTION TO COMPLETION OF INTERCOURSE? ❑ Did not attempt intercourse ❑ Extremely difficult ❑ Very difficult ❑ Difficult ❑ Slightly difficult ❑ Not difficult 6. HOW MANY TIMES HAVE YOU ATTEMPTED SEXUAL INTERCOURSE? ❑ No attempts ❑ One to two attempts ❑ Three to four attempts ❑ Five to six attempts ❑ Seven to ten attempts ❑ Eleven + attempts 7. WHEN YOU ATTEMPTED SEXUAL INTERCOURSE, HOW OFTEN WAS IT SATISFACTORY FOR YOU? ❑ Did not attempt intercourse ❑ Almost never/never ❑ A few times (much less than half the time) ❑ Sometimes (about half the time) ❑ Most times (much more than half the time) ❑ Almost always/always 8. HOW MUCH HAVE YOU ENJOYED SEXUAL INTERCOURSE? ❑ No intercourse ❑ No enjoyment ❑ Not very enjoyable

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❑ Fairly enjoyable ❑ Highly enjoyable ❑ Very highly enjoyable 9. WHEN YOU HAD STIMULATION OR INTERCOURSE, HOW OFTEN DID YOU EJACULATE? ❑ No sexual stimulation/intercourse ❑ Almost never/never ❑ A few times (much less than half the time) ❑ Sometimes (about half the time ) ❑ Most times (much more than half the time) ❑ Almost always/always 10. WHEN YOU HAD SEXUAL STIMULATION OR INTERCOURSE, HOW OFTEN DID YOU HAVE THE FEELING OF ORGASM OR CLIMAX? ❑ No sexual stimulation/intercourse ❑ Almost never/never ❑ A few times (much less than half the time) ❑ Sometimes (about half the time) ❑ Most times (much more than half the time) ❑ Almost always/always The next two questions ask about sexual desire. Let’s define sexual desire as a feeling that may include wanting to have a sexual experience (for example, masturbation or intercourse), thinking about having sex, or feeling frustrated due to lack of sex. 11. HOW OFTEN HAVE YOU FELT SEXUAL DESIRE? ❑ Almost never/never ❑ A few times (much less than half the time) ❑ Sometimes (about half the time) ❑ Most times (much more than half the time) ❑ Almost always/always 12. HOW WOULD YOU RATE YOUR LEVEL OF SEXUAL DESIRE? ❑ Very low/none at all ❑ Low ❑ Moderate ❑ High ❑ Very high

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13. HOW SATISFIED ARE YOU WITH YOUR

OVERALL SEX LIFE?

❑ Dissatisfied ❑ About equally satisfied and dissatisfied ❑ Very dissatisfied ❑ Moderately satisfied ❑ Very satisfied 14. H OW SATISFIED HAVE YOU BEEN WITH YOUR SEXUAL RELATIONSHIP WITH YOUR PARTNER? ❑ Dissatisfied ❑ About equally satisfied and dissatisfied ❑ Very dissatisfied ❑ Moderately satisfied ❑ Very satisfied 15. H OW DO YOU RATE YOUR CONFIDENCE THAT YOU COULD GET AND KEEPAN ❑ Very low ❑ Low ❑ Moderate ❑ High ❑ Very high REPRODUCED WITH PERMISSION OF THE AUTHOR.

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ERECTION?

ANNEX III USE OF SILDENAFIL (VIAGRA) IN PATIENTS WITH CARDIOVASCULAR DISEASE (ACC/AHA CONSENSUS) The American College of Cardiology and American Heart Association convened an Expert Consensus Panel to evaluate the use of Sildenafil in patients at risk for cardiovascular side effects. The full report has been published. The Writing Group reviewed the published data available on Viagra and also the unpublished data provided by the manufacturer of Viagra, Pfizer, Inc. The document was subjected to external review and approved by both the ACC and AHA.

congestive heart failure and borderline low blood pressure and borderline low volume status. These patients might be unusually sensitive to the hypotensive effects of Viagra. It is recommended that these patients be started at a very low dose to be sure that hypotension does not occur. The Viagra dose can then be titrated up without resumption of intercourse to be sure that the normal dose of 50 to 100 mg is well tolerated. If so, the patient could then be advised to resume sexual activity. A third group would be those patients on complicated multi-drug antihypertensive programs. Most of these patients should be able to take Viagra safely and indeed there is now more experience indicating that that is true. Nevertheless, it would be reasonable to be sure that the normal dose of Viagra does not cause and unusual drop in blood pressure in the individual patient before resuming sexual activity.

We wish to emphasize that most patients with cardiovascular disease can safely take Viagra. On the other hand, Viagra is absolutely contraindicated in patients taking nitrate therapy in any form. Nitrates should not be taken for twenty-four hours before or after the use of Viagra. Other groups of patients were identified where individual clinical evaluation should be made before prescribing Viagra. The first group is those with coronary artery disease and possible active ischemia. If these patients have not be evaluated for some time, a repeat exercise test might be indicated to rule out active ischemia which might be precipitated by resumption of intercourse. The second group of patients would be those with

It should be emphasized that sexual activity carries with it its own emotional and physical stresses. Thus, the cardiac patient resuming sexual activity should be advised to do so with relative equanimity.

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ANNEX IV

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287

288

289

290

291

292

293

294

295

ANNEX IV VIAGRA® (SIDENAFIL CITRATE) LABEL (Revised June 1999)

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297

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300

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Committee 9

Local Pharmacological Treatment Modalities

Chairman R.VIRAG

Members E. BECHER, S. CARRIER, F. GOVIER, K. M C VARY, H.C. MCMAHON, H. PORST

305

CONTENTS

D. CLINICAL STUDIES

A. INTRODUCTION AND HISTORICAL FEATURES

I. COMPARATIVE EFFICACY OF INTRACAVERNOUS MEDICATIONS

B. STATE OF THE ART INTERNATIONAL OVERVIEW I. STUDY DESIGN AND METHODOLOGY

II. COMPARATIVE EFFICACY OF INTRACAVERNOUS AND INTRAURETHRAL THERAPY

II. MEDICATIONS IN USE

III. COMPARATIVE EFFICACY OF ORALAND INTRACAVERNOUS THERAPY

III. TECHNIQUES

IV. LONG-TERM FOLLOW-UP IV. COMPLICATIONS V. DROP-OUT RATE (TABLE 5)

E. GUIDELINES FOR LPT

C. SPECIFIC MODALITIES

I. GENERAL OVERVIEW OF PRACTICE

I. GENERAL COMMENTS II. INJECTION TOOLS AND TECHNIQUES

II. INTRACAVERNOUS MONOTHERAPY

III. BEHAVIOR TOWARDS THE PARTNER

III. INTRACAVERNOUS BI THERAPY IV. INTRACAVERNOUS TRIPLE AND MULTIPLE COMBINATION THERAPY

F. THE FUTURE OF TOPICAL THERAPY

V. TRANSURETHRAL DRUG THERAPY

G. CONCLUSIONS

VI. TOPICAL THERAPY FOR ERECTILE DYSFUNCTION

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Local Pharmacological Treatment Modalities R.VIRAG E. BECHER, S. C ARRIER, F. GOVIER, K. M C VARY, H.C. M C MAHON, H. P ORST never been fully explained. The present review is an attempt to clarify the possibilities, results and main guidelines of the available local pharmacological treatment modalities (LPTM).

A. INTRODUCTION AND HISTORICAL FEATURES The concept of local pharmacological treatments of erectile dysfunction (ED) is found far back in history in the Arabian, Greek and Roman worlds when all sorts of ointments, herbs and medications were applied locally to the genitals to enhance “vigor”. The modern era started with the development of artificial erection as a tool for the diagnosis of ED: Michal and Virag [1] separately reported improvements after sessions of provoked erections with saline in patients with arterial impotence. Then came the first reports of pharmacologically induced erections with papaverine [2] and phenoxybenzamine [3]. The initial therapeutic use of injections was the use of artificial erection of mixed saline and vasoactive agents (papaverine and saline) to enhance natural erections. Then emerged the concept of self-injection therapy [4]. In the beginning, the main concern was priapism, followed by concerns about possible local modifi cations which limited the long-term use of treatment but strongly stimulated research for improved methods of treatments such as topical, intraurethral, or oral modalities. Nevertheless, the efficacy of local therapy was never challenged, and continuously improved. PGE1 was introduced in 1986. Several drug combinations have increased the overall efficacy rate of injection therapy to as high as 90% of the ED population. Automatic injection improved the acceptance of the technique. The use of α adrenergic agents to reduce the risk of priapism and a better knowledge of the medications and their dosage have made the technique safer and more effective [5]. Finally, until the recent appearance of oral therapy, intracavernous injections (ICI) were the most frequently used treatment for ED. Its long-term use is challenged by a high drop-out rate whose reasons have

B. STATE OF THE ART INTERNATIONAL OVERVIEW I. STUDY DESIGN AND METHODOLOGY Each committee member was given a questionnaire (Figure 1), which he had to distribute to as many colleagues as possible. We received 277 answers concerning about 100,000 patients. These results represent a trend which does not pretend to be a multicentre evaluation according to accepted standards. • Geographical origin: 60% of Centers are loca ted in North America, 20% in Europe, 13% in Latin America, and 1.2% in Asia and Africa. • Main speciality of each center: 83% are urologists and 4.4% are andrologists; while 11% are cardiovascular specialists; all but one from Europe. • Number of patients/center: the average number of patients followed is 175/center with great discrepancies from less than 50 to 5,000 • Duration of follow-up: 80% of centers started their programs at least 5 years ago; and 64% have a ten-year experience of injection therapy. • How are patients monitored ? Mostly by visits only (80%). Controls are performed twice-yearly for the majority of centers (58%) or yearly for 36%. 307

before considering treatment for priapism. Patients might be concerned by excessively pro longed erection and anxiety concerning priapism.

II. MEDICATIONS IN USE Two sorts of information are available: which medications are used and in what proportion. (Figure 2). Alprostadil is the leader and is used by 68% of the centers, as “first line” intracavernous medication in 47% of cases. Triple and multicombination therapy is used by more then 50% of centers, but only 14% use it as their most frequent medication.

6. DEPENDENCY ON THERAPY: 35% of patients use treatment for each sexual attempt; 35% use it 50 to 75% of the time. Almost 25% report intermittent use of the medication; mainly when they feel the need for it.

7. PREVENTION AND TREATMENT OF PRIAPISM:

III. TECHNIQUES (FIGURE 3) 1. HOW DO PATIENTS INJECT ? 62% manually, 31% with an automatic injector and 7% with both techniques. Some comments mention that many patients start with the automa tic injector because they fear to inject manually but subsequently give up the automatic tool, to simplify treatment.

2. HOW ARE MEDICATIONS AND DOSES DETERMINED ? A majority (58%) uses multidisciplinary evaluation, including pharmacological testing; 42% associate it with home trials. One third of the answers mention home trials as the usual way to titrate treatment. In one study, it appears that the dropout rate is much higher when patients were treated without any evaluation.

In 33% of centers, oral α blockers are prescribed, 9% use self-administered intracavernous α blockers, 40% use cold and exercise. Those centers using a preventive self injection technique did not observe any cases of priapism. (see below V. Gui delines for LPTM)

8. ADDITIONAL TREATMENTS: 75% of centers mention at least one additional treatment or regimen; stop smoking (69%) and anti fat treatment (47%) are much more common than sexual counseling (34%) and relaxation (22.5%)

IV. COMPLICATIONS Each center was asked about general and local complications and duration of erection (Figure 4) • general complications: no cerebral, 17 cardiac events (with one death) and 19 episodes of hypotension without consequences. • local complications: about 70% of centers mention nodules and fibrosis, and 57% Peyro nie’s like plaques. Nevertheless, they are present in less than 20% of patients and are responsible for drop-out in less than 10%. Pria pism is mentioned by 36% of centers, but in less than 10% of patients.

3. FREQUENCY OF INJECTIONS: 84% of patients use the injection once (34%) to twice (35%) per week. Frequent users (2.5 times and more) are less than 5%.

4. DURATION

OF ERECTION (average per injection per center): the majority (62%) reports durations between 60 and 90 minutes; in 4% the average duration exceeds 90 minutes, and in 6% it is less than half an hour.

V. DROP-OUT RATE (FIGURE 5)

5. TIME ALLOTTED BEFORE PRIAPISM TREATMENT:

The average drop-out rate for all centers is 40%; for one third of centers, the rate is less than 30%. In addition reasons for stopping treatment are not all related to the technique: stopping any sexual activity is mentioned by 56% of centers for about

60% of centers allow four hours and more, 33% limit it to three hours and 7% are restrictive giving a two-hour delay. There is a higher percentage of drop-out in those centers allowing a longer time

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Figure 1: Local pharmacological treatment modalities, international survey

Figure 2: International questionnaire data, medications in use in the different centers

Figure 3: International questionnaire data, practical design of self injection

309

Figure 4: International questionnaire data: duration of erection

Figure 5: International questionnaire data, indications of LPTM since the availability of oral therapy (n=46,000)

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20% of the patients stopping treatment. So-called “cured” (i.e. patients who no longer need the treatment) is present in 57% of the reports for 5 to 20% of the drop-out rate. Thus, the average dropout rate linked to the technique is close to 20%: it concerns decreased efficacy (mentioned in 66%), partner’s hostility (43%), cost (45%) and local side effects (67%), and switch to another treatment (see below and Figure 5).

because of the fear of injections, other local administration techniques were tested. Intraurethral therapy with alprostadil was approved in 1997 and topical administration still seeks its efficacy and development. All these aspects are discussed in this chapter.

II. INTRACAVERNOUS MONOTHERAPY

1. C HANGE IN LPTM SINCE ORAL THERAPY (FIGURE 5):

1. PAPAVERINE

• Switch to oral therapy: it concerns 60% of the centers; they announce between 10 to 50% switch to oral therapy. Nevertheless, the switch rate seems to have decreased during the last months of the study. Several centers reported variable number of returns to injection therapy.

The first published data on the use of papaverine in impotence, relates its injection into an epigastric artery bypassed into the corpus cavernosum of an impotent man (Michal I operation) which gave a 2hour injection, under anesthesia with clamping of the grafted epigastric artery Virag [1].

• Indications (Figure 5): In 37% of centers, oral therapy is proposed to all patients (these are mostly American centers); 22.5% rely on pharmacological testing to make a decision; 36% offer the choice to the patient, and 19% still consider LPTM as first-line treatment. Finally, 50% of the proposed local treatments were actually started.

a) Chemistry and penile pharmacodynamics Discovered by Merck in 1848 in the "papaverum somniferum", papaverine is a benzylquinoline synthesized from tyrosine. Known as a spasmolytic medication and used to activate cerebral circulation, the drug was well known by vascular surgeons for its capacity to strongly relax spasm in any artery. By non-specific inhibition of the phosphodiesterases which normally inactivate cGMP, papaverine is able to relax the erectile smooth muscle independently any sexual stimulation. The efficacy and duration of the "erectile blockade" is dose-dependent in functioning erectile tissue. Whether papaverine is able to act on the venous return remains controversial: studies by Wespes [6] and more recently by Virag and Sussman [7] show differences in the capacity to block the venous outflow, independently of intracavernous pressure, suggesting an active mechanism. Clinical experience using large doses (up to 80mg) of papaverine also suggests an active mechanism, as reversible prolonged erection (priapism) was achieved in 25% of cases. Mikhailidis and Jeremy [8] hypothesized that this might be the consequence of an increased production of prostacyclin by the penile endothelium. In any case, papaverine is the most powerful medication, used in isolation, to induce and maintain an erection. When injected in the penis at a low dosage (8mg), it cannot induce erection, by itself, but the effect of papaverine is

C. SPECIFIC MODALITIES I. GENERAL COMMENTS Numerous agents have been used as monotherapy, dual therapy or combination therapy since the initial use of papaverine by Virag [2] and phenoxybenzamine by Brindley [3]. Many of these agents had been marketed for other indications and were tried by clinicians in prospective trials without double-blind control. When monotherapy failed, dual or combination therapy was proposed as an alternative. In addition, economic concerns were raised when specific medications were developed by manufacturers and proved to be much more expensive than previous medications (see guidelines below). Basic and clinical research conducted following the development of ICI therapy gave support to the use of these compounds initially tested only on a clinical basis. Furthermore, and

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enhanced by sexual stimulation Virag [9]. Finally, it is the agent most frequently used in dual and combination therapy (see below). When injected in the systemic circulation, 90% of the medication is metabolized by the liver. Papaverine should therefore be avoided in patients suffering from liver disease. In a retrospective literature review (see below Porst Table 1), elevated liver enzymes were present in 1.6% of cases. Liver function should be monitored once a year in patients treated with papaverine.

2. ALPROSTADIL (PROSTAGLANDIN E1) a) History of alprostadil (PGE1) The name prostaglandin is derived from the discovery of U.S. Euler in 1935, who found a blood pressure lowering substance in considerable concentrations in seminal and prostatic secretions. The detailed chemical structure of PGE1 was described by Bergström et al [12] in 1963. Since 1973, PGE1 has been increasingly used for the treatment of peripheral arterial occlusive disease and was officially approved in 1984 in Germany for the parenteral treatment of Fontaine’s stage III and IV disease of the lower limbs. In 1983 PGE1 was also officially approved in the United States to maintain patency of the ductus arteriosus in socalled blue babies.

b) Clinical use The recommended formulation is papaverine hydrochloride in 30 (North America) to 40 mg/ml (Europe) vials. The solution is acidic and responsible for burning when injected. Some authors therefore recommend dilution in 10 ml saline vials to avoid burning and scarring. The relationships between scarring, penile fibrosis and papaverine are controversial. An experimental study (Lue [10]) in monkeys demonstrated an increased rate of fibrosis. Ageneral review (see below) showed a 5.7% rate of penile fibrosis with papaverine in 1056 cases. The role of papaverine in this effect is unclear. The injection technique, the volume injected, and the frequency seem to play a role as well. A retrospective study (Virag) of 1327 cases with a minimum 5 years follow-up, found a dose of papaverine over 40mg and volume injected over 1 ml to be the main factors responsible for fibrosis. In addition, personal susceptibility could also be part of the problem, as most of the fibrosis cases occur early in the course of treatment. Lastly, fibrosis rate is higher with papaverine phentolamine mixture than with papaverine alone (see below). This complication can be observed with alprostadil. The average efficacy of papaverine is 60% with dosages between 20 to 110 mg. c) Papaverine today In a very long-term study, Virag [10] on 2352 patients treated by ICI, 25% still use papaverine, at a dosage below 40mg/ml. Efficacy, low cost and available local treatment to reverse priapism (see below Prevention and management of complications) make papaverine still suitable for intracavernous therapy. Recommendations will be to use it at a dose not exceeding 40mg and at a maximum volume of 1 ml.

First reports on the beneficial effects of PGE1 in self-injection therapy in erectile dysfunction were presented by Akaikan et al [11] and Ishii et al [19]1986 at the Second World Meeting on Impotence in Prague. The promising preliminary results were confirmed by further studies by Stackl et al [36] and Porst [28] both publishing high efficacy and low side-effect rates. These first uncontrolled studies were the basis for the development of two different Alprostadil preparations: AlprostadilAlfadex and Alprostadil Sterile Powder which are now officially approved for self-injection therapy in many countries. b) Biological effects of PGE 1 in general Due to the fact that prostaglandins are distributed in many tissues especially in the cardiovascular system these compounds and especially PGE1 have been the subject of many investigational studies in various diseases. The most important biological effects of PGE1are summarized in the review article. The rationale for prostaglandin E1 in erectile failure is as follows: Relaxation of arterioles and precapillary sphincters resulting in increasing blood flow. Contractile effects on the venous system especially in the capacity veins. Inhibition of cholesterol biosynthesis and low-density lipoprotein receptor activity thus preventing cholesterol deposition into the arterial wall. This effect together with its inhibition of platelet function contributes to the antiatherosclerotic effects of PGE1.

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Positive impact on the cellular nutritive metabolism of ischemic tissue by lowering the lactate/ pyruvate ratio resulting in an improvement of the hypoxic state. Positive effects on red cell deformity and inhibitory effects on platelet aggregation with consecutively improved viscosity and blood flow. c) Special effects of PGE 1 on cavernous tissue (Figure 6) The family of E-prostaglandins, particularly PGE1, stimulates the membrane bound enzyme adenylcyclase leading to an intracellular increase of 3´5´cAMP (cyclic-adenosine monophosphate) [27]. This second messenger cAMP leads, via various biological activities, to a decrease of the intracellular Ca++ concentration and subsequently to smooth muscle relaxation. In this context, Hedlund and Andersson [17] showed in in-vitro studies that among all prostanoids investigated PGE1 shows the strongest relaxant power on the cavernous smooth musculature. PGE1 also inhibits the negative influence of the sympathetic tone on erection by modulation of noradrenaline release at alpha1-adrenoceptors in the cavernous tissue [23]. Collagen synthesis, stimulated by TGF-ß1 (transforming growth factor), is decreased by PGE1 in a dose-dependent fashion [26]. In addition, it is proven that PGE1 inhibits angiotensin II secretion by endothelial cells, which lie underneath cavernous smooth muscle cells. In this way PGE1 counteracts the contractile and therefore erection preventing effects of Angiotensin II [20]. Finally Zhang et al [39] provided evidence that PGE1 is able to directly activate the Maxi-K+-channels resulting in hyperpolarization and relaxation of smooth muscle cells. Although all the aforementioned effects mainly occur at the level of the cavernous tissue, PGE1 is also supposed to increase the activity of various cerebral neurons according to the experiments of Moltz [24]. For example, numerous PGE1 receptors were found in the hypothalamus and medial preoptic area, both regions well-known to be important for the control of erectile and ejaculatory behavior. All the cited biological and biochemical functions provide the basis for the marked efficacy of PGE1 observed in the treatment of erectile dysfunction.

d) Pharmacokinetics and metabolism of PGE1 (Figure 7) The original compound from which all prostaglandins are derived is dihomo-gamma-linolenic acid, an analogue of arachidonic acid. The final compound PGE1 is generated via various enzyme activities. The plasma half-life of PGE1 is less than 1 minute due to its rapid pulmonary clearance of up to 65 to 80% during the first lung passage. The cleavage of PGE1 is generally accomplished by two different pathways originating from the 15Keto PGE0 metabolite (Fig. 2). Although all the subsequent metabolites of the one pathway are biologically inactive, the PGE0 metabolite from the other pathway has proven biological activities, which may also be responsible for some of the systemic effects of PGE 1 [30]. With regard to the cavernosal activities, Roy et al [32,33] provided evidence that the corpora cavernosa were able to both generate and metabolize Eprostaglandins. In view of these findings it can be calculated that intracavernously injected PGE1 will be at least partially be metabolized within the cavernous tissue. On the other hand, Cawello et al [13] showed in 24 volounteers, in whom the peripheral plasma levels of PGE1 and its biological active metabolite PGE0 were measured after intracavernous injection of PGE1, that within 2 minutes after application the peripheral levels of PGE1 and PGE1 were elevated 15-20 fold and returned to baseline levels after 2 hours. Interestingly the levels of the biologically active metabolite PGE0 were considerably higher in non-responders to PGE1 who were suspected to suffer from venoocclusive dysfunction.

1. R ESULTS OF PGE1 IN THE DIAGNOSIS AND THERAPY OF ERECTILE DYSFUNCTION a) Diagnosis Due to its superior efficacy and tolerable side effects, PGE1 was recommended as first drug choice in self-injection-therapy by the USA clinical guidelines panel on erectile dysfunction [25]. In a diagnostic dose-escalation study, von Heyden et al [18] showed a dose-dependent increase of the efficacy curve for dosages between 2.5 – 20 µg. Dosages higher than 20 µg levelled up to a plateau and only 20% of failures to 20 µg PGE 1 profited from a dosage increase up to 40 µg. The same

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Figure 6: The impact of PGE1 (Alprostadil) on erectile function

Figure 7: Biosynthesis and metabolism of prostaglandin E1

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observation was made by Porst [30] in a similar diagnostic trial: in 91 (20%) of 450 patients, not responding with sufficiently rigid erections to 20 µg of PGE 1, rigid erections could be provoked by a dosage increase up to 40 µg. Acomparison of the literature as well as comprehensive personal experience with several vasoactive drugs provided evidence that PGE1 is 5-10% more effective than the combination of papaverine/phentolamine (Table 1). Nevertheless, several publications and personal experience have both shown that small subsets of impotent males only react to either papaverine/ phentolamine or PGE1 [14,16,34] (Table 2). Therefore, if a patient opts for self-injection therapy at home and does not respond to PGE1 alone, a trial with the papaverine/phentolamine combination, with or without PGE1, seems worthwhile. The prevailing advantage of PGE1 compared to papaverine or the combination of papaverine/phentolamine especially for diagnosis is the significantly lower risk of priapism (Table 3). b) Therapy A literature review of the relevant publications on self-injection therapy considering efficacy and side-effects of the aforementioned vasoactive drugs was also in favor of PGE1 especially concerning the occurrence of local fibrotic alterations (Table 3). But all the cited studies were conducted in a retrospective fashion with all the shortcomings inherent to retrospective trials. In the meanwhile several prospective trials with both PGE1-preparations i.e. Alprostadil-Alfadex and Alprostadil Sterile Powder were conducted worldwide and the final results of these long-term trials are available and published [21,22,31]. The most important findings of these prospective US and European trials are summarized in Tables 4-9. Indicative for all trials was the impressive high efficacy-rate in home-use with success-rates (successful coitus per attempt) between 90 and 95% with both Alprostadil-injectables (Table 4). These success-rates were considerably higher than those yielded with transurethral Alprostadil (IUA) in the European trial. Priapisms > 6 hours were encountered in about 1% and all these priapisms occurred within the first weeks of treatment when the dosefinding was not yet finalized and the optimal dosage not yet found. A special issue in self-injection therapy with Alprostadil is the occurrence of intrapenile painful sensations in the course of the PGE1-induced erec-

tion. These painful sensations were reported in up to 52% but are usually minimal or moderate. Only 2-4% of all patients complained of severe pain interfering with enjoyment of sexual activities and causing early drop-outs in a few cases. A further problem in long-term self-injection therapy with vasoactive drugs, irrespective of the drug used, is the manifestation of so-called penile fibrosis. The term “penile fibrosis” covers a variety of different fibrotic changes such as nodules or plaques in the tunica albuginea or septum penis, respectively, as well as fibrotic alterations of the cavernous tissue itself. In addition a part of these fibrotic alterations are accompanied by penile deviations which may interfere with vaginal penetration. In the long-term trials, penile fibroses were observed in 4 to 12% of cases and showed a clear dependence on the number of injections and/or the follow-up (Table 5-7). Fortunately in the majority of cases these fibroses were usually minimal or moderate consisting of small nodules or plaques and did not prevent the patients from enjoying sexual activities (Table 7). In two studies, namely in the European 4-year trial and the US trial with Alprostadil-Sterile Powder, the outcome of these penile fibroses was thoroughly followedup by reinvestigation of the affected patients. These reevaluations of the patients some time after first onset of the fibrosis revealed that 33 – 47% of all these alterations healed spontaneously without any detrimental sequelae on penile shape or function (Table 8). In some cases, spontaneous recovery from the fibrotic changes was supported by temporary discontinuation of treatment and, after resumption of self-injection therapy, by more careful instruction of the patient concerning the correct self-injection technique. To date there are no convincing data to suggest that some special patient-groups are at higher risk for the development of such fibroses or whether needle size (27 gauge to 30 gauge) or injection-technique (manual, semiautomatic or autoinjector) may be contributory factors to such fibroses. Both according to personal experience and some cases observed within the European trials, insulin-dependent diabetics seem to be especially more likely to develop penile fibrotic changes related to selfinjection therapy. Concerning penile fibroses, Chen et al. [15] were also not able to find obvious risk profiles for penile fibrosis in a retrospective study with 92 patients. 315

Table 1: Efficacy and complications in the diagnostic use of vasoactive drugs in erectile failure DRUG

DOSAGE

NO.PTS.

RESPONDERS (COMPLETE ERECTION)

PRIAPISM > 6 HOURS

PAIN

Papaverine Literature review

30-110 mg

2161

61% (987/16l6)

6.8% (144/2108)

Not stated

Personal series

12.5-50 mg

950

39% (370/950)

5.3% (50/950)

Not stated

15mg/1.25mg 60mg/2mg

3016

68.5% (2065/3016)

6% (73/1210)

Not stated

12mg/1mg 50mg/2mg

249

60.6% 5.2% (151 /249)

Not stated (13/249)

PGE1(Alprostadil) Literature review

5-40 µg

10353

72.6% (7519/10353)

0.25% (26/10353)

11.5% (881/7637)

Personal series

5-20 µg

4577

70% (3206/4577)

0.26% (12/4577)

9.2% (422/4577)

Papaverine/Phentol. Literature review Personal series

Source: Porst,H. J Urol 1996

Table 2: Intraindividual comparative trial on the efficacy of papaverine, papaverine/phentolamine and PGE1 (alprostadil)

316

Table 3: Complications and drop-out rates in self -injection therapy: literature-review of retrospective studies with various vasoactive Drugs DRUG

NO. PUBL.

PRIAPISM > 6 HOURS

FIBROTIC ALTERATIONS

LIVER ENZYMES ↑

PAIN

DROP-OUT

Papaverine

15

7.1% (92/1300)

5.7% (60/1056)

1.6% (5/314)

4% (18/452)

4.6% (417/895)

Pap./Phentol.

22

7.8% (122/1561)

12.4% (288/1843)

5.4% (43/799)

1.6% (141/1215)

45% (903/2005)

PGE1

10

0.36% (10/2745)

0.8% (18/2180)

0%

7.2% (40/558)

37% 608/1641)

Source: Porst, H. J Urol 1996

Table 4: Home success-rates of the prospective European trials with alprostadil (PGE1) in In-Office responders DRUG

NO.PTS.

SUCCESS-RATES (COITUS/ATTEMPTS)

FOLLOW-UP

Alprostadil-Alfadex (Viridal®,Edex®)

162

93.1% (15713/16886)

48 months

Alprostadil St. Powder (Caverject®)

848

88% (16233/1848 l )

1-6 months

Transurethral Alprostadil (MUSE®)

249

50% (4966/9866) 78% (3238/4177)

1-3 months

4-15 months

Table 5: Complications of Alprostadil Sterile Powder as a function of follow-up - results of the US studies MONTHS

0-6

7-18

19-30

31-62

No. Pts.

683

386

257

214

Pain

52% (352)

47% (181)

5% (14)

1% (2)

Fibrosis

2% (15)

10% (39)

4% (9)

3% (7)

Priapism

< 1% (5)

0

0

0

Source: Linet,O. Int J lmpotence Res 1998

317

Table 6: Adverse events in the European long-term trial with alprostadil-alfadex TOTAL

0-12

23-24

25-36

37-48 MONTHS

No.Pts

162

162

81

68

58

Pain

29% (47)

27% (43)

12% (10)

7% (5)

12% (7)

Fibrotic changes

12% (19)

7% (11)

2% (2)

7% (5)

2% (1)

Priapism> 6 h

1% (2)

1% (2)

0

0

0

Hematoma

33% (54)

30% (48)

23% (19)

10% (7)

12% (7)

Source: Porst,H. Int J Impotence Res 1998 Table 7: Severity of penile fibrotic alterations in long-term self-injection trials with alprostadil (PGE1) NO.PTS. (MONTHS)

FOLLOW-UP TOTAL

FIBROSES PLAQUES

Alprostadil-Alfadex European Trial

162

48

19 (11.7%)

Alprostadil St. Powder European Trial

848 511

6 7-18

34 (4%) 26 (5.1%)

Alprostadil St.Powder

683

18

51 (7.5%)

In addition, no increase of these fibroses could be observed during the course of Alprostadil-selfinjection therapy in patients with preexisting fibrotic changes due to self-injection therapy with papaverine/phentolamine or due to genuine Peyronie’s disease[15]. As we have seen in all the retrospective trials with various vasoactive drugs (Table 3), the prospective studies with Alprostadil were also characterized by relatively high drop-out rates (Table 4). For example, in the European Alprostadil-Alfadex trial, the drop-out rates after 12, 24 and 48 months were 28%, 54% and 67% and, in the European Alprostadil-Sterile Powder trial, the drop-out rate after 18 months was 55%. In the US trial with originally 643 patients involved, the completer-rate after 5 years was 22%. Main reasons for premature discontinuation of self-injection therapy were adverse events, not necessarily due to the drug, partner problems, or dissatisfaction with the therapy itself. Recurrence of spontaneous erections making self-injection therapy unnecessary accounted for only 6 – 10% of cases of premature discontinuation. Comparable to the cited trials Sharlip [35] came to the same conclusion after a thorough review of the literature with 2817 patients involved in 15 publications dealing with self-injection therapy: In only 9.2% of all evalua-

NODULES

DEVIATIONS

10

6

CAVERN. FIBROSES 3

Not published 22

8

21

ted patients, self-injection therapy improved the natural erectile capacity so that these patients could rely on their natural erecions and no longer required self-injection therapy. Although the self-injection trials were associated with considerable drop-out rates, these rates were higher in the European IUA trial with only 25% completers after 15 months (Table 9). Despite the relatively high discontinuation rates, all the worldwide prospective Alprostadil trials provided convincing evidence that self-injection therapy with PGE1 represents a reliable and satisfactory therapeutic option for many couples confronted with male impotence. For example, more than 90% of both affected males and confronted females were satisfied with PGE1-therapy once they have decided to continue treatment (Table 9). In addition, in both the European and US trials, more than 80-90% of males and females reported that the possibility engaging in satisfactory sexual relationships by means of Alprostadil (PGE1) had a considerable positive impact on self-esteem and personality as well as partnership [31,37,38]. None of these trials demonstrated any differences between Alprostadil powder and Alprostadil-Alfadex in terms of efficacy and side-effects as well as positive influences on personality and partnership (Table 10). 318

Table 8: Outcome of penile fibrotic alterations in self-injection therapy with alprostadil PGE1 NO.PTS.

Alprostadil-Alfadex

11.7% (19/162)

TIME TO ONSET NO. I NJECTION FOLLOW-UP 62 (16-132)

SPONTANEOUS HEALING-RATE

12months (4-48)

47% (9/19)

European Trial Alprostadil St.Powder

7.5% (51/683)

Not published

33% (17/51)

Table 9: Satisfaction rates of completers in the various European trials with alprostadil (PGE1) DRUG

FOLLOW-UP

COMPLETERS

SATISFACTION-RATE

Alprostadil-Alfadex

48 months

54/162 (33%)

90 - 92%

Alprostadil St. Powder (Caverjec®)

18 months

348/848 (41%)

92 - 95%

Transurethral Alprostadil

15 months

62/249 (25%)

67 - 71%

Table 10: Pharmacological profile of alprostadil (PGE1) in erectile dysfunction

History:

1986 first reports on PGE1 in self-injection therapy (Adaikan, Ishii)

Influence on Erection:

Stimulation of adenylcyclase → 3 5 -cAMP-accumulation Inhibition of noradrenaline-release on alpha1-adrenoceptors → antiadrenergic effect Inhibition of Angiotensin II-secretion → anticontractile effect Stimulation of Maxi-K+-channels → Hyperpolarisation

Dosage/Pharmacokinetics:

2.5 - 40 µg, (mean dosages 10 - 20 µg) Half-life 30 - 60 sec. Biological active metabolite: PGE 0

Efficacy:

70 - 80% of unselected ED patients

Side-effects:

10 - 20% painful sensations 5 -10% fibrotic alterations < 1% priapism No systemic side-effects at common dosages

Trade Names:

Alprostadil-Alfadex (Viridal® or Edex® Schwarz Pharma) Alprostadil-Sterile Powder (Caverject® - Pharmacia & Upjohn)

319

18. VON HEYDEN B., DONATUCCI C.F., MARSHALL G.A. et al: A prostaglandin E1 dose-response study in man. J Urol 150:1825, 1993.

REFERENCES 1.

VIRAG G. Papavérine et impuissance. Les Editions du CERI Paris, France 13-18, 1987.

2.

VIRAG. Intracavernous injection of papaverine for erectile failure. Lancet ii-938, 1982.

3.

BRINDLEY G. Cavernosal alpha-blockage: a new technique for investigating and treating erectile impotence. Brit. J. Psychiatry. 143: 332-337, 1983.

4.

ZORGNIOTTI A.N, LEFLEUR A. Autoinjection of the corpus cavernosum with a vasoactive combination for vasculogenic impotence. J. Urol. 133: 39-41, 1985.

5.

VIRAG. About pharmacologic induced prolonged erection. Lancet ii: 519-520, 1985.

6.

WESPES E. Personnal communication.

7.

SUSSMAN H., VIRAG R. L’evaluation vasculaire des dysfonctions erectiles par le test d’erection provoquée. Rev. Med. Interne. 18, supp. 1: 175-515, 1997.

8.

JEREMY J.Y, MIKHALIDIS D.P., DANDONNA P. Muscarinic stimulation of prostacyclin synthesis by the rat penis. Eur. J. Pharmacol. 123: 67-68, 1986.

9.

19. ISHII N., WATANABE H., IRISAWA C. et al: Therapeutic trial with prostaglandin E1 for organic impotence. In: Abstract Book Second World Meeting on Impotence. Prague, Czechoslovakia, 1986. 20. KIFOR J.,WILLIAMS G.H.,VICKERS M.A. et al: Tissue Angiotensin II as a modulator of erectile function. I Angiotensin peptide content, secretion and effects in the corpus cavernosum. J Urol 157,1920-1925,1997. 21. LINETO.J., OGRINC F.G.: Efficacy and safety of intracavernosal Alprostadil in men with erectile dysfunction. N Eng J Med 334, 873-877,1996. 22. LINET O.J.: Long-term safety of CaverjectTM (Alprostadil S.PO, PGE1) in erectile dysfunction (ED). Int. J Impot Res 10, Suppl.3, S 37, 1998. 23. MOLDERINGS G.J., VAN AHLEN H., GÖTHERT M.: Modulation of noradrenaline release in human corpus cavernosum by presynaptic prostaglandin receptors. Int J Impot Res 4:19,1992. 24. MOLTZ H.: E-series prostaglandins and arginine vasopressin in the modulation of male sexual behavior. Neurosci Biobehav Rev 14:109, 1990.

VIRAG R. Human penile erection: an extensive study of the effects of vasoactive drugs on the cavernous tissues and penile arteries. J. Urol. 133, part 2 191 A, Abstract 311, 1985.

25. MONTAGUE D.K., BARADA J.H., BELKER A.M. et al: Clinical guidelines panel on erectile dysfunction: summary report on the treatment of organic erectile dysfunction. J Urol 156, 2007-2011,1996.

10. VIRAG R. Round table on self injection therapy, satellite symposium. ISIR meeting 1999.

26. MORELAND R.B., TRAISH A., MCMILLIN M.A. et al: PGE1 suppresses the induction of new collagen synthesis by transforming growth factor ß1 in human corpus cavernosum smooth muscle: mechanism of penile ischemia associated fibrosis. J Urol 151,Part 2:431A, abstract 815, 1994.

11. ADAIKAN P.G., KOTTEGODA S.R., RATNAM S.S.: A possible role for prostaglandin E1 in human penile erection. In: Abstract Book Second World Meeting on Impotence. Prague, Czechoslovakia, 1986. 12. BERGSTRÖM S., RYHAGE R., SAMUELSSON B. et al: Prostaglandins and related factors. 15. The structures of prostaglandin E1, F1-alpha and F1-beta. J Biol Chem 238:3555,1963.

27. PAOLETTI R.:Biochemistry and pharmacology of prostaglandin E1:introductory remarks. In: Prostaglandin E1 in Atherosclerosis. Edited by H. Sinzinger and W.Rogatti. New York: Springer-Verlag, pp.3-7, 1986.

13. CAWELLO W., SCHWEER H., DIETRICH B. et al: Pharmacokinetics of prostaglandin E1 and its main metabolites after intracavernous injection and shortterm infusion of prostaglandin E1 in patients with erectile dysfunction. J Urol 158, 1403-1407, 1997.

28. PORST H.: Stellenwert von Prostaglandin E1 (PGE) in der Diagnostik der erektilen Dysfunktion (ED) im Vergleich zu Papaverin und Papaverin/Phentolamin bei 61 Patienten mit ED. Urologe A 27, 22-26, 1988. 29.

PORST H.: Prostaglandin E1 bei erektiler Dysfunktion. Urologe A 28, 94-98, 1989. 30. PORST H.: Review Article. The rationale for prostaglandin E1 in erectile failure a survey of world-wide experience. J Urol 155,802-815,1996. 31. PORST H., BUVAT J., MEULEMAN E. et al: Intracavernous Alprostadil Alfadex – an effective and well tolerated treatment for erectile dysfunction. Results of a long-term European study. Int J Impot Res 10, 225-231, 1998.

14. CHEN J.K., HWANG T.J., YANG C.R.: Comparison of effects following the intracorporeal injection of papaverine and prostaglandin E1. Br J Urol 69, 404-407,1992. 15. CHEN R.N., LAKIN M.M., MONTAGUE D.K. et al: Penile scarring with intracavernous injection therapy using prostaglandin E1: a risk factor analysis. J Urol 155, 138-140, 1996. 16. EARLE C.M., KEOGH E.J., WISNIEWSKI Z.S. et al: Prostaglandin E1 therapy for impotence, comparison with papaverine. J Urol 143, 57-59, 1990.

32. ROYA.C., TAN S.M., KOTTEGODA S.R. et al: Ability of human corpora cavernosa muscle to generate prostaglandins and thromboxanes in vitro. JRCS Med Schi 12, 608-609,1984.

17. HEDLUND H. AND ANDERSSON K.E.: Contraction and relaxation induced by some prostanoids in isolated human penile erectile tissue and cavernous artery. J Urol 134:1245, 1985.

320

33. ROY A.C., ADAIKAN P.G., SEN D.K. et al: Prostaglandin 15-hydroxydehydrogenase activity in human penile corpora cavernosa and its significance in prostaglandin mediated penile erection. Br J Urol 64,180182,1989.

dent relaxation of a norepinephrine-induced contraction of human corpus cavernosum strips [2]. Pretreatment with moxisylyte competitively reduced the norepinephrine-induced contraction.

34. SAROSDY M.F., HUDNALL C.H., ERICKSON D.R. et al: A prospective double-blind trial of intracorporeal papaverine versus prostaglandin E1 in the treatment of impotence. J Urol 141, 551-553, 1989.

In 1989, Buvat first reported that moxisylyte, although less efficacious than papaverine, resulted in erection suitable for intercourse within 2 hours of in office injection in 42 of 91 patients with ED [3]. Of 37 patients instructed in moxisylyte selfinjection, 92% achieved successful results without any significant side effect. In a dose-ranging placebo-controlled double-blind study of 73 men with psychogenic and neurogenic ED, Costa et al. reported a significantly higher response rate than with placebo, with 62 patients achieving either partial or complete rigidity sufficient for sexual intercourse [4]. The superiority of moxisylyte to placebo was confirmed by both Hermabessiere et al. and Navratil et al. in further placebo-controlled double-blind studies [5,6]. In a multicentre study of 307 patients, Hermabessiere et al. reported that 48% of patients responded to an office intracorporal injection with an erection suitable for intercourse. Furthermore, 62% of home administered injections resulted in sexual intercourse and 95% of these injections were free from adverse effects. More recently, Costa et al., in a placebo-controlled dose-ranging study, reported a dose-dependent response of tumescence sufficient for intercourse in 34.9% to 45.9% of patients for moxisylyte administered in the clinic [7]. At home, 54% to 71% of moxisylyte injections resulted in sexual intercourse.

35. SHARLIP J.D.: Does natural erectile function improve following long-term intracavernous injection of vasoactive drugs? Int J Impot Res 10 Suppl 3, S 17, 1998. 36. STACKL W., HASUN R., MARBERGER M.: Intracavernous injection of prostaglandin E1 in impotent men. J Urol 140:66,1988. 37. WILKE R.J., GLICK H.A., MCCARRON T.J. et al: Quality of life effects of Alprostadil therapy for erectile dysfunction in the US and Europe. Int J Impot Res 8, No.3, 113, 1996. 38. WILKE R.J., HASS S.L., BORG G.: Intracavernous Alprostadil therapy for diabetics: quality of life results from a clinical trial in Europe and South Africa. Int J Impot Res 10, Suppl 3, S 14, 1998. 39. ZHANG P., CHRIST G.J., BRINK P.R.: PGE1-induced alterations in Maxi-K+ - Channel activity in cultured human corporal smooth muscle cells. J Urol 155, Suppl 678 A, 1995.

3. M OXISYLYTE Moxisylyte is a competitive α-receptor antagonist which act preferentially on post-synaptic α-1 adrenoceptors. It was introduced more than thirty years ago for the treatment of cerebrovascular disorders and was recently shown to modulate urethral pressure and constitute a potential treatment for ED.

Arvis et al. reported an extensive series of 143 patients with a total of 7,509 home injections of moxisylyte [8]. A total of 1,041 adverse effects were reported by 90 patients which were predominantly local adverse effects such as injection pain, hematomas and ecchymoses. No severe adverse effects were reported.

In the treatment of impotence, intracavernous injection of moxisylyte at 10, 20 or 30 mg can induce an erection adequate for intercourse in most patients. Initial interest in moxisylyte was prompted by its role as a facilitator of erection with a lower rate of adverse effects compared to inducing agents such as papaverine and alprostadil. However, controlled clinical studies on efficacy and safety are limited, as moxisylyte is approved for treatment of ED only in Europe.

Moxisylyte appears less effective that alprostadil. In a retrospective study of 130 patients, Buvat et al. reported that alprostadil was significantly more effective than moxisylyte with 71% of patients using alprostadil at home reporting rigid erections as opposed to 50% with moxisylyte [9]. Although alprostadil induced pain and prolonged erections in significantly more patients, including 2 priapisms, moxisylyte was associated with a higher

Moxisylyte is a prodrug which is rapidly degraded into an active plasma metabolite, deacetylmoxisy lyte (DAM). This active metabolite is further degraded by N-demethylation, sulpho- and glucuro-conjugation and is excreted in the urine [1]. In vitro, moxisylyte produced a concentration-depen-

321

discontinuation rate. The authors suggested that moxisylyte is mainly indicated in patients with a history of priapism and significant pain following alprostadil. In a recent comparative study of 156 men with organic, psychogenic and mixed ED, Buvat et al. reported that 81% of patients achieved at least 1 rigid erection after intracorporal alprostadil α-cyclodextrin (Edex™, Schwatz Pharma) administered at home compared to 61% after moxisylyte [10]. Local injection related adverse effects occurred with the same frequency, but moxisylyte resulted in more systemic side effects and alprostadil resulted in more painful and prolonged erections. They concluded that alprostadil α-cyclodextrin is significantly more effective than moxisylyte in producing full penile rigidity. Although moxisylyte is less potent than alprostadil or papaverine, and may produce an insufficient response with an office challenge injection, Buvat et al. suggested that it be used as a first-line treatment for ED before resorting to alprostadil or papaverine, due to its favourable adverse effect profile [11]. Buvat reported a reduced rate of prolonged erections (1.3%) compared to papaverine (8.8%) and less corporal fibrosis (1.3% versus 32% with papaverine). Although alprostadil induced penile pain and prolonged erections occur in significantly more patients, moxisylyte was associated with a higher discontinuation rate [9]. This suggests that many patients choose treatment efficacy over a superior adverse effect profile.

2.

IMAGAWA A, KIMURA K, KAWANISHI Y, TAMURA M. Effect of moxisylyte hydrochloride on isolated human penile corpus cavernosum tissue. Life Sci;44 (9):619-23, 1989

4.

COSTA P, SARRAZIN B, BRESSOLLE F, COLSON MH, BONDIL P, SAUDUBRAY F. Efficiency and side effects of intracavernous injections of moxisylyte in impotent patients: a dose-finding study versus placebo. J Urol; 149(2):301-5, 1993

5.

HERMABESSIERE J, COSTAP, ANDRO MC. Efficacy and tolerance of intracavernous injection of moxisylyte in patients with erectile dysfunction: double-blind placebo-controlled study. Prog Urol; 5(6):985-91, 1995

6.

NAVRATIL H, COSTA P, LOUIS JF, ANDRO MC, SAUR P. Effectiveness of and tolerance to intracavernous injection of moxisylyte in patients with erectile dysfunction: effect/dose relationship versus placebo. Prog Urol; 5 (5):690-6, 1995

7.

PIERRE COSTA, NÎMES, FRANCE, JEAN A. JACOVELLAAND AGNÈS A. Bouvet, Efficacy and tolerance of moxisylyte and placebo injected intracavernously in patients with ED - a multicentre, double blind study. Abstract 1998 AUA

8.

ARVIS G, RIVET G, SCHWENT B. Prolonged use of moxisylyte chlorhydrate (Icavex) by intracavernous selfinjections in the treatment of impotence. Evaluation of long-term tolerance. J Urol;102(4):151-6, 1996

9.

BUVAT J, LEMAIRE A, HERBAUT-BUVAT M. Intracavernous pharmacotherapy: comparison of Moxisylyte and prostaglandin E1. Int J Impot Res; 8(2):41-6,1996

11. BUVATJ, BUVAT-HERBAUTM, LEMAIRE A, MARCOLIN G. Treatment of impotence with intracavernous auto-injections: moxisylyte diminishes the risks compared to papaverine. Contracept Fertil Sex 21(2):173-6, 1993.

_________________________

REFERENCES

COSTAP, BRESSOLLE F, SARRAZIN B, MOSSER J, NAVRATIL H, GALTIER M. Moxisylyte plasma kine tics in humans after intracavernous administration. Biopharm Drug Dispos 13(9):671-9, 1992

BUVATJ, LEMAIRE A, BUVAT-HERBAUTM, MARCOLIN G. Safety of intracavernous injections using an alpha-blocking agent. J Urol,141(6):1364-7, 1989

10. BUVAT J, COSTA P, MORLIER D, LECOCQ B, STEGMANN B, ALBRECHT D. Double-blind multicenter study comparing alprostadil alpha-cyclodextrin with moxisylyte chlorhydrate in patients with chronic erectile dysfunction. J Urol. 159(1):116-9, 1998.

However, moxisylyte appears to have a role in the treatment of ED in patients with a history of priapism related to other agents and significant pain following alprostadil.

1.

3.

322

erection, ranged from 66% in the vascular group, to 100% in the neurologic group. Four patients were treated for priapism, all in the neurogenic group.

III. INTRACAVERNOUS BI THERAPY

Nellans et al. reported on 69 patients in 1987 and found an overall success rate of 67% with 74% of these patients continuing on a self-injection program [7]. 50% of patients on their self-injection program noted a subjective improvement in the ability to maintain natural erections. One case of corporeal fibrosis was noted and 8.7% of patients reported prolonged erections, greater than 12 hours.

1. PAPAVERINE-PHENTOLAMINE The combination of papaverine and phentolamine for intracorporeal therapy was first described by Zorgniotti and LeFleur in 1985 [1]. Papaverine increases intracellular levels of cyclic adenosine3-5 monophosphate, blocks calcium channels, and increases calcium efflux from cells. It is acidic in solution (pH 3-4) and may precipitate at a pH greater than 5. Plasma half-life is 1-2 hours and it is metabolized in the liver [2]. Phentolamine is a competitive inhibitor of alpha-1 and alpha-2 adrenergic receptors. It also has an antiserotoninergic action and a direct relaxant effect on smooth muscle [3]. Unlike papaverine, it may not increase resistance to venous outflow from the corpora [4]. Plasma half-life is 30 minutes, and it is extensively metabolized before excretion. Phentolamine, as a single agent, has been largely ineffective in producing usable erections [5].

Bodner et al. studied a combination of papaverine plus phentolamine in 20 spinal cord injury patients in 1987 [8]. Six episodes of priapism in three patients led them to recommend starting with papaverine alone in this sensitive group. Stief and Wetterauer in 1988 performed a prospective study in 15 patients proving the increased efficacy of the combination over papaverine alone [5]. Alone six patients with papaverine and one with phentolamine achieved a full erection. Combined, 13/15 patients achieved a full erection. They proposed the combination as a first-line therapy for its better efficacy and the theoretical prospect of decreased scarring due to a lower total dose of papaverine.

Until 1985, papaverine was the standard for intracorporeal injection therapy. Zorgniotti and LeFleur expanded these horizons in 1985 with their introduction of combination therapy. They reported coital penetration was possible in 59 of 62 patients with impotence of diverse etiologies using a combination of papaverine and phentolamine [1]. Patients were injected with papaverine hydrochloride solution (30 mg/1 ml) and 0.5 to 1 mg phentolamine mesylate. The injection was performed slowly, alternating between sides and patients were sent home to attempt intercourse. Doppler ultrasonography detected an increase in pulse amplitude of the dorsal artery within 30 seconds, and penile lengthening denoting tumescence could be detected within 60 seconds. A single patient required treatment for priapism. Sidi, et al, reported results using the combination in 100 men with organic impotence in 1986 [6]. All patients had organic dysfunction and were injected with a mixture containing 25 mg of papa verine and 0.8 mg phentolamine per cc. Dosages ranged from 0.1 to 1.5 cc, with average injection volumes of 0.36 cc in the venogenic group, and 0.73 cc in the vascular group. Success, defined as a functional erection superior to their spontaneous

In 1989 a double-blind crossover study by Keogh et al. again confirmed the superiority of the combination [9]. In forty men, 40 mg of papaverine produced 27% complete and 65% partial erections. A combination of 20 mg of papaverine and 0.5 mg of phentolamine achieved 48% complete and 52% partial erections. The results were statistically significant at p<0.05 Side effects of corporeal scarring with the combination were reported in 1989 by Levine et al. [10]. Starting with a group of 111 patients, they found a percentage of men with intracorporeal scarring to increase significantly over time. Scarring was found in 8% at one month, 17% at three months, 32% at six months, and an astounding 57% at one year. They also noted mild to moderate transient elevations in alkaline phosphatase or lactic dehydrogenase in 40% of their patients over the one year study. They recommended careful follow-up in these patients. Seidmon and Samaha looked at pH as a possible

323

cause of scarring [11]. The combination of papaverine plus phentolamine had a pH of less than 4 and could not be buffered without precipitation. Prostaglandin E1 had a pH of less than 5, but could easily be buffered to 7.4, remaining in solution. The authors postulated the combination buffered by blood within the corpora may precipitate, causing intracorporeal scarring. Prostaglandin E 1 entered the arena in 1986 at the Second World Impotence Meeting in Prague. Adaikan [12] and Ishii [13] reported encouraging preliminary results with its use. Papers by Stackl et al. [14] Porst, [15] and Ishii et al. [16] confirmed its efficacy and low incidence of priapism. Lee et al. in 1989 studied prostaglandin E1 vs a papaverine-phentolamine combination in a double-blind trial [17]. In 25 patients, they found E1 was equal or superior to the combination of papaverine-phentolamine. Floth and Schramek in 1991 compared papaverine plus prostaglandin E1 to papaverine plus phentolamine in 49 patients, and papaverine plus prostaglandin E1 to prostaglandin E1 alone in 38 patients [18]. Their findings were that papaverine plus prostaglandin E1 was superior to either of the other combinations or prostaglandin E1 alone. They found moderate or severe pain occurring only in the E1 monotherapy group, and no erections required treatment in any of these groups. Their conclusions were that the combination of papaverine and prostaglandin E1 was overall superior. Since its introduction by Zorgniotti and LeFleur in 1985, multiple studies have borne out an improved efficacy of the combination of papaverine-phentolamine over papaverine alone [1,3,5,8,9]. Perhaps the largest, most dramatic, studies were those of Porst in 1993 [19]. Using dosages of 12.5 to 50 mg of papaverine, he reported an efficacy (complete response) of 39% in 950 patients. Using the combination at dosages of 15-50 mg papaverine, plus 1-2 mg phentolamine, his success was 60.6% in 249 patients. Priapism rates, defined as an erection greater than 6 hours, were identical at 5.3% and 5.2%, respectively. In a review article by Fallon in 1995, [3] the combination was effective (full erection) in 69% of 400 patients. This article also found identical priapism rates at 4.3% in 232 patients on papaverine

vs 115 on the combination in patients treated at the University of Iowa. In a review of the international literature by Porst in 1997, [20] papaverine alone at dosages of 30110 mg was effective (complete response) in 61% of 2161 patients. The combination in dosages of 15-60 mg of papaverine with 1.25 to 2 mg of phentolamine was 68.5% effective in 3016 patients. Again, priapism was little changed at 6.8% for the papaverine vs 6% for the combination. The above studies all confirm the superior efficacy of the combination of papaverine/phentolamine over papaverine alone [1, 3, 5, 9, 10, 19, 20]. The majority of these studies also revealed a similar rate of priapism between papaverine alone and the combination, ranging from 4.3 to 7.8% in two large reviews [3,20]. Other complications with papaverine-phentolamine combinations are changes in liver function tests, especially alkaline phosphatase and fibrosis of the corpora. Changes in liver function tests are related to the papaverine component and will be covered in the review of that agent. Intracorporeal fibrosis is a much more complicated topic that will be explored more fully in the section on trimix. (see below)

2. PAPAVERINE-IFENPRODYL Ifenprodyl tartrate is an alphablocker with a very low hypotensive capacity. It is stable in solution and also when associated with papaverine, which makes it very useful for use in dual or multiple combination therapy. The mixture contains 20 mg of papaverine and 1.25 mg of ifenprodyl tartrate per ml. Individual doses are adapted to the initial testing. (see that section). In a large retrospective study (Virag, ISIR Amsterdam 1998) this mixture was used in 23% of patients at the endpoint. Cheap, stable and giving a lower rate of local complications than papaverine-phentolamine, it might be proposed as a basic treatment for economically low income patients and countries.

3. VIP-PHENTOLAMINE a) Vasoactive Intestinal Polypeptide (VIP) and Phentolamine Mesylate

324

Vasoactive intestinal polypeptide (VIP) is a 28 amino acid peptide which is widely distributed in the male and female urogenital tracts as well as the central and peripheral nervous systems. VIP has been shown to produce a wide range of effects including potent vasodilation, inhibition of contractile activity in many types of smooth muscle, stimulation of cardiac contractility and stimulation of many exocrine secretions. It produces vasodilation by binding to a specific VIP smooth muscle membrane receptor which stimulates Gs protein, activates smooth muscle membrane enzyme adenylate cyclase, elevating intracellular cyclic adenosine monophosphate (cAMP), thereby lowering intracellular calcium.

and the distribution of VIP nerve fibers in human cavernous tissue were lower in men with organic ED than in men with psychogenic ED or in a control group. A reduction in VIP immunoreactivity was found in tissue from human diabetics with ED, suggesting that depletion of the peptide may play a key role in the development of impotence. In summary, these data suggest that VIP plays an important role in penile erection and that, in some patients, organic impotence is associated with low VIP content and poor distribution of VIP nerve fibers. Intracavernosal injection of VIP in anaesthetized dogs induces a relatively small dose-dependent erectile response and an increase in intracavernosal pressure which is blocked by administration of VIP-antibody [6]. In the anaesthetized cat, intracavernosal injection of VIP alone induced penile erection and had the same maximal effect on intracavernosal pressure as observed with the control combination of intracavernosal papaverine, prostaglandin E1 and Phentolamine [12]. These findings suggest that intracavernosal VIP induces penile erection in both the anaesthetized dog and cat, increasing arterial flow, decreasing venous flow and inducing sinusoidal relaxation. Intracavernosal injection of VIP in potent men induced tumescence and increases in penile length and diameter [13] but failed to produce a rigid penile erection in men with ED [13, 14, 15] or healthy volunteers [16] with doses up to 60 µg [13, 15, 17, 18]. In contrast, when used in conjunction with visual or vibratory stimulation, intracavernosal injection of VIP did facilitate a rigid erection response. The vasodilator effect of VIP is potentiated by blockade of the α-adrenergic receptors by Phentolamine mesylate. Phentolamine is an α-1 and α-2 receptor antagonist. Phentolamine reduces intracellular calcium by reducing the α-1 receptor induced elevation in inositol triphosphate and the α-2 receptor induced Gi protein inhibition of membrane adenylate cyclase enzyme activity.

VIP has since been found in the skin, circulatory system, gastrointestinal and respiratory tracts [1]. VIP-immunoreactive nerves are abundant in the male and female urogenital tracts. VIP has been demonstrated in the nerves of the epididymis, vas deferens, seminal vesicles, prostate, corpus cavernosum and spongiosum, and penile arteries and arterioles [2,3,4]. VIP-immunoreactive nerves have been demonstrated in the vagina, cervix, uterus, fallopian tubes and ovaries [5]. VIP is widely distributed in the central [6] and peripheral nervous systems where immunoreactive nerve fibers may have an important clinical role in the nervous regulation of urogenital functions. In the rat model, ageing is accompanied by a decline in male erectile function [7] but was not associated with any significant change in the density and pattern of VIP-immunoreactive nerve fibers in the penis crura, cavernosal artery or helicine branches. The cause of reduced male erectile performance in old age in the rat does not appear to be a direct result of impaired VIP-ergic innervation of the penile tissues [8]. However, a marked depletion of VIP-immunoreactivity in the penile tissue was evident in the ageing boar [9]. Ottesen et al. [10] reported that induction of an erection by either visual sexual stimulation, intracavernosal injection of vasoactive agents or saline administration resulted in an increase in the median concentration of VIP in the cavernous blood. He suggested that the increase in VIP in cavernous blood samples was due in part to local release of the polypeptide.

In vitro, Phentolamine mesylate potentiates the VIP-induced relaxation of phenylephrine contracted corpus cavernosum tissue strips in a dose-dependent manner [19]. In contrast,VIP does not appear to potentiate the modest dose-dependent relaxation effect to Phentolamine. Clearly, α-adrenergic contractility is the dominant force in modu-

Shirai et al. [11] demonstrated that VIP content of 325

lation of corpus cavernosum smooth muscle contractility and attenuation of α-activity with Phentolamine should enhance the smooth muscle relaxation of other pharmacologic agents, including VIP. Several authors have reported their experience with the combination of VIP and Phentolamine [20, 21, 22, 23] and conclude that a combination of 25 µg of VIP and 1 or 2 mg of Phentolamine mesylate (Invicorp ™, Senetek UK) is a safe and effective treatment for erectile dysfunction with a range of organic etiologies. Hacket [23], in a large open label study of 548 patients with ED, reported that Invicorp™ produced erections suitable for sexual intercourse in 82% of patients. In a subsequent double-blind, placebo-controlled of 411 patients, 74% of the Invicorp™ injections resulted in an erection suitable for intercourse, whereas only 12% of the matching placebo produced such responses. McMahon [21], in a study of 20 men with chronic impotence of various etiologies reported an erection, after sexual stimulation, sufficient for sexual intercourse in 16 patients (80%) following administration of Invicorp™. The erectile response was dose-dependent and inversely related to the severity of penile vascular disease, with only 1 of 3 patients with cavernosal venous leakage achieving an erection. Dinsmore et al. [22] in a study of 70 men with ED of various etiologies who were previously refractory to intracavernosal alprostadil or Phentolamine/papaverine, reported a Invicorp™ response rate of 67%, suggesting a potential salvage role in patients resistant to other agents.

REFERENCES

Current evidence suggests that VIP + Phentolamine is highly efficacious and well tolerated in a wide range of organic etiologies. Reported adverse effects were mild and transient and included facial flushing (15-53%), truncal flushing (5-9%), injection pain (10-11%) and bruising (20%). Priapism appears rare with only two cases reported in one study (<0.1%) [23]. VIP + Phentolamine has received regulatory approval in the UK and several other countries. Its clinical use is currently undergoing safety and efficacy testing in international multicentre, placebo-controlled, double-blind, randomized clinical trials in men with organic ED.

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1

KOEHN, F.-M., MISKA, W., SCHILL, W.-B., WEIDNER, W. AND WEISKE, W.-H.: Concentrations of vasoactive intestinal polypeptide in corpus cavernosum and peripheral venous blood during prostaglandin E1-induced erection. Arch Androl 31:217, 1993.

2

WILLIS, E.A., OTTESON, B., WAGNER, G., SUNDLER, F. AND FAHRENKRUG, J.: Vasoactive intestinal polypeptide (VIP) as a putative neurotransmitter in penile erection. Life Sci. 33:383, 1983.

3

SHIRAI, V.D., MAKI, A., TAKANAMI, M., ANDO, K., NAKAMURA, K., YANAIHARA, N., YANAIHARA, C., IGUCHI, K., FUJIOTA, T. AND IWANAGA, T.: Content and distribution of vasoactive intestinal polypeptide (VIP) in cavernous tissues of human penis. Urology 35:360, 1990.

4

POLAK, J.M., GU, J., MINA, S. AND BLOOM S.R.: VIPergic nerves in the penis. Lancet 2:217, 1981.

5

PALLE, C., OTTESON, B., JØRGENSON, J. AND FAHRENKRUG, J.: Peptide histidine methionine and vasoactive intestinal peptide: occurrence and relaxant effect in the human female reproductive tract. Biol. Reprod. 41:1103, 1989.

6

JUENEMANN, K.-P., LUE, T.F., LUO, J., JADALLAH, S.A., NUNES, L.L. AND TANAGHO, E.A.: The role of vasoactive intestinal polypeptide as a neurotransmitter in canine penile erection. J. Urol. 138:871, 1987.

7

STEGER, R.W., HUANG, H. AND MEITES, J.: Reproduction. In: Masoro, EJ (ed) Handbook of physiology in aging. CRC Press, Boca Raton, Florida, 1981.

8

AMENTA, F., CAVALLOTTI, C., DE ROSSI, M., FERRANTE, F. AND GEPETTI, P.: Vasoactive intestinal polypeptide levels and distribution in the penis of old rats. Neural Transm. 70:137, 1987

9

DALIN, A.-M. AND RODRIGUEZ-MARTINEZ, H.: Vasointestinal polypeptide (VIP)- immunoreactive nerves in the boar penis. J. Vet. Med. 39:792, 1992.

10

OTTESEN, B., WAGNER, G., VIRAG, R. AND FAHRENKRUG, J.: Penile erection: possible role for vasoactive intestinal polypeptide as a neurotransmitter. BMJ 288:9, 1984.

11

SHIRAI, M., MAKI, A., TAKANAMI, M., ANDO, K., NAKAMURA, K., YANAIHARA, N., YANAIHARA, C., IGUCHI, K., FUJITA, T. AND IWANAGA, T.: Content and distribution of vasoactive intestinal polypeptide (VIP) in cavernous tissue of human penis. Urology 35:360, 1990.

12

WANG, R., HIGUERA, T.R., SIKKA, S.C., MINKES, R.K., BELLAN, J.A., KANDOWITZ, P.J., DOMER, F.R. AND HELLSTROM, W.J.: Penile erections induced by vasoactive intestinal peptide and sodium nitroprusside. Urol. Res. 21:75, 1993.

13

ROY, J.B., PETRONE, R.L. AND SAID, S.I.: A clinical trial of intracavernous vasoactive intestinal peptide to induce penile erection. J. Urol. 143:302, 1990.

14

ADAIKAN, P.G., KOTTEGODA, S.R. AND RATNAM, S.R.: Is vasoactive intestinal polypeptide the principal transmitter involved in human penile erection? J. Urol. 135:638, 1986.

15

KIELY, E.A., BLOOM, S.R. AND WILLIAMS, G.: Penile response to intracavernosal vasoactive intestinal polypeptide alone and in combination with other vasoactive agents. Br. J. Urol. 64:191, 1989.

16

WAGNER, G. AND GERSTENBERG, T.: Intracavernous injection of vasoactive intestinal polypeptide (VIP) does not induce erection in man per se. World J. Urol. 5:171, 1987

17

WAGNER, G. AND GERSTENBERG, T.: Vasoactive intestinal peptide facilitates normal erection. In: Proceedings of the Sixth Biennial International Symposium for Corpus Cavernosal Revascularization and the Third Biennial World Meeting on Impotence. Boston, MA, Oct. 6-9, p.146, 1988.

18

OTTESON, B., WAGNER, G., VIRAG, R. AND FAHRENKRUG, J.: Penile erection: possible role for vasoactive intestinal polypeptide as a neurotransmitter. BMJ 288:9, 1984. KIM, N.N., GALLANT, C., DHIR, V., GOLDSTEIN, I., KRANE, R.J. AND TRAISH, A.M.: Potentiation of VIP-induced relaxation by phentolamine in corpus cavernosum. Abstract presented at ISIR, Amsterdam, 1998.

19

20

21

Erectile dysfunction is often clinically evaluated and treated by the intracorporal injection of a mixture of drugs, each drug action in synergism at a different point of the complex neurovascular cascade of physiological events that results in an erection. This mixture often includes an α-adrenergic antagonist such as phentolamine, a smooth muscle relaxant such as alprostadil and a phosphodiesterase inhibitor such as papaverine. Saenz de Tejada recently reported the concept of the synthesis of new molecules with a dual pharmacological action by chemically altering existing α-adrenergic antagonists so that they become nitric oxide donors while retaining the parent drug action [8]. An example of this new class of molecules is NMI-221 or nitrosylated moxisylyte (SNO-mox., Nitromed Inc. MA. USA). Nitrosylation of α-antagonists potentially offers both increased blood inflow by vasodilation of cavernosal and helicine arteries and relaxation of trabecular and lacunar smooth muscles, which are required for a full erection. Alpha receptor antagonists promote vascular dilatation while nitric oxide promotes relaxation of both vascular and cavernosal smooth muscles.

GERSTENBERG, T.C., METZ, P., OTTESON, B. AND FAHRENKRUG, J.: Intracavernous self-injection with vasoactive intestinal polypeptide and phentolamine in the management of erectile failure. J. Urol. 147:1277, 1992. MCMAHON, C.G.: A pilot study of the role of intracavernous injection of vasoactive intestinal peptide (VIP) and phentolamine mesylate in the treatment of erectile dysfunction. Int. J. Impot Res. 8:233, 1996.

22

DINSMORE, W.W. AND ALERDICE, D.K.: Vasoactive intestinal polypeptide and phentolamine mesylate administered by autoinjector in the treatment of patients with erectile dysfunction resistant to other intracavernosal agents. Br. J. Urol. 81:437, 1998.

23

HACKETT, G., CHARIG, C., DEAN, J., DINSMORE, W., GINGELL, C., KELL, P., SANDHU, D. AND SAVAGE, D.: The results of a 6 month multicentre placebo controlled study of Invicorp in the treatment of non-psychogenic dysfunction. J. Urol. 159:240, 1998.

In vitro, nitrosylated moxisylyte is more effective than moxisylyte alone in relaxing isolated endothelin contracted corporal smooth muscle strips [8]. Elevated tissue cGMPlevels are measured following incubation with the nitrosylated moxisylyte derivative compared with either control or moxisylyte incubated tissues. In anaesthetized rabbits, intracorporal injection of nitrosylated moxisylyte produces significantly higher and more sustained elevation of intracorporal pressure than moxisylyte alone. In vitro, the potent erectogenic activity of these compounds after intracavernosal injection in rabbits was confirmed [8]. A 1 mg dose of SNO-mox produced a comparable erectile response to the standard triple combination of papaverine, alprostadil and phentolamine. Moxisylyte was less effective and the response was ten-fold shorter than with SNO-mox. The incidence of systemic adverse effects including mild transient hypotension, was comparable with SNO-mox and moxisylyte. Similar results have been achieved with another nitrosylated alpha blocker, SNO-yohimbine (SNO-yoh).

4. NITROSYLATED ADRENERGIC RECEPTOR ANTAGONISTS Nitric oxide (NO) is a potent molecule that causes endothelium-dependent and neurally mediated relaxation of vascular and trabecular smooth muscle in the penis. The importance of NO in the complex physiological response of erection is well established by a review [1] and by several authors [2-7].

327

Enhancement of the NO pathway in the erectile response can also be achieved by nitrosylation of molecules that inhibit phosphodiesterases. Following the successful introduction of drugs such as sildenafil that potently and selectively inhibit phosphodiesterases and elevate cytosolic cGMP levels, the next generation of drugs may extend this concept into dual-acting pharmacology. Retaining the actions of NO while adding an additional mechanism of action, such as alpha receptor blockade or inhibition of phosphodiesterases into a single molecule may provide an even more effective therapy.

IV. INTRACAVERNOUS TRIPLE AND MULTIPLE COMBINATION THERAPY 1. THE CONCEPT OF MULTILEVEL ACTING MEDICATIONS Clinical experience has shown that combination therapy with one or two agents had several limits in terms of efficacy and use: a maximum of 60% of the overall population of patients were responders, several other agents were available corresponding to other routes for producing an erection, synergistic action lowered the volume injected and improved the response rate to almost 85 to 90% of the impotent population.

REFERENCES 1.

BURNETT, A.L. Role of Nitric Oxide in the Physiology of erection. Biol Reprod 52, 485-489 (1995)

2.

IGNARRO, L. J., BUSH. P.A., BUGA, G.M., WOOD, K.S., FUKUTO, J.M. AND RAIFTER, J. Nitric oxide and cyclic GMPformation upon electrical field stimulation cause relaxation of corpus cavernosum smooth muscle. Biochem. Biophys. Res. Commun. 170, 843-850, (1990) KIMOTO,Y., KESSLER,R., CONSTANTINOU,C.E. Endothelium dependent relaxation of human corpus cavernosum by bradykinin. J. Urol 144, 1015-1017, (1990) BUSH, P.A., ARONSON,W.J., BUGA, G.M., RAIFER, J. AND IGNARRO, L.J. Nitric oxide is a potent relaxant of human and rabbit corpus cavernosum. J. Urol 147, 1650-1655 (1992)

3.

4.

5.

AZADZOI, K.M., KIM, N., BROWN, M.L, GOLDSTEIN, I., COHEN, R.A. AND SAENZ DE TEJADA, I. Endothelium-derived nitric oxide and cyclooxygenase products modulate corpus cavernosum smooth muscle tone. J. Urol 147, 220 -225 (1992)

6.

KIM, N., VARDI, Y., PADMA-NATHAN, H., DALEY, J., GOLDSTEIN, I. AND SAENZ DE TEJADA, I. Oxygen tension regulates the nitric oxide pathway: physiological role in penile erection J. Clin. Invest. 91, 437-443 (1993)

7.

BURNETT, A.L., LOWENSTEIN, C.J., BREDT, D.S., CHANG, T.S.K. AND SNYDER, S.H. Nitric Oxide: a physiologic mediator of penile erection. Science 257, 401-403 (1992)

8.

I. SAENZ DE TEJADA, P. CUEVAS, B. CUEVAS, A. FERNANDEZ, S. GABACHO, MADRID, SPAIN, L. G. LETTS, J. D. SCHROEDER, T. SHELEKHIN, S. W. TAM AND D. S. GARVEY. Nitrosylated-Adrenergic Receptor Antagonists as potential drugs for the treatment of erecile dysfunction (ED). Abstract 1998 AUA

2. PAPAVERINE, IFENPRODYL, PIRIBEDIL, ATROPINE, DIPYRAMIDOLE WITH OR WITHOUT ALPROSTADIL This rather complicated mixture appeared in the English literature in 1991 (Virag et al). The rationale for its use was a careful study of each of its compounds and the various routes they activate in the erectile process. In addition to the well known effects of papaverine and alphabockers, Virag et al. added a dopaminergic agent, an acetylcholine receptor blocker and a long-acting additional phosphodiesterase blocker. Initially yohimbine was also used in this mixture, then abandoned for redundant activity. In the initial study, 102 patients who had failed to respond to papaverine alone and/or papaverine ifenprodyl were "rescued" with this mixture named "ceritine". The use of atropine in this mixture has been controversial; it is based on the property of this agent to activate erection, at a low dose. Goldstein et al. have confirmed (Virag et al) the enhancement of erectile function by adding atropine to trimix (see below): 73% of the patients failing with other mixtures responded to the atropine+trimix mixture. Montorsi reported that 96% of his patients with vasculogenic impotence responded to the same regimen. With the availability of alprostadil powder, it became obvious that PGE1 should be able to enhance the strength of "ceritine". Thus the use of "ceritine +" was designed with three versions: 20µg in 4ml, 2ml and 1ml of the initial mixture. The response rate in organic or mixed etiology patients was 90%.

_________________________

328

A simplified version of "ceritine" is a triple combination of 10 mg of papaverine, 2.5 mg of ifenprodyl tartrate and 5 mg of alprostadil powder in a 1ml solution which gives almost the same results as the US trimix.

now term trimix, in 1990 [23]. They reported a mixture of 2.5 mg of papaverine (30 mg per cc), 0.5 cc of phentolamine (5 mg per cc), 0.05 cc of alprostadil (500 micrograms per cc), and 1.2 cc of 0.9% normal saline to produce a vial of 4.25 cc. The solution was reported to be physiologically active for six months (refrigeration was recommended), with a pH of 4.0. This initial report, documented use in more than 100 men for both diagnostic testing and home therapy. The efficacy was felt to be good with only one prolonged erection and no pain or corporal fibrosis noted. A follow-up study published in 1991, looked more closely at the results in this group of 116 patients with a follow-up of 3 to 18 months [24]. Ninetyone percent (105/116) of patients tested had a usable erection at home. Prolonged erections requiring treatment were found in only two patients, pain at the injection site in two patients, and no patients were noted to have fibrosis.

3. PAPAVERINE, PHENTOLAMINE, PGE1 (TRIMIX) Earlier in this chapter we discussed combination therapy with papaverine and phentolamine introduced by LeFleur and Zorgniotti in 1985 [1]. The synergism between the smooth muscle relaxant papaverine and the alpha blocking agent phentolamine, has been unequivocally shown to be more effective than either agent alone, with similar rates of priapism [1,3,5,9,10,19,20]. Unfortunately intracorporeal scarring and changes in liver function tests remain a significant problem [10]. The introduction of prostaglandin E 1 by Ishii, Adaikan and Virag in 1986 opened a new era for injection therapy [12,13]. Multiple abstracts discussed earlier in the section on prostaglandin E1 confirm a similar efficacy and a much lower rate of priapism and intracorporeal scarring than the combination of papaverine plus phentolamine. Unfortunately penile pain, reported in up to 40% of patients, continues to be a significant drawback to prostaglandin E1 monotherapy [21,22].

Goldstein et al. presented data at the 1990 AUA meeting on "rescue" using trimix. Thirty-two patients who failed combinations of papaverine/ phentolamine (8 of whom also failed prostaglandin E 1 ) were treated with trimix. Sixty-two percent reported restoration of erectile potency with an average dose of 0.47 cc [25]. Goldstein concluded "the fact that the three drugs used in combination had previously failed to restore erections at higher dosages individually, and are successful in lower doses in combination, suggests a synergistic drug action."

Prostaglandin E1 (PGE1, alprostadil) belongs to the family of eicosanoids, which represent a large group of oxygenated metabolites of polyunsaturated 20-carbon fatty acids, including prostaglandins, thromboxanes, leukotrienes, lipoxins, epoxyeicosatrienic acids, hepoxilins and other compounds. Within the human corpora PGE1 leads to increased cyclic AMP by a modulation of the enzyme adenyl-cyclase. The accumulation of cyclic AMP after exposure to PGE1, leads to a decrease in free calcium concentration and, subsequently, to relaxation of the cavernous smooth muscle. PGE1 also possesses antiadrenergic effects by means of inhibition of noradrenalin output. The plasma half-life of PGE1 is less than one minute due to rapid pulmonary clearance of up to 65-80% during the first passage through the lung. A second local pathway exists within the penis for local metabolism of prostaglandin E1 [20].

McMahon reported a randomized cross-over study in 228 patients in 1991 [26]. The patients were evaluated and divided into arteriogenic (36%), venogenic (18%), mixed vasculogenic (23%), neurogenic (4%), and psychogenic (19%) impotence. Each patient received injections of prostaglandin E1, papaverine plus phentolamine, and triple mix in a randomized manner. Dosages were standardized depending on the etiology. Erectile responses were quantified using real time Rigiscan monitoring and adjuvant visual sexual stimulation. No difference in the response of prostaglandin E1 compared to the combination of papaverine plus phentolamine was found in any of the groups. The erectile response to the combination of triple mix was statistically superior compared to responses of the other two agents in men with severe arteriogenic impotence and mild venogenic impotence (P < 0.05).

Bennett et al. introduced a combination of papaverine, phentolamine and prostaglandin E1, that we

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In all other patients, although the trend suggested that triple mix was more effective, no statistical difference in response was found. Prolonged pharmacological erections lasting more than 5 hours occurred at a rate of 7.9% with papaverine plus phentolamine, 1.3% with prostaglandin E1, and 0.9% with triple mix. Persistent penile pain occurred in 24% after the injection of prostaglandin E1, and no pain was noted after the injection of triple mix in any patient. The authors theorized that the "use of combination intracavernous pharmacotherapy seems to produce a greater vasodilatory response of the cavernous smooth muscle effector junction than single agents. This response possibly relates to synergism of these agents, perhaps due to their differing sites and mechanisms of action on the cascade of neurovascular events which leads to erection." The authors concluded that triple mix is significantly more effective in men with severe arteriogenic impotence and mild cavernosal venous leakage and has a role in salvaging these patients. Authors also concluded that the triple mixture combination is associated with a significantly lower incidence of prolonged erections or injection pain than the other two agents studied.

Govier et al. reported usable erections in 81% (170/210) of patients with trimix in 1993 [30]. These patients were seen over a 26-month period, starting in December 1989. Early on, only those patients failing injections with other more established agents (papaverine, papaverine/phentolamine, prostaglandin E1) or those having significant pain with prostaglandin E1, were given the triple mixture. As experience grew, trimix became more of a first-line agent, largely due to the pain problems encountered with prostaglandin E1 monotherapy. One hundred forty-six patients were followed an average of 11.2 months (1-26 months) on a pharmacologic erection program. Injection volumes averaged 0.36 cc (0.01-1 cc). Excluding those patients given larger doses for a duplex scan (9 patients); priapism (tumescence greater than six hours) occurred in only 3 patients (1.7%). Pain was encountered in 6 patients (3.5%) and intracorporeal scarring was found in 7 (4.2%) patients. The authors felt the superior dose response over other agents, and a low incidence of pain, priapism, and scarring made this a first-line agent for intracorporeal therapy. Valdevenito and Melman reviewed a large injection program in 1994 [31]. In 301 patients, with a variety of etiologies, 84% could obtain effective erections with intracorporeal therapy and all entered a home injection program using a variety of agents. Initially, 80 patients utilized the triple mixture and by the time of their review, several patients having failed other agents were moved to triple therapy, leaving a total of 111 on triple therapy at the time of their review. Thirty-nine percent of their patients dropped out of the program at some point over the course of a 6-year period. They noted scar tissue in 1.8% of those patients on trimix (5.9% in the entire group). Priapism was found in 2.7% of patients on trimix (1.6% of the entire group).

Hamid et al. reported a response rate of 88% in a trial of 100 patients in the International Journal of Impotence Research in 1992 [27]. The authors found pain to be present in less than 5% and found only one episode of priapism. Allen et al. performed a double-blind cross-over study utilizing papaverine plus phentolamine, papaverine plus prostaglandin E1 and trimix[28]. The study included only 7 patients. They found those combinations containing prostaglandin E1 to have a longer duration but no significant improvement in rigidity. Triple mixture was no better than papaverine plus E1 in terms of duration or rigidity. Von Heyden et al. reported trimix again as a form of salvage therapy for prostaglandin E1 failures in 1993 [29]. In a retrospective review of 101 patients on injection therapy, 31 of cases were on trimix. These 31 patients had failed earlier attempts using prostaglandin E1 as monotherapy due to either insufficient erections or penile pain. The authors stressed the use of low dosages of medications and their average volumes of trimix injected were 0.34 to 0.46 cc.

Bechara et al. in 1996 reported on 32 patients having failed with a combination of papaverine plus phentolamine [32]. Twenty-two percent of these patients responded to prostaglandin E1 and 50% to trimix. Pain was reported in 41% of those receiving prostaglandin E1 and 12.5% receiving trimix. The authors concluded that trimix was more effective than prostaglandin E 1 with a lower incidence of pain.

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Table 1: Efficacy of trimix YEAR REPORTED

OF

NUMBER PATIENTS

% EFFICACY

AGENT USED

Bennett [24] 1991

116

92%

Trimix only

Hamid [27] 1992

100

88%

Trimix only

Fallen [3]

1995

160

77%

Trimix only

Casabe [35] 1998

189

85%

Trimix only

Govier [30] 1993

210

81%

Multiple agents and Trimix

Valdevenito [31] 1994

301

84%

Multiple agents and Trimix

1076

85%

Table 2a: Priapism with trimix in a home injection program YEAR

NUMBER OF PATIENTS

NUMBER OF PRIAPISMS

% PRIAPISM

TYPICAL USE

Bennett [24]

1991

105

1

1%

Injection program

Hamid [27]

1992

100

1

1%

Injection program

Govier [30]

1993

170

3

1.7%

Injection program

Collins [33]

1993

202

7

3.4%

Injection program

Valdevenito [31]

1994

111

3

2.7%

Injection program

Fallen [3]

1995

160

3

1.9%

Injection program

848

18

2.1%

Table 2b: Priapism with trimix for diagnostic injections YEAR

NUMBER OF PATIENTS

NUMBER OF PRIAPISMS

% PRIAPISM

USE OF AGENT

McMahon [26]

1991

228

2

.9%

1 injection various agents

Govier [34]

1995

280

12

4.3%

Duplex scans

Bechara [32]

1996

32

0

0%

Rescue

Casabe [35]

1998

189

4

3.7%

Diagnostic

729

18

2.5%

Table 3: Incidence of pain with trimix YEAR

NUMBER OF PATIENTS

PTS WITH PAIN

% OF PAIN

Bennett [24]

1991

105

2

1.9%

McMahon [26]

1991

228

0

0%

Hamid [27]

1992

100

5

5%

Govier [30]

1993

170

6

3.5%

Collins [33]

1993

202

4

2.0%

805

17

2.1%

331

Tables 1-4 summarize the literature on trimix. Table 1 looks at the efficacy of the triple drug mixture in several larger series. The first four groups listed were patients given only trimix. The second two studies were in larger groups of patients who were treated with multiple agents, but were all given a trial of trimix before therapy was deemed ineffective. In this population of more than 1000 patients, 85% responded to the triple drug mixture, including many patients who had failed single agents and other combination therapy. Many authors [25,26,29,30,31,32] have shown triple mix to be effective when prostaglandin E1 or papaverine phentolamine combinations are ineffective.

incidence of pain are the two factors that stand out for the utilization of trimix as a first-line agent. The slightly higher incidence of priapism, especially with the diagnostic use of trimix, would favor E1 therapy as the optimal first-line agent. The last important aspect to consider is penile fibrosis. Table 4 looks at the incidence of penile fibrosis/nodules with trimix. In 575 patients, penile fibrosis and/or nodules were noted in 3.3%. While efficacy, prolonged erections/priapism, and pain are relatively easy parameters to define and report; penile scarring and/or nodules are complex at best. In 1989 fibrotic nodules were reported in 5.4% of 1573 patients collected from different series using papaverine plus phentolamine combinations [36]. Yet Levine et al. also in 1989, reported nodules in 57% of their patients on papaverine phentolamine combinations with an injection duration of only 12 months [11]. How does one explain such a discrepancy? In an exhaustive review of the literature in 1996 [20], Porst found the following fibrosis rates; papaverine, 1527 patients, 5.7%; papaverine plus phentolamine, 2263 patients, 12.4%, and prostaglandin E 1, 2745 patients, 0.8%. In the Schwartz pharma scientific product information on Virilan (Alprostadil)[37], the incidence of penile fibrosis and penile deviation was listed as 0.05% based on pooled data from 44 studies involving 6145 patients. Yet in the product information on Caverject (Alprostadil) dated 17 March, 1995[38], Upjohn Pty. Ltd. warned of a frequency rate of 4.8% of penile fibrosis. Chen et al. in 1996 reported penile scarring in 16% of 92 patients on prostaglandin E1 [39]. The scarring was not severe, and most patients continued injection therapy. Only one patient had progression and had to dis-

Table 2a looks at the incidence of priapism in patients on home injection therapy with trimix. A variety of dosage combinations was utilized, as well as different techniques to titrate patients. Overall, in 850 patients, priapism requiring treatment occurred in 2.1%. Table 2b looks at the use of trimix during diagnostic injections. Again, different concentrations of medications were utilized and in 700+ patients, the priapism rate was 2.3%. Clearly these incidences are significantly lower than papaverine alone or papaverine plus phentolamine. Prostaglandin E1 monotherapy unequivocally has the lowest incidence of priapism, recently reported at 0.36% in almost 3000 patients in a recent review [20]. Table 3 looks at pain associated with injection of trimix. In approximately 800 patients, the incidence of pain during injection was 2.5%. This is a significant advantage over the use of prostaglandin E1 monotherapy with reported pain rates as high as 40% [21,22]. The ability to achieve superior efficacy with a low Table 4: Penile scarring with trimix YEAR

NUMBER OF PATIENTS

PATIENTS WITH SCARRING

INCIDENCE OF SCARRING

FOLLOW-UP (MONTHS)

Bennett [24]

1991

105

0

0%

14-24

Govier [30]

1993

170

7

4.2%

11.2 (mean)

Valdevenito [31]

1994

111

2

1.8%

1-24

Casabe [35]

1998

189

10

5.3%

16.95 (mean)

19

3.3%

575

332

continue therapy. Chew et al. [40], in 1997, reported a 23.3% incidence of fibrosis in 245 patients performing injections of prostaglandin E1 for an average of 29 months. Again, how do we explain these wide discrepancies? At present, our reporting of penile fibrosis includes too many variables to be of much value. How much fibrosis is really fibrosis? Do we need ultrasound confirmation? Does the patient, or examiner, note a deformity of the penis other than the fibrosis? Does the fibrosis need to persist or progress? If the fibrosis resolves, was it fibrosis? How often was the patient examined and by whom? Were variables of injection volume, needle diameter, and injection technique accounted for, and how frequently were the injections performed and over what period of time? Although our current literature will not answer these questions precisely, some consensus can be derived from this review and the author's personal experience. 1. Penile fibrosis is probably caused by a combination of trauma from the injection itself and a toxic effect of the agent involved.

REFERENCES 1.

ZORGNIOTTI AW, LEFLEUR RS. Auto-injection of the corpus cavernosum with a vasoactive drug combination for vasculogenic impotence. J Urol 1985;133;3941.

2.

HAKENBERG O, WETTERAUER U, KOPPERMANN U, et al: Systemic pharmacokinetics of papaverine and phentolamine: comparison of intravenous and intracavernous application. Int J Impot Res 2:247, 1990.

3.

FALLON B. Intracavernous injection therapy for male erectile dysfunction. Impotence 1995;22:833-845.

4.

WESPES E, RONDEUX C, SCHULMAN CC: Effect of phentolamine on venous return in human erection. Br J Urol 63:95, 1989.

5.

STIEF CG, WETTERAUER U. Erectile responses to intracavernous papaverine and phentolamine: comparison of single and combined delivery. J Urol 1988; 140: 1415-1416.

6.

SIDI A, CAMERON JS, DUFFY LM, LANGE PH. Cavernous drug-induced erections in the management of male erectile dysfunction: experience with 100 patients. J Urol 1985;135:704-706.

7.

NELLANS RE, LELAND RE, KRAMER-LEVIEN D. Pharmacological erection: diagnosis and treatment applications in 69 patients. J Urol 1986;138:52-54.

2. Papaverine or papaverine-containing mixtures have a higher incidence of penile fibrosis than prostaglandin E1 monotherapy.

8.

BODNER DR, LINDAN R, LEFFLER E, KURSH ED, RESNICK MI. The application of intracavernous injection of vasoactive medications for erection in men with spinal cord injury. J Urol 1987;138:310-311.

3. The penile fibrosis secondary to papaverine or papaverine-containing mixtures tends to be more severe and is less likely to resolve than that of prostaglandin E 1.

9.

KEOGH EJ, WATTERS GR, EARLE CM, CARATI CJ, WISNIEWSKI ZS, TULLOCH AGS, LORD DJ. Treatment of impotence by intrapenile injections. A comparison of papaverine versus papaverine and phentolamine: a double-blind, crossover trial. J Urol 1989;142:726727.

4. A longer duration and higher frequency of penile injections leads to a higher incidence of fibrosis.

10. LEVINE SB, ALTHOF SE, TURNER LA, RISEN CB, BODNER DR, KURSH ED, RESNICK MI.Side effects of self-administration of intracavernous papaverine and phentolamine for the treatment of impotence. J Urol 1988;141:54-57. 11. SEIDMON EJ, SAMAHA JR AM. The pH analysis of papaverine-phentolamine and prostaglandin E1 for pharmacologic erection. J Urol 1988;141:1458-59. 12. ADAIKAN PG, KOTTEGODA SR, RATNAM SS: A possible role for prostaglandin E1 in human penile erection. In: Abstract Book Second World Meeting on Impotence. Prague, Czechoslovakia, February 6, 1986.

5. Good injection technique using small needles, small volumes of agents, and penile pressure after the injection will lower the incidence of penile fibrosis. Overall, trimix has a superior efficacy and lower incidence of pain than prostaglandin E1 monotherapy. While the risk of priapism is low, it clearly is higher than that of prostaglandin E1 alone. While the literature on nodules and fibrosis is confusing, E1 monotherapy again has the edge. Hopefully in the future, we will have a single agent capable of achieving the best qualities of both prostaglandin E 1 monotherapy and trimix.

13. ISHII N, WATANABE H, IRISAWA C, KIKUCHI Y: Therapeutic trial with prostaglandin E1 for organic impotence. In: Abstract Book Second World Meeting on Impotence. Prague, Czechoslovakia, February 2, 1986. 14. STACKLW, HASUN R, MARBERGER M: Intracavernous injection of prostaglandin E1 in impotent men. J Urol 1988;140:66.

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15. PORSTH: Comparative usefulness of prostaglandin E1, papaverine and papaverine/phentolamine for the diagnosis of erectile dysfunction in 61 patients. Urologe A 1988;27:22.

tion with intracorporeal papaverine in combination with phentolamine and/or prostaglandin E1. J Urol 1992; 148:1181-1183.

16. ISHII N, WATANABE H, IRISAWA C, YOSHIHIRO K, KUBOTA Y, KAWAMURA S, SUZUKI K, CHIBA R, TOKIWA M, SHIRAI M. Intracavernous injection of prostaglandin E1 for the treatment of erectile impotence. J Urol 1988;141:323-325.

29. VON HEYDEN B, DONATUCCI CF, KAULAN, LUE TF. Intracavernous pharmacotherapy for impotence: selection of appropriate agent and dose. J Urol 1993;149:1288-1290. 30. GOVIER FE, MCCLURE RD, WEISSMAN RM, GIBBONS RP, PRITCHETT TR, KRAMER-LEVIEN D. Experience with triple-drug therapy in a pharmacological erection program. J Urol 1993;150:1822-24.

17. LEE M, STEVENSON RWD, SZASZ G. Prostaglandin E1 versus phentolamine/papaverine for the treatment of erectile impotence: a double-blind comparison. J Urol 1988;141:549-553. 18. FLOTH A, SCHRAMEK P. Intracavernous injection of prostaglandin E1 in combination with papaverine: enhanced effectiveness in comparison with papaverine plus phentolamine and prostaglandin E1 alone. J Urol 1991;145:56-59.

31. VALDEVENITO R, MELMAN A. Intracavernous selfinjection pharmacotherapy program: analysis of results and complications. Int J Impot Res 1994;6:81-91. 32. BECHARAA, CASABÉ A, CHÉLIZ G, ROMANO S, FREDOTOVICH N. Prostaglandin E1 versus mixture of prostaglandin E1, papaverine and phentolamine in nonresponders to high papaverine plus phentolamine doses. J Urol 1996;155:913-914.

19. PORST H: Komplikationen vasoaktiver Substanzen in der Diagnostik und Therapie der erektilen Dysfunktion. Urologe B 1993;33:13. 20. PORST H. The rationale for prostaglandin E1 in erectile failure: a survey of worldwide experience. J Urol 1996;155:802-815.

33. COLLINS J, THIJSSEN A. Experience with intracorporeal prostaglandin E1, papaverine and phentolamine in patients with erectile dysfunction. AUAMeeting; 1993; San Antonio.

21. STACKL W, HASUN R, MARBERGER M. Intracavernous injection of prostaglandin E1 in impotent men. J Urol 1988;140:66.

34. GOVIER FE, ASASE D, HEFTYTR, MCCLURE RD, PRITCHETT TR, WEISSMAN RM. Timing of penile color flow duplex ultrasonography using a triple drug mixture. J Urol 1995;153:1472-1475.

22. LEE LM, STEVENSON RWD, SZASZ G. Prostaglandin E1 versus phentolamine/papaverine for the treatment of erectile impotence: a double-blind comparison. J Urol 1989;141:549. 23. BENNETT AH, CARPENTER AJ. An improved vasoactive drug combination for a pharmacological erection program (PEP). J Urol, part 2, 1990;143:317A, abstract 514.

35. CASABÉ A, BECHARAA, CHELIZ G, ROMANO S, REY H, FEDOTOVICH N. Drop-out reasons and complications in self-injection therapy with a triple vasoactive drug mixture in sexual erectile dysfunction. Int J Impot Res 1998;10:5-9.

24. BENNETT AH, CARPENTER AJ, BARADA JH. An improved vasoactive drug combination for a pharmacological erection program. J Urol 1991;146:1564-65.

36. JUNEMAN KP, ALKEN P. Pharmacotherapy of erectile dysfunction: a review. Int J Impot Res 1989;1:71.

25. GOLDSTEIN I, BORGES FD, FITCH WP, KAUFMAN J, DAMRON K, MORENO J, PAYTON T, YINGST J, KRANE RJ. Rescuing the failed papaverine/phentolamine erection: A proposed synergistic action of papaverine, phentolamine and prostaglandin E1. J Urol, part 2, 1990;143:304A, abstract 463.

37. Schwarz Pharma Scientific product information: Virilan (Alprostadil) September 1994. 38. The Upjohn Company Product Information: Caverject (Alprostadil) 17 March 1995.

26. MCMAHON CG. A comparison of the response to the intracavernosal injection of a combination of papaverine and phentolamine, prostaglandin PGE, and a combination of all three agents in the management of impotence. Int J Impot Res 1991;3:113.

39. CHEN RN, LAKIN MM, MONTAGUE DK, AUSMUNDSON S. Penile scarring with intracavernous injection therapy using prostaglandin E1: a risk factor analysis. J Urol 1996;155:138-140.

27. HAMID S, DHABUWALA CB, PONTES EJ. Combination intracavernous pharmacotherapy in the management of male erectile dysfunction. Int J Impot Res 1992;4:109.

40. CHEW KK, STUCKEY BGA, EARLE CM, DHALIWALSS, KEOGH EJ. Penile fibrosis in intracavernosal prostaglandin E1 injection therapy for erectile dysfunction. Int J Impot Res 1997;9:225-228.

28. ALLEN RP, ENGEL RM, SMOLEV JK, BRENDLER CB. Objective double-blind evaluation of erectile func-

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334

be preceded by urination. The residual urine will disperse the micro-pellet, allowing alprostadil to be absorbed by the urethral mucosa in a biphasic phase. Initial absorption is rapid. About 80% of alprostadil is absorbed within 10 minutes [5-7]. The concentration of PGE1 in the semen after using intraurethral alprostadil does not seem to be significantly altered [8]. Alprostadil is absorbed initially into the corpus spongiosum from the urethra. A fraction (approximately 20%) of the drug is then transfered through intercommunicating vessels to the corpora cavernosa [9,10]. The rest passes into the systemic venous circulation. The peak plasma concentration of PGE1 is reached within 16 minutes. The plasma concentrations, however, are low and require gas chromatography to be detected. Alprostadil is a well known drug, which has been studied extensively. After its intravenous use, alprostadil is metabolized rapidly (first to 15-ketoPGE1 and then to 13,14-dihydro, 15-keto-PGE1, both inactive) during its passage through the lungs and 90% is excreted in the urine as metabolites within 24 hours – the rest in the feces [11]. The enzyme that catalyzes the first reaction is present in the urethra, prostate, corpus cavernosum and lungs. After one pass through the pulmonary capillary beds, between 60-90% of systemic PGE1 is inactivated [11,12]. Alprostadil half-life varies between 30 seconds and 10 minutes according to the patient’s physiological status.

V. TRANSURETHRAL DRUG THERAPY 1. ALPROSTADIL (PROSTAGLANDIN E1) Intraurethral alprostadil (IUA) is a novel delivery system design to administer a micro-pellet of alprostadil (PGE 1) topically to the urethral mucosa for absorption and transfer to the erectile bodies. Padma-Nathan and associates reported, at the AUAin 1995, for the first time, that men receiving intraurethral administration of alprostadil (500µg) could achieve a penile erection [1]. It has been approved for clinical use in USAsince January 1997. a) Presentation It is a single-use translucent hollow polypropylene applicator designed to deliver medication to the male urethra. The medicated pellet (semi-solid micro-suppository measuring 1.4mm in diameter by 3-6 mm in length) resides at the tip of the hollow applicator. The stem of the applicator measures 3.2 cm in length and 3.5 mm in diameter. Alprostadil is the active medication. It is suspended in polyethylene glycol 1450 (as excipient) and formed into the micro-pellet [2]. b) Pharmacology 1. ACTIONS Alprostadil is a synthetic prostaglandin with similar pharmacological actions to prostaglandin E1

c) Indications and contraindications

(PGE1). Alprostadil is a potent vasodilator acting through the cAMP pathway. Hedlund and Andersson showed that alprostadil caused relaxation of isolated strips of corpus cavernosum and spongio sum in vitro which have been pre-contracted with norepinephrine [3]. An increase of cAMP, induced by the activation of adenylate cyclase, is associated with this event. This increase activates ATPdependent pumps that release calcium ions out of the smooth muscle cell, which trigger relaxation.

1. INDICATIONS: IUA is indicated in the treatment of erectile dysfunction of any etiology. 2. CONTRAINDICATIONS: It is contraindicated in men with the following: • Known alprostadil hypersensitivity. • Abnormal penile anatomy: urethral stricture, balanitis, severe hypospadias and curvature, and acute or chronic urethritis.

PGE1 may also show various pharmacological actions. It produces transient platelet antiaggregant effects at high plasma levels [4]. PGE1can also promote mucus secretion in the stomach, stimulation of intestinal smooth muscle and stimula tion of uterine smooth muscle.

• Patients who have a hyperviscosity syndrome such as multiple myeloma, polycythemia, thrombocythemia, sickle cell anemia or trait. • For sexual intercourse with a pregnant women unless a condom barrier is used • In men for whom sexual activity is inadvisable.

2. PHARMACOKINETICS Intraurethral administrations of alprostadil must 335

e) Clinical experience

cy of transurethral alprostadil IUAin patients with ED who underwent prior intracavernous injection (ICI) therapy [16]. Of the original 1511 men enrolled, 452 reported prior ICI therapy. Prior ICI therapy was reported to be effective by 238 men, sometimes effective by 119 and not effective by 95. In the group that reported prior ICI as not effective, 58% obtained an erection sufficient for intercourse in the clinic using IUA; 47% of these responders achieved intercourse during the home treatment phase of the study. On the other hand, for men reporting ICI therapy as effective or sometimes effective, following IUA therapy 68% achieved an erection sufficient for intercourse in the clinic setting and 67% of these clinical responders reported intercourse at home. In another report, using the same patient population, the efficacy of transurethral alprostadil was evaluated in patients suffering from ED following radical prostatectomy (n=384 patients) [17]. The authors reported that 70.3% of these men had an erection sufficient for intercourse in the clinic and 57.1% of these responders on active medication had sexual intercourse at least once at home.

In 1996, Hellstrom and associates reported the results of a double-blind, placebo-controlled multicenter study evaluating 68 men with long-standing organic erectile dysfunction. In this study, 63.6% (42 of 66) of patients reported intercourse while 49.2% (32 of 65) judged their erection to be sufficient for intercourse with IUA [13]. PadmaNathan and associates published the largest series in the New England Journal of Medicine in January, 1997 [14]. They reported the results of a double-blind, placebo-controlled multicenter (in USA) phase III study using alprostadil delivered transurethrally that included 1511 men, 27 to 88 years of age, suffering from chronic erectile dysfunction due to various organic causes. In this trial, men were first administered alprostadil intraurethrally in the clinic (titration phase) up to four doses of the drug (125,250,500 and 1000 µg). During that phase of the study, 996 men (65.9%) had an erection response sufficient to enter the placebo-controlled “at-home” phase of the study. The authors reported that 299 of the 461 patients (64.9%) treated with alprostadil at home had intercourse, on at least one occasion, as compared with 93 of the 500 men in the placebo group (18.6%, p<0.001). Overall, 57% of applications or administrations of alprostadil (2797/4933) resulted in intercourse, orgasm, or an erection sufficient for intercourse for at least 10 minutes compared to 15.4% (669/4331) in the placebo group (p>0.001). Among the men in the alprostadil group who had sexual intercourse at least once, 7 of 10 applications of IUA resulted in intercourse. The authors reported that there was no difference in the efficacy of intraurethral alprostadil regardless of age or etiology of ED. The authors indicated that the inclinic response to IUA was not predictive of intercourse at home (64.9% of the clinical responders had intercourse at home). A similar double-blind, placebo-controlled multicenter study was conducted in Europe on 249 patients [15]. In the clinical phase of the study, 159 patients (64%) achieved an erection sufficient for intercourse and were randomized either to placebo or the active medication for home treatment. In the IUA arm, 69% of men reported intercourse at least once as compared to 11% of men in the placebo arm (p<0.001).

Other reports about the efficacy of IUA show varying results. Werthman and Rajfer reported the results of their first 100 cases in the clinical setting [18]. All patients had previous intracavernosal injection therapy. Using IUA, only 7% had wellsustained, rigid erection while 30% had full erections but with partial rigidity sufficient for penetration as compared with 49% who presented a well-sustained, rigid erection and 40% who had a full erection but with partial rigidity using intracavernosal injections. They concluded that injection therapy was more effective. In a similar study, Porst reported a total response rate of 43% using IUA (up to 1000 µg) vs 70% with intracavernous alprostadil (up to 20 µg) in 103 patients with ED [19]. In a letter to the editor in response to Porst’s article, Lewis made several points before considering this article to indicate that transurethral alprostadil is an ineffective therapy [20]. Lewis feels that IUA should be considered more as an intercourse facilitator rather than an erection inducer like injection therapy, making the comparison difficult between the two therapies. He stated that facilitatory treatment may be more desirable for couples as they work with ED as a couple. Furthermore, he mentioned that the concurrent use of a venous flow controller device with IUA impro-

Using the same patient cohort enrolled in the USA multicenter study [14], Engel evaluated the effica336

ved both the patient’s degree of erection and response and reduced the side effects [20]. Fulgham and associates evaluated the response to intraurethral alprostadil administration using IUA in men (n=115) with ED in an office setting study [21]. Only 27% of patients (31 of 115) tested in their office achieved an erection sufficient for intercourse (patients received up to 1000 µg IUA). Mulhall, at the AUA in 1998, presented data indicating that in clinic responders demonstrate wide variability of response to IUA therapy at home [22]. At home, in clinic responders (n=100 patients), 50±20% (range 25-75%) of administrations resulted in erections sufficient for penetration. In a study of 107 patients who either refused or failed prior ICI therapy, 7 patients developed erections rated good or very good, while 72% had partial erections. At three months follow-up, 24% of patients were satisfied and 8% refilled their prescription [23]. Bodner and associates evaluated the efficacy of intraurethral alprostadil using IUA in treating ED following spinal cord injury (SCI) in 15 patients. All of these patients had previous effective ICI therapy. Only 3 patients achieved an erection sufficient for intercourse in the clinic (with the use of a constrictive ring) and used it at home. At home, all 3 were dissatisfied with the quality of the erection and returned to ICI therapy [24]. It is possible that the urethral lining might be different in these patients because of metaplasia (frequent catheter users). In order to increase the success rate of at-home IUA therapy, an adjustable penile constriction band (ACTIS®) to block venous outflow was developed and is used in combination with administration of transurethral alprostadil to promote arteriolar inflow in men suffering from ED [25-27]. The IUAACTIS Study group reported that of the 144 patients who completed home titration, 71% (102/144) reported successful intercourse. Using the penile band, 75% of applications of transurethral alprostadil resulted in intercourse while 74% of patients were satisfied or very satisfied with the therapy [26]. Padma-Nathan reported an erection sufficient for intercourse in 6 of 8 patients who had previously failed IUA therapy [27]. Donatucci, at the 1998 AUA, reported the use of IUA as an effective alternative therapy in a small

group of patients (n=11) who had undergone prosthesis placement or removal [28]. Five patients responded to IUA alone with erection sufficient for intercourse and two responded to the combination of IUA and vacuum therapy. Hellstrom et al. presented results at the 1999 AUA concerning the efficacy of IUA in patients who failed sildenafil. 221 patients were enrolled at 62 sites in a postmarketing study either because they failed to respond to sildenafil or had a side effect resulting in discontinuation of sildenafil. Patients used 1 or 2 doses of transurethral alprostadil in the clinic, and the investigator and patient judged the erectile response. Overall, 125/221 (57%) of the patients achieved an erection sufficient for intercourse with transurethral alprostadil in the clinic. Of the 125 successful patients, 34 (27.2%) had to use the ACTIS® constriction band. Most patients (>70%) used either 500 or 1000 µg of IUA. Of the 221 patients, 14 (6%) rated their erectile dysfunction as mild, 100 (45%) as moderate, and 107 (48%) as complete [29]. At the same meeting, Nehra et al. reported their results of a combination therapy (IUAand Sildenafil) in patients who failed prior use of either medication alone. Sixteen patients (11 post radical prostatectomy and 5 with a diagnosis of organic erectile dysfunction, were part of this study. Combination therapy was initiated using 100 mg Sildenafil orally 60 minutes prior to intercourse and 500µg of IUA immediately before intercourse. The combination was effective in inducing an erection sufficient for intercourse. At three months, all patients reported excellent results. This might represent a salvage therapy, although more studies are needed before we can conclude on their effectiveness [30]. One of the advantages of IUA over injection therapy is the fact that IUA does not require the use of needles. In fact, 88% of men receiving or using IUArated the transurethral application of alprostadil as either “neutral”, “comfortable”, or “very comfortable” [14]. d) Adverse effects Penile pain is the most frequent reported side effect. During home treatment, penile pain was reported about 30% of men (29 to 35.7%) in 7.8 to 18.3% of IUA administrations (not every application leads to pain). Urethral pain was reported in 12%, minor urethral bleeding occurred in 5%, tes-

337

ticular pain in 5% and dizziness in 2%. Penile fibrosis were observed in 1.4% and priapism in less than 0.1% [13,14,16,19,31]. No man reported urethral stricture, penile fibrosis or priapism in series [14]. In the clinic, dizziness and hypotension occurred in 4% and 3-4%, respectively [13,14,16,19,31]. The frequency of hypotension increased with the dose in the series reported in the New England Journal of Medicine [14]. Defined by strict criteria, Fulgham reported, in his series, 41.2% of postural hypotension [21]. Syncope occurred in 0.43% [14,18,19]. Because of this potential effect, IUA titration should be carried out under medical supervision according to the monography [2]. However, Morales and the Canadian IUA investigators reported at the annual Canadian Urological Association meeting last June, 1999 that titration of IUA in clinic is not required. In fact, they randomized 643 patients to either titration in the clinic or at home with the use of a video explaining the use of IUA and its side effects. During the titration phase, they reported no differences in efficacy and safety between the at-home and in-clinic titration groups. In fact, no hypotension occurred in the at-home titration phase suggesting that titration could be safely done at home instead of the clinic [32]. The female partner reported vaginal burning/ itching in 5.8% of partners on active medication compared to 0.8% in the placebo group. e) Dosage and administration IUA is available in 3-4 dosage depending of the country (125-250-500-1000µg). Patient should receive the lowest dose to achieve sexual intercourse. The system is used on a prn basis, 10-15 minutes before intercourse, with a maximum of one unit every 12 hours. The patient must be instructed to urinate before insertion of the device. In summary, IUA has been shown to be safe and effective for use in the treatment of erctile dysfunction. Because of its limited systemic side effects and its acceptance by the patient, it can be offer as an option as a first line therapy for patient suffering from erectile dysfunction.

found in IUA, a group of California, USA, reported an in-clinic success rate of 56% (10 of 18 patients) in a small study [33]. Engelhardt compared the intraurethral application of liposomal PGE1with intracavernous injection of PGE1in a clinical setting in 25 patients (10 with psychogenic and 15 with organic ED). Intraurethral liposomal PGE1produce sufficient rigidity in only 6 of 25 patients (all responders had psychogenic ED) [34]. Because of the limited data on this new lyophilized liposomal PGE1, we can’t yet determine its role in ED treatment.

3. ALPROSTADIL (PROSTAGLANDIN E1) /PRAZOSIN

Because transurethral alprostadil using IUA delivery system has been shown to cause erections, the potential benefit of adding prazosin HCL, an α1–blocker (as for ICI therapy) to alprostadil has been studied. Pharmacology Prazosin hydrochloride is a quinazoline-derivative post-synaptic α1-adrenergic blocking agent. It reduces vascular resistance as a result of its vasodilating effects on both arterial and venous vessels. It produces a selective competitive inhibition of α1-adrenergic receptors. The plasma half-life after oral administration has been reported to be 2-4 hours. It is metabolized extensively in the liver, principally by demethylation and conjugation, and excreted as unchanged drug (5-11%) and metabolites. Four of its metabolites have been shown to posses 10-25% of the hypotensive effect of prazosin. Between 90-94% of a dose is excreted in the feces and the remainder in the urine [36]. a) Clinical experience At the VII World meeting in San Francisco (1996), Padma-Nathan reported two randomized, doubleblind, placebo controlled study evaluating the safety and efficacy of alprostadil (A), prazosin HCL (P) and a combination of both (A/P) administered intraurethrally to 460 men with chronic ED. Alprostadil was more potent than prazosin alone but some combination were better than alprostadil. The exact numbers were not published [37]. In another study, 415 patients were dosed (double-blind) with up to 4 alprostadil and 9 alprostadil/prazosin combinations on different days to allow within-patient comparisons. In the

2. LYOPHILIZED LIPOSOMAL ALPROSTADIL Using a lyophilized liposomal PGE1delivered intrameataly- a compound different from the one

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study, 68% of men reported intercourse on at least one dose. Each of the 9 combinations resulted in higher rates of intercourse than the alprostadil component alone [38]. Assessing the erectile response to transurethral alprostadil, prazosin and combination of A/P in a double-blind, placebocontrolled study, Peterson and associates showed that prazosin alone (9 to 2000 µg) was not better than placebo (12.7 vs. 2.7%) [39]. The most effective alprostadil dose (500µg) resulted in full enlargement or rigidity in 51.8% of administrations. The 500/2000µg A/P combination slightly improved the response rate to 58.9%. The combinations of 125/500 and 250/500µg A/P were more effective than 125 and 250µg of alprostadil given alone, respectively (p>0.01). Combination therapy could be beneficial for a subset of patients who do not respond to alprostadil alone. In another study comparing intraurethral alprostadil vs. combination therapy, intercourse was reported by 70% of men (276/394) [35]. Of the 276 responders, 89 succeeded only with the combination and did not have erection with alprostadil alone. These results indicate that transurethral alprostadil/prazosin combination could be an alternative therapy.

REFERENCES

b) Adverse effects Penile pain occurred in 7.6 to 19.8% of administrations. Hypotension occurred in 1.5 to 9.2% of applications, most frequently with high doses of the combinations [35,38].

1.

PADMA-NATHAN H, BENNETTAH, GESUNDHEIT N, et al. Treatment of erectile dysfunction by the medicated urethral system for erection (IUA). [Abstract] J Urol 1995;153:(Supplement)472A

2.

IUA (Alprostadil) Monography product. VIVUS Inc., Menlo Park, Ca, USA. 1997;

3.

HEDLUND H AND ANDERSSON K-E. Comparison of the response to drugs acting on adrenoreceptors and muscarinic receptors in human isolated corpus cavernosum and cavernous artery. J Auton Pharmacol 1985;5(1):81-8.

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SIMMETTH AND PESKAR BA. Prostaglandin E1 and arterial occlusive disease: pharmacological considerations. Eur J. Clin Invest 1988;18(6):549-54.

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GESUNDHEIT N, AZZAM SM, BALABANOV G. The pharmacokinetics of transurethral alprostadil (prostaglandin E1) in men with erectile dysfunction. [Abstract] EAU 1996; Notes: Presented at the 12th Congress of the European Association of Urology, September 1-4, 1996, Paris, France.

6.

OWEN JS, PETERSON CA, COWLEY C, et al. Pharmacokinetics of transurethrally administered alprostadil (prostaglandin E1) in men with erectile dysfunction. [Abstract] ACCP 1996; Notes: Presented at the American College of Clinical Pharmacology 25th Annual Meeting, September 26-28, 1996, Philadelphia,USA.

7.

PADMA-NATHAN H, PETERSON CA, TAM PY, et al. Transurethral alprostadil treatment of erectile dysfunction: Clinical and pharmacokinetic correlations. [Abstract] Int J Impot Res 1996;8:(3)146

8.

PETERSON CA, COWLEYC, DZERK AM, et al. The medicated urethral system for erection: does transurethral alprostadil affect the concentration of prostaglandins in human ejaculate or the viability and motility of human sperm. [Abstract] EAU 1996; Notes: Presented at the 12th Congress of the European Association of Urology, September 1-4, 1996, Paris, France.

9.

GESUNDHEITN, PETERSON CA, COWLEYC, et al. The pharmacokinetics of transurethral alprostadil (prostaglandin E1) in men with erectile dysfunction. [Abstract] J Urol 1997;157:(4,Supplement)259

4. DINOPROSTONE (PROSTAGLANDIN E2) Prostaglandin E2 is an oxytocic agent with vasodilatory effects similar to those of alprostadil. Wolfson and associates reported its use intraurethrally [40]. They formulated a dinoprostone cream (using dinoprostone suppository, 10 ml lidocaine 2% gel and 40 ml surgical lubricant gel) with a final concentration of 400µg/ml. Two ml were instilled into the urethra with a syringe. A full penile tumescence was achieved in 30% of the men and 40% showed partial tumescence. Rozas and associates reported an erection sufficient for intercourse in 19 of the 25 patients (patients with ED following prostatectomy) that they studied using a somewhat similar solution [41]. This medication has not been widely tested and a placebo-controlled study must be performed before we can draw any conclusions on its use as intraurethral therapy.

10. GARCIA-REBOLL L, MULHALL JP, AND GOLDSTEIN I. Drugs for the treatment of impotence. Drugs & Aging 1997;11(2):140-51. 1170-229X. Notes: Therapy-medication. 11. ROSENKRAKZ B, FISHER C, BOEYNAEMS JM, AND FROLICH JC. Metabolic disposition of prostaglandin E1 in man. Biochem Biophysiol Acta 1983;750(2):231-6. 12. ROBERTSON RP. Differential in vivo pulmonary degradation of prostaglandin E1, B1 and A1. Am J Physiol 1975;228(1):68-70. 13. HELLSTROM WJG, BENNETT AH, GESUNDHEIT

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N, KAISER FE, LUE T, PADMA-NATHAN H, PETERSON CA, TAM PY, TODD LK, VARADY JC et al. A double-blind, placebo-controlled evaluation of the erectile response to transurethral alprostadil. Urology 1996;48(6):851-6.

constriction band in men with erectile dysfunction: results from a multicenter trial. [Abstract] J Urol 1998;159:(5, Supplement)237 26. LEWIS RW, WELDON K, NEMO K, et al. Combined use of transurethral alprostadil and an adjustable penile constriction band in men with erectile dysfunction: results from a multicenter trial. [Abstract] Int J Impot Res 1998;10:(Supplement 3)S49

14. PADMA-NATHAN H, HELLSTROM WJG, KAISER FE, LABASKY RC, LUE T, NOLTEN WE, NORWOOD PC, PETERSON CA, SHABSIGH R, TAM PY et al. Treatment of men with erectile dysfunction with transurethral alprostadil. N Eng J Med 1997;336(1):1-7.

27. PADMA-NATHAN H, TAM PY, PLACE VA, et al. Improved erectile response to transurethral alprostadil by use of a novel, adjustable penile band. [Abstract] J Urol 1997;157:(4, Supplement)181

15. WILLIAMS G, ABBOU CC, AMAR ET, DESVAUX P, FLAM TA, LYCKLAMA A NIJEHOLT GA, LYNCH SF, MORGAN RJ, MULLER SC, PORST H et al. Efficacy and safety of transurethral alprostadil therapy in men with erectile dysfunction. IUA Study Group. Br J Urol 1998;81(6):889-94.

28. DONATUCCI CF, NELSON RF . Transurethral alprostadil after penile prosthesis placement. [Abstract] J Urol 1998;158:(5,supplement)222 29.

16. ENGELJD AND MCVARY KT. Transurethral alprostadil as therapy for patients who withdrew from or failed prior intracavernous injection therapy. Urology 1998;51(5):687-92. 17. COSTABILE RA, SPEVAK M, FISHMAN IJ, GOVIER FE, HELLSTROM WJG, SHABSIGH R, NEMO KJ, RAPPORT JL, TAM PY, WELDON KL et al. Efficacy and safety of transurethral alprostadil in patients with erectile dysfunction following radical prostatectomy. J Urol 1998; 160(4): 1325-8.

HELLSTROM WJG, CONCEPCION RS, DECHET GJ, et al. Efficacy of IUA_ (Alprostadil) in Patients with Erectile Dysfunction who Failed Viagra (Sildenafil) Therapy: Results from a Multicenter Post-Marketing Study. [Abstract] J Urol 1999; 161: (4)212

30. NEHRAA, JONES WR, HAKIM L, et al. Effectiveness of combination therapy of IUAand Viagra in the salvage of erectile dysfunction patients desiring noninvasive therapy. [Abstract] J Urol 1999; 161: (4)213 31. LABASKY RC, SPIVACK AP, IUA Study Group. Transurethral Alprostadil for the treatment of erectile dysfunction: Two-year safety update. [Abstract] J Urol 1998;159:(5, Supplement)237

18. WERTHMAN PAND RAFJER J. IUAtherapy:preliminary clinical observations. Urology 1997;50(5):809-11. 19. PORST H. Transurethral alprostadil with IUA(medicated urethral system for erection) vs intracavernous alprostadil--a comparative study in 103 patients with erectile dysfunction. Int J Impot Res 1997;9(4):187-92.

32. MORALES A, Canadian MUSE Investigators. Clinical assessment of the efficacy and safety of MUSE (alprostadil) in subjects with erectile dysfunction: a comparison of at-home versus in-clinic titration. [Abstract] Can J Urol 1999;6:(3)784

20. LEWIS RW. Transurethral alprostadil with IUA(medicated urethral system for erection) vs intracavernous alprostadil--a comparative study in 103 patients with erectile dysfunction. Letter to the editor. Int J Impot Res 1998;10(1):61-2.

33. SEE JR, WILLIAMS J, SPARKUHLA, et al. Lyophilized liposomal prostaglandin E1 released by a dilute detergent for intrameatal delivery to treat erectile failure. [Abstract] J Urol 1997;157:(4, Supplement)201

21. FULGHAM PF, COCHRAN JS, DENMAN JL, FEAGINS BA, GROSS MB, KADESKY KT, KADESKY MC, CLARK AR, AND ROEHRBORN CG. Disappointing initial results with transurethral alprostadil for erectile dysfunction in a urology practice setting. J Urol 1998;160(6 Pt 1):2041-6.

34. E NGELHARDT PF, PLAS E, HUBNER WA, AND PFLUGER H. Comparison of intraurethral liposomal and intracavernosal prostaglandin-E1 in the management of erectile dysfunction. Br J Urol 1998;81(3):4414.

22. MULHALL JP, PARKER M. Evaluation of the consistency of response to intra-urethral prostaglandin (IUA) during at-home use. [Abstract] J Urol 1998;159:(5, Supplement)238

35. COSTABILE RA, MUSE Study Group. Efficacy of transurethral alprostadil (MUSE) vs. transurethral alprostadil/prazosin (Alibra) in men with complete organic erectile dysfunction. [Abstract] J Urol 1998;159:(5, Supplement)237

23. GALCA G, BRITANICO J, VAPNEK JM. Disappointing results for transurethral alprostadil in a V.A. impotence clinic. [Abstract] J Urol 1998; 159: (5, Supplement) 236

36. MCEVOYGK. MCEVOY GK, editors. American Hospital Formulary Service. Drug Information. 1988th ed. Bethesda: American Society of Hospital Pharmacists; 1988; 24, Cardiovascular drugs. p. 763-968.

24. BODNER DR, HAAS CA, KRUEGER B, AND SEFTEL AD. Intraurethral alprostadil for treatment of erectile dysfunction in patients with spinal cord injury. Urology 1999;53(1):199-202.

37. PADMA-NATHAN H, BENNETTAH, GESUNDHEIT N, et al. Transurethral therapy with alprostadil and alprostadil/prazosin combinations in men with erectile dysfunction. [Abstract] Int J Impot Res 1996;8:(3)146

25. LEWIS RW, IUA-ACTIS Study Group. Combined use of transurethral alprostadil and an adjustable penile

38. LEWIS RW, BRENDLER CB, BURNETTAL, et al. A

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sed by patients at the time of treatment discussion. This being the case, it is important that the practitioner be aware of the issues pertaining to alternate therapy use such as topical treatments.

comparaison of transurethral alprostadil and alprostadil/prazosin combinations for the treatment of erectile dysfunction. [Abstract] J Urol 1997;157:(4, Supplement) 181 39. PETERSON CA, BENNETTAH, HELLSTROM WJG, KAISER FE, MORLEY JE, NEMO K, PADMANATHAN H, PLACE VA, PRENDERGAST JJ, TAM PY et al. Erectile response to transurethral alprostadil, prazosin and alprostadil-prazosin combinations. J Urol 1998;159(5):1523-7.

1. GENERAL PRINCIPLES OF TOPICAL AGENTS There have been several advances in the understanding of the pharmacokinetics of topical therapy. The transdermal route has a well established technology to provide durable and constant plasma levels of drugs such as hormone replacements, narcotics and vasodilators. When it comes to local penile therapy using direct smooth muscle relaxants, the durability and onset of action of such methods may not be useful attributes. In this regard there are several issues worth mentioning: 1) High systemic levels are undesirable as they may result in an unacceptable level of adverse events.

40. WOLFSON B, PICKETT S, SCOTT NE, DEKERNION JB, AND RAFJER J. Intraurethral prostaglandin E-2 cream: a possible alternative treatment for erectile dysfunction. Urology 1993;42(1):73-5. 41. ROZAS KP, GONZALEZ GJ, PETROS JA, et al. Intraurethral prostaglandin for the treatment of postprostatectomy impotence. [Abstract] J Urol 1995; 153: (4)473A _________________________

VI. TOPICAL THERAPY FOR ERECTILE DYSFUNCTION

2) Agents may be largely metabolized in the first pass through the lungs or liver. 3) Vasoactive agents need to reach the corpora cavernosa rapidly with an effective (highest) concentration.

Intracavernosal injections (ICI) and intraurethral suppositories (IUS) of vasoactive substances have improved the treatment of erectile dysfunction (ED) and enjoy widespread acceptance by patients and urologists. However, despite their initial acceptance, at least 50% of men using such therapies eventually discontinue treatment for reasons relating to pain, loss of effectiveness, and lack of interest [1]. This de facto dissatisfaction with proven effective treatments is the rationale for alternative routes for the delivery of vasoactive substances.

Topical penile therapy has an unique set of anatomic and physiologic issues that must be considered. There are several anatomic/fascial layers between the penile skin and the corpus cavernosum. The tunica albuginea is presumed to be difficult to penetrate due to its thick layers of collagen. Therefore, topical treatment trials have emphasized exposure to the glans penis as it has direct venous communication to the corpora cavernosa [2,3]. The skin itself is a relatively impermeable tissue due to the stratum corneum. The horny cells of the stratum corneum are bonded with a very tight intercellular lipid matrix bilayer that makes the passage of drugs challenging [4]. To overcome this barrier, investigators have used penetration enhancers which permeate this layer and reach the subdermis. Fortunately, the penis and scrotum are unique in that their stratum corneum is the most permeable of all anatomic locations tested. Depending on the molecular structure of the agent tested there can be nearly 100% absorption of topical agents applied to these areas. Again, exposure to the glans affords a more easily "breached" layer. Other skin regions (e.g. back and palms) are particularly impermeable [5]. An additional factor confounding efficient drug delivery is

Topical therapy for ED has been proposed as one means to circumvent some of the negative factors associated with ICI and IUS thereby presenting an intrinsic appeal to many patients. Topical therapies for the treatment of erectile dysfunction remain and are currently confined to clinical trials and have yet to be released for widespread use. They have the potential to avoid the systemic effects noted with oral therapies while being perceived as minimally invasive inasmuch as they do not require needles or intraurethral instrumentation. Topical therapy may also provide benefit to patients unresponsive to systemic therapy or who use medications which cannot be taken along with such oral treatments (nitrates). Questions regarding less invasive therapies for the treatment of ED using oral, topical or intraurethral methods are often rai341

the rich vasculature of the deep dermis which may "steal" the drugs to the systemic circulation.

process is not effective as an erection initiator as drug absorption is likely to be low. Investigators are currently trying permeation enhancers to increase the drug absorption rate. In order to achieve rapid and effective penetration, the formulation needs to have sufficient penetration enhancer to help transfer (flux) the active agent with good tolerance (no significant irritation), and release the drug at the site of action (right bondage). Several transdermal enhancers incorporated as one of the excipients in topical formulations have been reported [2,3,11,12]. The role of these enhancers is to: 1) Disrupt the stratum corneum lipid bilayer, 2) Interact with membrane keratin, 3) Produce a weak interaction with the drug molecule, and

With the above assortment of confounding factors one wonders exactly how gel applied to the penis could ever induce an erection. One attractive possibility is gel applied to the glans that is rapidly absorbed through the porous skin of the glans into the venous vasculature of the corpora spongiosum. From that location it could travel into the corpora cavernosa akin to intraurethral drug delivery [6,7]. The known absorptive nature of the penile skin and glans makes this a real possibility [5]. If this is the case, then drug delivery to the shaft of the penis would seem superfluous and possibly only contribute to penile skin discomfort. Alternatively, the drug applied to the skin of the penis could theoretically be absorbed through the skin, the tunica of the corpora cavernosa and thus into the cavernous tissues. The large distance, multiple tissue layers and unknown permeability of the tunica make this a formidable drug delivery challenge. A third more remote possibility involves the systemic absorption, recirculation and delivery of drug to the penile tissues. Systemic levels have been measured following penile skin application of papaverine and minoxidil proving that absorption does occur. However, its presence in the systemic circulation does not prove is role in the erectile response [8,9]. All of the above mentioned possibilities are expected to be inefficient to transfer active agents, thus requiring a large amount of drug to compensate for losses in the pathway.

4) Rapidly reverse all actions. The effectiveness of one of these agents (SEPA®) to enhance the transport of a variety of agents through human or porcine skin in vitro has been well established [12, 13]. The available evidence indicates that this agent enhances skin penetration by altering the fluidity of lipids in the stratum corneum, without any interaction with the chemical whose skin permeability is enhanced. A study by Morganti et al [14] examined the effect of SEPA on stratum corneum by performing FT-IR spectroscopy, differential scanning calorimetry and scanning electron microscopy on samples of isolated human stratum corneum. Changes seen suggested reversible conformational modification in stratum corneum lipids by SEPA, consistent with general lipid fluidization. When SEPA is removed in vacuo, the effect is reversed, suggesting that SEPA's effects are temporary, with lipid organization and barrier function being readily and spontaneously restored. During the phase of lipid fluidization, drugs can diffuse through the stratum corneum at a much higher rate than normal.

Anticipating that topical agents could be transferred through the skin and tunica to the cavernous tissues, Borges [10] tried to overcome the presumed permeation problem by performing a surgical procedure consisting of excision of a small area of tunica and covering the defect with a patch of deep dorsal vein, in order to apply a local medication onto the skin immediately above the defect. This concept did not progress perhaps related to failure of the patch, problem of absorption inherent to the skin or failure in the formulation of the topical agent.

2. TOPICAL THERAPY FOR ERECTILE DYSFUNCTION - B ACKGROUND

Most of the delivery systems currently in use for topical therapy are intended for slow and steady release of medications such as those used in hormonal, analgesic or narcotic patches. This slower

Organic nitrate donors were the first topical agents to be used in the treatment of erectile dysfunction [15]. Case reports have demonstrated that blood flow to the penis and tumescence are increased

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after application of a nitro-based paste [16, 17]. The local effects on penile blood flow appear to be crucial since application of such gels elsewhere on the body does not induce erections. Topical minoxidil has also been reported in placebo- controlled double-masked trials [9, 18]. In one study, Cavallini reported 2% minoxidil to be superior to 10% nitroglycerin cream in inducing improved penile hemodynamics with fewer side effects.

c) Pharmacokinetics Alprostadil has been administered by intravenous infusion, intracavernous injection, urethral suppository and topical administration. Intravenous administration of alprostadil requires a continuous infusion of the drug because approximately 80% of the dose is metabolized in the first pass through the lungs mostly by beta and omega-oxidation. Minimal systemic absorption occurs after cavernosal or intraurethral administration. Any alprostadil absorbed by these routes is rapidly metabolized. Tolerance to the beneficial vascular effects does not appear to occur when using alprostadil in either injection or intraurethral forms. Whether this is true of topical preparations has not been reported. Once in the systemic circulation, alprostadil is primarily bound to albumin (81%). No significant binding to erythrocytes or white blood cells occurs. Alprostadil is completely metabolized to several metabolites which are primarily excreted in the urine. There is no evidence of tissue retention of alprostadil or its metabolites following administration.

3. TOPICAL PGE-1 a) Introduction Alprostadil is a naturally occurring prostaglandin E1. Alprostadil and other prostaglandins in the E series are naturally present in the seminal vesicles, the cavernous tissues of males and in the placenta and ductus arteriosus of the fetus. Various formulations and techniques (injections, urethral suppositories and gels) using PGE-1 have been used in the treatment of erectile dysfunction over the past 15 years. b) Mechanism of action For the treatment of impotence, alprostadil relaxes smooth muscle of the corpus cavernosa. However, the exact mechanism of action is unknown. Its effects are due to increased intracellular concentrations of cAMP. Alprostadil interacts with specific membrane bound receptors that stimulate adenylate cyclase and elevate intracellular cAMP leading to activation of protein kinase and resultant smooth muscle relaxation. Alprostadil may also antagonize the vasoconstrictive actions of norepinephrine by preventing the neuronal release of norepinephrine and may enhance the actions of non-adrenergic, non-cholinergic vasodilatory transmitters. In treating impotence alprostadil induces erection by relaxing trabecular smooth muscle and dilating cavernosal arteries and their branches. Dilation of the cavernosal arteries is accompanied by increased arterial inflow velocity and increased venous flow resistance. As a result, the lacunar spaces expand and blood becomes entrapped secondary to compression of venules against the tunica albuginea. To achieve adequate tumescence and rigidity the tunica albuginea must be sufficiently stiff to compress the penetrating venules and thus block venous outflow. This process is also referred to as the corporal veno-occlusive mechanism. Alprostadil does not directly effect ejaculation or orgasm.

d) Response rates Kim and McVary in a placebo-controlled phase I/II trial of a topical PGE1 gel reported significant increases in systolic blood flow velocity as measured by color Doppler ultrasonography [11, 19]. In this largely neurogenic impotent population only 2 of 10 patients responded with a clinical erection (no response in the placebo group). Becher reported a double masked placebo study investigating the effect of 0.2% and 0.4% alprostadil combined with a skin penetration enhancing gel in 52 impotent men [20]. There was no statistically significant difference between active drug and placebo (66% vs. 39%, respectively) in this patient population. In a noncontrolled study using a formulation of 0.4% alprostadil and an enhancer, 0.5 g of the gel produced comparable cavernosal arterial changes to intracavernosal injection when measured with color Doppler. This suggested that the drug penetrates the skin and reaches the corpus cavernosum in a concentration sufficient to cause smooth muscle relaxation [2]. McVary reported a phase I/II single-blind study with a formulation of alprostadil (0.5 mg, 1 mg and 2.5 mg) using 5% SEPA as skin penetration enhancer [3]. Application of the PGE1 gel correla-

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ted positively with erectile response in a majority of patients on active drug. A significant response (clinical erection) to the 0.5 mg, 1.0 mg and 2.5 mg PGE1 doses was found in 67%, 75% and 67%, respectively (placebo 17%, p<0.001). This represented an advance over previous topical administration studies as significant erectile responses could be obtained with gel applications. Interestingly, the majority of patients had modest or absent responses to gel application in the initial 25 minutes after application. With the addition of visual or tactile stimulation this response was greatly augmented suggesting the role of topical gels in facilitation rather than initiation of erection. Facilitation was not seen in the placebo group. The augmentation of response with tactile stimulation has been found with several oral, intraurethral and intracorporal injection treatments [7, 22, 23].

neonates with restricted pulmonary or systemic blood flow which includes antibiotics (penicillin and gentamicin) vasopressors (i.e. dopamine, isoproterenol) cardiac glycosides and diuretics. Systemic drug interactions with IUA(alprostadil) urethral suppository are unlikely because low or undetectable amounts of the drug are found in the peripheral venous circulation following IUA administration. One would expect topical alprostadil to behave similarly. The potential for pharmacokinetic drug interactions between alprostadil administered via injection, topically or urethral suppositories and other agents has not been formally studied.

6. ADVERSE REACTIONS Adverse reactions of alprostadil are reported more frequently following intravenous administration, and may therefore not be relevant to a discussion of topical agents. Apnea has been reported in about 12% of neonates with congenital heart defects treated with alprostadil and was mostly seen in neonates weighing less than 2 kilograms at birth. Other respiratory adverse reactions occurring in less than 1% of patients include bradypnea, bronchial wheezing, hypercapnia, respiratory depression, respiratory distress, and tachypnea. Other common adverse reactions include fever (14%) and seizures (4%).

4. CONTRAINDICATIONS Anticoagulant therapy, bleeding disorders, polycythemia, sickle cell disease, thrombocytosis, and multiple myeloma are conditions in which the treatment of impotence with alprostadil is contraindicated. Alprostadil is also contraindicated in patients who are prone to venous thrombosis or who have hyperviscosity syndrome and are therefore at increased risk of priapism. This includes patients with sickle cell disease, thrombocytosis, polycythemia or multiple myeloma. In clinical trials of alprostadil urethral suppository, priapism (defined by rigid erection lasting greater than 6 hours) and prolonged erection (rigid erection lasting 4 but less than 6 hours) were reported in 0.1% and 0.3% of patients, respectively. Patients receiving intracavernosal alprostadil also reported prolonged erections (4%) and priapism (0.4%). Whether topical alprostadil induces a similar rate of priapism has not been reported. Alprostadil in any form should be used cautiously in patients with cardiovascular disease. Symptomatic hypotension and syncope occurred in 3 and 0.4% respectively of patients during in clinic dosing of alprostadil urethral suppository. Topical alprostadil has not been shown to have a similar risk [3,11].

Local adverse reactions associated with alprostadil used to treat impotence are usually mild and transient. However, as many as 7% of patients withdraw from therapy during trials because of adverse reactions. With alprostadil given intraurethrally, vaginal irritation (vaginal burning/itching) was reported by 5.8% of female partners of patients on active treatment vs 0.8% of patients on placebo. It is unknown whether these adverse reactions in female partners were the result of medication or sexual intercourse. Importantly, Becher performed a female safety study in 18 healthy volunteers using 1g of a gel consisting of 0.4% alprostadil (4,000 mcg) and applied on the vaginal wall and introitus. Ten postmenopausal and 8 premenopausal women showed good tolerance to this formulation despite one patient who experienced minor bleeding at the cervix. All patients showed labial and clitoral engorgement that was not described as uncomfortable [20].

5. DRUG INTERACTIONS No drug interactions have been reported for any of the formulations of alprostadil. Prostin VR pediatric has been used with the standard therapy for

Discomfort at the application site was reported in

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85% of participants after topical application of an alprostadil/SEPA® gel [3]. Most patients (85%) who received the SEPA® formulation, whether or not it contained PGE1, experienced a sensation of warmth that abated within 5-20 minutes after application. This time frame suggests that the SEPA formulation was the mediating substance. About 20% of patients classified this warmth as severe burning. As this severe discomfort was not noted in the placebo group, it appears that the active drug was the responsible agent. This discomfort was primarily localized to the shaft of the penis rather than the glans penis. One wonders whether application of the gel to the glans but not to the penile shaft could avoid this discomfort. It was probably related to both the carrier formulation and the active drug as it was noticed in the placebo group and increased in intensity with the addition of PGE 1.

use in the former rather than latter circumstance. Minoxidil is an antihypertensive agent while topical minoxidil is used for alopecia. Due to its potency and adverse reactions, oral minoxidil is used mainly for patients with severe drug-resistant forms of hypertension. Tolerance to prolonged therapy with oral minoxidil does not appear to be a problem. Subsequent to the oral dosage (approved by the FDA in 1979 for use in hypertension) topical formulations were approved for the treatment of alopecia in 1988. Investigation of topical formulations in the treatment of erectile dysfunction are limited and follow on the heels of its approval for alopecia. b) Mechanism of action Minoxidil does not have a direct vasodilatory minoxidil-O-sulfate effect on arterial smooth muscle. Instead it is converted to minoxidil-O-sulfate by the hepatic enzyme sulfotransferase [26]. This metabolite does have a direct vasodilatory effect on arterial smooth muscle causing a reduction in peripheral resistance in blood pressure. It does not inhibit CNS or adrenergic neuronal blocking effects. Minoxidil retains its activity despite adrenergic denervation. Minoxidil-induced delay in the hydrolysis of cAMP via inhibition of phosphodiesterase may also contribute to the drug’s vasodilatory action. All direct vasodilators produce a sympathetic response including an increase in heart rate, stroke volume, cardiac output, and a marked increase plasma renin activity. The latter effect leads to increased sodium and water retention. The mechanism responsible for minoxidil induced hair growth is not known. Although systemic therapy will stimulate hair growth, topical therapy does not cause hypotension. Minoxidil may either activate the hair follicle directly or stimulate the microcirculation around the follicle increasing cutaneous blood flow. Minoxidil may also alter the metabolism of androgens in the scalp.

Considering the ubiquitous anatomic distribution of the large family of eicosanoids to which PGE1 belongs, it is no surprise that an alprostadil gel would influence other processes besides erection when applied to the penis. Eicosanoids exist in nearly all somatic tissues and are known mediators of a large number of physiologic processes. Pain is one known side effect of this class of compounds. Receptors for PGE1 have been isolated in a diverse array of tissues including the nervous system [24]. The role of prostaglandins in the sensory afferents of pain perception is well documented although intermediates such as CGRP may be involved [25]. Interestingly, in the study by McVary et al. [3] there was no correlation between skin reaction, discomfort, side effects nor erythema with erectile response. This is important as the dissociation of the side effects from the positive attributes of erectile response allows the application site or drug to be modified to reduce adverse events without compriomsing erection.

7. TOPICAL MINOXIDIL

With regard to the treatment of erectile dysfunction, it is assumed that the active metabolite acts via a direct vasodilatory effect on arterial smooth muscle causing a reduction in peripheral resistance and cavernosal muscle relaxation. Presumably this promotes the veno-occlusive mechanism and results in erection. Such an effect from topical minoxidil is interesting when one considers that it is a prodrug that requires hepatic metabolism to

a) Introduction Topical minoxidil has been used in the recent past as an investigational drug in the treatment of erectile dysfunction. Although little can be said about its role in that regard, there is an extensive literature on its use as an antihypertensive and alopecia medication. Much of the information regarding this drug is drawn from the literature detailing its

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become active [26]. For this to be effective the topically absorbed minoxidil would have to be metabolized through the liver then recirculated to the penis to be active. This appears to be a substantial task. Issues regarding the site and efficacy of absorption have been addressed above.

used safely in patients with renal impairment. Minoxidil should not be used in patients with pheochromocytoma because the hypotensive effects of the drug can stimulate catecholamine secretion. d) Response rates

c) Pharmacokinetics

There are a limited number of reports of response rates for the treatment of erectile dysfunction. Using Rigi-scans to measure penile circumference changes induced by a topical 2% minoxidil solution, Cavellini reported a significant increase when compared to topical 10% nitroglycerin or placebo ointment [18]. Similarly, he reported a significant increase in penile rigidity with topical minoxidil when compared to the nitroglycerin or placebo controls. Doppler ultrasonography of cavernosal arterial flow was reported greater with minoxidil than to be with control, but no quantitative information was supplied. No mention of sexual intercourse was reported. In a slightly different study design, Clark reported on the treatment of erectile dysfunction in diabetic males using a 2% minoxidil solution combined with a penetration enhancer (SEPA®) [9]. Response was recorded by spring tonometer (rigidity), strain gauge (circumference change) and patient diary (vaginal penetration). He reported moderate, but no significant changes in erectile response to visual stimulation, penile tumescence or penetration.

Minoxidil can be administered topically or orally. Approximately 90% of an oral dose is absorbed from the GI tract, while topical minoxidil is poorly absorbed through the skin. The systemic absorption of topical minoxidil averages 2% (range 0.3-4.5%). The drug distributes widely throughout the body tissues and is extensively metabolized by the liver. Both the unchanged drug and its metabolites (primarily the glucuronide conjugate of minoxidil) are excreted in the urine. Antihypertensive effects are achieved within 30 minutes and although the plasma halflife of the drug is 4 hours, antihypertensive effects can last 2-5 days. Despite the prolonged duration of action, no drug can be detected in the plasma after 24 hours. This prolonged effect may be explained by retention of the drug in vascular smooth muscle tissues. Minoxidil is not significantly bound to plasma proteins. It is freely filtered, has no tubular secretion, thus renal clearance depends on glomerular filtration. This filtration accounts for approximately 10% of total clearance. Approximately 95% of a topical dose is eliminated after 4 days.

e) Drug interactions

In topical administration of minoxidil, solutions should only be applied to the skin of interest. Absorption is best when the hair and the skin are dry. If applied with finger tips the hands should be thoroughly washed after applying. Systemic effects resulting from topically administered Minoxidil are unlikely, but theoretically could occur if the drug is overused. Skin abrasion or irritation such as excoriations, psoriasis, or sun burn can increase the systemic absorption of topical minoxidil.

Reported drug interactions almost exclusively concern minoxidil used in its oral form. Little is known about its topical use for the treatment of erectile dysfunction. Regardless, drug interactions of minoxidil include antihypertensive agents, nitrates, diazoxide, diuretics, estrogen, nitroprusside, non-steroidal anti-inflammatories and sympathomimetics. Estrogens can cause fluid retention increasing blood pressure and thereby antagonizing the antihypertensive effects of minoxidil. Non-steroidal anti-inflammatories can reduce the antihypertensive effects of minoxidil by inhibiting prostaglandin synthase and/or increasing sodium and fluid retention. Sympathomimetics such as cocaine, dolbutamide, dopamine, ephedrine, epinephrine, norepinephrine, phenylephrine or phenylpropanolamine can antagonize the antihyper-

Minoxidil is relatively contraindicated in patients with cardiac disease, recent myocardial infarction or cerebrovascular disease because reflex increases in heart rate and decreases in blood pressure can exacerbate these conditions. Since approximately 10% of the active drug is eliminated unchanged via the kidney, minoxidil can be

346

tensive effects of minoxidil when administered concomitantly.

c) Pharmacokinetics Serum papaverine levels after topical administration have been measured in a single study [8] with a high performance liquid chromatography assay. At 60 minutes mean serum levels increased 50% suggesting that absorption did occur, but not significantly over baseline values. The papaverine levels in this study indicated that topical absorption is less than 1% of a comparable intravenous dose indicating minimal systemic uptake after topical administration to the genitalia. In contrast, papaverine is present in the blood at levels of 335 to 761 ng/ml within 3 minutes of IC injection of 40 mg as measured by similar techniques [28]. The pharmacokinetics and bioavailability of topical papaverine have been studied in animal models. 912.4% of papaverine is detected in the serum. The marked differences between animal models and clinical trials have been attributed to the gel formulation [29].

f) Adverse reactions The adverse reaction profile of minoxidil depends on its use. Systemic adverse reactions are unlikely from topical administration. Placebo controlled trials with topical minoxidil only showed an increase in dermatologic effects from the active drug. Oral minoxidil has occasionally been associated with the appearance of a bullous rash and Stevens-Johnson syndrome. Topical minoxidil therapy produces local dermatologic reactions including contact dermatitis, local burning pruritus, erythema, and xerosis. Many adverse effects have been reported during the administration of topical minoxidil preparations but none has been directly attributed to the drug.

8. TOPICAL PAPAVERINE a) Introduction Since the introduction by Virag in the early 1980s of injection of papaverine into the corpora cavernosa for the treatment of sexual dysfunction has become a widespread and well accepted method [27]. Its use as a topical therapy has a much shorter experience which has not progressed beyond preliminary clinical trials.

d) Response rates The use of topical papaverine was reported by Kim et al [8] in a phase I/II single-blind placebocontrolled trial on 20 patients with organic impotence. The formulation included 5.5% papaverine HCl gel, and 7%, 15% and 20% papaverine base gel along with a proprietary skin permeation enhancer. After application of the gel onto the penis, scrotum and perineum, a dose-dependent hemodynamic effect was found during duplex ultrasonography. Only 3 patients achieved full erections (also when exposed to placebo). The tolerability was good both locally and systemically. Similar findings were reported using up to 20% papaverine base gel [30].

b) Mechanism of action The most characteristic effect of papaverine is relaxation of smooth muscle, especially when it has been spasmodically contracted. Papaverine acts directly on the muscle itself by inhibition of the oxidative phosphorylation mediated inactivation of cAMP (via phosphodiesterase-PDE) and interferes with calcium mobilization during muscle contraction. This results in an increased half-life of the secondary messengers cGMP and cAMP. This relaxation is noted in the vascular system, bronchial musculature, gastrointestinal/biliary tracts and urinary tract (including the corpora cavernosa). This relaxation may be prominent in the presence of spasm. The relaxation is direct and unrelated to muscle innervation, as the muscle still responds to drugs and other stimuli causing contraction. Papaverine has a minimal action on the central nervous system, although very large doses tend to produce some sedation and sleepiness in selected patients. In certain circumstances, mild respiratory stimulation can be observed, but this is clinically inconsequential.

e) Contraindications Intravenous injection of papaverine is contraindicated in the presence of complete atrio ventricular heart block. When contraction is depressed, the drug may induce transient ectopic rhythms of ventricular origin either premature beats or paroxysmal tachycardia. Papaverine does not have FDA approval for the treatment of impotence by intracorporal injection or topical application. Intracorporal injection of papaverine is known to result in persistent priapism requiring either surgical or medical intervention. Whether or not topically applied drugs would have any impact on these types of complications is a mat347

ter of conjecture at this point. Based on the bioavailability studies mentioned above it is unlikely that a sufficient amount of topical drugs would be absorbed.

c) Pharmacokinetics Nitroglycerin transdermal delivery systems are designed to provide continuous controlled release of nitroglycerin through intact skin. The rate of release is linearly dependent upon the area of the system applied. In FDA-approved patch systems, each square centimeter of applied system delivers approximately 0.02 milligrams of nitroglycerin per hour. In general, after approximately 12 hours, each system has delivered about six percent of its original nitroglycerin content. Nitroglycerin is cleared from the body at extremely rapid rates with the resulting serum half-life of approximately three minutes. The observed clearance rate greatly exceeds hepatic blood flow suggesting extensive peripheral metabolism. Known sites of extrahepatic metabolism include red blood cells and vascular walls. The first products in the metabolism of nitroglycerin are inorganic nitrate and dinitroglycerols. Dinitrates are less effective vasodilators than nitroglycerin, but they are longer lived in the serum. Dinitrates are further metabolized to nonvasoactive mononitrates and ultimately to glycerol and carbon dioxide. In healthy volunteers, steady-state plasma concentrations of nitroglycerin are reached by about two hours after application of a patch and are maintained for the duration of wearing of the system. Whether any of these pharmacokinetic issues are relevant to topical nitroglycerin applied to the penis is not known.

f) Adverse reactions Opiate derived compounds such as papaverine may cause cholestatic hepatic dysfunction. This finding has been observed in geriatric patients taking papaverine for vascular insufficiency as well as with intracavernous injection [31, 32, 33]. Topical therapy has not been shown to have a similar risk in one study [8]. The following side effects have been reported for papaverine when given by injection: general discomfort, nausea, abdominal discomfort, anorexia, skin rash, malaise, vertigo, headache, intensive flushing of the face, perspiration, increased depth of respiration, increased heart rate, slight increase in blood pressure, and excessive sedation. Few of these effects have been reported when papaverine was administered topically.

9. TOPICAL NITROGLYCERIN a) Introduction The use of topical nitroglycerin is a standard treatment for unstable angina pectoris because predictable blood levels can be achieved. The use of nitroglycerin ointments, pastes, plasters or patches for the treatment of erectile dysfunction has been tried in several studies. b) Mechanism of action Relaxation of vascular smooth muscle is the principle pharmacologic action of nitroglycerin. Nitroglycerin produces, in a dose-dependent manner, dilatation of both arterial and venous beds, dilatation of the post-capillary vessels including large veins and decreases in venous return. This results in a reduction of left ventricular diastolic pressure. Arteriolar relaxation reduces systemic vascular resistance and blood pressure. Myocardial oxygen consumption and demand is decreased by both the arterial and venous effects of nitroglycerin resulting in a more favorable supply-demand ratio. Whether topical nitroglycerin for the treatment of erectile function can have similar effects on cardiac status is not known. Contraindications to the use of topical nitroglycerin include a history of allergic reactions to organic nitrates. These are extremely rare, but they do occur. Allergies to the adhesives used within the nitroglycerin patches have also been reported.

d) Response rates Owen et al. [16] reported a double-blind placebocontrolled study using a 2% nitroglycerin paste applied to the penile shaft in 30 impotent patients. The evaluation included penile tumescence measurement and duplex ultrasonography. Although the patients who received nitroglycerin achieved a better response, it was not significantly different from placebo. Headache was a common side effect that developed tolerance over the applications. Heaton et al. [34] reported a study in 174 patients who underwent duplex ultrasonography for an erectile dysfunction workup and received a topical application of nitroglycerin paste at the penile shaft. There was a significant difference in the four vessels diameter before and after drug application. Clinical evaluations in a home use environment are limited. Nunez et al. [17] reported 3 successful cases using 2% nitroglycerin paste. Sonksen [35] 348

reported "clinical response" in 12 of 17 spinal cord injured patients. However, only 5 achieved a "usable response" at home. Meyhoff studied 10 patients with nitroglycerin patches, 4 patients achieved a "usable" response and 3 preferred the patches over their usual I.C. papaverine treatment [36].

4.

GURNY R, TEUBNER A: Dermal and transdermal drug delivery: new insights and perspectives. Stuttgart: Wiss. Verl.-Ges., 1993.

5.

MAIBACH, H.I., FELDMAN, R.J., MILBY, T.H. AND SERAT,W.F.: Regional variation in percutaneous penetration in man. Arch. Environ. Health, 23: 208, 1971.

6.

WOLFSON, B., PICKETT, S., SCOTT, N.E., DEKERNION, J.B. AND RAJFER, J.: Intraurethral prostaglandin E-2 cream: a possible alternative treatment for erectile dysfunction. Urology, 42: 73, 1993

7.

PADMA-NATHAN, H., HELLSTROM, W., KAISER F., LABASKY, R., LUE, T., NOLTEN, W., NORWOOD, P., PETERSON, C., SHABSIGH, R., TAM, P., PLACE, V., GESUNDHEIT, N.. Treatment of Men with Erectile Dysfunction with Transurethral Alprostadil. N Eng J Med 1997;336-1-7.

8.

KIM ED, EL-RASHIDYR, MC VARY KT: Papaverine topical gel for treatment of erectile dysfunction. J Urol, 153:361-365; 1995.

9.

CLARK, R.V., MURRAY, F.T., HIRSHKOWITZ, M., FERRY, J., LIN, T., MURPHY, T.C. AND FRANCOM, S.F.: Treatment of erectile dysfunction in men with diabetes mellitus using a penetration-enhanced topical minoxidil solution. J. Androl, January/February supplement: abstract 140, p. 55, 1994

e) Adverse reactions The most frequent adverse reaction in patients who are administered nitroglycerin is headache, which occurs in approximately two percent of patients. Other reactions occurring in less than one percent of patients are tachycardia, nausea, vomiting, apprehension, restlessness, muscle twitching, retrosternal discomfort, palpitations, dizziness and abdominal pain. In a smaller number of patients, additional adverse reactions such as cutaneous flushing, weakness, drug rash or exfoliative dermatitis have been reported. f) Conclusion Advances in the understanding of penile physiology, basic erectile pharmacology and alternate drug delivery systems constitute an evolving technology that is potentially useful for the treatment of erectile dysfunction. With the association of modern skin penetration enhancers it is now possible to achieve acute transfer of drugs to the corpus spongiosum in order to take advantage of its vascular communications with the corpus cavernosum. The main advantages of topical therapy for erectile dysfunction are its safety and good tolerability in terms of local and systemic effects. Even in the era of oral treatments, an effective, safe and easy to apply topical agent will have its place in the physician's armamentarium to treat patients with erectile dysfunction in the near future.

10. BORGES, FD: A new approach to the pharmacologic treatment of impotence. Int J Impot Res, Vol.6 (3):137143; 1994. 11. KIM ED, MCVARY KT: Topical Prostaglandin-E1 for the Treatment of Erectile Dysfunction, J Urol 153(6):1828-1830, June 1995. 12. SAMOUR, C.M., DONARUMA, L.G., DASKALAKIS, S., FULTON, B.S., MARTY, J.P., DERVAULT, A.M., CHANEZ, J.F. AND DOUCET, O. SEPAS, A New Class of Percutaneous Absorption Enhancers. Proc. Intern. Symp. Control. Rel. Bioact Mater 16: 183184, 1989. 13. PELHAM, R. AND SAMOUR, C. SEPA-009-Safety and Efficacy Studies of a Broad Spectrum Transdermal Enhancer. Proceed. Intern. Symp. Control. Rel. Bioact Mater., 22:694-695, 1995

1.

LAKIN, M.M., MONTAGUE, D.K. MEDENDORP, S.V., TESAR, L. AND SCHOVER, L. R.: Intracavernous injection therapy: analysis of results and complications. J. Urol., 143: 1138, 1980

14. MORGANTI, F., BRAMANTI, E., SOLARO, R., NANNIPIENI, E., NARDUCCI, P., KRAUSER, S. F., SAMOUR, C. M., BENEDETTI, E. AND CHIELLINI, E. Thermal and Spectroscopic Characterization of Interactions Between 2-Nonyl-1,3-dioxolane and Stratum Corneum Components. J. Control Rel., (in press). 15. MUDD. J.W.: Impotence responsive to glyceryl trinitrate. Amer. J. Psych., 134: 922, 1977.

2.

BECHER E, BORGHI M, MOMESSO A, et al: Penile hemodynamic findings with a new topical formulation of alprostadil. J Urol, 159 No5 Suppl: 239; 1998.

16. OWEN, J.A., SAUNDERS, F., HARRIS, C., FENEMORE, J., REID, K., SURRIDGE, D., CONDRA, M. AND MORALES, A.: Topical nitroglycerin: a potential treatment for impotence. J. Urol., 141: 546, 1989.

3.

MCVARY KT, POLEPALLE S, RIGGI S, PELHAM RW: Topical PGE-1/SEPA Gel for the Treatment of Erectile Dysfunction, In press J Urol

17. NUNEZ BD, ANDERSON DC Jr: Nitroglycerin ointment in the treatment of impotence. J Urol, 150:12411243; 1993.

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18. CAVALLINI, G.: Minoxidil versus nitroglycerin: a prospective double-blind controlled trial in transcutaneous erection facilitation for organic impotence. J. Urol., 146: 50, 1991.

29. SHAAYA, A.N., KRAUS, C., BAUMAN, D.H. AND RITSCHEL, W.A. Pharmacokinetics and bioavailability of papavervine HCl after intravenous, intracorporeal and penis topical application in beagle dogs. Methods Find Exp. Clin. Pharmacol., 14: 373, 1992

19. MCVARY KT, KIM ED:Topical PGE1 Gel as treatment for Erectile Dysfunction. J Urol 153 Suppl: 982A; 1995.

30. CHIANG HS, KAO, YH, SHEU MT: Papaverine and prostaglandin E1 gel applications for impotence. Ann Acad Med Singapore, 24:767-769; 1995.

20. BECHER E, MOMESSO A, BORGHI M, et al: Topical prostaglandin E1 (PGE1) for erectile dysfunction. (abstract) J Urol 155 Suppl: 296A; 1996.

31. LEVINE, S.B., ALTHOF, S.E., TURNER, L.A., RISEN, C.B., BODNER, D.R., KURSH, E.D. AND RESNICK, M.I.: Side effects of self administration of intracavernous papaverine and phentolamine for the treatment of impotence. J. Urol., 141: 54, 1989

21. BECHER E, COHEN-SABBAN H, MOMESSO A, et al: Estudio de seguridad en mujeres con un gel de prostaglandina E1 para la disfuncion erectil. Proceedings of the IV Latin American Congress for Impotence Research. Linares, Chile. Abstract L25, p.41; 1997.

32. VIRAG, R. SHOUKRY, K., FLORESCO, J., NOLLET, F.,AND GRECO, E.: Intracavernous self-injection of vasoactive drugs in the treatment of impotence: 8 year experience with 615 cases. J. Urol., 145: 287, 1991

22. DONATUCCI CF, LUE TF. The combined intracavernous injection and stimulation test: diagnostic accuracy. J Urol 148(1):61-2, 1992 Jul. 23. GOLDSTEIN I, LUETF, PADMA-NATHAN, H, ROSEN RC, STEERS WD, WICKER PA. Oral Sildenafil in the treatment of Erectile Dysfunction. N Eng J Med 1998: 338: 1397-1404.

33. GOVIER, F.E., MCCLURE, R.D.,WEISSMAN, R.M., GIBBONS, R.P., PRITCHETT, T.R., AND KRAMERLEVIEN, D.: Experience with triple drug therapy in a pharmacological erection program. J. Urol., 150 1822, 1993

24. MOLTZ, H.: E-series prostaglandins and arginine vasopressin in the modulation of male sexual behavior. Neurosci. Biobehav Rev., 14:109, 1990.

34. HEATON JP, MORALES A, OWEN J, SAUNDERS FW, FENEMORE J: Topical glycerylnitrate causes measurable penile arterial dilation in impotent men. J Urol, 143:729-731; 1990.

25. VASKO MR., Prostaglandin-induced neuropeptide release from spinal cord. Prog Brain Res 104: 367-80, 1995).)

35. SONKSEN J, BIERING-SORENSEN F: Transcutaneous nitroglycerin in the treatment of erectile dysfunction in spinal cord injured. Paraplegia, 30:554-557; 1992.

26. MCCALL, J. M., AIKEN, J. W., CHIDESTER, C. G., DU CHARME, D. W., AND WENDLING, M. G. Pyrimidine and triazine 3-oxide sulfates: a new family of vasodilators. J. Med. Chem, 1983, 26: 1791-1793).

36. MEYHOFF HH, ROSENKILDE P, BODKER A: Noninvasive management of impotence with transcutaneous nitroglycerin. Br J Urol, 69:88-90; 1992.

27. VIRAG, R.: Intracavernous injection of papaverine for erectile failure. Letter to the Editor, Lancet, 2: 938, 1982 28. TANAKA, T.: Papaverine hydrochoride in peripheral blood and the degree of penile erection. J. Urol., 143: 1135, 1990

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Shabsig et al have studied the efficacy of PGE1 in 145 patients who did not respond to 4 weeks of sildenafil treatment with dose adjustment: 88% reported erection sufficient for intercourse. Mc Mahon studied the response of 93 patients with different etiologies, not reponding to intracavernous therapy: 34% responded to sildenafil.

D. CLINICAL STUDIES Since the beginnings of the clinical use of topical therapy, studies have been published to compare the effects of different compounds and medications. They are more and more controversial with the launching of marketed products and new routes of administration. Controversies rise from two concomitant factors, the lack of "in depth" evaluation of the etiology of ED and the weight of marketing. This culminated after 1997 with the launching of sildenafil.

Virag [2] (independent study) studied the feasibility and effects of sildenafil in 317 consecutive non selected patients who sought treatment during a 10 week period at the same istitution. This group consited of 38% naive patients and 54% of patients already on self intracavernous injections. The acceptability rate for oral was 82%, feasability 74.3%; global results were good for 32%, fair for 29 and ineffective for 39%. 32% of the patients after completing the trial were using sildenafil as their sole treatment, 34% chose self-intracavernous injections, and 25% decided to alternate between oral and local therapy (Fig. 2). Presence of non-sexually stimulated erection and absence of caverno-venous leak are the prominent factors predicting a good response to oral therapy.

I. COMPARATIVE EFFICACY OF INTRACAVERNOUS MEDICATIONS (FIG. 1) Vickers [1], using the Medline, has studied 20 years of publications dealing with intracavernous monotherapy and combination therapy, reaching the following conclusions: 1) In monotherapy papaverine and PGE1 are statistically equivalent in efficacy and side effects; 2) Drug combinations acting by different pharmacological pathways are able to induce functional rigidity when single-agent testing and/or therapy has failed. 3) By adding other agents, the pain induced by PGE1 is significantly decreased 4) The ideal order for combination therapy is not clearly defined varying with personal habits and availability of the medications.

In an open study conducted at 18 centers in France and Italy Montorsi et al [4] evaluated the success of switching patients with erectile dysfunction treated and stable with ICPGE1 to oral therapy with Sildenafil. 124 men receiving ICPGE1 for a mean of 21 months were switched to Sildenafil for 12 weeks. 75% of the patients choose to continue onto long-term Sildenafil therapy.

IV. LONG-TERM FOLLOW-UP

II. COMPARATIVE EFFICACY OF INTRACAVERNOUS AND INTRAURETHRAL THERAPY

Virag (see aboves p.302) studied the very long term effects of injection therapy in 2348 patients followed for between 5 and 14 years, not only in terms of efficacy but also quality of life.

A great deal of controversy concerns this issue. Generally, independent studies show a marked advantage in efficacy for intracavernous vs intraurethral. Percentages vary from 25 vs 80, to 40 vs 60 depending on etiology, age and selection criteria.

1. CHANGE OF MEDICATIONS: Only 17% of patients did not change their treatment, 20% diminished their dosage, 19% had to increase the dosage and 43% had to change it, mainly for more potent medications.

III. COMPARATIVE EFFICACY OF ORALAND INTRACAVERNOUS THERAPY

2. EFFICACY AND EJACULATION CONTROL: The average duration of erection was 75 minutes. The percentage of premature ejaculation decreased from 25 to 4%; 70% had a controlled unique ejaculation, 12% were able to repeat ejaculation and orgasm twice in the same session.

For methodological reasons there is no randomised, controlled studies comparing the oral versus intracavernous treatments. 351

Figure 1: Local pharmacological treatment modilities, pharmacological agents: efficacy

Figure 2: Local treatment vs. Oral therapy, final therapeutic choice in 157 patients (54% of whom were already on self injection) having tested sildenafil [2].

352

native and has some indications in patients fearing the injection or in circumstances such as insufficient rigidity after surgery of the penis.

3. SEXUAL LIFE AND QUALITY OF LIFE: 75% of the treated patients have one partner, 17% have two or more, and 8 none. 65% of the patients have kept the same partner and improved their relationships; for 25% the treatment helped in constructing a sexual and family life; in 6% the treatment, apart from its local efficacy, was unable to produce a satisfactory sexual and personal life.

5. HOME ATTEMPTS Titration and choice of medication should always be performed with sexual stimulation, ideally testing with the usual partner. A set of three to four tests of increasing doses is usually necessary to define treatment. This installation period is the one at major risk of priapism. Virag has proposed (see below) to provide the patients with antidotes (self injection of etilefrine or phenylephrine) to easily overcome priapism. Patients should always be able to contact the prescribing doctor day or night.

4. INTERCURRENT DISEASES: 25% are hypertensive and well controlled, 20% have a high blood cholesterol and 10% are diabetic. 15% have coronary heart disease with appearance of a clinical event during the evaluation period in 5% of the treated population; none during intercourse and no death related to the injection therapy. Depression, present in 25% of the patients at the begining of the treatment, was significantly decreased at the endpoint of the study.

II. INJECTION TOOLS AND TECHNIQUES Injectors or applicators essentially minimize the fear of injection. They therefore increase the acceptability rate of injection therapy. Every effort should be made to simplify the technique: low dose and volume to inject, no pain, simplicity and intimacy. The use of any technique to enhance erections frequently has to be integrated into a global approach to sexuality including psychosexual therapy

E. GUIDELINES FOR LPT I. GENERAL OVERVIEW OF PRACTICE Today, the only universally available local treatment is injection therapy. Intraurethral alprostadil is not available in all parts of the world. Topical alprostadil is still experimental.

1. DIAGNOSIS: THE NEED GICAL TESTING:

FOR

III. BEHAVIOR TOWARDS THE PARTNER

PHARMACOLO-

25 to 50% of local treatment users do not disclose to their partner that they are using a treatment to enhance their sexual performance (Virag, ISIR meeting Amsterdam 1998). Prescribers should be aware of the couple’s "real" situation when counselling their patients in aspects of the therapy. The partner’s attitude might be negative and ruin the issue. When possible, counselling should be proposed to the couple and specially the partners after having convinced them of the advantages of participating in therapy. In any case, therapy should be minimized and fully integrated in the intimacy of sexual activities without being prominent. Very few couples are able to integrate it as part of the "love games". It is usually better to perform injection and immediately forget about it.

There are three steps: 1) taking a medical and personal history, 2) evaluating spontaneous erectile activity 3) intracavernous testing (with dopler ultrasound when available, to test efficacy and show safety of the injection

2. WHICH MEDICATION TION ?

FOR

WHICH INDICA-

One should consider cost, and use of the smallest volume and possibly use an automatic injector when the fear of injection is high. PGE1 monotherapy is the safest medication, dual therapy (papaverine and alpha blocker or VIP phentolamine) is more or less equivalent to isolated PGE1 therapy; its use is related to economic necessity (cheaper for papaverine) or comfort (integrated injector for VIP phentolamine). Multilevel acting drugs have the advantage of tailoring the IC therapy to almost all etiologies at a relatively low cost. Association with oral therapy is still under clinical investigation. Intraurethral therapy at 500 or 1000 µg is an alter-

IV. FOLLOW-UP Follow-up should be performed on a twice a year basis. During the first two years after initiating treatment, physical examination must evaluate any 353

complications such as nodules or fibrotic areas. Dynamic ultrasound may be useful in such cases. Long-term evaluation requires telephone or written interviews and a yearly visit. Modifications of local or general conditions have to be adressed. Prostate cancer early diagnosis, decrease in testosterone, evaluation of current associated diseases or risk factors are part of follow-up as well as the individual’s and couple’s psychosexual environment.

papaverine containing mixtures they can also occur with any medication. • development and/or increase of Peyronie's like albugineal plaques. There are a lot of unresolved controversies concerning the interaction of intracavernous injections with Peyronie’s disease. Long-term surveys show that there is no statistical link between these two factors. Nevertheless, repeated injections in a Peyronie's plaque may trigger an increase of the plaque and the appearence of curvature. On the other hand, repeated reoxygenation induced by the local treatment might stabilize or even reduce Peyronie's disease. Relevant data with prospective studies are needed to conclude. The advice is to manage, this issue case by case, according to individual clinical status.

V. PREVENTION AND TREATMENT OF COMPLICATIONS 1. PRIAPISM Priapism is prevented by careful teaching of titration and dosage in the initial steps of therapy. Still, like any self-administered therapy, priapism may occur due to overdosing. Although some authors fixed the delay before medical intervention to six hours, the recommendations are to restrict the time of total pharmacologically induced erection to a maximum of three hours: corresponding to the time to inversion of the oxygen balance towards anoxia. In addition, physical and/or pharmacological treatment of priapism is much easier to achieve within the first 3 hours. Muscular exercise, cold local bathing might be sufficient to restore flaccidity. Otherwise, an intracavernous injection of an alpha adrenergic agent (etilefrine or phenylephrine) is able to relieve priapism in almost all cases seen early (within three hours). Using self injection with etilefrine, prevention of return to the clinic, has been achieved in a series of 172 cases Virag [3] without any complications.

F. THE FUTURE OF TOPICAL THERAPY The better knowledge of the mechanisms of erection will encourage the development of more powerful medications in the future. Manipulations should enhance and/or delay the release of drugs to ensure fewer injections and/or a longer duration of action. Gene therapy may appear soon. Automatisation and miniaturisation of the injection technique is one goal of local therapy as well as the development of molecules that are truly effective by transalbugineal percutaneous administration.

G. CONCLUSIONS

2. NODULES AND FIBROSIS The penis is an easy target for local treatments. At the present time, injection therapy gives the impotent patient a combination of high efficacy with a very low complication rate.

Clinical examination with ultrasonography will differentiate: • isolated nodules generally related to small local hemorrhages induced by injections. Benign and reversible after few weeks, they should be avoided by a careful technique and the use of thinner needles (30 gauge). • larger area of intracavernosal fibrosis occuring early in the first months of treatment, requiring immediate stopping of treatment. They are rare (less than 1%) and probably due to special susceptibility of the cavernous tissue and/or possibly larger hemorrhage secondary to the puncture of a large branch of deep arteries (?). More frequent with the use of

REFERENCES 1. 2. 3.

4.

354

VICKERS M. Personal communication VIRAG R.Indication and early results of sildenafil in erectile dysfunction. Urol. 54: 1073-1077, 1999. VIRAG R. Traitement ambulatoire et prévention du priapisme par medication α agonistes, à propos de 172 cas. Chirurgie, dec, 1996. MONTORSI F., GIULIANO F., SWEENEYM. Patients receiving intracavernosal (IC) PGE1 do well when switched to viagra (sildenafil citrate): results of a multinational european study. ESIR - Barcelona, Junuary 2000.

Committee 10

Surgical Treatment and Mechanical Devices

Chairman U. JONAS

Members C. EVANS, S. KRISHNAMURTI, D. MONTAGUE, J. P. SARRAMON, M. SOHN, E. WESPES, H. WESSELLS

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CONTENTS D. PENILE INJURIES: THE ROLE OF EARLY SURGICAL INTERVENTION IN PREVENTING ERECTILE DYSFUNCTION

A. EXTERNAL DEVICES, DRUG AND DELIVERY IMPLANTS I. VACUUM DEVICES IN THE TREATMENT OF ERECTILE DYSFUNCTION

I. INTRODUCTION

II. PENILE DRUG DELIVERY IMPLANTS [22]

II. PENILE FRACTURE

CONCLUSIONS

III. PENETRATING INJURIES OF THE PENIS

B. VASCULAR SURGERY IV. PENILE AMPUTATION I. SURGERY FOR ARTERIAL PATHOLOGY V. BLUNT TRAUMAAND ERECTILE DYSFUNCTION

II. SURGERY FOR CORPOROVENO-OCCLUSIVE DYSFUNCTION

VI. CONCLUSION ( TABLE 4) III. DISCUSSION E. PENILE RECONSTRUCTION

C. PENILE IMPLANTS I. INTRODUCTION / HISTORY

I. INTRODUCTION

II. MALLEABLE DEVICES III. INFLATABLE DEVICES

II. REVIEW OF THE LITERATURE ON TECHNIQUES FOR PHALLOPLASTY

IV. SURGICAL TECHNIQUES

III. CONCLUSIONS

V. COMPLICATIONS FOLLOWING PENILE IMPLANTATION

F. PENILE ENLARGEMENT SURGERY

VI. POSTOPERATIVE MANAGEMENT

I. CONCLUSION

CONCLUSIONS

RECOMMENDATIONS

356

Surgical Treatment and Mechanical Devices U. JONAS C. EVANS, S. K RISHNAMURTI, D. M ONTAGUE, J. P. SARRAMON, M. S OHN, E. W ESPES, H. WESSELLS

Gedding Osbon in 1960, in trying to improve his own sexual performance developed a device which became commercially available in 1975 but took till 1982 to be granted permission to market the device because of concerns with both safety and efficacy. His device was called the youth equivalent device and is now called ErecAid [3].

A. EXTERNAL DEVICES AND DRUG DELIVERY IMPLANTS

I. VACUUM DEVICES IN THE TREATMENT OF ERECTILE DYSFUNCTION

In 1986 Nadig reviewed the use of the device in 35 men [4] and in 1989 reviewed a total of 340 patients over 6 years, 83% of whom used the device [5]. Witherington also described the ErecAid system and reviewed 1517 users favourably [6, 7]. Turner found that sexual satisfaction and selfesteem improved whilst psychological symptoms decreased [8].

1. OVERVIEW The use of vacuum devices as part of the conservative management of erectile dysfunction is quite varied and relates to the judgement of the clinician and patient’s preferences. Their overall use is not common-place however.

In his early studies in 1986, Nadig [4] found the device to be safe, provided the negative pressure did not exceed 200 mm Hg and the constricting bands were not on longer than 30 minutes.

2. VACUUM DEVICES : DEFINITION Vacuum devices work by creating a vacuum negative pressure which increases the blood flow into the corpora cavernosa. The erection is maintained by trapping the blood in the penis by use of a constriction ring at the base, cutting off the venous outflow.

Negative comments at this time were however voiced: Benson stated “It is difficult to accept that a non-physiological erection, predicated upon trapping blood in the penis, with proximal crural flaccidity, urethral compression hindering ejaculation and general cooling of the phallus should elicit such a high favourable response rate” [9].

3. DEVELOPMENT Experiments with vacuum air pumps were described by J. van Musschenbrack in Leiden in 1694. Illustrations of this are available at the Library of the State University in Leiden. An American, John King, is credited with the first clinical use in 1874 of a vacuum device [1] but compression was added in 1917 by Dr. Otto Lederer who requested a patent for his surgical device to produce erections with vacuum [2].

4. TYPES OF EQUIPMENT The initial devices used mouth suction and elastic rings but are now much more sophisticated and easy to use. The vacuum devices are made of a clear plastic cylinder with either a battery or hand pump attachable and a collection of sizes of rings. The rings and applicator are also available separately, without the cylinder (table 1).

357

ding device; choosing the size of the ring is done by guesswork but most men start at the middle size. The inside of the plastic tube is liberally covered with lubricating jelly, to get a seal, and the flaccid penis is then inserted and the tube pushed against the pubic bone. The vacuum is then applied, by hand or by battery pump, and tumescence occurs.

Table 1: Type of equipment MAKER

NAME

COST US $

OSBON - ERECAID

Classic Standard Esteem Manual Esteem Battery

361.33 227.80 432.03 502.72

EUROSURGICAL

Post-T-vac

GENESIS

*Active II Impulse

OWEN MUMFORD

*Rapport

VET CO. UK

Vet Co

Battery: 389.61 Manual: 188.52- 351.90 Battery:

This initial tumescence may make it easier to put the penis in the cylinder before proceeding to continue pumping, usually for up to 3 minutes, till a satisfactory erection is achieved. Then the ring at the base of the tube is slipped onto the penis to maintain the erection. The rings should only stay on for 30 minutes maximum.

234.08 186.95 186.95 141.39

(not inc. VAT) MEDWATCH

Erectease

204.23

MENTOR

Response VES II VCS II

306.35 392.75

FARNHURST

Elite

212.09

This will finally give an erection which is colder, slightly bluish and hinged at the base where the ring is but many patients find it adequate for vaginal penetration.

* Lifetime guarantee

Most patients are instructed on the use of the device by verbal explanation, demonstration of the device, and watching a video. Additional technical advice is usually available from the manufacturer by a freephone number. If patients have problems with the device they can, in many instances, meet with the company representative to review the technique.

Correctaid, a reinforced semi-rigid condom with a mouth tubing to apply suction was available in the 1980s but fell out of favour. It was not effective and the silicon too thick to allow much feeling. The rings are now made of soft latex and have side handles for ease of removal. Some manufacturers make a notch in the ring the place over the urethral bulb to prevent trapping of the ejaculate (Fig. 1).

It is also possible to combine the use of intracorporal pharmacotherapy + oral treatment with both rings alone and the vacuum device [12].

5. REQUIREMENTS AND TECHNIQUE

• Contraindications

Vacuum devices require enthusiasm on the part of the patient and a sympathetic partner. It is therefore less likely that single younger men are going to use them but the middle and old age groups tend to choose this treatment modality. [10] The patient requires manual dexterity and a penis which is large enough to fit into the plastic tubing.

Contraindications to use are almost none. Nadig stated that patients with scarring and deformity of the penis due to Peyronie’s or post penile implant removal for infection are not likely to attain rigidity [13] but it is worth trying as others have had good results in this group [14] especially in keeping penile length after explanted penile implant.

The patient requires practice and this technique is not necessarily successful in the first few attempts. [7, 11] It is advisable to loan this device for one month or more so that the patient can practice peacefully in the leisure of his home at least daily.

Features which are against the successful use of vacuum devices are it is fiddly, noisy, the ring present makes the patient continually aware that he has a problem. The device may be expensive for the patient to buy and the partner may just dislike the look of the end result of a coldish, bluish erection.

In order to use the device, the constriction rings are placed over the clear plastic tube with a loa-

358

B A

Figure 1: New generation of vacuum devices (A), pump and rings (B) handling (C)

C

Pain occurs at the site of the ring. This lessens with use and also when an appropriate size ring is selected and in less than 3% of the patients did they stop using the device.

6. RESULTS Patient satisfaction varies enormously and is related to effectiveness. Ease of use : In one study [11] 94 out of 127 patients (74%) found the device straightforward, 12 needed to contact the manufacturer and 14 patients not achieving good results or experiencing pain had an instructional session with the manufacturer. Five out of these 14 then achieved a satisfactory result.

Ejaculatory changes, including pain on ejaculation up to 16% (15) and blocked ejaculation occurs in 25% [11]. Numbness during erection was a problem in 5% of patients [15]. Pivoting at the base occurred in a 6% [15].

7. COMPLICATIONS

Satisfaction rate

Petechiae skin bruising, especially at the site of the ring, occurs in 16 to 39% of patients. [11, 15, 16] Patients on anti-placelet therapy or warfarin do not appear to have any increase in bruising or ecchymosis.

Satisfaction rate, both short and long term, varies considerably from as low as 27% to 68% shortterm, to as high as 69% with 2 year follow-up. [15] The reasons for dissatisfaction [11, 15] are as follows:

359

• Inability to maintain full erection

12%

• pain

4%

• inconvenience/awkwardness

4%

• marital problems

5%

mean increase in length was 3.7cm +/- 0.7 and the increase in circumference 3.5cm +/- 0.9. This compared favourably with the increase in length and width for normal erections. The vacuum devices which are on prescription are well tried and tested, these devices are approved by the Food & Drug Administration for sale as over-the-counter medical devices in USA.

partner dissatisfaction with: • performance

11%

• penile temperature

7%

• appearance

13%

9. S PONTANEOUS IMPROVEMENT As with all other conservative forms of treatment for erectile dysfunction, patients will report the return of spontaneous erections in up to 25% of cases and many other patients will get improved erections. Daily use of a vacuum device for 30 minutes each day not only maintain dexterity but make use of the device part of a routine even if intercourse is not attempted as advocated in Sheffield, UK. [21]. The use of vacuum devices in Western Europe is summarised in table 2.

In one study [17], only 20 out of 74 patients were satisfied with the erections they achieved. These however, were patients who had all failed counselling and self-injection. All patients with psychological impotence failed. The authors did suggest that patient selection and lack of good initial instruction and freephone help may have contributed. However, many patients with erectile dysfunction are reluctant to even try vacuum devices . Of 1,236 patients who had the option to use vacuum device, only 6% tried the device and continued to use it. [18]

Table 2: Use of Vacuum Devices in Europe and America 1996

8. SAFETY

1998

USE OF VACUUM DEVICES

Initially part of the hesitancy to prescribe these devices was related to the effect of constriction of the penile blood flow. In order to have vaginal penetration, buckling pressures of between 60 and 100 mm Hg are needed, although usually in excess of 100mm Hg, this is certainly sufficient. In 1998, using penile plethymography, the penile blood flow was measured before, during and after the use of the ring. [19]. There was a 70-75% decline in the amplitude of the pulse volume curve but continuous blood flow was maintained in each case. In 33 patients, after removal of the ring there was transient increased amplitude consistent with post-ischaemic hyperaemia. These findings suggested an adequate penile blood flow and that the devices were safe. However, the thirty minute rule should be strictly adhered to, as the ring causes significant reduction in blood flow and in one report complete cessation. [20]

1996 l998 % UROLOGISTS OFFERING DEVICES

Western Europe

3%

6%

44%

49%

U.K.

7%

13%

80%

88%

France

1%

1%

36%

22%

Germany

4%

8%

76%

80%

Italy

0.1%

3%

6%

10%

Spain

1%

-

22%

At the request of American Medical Systems (AMS), N.O.P. Healthcare conducted quantitative research amongst urologists in the U.K, France, Germany, Italy and Spain. The purpose of the study was to assess the share of various impotence treatments performed by urologists in these countries. 50 urologists, randomly selected in each country, were interviewed by telephone, a total sample of 250 respondents.

In 72% of patients [19] with penile plethysmography, the pressure achieved was greater than 100mm Hg buckling pressure. In addition, the

360

The table shows that most urologists, excluding those in Italy and Spain, offer vacuum devices but the take-up rate by the patient is low. This will vary according to the enthusiasm of the urologists for this form of treatment.

B. VASCULAR SURGERY Several tests are available for evaluating the penile vascular inflow and outflow tract, ranging from simple pharmacotesting to enhanced pharmacotesting such as in pharmacopenile duplex ultrasonography (PPDDU), cavernosometry, selective penile angiography (Fig. 2 A, B, Fig.3).

II. PENILE DRUG DELIVERY IMPLANTS [22] These implants consist of a cannula which is inserted into the Corpus cavernosum and a combined scrotal reservoir and pump, containing a vaso-active drug. Compression of the reservoir pump gives a bolus of the vaso-active drug into the penile tissue to stimulate an erection.

I. SURGERY FOR ARTERIAL PATHOLOGY Cavernous body revascularisation procedures have been proposed to correct penile arterial insufficiency. [1-5] Direct anastomosis of the inferior epigastric artery to the corpus cavernosus has been abandoned because of a high rate of priapism and the short duration of success due to thrombosis. Using an end-to-side anastomosis of the inferior epigastric artery to the dorsal penile artery (Michal II procedure). Michal et al. obtained a 60% success rate. Other techniques for penile revascularisation have been described using the inferior epigastric artery anastomosed to the cavernous artery or to an arterio-venous fistula created by anastomosis of the dorsal penile artery and the dorsal penile vein; or using a vein segment interposed between the femoral artery and one or both of the dorsal penile arteries or cavernous arteries.

The first implant was inserted in 1986 and 36 have been implanted in 21 patients with varying causes of erectile dysfunction. Initially, papaverine and phentolamine was used but crystal formation caused tubal blockage so this has been replaced by sodium nitroprusside. These implants remain active for a mean of 14 months. 8 of the devices are still working with a follow-up of 4 years. There are a considerable number of failures; 7 leaking reservoirs, 6 blocked tubes, 9 mechanical failures, 3 infection. Two patients developed priapism. One patient with recurrent priapism has been managed with alpha sympathetico mimetic drugs. This implant has undergone many modifications but should continue to be considered investigational as an alternative to self-injection.

Penile deep dorsal vein arterialisation (DDVA) has been applied to patients with arterial, venous and mixed impotence [6]. This technique is though to produce a retrograde arterial flow into the cavernous bodies through the collateral deep dorsal venous network or through a surgical fistula between the arterialised vein and the corpus cavernosum. Several arterialisation procedures have been developed by Virag. The most widely applied operation is the Virag-5 (inferior epigastric artery anastomosed to deep dorsal vein, end-to-side, proximal and distal vein tied, circumflex and emissary collaterals tied, fistula between the dorsal vein and the corpus cavernosum). [6-7] This procedure was modified by Furlow and Fisher [8] (no creation of a veno-corporeal fistula but preservation of emissary veins to carry the arterial flow into the caver-

CONCLUSIONS Vacuum devices, although not in widespread use, have advantages in that they are re-usable (and therefore in the long-term less expensive), satisfactory for many patients who are offered them and safe. They should be kept available for use, improving design will make them more user-friendly.

361

A

B

Figure 2: Bilateral pudendal angiography reveals a total occlusion of penile arteries : a) Left side b) Right side

Figure 3: Left pudendal angiography shows multiples strictures (°) with respect to the common penile artery.

362

Figure 4 : a) Michal II procedure : arterioarterial revascularization. Epigastric artery (EA) is anastomosed end-to-side to the dorsal penile artery (PDA). CA : cavernous artery.

A

b) Epigastric angiography : demonstrates a revascularization of the dorsal artery.

B

Figure 5: Different procedures of the deep dorsal vein arterialization, DDVA Virag procedure and modifications.

363

nous bodies) and appears to enjoy the same success rate as the original Virag-5 procedure [9]. Globally, the success rate of DDVA for arterial, venous or mixed impotence is reported to be 4075%. Hauri proposed anastomosis of the epigastric artery on the deep dorsal vein together with the dorsal artery [10].

licus and transposed ingiunally to the base of the penis. The penis is opened at the dorsal aspect by longitudinal incision and the superficial penile vessels are dissected. One of the dorsal penile arteries and the deep dorsal penile vein are opened by a longitudinal incision of approx. 2 cm, and the median wound margins of both penile vessels are closed by 7-0 non-absorbable continuous sutures. The transposed inferior epigastric artery is then opened by a longitudinal incision of approx. 2 cm and anastomosed to the common arterio-venous lumen by a 70 non-absorbable continuous suture with a funnelshaped opening (Fig. 6).

1. SURGICAL TECHNIQUE DESCRIPTION Both Michal II and DDVA procedures were performed using the inferior epigastric artery. A paramedian incision was made along the external border of the rectus muscle. The inferior epigastric artery and its accompaning veins were isolated and divided at the level of the umbilicus. Papaverine was used to prevent arterial vasospasm. Five minutes before vessels were divided, 5,000 units of heparin were administered intravenously. The artery and veins were brought through a subcutaneous tunnel to the root of the penis.

5. ANTITHROMBOTIC THERAPY The patients received postoperative intravenous heparin for 72h, after which they were placed on subcutaneous calciparin 0.3 cm3 t.i.d. for 2 months and then on dipyridamole 75 mg o.d. and aspirin 500 mg o.d. for 3 months.

2. MICHAL II PROCEDURE

II. SURGERY FOR CORPOROVENO-OCCLUSIVE DYSFUNCTION

A dorsal longitudinal incision was made at the base of the penis. Buck’s fascia was incised and the dorsal penile artery was dissected with the aid of a microscope to prevent nervous system injuries. An end-to-side anastomosis was performed between the epigastric artery and the proximal part of the dorsal penile artery. Interrupted sutures of 90 nylon were employed using standard microsurgical techniques (Fig. 4 A, B).

The treatment of patients with caverno-venous insufficiency is based mainly on the reduction of venous outflow during erection. [11-12] Until now, it has been applied to the penile veins, although the defect of corporeal venous malfunction was within the penis itself. Success is defined as good erection during normal sexual intercourse. Embolisation of the deep venous network with detachable balloons and coils introduced through the deep dorsal vein dilated surgically provides satisfactory clinical results with a minimum follow-up of 1 year. The surgical approach addresses ectopic veins, deep dorsal veins and/or cavernous or crural veins (Fig. 7). Spongiolysis [13] or peri-cavernoplasty [14] with or without insertion of a prosthetic venous tourniquet or simple crural plication [15] has also been proposed. Also combined approaches of the before mentioned procedures have been published [16]. The different surgical procedures described do not invade the corpora cavernosa and are restricted to the veins. For this reason, the immediate results are satisfactory but relapse can be observed a few months later. Peri-operative measurement of the erectile flow rates is mandatory and makes it possible to monitor the operation. If they are not lower after resection of several veins then leakage is still occurring through other veins, which also must be ligated.

3. DDVA PROCEDURE After incision of the skin and Buck’s fascia at the penile root, the deep dorsal vein was dissected from the suspensory ligament to the distal retrocoronal plexus. A modified Furlow-Fisher procedure was performed (preservation of circumflex and emissary collaterals and no destruction of deep dorsal venous valves by a stripper). The dissection was performed with the aid of a microscope to prevent arterial or nervous system injuries. The epigastric artery was anastomosed end-to-side to the proximal part of the deep dorsal vein using interrupted sutures of 9-0 nylon. When the anastomosis was completed the dorsal vein was ligated proximal to the arterio-venous anastomosis and proximal to the distal retrocoronal plexus (Fig. 5).

4. HAURI’S PROCEDURE The inferior epigastric artery is isolated by means of pararectal incision, severed at the level of the umbi364

ced erections possible even when they were not present before correction of the caverno-venous leak. Reduction of the venous outflow decreases the amount of drug to be injected and avoids secondary effects attributable to immediate release of the drug into the systemic circulation [19]. It appears that potency remains stable if the effect of the surgical treatment persists beyond 6 months. Reassessments for secondary leakage reveal abnormal venous return, in most cases into the cavernous vein (when previous surgery has been limited to the deep dorsal vein) or into the Corpora spongiosa, ectopic veins or small veins not ligated during previous surgery. There is no significant difference in age between the patients whose potency improves and those with persisting impotence. [12] The extent of the leakage does not seem to have a role in the degree of success achieved. [12] Major resection of the venous return should provide the best immediate and also long-term results. [12] Embolisation of the venous system deeper under the pubic could provide greater reduction of the venous outflow and, therefore, better results than surgery. [18] However, in a long-term follow-up the success rate is similar. Venous surgery should not be restricted solely to the veins seen to be opacified on cavernosography but it must be extended to the 2 main drainage routes of the corpora: the deep dorsal vein and the cavernous veins.

Figure 6: Hauri’s Procedure.

Figure 7: Resection of the deep venous system.

Patient selection is highly important, and those with arterial disease must be excluded. If the arterial inflow is severely reduced, ligation of the veins does not lead to adequate penile tumescence for an erection [12]. Such patients might benefit from deep dorsal vein arterialisation if they are younger than 55 years but the results are not completely satisfactory. Anastomosis of the epigastric artery on the deep dorsal vein could decrease the venous outflow, and retrograde penile revascularisation through the emissary veins could improve the insufficient arterial inflow. [6-7] However, angiography of the epigastric artery performed after this surgery is unable to demonstrate opacification of the cavernous bodies when a deep dorsal vein-tunica albuginea fistula is not realised [17, 18]. This surgical approach improves intracorporeal pressure during erection but the resting pressure is also elevated. In older patients vaso-active intracavernous injections make pharmacologically indu-

III. DISCUSSION The role of vascular surgery in erectile dysfunction is still not well defined. In 1993 a Consensus Development Conference Statement of the National Institutes of Health on Impotence stated, that the tests for venous disease are incompletely validated [18]. Therefore it will be difficult to select patients with predictably good outcome. The conference concluded, that venous penile surgery should best be done in an investigational setting. Referring to revascularization procedures to the clinical investigational setting in specialized medical centers, due to the incompletely standardized preoperative measurements, interpretations and indications. In 1996 the Clinical Guidelines Panel on Erectile Dysfunction of the AUA searched the MEDLINE data base for all articles from 1979 through 1994 on treatment of organic erectile dysfunction by penile revascularization and venous 365

ligation procedures and concluded that for both types of surgery, chances of success do not appear high enough to justify routine use in urological practice [19]. In 1996 Vickers et al. [20] reevaluated all literature data available on penile revascularization and penile venous surgery and concluded, that the efficacy of these procedures have not been evaluated by studies which have utilized the criteria of any ideal experiment. In 1997 De Palma on the other hand concluded, that randomized clinical trials will not be possible in the field of vascular penile surgery for erectile dysfunction [21]. Only 5 to 7 percent of all patients, non-responsive to medical treatment, would be candidates for such procedures. He advised surgeons on that field to perform well structured case control studies of their patients to fulfill the critera for Evidence-Based-Medicine successevaluation. Anyhow, such studies have not been published up to now. In the following conclusions and contradictions with respect to indications, contraindications and long-term results from the actual literature shall be presented: In 1993 30 studies were available in the literature on short-term-success of venous ligation procedures [18]. The range of success went from 10 to 95 % with an average value of 62,3 %. Only 4 studies used objective methods for success evaluation. 22 studies presented longterm data of more than 12 months follow-up for success ranging from 13 to 74 % with an average value of 41,4 %. 12 studies presented longitudinal follow-up data with a drop of success from 70% to 37% (average values). A recent report on a well selected patient material with long-term follow up confirmed these results with a short term successrate of 45%, which dropped to a long-term suc-

cess-rate of 30,2 % [22]. Positive prognostic factors were preoperative duration of erectile dysfunction less than 7 years, a normal CC-EMG and a maintenance flow of less than 45 ml/min. [23, 24]. The same drop from reasonable good shortterm success to less than satisfying long-term results could be seen after percutaneous vein embolisation [25]. In the field of penile revascularization a compilation of all published data from 1988 to 1993 revealed an overall success-rate of 33 to 100% (average 72 %) [26]. Long-term data are difficult to find, a recent longitudinal followup study of 30 months revealed a drop of subjective success from an initial 85% to 54 %. Nearly half of these patients could only reach sufficient erections with the additional aid of intracavernous injection. Another longitudinal study showed a similar drop from an initial 53% to 40% after five years follow-up [27]. Concerning indications and contraindications for penile revascularization, it must be stated, that no agreement exists in the actual literature [28]. Manning et al. advised to select patients without venous leakage, with reduced erections after intracavernous injection and with an age lower 55 years for surgery [29]. For most authors diabetes mellitus, neurologic disorders and nicotine abuse are contraindications for penile revascularization. The role of venous arterialization (Virag I-V, Furlow-Fisher) remains obscure. A retrograde arterialization of the corpora could not be proven in the literature [15, 30, 31]. The fact that no single surgical technique seems to be superior to the others from the point of success, casts doubt on differential therapeutic algorithms as presented below. An algorithm for vascular surgery is summarised in fig. 8.

ALGORITHM FOR THE CHOICE OFTHE ADAPTED TECHNIQUE IN VASCULAR SURGERY

Figure 8: Algorithm for the choice of the adapted technique in vascular surgery

366

As long as no objective selection criteria exists for penile revascularization, venous arterialization or venous ligation procedures, it may only be concluded, that these operative techniques may have subjective success in less than 50% of patients in long-term follow-up studies. Recently, single potential analysis of cavernous electrical activity, another method for studying smooth muscle competence, has been suggested to be an important prognostic factor for the prognosis after venous surgery [23]. Histological study of the intracavernous structures seems also able to predict venous surgical outcome [24,32]. However, penile biopsies were mostly performed during the operation when the therapeutic decision was already made.

After having finally found the appropriate material (silicone rubber) and the exact implantation site (inside the tunica albuginea), prosthetic surgery for the treatment of erectile failure became more and more popular. In 1973, Scott and co-workers described a completely new concept using inflatable silicone cylinders which could be filled voluntarily via a pump which became implanted in the scrotum, transporting fluid to the cylinders from a reservoir which was positioned behind the rectus muscle. In 1976, Small/Carrion designed a prosthesis which was much easier to implant and had less complications, but which had the disadvantage of a more-or-less permanent erection due to rigid rods which were positioned inside the corpora cavernosa [9-10]. Table 3 summarises the individual features in the malleable and inflatable penile implants.

C. PENILE IMPLANTS

Table 3: Comparison of the individual features in malleable and inflatable penile devices: MALLEABLE IMPLANTS

I. INTRODUCTION / HISTORY In contrast to other mammal species such as the whale, dog, bear, gibbon, or otter, the human male does not have a penile bone inside his penis to enforce erection. Despite earlier surgical efforts to treat erectile impotence by the resection of the dorsal vein of the penis it seemed logical that Bogoras in 1936 used a part of rib cartilage in order to reinforce rigidity in the penis. However, the rib cartilage and bone implants were reabsorbed after several months and therefore the effect abolished [1-3].

INFLATABLE IMPLANTS

ADVANTAGES

DISADVANTAGES ADVANTAGES

DISADVANTAGES

Simple design

permanent «erection»

«physiologic» erection

mechanical failure

volontary control: erect - flaccid

hydraulic problems incidence for reop.

Low costs

impaired micturition ? Simple surgery cosmetic appearance

Need for pumping prior to intercourse

The first alloplastic implants were described in 1952 - according to unpublished data by Scardino - using acrylic prostheses. These devices were originally positioned between the corpora cavernosa; however, they were less successful than polyethylene prostheses which were implanted inside the tunica albuginea. Loeffler et al. stated that «It might seem like meddlesome surgery to insert a foreign body of considerable size into the adult male penis, but to the patient with an organic impotence, otherwise in good health and with normal desires, this is a real problem that is worth trying for correction.» In 1966, Beheri already reported on 700 penile implants. He used two polyethylene rods and placed each one inside the corpora cavernosa [2, 4-8].

However, these two types devices started the development and design of numerous new prostheses throughout the last 25 years such as the penile implants described by Subrini, Finney, Jonas, Mentor, Subrini and Krane [11 - 21].

II. MALLEABLE DEVICES In 1976 Small and Carrion described their device; it consisted of a pair of silicone rod prostheses which were implanted through a midline perineal incision. The prosthesis was available in 16 different lengths and 3 diameters, which already emphasised the inability to make a proper length 367

determination prior to surgery. Therefore, different sized prostheses had to be available in the operating room. In order to decrease hospital inventory, individual device trimming at the tails of all implants was finally introduced [10, 17, 22-23].

5000 double bendings at one specific point on a simulator ), the silver never protruded the silicone rubber nor was the function inhibited by fractures of the silver wires (stability). In order, however, to avoid future discussions of whether or not broken silver strands could lead to negative results, since 1984, the individual silver strands were embedded in thermoplastic Teflon, making further breakages impossible [16 – 19].

By December 1977 already a total of 260 patients had received implants and only 3 of 106 implanted patients had a poor result. However, due to the rigid characteristics of the device a more-or-less permanent erection resulted, and the need for improvements became evident. One solution was found by Subrini as well as by Finney; both authors used softer silicone-preparations positioned in the mid- part of the device in order to avoid permanent erection in the «resting position» [12,21].

The original device (standard version) was manufactured in three different diameters (9.5, 11, and 13 mm) in lengths between 17 and 24 cm. Atotal of 22 different prostheses were available. In order to diminish costs the „trimming-tip version“ was introduced, a device which could be shortened at its proximal end making only two pairs of different lengths necessary in two different diameters. In a multicenter trial performed in the early 1980s based on 1834 patients with implants, an overall success rate of close to 95% was achieved. Early complications were seen in 5. 1 %, later complications in 2.8%; only 19 of the 1834 implants had to be removed (1.04%).

Subrini described his preliminary experience in 1974 [24]. Between 1970 and 1982 he operated on a total of 283 impotent patients with an overall failure rate of only 1.7%. Success ranked as high as 95% after primary surgery and 98.3% if surgery had to be performed a second time [21, 24]. A different way of combining the features of malleability with simple design was done by Jonas when in 1978 he published a report on silicone silver penile prosthesis (fig. 9). This device was characterised by silver wires embedded inside the silicone rubber to stabilise the penis in different positions: downwards or against the body during the resting position or upwards for intercourse. Despite the fact that the silver strands could break after numerous bendings (following approximately

The concept of a metal strand inside the malleable silicone prostheses for reliable and flexible stability was copied later in the AMS Malleable 600 prosthesis in which instead of Teflon-coated silver strands a steel-capped, fabric-wrapped stainless steel core was used. Further features were the removable silicone jacket and the rear-tip extenders. The AMS Malleable 600 prosthesis has been replaced by the AMS Malleable 650 prosthesis (fig. 10).

Figure 9: JONAS (ESKA) silicone-silver penile implant: A total of 22 pairs of different sized devices (in 3 different dia meters) are available for individual fit. For further expla nation – s. text.

Figure 10: AMS 650 malleable device, using a fabric-wrap ped stainless steel core and rear-tip extenders.

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The MENTOR malleable penile prosthesis also contains a silver strand; however, this strand is coiled in a spiral, giving a corkscrew appearance. The silver strand is only positioned in the midportion of the device, therefore the proximal end can be trimmed to the exact length required [25-30].

device. The AMS 700 CX now has a 3-ply cylinder wall minimising the risk of cylinder bulging; the diameter of each cylinder can expand from 12 up to 18 mm, improving prosthetic erection in circumference; and tubing connectors allow easy handling and safe connection of the tubes to and from the cylinder [11, 13-14, 31-32]. The AMS 700 CXM prosthesis has a smaller reservoir, pump, and cylinders which expand from 9.5 to 14.2 mm. This smaller inflatable prosthesis is especially useful in implant recipients who have fibrotic corpora [42] (fig. 11).

The Duraphase penile prosthesis is a device in which rigidity and flaccidity are controlled using articulating segments, a stainless steel cable, and a spring on each end of the central part. It consists of 12 rigid polysulfone articulated disks with a centrally placed stainless steel cable and 2 spring mechanisms. The allowed angle of all 13 disk interspaces is 220°.

The AMS 700 CX was developed from the original inflatable Scott device and consists of three components: the cylinder, the pump and the reservoir . This concept also became adapted in the Mentor inflatable penile prosthesis, described for the first time in 1983 [22] (fig. 12).

According to the results of a multicenter trial consisting of 63 patients published in 1990, mechanical complications included cable breakage in four instances, and 55 out of 57 patients were satisfied with the results. The authors were encouraged by this preliminary experience, which showed fewer complications than the inflatable devices had and especially stressed the features of excellent bendability, superior concealability, and perfect rigidity. Longer follow-up, however, and a larger patient population will be necessary for final judgement of the quality of this specific device [29, 30]. The original Duraphase prosthesis has been replaced by the Duraphase II prosthesis.

III. INFLATABLE DEVICES Figure 11: AMS 700 CX – 3 component inflatable penile implant, consisting of 2 cylinders, a reservoir and a pump to control erection and deflation. Further explanations – s. text.

After the rather unsuccessful attempts before the 1970s (Lash, Loeffler [6-7], the tremendous breakthrough in alloplastic surgery for the impotent men came in February 1973 when the first inflatable penile prosthesis was implanted by Scott and coworkers [9]. Already by 1979, 21 physicians had performed penile implantation in a total of 1243 patients at different centers. The success rate was 91.5%; however, as stated by practically all authors in this period of time, there was a re-operation rate of around 30%.

1. THREE-COMPONENT PROSTHESES From 1973 up to date numerous alterations and improvements were applied. Today’s device, the AMS 700 CX has apparently mastered the majority of problems such as kinking of the tubings, cylinder wall aneurysms, and unequal filling of the

Figure 12: Mentor alpha I 3 component inflantable implant. Its charactristics are comparable to the AMS 700 CX device (Fig. 11). However, Bioflex polyurethane is used instead of silicone rubber. Further explanations – s. text.

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The essential difference between the very similar looking devices, however, is the material: the Mentor device is manufactured from Bioflex polyurethane, which was quoted to be more durable and less elastic than silicone. Such material should last longer and prevent cylinder aneurysms. In 1987 the results on 202 implantations were reported: Re-operation was necessary in 8%, of these approximately 50% were due to technical problems, later, the rate of complications dropped down to 3.5%. Again, using this device good results were obtained in far more than 90% [22]. The latest Mentor development is the Alpha 1 inflatable penile prosthesis, which features cylinders and pump that are firmly connected, leaving only one connector between the pump and reservoir. This diminishes mechanical problems [33-34]. The latest improvement in the three-component inflatable device is the AMS 700 Ultrex penile prosthesis which expands in circumference from 12 to 18 mm and extends in length within the corpora cavernosa depending on tissue elasticity. This should give the patient a more natural prosthetic erection than before. The cylinders consist of an inner and outer silicone layer and a woven Lycra and Dacron middle layer. The two-way stretch of this middle layer permits girth expansion and length extension. Recent experience shows that the AMS 700 CX device has a 5 year mechanical failure rate of 9.1% while the AMS Ultrex device has a 5 year mechanical failure rate of 35%. [35] Decreased cylinder survival is the primary reason for the increased failures seen with the Ultrex prosthesis. In 1993 the Ultrex cylinders were improved; the magnitude of improvement in survival with these modified cylinders remains to be demonstrated.

geon. Due to the connectorless one-piece device, depending on the surgical approach, scrotal and infrapubic types are available. In this two-component device, pump and reservoir are combined as «resipump.» Twelve differently shaped devices are offered for individual length fitting. In a Mayo Clinic study of 84 patients followed up to 13 months, especially the 13-mm prosthesis was seen to be nearly equal to the three-component devices. Surgical implantation time was reduced to on average 30 min; complications were similar to other devices, such as infection (3.6%), removal due to fluid loss (1.2%), and cylinder erosion (1.2%). The overall success rate was 95.2%. The AMS Ambicor prosthesis is a two component prosthesis produced by American Medical Systems (fig. 14). This device comes in 3 diameters (11, 13, and 15mm) and lengths varying from 14 to 22cm. Adjustments between lengths are made with the addition of rear tip extenders. Experience with this new prosthesis is still limited.

3. ONE-COMPONENT PROSTHESES The AMS Hydroflex self-contained penile prosthesis consists of two prefilled cylinders. In each cylinder there is a reservoir at the rear end, an inflation pump and deflation valve, and finally an inflation chamber. Through repeated pumping close to the glans the fluid moves from the rear reservoir into the inflation chamber and the penis becomes erect. When continuous pressure is applied to the deflation valve which is just behind the inflation pump, the fluid returns in the rear reservoir, and the penis becomes flaccid. The device comes in three different cylinder diameters, 11, 13, and 15 mm, and four different lengths, and all typical surgical approaches may be used for implantation. Preliminary clinical implantation results in 140 patients showed uncomplicated surgery with satisfactory results. A penoscrotal approach mainly used, in 64%. The Hydroflex is no longer available; it has been replaced by the AMS Dynaflex (fig 15). Mechanical device failure was seen in 7.5% of 120 recipients of the Dynaflex prosthesis who were followed for a mean of 42 months [36], however, further clinical experience has to provide proof of satisfactory function [37-39]. Today, the principle types of penile implants are the malleable, semi-rigid and (one- to three-component) inflatable devices (fig 16). The still exis-

2. TWO-COMPONENT PROSTHESES In order to reduce the possibility of mechanical failure many attempts have been made to reduce components, connectors, tubes in the concept of inflatable devices. Another consideration was the ease of surgical implantation, to offer a penile implant as «pre-prepared» as possible so as to reduce fitting, trimming, and fillings to an acceptable minimum. The Mentor Mark II prosthesis is an inflatable penile prosthesis which is preassembled and has no connectors, making any trimming and connecting procedures unnecessary (Fig. 13). The device, however, has to be filled interoperatively by the sur370

Figure 14: AMS-AMBICOR 2 COMPONENT INFLA TABLE IMPLANT. The device is Available in 3 diameters, from 14 cm to 22 cm in length.

Figure 13: MENTOR MARK II 2 COMPONENT INFLA TABLE IMPLANT. Pump and reservoir are combined as “Resipump” – Further details – s. text

Figure 15: AMS – DYNAFLEX 1 COMPONENT INFLATABLE IMPLANT. Combining cylinders, pump and reservoir.

Figure 16: Different penile prosthesis alternatives available in 1999. Principally, 2 types are used: the malleable and infla table penile devices.

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ting requests for further improvements are based on the patient’s wish for a more and more normal and «physiological» sex life. However, in the assessment of success, next to the overall rate from well above 90% «excellent results» in all types used, the postoperative complication rates as well as the chance for necessary repeated surgery plays an important role.

PENOSCROTAL

also suitable for the inflatable (3-component) device (choice between infrapubic and penoscrotal approaches depends on the preference of the surgeon)

MIDSHAFT

in corpora fibrose and reoperations

Looking back to the beginning of penile implants in the late 1960s and early 1970s it is evident that an effective treatment choice was already available without knowing too much (or anything at all) about the mechanisms of erections and the underlying pathophysiology. Only in the last 1015 years more and more knowledge has been gathered to diagnose impotence and to distinguish the different causes of erectile failure with the possibility of applying a cause-related therapy such as intracorporal injections, reconstructive surgery or venous ligation, shifting the role of penile implants towards the end of all therapeutic efforts. It is fair to say today that alloplastics should only be discussed after all other therapeutic modalities have failed or if the patient refuses one of the less invasive or reconstructive treatment modalities. The «mechanical success» rate following penile implant at around 95% is excellent, and more and more data are available indicating that patients and partners are handling their sex lives very well, even in impotence following spinal cord injury. Still, more efforts should be devoted to the psychological impact for patient and partner, and sophisticated pre-, peri- and postoperative guidance for both partners is mandatory [40-43].

SUBCORONAL

especially suitable for the malleable device

PERINEAL

only recommended if crural identification is necessary ( reop´s)

Small and Carrion initially suggested the perineal approach. This, however, became more and more abandoned due to the fact that perineally, the aseptic conditions are not the best and postoperative wound care is more difficult.. On the other hand, the most critical area of implantation is the distal end of the corpora cavernosa underneath the glans. Starting perineally, the corporal dilatation has to be carried out a rather long way to the distal end, and control of dilatation and prosthesis insertion may be more difficult. Therefore, this technique should be reserved only to those cases, where crural identification ( following e.g. perforation ) is necessary. If an inflatable device is used, the infrapubic approach seems to be appropriate, since all components may be positioned from one incision. This is also true for the penoscrotal incision; however, only in case of a revision or in difficult situation, a catheter should be placed during surgery to avoid injury to the urethra. Criticism has been made concerning the subcoronal approach, generally a hemicircular incision in the sulcus coronarius. It has been suggested that this approach may lead to injury of nerve supply with subsequent loss of sensitivity. This does not hold since all interventions along the corporus cavernosum are carried out in a longitudinal fashion, thus avoiding trauma to the nerves and vessels by pushing them away. The approach used by the one of the authors (U.J.) is the subcoronal approach, which has been applied in more than 300 cases. It is seen as the method of first choice since no catheter is necessary during implantation, and there is practically no visible scar left behind after surgery. The

IV. SURGICAL TECHNIQUES Different «classical» surgical approaches are known which are more-or-less compatible and may be used for the majority of the devices. The choice of approach is finally based on the surgeon’s own experience; no general rule can be established advocating one or the other specific access. The surgical approaches are: INFRAPUBICAL

especially suitable for the inflatable ( 3-component) device

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implantation of a penile implant (first surgery) in a non-fibrotic corpora does normally not cause any problems and may even be performed under local anaesthesia. However, it may be difficult following previous surgery, after priapism or in trauma patients when the corpora are fully or partially no longer existing. In these patients the fibrotic corpora may need to be cored or lyodura or vascular prostheses used to cover the penile implant and prevent proximal and distal migration. It also may be difficult to dilate the corpora, or it may even be almost impossible after repeated surgery and/or infection or after priapism. In these cases a small blade knife or the Otis urethrotom may be used to core the corpus prior to dilatation.

experience has shown that local or systemic antibiotic treatment is completely unsuccessful if the device is infected. Therefore, especially when the device communicates through the open wound, removal is the only possible treatment in order to avoid septic exacerbation. In these cases placement of suction drains may be useful. If, especially in case of the diabetic patient, the infection is not controlled efficiently after removal of the device, necrosis of the corpora may develop. This fact further backs the absolute need for removal of an infected device as soon as possible. The postoperative complication rates due to infection described in the literature are seen to be as high as 8.3%. Therefore specific attention has to be given to preoperative preparation, intra-operative handling and postoperative care [54-59].

For these manoeuvres it is wise to scalp the whole penis down to the base, or if necessary through a second infrapubic incision, in order to have good control during corporal dilatation. In case of the «Concorde» deformity surgical reposition of the glans may be necessary. In patients with Peyronie’s disease the malleable devices seem to be superior to the inflatable ones in straightening the deformity. Excising the plaques is generally not necessary, still incising the plaques and inserting a reinforced device, is a good alternative, even a Gore-Tec patch might be unnecessary. However, if one wishes to implant an inflatable prosthesis in a man with Peyronie’s disease, the AMS 700 CX prosthesis should be used rather than the AMS Ultrex as CX cylinders will usually straighten the penis without incision or excision of the plaque. [44] Another very specific indication may be the paraplegic patient who may need a malleable device in order to give a better support for the condom urinal [10, 16, 45-53].

Because penile prosthesis re-implantation after removal of an infected prosthesis is often associated with significant difficulties due to fibrotic corpora, there has been recent attention given to salvage procedures. In these procedures the entire infected device is removed and then the operative area is copiously irrigated with antibiotic solution, half strength hydrogen peroxide, and then half strength Betadine solution. The patient is then reprepped and re-draped, the surgical team scrubs and re-gowns and re-gloves, and then a new prosthesis is implanted using fresh instruments. Using this protocol, Brant and Mulcahy were able to achieve success in 10 of 11 patients (91%) with mean follow-up of 21 months. [60]

VI. POSTOPERATIVE MANAGEMENT Once the devices have healed nicely, there are no further problems to be expected besides infection (see above) and erosion. An infection certainly will provoke an erosion. The most crucial point for an implant perforation is the distal end of the device. The patient has to be informed to use the device in a «physiological» manner, he has to be aware that the friction during intercourse is an important factor to provoke perforation of the prosthesis. If the partner has no vaginal secretion during sexual stimulation, a lubricant may be advisable.

V. COMPLICATIONS FOLLOWING PENILE IMPLANTATION Prosthetic infection is the most problematic complication following surgery since the combination of infection and foreign body requires removal of the prosthesis; after 3 months of good healing, however, a re-implantation may be done. The patients most affected with infection problems are the diabetics where special care must be taken to avoid wound healing problems. The author’s own

Exact intra-operative length measurement is man-

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datory: if the device is too long, post-operative pain and finally prosthesis erosion may result. However in too short a device, the «Concorde» deformity with kinking of the glans during intercourse may occur and perforation laterally through the corpus cavernosum may be possible . Endoscopy is possible after implantation, especially if an inflatable device has been implanted. With a malleable prosthesis, the length of the penis may be the limiting factor of endoscopy. Special long instruments are commercially available (Storz); however, the penis may also be twisted around up to 270° for endoscopic work-up. Finally, a perineal urethrotomy might be needed eg. to perform a TUR B/P. This shortens the penis and enables the examination, still it may become problematic if, for example, a tumour at the bladderdome has to be resected. Prosthesis re-implantation may be necessary for different problems. The data from the literature show that re-implantation may also lead to satisfying results. However, due to scarring and fibrosis, the penis can shorten, therefore the first surgical attempt still offers the most promising results [61-64].

used. The inflatable devices are the most elegant and the ones which best imitate physiological behaviour; however, they are still biased by the possibility of mechanical failure. Therefore the different types of devices must be presented to the patient prior to surgery, and he should decide what type of prosthesis he would like to have implanted, after being fully informed of the advantages and disadvantages of the individual types. In case of complications or after removal of the device, reimplantation is possible. This, however, requires a more difficult surgical procedure with a decreased chance of success. Proper indication, careful patient selection, and sophisticated postoperative control not only of the mechanical aspects but also of the psychogenic impact is mandatory to fulfil the patient’s and his partner’s need of sexual satisfaction. However, the expectations of both the patient and his partner are often too high and both must learn to cope with the new situation. In the judgement of postop. success it is important to give the patients a realistic scenario of outcome in order to bring his expectations in realistic range,

Due to more and more sophisticated diagnostic techniques, the specific causes of impotence can be identified and a cause-related therapy will follow. Due to the fact that treatment modalities which are not or minimally invasive or surgically reconstructive procedures are available, these modalities should be used before considering the implantation of a penile prosthesis. Nevertheless penile implants still offer the best rate of success, over 95% - inclusively partner’s satisfaction-, independent of etiology or the type of prosthesis

CONCLUSIONS Penile implants are the last resort of treatment despite the fact that with this type of surgery, still the best outcome might be expected, However, only +/- 10% of all patients with erectile dysfunction finally will receive an alloplastic implant.

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of penile replantation successfully restore penile erection. Unfortunately blunt injuries may be a major cause of ED in young men but are usually not amenable to early surgical correction.

D. PENILE INJURIES: THE ROLE OF EARLY SURGICAL INTERVENTION IN PREVENTING ERECTILE DYSFUNCTION

II. PENILE FRACTURE

I. INTRODUCTION The mammalian penis is remarkably resistant to injury; by allowing alternation between flaccidity and rigidity, vascular erection provides protection from serious injury to a structure vital to reproduction. The NIH Consensus Conference on Impotence recognised that penile or pelvic trauma can be an important cause of erectile dysfunc tion. [1] Penile amputation represents the most severe injury requiring surgical intervention to preserve function, but numerous penile injuries may lead to erectile dysfunction. Whereas injuries to the erect penis occur during intercourse, injury to the flaccid penis is rare, mainly occurring as a result of penetrating trauma and machinery accidents. The rise in violent crimes has been paralleled by an increase in genital injury, which have the potential to damage normal erectile mechanisms. Still more epidemiological research is essential to further understand the distribution as well as the prevalence of ED as a result of surgery and trauma. [2] Mechanism of injury allows a general classifica tion of urogenital trauma causing erectile dys function. 1. Penile fracture, a unique injury of the tunica albuginea which occurs only with full penile rigidity 2. Penetrating trauma to the corpora cavernosa, commonly associated with urethral and other genital injuries. 3. Penile Amputation 4. Blunt penile, perineal, or pelvic trauma, which may lead to arterial injury, neuropathic dysfunction, and high flow priapism. Of these four injuries, penile fracture is the most studied. Recovery of erectile function can be expected after such injuries, and by extrapolation after penetrating injury. Remarkably, many cases 375

Penile fracture is a traumatic injury which, when untreated, can lead to erectile dysfunction and penile deformity. First reported approximately 1000 years ago by Abul Kasem, an Arab physician in Cordoba Spain [3], this injury remains perplexing to the lay public and many physicians. The injury is perceived to be uncommon, but many cases are probably not reported in the literature. [4] No prospective trials exist determining the most appropriate management of this entity: case reports and case series, subject to significant bias, represent the evidence on which the present analysis is based. [5]

1. MECHANISM OF INJURY Rupture of the tunica albuginea results from excessive buckling forces on the erect penis. Full penile rigidity is necessary for this injury to occur; one case has been reported after intracavernous injection therapy. [6] The vast majority of cases occur as a result of abnormal bending of the penis during intromission into the vagina , although sexual manipulation, masturbation, rolling over during sleep and other explanations have been reported [7-8]. Increases in intracavernous pressure due to acute bending, along with the normal thinning of the tunica with erection, lead to rupture of the tunica. Acute abrupt loading of the erect penis causes marked increases in intracavernous pressure, with pressures exceeding 450 mm Hg [9]. The normal thickness of the tunica when flaccid varies from 0.8 to 2.2 mm, and is reduced to 0.25 to 0.5 mm with normal erection. [10-11] The ruptures occur at areas of stress and weakness, commonly in the ventral and lateral pendulous penis adjacent to the urethra, where the tunica is thinner and weaker than other areas [12]. The tears in the tunica tend to be unilateral, transversely oriented, and lead to haematoma formation, swelling, and skin discoloration [13]. Occasionally both corpora are injured; urethral injury has been reported with enough frequency to war rant a high index of suspicion [10, 14-16].

contributing to the development of site specific venous leakage. A second hypothesis for focal ven o-occlusive dysfunction is the development of focal poorly compliant areas of erectile tissue due to intracavernous trauma. [9]

2. PATHOPHYSIOLOGY OF SEXUAL DYSFUNCTION AFTER PENILE FRACTURE Non-operative management was the mainstay of treatment in the 1950’s, but the preponderance of evidence based on over 500 cases reported in the world literature suggests that surgical therapy leads to better outcomes. Disruption of the tunica albuginea of the corpus cavernosum may lead to penile deformity and erectile dysfunction. The unrepaired defect in the corpus cavernosum and unevacuated haematoma are postulated to lead to inflammation and fibrosis of the tunica. [7]

Thus, based on the existing data, immediate sur gical intervention in cases of suspected penile fracture is likely to prevent the rare occurrence of erectile dysfunction and reduce the incidence of post-operative fibrosis and penile angulation. In addition, evacuation of the haematoma and closure of the tunical defect should reduce post-operative convalescence and allow a shorter hospitalisation with less need for analgesics. [13]

The resultant loss of tunical elasticity after trauma can cause penile angulation and painful erection similar to Peyronie’s disease. The incidence of this complication is considerably higher in cases treated non-operatively than in surgically managed patients. Although no prospective comparison has been carried out, several investigators have compared individual surgical series with historical controls from the literature. Overall, the complication rate of operative intervention is very low, with persistent angulation ranging from 2 to 15%. [8, 13, 17-20]

3. CLINICAL PRESENTATION

In contrast, significant numbers of men treated non-operatively may develop angulation and coi tal (21) difficulty. The complication rate, including abscess, angulation, and need for subsequent surgery ranges from 39 to 53%. [13, 20] Resumption of sexual intercourse is rapid after surgical repair: in one series, mean time to sexual activity was 13 days [18], and long-term erectile dysfunction has not been reported. [8-14, 18-20, 22-26] A more potentially serious complication of penile fracture is damage to underlying corpus cavernosum vascular mechanisms. Site-specific venoocclusive dysfunction, arteriovenous fistulae, and pseudoaneurysms all have been reported after non-operative management of penile frac ture. [9, 26] Damage to the cavernous arterial system as a result of the blunt trauma of penile fracture may lead to arteriovenous fistula or pseudoaneurysmal vascular anomalies (fig. 17, 18), both of which may impair normal penile erection. [2627] Penson et al (9) hypothesise that the focally damaged tunica fails to provide an adequate backwall for subtunical venule compression, thus

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The classic presentation of penile fracture includes missed intromission, acute bending of the penis, and a snapping or popping sound followed by acute pain and immediate detumescence. The patients develop penile swelling which is usually limited by Buck’s fascia to the shaft of the penis. Deviation of the penis away from the injured corpus is an inconsistent finding. Occasionally, if the integrity of Buck’s fascia has been violated, scrotal and perineal ecchymosis is seen. A delay in presentation is not uncommon due to embarrassment on the part of the patient; voiding difficulties or haematuria prompt earlier evaluation. Urination is usually unimpeded unless an associated urethral injury is present, although compression of the urethra by haematoma may lead to obstructive urinary symptoms or even urinary retention. [13, 28-29] The inability to void, gross hae maturia, or blood at the meatus are suggestive of urethral injury and warrant further investiga tion.

4. DIAGNOSIS The diagnosis of penile fracture is based on careful history and physical examination. The combination of acute bending of the penis with pain, sudden detumescence, and a haematoma is classic and warrants surgical exploration (fig. 19). Because the morbidity of exploration is no greater than the morbidity of non-operative treatment, and because imaging techniques can miss injuries [7], radiographic studies are not routinely advocated

B

A

Figure 17: Delayed presentation of penile fracture. A: Colour Duplex Doppler ultrasonography demonstrating large pseu doaneurysmal dilatation of the corpus cavernosum B: Operative appearance of corporal pseudoaneurysms. (courtesy of Gre gory A. Broderick, M.D.)

Figure. 19: Ecchymotic appearance of penile shaft after documented penile fracture

Figure 18: Duplex colour Doppler demonstrating abnor mal arteriovenous fistula after blunt penile injury

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to diagnose penile fracture or localise the site of rupture. Rarely a ruptured or torn superficial or deep dorsal vein may simulate fracture [19], but the overwhelming majority of men with this scenario will have a tear in the tunica albuginea.

sum is identified by active bleeding and a defect in the fibrous tunica albuginea (fig. 20). Careful exploration and inspection of the corpus spongiosum is mandatory, even if urethrography shows no extravasation. Catheterisation of the urethra under direct vision, once the penis is degloved, allows easy identification of any defects, and prevents further trauma in cases of partial urethral injury. [7] Tears to both the cavernosum and urethra are generally transversely oriented and should be closed in this same direction. Tunical ruptures sometimes extend behind the spongiosum and this structure may need to be mobilised and retracted in order to completely close the defect.

No well-designed, prospective studies exist to define the appropriate use of radiographic techniques in the evaluation of penile fracture; thus at the present time imaging studies should play a limited role in the evaluation of the suspected penile fracture. Cavernosography, ultrasonography, and magnetic resonance imaging have been used to make the diagnosis of penile fracture [3135]. Limited availability and dependence on experienced radiological interpretation make these modalities of variable utility in the evaluation and management of penile fracture. Because virtually all tears in the tunica can be identified and repaired through a circumferential penile incision, the use of cavernosography to lateralise the site of the corporal injury is unnecessary. Advocates of a direct incision over the site of rupture may find this modality preferable to physical examination alone.

Interrupted slowly absorbable sutures (3-0 or 40) allow a strong hemostatic closure of the tuni ca albuginea. Debridement and curettage have been used in some series, but generally should be

In cases of suspected urethral injury (haematuria, blood at the meatus, inability to void), retrograde urethrography should be performed to document the injury. If, as advocated by the authors, all patients thought to have a penile fracture are explored, passage of a catheter on the operative field with inspection of the pendulous urethra allows identification and primary repair of a lacerated or transected urethra.

5. SURGICAL REPAIR Once the diagnosis of penile fracture has been made on clinical grounds, prompt surgical explo ration is indicated. The patient is anaesthetised in the supine position; a single dose of prophylactic antibiotic is recommended prior to incision. In cases of suspected or documented urethral injury, the patient should not be allowed to void prior to surgery to eliminate potential urinary extravasation. A circumferential subcoronal incision allows adequate exposure for corporal and urethral repair. Once through the tunica dartos, the superficial layers and skin are bluntly degloved back to the base of the penis. Rupture of the corpus caverno-

Figure 20: Operative appearance of tear in tunica albugi nea due to penile fracture

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reserved for late presentations after organisation of the haematoma has progressed. In cases of urethral injury, experience with penetrating injuries has shown that a sutured closure is preferable to simple urinary diversion with a urethral or suprapubic catheter. [36] Thus transverse closure of a urethral laceration in one or two layers is recommended. Fine interrupted slowly absorbable suture will minimise the likelihood of stricture formation. Extensive mobilisation of the urethra is generally not necessary since no tissue loss occurs with these lacerations or transections.

the tunica is important, but associated urethral, scrotal, pelvic, gastrointestinal and vascular injuries make the management of these injuries much more complex and are beyond the scope of this review. [40] The incidence of erectile dysfunction after penetrating injury is difficult to determine. Post-operative follow-up is notoriously difficult. Anecdotal evidence of favourable outcomes with a non-operative approach should be viewed with a degree of scepticism. Gunshot wounds to the penis vary from the simple through and through injury of a low calibre weapon to the tissue devitalization and destruction due to high velocity close range wounds (fig. 21, 22) If considerable loss of corporal tissue occurs, erectile dysfunction has been reported. [36, 41]

Skin closure with interrupted chromic sutures provides a cosmetic incision and allows drainage of residual blood between the sutures. A lightly compressive dressing is sufficient; tight wraps may lead to ischaemic necrosis of the swollen shaft skin. Erections return quickly. Pharmacological therapy to inhibit erections is probably unnecessary; an ice pack at the bedside can be used to cause detumescence for painful nocturnal erections.

A review of 65 penile injuries from Ben Taub Hospital revealed a 67% incidence of injury to the corpus cavernosum and a 32% incidence of urethral injury. [42] No erectile dysfunction was reported in the 40% of patients returning for follow-up. Gomez et al reported normal erections in 6 patients who underwent primary closure of corporal gunshot wounds. [40] In a series of 26 patients with penile gunshot injuries, all those returning for follow-up had normal erections. [43] All but two underwent exploration and repair, while the 2 managed nonoperatively had “minimal injuries” and did well. Another large series concluded that good functional integrity of the male genitalia after gunshot injury can be maintained by following a strict diagnostic and therapeutic