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 regimen. [44]

Patients should refrain from sexual intercourse for 1 month. In the event of a urethral injury, urethral catheterisation for 3 weeks is sufficient urinary diversion. A voiding cysto-urethrogram is recommended to document resolution of extravasation.

III. PENETRATING INJURIES OF THE PENIS Penetrating genital trauma is increasing, both due to the rise in civilian injuries, the advent of the bullet-proof vest, and the exceptional destructive power of modern explosives. While the flak jacket prevents lethal chest and abdominal wounds, it was associated with more bullet and shrapnel injuries of the genitalia as reported in the Gulf war. [37] In the war in Croatia, among those with urogenital trauma penile injury occurred in 9.15%. [38] As a rule all penetrating injuries to the penis should be explored and repaired. Injury to the tunica albuginea causes the same pathophysiolo gical changes seen in penile fracture, but the likelihood of underlying corporal damage is much greater . [39] Penetrating trauma can result in traumatic occlusion of multiple arteries in the hypogastric-cavernous bed. [39] Prompt repair of

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In summary, penetrating injuries to the penis and perineum may have a profound impact on sexual function. Mechanism of injury clearly plays a role in determining outcomes: low velocity gunshot and stab wounds are not likely to cause permanent erectile dysfunction if corporal injuries are closed in an expeditious fashion. Large calibre weapons, however, are more likely to lead to long-term impairment. Management should be primarily centred on identifying major associated injuries of the lower urinary tract and bowel. Surgical exploration and primary closure of corporal injuries is the cornerstone of therapy. Non-operative management should be reserved for cases in which potentially life-threatening injuries preclude penile exploration.

Fig. 21: Low velocity gunshot wound to the penis: A: shaft entry wound;

A

B: Through and through tunical inju ries before primary closure.

B

Figure 22: Gunshot wound of glans with significant tissue injury.

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• SURGICAL APPROACH Penetrating injuries are usually explored through a circumferential incision in a manner similar to penile fracture. [45] Control of hemostasis is achieved by closure of corporal defects; with large glans injuries manual compression of the shaft will usually allow repair in a clear field.. Unless major contamination is present, the vast majority of all gunshot and stab wounds can be closed pri marily at all levels. The vascularity of the skin and glans is so abundant that healing is quite reliable. Deeper injuries, proximal to the suspensory ligament or in the crura, may require a penoscrotal or perineal incision to gain access to the corpus cavernosum. Skin defects can often be closed primarily, although in close range shotgun blasts it may be necessary to bury the denuded penis in the scrotum until subsequent grafting procedures can be carried out.

IV. PENILE AMPUTATION Penile amputation, whether due to self-mutilation or felonious assault at the hands of a jealous lover, is a catastrophic event (fig. 23). [46] Penile replantation, first reported by Ehrich in 1929, has a very high likelihood of restoring erections [47]. The advent of microscopic reconstruction now also a l l ow s restoration of sensation and orgasmic function. [48-49]

Figure 23: Photograph of amputated penis prior to replan tation. A Foley catheter has been placed through the ure thra in anticipation of re-anastomosis.

skin and the possibility of a sensate glans and normal orgasmic function. Reviews of the literature shows the advantages of the microsurgical technique, but also the astonishing results by the former, conventional technique of corporal reattachment without re-anastomosis of the dorsal neurovascular structures. Many of these men will have return of normal erectile function. [46, 52-56]

• SURGICAL APPROACH Microsurgical replantation differs from simple corporal reattachment in that the dorsal neurovascular structures are re-anastomosed in addition to urethral and tunical suturing. With corporal reattachment, a spatulated end to end urethral anastomosis is first performed with fine slowly absorbable suture over a urethral catheter. The adventitia of the corpus spongiosum is re-approximated, after which the tunica albuginea and its septum are also connected. [46] The corporal circulation usually allows preservation of distal corpora, glans and urethra. Ischaemic skin loss is not uncommon without re-anastomosis of the dorsal artery and vein. When microsurgical techniques are available, the dorsal nerves, arteries, and the deep dorsal vein are each re-anastomosed with fine nonabsorbable suture. Meticulous closure of the remaining dartos layer and skin completes the repair (fig. 24). Temporary ectopic replantation of the penis is a useful salvage procedure when the perineum is heavily contaminated or too extensively damaged for immediate replantation. [58] Post operative care includes urinary diversion, bed rest, hydration, and monitoring of arterial flow in the distal penis.

Preservation of the amputated phallus is critical to successful restoration of function. The amputated part should be placed on saline-soaked gauze inside a clean bag, which is then sealed and placed inside a second bag of ice slush. [46] Cold ischaemia times greater than 24 hours are not unreasonable, allowing most patients to be transported to a centre where replantation can be performed. Even at normal temperatures, replantation 16 hours after injury has been successful. [50] Microsurgical replantation was first reported in 1977 and numerous authors have documented that sexual function can be preserved. Erection has been documented by patient report, nocturnal penile tumescence, and more sophisticated testing with corpus cavernosum electromyography. [5156] The advantages of microsurgical techniques include better preservation of the penile shaft

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occur. A controversial but under-studied problem is the significance of bicycle-riding associated ED. Researchers at Boston University have documented a correlation between incidence of erectile complaints and hours per week of bike riding. [66] A cohort of men with ED related to cycling probably does exist, and both acute perineal crush injuries and chronic compression can lead to vascular and possibly neural pathologies. [67] The common thread of these seemingly disparate entities is that, unlike a penile fracture or gunshot wound, surgical intervention plays no role in pre venting the development of erectile dysfunction after blunt injury. The mechanisms of injury are diverse, and include arterial and neural damage as the pathophysiological process leading to ED. Initial management is non-operative, and if ED does develop after the injury, detailed evaluation may be indicated to identify correctable causes.

Figure 24: Postoperative appearance after microsurgical reattachment of amputated penis.

V. BLUNT TRAUMAAND ERECTILE DYSFUNCTION Seemingly minor blunt injuries to the penis, perineum, and pelvis may play a more important role in the pathogenesis of erectile dysfunction than presently recognised. [9, 59-62]

VI. CONCLUSION ( TABLE 4)

Pelvic fracture with prostatomembranous ure thral disruption is associated with a significant incidence of ED which is related to the injury itself and not therapies aimed at restoring urethral continuity. [63] Up to half of men with this injury have ED [64], and vasculogenic and neurogenic aetiologies may be involved. [59] Embolisation of the pudendal cavernous arterial tree may also lead to impairments of penile erec tion. Selective embolisation of the internal pudendal artery to control pelvic haemorrhage may further impair arterial inflow into the penis in men with pelvic fractures (fig. 25 a+b). Blunt injury to the penis can lead to high-flow priapism (fig. 26). Embolisation of abnormal post-traumatic arterial structures, while useful in controlling the abnormal arterial inflow or bleeding, may lead to erectile dysfunction. Men with a history of trauma to the flaccid penis may have haemodynamic abnormalities, which included site specific venous leakage and arterial insufficiency (fig. 27). [9, 65] A history of blunt trauma to the penis was elicited in 37% of impotent men versus only 11% of an age matched control group. [62] Straddle injury is an obvious mechanism by which penile vascular injury might

Acute injuries to the tunica albuginea, regardless of mechanism of injury, are best managed by immediate repair. Failure to treat such injuries may lead to angulation and erectile dysfunction due to tunical fibrosis and site specific venous leakage. Thus penile fracture as well as penetrating injures do not need extensive diagnostic testing; the morbidity of a non-operative approach appears to be greater than the operation itself. Expeditious repair significantly reduces the likelihood of deformity and erectile dysfunction. Penile amputation, while catastrophic, if reattached within 24 hours, has remarkably good outcomes both cosmetically and functionally. Even if the organ cannot be cooled and microsurgical re-anastomosis is not possible, corporal reattachment should preserve erectile function. Finally, blunt injuries to the penis, perineum, and pelvis represent a divergent group of clinical entities that do not benefit from early surgical intervention. Efforts at prevention, and a better understanding of the pathophysiology leading to erectile dysfunction, may improve outcomes for these younger men.

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B Figure 25: Arteriogram of patient with pelvic fracture, urethral dis ruption, and bleeding due to lacerated internal pudendal artery. A: prior to embolisation. (see arrow) B: post embolisation with coils. (see arrow)

A

Figure 26: Colour Doppler of penis in patient with high flow priapism due to blunt penile trauma. Transverse of penis demonstrating abnormal arterial blood pooling in right corpus cavernosum. Arteriography of right internal pudendal artery was subsequently performed and selective embolisation carried out.

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Figure 27: Cavernosogram revealing right sided site specific venous leakage in young man who suffered pelvic fracture with right proximal corpus cavernosum injury. Visible cavernosal and crural leak is evident.

Table 4: Traumatic injuries associated with erectile dysfunction MECHANISM

LIKELIHOODE OFED

ETIOLOGY OFED

MANAGEMENT

PENILE FRACTURE

0-2%

Pseudoaneurysm Arteriovenous Fistula Site-specific CVOD1

Exploration and Repair

PENETRATING PENILE INJURIES

Variable

Arterial injury Site-specific CVOD

Exploration and repair

PENILE AMPUTATION

Very low

Lack of sensation penile loss

Immediate replantation

PELVIC FRACTURE

19- 56%[64]

Neurogenic Arteriogenic Site-specfic CVOD

Delayed evaluation of ED

BLUNT INJURYTO PERINEUM OR FLACCID PENIS

unknown but potentially important cause

Arterial injury Site-specific CVOD Post-embolization for priapism

Delayed evaluation of ED

1. CVOD: Corporal veno-occlusive dysfunction.

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surgical techniques and indications. Case reports are only included in the analysis if they had or have impact on actual or future surgical trends. The analysis is limited to the fields of neophallus formation and penile enlargement.

E. PENILE RECONSTRUCTION

I. INTRODUCTION

II. REVIEW OF THE LITERATURE ON TECHNIQUES FOR PHALLOPLASTY

The field of penile reconstruction is ample and not well defined. It may cover topics like penile restoration after traumatic lesions, penile neoformation in intersex abnormalities, neophallus-construction in transsexual patients and penile enlargement or elongation in patients with micropenises up to aesthetic surgical procedures like uncircumcision. In many of these fields it will not be possible to define future guide-lines for indications and therapeutic regiments without close co-operation with leading experts in psychiatry, paediatrics, plastic- and reconstructive surgery or gynaecology and endocrinology. This task would overstress the actual committee.

The development of techniques for phalloplasty has paralleled the evolution of flap development in reconstructive surgery [ 2] . The plethora of surgical techniques in the literature is nearly as ample as in hypospadia repair. At this very moment, more than 20 different flaps are recommended for penile reconstruction[2-5, 6]. All these techniques have been used in a broad variety of indications: penile agenesis, penile loss due to trauma or surgery, micropenis, intersex disorders or female- to male transsexualism. Whereas in non-transsexual males without intersex-disorders scrotum and perineal part of the urethra do not have to be reconstructed, transsexuals and children with intersex disorders represent the most challenging groups for genital reconstruction. Phalloplasty has been recommended as a single-stage operation or as multi-stage procedures [ 4, 7, 8, 9]. General agreement exists, that even in attempted single-stage procedures subsequent corrective interventions in most cases are necessary [ 8, 10, 11].

In the following, only key topics of actual or future numeric relevance in the field of penile reconstruction shall be discussed. A further obstacle to the definition of possible standards of care or clinical guide-lines is reflected by the actual rapid development in microsurgical tissue transfer techniques and in the new field of extracorporal in vitro tissue expansion on biodegradable carrier systems. Most of the recent publications on these techniques refer to small patient groups and lack of long term follow up data. Most studies on penile reconstruction do not permit a stringent efficacy-evaluation based on the criteria of evidencebased-medicine (EBM) (1). After a profound analysis of all publications on penile reconstruction of the last ten years (MEDLINE research 1988 – 1998), no randomised cohort-studies could be found. Even large series containing data of more than 50 patients do not permit a potential metaanalysis due to the lack of common inclusion criteria, common surgical techniques or common parameters for success evaluation. Most relevant surgical techniques have been published after 1992, which may explain the lack of long-term follow up data.

The first series of successful phalloplasties has been published in 1936 by Bogoras [12] using a tubed abdominal flap. During the following decades the search for the best method encompassed numerous variations of abdominal flaps, scrotal skin flaps, tubed thigh flaps , gracilis musculocutaneous flaps, groin flaps and iliac crest flaps. [2, 3, 4, 5, 7, 13, 14 15, 16, 17, 18, 19]. In 1984 Chang and Kao published the first results of neophallus formation derived from microsurgically transplanted free radial forearm flaps [20, 21]. The free radial forearm flap had been first described by Song for other indications in face and neck surgery [ 22] . Laub combined this free flap for urethral reconstruction with a standard midline abdominal flap and split-thickness skin grafts, which he later called «Postmodern Phalloplasty» [23]. Others changed the design of the forearm flap following

Thus the task of this report shall be seen in a compilation of expert opinions on a limited number of

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the „tube-in-a-tube“ principle and used it as a single flap for both penile and urethral reconstruction ( 2,3, see fig. 28 a). The availability of microsurgical neuro-vascular anastomoses enabled reconstructive surgeons to look for other less exposed donor areas for free-flap retrieval, including upper medial arm, upper lateral arm, saphenous, deltoid, latissimus dorsi and fibula osteocutaneous flaps [ 2, 3, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33].

breast surgery have been defined by the „Harry Benjamin International Gender Dysphoria Association“ . Actually the fifth version of „ The Standards of Care“ can be drawn from Draft Nine B June 15, 1998 under http:// www. symposion. com/ijt International Journal of Transgenderism [36]. The most actual information on the desiderata of female-to-male transsexuals can be drawn from a study from Amsterdam from 1993 [37]. The Amsterdam Transgender-Team is in a favourable position for these surveys, because their data-base includes information on about 97% of all hormonally treated transsexuals in the Netherlands [35].

The actual variety of free and pedicled flaps used for phalloplasty suggest that there does not exist one single technique, which could fulfil all demands in neopenis formation:

A questionnaire was sent to 200 female-to-male subjects and was returned by 150. 52% of all female-to-male transsexuals asked for a phalloplasty as part of reassignment surgery additional to breast reduction, hysterectomy and bilateral oophorectomy. Of these patients 96% desired to have a scrotum, 92% a glans and 91 % respectively 81% an aesthetically appealing look wearing a tight swim-suit or being nude. 86% declared their wish for a intrapenile stiffener or prosthesis and all but one patient wanted to be able to void in a standing position [37]. Increasing knowledge by the subjects on the technical boundaries of phalloplasty will probably increase the percentage of patients desiring the construction of a completely functional aesthetically appealing penis [ 4, 8, 10 ]

1. A one stage-procedure that can be predictably reproduced 2. Creation of a competent neo-urethra to allow for voiding while standing 3. Return of both tactile and erogenous sensibility 4. Enough bulk to tolerate the insertion of a prosthetic stiffener 5. A result that is aesthetically acceptable to the patient 6. Minimal scarring or disfigurement 7. No functional loss in the donor area [3, 4, 8, 13, 24, 34]. In the following, the actually most promising techniques shall be described. Indications are focused on female-to-male transsexualism, because this group of patients is assumed to be the most homogenous and at the same time numerous one.

Patients who do not want a neophallus but only demand for a more masculine look of their external genitalia can be advised to undergo clitoral advancement and enlargement, combined with urethral advancement enabling the patient to void in the standing position. The resultant microphallus depends in its size on the androgen- induced enlargement of the clitoris after long time contrasexual hormonal therapy. The procedure is called metaidoioplasty and may be combined with the construction of a bifid scrotum by dorsal transposition of the labia majora and insertion of testicular prosthesis [23, 39].

The prevalence of transsexualism (ICD –10; DSM-IV ) seems to rise during the last decades and differs enormously world-wide. The most recent information derives from Holland and amounts a prevalence of 1:11900 for male-tofemale transsexuals and 1:30400 for female-tomale transsexuals [35]. In the United States, England and Sweden the incidence of transsexuals is suspected to be around 1:50.000 overall [3]. Even if epidemiological studies established that a similar base rate of gender identity disorders existed all over the world, it is likely that cultural differences from one country to another would alter the behavioural expressions of the disorder [36]. The requirements for genital reconstruction and

The largest and best documented series has been published in 1996 referring to the results of metaidoioplasty in 32 patients operated by the Amsterdam team [39]. In 20 patients a sufficient followup of 6 to 36 months (average 22 months) was evaluated. One flap loss and 7 urethrocutaneous

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or urethrovaginal fistulae were noted. Urethral strictures were seen in 3 patients. 50% of all patients were able to void in a standing position. Meatoidoioplasty is considered by the author as the method of choice in cases were the clitoris seems large enough to provide a phallus that will satisfy the patient. Although this method represents the least extended procedure for phalloplasty, it becomes obvious from the complications, that it requires more than one operative session in the majority of patients.

The largest study on 136 cases of penile reconstruction has been published in 1995 by Cheng et al [14]. 93 of these patients received a free radial forearm flap. None of the patients were transsexuals, the majority underwent phalloplasty for micropenis ( 50,7%). The authors describe a postoperative atrophy of the penis loosing from 12 to 21,7% of its circumference. The operation was performed in one session in the majority of patients. Even a penile stiffener (autogenous rib cartilage) was inserted in all phalloplasties immediately. The authors claim that cartilage absorption did not occur. Only 18 patients developed complications. 6 partial necroses of the flaps occurred. 7 patients developed urethrocutaneous fistulae. In 53 patients nerve anastomoses to the proximal stumps of the dorsal penile nerves were performed. About 20 to 24 months postoperatively 43 patients reported having erogenous sensibility in their neophalluses. Vibratory sensation and temperature differentiation was confirmed in these patients. Overall 77 percent of all patients, who reported to have a sexual activity, regained sexual satisfaction. The authors conclude, that the radial forearm flap, the superficial inferior epigastric artery flap and the superficial circumflex iliac artery flap are the flaps of first choice in penile reconstruction. In a subsequent discussion of the paper the Amsterdam group lines out, that sensitivity of nerve adapted free flaps is always better than in pedicled flaps [ 44] . Postoperative atrophy of free flaps shall be judged cautiously due to immediate postoperative oedema and swelling which renders the interpretation of serial circumference measurements difficult.

With few exceptions [9, 14] there is general agreement, that the more recently introduced microsurgical free flap phalloplasties lead to better results, compared to pedicled flaps [3, 4, 5, 6, 8, 10, 11, 24, 27, 28, 34, 38, 41, 42, 43]. The most commonly used free flap for phalloplasty today still is the radial or ulnar free forearm flap [6, 28]. There is no agreement on flap design , inclusion of auto genous bone, number of operative sessions or prosthetic material. Most reports deal with inhomogeneous patient groups and only few reports enclose more than 10 patients each. Follow up for evaluation of success and complications is mostly incomplete or too short for allowing comparative conclusions. The following publications were selected for quantity and quality of information on patient material and results: Hage et al published the results of 11 forearm free flap procedures in transsex patients. Vascular anastomosis had to be revised in two patients, no flap was lost. Microsurgical nerve anastomoses between a clitoral nerve and a subcutaneous forearm nerve permitted recurrence of tactile sensibility of the neophallus in all patients. 4 patients regained erogenous phallic sensibility. The operation was primarily planned as a two-session procedure, while in the first session only the perineal part (fixed part ) of the urethra was reconstructed including a complete vaginectomy [34]. The two-stagetechnique could not prevent the manifestation of urethral fistulae or stenoses.

In 1995 Gilbert et al published their large experience in 21 patients with ulnar forearm flaps in a mixed patient group [28]. They used 3 different flap designs, always incorporating the neo-urethra in the flap and planning the operation as a one session procedure without prosthesis-implantation. No flap was lost, 7 patients developed urethral complications. 14 patients regained sensibility in their neophalluses. 5 of them received a successful insertion of a multicomponent hydraulic prosthesis, covered by a Gore-Tex vascular graft.

Levine et al most recently reported on 15 free forearm flaps in penile reconstruction. 8 patients (57 %) developed a neo-urethral stenosis which required operative repair. Buccal mucosa grafts showed the best results in fistula repair in this patient group [40].

Fang and co-workers reported on the use of free forearm flaps without clitoral nerve anastomosis in 56 patients with female-to-male-transsexualism

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[38]. The operation was always done in two sessions, in 28 patients the urethra was prefabricated by implanting tubed vaginal mucosa into a subcutaneous tunnel, created in the radial side of the forearm. One flap loss occurred, partial loss was noted in 6 patients. 45 patients developed urethral fistulae or stenoses. No fistulae were noted in the prefabricated neo-urethras 40 patients regained tactile sensation of the neopenis. In a most recent report, the same group summarised their experience with free radial forearm osteocutaneous flaps in 22 patients with primary female transsexualism. [64]. The operation was now performed as a three-stage procedure and the donor defect was covered with a pre-expanded abdominal flap. One partial flap loss and a 40,9% fistula rate respectively 13,7% stricture rate was noted. Significant donor forearm morbidity and radius bone fracture was noted in two cases. In our own group 35 female-to-male transsexuals have been operated during the last 8 years [10, 45, 52]. All operations were done in one session, using the radial free forearm flap as only method in this group. In the same session vaginectomy and scrotum reconstruction was performed. (Figures 28 AD) 1 flap loss and 2 partial necroses were observed. 27 patients developed urethral fistulae or stenoses which needed one to three operative sessions for repair. Prostheses-implantation has been done in 15 patients after recurrence of erogenous sensation. In the first of these implantation-sessions two testicular prosthesis and one penile cylinder was implanted, covered by a Dacron sheet [ 46] (figures 29 A, B). Three months later, the pump replaced one testicular prosthesis and a reservoir was implanted into the retropubic space (Figure 29 C). None of the patients regrets to have undergone these procedures. An infection rate of 20% has to be awaited, following the experience in complicated prosthesis insertion in impotent men [47].Tactile and temperature sensitivity returned in the majority of patients after microsurgical clitoral dorsal nerve anastomoses, which coincides with the experience of other authors [14, 28, 41, 42, 43, 48, 49]. Other authors tried to spare prosthesis implantation to their patients by including autogenous bone with sufficient vascular supply into the flap planned for phalloplasty [30, 42].

The first report on inclusion of vascularised radial bone into the forearm free flap was published as a case report by Koshima et al in 1986 [49]. Byun et al used a similar segment of radial bone in 5 patients receiving free forearm flaps for various indications [42]. 3 patients developed urethral fistulae and mild to moderate bone resorption was noted in 2 patients. Fang et al recently reported a series of 22 neopenis reconstructions from free radial forearm osteocutaneous flaps [64]. One case of consequent radial fracture was noted. Sadove et al reported on 6 successful osteocutaneous fibula flaps in 1993 [30]. In some of these patients also the neo-urethra was formed from flap tissue during the one-session procedure. Following his recommendations Capelouto et al recently published a case report on the same procedure, including a complete segment of the fibula into the flap. The urethra was prefabricated from fullthickness-skin and tubed into the flap in a previous session [26]. The patient experienced no severe complication or loss of ankle stability. In 1996 the Amsterdam group published a further case report on a fibula containing free flap phalloplasty, performed in 3 sessions [ 25] . The urethra had to be prefabricated from full thickness skin, tubed into the planned flap area. Several interventions were necessary for relief of subsequent urethral stenoses and the patient experienced reduced ankle stability. Unlike the phalloplasty results, the donor area results after radial forearm flap removal are undesirable [34]. The attempt to find more suitable donor sites led to the development of lateral upper arm flaps [3, 27, 31, 32, 50, 51]. Recently Khouri published the results of 4 prefabricated lateral arm free flaps in 3 female-to-male transsexuals and in one man after penile amputation [27]. In the first session the neo-urethra constructed from tube skin grafts was embedded in the region of the lateral arm flap. After 3 to 6 months the flap was raised and a neophallus formed and transplanted to the infrapubic area. Inflatable penile prosthesis were implanted during the same session without covering them with GoreTex sleeves. All patients needed at least two further interventions for complications, in two patients the prosthetic device was lost.

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Figure 28A: Radial forearm-flap based on the radial artery. Urethra-formation following the “tube-in-a-tube” principle

Figure 28B :Vaginal exstirpation. Formation of the proximal urethra by an anterior vaginal wall flap, based at the urethral meatus.

Figure 28C: Schematic drawing of the vascular and nerve anastomoses needed for penile neo formation from radial forearm flap; lower epigastric artery, saphenous vein, dor sal clitoral nerve and branch of genito-femoral nerve.

Figure 28D: Completed neopenis and neoscrotum forma tion from radial forearm flap

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Figure 29B: Session I for Prosthesis implantation : Dacron®-sock with cylinder implanted. Implantation of two testicular prosthesis for tissue expansion. ( One testicular prosthesis is removed in session II for pump placement ).

Figure 29A: Schematic drawing of implantation of a multicomponent prosthetic device (Cylinder in a Dacron® sock).

Figure 29C : End result after penile reconstruction and prosthesis implantation . Deflated device (left), inflated device (right).

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ad 1.) Several reports describe the feasibility of penile reconstruction even in young infants. Microsurgical flap transfer and micro-anastomosis of growing vessels can be accomplished [54, 55, 56, 57]. The newer possibilities to reconstruct a functional neophallus cast doubt on the former strategy to reassign children with ambiguous genitalia to the female sex [3, 54, 56]. If a phalloplasty in children and adolescents is planned, only somatic growth of the neophallus has to be expected during puberty, due to the lack of enzyme 5-α-reductase in the flap tissue. The disparity between the somatic and genital growth curves has to be factored into the calculation of the neophallic size [55]. ad 2.) The long distance of neo-urethra, which has to be reconstructed especially in female-to-male transsexuals still is the main source of complications in penile reconstruction [57]. Actually no consensus exists on the ideal tissue and timing for urethral reconstruction. Staged procedures, which are favoured by some authors cannot eliminate the risk of fistula or stenosis formation [8,11, 28]. In vitro growth and expansion of squamous or urothelial cells on biodegradable carriers could be a future solution in this field [59]. ad 3.) Also in this field, future solutions can be expected from in vitro cartilage expansion and replantation on absorbable carrier systems, which recently has been realised in animal models [58]. Even if synthetic inflatable prosthesis implantation has led to unsatisfying results in the hands of others [60, 61], several reports recommend this technique in combination with GoreTex or Dacron sleeves for replacement of the missing tunica albuginea [9, 10, 45, 46, 53, 62, 63 ]. The sleeve should be fixed to the periosteum in order to eliminate migration of the prosthesis [63]. The implantation of inflatable multicomponent prosthetic devices is technically more challenging but permits superior results in concealment and rigidity . Protrusion is less probable in inflatable devices [45, 46, 53, 63]. There exist no data on long-term-function of these devices in phalloplasty.

III. CONCLUSIONS Use of free flaps seems to be the method of choice for penile reconstruction [ 6, 34]. If a prosthesis of stiffener is desired, obtaining a phallus with at least tactile sensibility is a condition of utmost importance. This condition can best be fulfilled by selective microsurgical nerve anastomoses to the clitoral or dorsal penile nerves. Recurrence of tactile or even erogenous sensibility to the neophallus can be expected in up to 80 % of the cases. Most experience in phalloplasty using free flaps has been gained by using the radial or ulnar forearm flap [6]. The major drawback of this flap is the visible extended scar formation in the donor area. Usually motor function of the arm and hand is fully restored 3 months after flap transplantation. Long-term reduction of grip strength or cold intolerance has not to be expected, as could be shown in a large series of radial donor site defects [51]. Nevertheless other free flap donor sites to be used for phalloplasty should be sought [3, 34]. Up to now no other standard free flap seems superior to free forearm flaps in penile reconstruction. On the other hand it should be noted, that pedicle flaps still remain a valuable option in phalloplasty , if patients refrain from complicated free flap transfer and only desire partial aspects of aesthetic and functional penile reconstruction [8, 9, 14]. Penile reconstruction by free flap phalloplasty can be done in a one-session or multiple-session procedure. If all goals of ideal phalloplasty should be obtained [3, 4, 8, 13, 24, 34] multiple sessions seem inevitable in the vast majority of patients [8]. Penile prosthesis implantation should not be undertaken before urethral healing is complete and sensibility of the neophallus has returned [10]. Apart from the ongoing discussion concerning the ideal donor area for flap retrieval, several other topics in penile reconstruction remain obscure from the actual scientific literature: 1. Shall phalloplasty be recommended in children with intersex abnormalities or ambiguous genitalia ? 2. Shall the urethra be prefabricated before phalloplasty ? 3. What is the ideal concept for restoration of erectile function ? 391

F. PENILE ENLARGEMENT SURGERY Penile advancement and lengthening have been used for more than ten years in patients with webbed or buried penis, in patients with penile fibrosis or in patients with spinal cord injury with retracted phalluses [1-5]. In children with a micropenis, mostly in connection with the epispadia / exstrophy-complex , penile advancement also is a wellknown, beneficial procedure [4, 6-10]. The surgical steps of the procedure ( excising the fundiform ligament, suprapubic lipectomy, tacking of the suprapubic skin to the pubis, division of the suspensory ligament, infrapubic Z-plasty or VY-plasty) have been extensively described in this context [4]. Nevertheless, there are no conclusive quantitative data on penile length gain in the literature. Whereas urologists have used these techniques for many years with the intention to eliminate disease and to treat deformities, the use in aesthetic surgery in patients without obvious somatic pathology or deformity is investigational [11]. Recently we have gained reliable data on average penile length in the flaccid, erect and stretched state [2, 13-15]. Mean stretched length of the penis was 12,4 cm in a group of 80 physically normal men with a mean erect length of 12,9 cm [12]. The authors consider normal penile dimensions to be any length within 2 standard deviations of the mean. Consequently they recommend penile lengthening procedures only in patients with a stretched or erect penile length of less than 7,5 cm or in men with a flaccid length of less than 4 cm . Recently a significant and growing number of men with normal penile dimensions demand peni le enhancement surgery, mostly performed by plastic and reconstructive surgeons [16]. There are no data available from peer-reviewed journals that contain evidence to support the effi cacy of penile enhancement. On the other hand there is a growing number of reports on compli cations and deformities resulting from this kind of surgery [4, 16-17]. The chief complaints were poor cosmetic appearance and retraction of the penis. Also postoperative sexual dysfunction and numbness of the glans was reported. Most of these patients needed re-operations for relief of their complaints. From the scientific literature only one

392

recent report by Gary J. Alter could be found, which defines actual recommendations on operative techniques in detail [11]. The author considers a 1-inch gain of penile length in the flaccid state as postoperative success, without giving data on success-rates in his patient material. He claims that this kind of length gain may only be reached by a complete operative lengthening procedure followed by the application of penile weights of at least 10-pounds, several times a day for a period of months. Operative penile lengthening should include an infrapubic double-Z-plasty , release of the suspensory ligament and incision of restraining bands of Scarpa’s fascia on both sides. Infra- or suprapubic liposuction may be seen as an optional procedure. In order to prevent reattachment of the corpora and the pubis, the space is filled with a pedicled regional fat flap. If girth enhancement of the penis is also desired by the patient, Alter recommends the interposition of extended de-epithelialised dermal fat grafts between Dartos‘ and Buck’s fascia of the penis. This procedure shall not be combined with lengthening procedures. If penile lengthening and girth enhancement is desired, several months should separate both interventions. There are no reliable data in the literature on the results after such extended procedures. Autologous fat injections , which previously had been recommended for girth enhancement, should be abandoned. There are sufficient data, that less than 50% of injected fat survives. The results are unpredictable and severe deformities have often been reported [4,11, 16-19].

I. CONCLUSION Penile enlargement surgery has evolved rapidly during the past 5 years, mostly performed by plastic and reconstructive surgeons in men without genital deformities and pathologies. Peer-reviewed reports on postoperative results and complications are lacking. Patients must be informed that these procedures are investigational [11]. Penile lengthening oradvancement procedures in patients with deformities as concealed or webbed penises, epispadia or exstrophy and penile fibrosis or scarring may have therapeutic sense, even if sufficient quantitative data on postoperative outcome are lacking [2-3, 5, 9, 20].

SUMMARY & RECOMMENDATIONS 2. PENILE DRUG DELIVERY IMPLANTS

I. MECHANICAL DEVICES

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. Only few implants were performed since 1986. It was developed as an alternative to the self-injection therapy, however there is still room for refinements and this procedure should be considered investigational.

1. VACUUM DEVICES The use of vacuum devices as part of the conservative management of erectile dysfunction is not common-place. Vacuum devices work by creating a 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.

II. VASCULAR SURGERY

a) Complications Petechiae skin bruising, especially at the site of the ring Pain at the site of the ring. Ejaculatory changes, including pain on ejaculation Numbness during erection Pivoting at the base

Impressive progress in understanding and treatment of impotence occured in the last two decades. Although most erectile dysfunctions respond to vacuum device, prostaglandine E1and sildenafil, vascular surgery is an effective therapy in selected cases. It may offer an advantage in men failing in conservative therapy for those not desiring a penile implant.

b) Satisfaction rate

1. SURGERY FOR ARTERIAL PATHOLOGY

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. The reasons for dissatisfaction mainly are : Inability to maintain full erection

12%

pain

4%

inconvenience/awareness

4%

marital problems

5%

partner dissatisfaction with: performance penile temperature appearance

The Michal procedure is performed using the inferior epigastric artery. An end-to-side anastomosis is done between the epigastric artery and the proximal part of the dorsal penile artery..In the DDVA procedure, the epigastric artery is anastomosed end-to-side to the proximal part of the deep dorsal vein. Hauri uses the inferior epigastric artery, which is anastomosed to one of the dorsal penile arteries and the deep dorsal vein.The results are discussed controversly, ranging between 38% and 79%, showing decline of success with time. Widely used is the VIRAG V procedure, anastomosing the inferior epigastric artery end-to-side to the deep dorsal vein in combination with ligature of the proximal and distal vein and the emissary collaterales and the formation of a fistula between the dorsal vein and the corpus cavernosum,

11% 7% 13%

c) Safety The devices are safe, as long as the ring application is limited to 30 minutes.

2. SURGERY FOR VENOUS PATHOLOGY The treatment of patients with caverno-venous insufficiency is based mainly on the reduction of

393

venous outflow during erection. Embolization of the deep venous network with detachable balloons and coils and surgery are an alternative, but are discussed controversially. The surgical approach addresses ectopic veins, deep dorsal veins and/or cavernous or crural veins. Spongiolysis or pericavernoplasty with or without insertion of a prosthetic venous tourniquet has also been proposed. 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. Patient selection is also 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. Such patients might benefit from deep dorsal vein arterialization if they are younger than 55 years but the results are not completely satisfactory. It appears that potency remains stable if the effect of the surgical treatment persists beyond 6 months. Venous surgery should not be restricted solely to the veins seen to be opacified on cavernosography but it must be extended to the 3 main drainage routes of the corpora: the deep dorsal vein, the cavernous veins and the crural veins (see Algorith for vascular surgery). Microvascular arterial bypass- and venous ligation surgery may achieve the goal of increasing arterial inflow and improving veno-occlusion. Certain young patients may be candidates for surgical cure or improvement of ED. These patients must be evaluated by specialized testing and should be treated at centers capable of providing both longitudinal followup, if possible within research protocols.

IV. PENILE INJURIES: THE ROLE OF EARLY SURGICAL INTERVENTION IN PREVENTING ERECTILE DYSFUNCTION The mechanism of injury allows a general classification of urogenital trauma causing erectile dysfunction: Penile fracture, a unique injury of the tunica albuginea which occurs only with full penile rigidity; Penetrating trauma to the corpora cavernosa, commonly associated with urethral and other genital injuries; Penile Amputation; and Blunt penile, perineal, or pelvic trauma, which may lead to arterial injury, neuropathic dysfunction, and high flow priapism. Acute injuries to the tunica albuginea, regardless of the mechanism of injury, are best managed by immediate repair. Failure to treat such injuries may lead to angulation and erectile dysfunction due to site specific venous leakage Thus penile fracture as well as penetrating injures do not need extensive diagnostic testing; the morbidity of a non-operative approach appears to be greater than the operation itself. Expeditious repair significantly reduces the likelihood of deformity and erectile dysfunction. The major problem in non-repaired cases is erectile deformity due to plaques. Penile amputation, while catastrophic, if reattached within 24 hours, has remarkably good outcomes both cosmetically and functionally. Even if the organ cannot be cooled and microsurgical reanastomosis is not possible, corporal reattachment should preserve erectile function. Finally, blunt injuries to the penis, perineum, and pelvis represent a divergent group of clinical entities which do not benefit from early surgical intervention. Efforts at prevention, and a better understanding of the pathophysiology leading to erectile dysfunction, may improve outcomes for these younger men. Table 4 summarizes the correlation between traumatic injury and erectile dysfunction

III. PENILE IMPLANTS Principally, 2 different types of implants are available today: the malleable and inflatable penile devices, the devices available 1999 are (Fig. 29): Complications are seen in 16 %, the overall success rate is between 70 and 98%. Penile implats 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.

V. PENILE RECONSTRUCTION The field of penile reconstruction is ample and not well defined. It may cover topics like penile restauration after traumatic lesions, penile neoformation in intersex abnormalities, neophallus-

394

Table 4: Traumatic injuries associated with erectile dysfunction MECHANISM

LIKELIHOODE OFED

ETIOLOGY OFED

MANAGEMENT

PENILE FRACTURE

0-2%

Pseudoaneurysm AV Fistula Site-specific CVOD1

Exploration and Repair

PENETRATING PENILE INJURIES

Variable

Arterial injury Site-specific CVOD

Exploration and repair

PENILE AMPUTATION

Very low

Lack of sensation penile loss

Immediate replantation

PELVIC FRACTURE

19- 56% [64]

Neurogenic Arteriogenic Site-specfic CVOD

Delayed evaluation of ED

BLUNT INJURYTO PERINEUM OR FLACCID PENIS

anknown but potentially important cause

Arterial injury Site-specific CVOD Post-embolization for priapism

Delayed evaluation of ED

1. CVOD: Corporal veno-occlusive dysfunction.

construction in transsexual patients and penile enlargement or elongation in patients with micropenises up to esthetic surgical procedures like uncircumcision. In many of these fields it will not be possible to define future guide-lines for indications and therapeutic regiments without close cooperation with leading experts in psychiatry, pediatrics, plastic- and reconstructive surgery or gynecology and endocrinology. The use of free flaps seems to be the method of choice for penile reconstruction. The restauration of tactile sensibility can best be fulfilled by selective microsurgical nerve anastomoses to the clitoral or dorsal penile nerves. Reoccurence of tactile or even erogenous sensibility to the neophallus can be expected in up to 80 % of the cases. Most experience in phalloplasty using free flaps has been gained by using the radial or ulnar forearm flap . The major drawback of this flap is the visible extended scar formation in the donor area. Usually motor function of the arm and hand is fully restored 3 months after flap transplantation. Longterm reduction of grip strength or cold intolerance has not to be expected, as could be shown in a large series of radial donor site defects. Nevertheless other free flap donor sites to be used for phalloplasty should be sought. Up to now no other standard free flap seems superior to free forearm flaps in penile reconstruction. On the other hand it should be noted, that pedicle flaps still remain a valuable

option in phalloplasty, if patients refrain from complicated free flap transfer and only desire partial aspects of esthetic and functional penile reconstruction. Penile reconstruction by free flap phalloplasty can be done in a one-session or multiple-session procedure. If all goals of ideal phalloplasty should be obtained multiple sessions seem inevitable in the vast majority of patients. Penile prosthesis implantation should not be undertaken before urethral healing is complete and sensibility of the neophallus has returned.

VI. PENILE ENLARGEMENT SURGERY Penile enlargement surgery has evolved rapidly during the past 5 years, mostly performed by plastic and reconstructive surgeons in men without genital deformities and pathologies. Peer-reviewed reports on postoperative results and complications are lacking. Patients must be informed that these procedures are investigational. Penile lengthening or advancement procedures in patients with deformities as concealed or webbed penisses, epispadia or exstrophy and penile fibrosis or scarring may have therapeutic sense, even if sufficient quantitative data on postoperative outcome are lacking. 395

SUMMARY

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Vacuum devices, although not in widespread use have advantages that they are re-usable, satisfactory for many patients and safe. They should be kept available for use and improving design will make them more userfriendly

A. EXTERNAL DEVICES, DRUG DELIVERY IMPLANTS

Vascular Surgery Microvascular arterial bypassand venous ligation surgery may achieve the goal of increasing arterial inflow and improving venoocclusion. Certain young patients may be candidates for surgical cure or improvement of ED. These patients must be evaluated by specialized testing and should be treated at centers capable of providing both longitudinal followup, if possible within research protocols. 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 Penile Injuries: Acute injuries to the tunica albuginea are best managed by immediate repair. Penile fracture and penetrating injuries do not need extensive testing. The morbitidy of surgery is less then in conservative treatment. Penile amputation, if reattached < 24 hours has remarkably good outcomes. Blunt injuries not necessarily benefit from early surgical intervention Penile Reconstruction: The use of free flaps is the method of choice, mainly using the radial- or ulnar forearm flap. Microsurgical nerve anastomoses assure the sensibility in the neophallus in up to 80 %. Penile implants should not be performed before urethral healing and sensitivity are accomplished. Penile enlargement surgery has evolved rapidly in the past 5 years (plastic- and reconstructive surgeons) in absence of genital pathologies! Peerreviewed reports and p.o.results are lacking, information on the investigational character of this procedure is mandatory ! Penile lenghtening in deformities ( e.g.webbed penis, epispadia, penile fibrosis) is justified, even if sufficiant good data are still not available.

396

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BOMERS TML, DE JONg TPVM : The surgical correction of buried penis: a new technique. J Urol 1995; 154: 550-552

10.

BAKA-JAKUBIAK M : Genital reconstruction. Current Opinion in Urology 1998; 8: 501-504 ALTER, GJ: Penile enlargement surgery. Techniques in Urol 1998; 4 : 70-76

11. 12.

WESSELLS H, LUE TF, MCANINCH JW: Penile length in the flaccid and erect states: Guidelines for penile augmentation. J Urol 1996; 156 : 995-997

13.

SCHONFELD WA, BEEBE GW: Normal growth and variation in the male genitalia from birth to maturity. J Urol 1942; 48: 759 - 761

14.

DA ROS, TELOKEN C, et al: Caucasian penis: What is normal size? J Urol 1994; 151: 323 A

15.

LIGHT JK, Editorial: Potpourri. J Urol 1996; 156 :998 – 1000 WESSELLS H, LUE TF, MC.ANINCH JW: Complications of penile lengthening and augmentation seen at 1 refferal center. J Urol 1996; 155 :1617-1620 ALTER GJ: Reconstruction of deformities resulting from penile enlargement surgery. J Urol 1997; 158: 2153-2157 NIECHAJEV I, SEVCUK´ O: Long-term results of fat transplantation : Clinical and histologic studies. Plast and Reconst Surg 1994; 94 : 496-506 ERSEK RA; Transplantation of purified autologous fat: a 3-year follow-up is disappointing. Plast and Reconstr Surg 1990; 87: 219-228 PRYOR JP, HILL JT: Abnormalities of the Suspensory Ligament of the Penis as a Cause for Erectile Dysfunction. Brit J Urol 1979; 51: 402-403

16.

HAGE JJ: Dynaflex prosthesis in total phalloplasty Plast and Reconstr Surg , 1995; 99 : 479-485 LEVINE LA, ZACHARY LS, GOTTLIEB, LJ: Prosthesis placement after total phallic reconstruction J Urol, 1993; 149: 593-598 FISCH M, WAMMACK R, AHLERS J ,et al: Osseous fixation of a penile prosthesis after transsexual phalloplasty: A case report J Urol, 1993; 149: 122-125 FANG RH, KAO YS, MA S et al: Phalloplasty in female-to-male transsexuals using free radial osteocutaneous flaps: a series of 22 cases . Brit J Urol, 1999; 52: 217-222

17.

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F. PENILE ENLARGEMENT SURGERY 1.

2.

DEVINE : Eingegrabener Penis , In: Atlas urologischer Operationen , ed.; Hinmann F, Enke-Verlag, Stuttgart 1994; 66-68 KABALIN JN, ROSEN J, PERKASH I: Penile

advancement and lengthening in spinal cord injury patients with retracted phallus who have failed penile prosthesis placement alone. J Urol 1990;144 : 316318 KNOLL D, FISHER J, BENSON R, et al: Treatment of penile fibrosis with prosthetic implantation and flap advancement with tissue debulking. J Urol 1996;156: 394-397 ALTER GJ: Augmentation phalloplasty. Urol Clin N America 1995; 22: 887-902

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Committee 11

Psychological Issues in Diagnosis and Treatment

Chairman A. M ELMAN

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

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CONTENTS

D. QUESTIONNAIRE ASSESSMENT OF PATIENTS WITH ERECTILE DYSFUNCTION

SUMMARY STATEMENT

A. PSYCHOGENIC ERECTILE DYSFUNCTION

I. MAJOR SEXUAL FUNCTION INSTRUMENTS IN CURRENT USAGE

B. ERECTILE FUNCTION AND DYSFUNCTION: A CONTEXTUAL VIEW

II. GENERAL PSYCHIATRIC EVALUATION

ABSTRACT - SUMMARY III. RECOMMENDATIONS I. INTRODUCTION REFERENCES II. THE DISTINCTION BETWEEN “REFLEXIVE” AND “PSYCHO-GENIC” ERECTION

E. PRACTICAL GUIDELINES FOR GENERAL UROLOGICAL PRACTICE

III. THE PHYSIOLOGY OF ERECTION VARIES WITH CONTEXT

ANNEXES

IV. THE DISTINCTION BETWEEN “ORGANIC” AND “PSYCHOGENIC” ERECTILE DYSFUNCTION

I. INTERNATIONAL INDEX OF ERECTILE FUNCTION QUESTIONNAIRE II. THE C-MASH

C. PSYCHOLOGICAL ISSUES IN DIAGNOSIS AND TREATMENT OF ERECTILE DYSFUNCTION (ED)

III. ARIZONA SEXUAL EXPERIENCES SCALE ( ASEX ) -MALE IV. MARITAL-ADJUSTMENT TEST V. THE F.E.A.R.

REFERENCES

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Psychological Issues in Diagnosis and Treatment A. MELMAN S. LEVINE, B. SACHS, T. SEGRAVES, M.F. VAN DRIEL

utilized would be to assist the clinician in the assessment of patients with sexual dysfunction. In these cases, the instrument might be used to guide the clinical interview to problem areas and to help identify problem areas that the clinician might otherwise overlook. In such cases, brevity of the instrument and its formal psychometric properties might be of less importance as the clinician would not necessarily be using the instrument as the primary assessment intervention. It used be emphasized that attempts to use psychometric instruments to establish psychological characteristics of men with psychogenic erection problems have generally be unsuccessful. Structured interviews focusing on presenting symptoms have shown promise as generalized screening instruments indicating when further organic assessment is indicated or when a psychological etiology can be safely assumed.

SUMMARY STATEMENT

Urologists who treat patients with erectile dysfunction should be sensitive to the emotional meanings patients unconsciously attach to that problem. In addition, because intercourse involves two people it is important, if possible, to include both the patient and his sexual partner in both the diagnosis and the planned treatment. The treating physician should try to get the partner involved early in the process of diagnosis and treatment. That participation enhances communication, enhances reliability of the history, and can reduce stress and anxiety for all involved. Education of the couple is important. One should explain in detail, verbally and with educational tools, the mechanism of erection and the multicausal nature of erectile dysfunction. Any myths concerning penile erection should be dispelled. It should be emphasized that almost everyone has a psychological reaction to erectile dysfunction even when the cause is primarily a physical one. A variety of self-report questionnaires are available for the assessment of patients with erection dysfunction and there is some overlap between questions asked in different questionnaires. These questionnaires can be assessed by consideration of their psychometric properties, the availability of validated instruments in various languages, the brevity of the instrument, whether the instrument has been shown to demonstrate effects of pharmacological interventions, and the purpose the clinician or investigator has for the use of the instrument Another purpose for which an instrument could be

A problem facing the non-psychiatric physician in the evaluation of patients with erectile disorder is the co-morbidity of sexual disorders with certain psychiatric syndromes. Although, various treatment approaches may reverse erectile failure in psychiatric patients, the clinician would not want to miss an underlying treatable and possibly fatal psychiatric disease such as major depressive disorder and panic disorder. Both of these disorders have high suicide rates. A number of studies have repeatedly demonstrated that general physicians under diagnose psychiatric disorders such as depression and anxiety disorders. The primary conditions which the physician needs to screen are depression and anxiety disorders. A variety of general surveys for the measurement of depression

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anxiety are available but are too long to be easily incorporated in a practice setting. Recent research suggests that two questions are sufficient for brief screening of depression. These could be incorporated into a questionnaire format.

A. PSYCHOGENIC ERECTILE DYSFUNCTION PSYCHOGENIC ERECTILE DYSFUNCTION FALLS INTO TWO BROAD NATURAL VARIETIES:

The questions are: 1) During the past month, have you often been bothered by feeling down, depressed or hope less? 2) During the past month, have you often been bothered by little interest or pleasure doing things? Anxiety can be rapidly screened by using the Fear, a rapid screening instrument for anxiety consisting of four questions. Two other issues that the urologist might want to address are dependent on the cultural context. If the primary sexual partner is the spouse and if considerable marital discord is present, the urologist might want to consider referral for counseling as well as correcting the erectile problem. A reasonably rapid tool for screening for the presence of marital discord is the Locke Wallace Marital Adjustment Test, a 15 item questionnaire requiring minimal time to complete. The advantage of a standardized questionnaire is that it may pick up information that the clinician or investigator might otherwise overlook. For example, it is not uncommon for a man to complain of impotence when it is not the primary problem. Some men may complain of impotence when the major problem is premature ejaculation for which alternative treatments are available. Also, men with decreased libido may complain of impotence when the problem is primarily decreased libido. In such cases, the clinician would probably want to consider endocrinological etiologies of the problem. Also some men will complain of impotence because of unrealistic performance expectations. Each of the treatment options, including sex and marital theraapy, and their risks should be discussed and made available the patient and couple. It is very important to let the patient know that if one treatment fails that other therapies can be used and that penile implant surgery is available as the ultimate choice if less invasive choices fail.

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Lifelong and Acquired. Lifelong Psychogenic Erectile Dysfunction has a lower prevalence, a far more complicated pathogenesis, and a lower treatment response rate than acquired varieties. Lifelong patterns among heterosexuals are generally associated with hidden unconventional sexual identity patterns—such as transvestism, gender identity disorder, homosexual orientation, paraphilia—profound fear of closeness to women because of egregious difficulties as a child with parents, or extreme religious orthodoxy associated with obsessive-compulsive disorder. Lifelong Psychogenic Erectile Dysfunction is often best dealt with directly by a mental health professional, but even with these professionals the underlying disorder often proves to be incompletely reversible. The use of the diagnosis of Acquired Psychogenic Erectile Dysfunction implies that the patient has at some period in his adulthood been capable of adequate erectile function with a woman. Men develop Acquired Psychogenic Erectile Dysfunction in response to an array of precipitating circumstances: job loss, relationship deterioration, divorce, loss of physical or mental health, loss of partner’s health, personal or partner infidelity, panic about sexual decline, guilt over hidden addiction, failure to overcome another sexual dysfunction, etc. As performance anxiety is a final common pathway in most forms of ED, and particularly psychogenic ED, the precipitating cause is typically not the only contribution to the pathogenesis of the problem. Mental health interventions can often be effective in restoring men with Acquired Psychogenic Erectile Dysfunction, but psychotherapy cannot be expected to erase the impact of the forces that created the problem in the first place, particularly if the therapy consists only of a few sessions. Often in pursuing the reversal of Acquired Psychogenic Erectile Dysfunction, the therapy focuses for a while on marital problems, improving mood, coping with guilt and disappointment, supporting a man through a job search that is, the therapy focuses on nonsexual matters.

For all practical purposes, the diagnosis of psychogenic ED is made most often in men <50 years old and some significant organic contribution is assumed in those>50 years of age. This overly simple clinical distinction reflects the more basic fact that there is a widespread sexual physiological decline that occurs in healthy men during their 50s. ED is most strongly correlated with age in both physically healthy men and patients with various forms of cardiovascular disease. This makes it difficult to assign with certainty an etiology to many men with ED in their late 50s and beyond. Much ED is probably a mixed etiology of aging, disease, medication, psychological, and interpersonal factors. Clinicians should consider using the term «presbyrectia» to describe the patient in his late 50s or older who complains of recent steadily declining potency who lacks any apparent dramatic organic or psychogenic cause for his ED. This diagnosis recognizes that as men age they often lose reliable erectile function associated with a subtle decline of sexual drive. They are entering an era of less efficient sexual functioning. Presbyrectia implies that aging is the cause—not vascular disease, diabetes, spinal cord trauma, prostatectomy, etc. Presbyrectia can coexist with cardiovascular disease without implying, for instance, that the patient’s remote inferior wall myocardial infarction is part of the same process that creates erectile dysfunction.

3) whether the lumbosacral spinal cord is sufficient to maintain that class of erection or whether the brain is also involved. Inherent in the original distinction was the idea that different stimuli promote erection through different physiological systems. This view has not been confirmed for the classic example, the differential role of the hypogastric nerve. However, there is compelling evidence that the neural, endocrine, and neurochemical mediation of erection varies with the context in which erection occurs. If the psychogenic-reflexive distinction is flawed, so too is the one between psychogenic and organic erectile dysfunction (PED and OED). Because it is axiomatic that all mental processes have an organic basis, PED means little more than OED of unknown brain origin. The diagnosis of PED is often arrived at by subtraction (no identifiable organic dysfunction) and by evidence that erection is present in some contexts (e.g., sleep), but not in others. Therefore, “situational erectile dysfunction” (SED) is recommended as a more descriptive alternative to PED. By implication, another term should replace OED. Some pharmacological treatments may be no less effective in treating SED than OED, and their differential efficacy may promote an understanding of the organic origins of SED. Conversely, effective psychotherapeutic approaches to SED may act in part by modifying brain chemistry.

B. ERECTILE FUNCTION AND DYSFUNCTION: A CONTEXTUAL VIEW

I. INTRODUCTION Among the traditional distinctions made by professionals concerned with the process of erection are those between “reflexive” and “psychogenic” erection and between “organic” and “psychogenic” erectile dysfunction. Each of these distinctions is flawed and probably counterproductive in gaining understanding of the processes underlying erectile function and dysfunction. Closer attention to the context, or situation, in which erection occurs or fails to occur offers an alternative to the traditional distinctions, an approach that furthers research into the underlying mechanisms.

ABSTRACT - SUMMARY There is increasing recognition that the traditional distinction between reflexive and psychogenic erection is based on false assumptions and has little utility. This distinction in fact identifies only 1) whether tactile or nontactile stimulation is involved, 2) which peripheral afferent nerves mediate the erection, and

This approach may also offer a useful alternative terminology.

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dependent regulation of erection was first developed with regard to the peripheral nerves, it seems reasonable to start by revisiting some of this evidence.

II. THE DISTINCTION BETWEEN “REFLEXIVE” AND “PSYCHOGENIC” ERECTION The utility of the terms “reflexive” and “psycho genic” erection is questionable, as is the interpretation of the evidence that gave rise to the distinction between them [1]. Erections in response to perigenital touch were termed reflexive because these erections only require an intact lumbosacral spinal cord; higher central nervous system lesions facilitate these erections or have no effect. As spinally mediated responses, it was assumed that reflexive erections were simpler than psychogenic erections, whose processing requires the cranial nerves and the brain. However, there is no evidence that touch-based erections necessarily (1) have shorter latencies than erections in response to nontactile stimuli, or (2) have fewer synapses between stimulus and response, or (3) have less complex interactions among excitatory and inhibitory systems, or (4) are less affected by cognitive processes, all of which are implied by the term “reflex.” In fact, the reflexive-psychogenic distinction is simply a statement that different sense modalities mediate the respective erections, and that there is a resultant difference in the afferent nerves and relevant portions of the central nervous system. Despite these problems, there may be a useful kernel to take from this distinction, namely that the physiology of erection varies from one context to another, and may do so in ways more fundamental than the particularity of the afferent nerves carrying the proerectile stimuli or whether the spinal cord can mediate erection when separated from the brain. Some examples may prove useful.

III. THE PHYSIOLOGY OF ERECTION VARIES WITH CONTEXT

1. PERIPHERAL NEURAL REGULATION There is a widespread view that the primarily parasympathetic pelvic nerves mediates touch-based (reflexive) erection, whereas the primarily sympathetic hypogastric nerves (HgN) mediate nontactile (psychogenic) erections. This hypothesis is mainly based on research in which electrical stimulation of HgN led to penile tumescence in dogs, cats, and rabbits. (For reviews see [2,3]). Reports on erectile function in paraplegic men were also used to support the idea that there are at least two proerectile pathways which, depending on context, are differentially involved in erection [4]. Recent evidence, however, indicates that the HgN does not serve a proerectile function in any context, at least in rats. Stimulation of the HgN of intact males does not result in erection in this species [5], and HgN transection does not impair erections resulting from hypothalamic stimulation [6]. Also, transection of rat HgN does not affect erection in response to remote cues from females [7], a context analogous to psychogenic erection [8]. At present, there is no good evidence that the HgN has a normal proerectile function in intact males of any species, or that the pelvic and hypogastric nerves differentially mediate erection in different contexts. It is doubtful – but not inconceivable – that there is a species difference between rats and other tested mammals regarding the erectile role of the HgN. Nonetheless, in view of the evidence from rats, the burden of proof is now on demonstrating a proerectile function for the HgN in normal, intact males.

2. ENDOCRINE REGULATION In contrast with the weak case for context dependency in the peripheral efferent nerves mediating erection, there is strong evidence for differential endocrine regulation. It is widely understood that normal penile erection depends on androgenic steroids, especially testosterone (T), and castration of adult males impairs erection [3]. However, there is ample evidence of erectile function surviving the

The idea that the physiology of erection varies from context to context is not new; indeed, its foundations were laid at least 50 years ago. However, recent research has cast doubt on some of those foundations, while providing substantial new evidence. Because the principle of context-

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absence of gonadal androgen. Even when T is present, the effective metabolite of this hormone may vary with the erectile context: either dihydrotestosterone (DHT) or estradiol (E2) can support penile erection.

intact. Doubt about an erectile function for the mPOA stems from lesion experiments that have demonstrated that the rat mPOAis dispensable for touch-based erection [16] and for NCE [17]. To be sure, these studies do not rule out a role for the mPOAin the normal mediation of erection; rather, the mPOAmay be a redundant part of two or more parallel proerectile pathways.

Prepubertal boys provide an obvious example of erection in the absence of androgen. From soon after birth to near the onset of puberty, plasma T in boys is very low and indistinguishable from that of girls [9], but throughout these years the penis exhibits sleep-related and touch-based erection [10,11]. Another clear example of androgen-independent erection is the ability of castrated male rats to continue to copulate indefinitely if they are treated with large doses of E2. Despite atrophy of the penis and other androgen-dependent structures, the males nonetheless gain intromission at about the same rate as intact males [12]. Even female rats treated with E2 can exhibit the motor patterns of intromission and ejaculation, though of course there is no ejaculate [13]. As noted above, rats exhibit behavior analogous to “psychogenic” erection, in that they have erec tions when exposed to remote cues from estrous females [8]. Recently, we asked which steroids would support these noncontact erections (NCEs) [14]. No males had NCEs after castration, even in the first test three days after surgery. Males receiving treatment T or DHT two weeks after castration resumed NCEs within 3-6 days, whereas males receiving E2 or no hormone had no NCEs. Clearly, NCE and touch-based erections are androgen-dependent erectile contexts for rats, whereas erection during copulation is indepen dent of androgen.

3. CENTRAL NEURAL REGULATION Medial preoptic area (mPOA). Male copulatory behavior in all vertebrates is critically dependent on an intact mPOA, where lesions prevent males from mounting receptive females [3]. But as important as the mPOA is for copulation, it appears to be superfluous for penile erection. The inference that the mPOA has some role in erection has been based on research in which direct stimulation of the mPOA has resulted in penile tumescence [e.g., 6,15]. However, the stimulation in those experiments may have acted indirectly via other brain areas, since all the connections of the mPOA with other brain areas were

Medial amygdala (mAm). Lesions of the mAm impair copulatory behavior. Sexually inexperienced male rats with such lesions may not copulate at all [18], and sexually experienced rats are less likely to achieve ejaculation [19,20]. Is the mAm, like the mPOA, superfluous to erection? The answer depends on the erectile context. Lesions of mAm do not reduce erectile competence during copulation, at least as measured by the percentage of mount attempts that result in intromission [19,20]. Touch-based erections are also unaffected by mAm lesions, but NCEs are dramatically impaired [20]. In brief, some areas of the brain may be considered to be organs of erection in some contexts but not in others.

4. NEUROCHEMICAL MEDIATION Dopamine is one of the most frequently studied of the neurotransmitters that regulate sexual activity, but its role in sexual behavior is incompletely understood, especially in relation to penile erection and ejaculation. The general view that dopamine facilitates erection comes from drug-injection studies and from research showing that brain dopamine increases during sexual activity or even exposure of males to sexual stimuli [3,21,22]. At issue is which specific dopamine receptors mediate the erectile response. Dopaminergic agents such as apomorphine that bind to both D1 and D2 receptors clearly increase the probability of erection in rats and humans [23]. However, conflicting views have emerged from research using drugs that act more specifically on D1 or D2 receptors. Some investigators view stimulation of D1 receptors as excitatory for erection, and activation of D2 receptors as inhibitory [21,24]. Others have come to exactly the opposite conclusion [25]. These conflicting conclusions have emerged from research in different laboratories in which opposite effects have been observed in rats after treatment with the same or similar drugs. Naturally, many procedural differences distinguish the research in

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these laboratories, but especially noteworthy are differences in the context in which erection was observed. Those who attribute proerectile function primarily to D2 receptors [25] have observed freely moving solitary rats (i.e., drug-induced erection with no sexual context). Those who ascribe prorectile influence primarily to D1 receptors have studied either copulation and touch-based erection in rats [21], or have observed rhesus monkeys during noncontact erection tests [24]. It may well be that the competing hypotheses of dopaminereceptor function are not mutually exclusive. Rather, the relative dependence of erection on D1 and D2 receptors may depend on the context in which erection is evoked.

In view of the evidence reviewed above, it now seems clear that there can be organic dysfunction in various areas of the brain that could affect erection in some contexts while leaving sleep-related erection undisturbed. Certain origins of ED are unambiguously organic in origin, e.g., neural pathology due to spinal cord injury or vascular problems due to diabetes. But in many cases the diagnosis of PED neglects the richness of our understanding of physiological psychology and the true implication of the term “psychosomatic.” Simply put, it is axiomatic that all mental processes have an organic basis. It fol lows that there can be no psychogenic dysfunc tion that does not have an organic origin. Paradoxically, by current terminology, research into the physiology of PED translates into the search for the organic basis of a nonorganic disorder.

In summary, there is ample evidence for contextdependent variation in the physiological systems that mediate erectile function. A skewed picture of the erectile role of any given system can be avoided only by testing males in multiple contexts, rather than overgeneralizing from tests in one or two contexts.

IV. THE DISTINCTION BETWEEN “ORGANIC” AND “PSYCHOGENIC” ERECTILE DYSFUNCTION If the physiology of erectile function varies signi ficantly from one context to another, then it fol lows that the physiology of erectile dysfunction (ED) may also vary from context to context. This principle is implicitly recognized in some tests used by clinicians to determine whether instances of ED are due to “organic” or “psychogenic” causes (OED and PED respectively). Too often, however, this differential diagnosis is made by subtraction, i.e., in the absence of evidence for organic dysfunction, PED is assumed. For decades, sleep-related erection (also called nocturnal penile tumescence) has been the primary test for this differential diagnosis [26]. If men had normal sleep-related erection, then the erectile physiology was assumed to be functioning normally, and ED with a sexual partner was assumed to be psychogenic. However, the occurrence of normal sleep-related erection only demonstrates normal function of the penile corpora and the related blood vessels, peripheral nerves and spinal cord.

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The problem, in any case, is to identify the organic basis of PED in light of our very limited knowledge of central mechanisms of erection, but some first steps are promising. It is increasingly understood that erection and detumescence reflect an algebraic summation of neural pro- and anti-erectile influences [e.g., 3,6,10]. Failure to achieve erection in the presence of adequate excitatory influences can result from an excess of inhibitory influences, which may include such normal factors as postejaculatory refractoriness and side effects from drugs (e.g., beta-adrenergic blockers). However, a net inhibition of erection can also result from “psychogenic” factors arising from the sexual situation: a too-public place, a concern about disease or pregnancy, or performance anxiety (e.g., about erectile function or rapid ejaculation). In extreme cases, masturbation may be the only waking context in which the net of excitation over inhibition is sufficient to achieve and maintain erection. But it bears repeating that in all such cases of “psychogenic” ED there are, axiomati cally, physiological mechanisms underlying this dysfunction. These mechanisms may well be imperfectly understood or even awaiting discovery, but they are no less organic than the effects of diabetes or prostate surgery, and no more “all in your mind” than such centrally acting conditions as hypogonadism or hyperprolactinemia, which also impair erection. It should also be noted that because a man’s concern about his sexual perfor-

mance is likely to increase with each episode of erectile inadequacy, performance anxiety is probably a major aggravating factor even when the initial cause of ED is clear organic pathology of proerectile systems. (It has been said that “fear” is the first time a man can’t do it twice; “panic” is the second time he can’t do it once.) If “psychogenic erectile dysfunction” means nothing more than that the problem has its origin in undetermined brain dysfunction, then the term should be changed to reflect that meaning. Because of the indeterminate causes of PED, “idiopathic erectile dysfunction” may be a sui table term. However, because the diagnosis of this condition depends so much on determining the contexts in which dysfunction occurs, I recommend the adoption of the term “situational erectile dysfunction” (SED). Diagnosis and treatment of SED clearly presents a major challenge, but even when an organic cause for a sexual problem is not identifiable, that does not mean that there is not an organic cure for it. For example, acetylsalycilic acid (aspirin) treated pain effectively long before its action on prostaglandin was understood. For a more relevant example, consider developments in the treatment of another common sexual dysfunction, namely rapid ejaculation. (The former term, “premature ejaculation,” is considered pejorative.) This problem has usually been assumed to be “psychogenic,” and men have commonly been referred for psychotherapy to treat the condition [27]. However, it seems quite plausible that men who routinely ejaculate rapidly are outside of the normal male range with respect to the brain chemistry that regulates ejaculation. It should not surprise us, then, that serotonergic and anti-adrenergic drugs offer help in most such cases [28,29].

(e.g., depression, obsessive-compulsive disorder) that are commonly called “mental” disorders. So too it seems likely that as we gain greater unders tanding of the neurochemistry of erection, drug treatments will increasingly become available to treat SED. Furthermore, the differential efficacy of these treatments (e.g., via action on particular receptors) may promote our understanding of the organic origins of SED. However, the advent of effective medical treatments for SED should not be interpreted as denying the utility of various psychotherapeutic approaches. Just as psychotherapy for other “mental disorders” can normalize the brain physiology that characterizes such disorders [30], so too it is reasonable to infer that effective psychotherapy for ED [27] acts by increasing the balance of excitation over inhibition. If it is conceded that “psychogenic erectile dysfunction” means little more than “organic erectile dysfunction of unknown brain origin,” then it follows that all ED is of organic origin, and an alternative to the term “organic erectile dysfunction” is desirable. One option is to classify ED by the tissue(s) thought to be primarily responsible for the disorder, e.g., neuropathology, vascular disorder, penile mechanics, neuroendocrine function, and so on.

REFERENCES

SED may similarly reflect abnormal brain neurochemistry. And again, even without understanding the physiology of SED, pharmacological treatments are increasingly available to change the balance of the excitation-inhibition equation. At present these drugs (e.g., alprostadil, sildenafil) are thought to act primarily on peripheral tissues, but agents presumed to act on the central nervous system (e.g., apomorphine) are under investigation. Drugs have proliferated for the treatment of several neurochemical dysfunctions of the brain

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2

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3

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4

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CRUZ MR, LIU Y-C, MANZO J, PACHECO P, SACHS BD: Peripheral nerves mediating penile erection in the rat. J. Auton. Nerv. Syst. 1999;76:15-27.

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8

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20

KONDO Y, SACHS BD, SAKUMA Y: Importance of the medial amygdala in rat penile erection evoked by remote stimuli from estrous females. Behav. Br. Res. 1997;88:153-160.

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HULLEM: Dopaminergic influences on male rat sexual behavior. In Micevych PE, Hammer R (eds) "Neurobiological effects of sex steroid hormones." Cambridge: Cambridge Univ. Press, 1995:234-253.

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24

POMERANTZ SM: Monoamine influences on male sexual behavior of nonhuman primates. In Bancroft J (ed) "The pharmacology of sexual function and dysfunction." Amsterdam: Elsevier, 1995:201-211.

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25

ZARRINDAST M-R, SHOKRAVI S, SAMINI M: Opposite influences of dopaminergic receptor subtypes on penile erection. Gen. Pharmacol. 1992;23:671-675.

14

MANZO J, CRUZ MR, HERNANDEZ ME, PACHECO P, SACHS BD: Regulation of noncontact erection in rats by gonadal steroids. Horm. Behav. 1999;35:264270.

26

BENETAE, REHMAN J, HOLCOMB RG, MELMAN A: The correlation between the new Rigiscan Plus software and the final diagnosis in the evaluation of erectile dysfunction. J. Urol. 1996;156:1947-1950.

15

COURTOIS FJ, MACDOUGALL JC, SACHS BD: Erectile mechanism in paraplegia. Physiol. Behav. 1993;53:721-726.

27

HEIMAN JR, MESTON CM: Empirically validated treatment for sexual dysfunction. Ann. Rev Sex Res. 1997;8:148-194.

16

STEFANICK ML, DAVIDSON JM: Genital responses in noncopulators and rats with lesions in the medial preoptic area or midthoracic spinal cord. Physiol. Behav. 1987; 41:439-444.

28

BALON R: Antidepressants in the treatment of premature ejaculation. J. Sex Marital Ther. 1996;22:85-96.

29

HAENSEL SM, KLEM TM, HOP WC, SLOB AK: Fluoxetine and premature ejaculation: a double-blind, crossover, placebo-controlled study. J. Clin. Psychopharmacol. 1998;18:72-77.

30

SCHWARTZ JM, STOESSEL PW, BAXTER LR JR, MARTIN KM, PHELPS ME: Systematic changes in cerebral glucose metabolic rate after successful behavior modification treatment of obsessive-compulsive disorder. Arch. Gen. Psychiat. 1996;53:109-113.

17

18

LIU Y-C, SALAMONE JD, SACHS, BD: Lesions in medial preoptic area and bed nucleus of stria terminalis: Differential effects on copulatory behavior and noncontact erection in male rats. J. Neurosci. 1997;17:52455253. KONDO Y: Lesions of the medial amygdala produce severe impairment of copulatory behavior in sexually inexperienced male rats. Physiol. Behav. 1992;51:939943.

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end result of current available therapies to create an erection are so successful.

C. PSYCHOLOGICAL ISSUES IN DIAGNOSIS AND TREATMENT OF ERECTILE DYSFUNCTION (ED)

The search for the answer is contingent on several factors that are independent of the physician’s therapeutic ability to create penile rigidity. Both LoPiccolo [1] and Mohr and Beutler [2] have emphasized that formulation of the best treatment plan is the primary purpose of the diagnostic assessment. The prognosis of the effects of therapy as determined by assessment of the patient and sexual partner is of paramount importance in the specific recommendation for therapy. That raises the question how can one assess the prognostic application of a therapy in goal directed treatments if absolutely no assessment is done of the patient and sexual partner. Furthermore, as many as 25% of men who present themselves to the Urologist’s office only want information and not therapy for their problem. They will not use therapy of any type offered to them. Those men will drop from the therapy program and will be incorrectly viewed as treatment failures if follow-up questioning is done.

A 55 year old man is seen in the office because of a sexual problem. A careful, focused medical history reveals that he has hypertension treated with a beta-blocker, recent onset adult onset diabetes controlled by diet and recently married to a woman 12 years younger than he. He says he is not able to achieve and maintain an erection sufficiently hard to have coitus and wants to be treated. His states that his wife not complaining about his inadequate erections but he feels that he is letting her down sexually. By the way,” he says, “he is somewhat disappointed with her because since his marriage she has had breast implants removed and not replaced without asking his advice.” That vignette is an actual history. The complexities of the story typify the dilemma that physicians who treat the problem of erectile dysfunction must deal with. ED in most cases is a couple’s problem and its evaluation and treatment should be thought of in that way by both the patient and the physician.

The interaction of conscious and unconscious stimuli from the brain, i.e., the psychological effect, on erection and 2) the patient (and partner’s) need for treatment, preference of treatment, and satisfaction with the treatment must be taken into consideration. In addition, there is the issue of the physician’s obligation to offer the patient the most appropriate (and successful) treatment particularly if the condition is reversible as is true with psychogenic ED.

At the present time, the availability, effectiveness and ease of administration of oral medication as first line therapy for the treatment of ED has for many diminished the need to diagnose the cause of the problem. Moreover, Viagra, the only oral agent approved by the United States Food and Drug Administration for treating erectile dysfunction is particularly successful in treating men with psychological, i.e., normal endorgan, causes of the ED. The issue of treatment without evaluation is further compounded by the cost (of diagnostic tests, physician charges, time lost from work) and time (multiple visits to the office) needed to establish an accurate diagnosis. During an era of increased pressure by government agencies insurance payers, or the simple absence of resources in developing countries, to limit medical costs there are further demands to offer a “goal directed” (i.e, limited, rapid and cheap) approach to treatment. Thus, the question is what evaluation, if any, is either needed or necessary to establish the case for a psychological cause of erectile dysfunction in a man seeking treatment for the problem when the

We are presently in an era when there is great emphasis on penile failure as a cause of ED. There are several recently published studies that document the high incidence of erectile dysfunction that occur with aging in the general population. These studies, which emphasize the physical nature of the problem, are in contrast to the psychological predominance of diagnoses of only two or three decades ago. Despite the swing of the medical pendulum to the physical nature of ED, the importance of the effect of the brain on erectile mechanisms in healthy and aging men cannot be overlooked. Reports in this section by Sachs, highlight the effect of central inhibitory stimuli on penile erection. Those inhibitory signals from the erectile center of the brain translate into increased release of contractile neurotransmitters by nerve fibers in the penis that cause smooth muscle contraction. In the penile corpora 415

contraction results in a flaccid penis and if the tone is sufficiently high, ED is the outcome. Functional antagonism in the penis is a concept developed in our laboratory (see Lerner et al. [3]), shown in figure 1, that describes the effect of diverse mechanisms on the physiology of erection.

favors contraction over relaxation. The clinical correlate is the patient with performance anxiety. The high outflow of the catecholamines norepinephrine and epinephrine, that are present in the fight or flight anxiety state, causes the penis to remain contracted even in presence of the most intense sexual stimuli. ED is the visible result.

This figure highlights the interplay of contractile and relaxant forces on the penile smooth muscle and what might happen when aging, disease, or an overabundance of contractile agonists impacts upon those muscle fibers.

In an important study by Lo Piccolo [5] he determined the etiology of erectile failure in 63 men independently evaluated for the degree of psychological and organic impairment. That evaluation followed complete psychological, vascular, hormonal, neurological, and NPT determinations. Three clinicians separately reviewed the clinical and psychological data and each arrived at a score ranging from 0 (purely psychological) to 4 (purely organic). The results showed that the vast majority of men had combinations of problems of organic and psychological etiology. In fact in that group only 10 of the men were diagnosed with pure psychogenic and 3 with a purely organic etiology. In a similar study in which the patients were referred to a Urologist’s office the breakdown in diagnosis was pure organic (28.8%, pure psychogenic 39.7%, mixed 25.1% and unknown 6.4%. The implication is that even in men with clear physical causes of their erectile component there are psychological issues that can cloud the results of medical therapy. Lo Piccolo has emphasized that erectile failure is a continuum with a small percent

This concept is further documented in a paper by Taub et al. [4] In that report strips of erectile tissue obtained at surgery from two types of patients were studied in an organ bath (figure 2). One patient (triangles) had normal erectile activity the other (closed circles) had ED caused by diabetes. Both tissues were maximally contracted with the α-agonist phenylephrine and then made to relax with the addition of the nitric oxide donor nitroglycerine to the organ bath. At every level of prior contraction the corporal tissue from the man with ED relaxed less that the tissue from the control patient in response to the same relaxation stimulus. Moreover, even the normal tissue could not be relaxed more than 60% of its maximal response in the presence of the maximal contractile stimulus. This in vitro study demonstrates the in vivo response of the smooth muscle fibers of the corpora

FUNCTIONAL ANTAGONISM In the normal state smooth muscle relaxation allows erection to occur ERECTION ERECTION DYSFUNCTIONAL ANTAGONISM Two little relaxation or augmented contraction causes erectile dysfunction Incomplete relaxation ED Heightened contraction Figure 1: Functional Antagonism

Figure 2: Strips of Erectile Tissue Obtained at Surgery from Two Types of Patients are Studies in an Organ Bath

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of men with a pure state at the extreme ends and the majority with mixed conditions in the center.

and dysfunctional men subjected to both erotic and anxiety inducing stimuli [10].

In a new study reported by Lee et al., from Kingston, Ontario, Canada [6] the authors sought to identify the number of men with psychopathology in a group referred to the institution’s Urology Department for ED. The prevalence of significant psychiatric disease was as high as 33% (40/120). 37.5% of that group suffered from major depression, and 10% were schizophrenic. The report highlights the need to identify the presence of psychological issues during the focused history taking. The identification of depression, schizophrenia, drug and alcohol abuse require that those problems be treated before an effort is made to correct the ED.

Those results are summarized in the flow diagram shown below. If it is the intent of the treating physician and the goal of the patient that therapy be as specific as possible the results of these important studies emphasize the importance of not relying solely on the patient’s self-reported history to establish an accurate diagnosis. The presence of a psychogenic cause for the ED has several implications. Clearly whatever treatment is employed may have a high rate of success because of the possibility of placebo effect and the fact that the end organ tissues are capable of erection as a result of the therapy because there is no end organ disease. More important, is that the psychological cause of the problem might be related to inner or self-directed issues (such as lack of esteem or performance anxiety) that might be overridden by an effective medical therapy. However, the psychological problem could also be caused by relationship issues for which the ability to have an erection might not have a corrective effect and thus lead to continued dissatisfaction with sex.

Recently, the advent of self-administered tests to categorize the presence of ED by symptom score has come into vogue. The prominent use of the brief sexual function inventory and the use of the International Index of Erectile Function (IIEF) [7] during the Viagra trials has promulgated the use of such devices not only to test the effect of therapies upon the erectile condition but to describe the erectile condition based upon the patients observations of his erectile capacity. The question is whether men with psychogenic erectile dysfunction are good observers of their erectile capacity or do they tend to minimize their erectile capacity for a range of reasons. That question was addressed in a report by Davis-Joseph et al., [8] who studied the accuracy of a formal history of sexual function and general physical examination to establish a diagnosis for the cause of ED. The study was completed in 45 men with a mean age of 57 years. Most importantly 20% of men initially diagnosed with organic ED because of their history were eventually classified as having normal erectile capacity after multidisciplinary testing. Others have also studied this underreporting of erectile capacity. In their recent review Ackerman and Carey [9] note that the affect associated with ED such as performance concerns and apprehension can lead to interference and distraction from erotic cues. Barlow ha shown that men with ED underestimate the amount of erection response and decreased their erection response when demands to obtain an erection were made upon them. Barlow also has outlined the results on the erectile ability of several studies of sexually functional

The importance of interviewing the wife or sexual partner for diagnostic and therapeutic reasons is well documented. Ackerman and Antoni [11] found that wives in troubled marriages were not able to corroborate their husband’s self-reported erectile function symptoms. There may be as much as a 50% discrepancy in the history given by the sexual partner of the men who are seeking therapy when the interview is done as a separate, private confidential process [12]. The major discrepancies noted are duration of the problem, drug, smoking, and alcohol intake, marital issues and satisfaction; these items are summarized in Table 1 and figure 3. Outcome of successful treatments for ED with vacuum devices, intracavernous injection therapy, intraurethral therapy, and penile prosthetic implants have shown durable responses with enhanced satisfaction, higher levels of arousal and frequency of intercourse in the female partners [14,15]. However, none of the reports however documented the response to any of the therapies when marital dissatisfaction with the relationship is the primary issue. There is no published data 417

Table 1: Specifics of patient-partner Discrepancies

1.

2.

3. 4.

5.

6.

NATURE OF SEXUAL PROBLEM 20% (8 CASES) Patient says erectile difficulty, partner says: Inhibited desire Normal age changes Retarded ejaculation

3 cases 2 cases 2 cases 1 cases

DURATION OF SEXUAL PROBLEM 30% (12 ) Patient’s estimate longer Partner’s estimate longer

3 cases 9 cases

PATIENT’S DRUG/ALCOHOL HISTORY 8% (3 Partner’s estimate longer MARITAL SATISFACTION Patient’s estimate greater Partner’s estimate greater

CASES)

3 cases

45% (18 CASES)

PARTNER’S SEXUAL INTEREST 25% ( 10 Patient says partner interested/ Partner disagrees Patient says partner not interested/ Partner disagrees

6 cases 12 cases CASES)

3 cases 7 cases

OTHER Discrepant medical history Discrepancy in additional sexual problems Discrepancy in adequacy of current function Discrepancy in recount of previous sex therapy

4 cases 8 cases 2 cases 3 cases

Figure 3: Types of Discrepancy Between Patients and Partners . (adapted from Tiefer, L., and Melman, A. Sexuality and Disability 3/4167-175,1983. [13])

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FUNCTIONALS (Positive Feedback loop)

DYSFUNCTIONALS (Negative Feedback Loop)

Explicit or Implicit Demands for Sexual performance (e.g., a responsive Partner or other contexts) leading to Public expectation of performance (erection)

Positive affect and expectancies, Accurate reporting of Erections, perception of control

APPROACH

AVOIDANCE

Negative affect and expectancies, inaccurate underreporting of erection, Perceived lack of control

Attenional focus on erotic cues

Attenional focus on public Consequences of not Performing or other nonerotic issues

Increased autonomic arousal

Increased autonomic arousal

Increasingly efficient Attentional focus on erotic clues

Increasingly efficient Attentional focus on Consequences of not Performing

Functional performance

dysfunctional performance

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available as yet for long term satisfaction in the sexual partners of men on Viagra therapy.

Immigration, religion, ethnic background Medical and psychiatric history - Current levels of fatigue, pain - Current medications, smoking, alcohol, drugs

The knowledge of what one is seeking when questioning patients or patient sexual partners for psychological issues is necessary to be as accurate as possible. An excellent summary of the Psychological causes of sexual dysfunction by Hawton [16] and the topics to be covered in a psychosexual interview were recently outlined by reviewed by Tiefer and Scheutz-Mueller [17].

• Sexual history Childhood and adolescent sexual learning and activities Masturbatory history, specific practices Interpersonal sexual activity history Breadth and flexibility of sexual script with all partners

PYSCHOLOGIC CAUSES OF SEXUAL DYSFUNCTION • Predisposing factors Restrictive upbringing Disturbed family relationships Inadequate sexual information Traumatic early sexual Experiences Early insecurity in psychosexual role

• Current sexual function Current Masturbatory and interpersonal sexual activities (with all partners) Nature of problem ,onset, course, frequency, (with all partners) Spontaneous sexual experiences (e.g., morning erections)

• Precipitants Childbirth Unreasonable expectations Dysfunction in the partner Ransom failure Discord in the general relationship Reaction to organic factors Depression and anxiety Traumatic sexual experience Aging, infidelity

• Relationship harmony, communication, partner’s health Current/recent life stresses, losses Expectations and goals for evaluation and treatment Until 30 years ago the only therapy available for any type of sexual dysfunction was psychotherapy. Behavioral modification techniques have been employed most frequently in the past 25 years. Long-term, controlled, comparative outcome of that therapy is scant. The good prognostic indicators for successful outcome of psychotherapy has been recently reviewed by LoPiccolo [1]. The positive factors include: 1. The presence of lack of adequate sexual stimulation of the man by his partner; 2. the wife’s sexual satisfaction is dependent entirely on of knowledge of the couple of age-related changes in male sexuality; 4. unrealistic expectations of the male’s sexual capability, 5. relationship issues that give positive reinforcement to the man’s continued erectile failure. Hawton, has also noted that a good general relationship of the couple, a motivation for therapy, the quality of the sexual relationship despite the presence of the sexual problem and early engagement in home-work assignments led to a better outcome [ 18].

• Maintaining factors Performance anxiety Guilt Inadequate sexual information Psychiatric disorder Discord in the general relationship Loss of attraction between partners Fear of intimacy Impaired self-image Restricted foreplay Sexual myths Poor communication TOPICS COVERED IN PSYCHOSOCIAL INTERVIEW • Background variables Age, marital history, children Current living arrangement Educational level (social class assessment), occupation 420

Negative prognostic factors listed by LoPiccolo include:

tile dysfunction:new insights and more questions. J. Urology 149;1993:1246-1255.

1. An unwillingness on the part of either the man or his wife to reconsider male sex-role demands; 2. the presence of pedophilia or transvestism;

4.

TAUB HC, LERNER SE, MELMAN A, CHRIST GJ: Relationship between contraction and relaxation in human and rabbit corpus cavernosum. Urology 1993; 42:698-703.

5.

LOPICCOLO J: Post modern sex therapy for erectile failure. In: Rosen RC, Leiblum SR (eds):Erectile disorder:assessment and treatment. New York:Wiley Liss, 1992.

6.

LEE JC,SURRIDGE D,MORALES A, HEATON JPW. The prevalence and influence of significant psychiatric abnormalites in men undergoing comprehensive management of organic erectile dysfunction. IJIR (in press) ROSEN R, RILEYA, WAGNER G,et al. An international index of erectile dysfunction (IIEF);a multidimensional scale for assessment of erectile dysfunction. Urology 1997:49:822-830. DAVIS-JOSEPH, B, TIEFER, L, MELMAN, A. Accuracy if the initial history and physical examination to establish the etiology of erectile dysfunction. Urology 1995;45:498-502. ACKERMAN MD, CAREY MP: Psychology’s role in the assessment of erectile dysfrunction:Hoistorical Precendents, current t knowledge, and Methods. J Consulting and Clinical Psychology 1995;63:862-876.

3. extreme, deep seated religious beliefs; 4. clinical depression. In an unpublished follow-up study at our institution we observed that the majority of men who were thought to have a predominant psychological etiology of their erectile problem, who were referred for sex therapy refused the treatment. The men who came to the office seeking a physical cause of the problem did not want to believe that the problem was “in their head.” Most had no treatment of any type. They simply ignored the recommendation. Today the availability of Viagra ® will allow the internist or general practitioner to treat those patients prior to referall to a specialist. However, the relapse rate in those men in whom the basic problems that caused the ED in the first place will not be resolved. Hawton has emphasized that one of the most important outcomes of couples sex therapy is the teaching of the couple how to cope with relapse.

7.

8.

9.

10. BARLOW D: Causes of Sexual Dysfunction: The Role of Anxiety and Cognitive Interference. J Consult Clin Psychol. 1986;54:140-148. 11. ACKERMAN MD, ANTONI MH: Unhappy wives do not corroborate details of their husband’s erectile difficulties: Disparities in attribution of symptoms. Citation presented at the 15th annual scientific session of the Society of Behavioral Medicine. Boston ,1994.

In summary, in the awake male the brain and the penis function as a symbiotic unit. The physician who is trying to treat men with erectile dysfunction, be it of central nervous system or end organ origin must begin his evaluation with a detailed, structured interview of the patient and, if possible, his sexual partner. A thorough physical examination accompanied by physical and laboratory testing should be done that is consistent with the goals of the physician and patient. That triad history, examination, and testing will be help plan for appropriate successful and long lasting therapy.

12.

TIEFER, L., AND MELMAN, A., Inteview of wives: A necessary adjunct in the evaluation of impotence. Sexuality and Disability 1983: 6:167-175.

13. COOKSON MS, NADIG P. Long -term results with vacuum constiction device. J. Urology 1993;149:290. 14. TURNER LA, ALTHOF SE, LEVINE,SB, BODNER DR, KURSH ED AND RESNICK MI. Twelve-month comparison of two treatments for erectile dysfunction: self injection versus external vacuum devices. Urology 1992;39:139 –144.

REFERENCES

15

PEDERSEN, B., TIEFER L., RUIZ, M. AND MELMAN, A.: Evaluation of Patients and Partner One to four years following penile prosthesis surgery. J. Urology, 1988;139:956-958.

16

HAWTON K. Sex Therapy: practical guide . New York Oxford University Press. 1985 p 57.

1.

LOPICCOLO J: Psychological assessment of erectile dysfunction. Isis Medical Media Ltd. (eds): ATextbook of Erectile Dysfunction, Oxford: OS1 1ST, UK

17. TIEFER L. SCHEUTZ-MUELLER D. Pyschological issues in Diagnosis and Treatment of Erectile Disorders Urol Clin North America 1995:22:767-774.

2.

MOHR D, BEUTLER, L: Erectile Dysfunction: A Review of Diagnostic and Treatment Procedures. Clin Psychol Rev. 1990;10:123- 150.

18. HAWTON K AND CATALAN J. Prognostic factors in sex therapy. Behaviour Research and Therapy 1986; 24:377-385.

3.

LERNER SE, MELMAN A, Christ GJ.Areview of erec-

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plain of impotence when it is not the primary problem. Some men may complain of impotence when the major problem is premature ejaculation for which alternative treatments are available. Also, men with decreased libido may complain of impotence when the problem is primarily decreased libido. In such cases, the clinician would probably want to consider endocrinological etiologies to the problem. Also some men will complain of impotence because of unrealistic performance expectations.

D. QUESTIONNAIRE ASSESSMENT OF PATIENTS WITH ERECTILE DYSFUNCTION A variety of self-report questionnaires are available for the assessment of patients with erection dysfunction and there is some overlap between questions asked in different questionnaires. Each instrument has a slightly different focus, primarily reflecting the purpose for which the instrument was developed. These questionnaires can be assessed by consideration of their psychometric properties, the availability of validated instruments in various languages, the brevity of the instrument, whether the instrument has been shown to demonstrate effects of pharmacological interventions, and the purpose the clinician or investigator has for the use of the instrument. An instrument utilized in pharmacological trials might be valued more for brevity, demonstrable ability to pick up changes in function with pharmacotherapy, and its psychometric properties. Another purpose for which an instrument could be utilized would be to assist the clinician in the assessment of patients with sexual dysfunction. In these cases, the instrument might be used to guide the clinical interview to problem areas and to help identify problem areas that the clinician might otherwise overlook. In such cases, brevity of the instrument and its formal psychometric properties might be of less importance as the clinician would not necessarily be using the instrument as the primary assessment intervention. It used be emphasized that attempts to use psychometric instruments to establish psychological characteristics of men with psychogenic erection problems have generally be unsuccessful. (Segraves [24], 1981). Structured interviews focusing on presenting symptoms have shown promise as generalized screening instruments indicating when further organic assessment is indicated or when a psychological etiology can be safely assumed.(Segraves [25], 1987; Abel [1], 1982; Kockett [11], 1980).

The purpose of this report will be to review the major instruments in current usage with an English language version. Numerous instruments with a more specialized function will not be reviewed. This review will also consider whether instruments which might pick up psycholo gical causes of erection problems should be employed in assessment. An argument can be made that instruments to assess marital discord and depression should be employed in a screening battery.

I. MAJOR SEXUAL FUNCTION INSTRUMENTS IN CURRENT USAGE The International Index of Erectile Function (IIEF) is a 15 item self-report inventory was specifically designed to assess changes in erectile function in response to pharmacological interventions (Rosen [21], 1997). It measures erectile function, orgasmic function, libido, and satisfaction. This measure has the advantage of being available in many languages, being simple to administer, having high reliability coefficients, and requiring less than 15 minutes to complete. It has been shown to detect change in sexual function with treatment. A briefer five question instrument is also available (Rosen [22], 1998).The dimensional structure of this instrument has been confirmed by factor analysis. Norms are under development. This instrument merits serious consideration in any trial of the treatment of erectile dysfunction. It is less clear that this instrument has value as a supplement to the sexual interview in clinical practice or that this instrument is sensitive in detecting changes in orgasmic function or sexual desire during treatment.

The advantage of a standardized questionnaire is that it may pick up information that the clinician or investigator might otherwise overlook. For example, it is not uncommon for a man to com-

422

The questions contained in this instrument are listed in Annex I.

The Golombok Rust Inventory of Sexual Satisfaction (GRISS) was developed primarily for research purposes although it can be used both as an assessment instrument as well as a therapy outcome measure ( Kuile and Golombok, 1999; Rust and Golombok,1985). This instrument has both a male and female form. Each form contains 28 items and can be completed in approximately 10 minutes. Partner’s aggregated scores provide a profile of a couple’s sexual functioning within a relationship. Twelve subscales are scored. The scales include impotence, premature ejaculation, female anorgasmia, vaginismus, frequency of sexual contact, sexual noncommunication, male and female sexual dissatisfaction, male and female dissatisfaction, male and female nonsensuality, male and female sexual avoidance. The psychometric properties of this instrument are excellent. It was developed in Great Britain and has been translated into Dutch It has been shown to demonstrate sex therapy induced change. This instrument appears to be primarily of use for the evaluation of the efficacy of nonpharmacological therapies. However, the impact of pharmacological therapy on some of the indices not usually measured in drug studies could be of theoretical importance.

A similar instrument is the Brief Male Sexual Function Inventory (BMSFI) developed in a urologic context by O’Leary and colleagues (O’Leary,1998; O’Leary [18], 1995). This 11 question inventory is easy to use, psychometrically sound, and available in over one dozen languages. It measures drive, erectile function, ejaculation, and satisfaction. It was developed to help evaluate patients in clinical practice as well as to measure outcome in clinical trials. Discriminant sensitivity has been demonstrated and norms are in the process of development. Many of the items in this instrument overlap with those in the IIEF. There is minimal evidence to recommend use of one of these instruments over the other except that the IIEF was utilized extensively in sildenafil trials and thus is a widely accepted instrument in numerous countries. The Derogatis Sexual Interview for Sexual Functioning was developed by Lyn Derogatis, a highly respected psychometrician in the United States (Derogatis [5] 1997, Derogatis [6] 1998). The advantage of this instrument is that it comes both with a self report and a semi-structured interview format. Each contains 25 items and takes approximately 15 minutes to administer. The psychometric properties of both versions are exemplary., and it has both a male and a complimentary partner version. It is available in 9 languages. Domains measured include sexual fantasy, sexual arousal, sexual experience, orgasm, arousal, and sexual drive. This instrument has a companion female version. This instrument is perhaps longer than necessary for clinical trials yet contains information of value to the clinician such as measures of the patient’s sexual experience and activity. The items on sexual fantasy can also be valuable to clinicians. As both questionnaire and structured interviews have different advantages in different contexts, this instrument has the advantage of being able to use sister instruments in different contexts. The respect with which this instrument is held by other psychometricians can be appreciated when it is realized that most of the other instruments mentioned in this report used correlations with the DSFE to validate their instruments.

Two other scales which show promise for clinical trials include the Center for Marital and Sexual Health Sexual Functioning Questionnaire (CMASH-SFQ) and the Arizona Sexual Experience Scale (ASEX). The CMASH-SFQ was previously known as the Case Western Reserve Sexual Functioning Questionnaire and was developed primarily by Stan Althof and his colleagues as part of a study of the efficacy of intracorporeal injection of vasoactive substances (Glick [7], 1997). It is a 21 item questionnaire which address specific items from both the patient’s and the partner’s perspective. Domains measured include frequency of sexual activity, quality of erections, quality of orgasm, and sexual satisfaction. The instrument has sound psychometric properties. One advantage of the instrument is that the questionnaires from both partners are keyed to one another and this factor can be used to correct for possible distortion of responses by the patient. Another advantage of this instrument is that it was developed by a clinician actively involved in

423

the psychological as well as pharmacological treatment of sexual disorders. Norms are not available and to this author’s knowledge, it has not been translated into other languages. This instrument has been shown to be sensitive to therapeutically induced changes. The questions in this instrument are listed in (annex II).

mer,1987; Lindal and Stefansson, 1993). Although, various treatment approaches may reverse erectile failure in psychiatric patients, the clinician would not want to miss an underlying treatable and possibly fatal psychiatric disease such as major depressive disorder and panic disorder. Both of these disorders have high suicide rates. A number of studies have repeatedly demonstrated that general physicians under diagnose psychiatric disorders such as depression and anxiety disorders (Hirshfield [9], 1997; Lecrubier, 1998; Kessler [10], 1999; Weiler [29], 1998). Omnibus psychometric instruments such as the MMPI are too comprehensive to be useful as a screening instrument. The clinician has several options. One is to use a brief instrument, which screens several psychiatric conditions such as Primary Care Evaluation of Mental Disorders (PRIME-MD). However, this instrument covers some disorders of peripheral interest to the treatment of erectile disorder. (Spitzer [28], 1994). The primary conditions which the physician needs to screen are depression and anxiety disorders. A variety of general surveys for the measurement of depression such as the Beck Depression Inventory (Beck [3], 1961, [2] 1979) and anxiety (e.g. Spielberger State-trait Anxiety Inventory, Spielberger [27], 1970, Whooley [31], 1997) are available but are too long to be easily incorporated in a practice setting. Recent research suggests that two questions are sufficient for brief screening of depression. These could be incorporated into a question-naire format. The questions are:

A new instrument recently developed which shows promise because of its inherent simplicity and ease of use if the Arizona Sexual Experiences Scale ( ASEX) (annex III). This instrument was developed to measure sexual dysfunction in psychiatric patients (Mc Gahuey [16], 1999). It consists of both a male and a female version. Each version consists of 5 items only which ask questions about desire, arousal, erection or lubrication, orgasm, and satisfaction. Its psychometric properties appear sound. Norms are not available. It is only available in English but translation should be relatively easy. Each question is answered on a 6 point scale. For example, sex drive is rated from extremely strong to no sex drive. The brevity and simplicity of this questionnaire are intriguing. Further study will indicate how robust it is in detecting change in clinical trials. Two other questionnaires in development require mention. The Brief Sexual Function Questionnaire was developed by the depression study group at the University of Pittsburgh to assess erectile function in men with depression (Reynolds [20], 1998). This brief scale has a brief companion scale for the partner and preliminary studies indicate good psychometric properties. A similar scale was developed by Anita Clayton at the University of Virginia to measure antidepressant induced sexual dysfunction (Clayton [4], 1997). Preliminary studies indicate that this instrument has acceptable psychometric properties. Assessment of Psychiatric Status

1) During the past month, have you often been bothered by feeling down, depressed or hope less? 2) During the past month, have you often been bothered by little interest or pleasure doing things? Anxiety can be rapidly screened by using the Fear, a rapid screening instrument for anxiety consisting of four questions. (Krasuchi [12], 1999;Willchen [30], 1998).Two other issues that the urologist might want to address are dependent on the cultural context. If the primary sexual partner is the spouse and if considerable marital discord is present, the urologist might want to consider referral for counseling as well as correc-

II. GENERAL PSYCHIATRIC EVALUATION A problem facing the non-psychiatric physician in the evaluation of patients with erectile disorder is the co-morbidity of sexual disorders with certain psychiatric syndromes (Othmer and Oth-

424

ting the erectile problem. A reasonably rapid tool for screening for the presence of marital discord is the Locke Wallace Marital Adjustment Test (annex IV), a 15 item questionnaire requiring minimal time to complete. Alonger instrument in common use is the Dyadic Adjustment Scale (Spanier, 1976). Another issue which may be different in different cultures is whether the urologists wishes to assess the sexual function of the usual sexual partner prior to correcting erectile function in the male. If a man has erectile function restored, his spouse may or may be pleased. If his partner is postmenopausal without hormone replacement and has dyspareunia, a unilateral approach to the couple’s sex life may create difficulties for the relationship, which might be avoided by recognition of the spouse’s difficulty and referral of the spouse to a gynecologist.

sible in some settings. In some locations, there may be a scarcity of clinicians with clinical skills in sexual interviewing. In these settings, the use of questionnaires may serve to augment the clinician in his or her diagnostic and treatment decisions. Although any of the instruments mentioned above would suffice, the IIEF has the advantage of being brief and being available in many different languages. The two questions about depression could be combined with the Fear anxiety scale providing a quick screen of anxiety and depression. The physician can always question the man about his relationship with the partner and about his partner’s health. In clinical trials, a standardized questionnaire offers the advantage of ratings, which are independent of clinician skill and bias. Again, the IIEF is an excellent instrument, which can detect changes in arousal , ejaculation, and libido. It should be combined with instruments to detect anxiety, depression, and marital discord.

III. RECOMMENDATIONS In the ideal setting, a clinician skilled in sexual interviewing would assess the patient, determine the precise nature of his problem, determine whether it is secondary to treatable psychiatric disease, whether it secondary to relationship discord, and assess the impact of restored function on the relationship. The interviewer would also interview the partner. This is important as many men seeking therapy for erectile dysfunction are in their late 50’s, an age during which their partners may be postmenopausal. In most contexts, such an ideal situation is impossible to obtain. Many men refuse to involve their partners in treatment and cultural tradition may render this impos-

ANNEXES I. INTERNATIONAL INDEX OF ERECTILE FUNCTION II. THE C-MASH III. ASEX IV. L OCKE-WALLACE MARITAL ADJUSTMENT TEST V. THE FEAR

425

REFERENCES 1

2. 3

4

5

6

7

8 9

10

11

12

13

14

15

16

ABEL GG, BECKER JU, CUNNINGHAMATHER J, MITTELMAN M, & PRIMACK M. Differential diagnosis of impotence in diabetics. Neuro Urodynamics, 1982, 1,57-69. BECK AT, RUCH AJ, SHAW BF, EMERY G. Cognitive therapy of depression. New York, Guilford, 1979. BECK A, WARD C, MENDELSON M. An inventory for measuring depression. Arch Gen Psychiatry, 1961, 4, 5363. CLAYTON AH, MCGARVEY EL,CLAVET GJ, PIAZZA, L. Comparison of sexual functioning in clinical and nonclinical populations using the Changes in Sexual Functioning Questionnaire (CSFQ). Psychopharmaco Bull, 1997,33,747 53. DEROGATIS LR . The Derogatis Interview for Sexual Functioning ( DISF/DISF-SR ):an introductory report. J of Sex Marit Ther, 1997,23,291-304. DEROGATIS LR. , LABAN MP. Psychological assessment measures of human sexual functioning in clinical trials. Int Impot Res, 1998,10,Suppl 2, S13-20. GLICK HA, MCCARRON TJ., ALTHOF SE, CORTY EW, WILLKE RJ. Construction of scales for the center for marital and sexual health ( CMASH ) sexual functioning questionnaire. J Sex Marit Ther, 1997,23,103-117. HAMILTON M. A rating scale for depression. J Neurol Neurosurg Psychiatry, 1960,22,56-62. HIRSCHFIELD RMA, KELLER MD. PANICO S. The national depressive and manic-depressive association consensus statement on the undertreatment of depression. JAMA, 1997, 275,233-340. KESSLER D,LLOYD K, LEWIS G, GRAY DP. Cross sectional study of symptom attribution and recognition of depression and anxiety in primary care. BMJ, 1999,318,436-440. KOCKETT G, FEIL W, REVENSTORF D, ALDENHOFF J, BESINGER U. Symptomatology and [psychological aspects of male sexual inadequacy:results of an experimental study. Arch Sex Behav,1980,9,457-475. KRASUCKI C, RYAN P, ERTAN T, HOWARD R, LINDESAY J, MANN, A. The FEAR:a rapid screening instrument for generalized anxiety in elderly primary care attenders. Frequency of anxiety, enduring nature of anxiety, alcohol or sedative ,restlessness of fidgeting. Int J Geriatr Psychiatry,1999,1,60-68. KUILE MMT., LANKVELD JJMV, KALKHOVEN P, EGMOND MV. The Golombok Rust Inventroy of Sexual Satisfaction ( GRISS ) :Psychometric Properties within a Dutch Population. J Sex and Marital Ther, 1999,25,5971. LECRUBIER Y. Is depression under-recognized and undertreated? Int Clin Psychopharmacol, 1998, suppl5, S3-6. LINDAL E, STEFANSSON JG. The lifetime prevalence of psychosexual dysfunction among 55 to 57-year olds in Iceland. Soc Psychiatr Epidemiol, 1993, 2,91-95 MCGAHUEY CA, GELENBERG AJ, LAUKES CA,

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MCKNIGHT KM, MANBER R, MORENO FA, DELGADO PL. The Arizona Sexual Experience Scale (ASEX): reliability and validity. J Sex Marit Ther, 1999 (In Press ) OTHMER E & OTHMER SC. Evaluation of sexual dysfunction. J Clin Psychiat,1987,48,191-193 O’LEARY M.P. Clinical trials in sexual dysfunction. Int J Impot Res, 1998,10,suppl2,S7-12. O’LEARY MP ,FOWLER FJ, LENDERKING WR, BARBER B, SAGNIER PP,GUESS HA, BARRY MJ. A brief male sexual function inventory for urology. Urology,1995, 46, 697-706. REYNOLDS CF, FRANK E, THASE ME, PATRICIA R, HOUCK J, JENNINGS R, HOWELL JR, LILIENFIELD SO, KUPFER DJ. Assessment of sexual function in depressed, impotent, and healthy men: factor analysis of a brief sexual function questionnaire for men, Psych Res,1998,24,231-250. ROSEN R, RILEY A.,WAGNER G.,OSTERLOH IH, KIRKPATRICK J,MISHRA A.. The index of erectile dysfunction: a multidimensional scale for assessment of male erectile dysfunction. J Urol, 1996,155,466A. ROSEN R., CAPPWLLERI J.C.,SMITH MD, LIPSKY J,PEFIA BM. Constructing and evaluating the sexual health inventory for men:IIEF-5 as a diagnostic tool for erectile dysfunction. Int J Impot Res, 1998,10,S35. RUST, J, GOLOMBOK S. The Golombok Rust Inventory of sexual Satisfaction ( GRISS ). Brit J Clin Psychol,1985,24,63-64. SEGRAVES RT, SCHOENBERG HW, ZARINS CK, KNOPF, J & CAMIC P. Discrimination of organic versus psychogenic impotence with the SDFI: a failure to replicate. J Sex Marit Ther, 1981,7,230-238. SEGRAVES KA, SEGRAVES RT, SCHOENBERG HW. Use of sexual history to differentiate organic from psychogenic impotence. Arch Sex Behav, 1987,16,125-137. SPANIER BG. Measuring dyadic adjustment:new sclaes for assessing the quality of mariage and similar dyads. J Marr Family,1976,24,15-26. SPIELBERGER CD, GORSUCH ZRL, LUSHENE RE. STAI Manual. Palo Alto,Consuting Psychology Press, 1970. SPITZER RL, WILLIAMS JB, KROENKE K, LINZER M, DEGRUY FV, HAHN SR, BRODY D, JOHNSON JG. Utility of a new procedure for diagnosing mental disorders in primary care. The Prime-MD 1000 study. JAMA, 1994,272,1749-1756. WEILLER E, BISSERBE JC, MAIER W, LECRUBIERY. Prevalence and recognition of anxiety syndromes in five European primary care settings.A report from the WHO study on psychological problems in general health care. Br J Psychiatry ,1998,suppl,34,18-23. WITTCHEN HU, BOYER P. Screening for anxiety disorders. Sensitivity and specificity of the anxiety screening questionnaire ( ASQ-15 ). Br J Psychiatry Suppl, 1998, 34, 10-17. WHOOLEY MA, AVINS AL, MIRANDA J, BROWNER WS. Case finding instruments for depression. Two questions are as good as many. J Gen Intern Med, 1997, 12, 439-445.

some degree of emphasis on mutual pleasure, communication and creativity; and both men and women are invited to participate. Neither the man nor the woman is excluded, nor kept in the dark.

E. PRACTICAL GUIDELINES FOR GENERAL UROLOGICAL PRACTICE

Obviously some women will find more enjoyment in harder and more long-lasting erections; and some women will benefit more if their partner is no longer weighed down by fear of failure and has regained sufficient self confidence to be able to have sex

To be able to offer men with erectile dysfunction the best possible help, urologists will have to be prepared to continue to work with qualified psychologists or sexologists.

Hard and long-lasting erections are not automatically a blessing for mankind! Many women will probably not be pleased with the idea of frequent confrontations with a rigid penis when they are in their seventies or eighties. Female sexologists have very good reason to point out carefully that the vagina of a post-menopausal woman does not usually become very well-lubricated, in other words, is no longer meant to be penetrated.

If a case presents itself, general practitioners should refer patients primarily to sexologists or urologists trained in sexology, who closely work together, not competitve. Urologists treating patients with erectile dysfunction should be sensitive to the emotional meanings patients unconsciously attach to this sexual dysfunction. These meanings are often extremely important, self-evident, unquestionable truths to the patient and his partner, based on long-held beliefs about sexual dysfunction, but are not necessarily self-evident to the urologists.

Growing older means an unpleasant physical decline. That will never change. However, many of us live in western society in which a healthy, vigorous, ‘young’, beautiful and potent body has been elevated to measuring-rod status. In fact, the ideal view of the body as ‘a machine that must function well for ever and ever’ is based on suppression, not only by present-day Young-One culture, but also by ourselves. Suppression of the undeniable reality that every single one of us lives in a body that is mortal, that can let us break down, that becomes ill, and that one day day will die.

Our first task is to try to understand the patient’/partner’s beliefs, and to offer the best understanding of the likely causes of the erectile dysfunction. The challenge is to help patients approach their sexual problem as they do other health problems: to understand what might be contributing to it, to evaluate the treatment options, and to proceed with the treatment that best meets their physical and emotional needs.

Patients as well as their partners may have serious emotional reactions (anxiety, depression and even fear for death) to what they believe erectile dysfunction represents. These reactions are not necessarily relieved by an oral drug, an intra-urethral prostaglandine, an intracavernous injection, a vacu-pump, or a penile prosthesis.

If erectile dysfunction and other sexual complaints, such as premature ejaculation, are viewed purely as physical abnormalities, then we run the risk of medicalising sexuality too much. In addition, there is the risk of further standard isation, perfectionism, mechanisation and dehumanisation of sexual relationships.

Unsuccessful treatments are often due to one or more of the following elements:

A ‘mechanical’approach is the biggest turn-off for a woman. She will feel that she is being treated like a machine or a doll: no emotional communication, no fun, just pure calculation to get the job done as effectively as possible.

unrealistic expectations on the part of the patients, unclear communication, misunderstandings on the part of the partner, and/or unresolved conflicts in the relationship which the restoration of erectile functioning does not resolve.

Some psychologists and sexologists, not surprisingly, are sickened by the fact that today so much attention is paid to the phallus. Despite all the shortcomings of sex therapy, it does at least lay

In many cases, the fundamental problem is not so much erectile dysfunction, as the sexual relation-

427

ship. In this situation we must be careful that erection and coitus do not become the ultimate goals of urological treatments.

• Emphasize that almost everyone has a psychological reaction to erectile dysfunction even if its cause is primarily physical.

Our main goal must be to restore both a healthy physical and emotional outlook to the patient and his partner and therefore to improve their ultimate satisfaction with our treatments [1].

• Discuss all the current (symptomatic) treatment options including thier risks. • Help the couple to take responsibility for their choice(s) including the unknown outcomes.

In order to achieve this the following recomman dations can be given: • Realize that when a man has an erection problem, the couple has a sexual problem.

• Support a couple with counseling in adjusting to the new situation (‘the rigid penis’) and reevaluate them in case of difficulties. • Let them know that failure of one treatment does not mean they need to give up!

• Try to get the partner involved early in the process of diagnosis and treatment. Such participation enhances communication and can reduce stress and anxiety for everyone.

REFERENCE

• Educate the couple: explain in detail the mechanism of erection and the multicausal nature of erectile dysfunction; dispel any myths that they have concerninq penile

1.

• Learn each partner’s reaction to the erection problem, no matter what its cause(s), and help the couple to understand her reaction. The partner in a couple with erectile dysfunction may need as much or even more help than your ‘patient’.

BERGER RE, BERGER DM, HAPPE-HARTSELL, HEIMAN JR. Couples: The art of solving impotence problems. AUA Update Series, Lesson 20, Volume VII, 1988.

________________________

428

ANNEX I. 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 sexual activity? • 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 4. During 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 429

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 • 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

430

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 13. How satisfied are you with your overall sex life? • Dissatisfied • About equally satisfied and dissatisfied • Very dissatisfied • Moderately satisfied • Very satisfied 14. How satisfied have you been with your sexual relationship with your partner? • Dissatisfied • About equally satisfied and dissatisfied • Very dissatisfied • Moderately satisfied • Very satisfied 15. How do you rate your confidence that you could get and keep an erection? • Very low • Low • Moderate • High • Very high REPRODUCED WITH PERMISSION OF THE AUTHOR. 431

ANNEX II. THE C-MASH 1. Have you had any difficulties obtaining a firm hard, long-lasting erection? YES NO 2. Are you currently having any difficulties obtaining a firm, hard, long-lasting erection? YES NO 2A. HOW LONG AGO DID THIS CURRENT ERECTILE PROBLEM BEGIN?

_____________________

3. THE FOLLOWING QUESTIONS ASK YOU TO THINK ABOUT YOUR SEXUAL DRIVE DURING THE PAST 30 DAYS. 3A. HOW MANY TIMES IN THE PAST 30 DAYS DID YOU FEEL SEXUAL DESIRE ( HORNEY, THE DESIRE TO HAVE SEX? ____________________ 3B.HOW MANY TIMES IN THE PAST 30 DAYS DID YOU ENGAGE OR ATTEMPT TO ENGAGE IN INTERCOURSE? _____________________ 3C. HOW MANY TIMES DID YOU AND YOUR PARTNER ENGAGE IN OTHER SEXUAL ACTIVITY IN THE PAST 30 DAYS? _____________________ 3D. HOW MANY TIMES DID YOU

MASTURBATE IN THE PAST

30 DAYS? _____________________

4. These next questions ask you to judge the quality of your erections under different circumstances during the past 30 days. • Each rating scale goes from 0 to 8 ( no erection to full erection ) • Please circle the number ( 0 to 8) on each scale that best reflects the quality of your erection under each of the following circumstances. • If you have not engaged in that particular activity, circle NA ( not applicable ) Please rate the quality of your erections during the past 30 days. 4a. Quality of erection during the night or upon awakening NO ERECTION 0 1

2

3

SEMI-FIRM 4 5

6

7

FULL 8

4b. Quality of erections spontaneously or when reading about. Looking at, or thinking about something sexy NO ERECTION 0 1

2

3

SEMI-FIRM 4 5

6

7

FULL 8

4c. If you have engaged in masturbation during the past 30 days, rate quality of erection during masturbation. NO ERECTION 0 1

2

3

SEMI-FIRM 4 5

6

7

FULL 8

4d. If you have engaged in foreplay in the past 30 days, rate quality of erection during foreplay. NO ERECTION 0 1

2

3

SEMI-FIRM 4 5

6

7

FULL 8

4e. If you have engaged in intercourse during the past 30 days, rate quality of erection during intercourse NO ERECTION 0 1

2

3

SEMI-FIRM 4 5 432

6

7

FULL 8

5. Now think back over the past 3 months. The following questions concern your experience with orgasm ( ejaculation or “coming”) during this time period. • Please circle the number (0-8) on each scale that best reflects how often you have reached orgasm under each of the following circumstances. • If you have not engaged in a particular activity during the past 3 months, circle NA (not applicable for that activity. 5a. How often in the past 3 months have you had an orgasm during intercourse?

NA

ALMOST NEVER 0

SOMETIMES 1

2

ABOUT HALF

MOST OF

OF THE TIME

THE TIME

3

4

5

6

7

ALMOST ALWAYS 8

5b. How often have you had an orgasm during masturbation in the past 3 months?

NA

ALMOST NEVER 0

SOMETIMES 1

2

ABOUT HALF

MOST OF

OF THE TIME

THE TIME

3

4

5

6

7

ALMOST ALWAYS 8

5c. How often did you ejaculate (come ) more quickly than you would like during intercourse in the past 3 months?

NA

ALMOST NEVER 0

SOMETIMES 1

2

ABOUT HALF

MOST OF

OF THE TIME

THE TIME

3

4

5

6

7

ALMOST ALWAYS 8

5d. How often did it take you longer than you’d like to reach orgasm during intercourse in the past 3 months?

NA

ALMOST NEVER 0

SOMETIMES 1

2

ABOUT HALF

MOST OF

OF THE TIME

THE TIME

3

4

5

6

7

ALMOST ALWAYS 8

6. The final two questions concern your overall satisfaction with your sexual life during the past 3 months. • Please circle the number ( 0-5) on each scale which best reflects your degree of satisfaction. • If you have not engaged in any type of sexual activity in the past 3 months, circle NA. 6a.How satisfied have you felt after a typical sexual encounter in the past 3 months?

NA

EXTREMELY UNSATISFIED 0

MODERATELY MILDLY UNSATISFIED UNSATISFIED 1 2

MILDLY SATISFIED 3

MODERATELY SATISFIED 4

EXTREMELY SATISFIED 5

6b. How satisfied do you think your partner has felt after a typical sexual interaction during this time period?

NA

EXTREMELY UNSATISFIED 0

MODERATELY MILDLY UNSATISFIED UNSATISFIED 1 2

MILDLY SATISFIED 3

REPRODUCED WITH PERMISSION OF THE AUTHOR.

433

MODERATELY SATISFIED 4

EXTREMELY SATISFIED 5

ANNEX III. ARIZONA SEXUAL EXPERIENCES SCALE ( ASEX ) -MALE For each item, please indicate your overall level during the past week including today. 1. How strong is your sex drive? 1 extremely strong

2 very strong

3 somewhat strong

4 somewhat weak

5 very weak

6 no sex drive

4 somewhat difficult

5 very difficult

6 never aroused

4 somewhat difficult

5 very difficult

6 never

3 somewhat easily

4 somewhat difficult

5 very difficult

6 never reach orgasm

3 somewhat satisfying

4 somewhat unsatisfying

5 very unsatisfying

6 can’t reach orgasm

2. How easily are you sexually aroused ( turned on ) ? 1 extremely easily

2 very easily

3 somewhat easily

3. Can you easily get and keep an erection? 1 extremely easily

2 very easily

3 somewhat easily

4. How easily can you reach an orgasm? 1 extremely easily

2 very easily

5. Are your orgasms satisfying? 1 extremely satisfying

2 very satisfying

ARIZONA BOARD OF REGENTS, COPYRIGHTED 1997, REPRINTED WITH PERMISSION.

434

ANNEX IV. MARITAL-ADJUSTMENT TEST 1. Check the dot on the scale line below which best describes the degree of happiness, everything considered, of your present marriage. The middle point, "happy", represents the degree of happiness which most people get from marriage, and the scale gradually ranges on one side to those few who are very unhappy in marriage, and on the other, to those few who experience extreme joy or felicity in marriage. VERY UNHAPPY

HAPPY

PERFECTLY HAPPY

State the approximate extent of agreement or disagreement between you and your mate on the following items. Please check each column.

Always Agree

Almost Always Agree

Almost Occasionally Frequently Always Always Disagree Disagree Disagree Disagree

2. Handling family finances 3. Matters of recreation 4. Demonstrations of affection 5. Friends 6. Sex relations 7. Conventionality (right, good, of proper conduct) 8. Philosophy of life 9. Ways of dealing with in-laws For the questions below please check the most appropriate answer. 10. When disagreements arise, they usually result in: Husband giving in ( ) Wife giving in ( ) Agreement by mutual give and take ( ) 11. Do you and your mate engage in outside interests together? All of them ( ) Some of them ( ) Very few of them ( )

None of them ( )

12. In leisure time do you generally prefer: To be "on the go" ( ) To stay at home ( ) Does your mate generally prefer: To be "on the go" ( ) To stay at home ( ) 13. Do you ever wish you had not married? Frequently ( ) Occasionally ( )

Rarely ( )

Never ( )

14. If you ever had your life to live over, do you think you would: Marry the same person ( ) Marry a different person ( )

Not marry at all ( )

15. Do you confide in your mate: Almost never ( ) Rarely ( )

In everything ( )

In most things ( ) 435

ANNEX V. THE F.E.A.R.

1. IN THE PAST MONTH HAVE YOU FELT SO FIDGETY OR RESTLESS THAT YOU COULDN'T SIT STILL? IF YES : DO YOU KNOW WHAT BROUGHT IT ON?

Please circle or tick your Responses in this column

WAS IT DUE TO WORRY, FEAR, OR SOMETHING ELSE?

Restlessness due to Worry/fear/anxiety No Yes

0 1

2. HOW OFTEN, IF AT ALL, HAVE YOU WORRIED IN THE PAST MONTH? Never

0

Some Days

0

Most Days

0

All the time

1

3. IN GENERAL, WOULD YOU DESCRIBE YOURSELFAS A WORRIER?

4. DO YOU TAKE ANYTHING TO HELP YOU RELAX?

Sedative tablets Or alcohol to relax

No Yes

0 1

No Yes

0 1

WHAT ABOUT SEDATIVE TABLETS OR ALCOHOL?

*REPRODUCED WITH PERMISSION BY THE INSTITUTE OF PSYCHIATRY, DENMARK HILL, LONDON

436

Committee 12

Peyronie’s Disease

Chairman T.F. LUE

Members M.K. GELBARD, G.GUEGLIO, G.H. JORDAN, L. A. L EVINE, R. MORELAND, J. PRYOR, D. R ALPH, D. YACHIA

437

CONTENTS

I. INTRODUCTION

VIII. CLINICAL FEATURES

II. INCIDENCE

IX. MEDICAL MANAGEMENT

III. ETIOLOGY

X. SURGICAL TREATMENT

IV. PATHOLOGY

XI. PENILE ANOMALIES THAT MAY CAUSE ERECTILE DYSFUNCTION

V. MOLECULAR BASIS OF PEYRONIE’S DISEASE XII. CONCLUSION VI. NATURAL HISTORY

XIII. RECOMMENDATIONS

VII. PSYCHOLOGICAL ISSUES

REFERENCES

438

Peyronie’s Disease T.F. LUE M.K. GELBARD, G.G UEGLIO, G.H. J ORDAN, L. A. L EVINE, R. M ORELAND, J. P RYOR, D. R ALPH, D. YACHIA-

I. INTRODUCTION

II. INCIDENCE

Peyronie's disease was first reported by Fallopius in 1561 and popularized in 1743 by Francois Gigot de la Peyronie, surgeon to King Louis XVof France, a disease that has since born his name. Peyronie’s disease (indurato penis plastica) is a condition which is characterized by the formation of fibrous nodules within the tunica albuginea. These plaques impede tunical expansion during erection resulting in penile bending. In some extreme cases, these plaques may induce a collarlike or an hourglass-like appearance in the erect penis.

Peyronie’s disease has been reported to occur in association with Dupuytren’s contractures, plantar fascial contractures, tympanosclerosis as well as trauma, urethral instrumentation, diabetes, gout, pagets disease, and the use of beta blockers [1]. This condition can occur in a familial pattern [2]. There is a 10 to 40% chance that the descendent of a patient with Dupuytrens contracture will develop that problem, and a 15% chance that a man so afflicted will develop Peyronie’s disease. Dupuytren’s contracture is a genetic disorder known to be transmitted in an autosomal dominant pattern.[2], [3].

Peyronie's disease has a colorful history, a voluminous literature, but not, unfortunately, a cure. However, most patients benefit from medical attention. For some, reassurance is sufficient. For others, medical therapy may promote stabilization or improvement. A minority of patients, afflicted with disabling deformity, may find palliation in surgical procedures. That somewhat negativesounding opening statement summarizes the clinical management of this disorder. Fortunately, ignorance of origin and cure does not translate into therapeutic nihilism. To tell patients that nothing can be done is to misinform them; to offer surgery indiscriminately is worse. The physician’s challenge is to steer a course between these two extremes, providing a combination of counseling, guidance, supportive therapy, and when necessary, surgery uniquely tailored to each individual.

One university-based survey placed the incidence of Peyronie’s disease at approximately one in a hundred [4]. A thirty-five year retrospective study in Rochester, Minnesota is notable. In this study, comprised primarily of Caucasian men, the average age of onset was 53 years old, with a prevalence of 388.6/ 100,000 (0.4%) [5]. Further, over a thirty-five year period, both total Peyronie’s disease and Peyronie’s disease associated with pain and impotence increased. This may be an actual increase in disease occurrence or due to heightened patient awareness and seeking of medical attention. Interestingly, rheumatoid arthritis (p < 0.0001) and hypertension (p < 0.01) were the most commonly associated conditions reported in this group of Peyronie’s disease patients. It should be noted that the study described above probably

439

underestimates the true prevalence of Peyronie’s disease as indicated by autopsy studies. In a study of 100 men who had no known Peyronie’s disease, 22/100 has asymptomatic, fibrotic lesions of the tunica albuginea [6]. This suggests that in the natural course of aging and sexual activity, these asymptomatic lesions may develop. The prevalence of Peyronie’s disease probably is much higher than 0.4% if one includes subclinical and asymptomatic cases [4].

the effects of repeat tensile stress. Fibrin deposition is recognized as one of the initial consequences of microvascular injury, and it may be the precursor to Peyronie’s plaque formation [9]. Force-deformation analysis of tunica albugenea during erection reveals the dorsal midline region experiences internal destructive stress, and is surrounded by a region of shear stress. These regions both predispose to delamination, and are located anatomically where the disease usually develops [7, 8]. The observed pattern of plaque location may be closely approximated by utilizing the known relationship between tensile stress and fibrosis, then mapping this according to the particular stress distribution found throughout the tunica during erection [10]. Genetics and Occurrence. The search for a genetic link for Peyronie’s disease has yet to identify a genetically predisposed population. However, there are reports associating this condition and Paget’s disease of the bone [11], Dupuytren’s contracture (2)and specific HLA subtypes [2, 3, 12]. In all of these studies, patients reporting one of the traits (Paget disease of the bone, Dupuytren’s contracture or specific HLA subtypes) did not always report symptoms of Peyronie’s disease. Studies of Peyronie’s patients have implicated an auto-immune component. It has been reported that Peyronie’s disease patients had at least one abnormal immunologic test (75.8%), alterations in cellmediated immunity (48.5%) and in markers of auto-immune disease (37.9%) [13]. Another study found higher than normal levels of anti-elastin antibodies in the serum of patients with Peyronie’s disease, suggesting an autoimmune etiology[14]. It is likely that a certain proportion of men in this age group respond to mechanical tunical stress and microvascular trauma[15] [7, 8] with an aberrant or hyperactive wound healing response [16]. Thus, there may be a subpopulation whose genetic background is such that response to wound healing predisposes development of Peyronie’s plaques.

Disease incidence peaks in the mid-fifties coinciding with a more generalized age-related loss of tissue elasticity. While there is no evidence to suggest the epidemiology of this disease is changing, some believe the clinical incidence is increasing. This may be less a consequence of pathobiology than of the increasing number of men using medications for erectile dysfunction. Patients previously sexually inactive may resurrect themselves with drugs only to discover a bent penis.

III. ETIOLOGY Contemporary thinking suggests Peyronie’s disease represents a localized abberation of the wound healing process. Pathologically, Peyronie’s plaques begin with fibrin deposition and end up looking like scars. A number of factors may contribute to the initiation of this process. Intermediary steps on route to scar maturation have long been sought as pharmacological entry points for the modification or abrogation of this ubiquitous process. Drug based modification of scarring has been more of a theoretical goal than a practical reality to date, though research in connective tissue biology has expanded the knowledge base in this field considerably. Clinical data, anatomical pathology, and bioengineering analysis all implicate trauma as an initiation factor in Peyronie’s disease [7]. A survey among 732 patients demonstrated an association between penile trauma and both Peyronie’s disease and erectile dysfunction [8]. Peyronie’s disease is most prevalent after the fifth decade, when collagenous connective tissue has begun to loose its protective elasticity. Documented by studies of elastic fiber fragmentation in Peyronie’s disease, this change renders the tunica more vulnerable to

IV. PATHOLOGY Perivascular round cell infiltration can be found adjacent to the tunica albuginea in association with Peyronie’s disease, though this is not a constant feature of the disease [17]. It may repre-

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sent no more than a response to trauma, as one study turned up this histologic finding in 23% of cadavers without evidence of Peyronie’s disease. [6] Fibrin deposition, presumably from microvascular injury, has been found in relation to Peyronie’s plaques, but not in normal or scarred tunica from individuals without Peyronie’s disease. [9] Centrally, plaques consist of dense collagenous connective tissue. Elastic fibers are reduced in number, and often display fragmentation. Cartilaginous metaplasia can occur, and in about one third of patients, radiologically demonstrable dystrophic calcifications is present [18]. The scar tissue of Peyronie’s disease contains excessive amounts of type III collagen, which renders it particularly responsive to the wound contraction process [19] The microscopic anatomy of the tunica albugi nea and its impact on Peyronie’s disease plaques. The tunica albuginea is a multilayered structure of inner circular and outer longitudinal layers of connective tissue encompassing the pair of corpora cavernosa [20] [21]. An incomplete septum separates the two corpora cavernosa and anchors into the circular inner layer. 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 of these pillars at the five and seven o’clock positions. It has been demonstrated that tunical thickness varies from 1.5 to 3mm thick depending on the circular position around the tunica[20] [21]. 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 [21]. It has been proposed that this design allows unrestricted expansion of the corpus spongiosum such that ejaculation is unimpeded during penile erection [21]. 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 [20]. Patients with Peyronie’s disease most often show plaque formation on the dorsal side of the penis [22] [10] [23]. There may be two possible reasons for this observation. First, the dorsal aspect is opposite the portion of the tunica lacking longitudinal fibers and thus upper bending during erection is possible [3]. Further, the joining of the septum into the cir-

cular inner layers of the tunica may be particularly susceptible to microvascular trauma and tunical delamination [15] [8] [7]. The tunica albuginea is composed of fibrillar (mainly type I but also type III) collagen in organized arrays interlaced with elastin fibers [21]. Peyronie’s plaques are also composed almost entirely of types I and III collagen [24]. While collagen has a greater tensile strength than steel, it is unyielding. In contrast, elastin can be stretched up to one hundred fifty percent of its length [21]. It is the elastin content that allows the compliance of the tunica albuginea and helps to determine stretched penile length [25]. Disorganization of the circular or longitudinal layers in the tunica as well as disruption of elastin or a decrease in elastin content has been reported in Peyronie’s disease and can result in penile deformities during erection as well as erectile dysfunction [26].

V. MOLECULAR BASIS OF PEYRONIE’S DISEASE 1. TUNICAL MECHANICAL STRESS AND MICROVASCULAR TRAUMA One of the most likely causes of Peyronie’s disease may be repeated tunical mechanical stress and microvascular trauma. Excessive bending during erection or blunt trauma to the erect penis may result in bleeding into the subtunical spaces or tunical delamination at the point where the septum integrates into the inner circular layer of the tunica albuginea [15] [8] [7]. Such microvascular trauma may come from sexual intercourse; either with the woman on top (torque to the penis with an upward twist applying pressure to the septum tunica junction) or an accident during penetration where the man misses the vagina and fractures the penis. Microvascular trauma or subtunical bleeding can result in fluid and fibrinogen in the subtunical layers. The resulting fibrin deposits may be key in the initiation of a wound healing response which encompasses pain, hematoma and subsequent inflammatory response with recruitment of macrophages and neutrophils [16] [27] [9].These cells, in response to clot formation, release a variety of cytokines, autocoids and vasoactive factors which may precipitate a fibrotic reaction (see

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below). The unique anatomy of the tunica albuginea with its multiple subleyers of dense fibrous tissue and hypovascularity may "trap" the inflammatory reaction, prolonged the process to months or years and therefore foster the formation of Peyronie's plaque.

teases [16]. In Peyronie’s disease, defects in overproduction of collagen and other tissue remodeling mechanisms result in an inability to resolve the injury and in plaque formation.

In order to better understand the molecular pathology of Peyronie’s disease, it is helpful to review the events in a normal wound healing response [16] [27] [9]. Microvascular trauma leads to extravascular leakage of blood, with thrombus formation. Platelets release their contents including serotonin, platelet derived growth factors (PDGFA and PDGF-B) as well as transforming growth factor-b1 (TGF-b1). Thrombus formation leads to deposition of fibronectin, which binds a variety of growth factors, localizing them to the wound site. Fibrinogen leakage results in fibrin deposits. Fibrin forms a meshwork of fibers which will be the sites of attachment for inflammatory cells and fibroblasts later in the healing process [27] [9].

• Involvement of TGF-b1.

2. MOLECULAR MECHANISMS: Fibrosis is defined as the over accumulation of connective tissue or the replacement of normal cellular material with connective tissue [16]. Transforming growth factor-b1 has been implicated in a number of soft tissue fibroses [28, 29] as well as erectile dysfunction [30]. The pathology observed in these conditions is worthy of consideration here before discussing Peyronie’s disease. Transforming growth factor-b1 is synthesized as an inactive, latent peptide by a variety of cell types including platelets, macrophages and fibroblasts [28, 29]. Upon activation, TGF-b1 binds to specific cell surface receptors and through a signal transduction cascade, results in an increased synthesis of connective tissue and an inhibition of collagenases. It also can induce its own synthesis as well as that of its receptors [28, 29, 30]. This autoup regulation can set into motion a chain of events that results in continued connective tissue accumulation and what has been termed “the dark side of fibrosis” [28]. The negative regulators of this process are not well characterized. However, in the lung and in the corpus cavernosum, a role for prostaglandin E has been proposed [28]. PGE inhibits TGF-b1-induced collagen synthesis both in lung fibroblasts and in corpus cavernosum smooth muscle via cAMP dependent pathways [30]. Despite these initial clues, a number of autocoids, vasoactive substances and cytokines can regulate connective tissue metabolism so that these two factors may be involved but not exclusive to the process.

The combination of these factors attracts a variety of inflammatory cells to the wound site including macrophages, neutrophils and mast cells. Neutrophils, the predominant inflammatory cells in the site in the first 24 hours, function to remove bacteria and debris from the site [16]. Macrophages become the predominant cell type by 48 hours and in addition to removal of cell and foreign debris from the wound, release a variety of growth factors including TGF-b1. Fibroblasts migrate into the site attracted by growth factors and autocoids released by platelets and macrophages and begin to proliferate as a result of PDGF. These cells probably provide the bulk of the connective tissue synthesis during tissue repair. The myofibroblast is a mesenchymal cell type which has characteristics of both smooth muscle (contractile) and fibroblast (synthesis of connective tissue) [16]. There has yet to be a detailed examination of this cell type in the pathology of Peyronie’s disease. Transforming growth factor-b1 has a pleotropic effect on fibroblast function by increasing transcription and synthesis of collagen, proteoglycans and fibronectin while also increasing synthesis of tissue inhibitors of collagenase which prevents connective tissue breakdown. The collagen and connective tissue repair damage while in dermal wounds, re-epithelialization takes place. Finally, in the later stages of healing, the connective tissue is remodeled by specific collagenases and pro-

A role for TGF-b1 has been proposed in the pathogenesis of Peyronie’s disease [31, 32, 33]. Peyronie’s disease plaques and tunica albuginea biopsies were examined for the presence of expression and compared to specimens from non-Peyronie’s disease patients. In thirty Peyronie’s disease patients, increased protein expression of TGF-b1 (26/30), TGF-b2 (7/30) or TGF-b3 (5/30) were noted as compared to only 1/6 in the non-Peyronie’s disease group [31]. This single patient in the control group had a localized tunical fibrotic reaction. In all of the Peyronie’s disease patients with 442

A

B

Figure 1: Micrographs of normal tunica albuginea and Peyronie’s disease. A) is a 40 micron thick section of the tunica albuginea from a man with ED stained with Hart elastic fiber stain, the irregular elastic network onto which the collagen component rests is seen. B) is from a patient with Peyronie’s disease, elastic fibers appear broken, shortened and irregularly displaced by nodularly arranged collagen fibers.

Blood clot fibrin

ELASTASE

Emissary vein

Circumflex vein

Inflammatory cells

Outer longitudinal layer

TGF-ß Elastic fibers

Tunica albuginea

Inner circular layer

Fibroblast Superoxide

Collagen (triple helix structure) Figure 2: Molecular pathogenesis of Peyronie’s disease. A minor injury to the tunica albuginea may rupture an emissary vein and cause bleeding within the densely packed sublayers of the tunica albuginea. The ensuing fibrin deposition and accumulation of inflammatory cells may cause obstruction of the draining veins and resulting in a “trapped” inflammatory process. The inflammatory cells produce a number of cytokins, metalloproteinases and reactive oxygen radicals. Among them, the superoxide and TGF-beta can stimulate the adjacent fibroblasts to produce collagen fibers. TGF-beta can also stimulate the inflammatory cells to produce more TGF-beta and forming a vicious cycle. The elastase can destroy the elastic fiber network and impair the elasticity. Together, these processes produce the typical symptoms of Peyronie’s disease: pain, plaque and deformity.

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increased TGF-b1 expression, fibrotic changes in tunica albuginea biopsies were reported [31]. If increased expression of TGF-b1 is causal in Peyronie’s disease, one would like to validate this mechanism in a cell culture or animal model where the progression of disease can be followed. As described above, wound healing processes involve a number of different cell types including neutrophils, macrophages and fibroblasts. These cell types can modulate each other and themselves via complex autocrine and paracrine mechanisms. Further, the collagenous connective tissue matrix plays a poorly understood role, as neutrophils, macrophages and fibroblasts must migrate through this diffuse connective tissue to the wounding site. Thus, while Peyronie’s disease fibroblasts may be cultured and grown in confluent monolayers, this cell culture model may be of little use in the study of the progression of Peyronie’s disease. A rat model of Peyronie’s disease has been developed using subtunical injections of a synthetic heptapeptide, cytomodulin, which induces increased TGF-b1 expression and/or inflammatory cell recruitment [32, 33]. Six weeks after cytomodulin injection 15/18 rats exhibited tunical thickening and plaque formation as well as increased TGF-b1 mRNA and protein expression [32]. No increases were observed in either TGF-b2 or TGF-b3 mRNA or protein expression [32]. Finally, electron microscopy revealed the infiltration of inflammatory cells as well as disorganized collagen fibrils [33]. This model is indeed a significant advance as it allows following the progression of disease as well as a system for the evaluation of pharmacotherapeutics for Peyronie’s disease.

the onset of deformity associated with the active phase is gradual or sudden, pain resolves and the pathologic process itself seems to stabilize after 12 to 18 months. A relatively quiescent secondary phase follows, which is characterized clinically by painless stable deformity, and pathologically by mature scar. Earlier series characterized Peyronie’s disease as a process of gradual spontaneous resolution. More recent data does not bear this out. Out of 97 patients with Peyronie’s disease of 1 to 5 years duration polled at UCLA, 14% called their disorder resolving, 40% termed it progressive and 47% felt it to be unchanging [34]. Erectile pain almost always resolves with time; penile deformity usually does not. Features associated with a lack of spontaneous resolution include long-standing duration at presentation (greater than 2 years), the presence of Dupuytren’s contractures or plaque calcification, and bending in excess of 45%.

VII. PSYCHOLOGICAL ISSUES The relationship of erectile dysfunction to Peyronie's disease is a very difficult one to ascertain. Discussions of erectile dysfunction after surgery begin with the first report of surgery for Peyronie's disease using excision and grafting by Lowsley in the 1940s [35]. In that series, postoperative erectile dysfunction was a major source of failure. In that series, patients with ventral curvature were singled out as a particularly at risk group. That series, however, was not stratified preoperatively for erectile function, and erectile function postoperatively was based on patients complaints and not testing. In 1970, Williams and Thomas [36] described a group of 25 patients and followed their natural history. Of those 15 patients, 4 were described as being "impotent". Again, there was no testing in that series, and the plea of that series was to avoid surgical correction. Gelbard in 1990 [Gelbard, 1990 #414] again attempted to describe the natural history of Peyronie's disease. In his manuscript, he describes "impotence" as an end point, an inadequate one. He did, however, describe in that series a large number of patients who discussed poor erections/ erectile dysfunction. In that analysis, almost 80% of the patients complained of "psychological effects" due to Peyronie's disease. Over

VI. NATURAL HISTORY Palpable nodularity and scarring to the Tunica Albuginea in Peyronie’s disease develops over time, and seems to correspond to a pattern that is at least somewhat predictable. This tendency for the disease process to evolve over time, in the absence of therapy, has been the subject of several studies. In most cases, onset is associated with an active phase, consisting of painful erections, and a changing configuration of plaque and or bending. Up to a third of patients with Peyronie’s disease present with painless curvature, however. Whether

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time, of those 80%, about 70% complained that their psychological complaints did not improve. The problem with trying to separate out the functional issues from organic issues is that in the literature seldom are they stratified in that fashion, and the existence of erectile dysfunction soley on the basis of functional aspects is mentioned only in passing in many articles.

cites a number of psychologic complaints based on an experience at the time of writing of interviews in over 1,500 men with Peyronie's disease. Men discussed with him the fact that their body image was disturbed and hampered, and the thoughts of painful treatment being necessary was devastating. Many agreed that their sexual dysfunction which they complained of in addition to mechanical difficulty with coitus was due in large part to emotional factors. Jones describes the counseling as being much the same as counseling a person who has suffered death in grieving. As with death, men's grieving is complicated by a denial, ambivalence, anxiety, depression, shame, embarrassment, and in the case of this particular group of patients self disgust. Many of these patients are not good talkers. In review of patient information from the group in Norfolk, Peyronie's disease has been described as a disease of youthful libido in an aging body. Peyronie's patients seem to have intercourse more frequently and more vigorously than aged matched adult cohorts. This data has been criticized in that the analysis was accomplished in the 50 and 60s, and the point has been made that the adult population now in general may be more sexually active and more vigorously so. This new data is in the process of being gathered. Thus, the issue of whether Peyronie's patients are better at intercourse than perhaps verbal relations with their partners remains an unknown. It is safe to say from Jones' review that Peyronie's patients tend not to like to talk about their problem with their spouses and spurn counseling in many instances.

Since Brock and Lue’s analysis of 1993 [37] approximately 8-9 papers have been published that deal with stratification preoperatively with functional testing. In those papers, there is a wide variance of opinion concerning erectile dysfunction coexisting with Peyronie's disease, with Jordan and Angermier's paper [38] showing erectile dysfunction in almost 100% of patients, and Jarrow's analysis reporting 76 of 95 patients who by testing were "impotent"[8]. Further review, however, showed only abnormalities of vascular erectile parameters in those patients. In Ralph's analysis in 1992, 20 patients with ED were studied with duplex ultrasonography and the conclusion was that 90% of these patients had complaints of ED because of functional aspects, and not organic aspects [39]. The existence of functional erectile dysfunction following surgery is mentioned in a number of articles beginning with Melman's negative report concerning excision with dermal graft in which one of his failures was clearly a failure due to emotional causes [40]. Jones' analysis of 20 men [41] who failed to resume coitus after excision with dermal grafting, while a different population, comes close to the same numbers reported by Ralph [39]. In the 20 men studied, 15 men were found not be able to have coitus because of psychogenic causes. Pryor's recent report of incision and vein grafting also report patients who failed to resume coitus because of psychogenic causes, and these patients have been stratified pre and postoperatively by duplex ultrasound examination.(unpublished data)

Jones further makes the point in dealing with Peyronie's patients, in order to avoid emotional factors, that patients need to hear the suggestion that they must "keep sexual expression alive, be active to whatever degree possible at every stage of the progression or regression of a Peyronie's disease course." He emphasizes that men do not hear that. The physicians that they initially consult and clearly the functional aspects of Peyronie's disease are made worse by general misunderstanding of the disease among urologists and primary care physicians in general. Many patients have been told that Peyronie's disease probably is the end of their sex. It is clear from Jones' review that most couples eventually show regret that discussion of sexual behavior was not entered in earlier their

Unfortunately, from what is in the literature, little is clear other than the fact that patients preoperatively complain in large numbers of the psychologic impact of their Peyronie's disease, and psychologic aspects continue to plague good surgical results. In a review by Jones [42] dealing with the counseling of men with sexual dysfunction, he

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course of Peyronie's disease. They admit that they cope poorly; and, because of that, sexual expression and happiness suffered. In that review, many men said that the belief that "sex was intercourse", thus when coitus is precluded avoid other sexual activity, thus increasing their frustration. Most ignored the pleas of their partners who asked for intimacy regardless of whether or not there was intercourse.

that 52% of 106 patients had coital difficulties and 17% had poor penile rigidity distal to the plaque [44]. However, only 8% of patients described coital difficulties at the initial presentation suggesting that this was probably a late feature of the disease. Stecker and Devine found abnormal nocturnal penile tumescence in 29% of patients with Peyronie’s Disease with suspected organic impotence although in only 5% of patients could the Peyronie’s Disease plaque be the sole cause of the dysfunction [47]. Other series have reported an incidence of erectile dysfunction of 19% [46]. Amin discovered that out of 208 patients investigated routinely by colour Doppler ultrasound for erectile dysfunction, 20% had undiagnosed Peyronie’s Disease [48]. It is clear, therefore, that erectile dysfunction in Peyronie’s Disease is common and is usually due to one or more of four factors [49]. 1. Psychological (Performance anxiety). The physical abnormality of the penis can cause anxiety which may be severe enough to interfere with the ability to obtain or maintain an erection. 2. Deformity preventing coitus. The penile deformity may be so severe that penetration is made difficult or even impossible. This is more likely to occur if the deformity is in a ventral or lateral direction, where deviation from the normal angle of vaginal entry is maximal. The pain that is sometimes experienced in Peyronieís Disease may also interfere with the erectile capacity. 3. Flail penis. There is a small group of patients with extensive Peyronieís disease who have circumferential plaques and a degree of cavernosal fibrosis. Tumescence is absent from this segment and if extensive it may result in a hinge effect and an unstable penis. 4. Impaired erection. It is often difficult to decipher the cause of the impaired erectile capacity. It may be due to concomitant vascular disease that occurs in 30% of patients with Peyronie’s Disease [50] or to veno occlusive dysfunction (VOD) [51,52]. Most studies have used both colour Doppler ultrasound and cavernosometry to investigate the impaired erection in Peyronie’s Disease. Lopez showed that out of 76 patients, 36% had arterial disease and 59% had VOD [53]. Others have also suggested there is a mixture of arteriogenic and

All of the above states that the functional aspects are recognized but poorly categorized. In order to better define the functional aspects, there must be uniformity in history taking in centers that deal with Peyronie's disease; there must be uniformity in preoperative assessment with regards to erectile function; and in failures of surgical therapy, where possible, there must be uniformity in evaluation of erectile function postoperatively.

VIII. CLINICAL FEATURES The presenting symptoms of Peyronie’s Disease include: 1. Penile pain. 2. Penile deformity or shortening during erection. 3. Presence of a plaque or induration. 4. Erectile dysfunction. All the patients have either a well defined plaque or an area of induration that is palpable on physical examination, even though 38-62% of patients are unaware of [43, 44, 45, 46]. The plaque is usually located on the dorsal surface of the penis with a corresponding dorsal penile deformity. Lateral and ventral sited plaques are not as common but result in more coital difficulties as there is a greater deviation from the natural coital angle. Multiple plaques located on opposite sides of the penis or plaques appearing in the pectinate septum may cause shortening with or without a penile curvature. Penile pain may be persistent in the inflammatory stage of the disease but is usually only present during erection. The pain is not usually severe in nature but may interfere with sexual function although spontaneous improvement usually occurs as the inflammation settles. The reported incidence of erectile dysfunction in Peyronie’s Disease is variable. Bystrom reported

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venogenic factors [54, 55]. It is thought that the venous leakage may occur through the emissary veins that pass through the Peyronie’s plaque into the dorsal vein of the penis. The reduced compliance of the tunica albuginea of the plaque prevents the normal compression of these veins during rigidity and therefore does not compress the venous channels. This site specific VOD has also been found in 80% of 19 patients with an impaired erection secondary to trauma, one of the suggested aetiological factors in Peyronie’s Disease [56].

A detailed psychosexual history should also be sought. This includes penile rigidity during erection, shortening, induration, hourglass constriction, or pain with or without erection. Other important information should also be determined such as ability to have intercourse, adequacy of erection (rigidity and duration), frequency of intercourse, libido, psychological impact. A photograph of patient's erect penis to identify the extent, direction, and character of erectile distortion is helpful.

2. PHYSICAL EXAMINATION Examination of the penis in patients with Peyronie's disease is facilitated by gentle stretching of the penis. This will help identify the size, location and consistence of plaques which may be helpful in determing the stage and monitoring the progression. The patient should also be examined for the presence of Dupuytren's or planter fascial contractures. Further diagnostic studies should include photography or drawing of the erect penis after intracavernous injection or vacuum erection device. The stretch length of the penis should also be documented.

The findings that there is reduced elastic fibre content of the tunica and an increased type III collagen content also supports the findings that Peyronie’s Disease is associated with veno-occlusive dysfunction as these pathological abnormalities can also be seen in patients with veno-occlusive dysfunction disease without Peyronie’s Disease [57] [26]. Patients may present with only a flaccid distal portion of the penis or a soft glans penis, the proximal segment being normal. There is controversy as to the mechanism of this, be it arterial, venous or fibrotic in nature. One study has shown that this feature is likely to be of mixed pathology in that patients are likely to have extensive cavernosal fibrosis which impedes the distal arterial flow as measured on colour Doppler ultrasound [39]. This would be supported by the fact that the inflammation in the early stage of Peyronie’s Disease and the fibrosis in the latter stages can extend into the erectile tissue [58]. Patients with a soft glans only are likely to have extensive dorsal plaques with interference of the dorsal neurovascular bundle. The diagnosis of Peyronie's disease is usually apparent by the patient history and physical examination of the penis. If surgery is contemplated, a detailed evaluation of penile vascular function in patients with Peyronie’s disease is highly recommended.

3. VASCULAR TESTING Many patients have little in the way of symptoms and reassurance, particularly that the palpable lump is not cancer, is all that is necessary. The majority of patients with Peyronie’s Disease may be managed without vascular investigation. Patients usually give an accurate description of their deformity to within 10-20º and it is therefore often unnecessary to obtain clinical confirmation of this either with a photograph or an intracavernosal injection of a vasoactive agent [59, 60]. However with complex deformities or where patients cannot give an accurate description the intracavernosal injection of a vasoactive agent is important, particularly when planning a surgical correction of the deformity. When the site and size of the Peyronie’s plaque needs to be assessed, ultrasound usually will suffice [61] and is particularly helpful in monitoring the progress of medical treatment.

1. HISTORY The medical history should include time and mode of onset (sudden or gradual), course of disease (stable or progressive), history of penile surgery, urethral instrumentation or trauma, medication or drug abuse and family history of Peyronie's disease or Dupuytren's contracture. In patients complain of ED, the risk factors for ED should also be assessed.

In patients who also complain of an impaired erection further evaluation is essential and this should be either with color Doppler ultrasound or dynamic infusion cavernsometry as arterial and/or venous pathology may be present to account for this.

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a) Color duplex ultrasonography High resolution sonography allows for detailed objective assesment of the plaque, calcification as well as defining multiple areas of the involvement. Sonography can also be used to follow plaque progression, after medical therapy or surgery. Therefore, sonography is the most objective means of assessing plaque dimensions at any stage of the disease. Color duplex sonography performed before and after intracavernous injection of a vasodilator allows for a thorough assessment of the structure of the corpus cavernosum, tunica albuginea and cavernous arterial and venous function. Furthermore, it is an excellent tool to detect collateral arterial connections between the dorsal and cavernous as well as the cavernous and spongioal arteries. In some patients the dorsal artery may give a large branch to supplement the cavernous artery. Surgerical damage to this large branch during dissection of the neurovascular bundle may results in impotence. b) Dynamic infusion cavernosometry After intracavernous injection of vasodilators, infusion of normal saline can determine the degree of venous leakage. Jordan and Angermeier [38] reported that there is a linear association between preoperative erectile function and postoperative results. If the patient is noted as having adequate erectile function, his chance of having good results from penile straightening alone is in excess of 90%,however, if a patient has obviously inadequate erectile function, although the penis may be straightened by surgery the lack of rigidity will persist, causing difficult penetration during intercourse [38]. Whereas many treatment protocols have been suggested for the management of patients with Peyronieís disease these should be used as a guide only: individual patient requirements and assessment are more important in determining which patients require simple reassurance, which need investigation and which will be appropriate to treat surgically.

with or without hypospadias, penile dorsal vein thrombosis, cavernosal fibrosis secondary to local trauma, leukemic infiltration of the corpora cavernosa, ventral curvature secondary to urethral instrumention, benign or malignant primary or secondary tumors, late syphilitic lesion, penile infiltration with lymphogranuloma venerum. There is no symptom score or quality of life instrument designed specifically for Peyronie’s disease. The following is a proposal by the committee. Symptoms Scores proposed by the committee

1. PAIN 0 = Absent 1 = Slight, during erection 2 = Slight, during sexual intercourse 3 = Moderate 4 = severe 5 = constant

2. PLAQUE

SIZE (CUMULATIVE)

0 = None 1 = 1 cm 2 = 2 cm 3 = 3cm 4 = 4cm 5 = 5 cm or more

3. DEFORMITY Prefix D, L, V, S Dorsal Lateral Ventral Shortening

0 = Absent 1 = 15º 2 = 30º 3 = 45° 4 = 60° 5 = >75°

4. ERECTION

c) Differential diagnosis

0 = Normal

Although the diagnosis of Peyronie's disease is fairly straightforward, a rare sarcoma may be confused with Peyronie's disease. This possibility must be ruled out with a biopsy, especially when the plaque has grown rapidly. When evaluating patients with Peyronie’s disease, many other causes of bending and induration of the penis must also be considered such as, congenital curvature of the penis, chordee

1 = Functional

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2 = Impaired – penetration possible 3 = Impaired – no penetration 4 = Distal flaciddity 5 = Absent

ability for intercourse, and over-all perception of disease progression. At this time, vitamin E continues to be the primary mode of treatment despite the lack of a controlled study showing its benefits.

IX. MEDICAL MANAGEMENT In spite of various treatment options, Peyronie's disease remains a therapeutic dilemma for the practicing urologist. Peyronie advocated use of Barege spa water and mercurial ointments. In the 1800’s iodine, arsenic and camphor were used. Throughout the years, different modes of energy transfer including orthovoltage radiation, ultrasound, short wave diathermy, laser therapy, and shock wave lithotripsy have been used to treat Peyronie's disease [62, 63, 64]. None of these methods are recommended at this time. The following discussion will review current treatment options based primarily upon experiences reported in the English literature. Unfortunately, most studies are compromised by poorly characterized, limited numbers of patients, short follow-up times, no placebo or control groups, and little objective measure of change. We will first review systemic and then local or intralesional therapy for Peyronie's disease.

b) Potassium aminobenzoate

1. ORAL AGENTS a) Vitamine E The use of oral agents for the treatment of Peyronie's disease began in 1948. Scott and Scardino [65] reported on treatment of 23 patients with vita min E, a tocopherol with antioxidant properties. The proposed dose was 200 to 300 mg per day. Based on changes in pain, plaque size and angulation, they reported a beneficial effect in 11 patients, some improvement in 10 and no change in 2 patients. The study did not compare the effect of the treatment with the natural history of the disease. Use of vitamin E continued and, over time, became widely accepted because of its mild side effect profile and low cost. Several studies have claimed favorable outcomes with vitamin E, however, the majority did not compare the outcomes with the natural history of the disease or a placebo controlled group. In 1990, Gelbard et al. [34] compared the effects of the vitamin E treatment and natural progression of the Peyronie's disease. They described 27 patients who received no treatment and 59 patients who were taking vitamin E. They noted no significant differences between the two groups with respect to pain, bend,

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In 1959, Zarafonetis [66] studied potassium ami nobenzoate (Potaba) as a systemic therapy agent. This substance is classified as "possibly effective" by the Food and Drug Administration for the treatment of Peyronie's disease, scleroderma, dermatomyositis, linear scleroderma, and pemfigus. One of the most extensive reviews of this therapy is a summary of 214 European urologists' experience with 2653 patients on Potaba [67]. The treatment was considered unsuccessful in 42.7% of the cases and successful in 57.3%, with complete resolution in 9.3%. The mechanism of action is not well understood. It has been suggested that Potaba increases utilization of oxygen by tissues and increases activity of monoamine oxidase, which decreases concentration of serotonin, a substance thought to be responsible for fibrogenesis. Carson reported a retrospective review of 32 patients treated for at least 3 months with 12 grams of Potaba powder daily and followed for 8 to 24 months. Subjective symptoms analysis demonstrated improvement in penile discomfort in 8 of 18 (44%), decreased plaque size in 18 of 32 (56%) and improvement in penile angulation in 18 of 31 (58%) patient. Complete resolution of angulation was reported in 8 of 31 (26%) patients. Carson suggested that a prospective, double-blind, multicenter, study with objectives criteria was needed to control for the natural history of spontaneous resolution of Peyronie’s disease symptomatology and to confirm the role of Potaba in the treatment of Peyronie’s diseae as suggested in the above noted non-controlled studies [68]. Based upon these modest results, unsubstantiated mode of action, its relatively high cost, and side effects including gastrointestinal intolerance, which often results in noncompliance, enthusiasm for the use of Potaba is cautiously guarded. c) Tamoxifen Ralph et al. described their experience with oral tamoxifen in 1992 [69]. It has been suggested that tamoxifen facilitates the release of transforming growth factor-beta (TGF-b) from fibroblasts [70]. TGF-b has been shown to play a central role in

regulating immune response, inflammation and tissue repair by deactivating macrophages and T lymphocytes. Tamoxifen results in a reduced inflammatory response and, therefore, diminished angiogenesis and fibrogenesis [71]. Their prelimi nary study showed encouraging results in patients with recently (less than 4 months) acquired Peyronie's disease. Their regimen included 20 mg of tamoxifen twice a day for 3 months. Eighty percent of patients reported an improvement in pain, 35% showed improvement in deformity, and 34% experienced plaque shrinkage. An unpublished anecdotal report by Toloken of a controlled trial of oral tamoxifen (20 mg BID) vs placebo demonstrated no therapeutic advantage to tamoxifen and several men reported scalp hair loss [72]. Like many of the newer treatment options, tamoxifen is difficult to recommend since long term results, side effects, and larger cohorts are not available. Yet this type of therapy is particularly interesting in light of better understanding of scar formation.

bits cell mitosis by disrupting the spindle fibers. It also blocks the lipoxygenase pathway of arachidonic acid metabolism, thus diminishing chemotaxis and inflammatory response. Lastly, it interferes with transcellular movement of protocollagen. Akkus et al recommended an initial dose of 0.6 to 1.2 mg daily during the first week of treatment followed by a gradual increase to 2.4 mg over three to five months. Although not qualified further, penile curvature was slightly improved in 2 (11%) and markedly improved in 5 (26%) of the 19 cases. Seven of nine patients with painful erections reported significant relief. Palpable plaque disappeared in 2 and decreased in 10 patients. The investigators also performed ultrasound on five patients and described a decrease of approximately 50% in plaque size. However, the authors pointed out that a double blind study is needed to better evaluate the usefulness of this medication. The primary reported side effect of colchicine is gastrointestinal upset with diarrhea reported in 33% of subjects [74].

d) Procarbazine (Natulan)

2. INTRALESIONAL INJECTION

The use of procarbazine (Natulan) has brought largely disappointing results. This cytotoxic alkylating agent was commonly used for treatment of Hodgkin's lymphoma. In spite of the initial favorable reports in patients with Dupuytren's contractures, studies have not shown a benefit in men with Peyronie's disease. Theoretically, procarbazine should inhibit proliferation of rapidly dividing fibroblasts. Oosterlick and Renders in 1975 saw no improvement in 9 out of 10 patients following treatment with 100 mg of procarbazine daily for 27 to 150 days [73]. Similarly, Morgan and Pryor [74] reported that 91% of 34 patients in their study failed to improved or worsened. They also pointed out several toxic side effects including intestinal disturbances, severe headaches, skin eruptions, alcohol intolerance and leukopenia. From this experience, there does not appear to be any value in the use of this toxic agent.

a) Steroids Based upon anti-inflammatory properties, as well as decreased collagen synthesis by unclear mechanisms, steroids have been employed as an intralesional therapy for Peyronie's disease. In 1954, Teasley [80] described the intralesional use of steroids in 29 poorly characterized patients with unclear results. Also in 1954, Bodner reported good results of intralesional cortisone and hydrocortisone treatment in 17 patients [77]. In 1975, Winter and Khanna published their results on the use of mechanically aided injection (Dermo-Jet) of dexamethasone [82]. They reported on 21 patients who were managed with 6 to 10 injections of 0.4% dexamethasone solution per treatment, repeated monthly for a total of 1 to 6 months. Although they noticed a decrease in both plaque size and pain during intercourse, no statistical difference was evident in comparison to the natural history of the disease. The authors also failed to objectively quantify the changes in plaque size and degree of the curvature.

e) Colchicine Oral colchicine therapy was recently reported in a non-controlled study by Akkus et al. [75]. This agent is known to induce collagenase activity and decrease collagen synthesis [76, 77, 78, 79]. Colchicine acts in four ways. It binds to tubulin and causes it to depolymerize, and subsequently, inhibits mobility and adhesion of leukocytes. It inhi-

In 1980, Williams and Green [83] described a prospective study on the use of intralesional triamcinolone, a long-acting glucocorticoid with low solubility, which theoretically produces maxi-

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mal local action with minimal systemic side effects. Forty-five patients were followed for one year without treatment and then treated with intralesional triamcinolone hexacetonide at 6-weekly intervals for 36 weeks. During the one year observation period only three patients (6%) had spontaneous resolution of their symptoms. After the initiation of therapy, 33% of the patients noticed marked improvement. The mean duration of treatment which resulted in clinical improvement was 18 weeks. Pain, when present, improved first and most consistently, followed by plaque and then curvature. They also identified that patients under the age of 50 with small, firm, discrete plaques are more likely to respond to triamcinolone treatment. This treatment has also been shown to benefit Dupuytren's contractures and hypertrophic scars. [83, 84].

production of a collagenolytic factor in bone by this hormone [86]. It has been suggested that injection of PTH into the plaque may depress collagen synthesis and promote collagen degradation. In spite of this single study, the use of PTH has not been substantiated by further reports in the literature.

We now recommended that treatment of Peyronie's disease with intralesional steroids be elimi nated or at least initiated with extreme caution because of local side effects and the inconsistent pattern of improvement in well-established curvature. Although steroids are known to suppress fibroblast production of collagen, this effect is unpredictable and may result in local tissue atrophy. Anecdotally, in one unreported case, a patient developed adrenal insufficiency due to excessive use of steroid injections. In addition, steroid injections make surgery more complex due to the difficulty in subsequent separation of tissue planes between Buck's fascia and the tunica albuginea.

In 1993, results of the only double-blind study of any type of medical therapy for Peyronie's disease were published [89] In this study of 49 men, a statistically significant improvement in plaque size was found following collagenase treatment as compared to placebo control. The patients were stratified according to the severity of their disease and a modified Kelâmi system was used for classification [59] Category 1 patients had a bend of 30 degrees or less, and/or a palpable plaque of less than 2 cm. Category 2 patients displayed 30 to 60 degrees of angulation and/or a palpable plaque between 2 and 4 cm. Category 3 patients had greater than 60 degrees penile bending and/or greater than a 4 cm plaque. The researchers used vacuum chamber photography to document the degree of angulation. Patients in the category 1 received 6,000 units of purified clostridial collagenase, patients in group 2 received 10,000 units and patients in group 3 received 14,000 units. The category 1 patients responded best to the treatment ( 3 of 3 (100%) who received the study drug noted some improvement), followed by category 2 (36%), and category 3 (13%). The authors cautioned, though, that maximal angular improvement observed ranged from 15 to 20 degrees, which was acceptable only in category 1 patients. In more severe cases, change in curvature was detectable but not clinically significant. No side effects were noted by the authors. Currently, this mode of therapy is a promising option for mild to moderate degrees of Peyronie's disease and is being evalua-

c) Collagenase Purified clostridial collagenase was first studied in vitro with surgically excised Peyronie's plaques by Gelbard et al [87] in 1982. Three years later, Gelbard et al. [88] published data on the use of a single intralesional collagenase injection in 31 patients. The results of this study were encouraging, with objective improvement in 20 patients within 4 weeks. Only one recurrence during the 9.8 month follow-up period was noted.

b) Parathyroid hormone Other hormones used in the intralesional treatment include parathyroid hormone (PTH). Morales and Bruce [85] described the use of PTH in 12 patients with a mean duration of illness prior to treatment of 23 months. Fifty units of PTH were injected into the plaque weekly for 8 weeks. They described their criteria of "markedly improved" as a reduction of a particular symptom by 50 to 90%. After the course of therapy, seven of 12 patients reported absence or marked improvement in plaque, while 5 of 12 remained unchanged or minimally improved. Six of 12 noted marked improvement in curvature, and five out of six, who complained of pain, were cured or markedly relieved of pain. The rationale for using PTH in Peyronie's patients is based upon reports of increased

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ted in an FDA approved multi-center study. Further study may demonstrate added benefit when this drug is given as a course of several injections resulting in a better reduction of curvature.

respectively, indicating decreased synthesis and secretion of these cellular products. They also noted that the doses necessary to inhibit extracellular matrix formation are much greater than the typical doses in systemic use of these drugs for hypertension. Therefore, local injections of verapamil were necessary to avoid systemic toxicity and to expose fibroblasts within the plaque to an adequate verapamil concentration.

d) Orgotein Orgotein, an anti-inflammatory metalloprotein with pronounced superoxide dismutase activity, was first studied in Europe. Gustafson et al. [90] used this agent on 22 patients and Bartsch et al [91] treated 23 patients. The drug was delivered intralesionally and both investigators achieved results in decreasing the plaque size and increasing sexual function. Verges and Chateau [92] delivered orgotein via ionophoresis. The authors showed decrease in pain, induration, and curvature which permitted the resumption of sexual activity in over 75% of the cases. Primus [93] recently published a report of marked improvement with intralesional orgotein use on a selected group of patients with severe symptoms. Orgotein is not available in the U.S. and was recently restricted from intralesional use in Germany due to a severe toxicity profile.

In the first non-controlled, non-randomized study of intralesional verapamil for Peyronie's disease, 14 men with a mean age of 51 years received this therapy in a dose escalating fashion. [94]. The patients had a mean duration of disease of 20 months, and 11 of the 14 had failed prior oral therapy with vitamin E and/or Potaba. Prior to administering verapamil, a penile block with xylocaine was given. Verapamil was then injected using a 10cc syringe with a 25 gauge needle in a multiple puncture technique (100-150 punctures per dose). The starting concentration was 1 mM and was doubled monthly. All patients received twelve injections over six months with a maximum dose of 10mg in 10 mL of solution. Ninety-one percent of patients who had experienced pain at the initiation of the study had rapid resolution of the pain within 1-2 injections. Penile deformity, including shaft narrowing, decreased in 100% of patients, but curvature improved in only 42%. Fifty-eight percent reported that their sexual performance had improved. Objectively, a decrease in plaque volume of greater than 50% was noted by ultrasound in 4 of 12 (30%) patients, but all noted plaque softening. Overall, 83% noted that the disease had arrested or improved with no recurrence of symptoms or deformity within the eight month followup period. In addition, 4 patients who had incomplete response to verapamil underwent successful surgical repair without added difficulty caused by the injection therapy.

e) Verapamil The calcium antagonist verapamil was first reported as an intralesional therapy by Levine et al in 1994 [94]. The rationale for use of verapamil comes from the experiments by Kelly [95] who in 1985 demonstrated that exocytosis of extracellular matrix molecules including collagen, fibronectin and glycosaminoglycans, the primary components of a Peyronie's plaque, is a calcium ion dependent process. Aggler and associates demonstrated that when fibroblasts were exposed to anti-tubular agents and calcium antagonists in vitro a change in cell shape was noted. This morphogenic change resulted in an altered protein secretion phenotype, manifested by increased extracellular matrix collagenase secretion as well as decreased collagen and fibronectin synthesis and secretion [96]. Similar changes have been seen when fibroblasts have been exposed in vitro to other agents such as colchicine, tamoxifen and interferon. Lee and Ping [97] reported in 1990 on their experiments with cultured bovine fibroblasts exposed to increasing concentrations of verapamil and nifedipine. They found a dose-dependent decrease in the incorporation of radiolabelled proline and sulfate into extracellular matrix collagen and glycosaminoglycans,

More recent research has also demonstrated the effects of verapamil to modulate extracellular matrix metabolism by inhibiting the expression of collagen as well as by increasing the proteolytic activity of collagenase, thereby enhancing matrix remodeling by human fibroblasta in burn scars and vascular smooth muscle cells in vitro. [98, 99]. In addition, verapamil and other calcium channel blockers were found to affect cytokine expression associated with early phases of wound healing and

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inflammation, including platelet-derived growth factor-BB, interleukin-6 and interleukin-8 [99, 100]. All of this work indicated the importance of regulating the balance between matrix biosynthesis and degradation by fibroblasts.

2) modest improvement of penile deformity, 3) improved rigidity and/or sexual performance in approximately 75%, and 4) no acute or chronic side effects. the ideal candidate for intralesional verapamil treatment appears to be those who present with pain, refuse surgery, have curvature less than 90o and do not have extensive plate-like plaque calcification Further published studies on the use of verapamil for Peyronie’s disease includes a report by Teloken et al who noted no advantage to verapamil over placebo or steroids when given in a controlled fashion. Yet, the study agents were not injected into the plaque; rather, they were injected around the plaque [103]. It seems that if a change in fibroblast metabolism and plaque behavior is expected a more concentrated direct distribution of drug is necessary. Rehman et al in a randomized singleblind trial of intralesional verapamil vs saline reported on 14 patients in which there was a decreased plaque volume of 57% in the verapamil gorup vs 28% in the control group, a non-significant improvement trend in penile curvature in the verapamil group of 38o vs 30o in the control group and a subjective improvement in penile narrowing in all verapamil patients with improved quality of erection in 43% vs none in the control group. [104]. Of note, there was no local or systemic toxicity except occasional ecchymosis at the injection site similar to the Chicago experience. f) Interferon

In a second published study, Levine reported on 46 Peyronie's patients who participated in a non-randomized, non-placebo controlled phase II study of verapamil [101]. Ten mg of verapamil diluted to 10 mL with saline was injected every two weeks for six months. The maximum dose of 10 mg was chosen because of the optimal response demonstrated in the previous study as well as limited cardiovascular risk following intravenous injection of 10 mg as suggested by pharmaceutical industry safety data. The mean age and disease duration were 51 years and 17.2 months, respectively. Fifty-nine percent of these 46 men had failed prior oral therapy and 61% had painful erections. Only 26% were fully potent prior to therapy and 48% had stuffable erections. Mean plaque volume was approximated with duplex ultrasound (DU) at 3.9 mL (range 0.8 - 11.6 mL) and mean penile curvature was assessed after injection of 60 mg Papaverine at 50° (range 10 - 90°). Thirty-eight men have completed the therapy. Subjectively, 97% (26/27) had rapid resolution of pain after a mean of 2.5 injections. Penile curvature improved in 76% (32/38), mean 38 degrees, range 5 to 70 degrees), with improved distal rigidity in 93% (25/27), reduction in hour-glass deformity in 86% (19/22) and increased sexual performance in 72% (27/38). Thirty-five men underwent objective evaluation included pre- and post-treatment duplex ultrasound, which demonstrated a decreased curvature in 54% (19/35) with a mean decrease of 25° (range 10 - 40°), no change in DU parameters, and no significant change in plaque volume.

The potential use of interferons as an intralesional therapy for Peyronie's disease was demonstrated in a 1991 study by Duncan et al. [106] in which fibroblasts from Peyronie's plaques were cultured in the presence of interferons alpha-2B, betaSer17, and gamma. The rationale for interferon therapy originates from studies illustrating similar fibroblast activity in Peyronie's plaque, keloid scars and scleroderma [107, 102]. In these cases, fibroblasts are activated and produce excessive amounts of extracellular matrix components, including collagen, glycosaminoglycans, and fibronectin. In vitro study indicates that interferons normalize the activity of fibroblasts derived from patients with scleroderma and keloids [102, 107, 108]. In fibroblasts derived from Peyronie's plaques, the addition of interferons decreased the rate of proliferation in a dose dependent fashion, decreased the production of extracellular collagen,

There were no substantial differences in response to treatment noted on duration of disease (greater or less than 12 months), or within the 3 Kelami classification groups as discussed before with the intralesional collagenase studies [102]. The Rush-Presbyterian-St. Luke’s Medical Center, Chicago experience with over 170 non-randomized patients suggests that intralesional injection of Verapamil results in 1) rapid resolution of pain,

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and increased the production of collagenase. These in vitro results suggest the potential of interferons as an in vivo treatment for Peyronie’s disease. Interestingly, interferon-gamma increased the production of fibronectin and glycosaminoglycans. These in vitro results suggest the potential of interferons as an in vivo treatment for Peyronie's disease.

Beta-aminopropionitrile irreversibly binds to lysil oxidase, an enzyme responsible for the cross-linking of collagen fibrils, and prevents normal collagen fibrogenesis. A four-week course of twice a day topical application brought only subjective improvement in 3 patients. No changes in plaque diameter were noted by ultrasonography or penile deformity following intracorporal infusion.

Several clinical trials of intralesional interferon for Peyronie’s disease have been published. Wegner and associates studied 25 men who were given 5 local injections of 1 million units of interferonalpah-2b on a weekly basis [109]. The condition improved clinically in only 1 case. Side effects including myalgia and fever, occurred in 4 pateints.

b) Various energy modalities Reports have also been presented at international meetings, in the past three years, using various energy modalities alone or in combination with agents, including steroids, verapamil and orgotein. In an Italian study of 68 patients receiving orgotein infiltration with or without topical laser and ultrasound therapy pain rapidly resolved, but there was no improvement of penile bending [112].

Further dose-finding studies by Wednger in 30 patients with 3 million units IFN-alpha 2b given weekly for 3 injections demonstrted clinical improvement in only 1 subject [110]. Three worsened and 10 new plaques developed. 25% of patients had untolerable side effects, including 74 of 90 injections causing fever > 38 degrees C. They concluded that this agent is not useful for the treatment of Peyronie’s disease with this regimen. Using a different dosing regimen with IFN-alpah 2b of 1.5 million units three times a week for 3 weeks, Judge and Wisniewski reported on 10 patients again treated without a control arm. [111]. Six of ten had disappearance of pain and subjective improvement in deformity. Objective improve ment in deformity was considered small with mean improvement of 20 degrees. Patients with small plaques (< 4 cm) were more likely to have a better response. All patients experience brief influenza-like side effects.

c) Iontophoresis Iontophoresis was examined as a means of enhancing topical delivery of verapamil (10 mg) and dexamethasone (4 mg) with a local electric field in 15 patients with Peyronie’s disease. This treatment was given 3 sessions a weeks for three weeks for 20 minutes per session using a 3 mA current. At a mean 5 month follow-up penile pain resolved in 66%, curvature improved in 53% and plaque size reduced or softened in 40% of cases [113]. We are likely to see more and hopefully better controlled studies of topical drug enhancing technologies for the treatment of this difficult disease. d) Local penile lithotripsy Local penile lithotripsy has also been proposed as topical therapy for Peyronie’s disease with limited numbers of patients reporting subjective results. [63]. The rationale for this approach is not known.

In a study of IFN-alpha-2A intralesional injection in 15 patients was evaluated by magnetic resonance imaging. This study demonstrated plaque size reduction only, particularly in small plaques (< 1 cm) where there was complete plaque disappearance.

4. FUTUR TRENDS Clearly, the need for continued controlled clini cal trials is in order as well as basic research into the pathophysiology of this disorder. Breakthroughs in understanding the role of cytokines and fibroblast activity as well as their interaction with extra-cellular matrix macromolecules, including collagen but likely other components, will enhance our ability to offer reasonable and effective non-surgical therapy.

3. OTHER APPLICATIONS a) Topical Beta-aminopropionitrile Topical beta-aminopropionitrile, a potent collagen cross-link inhibitor, was employed by Gelbard et al. in 9 patients with Peyronie's disease [105]

In addition, further investigation will be necessary

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to establish standards for evaluating objective measures of plaque and deformity change. Ultra sound has been demonstrated to be a relatively inexpensive, reliable and non-invasive technique to measure plaque dimensions and calcification [55-114]. Vacuum chamber photography [89] was used in concert with vasoactive intracavernosal injectin in an effort to obtain the optimum erect state in study patients so that intra and inter-subject variation in the ability to measure deformity would be minimized. Unfortunately, in this investigator’s experience it appears that due to the substantial extra-tunical penile engorgement that occurs with vacuum chambers this may conceal the underlying shaft deformity caused by the tunica albuginea scarring. Therefore, the key to reducing variability in erectile response which is critial to accurate measurement of deformity (curvature and narrowing) will be complete smooth muscle relaxation and patient confirmation of a full erection.

5. SUMMARY OF NON-SURGICAL THERAPY (TABLE 1) a) Oral Treatments Vitamin E – In general a safe, inexpensive, nontoxic therapy showing at best a modest improvement in deformity (10-15 %). Most studies are small in number, non-controlled with subjective reporting on outcome. [Dose 800-1000 mg/day]

ded for longer than 3 months due to possible bone marrow suppression [Dose 0.6 mg TID]. Tamoxifen – Several small, short-term reports suggest moderate benefit based upon response seen with idiopathic retroperitoneal fibrosis. Usually well tolerated but gastrointestinal distress and alopecia reported. No significant difference reported in deformity improvement in single controlled trial [ Dose 20 mg BID]. b) Intralesional Injection Orgotein – Mechanism unclear may be due to change in superoxide dismutase activity. No controlled studies found. Subjective reported benefits high at 80-90 %, yet significant toxicity. Not available in US and taken off market in several European countries. Steroids – Several short-term non-controlled subjective reports on response using various steroids and doses with mean reported benefit in deformity around 60 %. Risk with this therapy outweigh benefits and include tissue atrophy, skin thinning and making surgical repair more difficult due to loss of tissue plane between Buck’s fascia and tunica. Not recommended for use. Verapamil – Several studies reported, two controlled trials, one showing benefit in all objective measures, the other showing no statistical benefit over saline control. Its action is based on change in fibroblast behavior and cytokine inhibition. Goals of this treatment are to stabilize disease process and in responders reactivate a more “normal” remodelling process, yielding gradual improvement in deformity. This is why multiple doses over time given. Reported side-effect primarily ecchymosis with objective measures of deformity improvement in 50-60 % of patients treated. [Dose 10 mg verapamil in total of 10cc volume injected every 2-4 weeks x 12].

Potaba – A therapy which has no clear rationale for its use. Yet, frequently employed for obscure historical reasons. Virtually all reports with no control and only subjective reporting of outcome. Recent placebo-controlled trial with one year follow-up showed statistically significant improvement in plaque size but no significant change in deformity. This drug is also relatively expensive with significant gastrointestinal intolerance [Dose 12gm/day].

Interferon – Several small non-controlled studies with short follow-up. Mechanism may be similar to verapamil by affecting fibroblast function and acute reactive cytokine activity. Yet improvement in deformity limited 4-60 %. This mediation is expensive with a high rate of flu-like symptom side-effects. Await further controlled trials.

Colchicine – The newest oral therapy : again limited published studies and no controlled trials. The rational for its use is sensible with respect to change in fibroblast function, yet getting adequate tissue levels into the tunica has not been demonstrated. Objective measures of improvement in deformity reported in 30-40 % of patients primarily with early stage disease (< 3 month duration). Significant gastrointestinal intolerance 30-50 %. Not recommen-

Collagenase – Not yet available but several published reports including one controlled trial showing benefit for deformity less than 30 %. Mecha455

nism to alter collagen content of plaque. Toxicity profile low. Further study ongoing.

There is considerable variation in the deformity that makes penetration difficult. In young men particularly with congenital deformities the bend causes more psychological distress than physical disability and it may be necessary to correct deformities as little as 20-30 degrees. In contrast, a man who is in a stable relationship and with a partner who has had several children is able to cope with a much more severe deformity. It should however be noted that a ventral deformity causes more difficulty than a dorsal or lateral one.

Overall, therapeutic advances in Peyronie's disease have not resulted in a reliable cure. This appears primarily due to an incomplete understanding of the basic pathophysiology of this disease and the lack of an animal model for study. Recent advances in the understanding of disorders of wound healing have allowed forward strides in the understanding of this disease and may offer new therapies, such as the injection of calcium antagonists. The similar response of cultured fibroblasts to colchicine, vinblastine, interferons, and the calcium antagonists, verapamil and nifedipine, suggests that through medical therapy some common primary cellular metabolic events may be altered in Peyronie's plaques. Whether this is at the cytokine level such as TGF-b will require further investigation. Ultimately, a multi-modality therapy such as verapamil with collagenase and possible oral therapy, may be indicated as a non-operative approach. This may allow stabilization or improvement of the Peyronie's deformity. In addition, in advanced cases, which do not respond to conservative therapy, surgery may offer considerable relief.

b) Erectile dysfunction Unless the dysfunction is for psychological reasons, the patients may be better served by the implantation of a penile prosthesis if non-surgical ED treatment is not satisfactory. Some improvement of function may occur postoperatively by reducing the volume of the corpora [115] or by ligating a prominent dorsal penile vein.

2. PREOPERATIVE ASSESSMENT The surgeon should be convinced that there is adequate erectile function (natural or in response to non-surgical ED therapy) before embarking on an operation to correct the deformity and document if there is an organic impairment of erection before implanting a prosthesis. Informed patient consent is essential.

X. SURGICAL TREATMENT

An operation to correct a penile deformity should be delayed until the disease process has stabilized. This is usually taken to be a year after the onset of the disease, pain on erection is no longer usually a feature, and the bend has been stable for three months. In older men with a vasculogenic ED not responding to non-surgical therapy there is no necessity to delay implanting a penile prosthesis.

The replacement of diseased tunica albuginea in Peyronie’s disease was largely unsuccessful until the introduction of a dermis graft. Numerous operations have been described subsequently and it is only now that there is an element of consensus as to the choice of operation. This is because decisions have been based largely on personal experience, and bias, and due to the paucity of good data with regard to outcome - and in particular clinical trials. In looking at outcome it would be rea sonable to only review those series consisting of more than 50 patients who preferably had the same operation and where the indications are given and there is some statement as to the means of assessing outcome.

• Relative contraindications Reconstructive surgery is not recommended in the acute phase of the disease. Patients with unrealistic expectations will not be satisfied with any outcome and are not good candidates for surgery. Although many penile implants have been performed in patients with normal penile rigidity in the past, we feel that penile implant should be reserved for Peyronie's patients who also have erectile dysfunction and do not respond to non-surgical therapies such as sildenafil, vacuum device, transurethral or intracavernous injection.

1. INDICATIONS FOR OPERATION • These fall into two categories: a) Deformity

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• Anaesthetic and Incision

procedure was good in 94% of 65 patients with normal preoperative erectile function but only satisfactory in 77% of 53 patients with preoperative impairment of erectile function [129].

The fitness of the patient to undergo surgery is rarely a consideration as the operations may be performed under local or general anaesthesia and as outpatients or inpatients. Outpatient surgery requires more expertise and better patient selection. A degloving circumglandular incision would seem to be the most popular and consideration should be given whether or not to circumcise the man in order to reduce postoperative complications. In a Nesbit type operation for dorsal curvature, a longitudinal skin incision over the apex of the convex curve is a better approach.

The complications from the Nesbit procedure are relatively minor [127] and the main drawback is the question of penile shortening. A feature of Peyronie’s disease is the formation of scar tissue and penile shortening is always more than is suggested by the deformity alone. The width of the ellipse excised to correct Peyronie’s disease was found to average 7 mm in width and the average of deformity was 68 degrees. [127] (Figure 3). In reality the shortening of the Nesbit operation is rarely troublesome and was only of more than 2 cm in 17 of 359 men and intercourse was possible in 15 of these [127]. Several modified approaches such as the Yachia procedure have also been reported to have excellent results (Figure 4). Incision or wedge resection of the tunica requires dissection of the neurovascular bundle or the corpus spongiosum and placement of sutures to shortened the longer side of the tunica. A simplified approach is to perform plication on an erect penis produced by intracavernous injection of papaverine or alprostadil. For ventral curvature, 2-3 pairs of non-absorbable sutures (2-0 Ticron or Tevdex) are placed between the deep dorsal vein and the dorsal arteries. For dorsal curvature, same sutures are placed in the paraurethral ridges. No dissection of the neurovascular bundle or corpus spongiosum is necessary. Because the procedure is performed on an erect penis and the sutures are tied partially until the penis is straight, this procedure is less invasive and equally successful (Figure 5).

3. SURGICAL TREATMENT a) Plication or wedge resection Reed Nesbit [116] described the correction of erectile deformities due to congenital abnormalities by shortening the opposite side of the penis using a plication technique or by the excision of an ellipse of tunica albuginea. The results of correction of congenital deformities have been excellent. Although Nesbit described the plication technique it was not until two decades later that plication was rediscovered [117, 118]. In addition to the plication technique a variety of corporoplasties have been described [119, 120, 121, 122, 123, 124, 125]. The plication techniques are simpler but the outcome is less reliable. The Nesbit technique was introduced for Peyronie’s disease in 1979 [126] and in 359 men operated upon between 1977 and 1992, 295 (82%) had good results and were able to have intercourse. [127]. A literature review confirmed the favorable results [128].

b) Excision or incision of tunica and grafting

In considering the outcome of the Nesbit procedure it is apparent that the prognosis is worse than in patients with congenital deformities. It is also apparent that with increasing time since the operation there is a decrease in the satisfaction rate although this is usually a change from excellent results to satisfactory results. The overall results of the Nesbit procedure improved in the operations performed after 1985. It was by that stage that pharmaco-testing for erectile function had become a routine and this eliminated many of the patients having an operation with impaired erectile function due to vasculogenic causes [127].

Plaque excision was general unsuccessful until a dermal graft replacement of the tunica albuginea was described by Bystrom et al [130] in Scandinavia and by Devine and Horton [131] in the United States (Figure 6). Bystrom et al (1982) reported that despite good early results the later results were disappointing with only 6 of 17 men having a good result after 10 years. A review of the literature [128] showed that there was great variability in the outcome of plaque excision and dermal graft and in a recent large series of 418 men [132] it was found that 17% of patients required further surgery for curvature and 20% of patients had significant impairment of erection.

Porst also noted that the outcome of the Nesbit 457

458

459

460

461

A

B

C

D

E

F

Figure 3: Nesbit's wedge resection. (A), Penile curvature is assessed by an artificial erection. The incision line is marked. (B), The tunica albuginea is exposed after incising the Buck's fascia. (C). The ellipse of tunica to be removed is marked. (D), The tunica is excised. (E,) The edges are approximated. (F), The penis is straight as assessed by artificial erection.

462

A

B

C

Figure 4: Yachia procedure for correction of curvature. (A), Buck's fascia is reflected exposing the tunica albuginea. (B), Longitudinal incisions are created at the area of maximal curvature as demonstrated by artificial erection. (C), The longitudinal closures are closed transversely, with artificial erec tion demonstrating straightening of the penis.

Figure 5: Plication procedures performed on an erect penis (after intracavernous injection of papaverine) (Donatucci and Lue,1992) [146]. The location of paired non-absorbable plication sutures is shown: (A), perispongiosal for dorsal curvature. (B), between dorsal vein and dorsal arteries for ventral curvature.

463

A

B

C

D

E

F

Figure 6: Plaque excision and dermal grafting (Devine's technique) (A), An artificial erection demonstrates the dorsal curvature of the penis. The incision is made in the scar of the previous cir cumcision. (B), The skin is de-gloved to the base of the penis. An incision in the deep dorsal midline of Buck's fascia exposes the deep dorsal vein. (C), The deep dorsal vein is mobilized and (D), resected. (E), The neurovascular bundle is freed from the plaque. (F,) An artificial erection demonstrates the curvature caused by the inelastic plaque. Stellate releasing incisions have been marked.

464

G

I

H

J

K

(G), Prolene sutures have been placed distal and proximal to the plaque and at the tip of each of the releasing incisions. An incision has been made outlining the plaque, and the plaque is excised. (H), The plaque has been excised. This defect must now be filled with a dermal graft. (I )The dermal graft has been obtained and inlaid in the defect. An artificial erection shows the penis to be straight. If there is a leak in a suture line, it is oversewn. (J), Buck's fascia is loosely re-approximated in the midline with interrupted sutures. One or two small suction drains are left in the space superficial to Buck's fascia. (K), The skin is closed with interrupted sutures

465

Erectile dysfunction following plaque excision is due to a combination of factors ranging from damage to the underlying erectile tissue adherent to the plaque, loss of compliance of the dermal graft, new venous channels forming to give veno occlusive dysfunction [133] and deterioration of the underlying aetiological factors which are generally thought to be ischaemic or vasculogenic in origin. It is now recognized that the histological changes of Peyronie’s disease are not confined to the plaque but may also be seen in the normal tunica albuginea excised during the Nesbit procedure [134,135]. In some instances the plaque extends into the erectile tissue [136]. Jordan and Angermeier [38] showed that the outcome of plaque excision and grafting was related to the preoperative findings on dynamic cavernosometry. All four men with normal preoperative function had an excellent outcome whereas 9 of the 12 men with some impairment had a satisfactory outcome and only 1 of 4 with poor perfusion characteristics was potent postoperatively. In view of the relatively poor outcome of plaque excision and dermal grafting great care is required in patient selection for this procedure. Subsequently, many autologous tissue (dermis, temporalis fascia, dura mater, tunica vaginalis and dorsal or saphenous vein) and synthetic material (Dacron and Goretex) have been used with different results. Excision of the plaque has been the standard approach. However, it is now known that the pathologic process of Peyronie's diease extends far beyond the plaque and removing a large area of tunica albuginea may impair erectile function. In 1991, Gelbard and Hayden [137] proposed plaque incision and grafting rather than excision and this has becoming a more popular technique (Figure 7). So far there is no graft material that is perfect for replacing the diseased tunica albuginea. The synthetic material, dura and fascia may provide a strong covering for the tunica but they don't stretch as the normal tunica and curvature may recur after the graft is fixed to the surrounding tissue. Synthetic material also has some risks of foreign body reaction and infection. Dermis is a good substitute and plentiful but it tends to contract after several months and cause recurrence unless a larger graft (1/3 larger than the defect) is placed to allow contraction. Recently some proposed saphenous vein graft because

Neurovascular bundle

Midline plaquie A

penis stretched

3 Relaxing incision in tunica B

Middle relaxing incision darted at apex C

Gaps filled with tailored grafts of temporalis fascia D Figure 7: Plaque incision and temporalis grafting (Gel bard's procedure) (A). Dissection of the neurovascular bundles. (B) Effect of multiple relaxing incisions in tunica albugeniea--plaque completely divided in three locations. (C) Relaxing incision darted. (D). Relaxing incisions graf ted with temporalis fascia free grafts.

466

1) it regains blood supply within minutes,

from AMS and Alpha 1 from Mentor) are better choices in patient with penile curvature [142]. The satisfactory outcome of inflatable prostheses was also found in publications of Knoll et al. (1990) [143], Eigner et al (1991), [144] and Carson (1998) [145]. In the surgical management of Peyronieís disease, patient selection and attention to surgical detail are both important. For the less experienced surgeon it is probably better to rely upon the tried combination of the Nesbit technique to correct the deformity and the implantation of a penile prosthesis in those patients with additional vasculogenic erectile dysfunction. In a patient with normal potency there is still a place for plaque excision/incision and dermal grafting. In the light of current experience, and particularly in the short stubby penis, plaque incision and the insertion of a vein patch is well worth considering for the experienced surgeon.

2) the endothelium limit permeation of blood and therefore will not cause hematoma at the graft site and 3) its smooth muscle coat reacts to high pressure in the penis and becomes thicker and stronger in about 3 months. There is experimental evidence to suggest that a vein patch is superior to dermal flap or synthetic tissue [138] and in the only large series using the Lue technique [139, 140] (Figure 6) follow-up was possible in 112 of 145 men. Of these, 95% reported that the penis was straightened but 17% complained of penile shortening and 13% of preop potent patients reported decreased penile rigidity after surgery [140]. c) Implantation of a Penile Prosthesis with or without grafting This is the treatment of choice for those men with Peyronie’s disease and erectile dysfunction not responding to non-surgical ED treatment. Literature review [128] showed excellent results provided men had realistic expectations. Although there may be some intrusion on the corporal bodies, this does not usually cause any difficulty in the implantation. In the past, if a patient has both penile deformity and erectile dysfunction, he is automatically recommended for insertion of penile prosthesis. However, this indication has been modified since the less invasive treatments (oral sildenafil, intracavernous injection, intraurethral medication and vacuum constriction device) has now replaced penile prosthesis as the initial treatment options for erectile dysfunction. In most patients with mild to moderate deformity, insertion of a penile prosthesis tends to straighten the penis and no additional procedure is necessary. However, if severe deformity still persists after prosthesis is inflated, one can perform an incision of the plaque and cover the defect with synthetic material such as Goretex. The use of operative molding of the penis over the prosthesis may give good correction of the deformity [141]. A malleable prosthesis usually corrects the deformity but gives less overall functional satisfaction. If inflatable penile prosthesis is used in Peyronie's disease, it is recommended not to use the distally expanding prosthesis (such as Ultrex, from American Medical Systems [AMS]) because when the device lengthens it also tends to bend the penis. The girth expansion-only devices (such as CX

XI. PENILE ANOMALIES THAT MAY CAUSE ERECTILE DYSFUNCTION Most congenital anatomical penile abnormalities do not cause erectile dysfunction. Usually the patients are fully able to reach a rigid erection. However in some cases the shape or size of the penis makes penetration difficult or may cause discomfort or even pain to the partner, as a result of the anomaly a sexual dysfunction starts to develop. This later can become a psychosexual dysfunction which may result in erectile dysfunction. The effect of acquired penile abnormalities to the patients erectile ability is variable. While in some patients the erectile ability does not change as the result of the disease, the change in the shape of the penis may cause severe sexual dysfunction to the patient or the couple. In others the disease has a direct effect on the erectile ability. What has not been objectively evaluated is the impact of the various penile deformities to the sexual well being of the patients or the couples. Such evaluation can be done using a symptom score for the patient and a quality of life index, which can be divided into 2 parts: for the patient himself and of the couple. Table 2 comprises the congenital and acquired penile abnormalities which may have an effect on erectile or sexual dysfunction. 467

Table 2: Penile abnormalities that may cause erectile and/or sexual dysfunction

CONGENITAL PENIS Curvature Micropenis: - Endocrinic - non-endocrinic Concealed Hypospadias Epispadias Shaft rotation PREPUTIUM: Phymosis Paraphymosis Short Frenulum ACQUIRED PEYRONIE’S DISEASE URETHRAL Iatrogenic: Hypospadias Cripples Extrophy/epispadias cripples Kelami Sydrome Traumatic: URETHRAL: Self induced (Kelami Syndrome) CORPORAL: Accidental (T. albuginea tears) Self induced (T. albuginea tears) Iatrogenic - After hypospadias repair - After curvature repair - ICI induced - Penile prothesis erosion NEURO-VASCULAR: Pelvic fractures PENILE: Retraction (after surgery or circumcision) Amputations: Self induced Accidental (circumcision) Medical (penile tumors) Disease: Ca of penis Penile lymphedema Penile condyloma Skin inflammations Foreign bodies (Self implanted)

ERECTILE DYSFUNCTION

PSYCHO-SEXUAL DYSFUNCTION

N Y N

S Y Y

N N N N

Y S Y S

N N S ERECTILE DYSFUNCTION S

S S S PSYCHO-SEXUAL DYSFUNCTION S

S S N

Y Y S

N

S

S S

S/N S

N N Y Y

S S Y Y

S

S

N

Y

Y Y Y

Y Y Y

S N N N N

Y Y S/N S S

Y = yes, N = no, S = sometimes

468

B

A

D

C

D

Figure 8 : H-incision and saphenous vein grafting (Lue et al, 1998). (A). dissection of neurovascular bundles (medial to lateral) with tenatomy scissors under 3x or 5x magnification loupes. (B), H-shaped transverse relaxing incision in center of plaque for correction of penile curvature and longitudinal incisions for hourglass deformity. (C). The tunical defect is measured by stretching the penis longitudinally and transversely. (D). A seg ment of saphenous vein is resected, opened, cut into several pieces and stapled together with vascular clips. The vein graft is then sutured to the tunical defect with the endothelial surface facing the inside of the corpus cavernosum.

469

HISTORY

• Medical • Sexual • Family

PHYSICAL EXAMINATION PLAGUE SIZE, LOCATION DUPUYTREN’S STRETCHED PENILE LENGTH

BLOOD TESTS FOR

PATIENT WITH ED

Penile sonography if necessary (Duplex sonography optional)

ASSESS : FINDINGS EDUCATE : PATHOPHYSIOLOGY COUNSEL : OPTIONS

SHARED mild or

DECISION

ASSURANCE, VITAMIN E (±) asymptomatic

MAKING long standing peyronies with severe deformity (more than one year)

moderate or severe symptons Non-surgical therapy for 3-6 months ORAL - colchicine potaba Tamoxifen Intralesional - Verapamil

Mild or no deformity

CONTINUE NONSURGICAL THERAPY OR

WATCHFUL WAITING

Persistent pain > 1 year Moderate or severe deformity DOCUMENT: - deformity - penile - length WITH - photograph - drawing - vacuum device with ED

Poor response to non-prosthetic ED therapy

PENILE PROSTHESIS

LOW DOSE RADIATION (±] OR

SURGERY (±]

without ED

Gool response Moderate to non-prosthetic deformity ED therapy Nesbit Wedge or Modified Nesbit or plication Procedure

Figure 9 : Algorithm for the management of Peyronie’s disease

470

Severe deformity hour glass deformity hinged penis short penis vascular testing Duplex or GRAFTING DICC PROCEDURE

offers the best overall results. Grafting procedures should be performed by more experienced surgeons because more advanced skills are required in dissection of neurovascular bundles and grafting.

XII. CONCLUSION Peyronie's disease is one of the most puzzling diseases in urology: the pathogenesis is still not certain, the medical treatments are unpredictable and effective in less than 50 % of patients, and controversies still exist regarding surgical approach. A recommended algorithm for the management of Peyronie’s disease is shown in Figure 7. New research on the etiology and pathogenesis is urgently needed which hopefully will improve our understanding and management for patient with this frustrating disease.

In those with disabling penile deformity and ED not satisfied with non-surgical treatment, penile prosthesis implantation gives the best outcome.

REFERENCES

XIII. RECOMMENDATIONS In dealing with Peyronie’s disease, a detailed medical and psychosexual history followed by a focused examination of the penis to assess the location, size, number, and consistency of the plaque is essential in planning the management strategy. Because Peyronie’s disease is not a lifethreatening condition, the treatment can be tailored to patient’s treatment goal (a goal-directed approach). Education of the pathogenesis, natural history and treatment options of the disease will help the patient and his partner make an informed choice.

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GELBARD M.K., JAMES N. RIACH P., DOVR F.: Collagenase versus placebo in the treatment of Peronie's diseas: a double blined study. J Urol 149:56-58, 1993. GUSTAFSON H, JOHANSSON B, EDSMYR F. Peyronie's disease: experience of local treatment with Orgotein. Eur Urol 1981;7(6):346-8. BARTSCH G, MENANDER-HUBER KB, HUBER W, MARBERGER H. Orgotein, a new drug for the treatment of Peyronie's disease. Eur J Rheumatol Inflamm 1981;4(2):250-9. VERGES J, CHATEU A. Nouveau traitment della maladie La Peyronie: la superoxyde desmutase par ionisiations. Comparison avec une serie ancienne clasique. Ann Urol (Paris) ;22:143-4. PRIMUS G. Orgotein in the treatment of plastic induration of the penis (Peyronie's disease). Int Urol Nephrol 1993;25(2):169-72. LEVINE L, MERRICK P, LEE R. Intralesional verapamil injection for the treatment of Peyronie's disease. J Urology 1994;151:1522-4. KELLY R. Pathways of protein secretion in erkariots. Science 1985;230:25,. AGGLER J, FRISCH S, WERB Z. Changes in cell shape correlate with collagenase gene expression in rabbit synovial fibroblasts. Journal of Cell Biology 1984;98:1662,. LEE R, PING J. Calcium antagonists retard extracellular matrix production in connective tissue equivalent. J. Surg Res 1990;49:463.

106. DUNCAN M, BERMAN B, NSEYO U. Regulation of the proliferation and biosynthetic activities of cultured human Peyronie's disease fibroblasta by interferonsalpha,-beta and -gamma. Scand. J Urol Nephrol 1991;25:89-94. 107. BERMAN B, DUNCAN MR. Short-term keloid treatment in vivo with human interferon alfa-2b results in a selective and persistent normalization of keloidal fibroblast collagen, glycosaminoglycan, and collagenase production in vitro. J Am Acad Dermatol 1989;21(4 Pt 1):694-702. 108. KAHARI VM, HEINO J, VUORIO T, VUORIO E. Interferon-alpha and interferon-gamma reduce excessive collagen synthesis and procollagen mRNAlevels of scleroderma fibroblasts in culture. Biochim Biophys Acta 1988;968(1):45-50. 109. WEGNER H, ANDRESEN R, KNISPEL H, MILLER K. Treatment of Peyronie's disease with local interferon-alpha 2b. Eur Urol 1995;28:236-40. 110. WEGNER HE, ANDRESEN R, KNISPEL HH, MILLER K. Local interferon-alpha 2b is not an effective treatment in early-stage Peyronie's disease. Eur Urol 1997;32(2):190-3. 111. JUDGE IA. AND WISNIEWSKI, ZS Intralesional interferon in the treatment of Peyronie's disease: in a pilot study. Bri J Urol; 70:42, 1997 112. FELIPETTO R, VIGANO L, PAGNI GL, MINERVINI R. [Laser and ultrasonic therapy in simultaneous

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113. TREFFILETTI S, ANNOSCIA S, MONTEFIORE F, BOCCAFOSCHI C. [Iontophoresis in the conservative treatment of Peyronie's disease: preliminary experience]. Arch Ital Urol Androl 1997;69(5):323-7.

132. AUSTONI E, COLOMBO F, MANTOVANI F, PATELLI E, FENICE O. [Radical surgery and conservation of erection in Peyronie's disease]. Arch Ital Urol Androl 1995;67(5):359-64.

114. ANDRESEN R, WEGNER HE, BANZER D, MILLER K. Ultrasound and soft-tissue radiography to monitor local interferon- alpha 2B treatment in Peyronie's disease. Acta Radiol 1996;37(3 Pt 1):352-6.

133. DALKIN B, CARTER M. Venogenic impotence following dermal graft repair for Peyronie's disease. J Urol 1991;146:849-51.

115. CLAES H, BAERT L. Corporeal plication for surgical correction in Peyronie's disease improves rigidity. Int J Impot Res 1995;7(2):119-22.

134. IACONO F, BARRA S, DE ROSA G, BOSCAINO A, LOTTI T. Microstructural disorders of tunica albuginea in patients affected by Peyronie's disease with or without erection dysfunction. J Urol 1993;150(6): 1806-9. 135. ANAFARTAK, BEDUK Y, ULUOGLU O, AYDOS K, BALTACI S. The significance of histopathological changes of the normal tunica albuginea in Peyronie's disease. Int Urol Nephrol 1994;26(1):71-7. 136. PRYOR J. The Management of Peyronie's disease. In: Porst H, editor. Penile Disorders. Berlin Heidelberg: Springer-Verlang; 1997. p. 35-56. 137. GELBARD M, HAYDEN B. Expanding contractures of the tunica albuginea due to Peyronie's disease with temporalis fascia free grafts. J Urol 1991;145:772-6. 138. BRANNIGAN RE, KIM ED, OYASU R, MCVARY KT. Comparison of tunica albuginea substitutes for the treatment of Peyronie's disease. J Urol 1998;159 (3):1064-8. 139. LUE TF, EL-SAKKAAI. Venous patch graft for Peyronie's disease. Part I: technique. J Urol 1998;160(6 Pt 1):2047-9. 140. EL-SAKKA AI, RASHWAN HM, LUE TF. Venous patch graft for Peyronie's disease. Part II: outcome analysis. Journal of Urology 1998;160(6 Pt 1):2050-3. 141. WILSON SK, DELK JR, 2nd. A new treatment for Peyronie's disease: modeling the penis over an inflatable penile prosthesis. J Urol 1994;152(4):1121-3. 142. MONTAGUE DK, ANGERMEIER KW, LAKIN MM, INGLERIGHTBJ.AMS 3-piece inflatable penile prosthesis implantation in men with Peyronie's disease: comparison of CX and Ultrex cylinders [see comments]. J Urol 1996;156(5):1633-5. 143. KNOLL LD, FURLOWWL, BENSON RC, Jr. Management of Peyronie disease by implantation of inflatable penile prosthesis. Urology 1990;36(5):406-9. 144. EIGNER EB, KABALIN JN, KESSLER R. Penile implants in the treatment of Peyronie's disease. J Urol 1991;145(1):69-71; discussion -2. 145. CARSON CC. Penile prosthesis implantation in the treatment of Peyronie's disease. Int J Impot Res 1998;10 (2):125-8. 146. DONATUCCI CF, LUE TF. Correction of penile deformity assisted by intracavernous injection of papaverine. Journal of Urology 1992;147(4):1108-10.

116. NESBITR.Congenital Curvature of the phallus: report of three cases with description of corrective operation. J Urol 1965;74:497-500. 117. EBBEHOJ J, METZ P. New operation for "krummerik" (penile curvature). Urology 1985;26(1):76-8. 118. ESSED E, SCHROEDER FH. New surgical treatment for Peyronie disease. Urology 1985;25(6):582-7. 119. LEMBERGER RJ, BISHOP MC, BATES CP. Nesbit's operation for Peyronie's disease. Br J Urol 1984;56(6): 721-3. 120. KELAMI A. Congenital penile deviation and its treatment with the Nesbit-Kelami technique. Br J Urol 1987;60(3):261-3. 121. YACHIA D. Modified corporoplasty for the treatment of penile curvature. J Urol 1990;143(1):80-2. 122. SASSINE AM, WESPES E, SCHULMAN CC. Modified corporoplasty for penile curvature: 10 years' experience. Urology 1994;44(3):419-21. 123. GEERTSEN U, BROK K, ANDERSEN B. Peyronie curvature treated by plication of the penile fasciae. Br J Urol 1996;77:733-5. 124. LICHT MR, LEWIS RW. Modified Nesbit procedure for the treatment of Peyronie's disease: a comparative outcome analysis [see comments]. J Urol 1997;158(2): 460-3. 125. REHMAN J, BENET A, MINSKY LS, MELMAN A. Results of surgical treatment for abnormal penile curvature: Peyronie's disease and congenital deviation by modified Nesbit plication (tunical shaving and plication). J Urol 1997;157(4):1288-91. 126. PRYOR J, FITZPATRICK J. A new approach to the correction on the pinile deformity in Peyronie's disease. J Urol 1979;122:622-3. 127. RALPH D, AL-AKRAA M, PRYOR J. The Nesbit operation for Peyronie's disease: 16-year experience. J Urol 1995;154:1362-3. 128. PRYOR J. Peyronie's disease. In: Hendry W, editor. Recent Advances in Urology. London: Churchill Livingston; 1987. p. 245-61. 129. PORST H. Congenital and acquired penile deviations and penile fractures. In: Porst H, editor. Penile Disorders. Berlin Heidelberg: 37-56: Springer-Verlang; 1997. p. 37-56.

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Committee 13

Male Orgasmic and Ejaculatory Disorders

Chairman W.F. HENDRY

Members S.E. ALTHOF, G.S. B ENSON, S.M. HAENSEL, E.M. HULL, K. KIHARA, R.J. OPSOMER

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CONTENTS 4. NEUROGICAL DISORDERS 5. THE EFFECTS OF DRUGS ON ORGASM AND EJACULATION 6. FUNCTIONAL DISORDERS

DEFINITIONS I. PHYSIOLOGY OF NORMAL EJACULATION

V. INVESTIGATION 1. PRODUCTION OF SEMEN 2. PROPULSION OF EJACULATE 3. O RGASM

1. EVALUATION OF PATIENTS WITH RAPID/ PREMATURE EJACULATION 2. ASSESSMENT OF DELAYED RETARDED EJACULATION 3. HAEMOSPERMIA 4. ASSESSMENT OF SMALL VOLUME EJACULATE 5. ASSESSMENT OF EJACULATORY DUCT OBSTRUCTION ON IMAGING

II. NERVOUS PATHWAYS AND AREA CONTROLLING EJACULATION AND ORGASM 1. SENSORY RECEPTORS AND AREAS 2. AFFERENT PATHWAYS 3. CEREBRAL RECEPTOR AREAS 4. SPINAL MOTOR CENTERS 5. EFFERENT PATHWAYS

VI. TREATMENT 1. PSYCHOLOGICAL TREATMENT FOR RAPID EJACULATION 2. PSYCHOLOGICAL TREATMENT FOR DELAYED EJACULATION 3. DRUG TREATMENT FOR RAPID EJACULATION 4. SPINAL INJURIES 5. LOSS OF EJACULATION AFTER RETROPERITONEAL LYMPH NODE DISSECTION 6. SURGICAL TREATMENT OF EJACULATORY DUCT OBSTRUCTION

III. ELECTROPHYSIOLOGICAL EVALUATION OF THE NERVOUS PATHWAYS CONTROLLING EJACULATION 1. PUDENDAL SOMATOSENSORY EVOKED POTENTIALS (PUDENDAL SEPS) 2. PUDENDAL MOTOR EVOKED POTENTIALS (PUDENDAL MEPS) 3. SACRAL REFLEX ARC TESTING: THE SOMATIC-SOMATIC REFLEX ARC 4. S YMPATHETIC SKIN RESPONSES (SSRS)

VII. CONCLUSIONS IV. PATHOPHYSIOLOGY OF EJACULATORY DISORDERS VIII. RECOMMENDATIONS 1. EMBRYOLOGY AND CONGENITAL ANOMALIES 2. TRAUMATIC DAMAGE 3. INFECTIVE DISORDERS

REFERENCES

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Male Orgasmic and Ejaculatory Disorders W.F. HENDRY S.E. ALTHOF, G.S. B ENSON, S.M. H AENSEL, E.M. H ULL, K. K IHARA , R.J. O PSOMER

Orgasm and ejaculation constitute the final phase of the sexual response cycle. Although erection and ejaculation are co-ordinated, the mechanisms that produce them are different. We must, therefore, commence by defining our terms, before considering the physiology of normal ejaculation. Disorders of male sexual function affect erection and ejaculation quite differently.

Retrograde ejaculation: Backward passage of semen into the bladder after emission usually due to failure of closure of the bladder neck mechanism, demonstrated by presence of spermatozoa in the urine after orgasm.

I. PHYSIOLOGY OF NORMAL EJACULATION

DEFINITIONS 1. PRODUCTION OF SEMEN

Orgasm: A pleasurable feeling (a cerebral event) usually associated with emission and/or ejaculation.

The spermatozoa are stored in the tails of the epididymides and the ampullary parts of the vasa, and they normally constitute less than 0.1 % of the semen volume. The ejaculate is produced by combining the secretions of the prostate with the contents of the ampullary parts of the vasa deferentia, followed by their expulsion from the urethra washed out by fluid from the seminal vesicles [1]. The normal ejaculate can be split into four to six fractions [2]. Serial biochemical analysis indicates that the first part contains the maximum number of spermatozoa, and subsequent fractions contain sequentially less. Acid phosphatase, citric acid and zinc, emanating from the prostate, are in highest concentration in the first part of the ejaculate, whereas fructose, coming from the seminal vesicles, increases in concentration towards the end of the ejaculatory process. Alteration of the pH values in successive parts of the split ejaculate indicates how the acid component provided by the prostate is serially mixed with the more alkaline contribution of the fructose rich fluid from the seminal vesicles. Approximately 15 - 30% of the entire ejaculate is contributed by the prostate, and

Emission: deposition of seminal fluid components from the ampullary parts of the vasa deferentia, seminal vesicles, and prostate gland into the posterior urethra. Ejaculation: passage of seminal fluid through the urethra and its expulsion from the urethral meatus. Rapid or premature ejaculation: Inability to delay ejaculation sufficiently to enjoy lovemaking. Persistent or recurrent occurrence of ejaculation with minimal sexual stimulation before, on, or shortly after penetration and before the person wishes it. Delayed ejaculation: undue delay in reaching a climax during sexual activity Anorgasmia: Inability to achieve an orgasm during conscious sexual activity, although nocturnal emission may occur. Anejaculation: Absence of ejaculation during orgasm.

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50 - 80% by the seminal vesicular secretion; there is, in addition, a small contribution to the first part of the ejaculate from the bulbo-urethral (Cowper’s) glands which is rich in enzymes and plasminogen activator [3].

1. SENSORY RECEPTORS AND AREAS The glans penis constitutes the primary erogenic area, where Krause-Finger corpuscles are located in the mucosa. These corpuscles act as sensory receptors and seem to function as condensers when repetitive and cumulative stimulation is applied to the glans penis during sexual intercourse. These corpuscules discharge as soon as a certain level of excitation is achieved. The sensory information is transmitted to the spine and the brain.

2. PROPULSION OF EJACULATE Propulsion of the ejaculate is obtained by contraction of the containing chamber (proximal urethra) combined with proximal closure of the bladder neck to prevent retrograde flow and distal urethral patency. Expulsion is achieved by rhythmic contractions of the bulbospongiosus and bulbocavernosus muscles, which forces the contents through the distal urethra. Intermittent contraction of the urethral sphincter prevents retrograde flow into the proximal urethra [4,5].

The external genital organs (penis and testicles) should be distinguished from the extragenital erogenic organs (these areas are highly variable from one subject to another). The stimulation of these secondary erogenic areas contributes to maintaining the erection and provides sensory information enhancing the information from the KrauseFinger corpuscules.

3. ORGASM The orgasmic pleasure comprises 2 phases: the increase in tension in the prostatic urethra wall, and sensory stimuli arising in the area of the verumontanum. From that point the ejaculatory reflex can not be blocked or delayed anymore. This is followed by the expulsive phase, when stimuli and information are sent to the central nervous system from the glans penis and the whole length of the urethra. In summary, a normal sensation of orgasm needs a rigid erection, the discharge of the tension from the orgasmic center and good coordination between the 2 phases of ejaculation (emission and expulsion). The exact mechanism of nocturnal ejaculation with or without orgasm during sleep is unknown. Several hypotheses have been suggested: autonomic activity of the spinal centers (ejaculation without orgasm), lowering of the neurosensory control of the brain, or autonomic discharge of the «condensors» - see below.

2. AFFERENT PATHWAYS Sensory information from the glans penis travels along two different pathways: first, via the sensory fibres of the pudendal nerve (dorsal nerve of penis) up to S4. The afferent «volley» then travels into the spine. It has been demonstrated in the monkey that destroying the dorsal nerves of penis will abolish or delay ejaculation. Secondly, via the hypogastric plexus that transmits information to the ganglia of the paravertebral lumbo-sacral sympathetic chain. It seems that there is a close contact between these autonomic and cerebrospinal nervous pathways.

3. CEREBRAL RECEPTOR AREAS Seminal emission and ejaculation are integrated into the complex pattern of copulatory behavior by forebrain structures that include the medial preoptic area (MPOA) and the paraventricular nucleus of the hypothalamus (PVN). The MPOA, immediately rostral to the anterior hypothalamus, is essential for male copulatory behavior in all vertebrate species that have been tested (reviewed in Meisel & Sachs, [7]). Electrical stimulation of the MPOA can elicit ex copula seminal emission or ejaculation in monkeys [8] and rats [9]. Moderate doses of a mixed D1/D2 dopamine agonist (apomorphine) [10] or of a D1 agonist (thienopyridene) [11], microinjected into the MPOA, promote

II. NERVOUS PATHWAYS AND AREA CONTROLLING EJACULATION AND ORGASM The ejaculatory reflex comprises sensory receptors and areas, afferent pathways, cerebral sensory areas, cerebral motor centers, spinal motor centers and efferent pathways [6].

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erections and facilitate copulation of male rats, apparently by increasing parasympathetic tone. Higher doses of a mixed D1/D2 agonist, or of a selective D2 agonist, shift the autonomic balance to favour seminal emission and ejaculation [11].

sed libido and difficulty achieving ejaculation or orgasm. The postejaculatory decrease in libido may result in part from decreased dopamine release in the nucleus accumbens, a major terminal of the mesolimbic dopamine tract [18]. Dopamine in the nucleus accumbens has been related to motivation and/or reward related to numerous behaviors, including eating, drinking, copulation, and drug addiction. Therefore, one site at which SSRI drugs may inhibit both libido and ejaculation is the LHA. While the N. accumbens probably mediates the SSRI-induced decrease in libido, it probably does not influence ejaculation directly. The structure mediating that effect is not known; however, neurons from the LHA do descend to the lumbar spinal cord, where the neurons controlling genital reflexes reside.

Dopamine is released in the MPOAof male rats in the presence of an estrous female, and increases more during copulation [12]. Thus, the levels of extracellular dopamine in the MPOA may regulate the phases of copulation, with high levels triggering ejaculation. Electrical stimulation of the MPOAalso elicits the urethrogenital reflex in rats, which may mimic orgasm in humans [13]. This reflex is usually elicited in anesthetized, spinally transected rats by distending the urethra with saline and then suddenly releasing the pressure. This results in rhythmic firing of the hypogastric, pelvic, and motor pudendal nerves and rhythmic contractions of the perineal muscles, similar to those seen during orgasm in humans. However, stimulation of the MPOA elicited the reflex, even without genital stimulation.

Another major inhibitory influence on both erections and ejaculation is the nucleus paragigantocellularis (nPGi) in the ventral medulla, which tonically inhibits the spinal nuclei that program the motor output to the genitals and the pelvic musculature. Lesions of the nPGi facilitate the elicitation of the urethrogenital reflex and also reflexive penile erections and anteroflexions [19]. Approximately 78% of the descending neurons from nPGi are serotonergic [13]. Selective serotonin neurotoxin lesions depleted serotonin in the lumbosacral spinal cord and released the urethrogenital reflex from its tonic inhibition [20]. Spinal transection releases the spinal neurons from inhibition and allows the reflex to be elicited by urethral distension. Therefore, either a lesion of the nPGi (the site of serotonergic cell bodies) or spinal transection (cutting the descending axons) will release the spinal neurons from inhibition. It is interesting that stimulation of the MPOAcan elicit the reflex, even if the nPGi and spinal cord are intact. This suggests that the MPOA may inhibit the nPGi, as well as stimulating an excitatory site.

There are no neurons that extend from the MPOA to the lumbosacral spinal cord; therefore, its facilitative effects must be mediated via other structures. One possible mediator is the periaqueductal gray (PAG) of the midbrain, which receives input from the MPOA and sends efferents to the lumbar spinal cord. Another possible mediator is the PVN. There are reciprocal connections between the MPOAand the PVN. Stimulation of mixed D1 and D2 receptors [10,14] or specifically of D2 receptors [15] in the PVN also increases the number of ex copula erections and seminal emissions. Neurons that contain a marker (neurophysin) associated with oxytocin descend from the PVN to the lumbosacral spinal cord [16], where they may elicit seminal emission/ejaculation. Whereas dopamine, via D2 receptors, promotes seminal emission/ejaculation, serotonin is inhibitory. Serotonin is released in the anterior lateral hypothalamus (LHA) of male rats at the time of ejaculation [17]. Microinjection of a selective serotonin reuptake inhibitor (SSRI) into the LHA delayed both the onset of copulation (as though the male had just ejaculated) and also delayed ejaculation after copulation had begun [17]. This effect is similar to the reported side effects of SSRI antidepressant drugs, which include decrea-

The control of copulation and ejaculation is, in many ways, similar in humans and other mammals. The evolutionarily older brain areas that subserve these functions are highly conserved across species. Dopaminergic drugs enhance, and serotonergic drugs impair several measures of sexual behavior and ejaculation in humans, monkeys, and rats. Seminal emission is elicited by sympathetic innervation in all species that have been studied. One difference, however, is that rats

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typically have much shorter postejaculatory intervals than do men. Indeed, one to three prior ejaculations actually increase the number of ex copula erections and shorten the interval before the next ejaculation in rats [8].

matter in the thoracolumbar segments of the spinal cord. Sympathetic nerve fibers exit the spinal cord via the ventral roots and reach the sympathetic chains bilaterally. The nerves proceed via the thoracic sympathetic chain to the caudal (inferior) enteric plexus, the major/minor splanchnic nerves, the celiac/cranial mesenteric plexuses, and the intermesenteric nerves. The nerves proceed via the lumbar sympathetic chain and the lumbar splanchnic nerves to the caudal mesenteric plexus.

Possible treatments for ejaculatory dysfunction, due either to a primary disorder or secondary to SSRI antidepressants, may include administration of either D2 agonists or selective serotonin receptor antagonists. Ferrari and Giuliani [21] reported that a selective D2 agonist, systemically administered, produced «premature ejaculation,» which was counteracted by a D2 antagonist. On the other hand, administration of serotonin 5-HT1B or 5HT2 antagonists may reverse the effects of serotonergic inhibition from either the LHA or the nPGi.

In animals, the intermesenteric nerves and all lumbar splanchnic nerves merge into one plexus, the caudal mesenteric plexus, from which the colonic nerve and paired hypogastric nerves exit to the colon and the pelvic plexus, respectively (Fig. 2A). The caudal mesenteric plexus in animals corresponds to two plexuses, whereas in humans, the inferior mesenteric and superior hypogastric plexuses are separate [22] (Fig. 2B). The former plexus mainly innervates the colon and from the latter spring paired hypogastric nerves. The junction of the hypogastric nerve and the pelvic nerve constitutes the pelvic plexus in the pelvis, which is an integration of sympathetic and parasympathetic nervous systems. The branches from this plexus innervate the epididymis, vas deferens, seminal vesicle, prostate, bladder neck and urethra (Figs. 1 and 2). The pudendal nerve emanates from the sacral spinal cord and does not enter the pelvic plexus, but exits the pelvis through the greater sciatic foramen, reenters it through the lesser sciatic foramen, and innervates the perineal striated muscles (Fig. 1).

4. SPINAL MOTOR CENTERS A «secretory center» is located at the Th12-L1-L2 spinal level. It is controlled by the sympathetic nervous system and is responsible for emission. A «mechanical center» is located at the S2-S4 level. It is controlled by the somatic nervous system and is responsible for expulsion.

5. EFFERENT PATHWAYS The efferent sympathetic nerves emerge from the spinal column at Th12-L2 to form the lumbar sympathetic ganglia from which the descending nerves encircle the aorta on each side before coming together in the midline to form the hypogastric plexus just below the bifurcation of the aorta. From there the preganglionic sympathetic fibres conveyed by hypogastric nerves pass through the pelvis to synapse with postganglionic neurons in the pelvic plexus which terminate on the bladder neck, prostate, seminal vesicles and vasa deferentia [22]. The efferent somatic fibres emerge from the anterior horn of the S2-S4 spinal segments (Onuf’s nucleus), they travel in the motor branch of the pudendal nerve to innervate the pelvic floor muscles including the bulbospongiosus and bulbocavernosus muscles.

b) Neurophysiology Application of retrograde axonal tracing methods to the vas deferens [23] revealed that the majority of postganglionic neurons distributed in the vas deferens originate from the pelvic plexus. The pelvic plexus receives neural input from both the hypogastric and pelvic nerves (Fig. 2). Electrical stimulation of the hypogastric nerve elicited contraction of the vas deferens in many mammalians [24, 25], while stimulation of the pelvic nerve caused no detectable motor responses [25, 26]. Histochemical studies of the vas deferens have also shown that the adrenergic fibers mainly innervate the smooth muscle layers, whereas cholinergic ones chiefly innervate the subepithelial layer [4]. Stimulation of the hypogastric nerve has also elicited contraction of the bladder neck and

a) Anatomy The abdominal and pelvic sympathetic nervous system fundamentally shows a common structure in mammalians including humans (Fig. 1). The cell bodies of the preganglionic sympathetic neurons are located in the lateral columns of the gray 482

Figure 1: Diagram showing the nervous system controlling ejaculation. Emission from both the ejaculatory orifice and pros tate, and bladder neck closure are controlled by the signals from the pelvic plexus. The pudendal nerve principally controls propulsion out of the urethra. The sacral splanchnic nerve (SSN) is found in about 30-50% of humans. BCM: bulbocaverno sus muscle, Epi: epididymis, EUS: external urethral sphincter, HGN: hypogastric nerve, LSN: lumbar splanchnic nerve, PuN: pudendal nerve, PN: pelvic nerve, SC: spinal cord, SHP/CMP: superior hypogastric plexus in humans/caudal mesenteric plexus in animals, SV: seminal vesicle, SyC: Sympathetic chain

Figure 2: Diagram showing the com mon sympathetic pathways controlling ejaculation (black) in mammalians (A). The caudal mesenteric plexus in ani mals is divided into two plexuses in humans, inferior mesenteric plexus (IMP) and superior hypogastric plexus (SHP) (B). The pathways in blue is of minor importance in motor activity of the seminal tract. CM: cranial mesente ric, CMA: caudal mesenteric artery, CoN: colonic nerve, InMP: intermesen teric plexus. See Fig. 1 legend for addi tional abbreviations.

483

prostate as well as the vas deferens. On the proximal pathway to the hypogastric nerve, stimulation of the lumbar splanchnic nerve caused contraction of the vas deferens, prostate and bladder neck, whereas that of the intermesenteric nerve elicited no observable responses in any of those organs in many mammalians [27].

interaction. A combination of adrenergic and purinergic (ATP) mechanisms are necessary for contraction of the animal vas deferens, while norepinephrine is most probably the only significant neurotransmitter for contraction of human vas deferens. Transmitter release, or the basal tone of the smooth muscle of the vas deferens, might be variably modulated by many substances, i.e. acetylcholine, neuropeptide-Y. Once contraction of the smooth muscle of the seminal tract occurs, marked elevation of intraluminal pressure might occur at the cauda epididymis/ proximal vas, which might push the spermatozoa out to the ampulla. Both nerve signal and distention of the wall of the ampulla might trigger contraction of the ampulla to emit the content into the posterior urethra.

The levels of the lumbar splanchnic nerves which elicited motor activity of the seminal tract were 2nd-5th in rats [27] and dogs, and 1st-3rd in humans [28,29]. Recent human anatomical study has revealed that almost all the lumbar splanchnic nerves originate from L2 and/or L3 lumbar sympathetic ganglia (corresponding to L1-2 spinal levels) [22]. Clinically, preservation of the L2 and/or L3 lumbar splanchnic nerve in retroperitoneal lymph node dissection of testicular cancer demonstrated restoration of ejaculatory function [29]. Partial and complete interruption of the pathway from the spinal cord to the seminal tract might cause retrograde ejaculation and emission loss, respectively. Partial inhibition might cause insufficient closure of bladder neck that permits the partially emitted seminal fluid to flow back into the bladder.

When the common pathways described above are interrupted, the occurrence of compensatory mechanisms such as enhancement of the remaining sympathetic pathways and reorganization of synaptic connection in the pelvic plexus has been reported. After transection of the canine hypogastric nerve, surgical reconstruction is possible and cross-innervation through the hypogastric nerve described above can also be preserved [30].

The cross-innervation of the peripheral sympathetic nervous system, which has been suggested from its architecture (Fig. 2), has been revealed in the dog and rat [27]. On the way of the common pathway from the lumbar splanchnic nerve to the seminal tract, some signals cross to the other side of the body at the level of the caudal mesenteric plexus and/or the pelvic plexus (Fig. 3). The preganglionic axons passing through the hypogastric nerve very likely provide a bilateral innervation to postganglionic neurons in the pelvic plexuses, which also exhibit crossing to the bilateral vasa deferentia [27]. A similar pattern of multiple crossinnervation has also been identified in the rodent bladder neck.

The sympathetic nerves reaching the adrenal medulla via the thoracic sympathetic chain and the major/minor splanchnic nerves may have a possibility of affecting ejaculation through hormonal system. Catecholamines secreted from the adrenal medulla can elicit similar systemic reactions as those accompanying ejaculation, such as marked elevation of blood pressure, tachycardia, tachypneoa and perspiration as well as local ejaculatory reactions. Propulsion of the seminal fluid is caused by rhythmic contractions of the perineal striated musculature including the bulbocavernosus and ishiocavernosus muscles. Such muscles are innervated by the pudendal nerve and show excitement during ejaculation. The patients with sacral cord injuries usually show dribbling ejaculation due to the lack of contribution of the musculature. The peripheral nervous system controlling ejaculation has elaborate mechanisms for preserving its function against various injuries.

When the sympathetic signals passing through the above pathway reach the seminal tract, norepinephrine is released from the terminal of the postganglionic neuron. Norepinephrine induces activation of alpha 1-adrenergic receptors on the smooth muscle cells, which elicits a rise in cytosolic calcium and results in the actin-myosin

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Figure 3: Diagram showing bilateral sympathetic efferent pathways projecting from a lumbar splanchnic nerve to the vasa deferentia on both sides. Four routes and two points of crossing to the other side are indicated. Similar cross-innervation is present in bladder neck and prostate. See Fig. 1 legend for abbreviations.

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then during a voluntary contraction of the pelvic floor (facilitation procedure). Sacral root stimulation is performed only at rest. The response is measured at the onset of the first reliable deflection. By stimulating the central nervous system at 2 levels, 3 different transit times will be obtained: a total transit time (from brain to target muscle), a peripheral transit time (from sacral roots to target muscle) and a central transit time (obtained by subtracting the peripheral from the total transit time) (Fig 6). The total transit time measured in the bulbocavernosus muscles is respectively 28 msec (brain stimulation patient at rest) and 23 msec (brain stimulation patient contracting the pelvic floor). The peripheral transit time is 7 msec (sacral root stimulation) [32].

III. ELECTROPHYSIOLOGICAL EVALUATION OF THE NERVOUS PATHWAYS CONTROLLING EJACULATION Neurophysiological tests allow objective evaluation of the nervous pathways controlling ejaculation. Four tests are routinely used.

1. P UDENDAL SOMATOSENSORY EVOKED POTENTIALS (PUDENDAL SEPS) Somatosensory evoked potentials (SEPs) are defined as a transient alteration of the electroencephalogram (EEG) following peripheral nerve stimulation. They provide objective information concerning the afferent volley from the dorsal nerve of penis to the cortex. The technique consists of electrical stimulation of the dorsal nerve of penis with recording of the evoked responses over the spine and the scalp (2 cm behind the central vertex) (Fig. 4). First the sensibility threshold is measured. By definition, the sensibility threshold is the lowest perceivable sensation of the electrical current at the point of stimulation. The latency of the response is measured both at the onset of the response and the peak of the first reproducible deflection. By recording the response at 2 different levels, 3 different transit times are obtained: a total transit time (from penis to brain), a peripheral transit time (from penis to spine), and a central transit time (which is obtained by subtracting the peripheral from the total transit time). The peripheral transit time is approximately 13.5 ms. The total transit time is approximately 34 msec (onset) and 43 msec (top of P1 deflection) [31,32].

3. SACRAL REFLEX ARC TESTING: THE SOMATIC-SOMATIC REFLEX ARC The test allows the investigation of the sensory and motor branch of the pudendal nerve and of the sacral segments S2, S3, S4. The technique consists in stimulating the dorsal nerve of the penis and recording the response from the bulbocavernosus muscles. The response consists usually of 2 deflections. The mean latency of the first deflection is 35 msec, although a late deflection is often observed at 80 msec [32,33].

4. SYMPATHETIC SKIN RESPONSES (SSRS) Electrical activity from the sympathetic nerve terminals controlling the sweat glands of the skin can be recorded following electrical stimulation of any peripheral nerve trunk. The test allows evaluation of the sympathetic efferent outflow to the skin of the genital organs. The dorsal nerve of the penis is stimulated using 2 ring electrodes wrapped around the penile shaft, the cathode being proximal. The stimulation consists of single electrical pulses applied at a rate of 0.05 Hz. Sympathetic skin responses are recorded from hand, foot, and perineum using disc electrodes affixed to the skin. Two tracings are superimposed to check the reproducibility of the response. The right median nerve is then stimulated, and SSRs are recorded from the hand, foot, perineum, and penis. The mean latency of hand, foot, and perineum SSRs following dorsal nerve of the penis stimulation are, respectively, 1.40 sec, 2 sec, and 1.4 sec. Following median nerve stimulation, the latency of penile SSRs is 1.50 sec [34,35].

2. PUDENDAL MOTOR EVOKED POTENTIALS (PUDENDAL MEPS) Motor Evoked Potentials (MEPs) explore the efferent pathways (pyramidal tracts) from brain to target muscle (bulbocavernosus muscles). The technique consists of stimulating the motor cortex and sacral roots by means of a magneto-electric stimulator. For brain stimulation, the coil is applied 2 cm behind the vertex (Fig. 5). For sacral root stimulation, the coil is applied laterally to the spine. The response is picked up from the bulbocavernosus muscles with co-axial EMG needle electrodes. Brain stimulation is performed, first at rest, and 486

Figure 4: Pudental Somatosensory Evoked Potentials (Pudendal SEPs). The response is recorded 2 cm behind the central vertex.The latency of the first positive deflection (P1) is 38 msec.

Figure 5: Pudendal Motor Evoked Potentials (Pudendal MEPs): sites of stimulation and position of the coil. A : Transcranial magnetic stimulation : the posterior edge of the coil is applied 2 cm behind the entral vertex B: Sacral root magnetic stimulation : the coil is applied laterally to the spine at the level of the iliac crest (from R.J. Opsomer et al, 1992, with permission for reproduction of Peeters Publishers [94])

Figure 6 : Pudendal Motor Evoked Potentials (Pudendal MEPs) recorded from the periurethral sphincter in a normal subject. A: Transcranial magnetic stimulation. Subject at rest. Latency of the response is 21.5 msec. B: Transcranial magnetic stimu lation. Latency of the response in 30msec. Notice the increase in amplitude and shortening of the latency of the response when the patient contracts the pelvic floor : Facilitation procedure. C : Sacral root magnetic stimulation. Latency of the response is 7.7 msec (from R.J. Opsomer et al, 1992, with permission for reproduction of Peeters Publishers [94])

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seminal vesicles and ejaculatory ducts. Several complex anomalies may occur in this area leading to ectopic opening of the vas deferens and sometimes associated with anorectal anomalies [36]. If too much of the proximal vas precursor is absorbed, a variable amount of the proximal vas, seminal vesicle and/or ejaculatory duct may be absent. There may also be coexisting abnormalities in the ipsilateral kidney or ureter.

IV. PATHOPHYSIOLOGY OF EJACULATORY DISORDERS 1. EMBRYOLOGY AND CONGENITAL ANOMALIES As the male foetus develops, the Mullerian ducts normally disappear from above downwards under the influence of Mullerian inhibitory factor (MIF) which is produced by the Sertoli cells in the primitive testis. Failure of complete absorption may leave a small Mullerian duct remnant at the lower end that lies between the ejaculatory ducts. The Wolffian (mesonephric) ducts are composed of three distinct areas. The upper part forms the epididymis and distal vas deferens, while the proximal vas deferens, seminal vesicle and ejaculatory duct are derived from the middle area. The most caudal part is the common mesonephric duct, from which the ureteric bud springs at approximately 4 weeks of development: this becomes the ureter, and will induce the metanephric blastema to form the kidney. The urogenital sinus reabsorbs the lower end of this structure, and the ureteric orifices are thus separated from the vasa deferentia,

a) Mullerian duct cyst Persistence of a small remnant of the Mullerian duct may lead to a cyst forming between the ejaculatory ducts which can become obstructed and cause diminution of the volume of the ejaculate and infertility. Haemospermia is not uncommon in these patients. Seminal analysis shows the changes characteristic of ejaculatory duct obstruction with a small volume (less than 1.5 ml), acid pH and little or no fructose. Both vasa are palpable and the epididymes usually feel distended. The diagnosis is established by transrectal ultrasound scan (TRUS), and the lesion can be delineated by percutaneous puncture of the cyst with instillation of radio-opaque medium (figure 7). The cyst can be incised or deroofed endoscopically after delinea-

Figure 7: Mullerian duct cyst shown by a. transrectal ultrasound scan, and b. percutaneous puncture (reproduced from the British Journal of Urology with permission).

488

ting its extent by injection of blue dye (see below). Improvement in ejaculate volume and seminal quality follows in most cases [37].

20 subfertile males who had repair of imperforate anus in infancy indicated that 7 had no ejaculate, 11 were azoospermic, 1 was severely oligozoospermic and only 1 had a normal sperm concentration in a very small volume ejaculate [41]. Investigation revealed that both vasa were blocked in 5 men and one vas in a further 8 patients, apparently as a result of the original operative procedure.

b) Wolffian duct abnormalities Congenital anomalies may be either sporadic, with a localized defect in the proximal part of the vas deferens or there may be a generalized maldevelopment due to a systemic genetic abnormality. Local Wolffian duct abnormality involves loss of a variable amount of the vas deferens, seminal vesicle and/or ejaculatory duct, and sometimes part of the ipsilateral urinary system as well. This may be associated with maldevelopment of the bladder neck and trigone, which fails to close effectively producing retrograde ejaculation.

b) Operations on the prostate Antegrade ejaculation requires a closed bladder neck (and proximal urethra). Surgical procedures that compromise the bladder neck closure mechanism may result in retrograde ejaculation. Transurethral incision of the prostate (TUIP) results in retrograde ejaculation in 5% [42] to 45% [43] of patients and is probably related to whether one or two incisions are made and whether or not the incision includes primarily the bladder neck or extends to the level of the verumontanum.

Bilateral abnormalities are often associated with carriage of the cystic fibrosis gene [38]. Unilateral absence of the vas deferens was observed in 5%, and bilateral absence in 18% of 370 azoospermic males with normal serum FSH levels investigated by the author [39].

The importance of contraction of the urethral smooth muscle at the level of the verumontanum has been hypothesized to be important in preventing retrograde ejaculation [42]. Transurethral resection of the prostate (TURP) carries a higher incidence of retrograde ejaculation than does TUIP. The reported incidence of retrograde ejaculation following TURP ranges from 42% [44] to 100% [45]. It occurs less frequently following open prostatectomy (either suprapubic or retropubic) then after TURP. In one series, the incidence of retrograde ejaculation following open prostatectomy was zero [44]. TURP is thought to disrupt the closure mechanism of the vesical neck, whereas open enucleation is less apt to produce this alteration.

c) Prune belly syndrome Patients with Prune Belly syndrome have normal libido, erections, and orgasms. Most have abnormal ejaculation and probably emission. In a study involving nine patients, seven had retrograde ejaculation and two produced ejaculates [40]. Five patients provided semen or urine passed after masturbation. Two produced ejaculated semen. One of the ejaculated specimens consisted of 4.5 cc of fluid indistinguishable from urine and one was 2.5 cc of fluid with the appearance of watery semen. Post masturbation urine specimens were of normal urinary appearance. None of the specimens contained sperm: no mention was made of the fructose content. Abnormal ejaculation thus appears to be present in the vast majority of patients with Prune Belly syndrome. Whether the primary abnormality is retrograde ejaculation or lack of emission is not clear

After radical prostatectomy, ejaculation is bound to be lost since the seminal vesicles are removed with the prostate gland. Erectile impotence was the rule until detailed anatomical studies showed where the parasympathetic nerves ran on the surface of the prostate gland, and a nerve sparing operative technique was developed [46]. A sensation of orgasm can sometimes be preserved despite loss of ejaculation.

2. TRAUMATIC DAMAGE a) Imperforate anus Ejaculatory duct obstruction may follow correction of imperforate anus. The pull through procedure passes close to the posterior aspect of the prostate, and damage is most likely if there has been closure of a recto-urethral fistula. Analysis of

3. INFECTIVE DISORDERS Genital infection such as gonorrhoea or non-specific urethritis can produce cicatrisation and obs-

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truction anywhere in the male reproductive tract, especially if treatment is delayed. Urinary infection, especially if complicated by epididymitis, can also produce obstruction that may be situated at ejaculatory duct level. Routine vasography in subfertile men with azoospermia and normal serum FSH levels revealed post-infective vasal blocks in 8% and acquired ejaculatory duct obstruction in 4% [39].

necessary to produce spermatozoa that can be used for insemination. If the spinal reflex arc is intact, a hypogastric plexus stimulator can provide ejaculation in the comfort and security of the patients' home [49]. Alternatively, direct electroejaculation by rectal probe may be effective, but this may require a general anaesthetic and is done in hospital [50]. In a recent collective analysis of 40 paraplegic patients, 22 successfully produced pregnancies by natural insemination or assisted reproductive techniques [51].

Schistosomiasis is endemic in large parts of Africa, and is seen with increasing frequency in tourists returning from Africa who have contracted the disease whilst enjoying water sports: Lake Malawi has acquired an evil reputation in this respect. The disease may present with haemospermia [47] and fibrosis and calcification may lead to genital obstruction.

Orgasm has been noted to occur in men with spinal cord injuries. Via self-report 42% to 61% of men reported the ability to achieve orgasm. Orgasms were also noted to occur in men with complete spinal cord injuries; however, overall orgasms were described as different than prior to their injuries. No laboratory-based analysis has been performed of the physiologic events occurring during orgasms in the male with spinal cord injury [52].

Genito-urinary tuberculosis can cause great damage to the male reproductive tracts, and since healing occurs with calcification, the lesions may be irreparable. Plain X-ray will often show the extent of the disease.

b) Paraaortic lymphadenectomy

Haemospermia is seldom as ominous a symptom as haematuria, but this complaint should not be ignored. Analysis of the findings in 81 patients revealed that an inflammatory cause could be defined in most men under 30 years of age; however, there were a few (8%) with more serious disease including carcinoma of prostate and bladder [48]. It should be remembered, also, that schistosomiasis and tuberculosis could present in this way. Routine investigation of haemospermia by TRUS not uncommonly reveals the presence of small stones in the ejaculatory ducts, which may be associated with obstruction and dilatation of the seminal vesicles. Such stones usually pass spontaneously.

This operation is usually done to clear lymph node metastases from testicular tumours, when the sympathetic nerves and ganglia may also be removed leading to loss of ejaculation. Early studies showed that up to three-quarters of patients lost antegrade ejaculation after full bilateral retroperitoneal lymph node dissection. As a result of careful anatomical studies, the technique of retroperitoneal lymph node dissection has been modified with nerve sparing so that antegrade ejaculation is now maintained in 70-90% of patients. One quarter of the patients who complete chemotherapy for advanced testicular tumour have residual masses in the para-aortic region [53]. Amongst 231 consecutive patients undergoing para-aortic lymphadenectomy after chemotherapy at the Royal Marsden Hospital, there was persistent undifferentiated tumour in 21% [54]. In our experience of 186 patients, a nerve sparing operative technique introduced in 1984 lead to a significant reduction in ejaculatory dysfunction from 37% to 19% [55]. Loss of ejaculation occurred significantly more often after bilateral (46%) compared to unilateral (14%) dissection, and was related to the size of the excised mass (<4 cm 4%; 48 cm 19%; >8 cm 60%).

4. NEUROGICAL DISORDERS a) Spinal cord injury Damage to the spinal cord at the level of T12 to L2 may affect central reflex pathways and lead to permanent loss of ejaculation. Injury above T11 may allow reflex erection and ejaculation, although this can provoke autonomic dysreflexia with marked rise in blood pressure. In some paraplegic patients, application of a vibrator to the penis will lead to ejaculation; in others, electroejaculation may be

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It is important to anticipate this complication in young men with testicular tumours who may need chemotherapy or node dissection, and arrangements should be made for sperm storage before treatment commences. Excellent results can be obtained with artificial insemination using cryopreserved spermatozoa [56].

Since psychiatric drugs and physical conditions like erectile dysfunction can cause secondary premature ejaculation, it is important to exclude and/or treat these causes before treating the symptom of premature ejaculation. For example, when a man is able to achieve a rigid erection, but not to maintain this erection for a certain amount of time, he could condition himself to ejaculate rapidly. It is very likely that his secondary premature ejaculation will be successfully treated by oral sildenafil or local vasoactive drugs, and not by SSRIs.

5. THE EFFECTS OF DRUGS ON ORGASM AND EJACULATION a) Animal studies

c) Side effects of specific drugs on ejaculation

Ever since the late sixties, serotonin (5-HT) has been known for its involvement in male rat sexual behaviour. It is generally assumed that central 5HT has an inhibitory role in the neural control of masculine sexual behaviour in the rat. A decrease in 5-HT neurotransmission decreases the number of intromissions preceding ejaculation and shortens the time to ejaculation, whereas an increase in central 5-HT neurotransmission produces the opposite effect [57]. Administration of the selective 5-HT1A receptor agonist 8-OH-DPAT lowers 5-HT levels in some parts of the brain, and causes male rats to ejaculate at the first or second intromission and within seconds after being put in the vicinity of an estrous female rat. Therefore, it could be stated that 8-OH-DPAT renders male rats to be premature ejaculators [58]. Administration of different selective serotonin reuptake inhibitors (SSRIs), which results in higher levels of 5-HT, suppresses sexual behavior in male rats [59].

1) Dopamine The centrally acting neurotransmitter dopamine is known for its involvement in control of male rat sexual behavior. Taking the parameters of mount and intromission frequencies and latency to ejaculation as measures of copulatory activity, most reports indicate that dopamine has a stimulatory effect that is exerted via D2 receptors. Enhancement of the ejaculatory behavior and the decrease in intromission frequency stimulated some authors to call this altered behaviour a rat model for "premature ejaculation". 2) Morphine Several studies have shown that systemic and central administration of morphine inhibits male rat sexual behavior. However, in one study [76], a small proportion of male rats reacted differently on a low dose of systemic morphine: there was a decrease of ejaculation latency, and in the number of intromissions prior to ejaculation. These conflicting results indicate that at least there is a role for the enkephalines in the modulation of sexual behavior in the male rat. 3) Ecstasy The amphetamine analog MDMA, better known as the recreational drug ecstasy, is known and feared for its neurotoxic properties. It reduces brain concentrations of serotonin by inhibition of the metabolism and by long-lasting degeneration of 5HT nerve terminals, as well as by decreasing the number of 5-HT uptake sites. In an experiment with male rats, Dornan and collaborators [77] found that a chronic administration of MDMA, caused less rats to display mounting behavior, and an increase in ejaculation latency in the responders. These results are conflicting with the abovedescribed studies with serotonin receptor agonists

b) Human studies In humans, the side effects of antidepressants on sexual function have been known for more than 25 years. In general, these substances increase the 5HT concentration in the synapses, usually by uptake inhibition (e.g., SSRIs) [95]. The most commonly reported side effects are delay or absence of orgasm/ejaculation. In 1973, the English psychiatrist Eaton was the first to report on the beneficial aspects of this side effect. He administered the tricyclic antidepressant clomipramine to men with premature ejaculation without psychiatric disorders [60]. To date, many studies have been performed to investigate the effects of fluoxetine, paroxetine, sertraline (SSRIs) and clomipramine [61]. Table 1 shows the results of the most relevant studies [6275]. Although no studies with long-term treatment with SSRIs have been published, it has become an accepted treatment for premature ejaculation. 491

Table 1: The influence of different serotonin reuptake inhibitors on ejaculation latency in men with premature ejaculation: a summary of selected studies AUTHOR(S) & REFERENCE

N

DOSE

STUDYDESIGN*

EFFECT/REMARKS

CLOMIPRAMINE (tricyclic serotonin reuptake inhibitor) Segraves et al [62] 20 25-50 mg/day

DB, PC, crossover

placebo: 51 sec, clomipramine: 366 sec

Althof et al [63]

15

25-50mg/day

DB, PC, crossover

baseline: 81 sec 25 mg: 202 sec, 50 mg: 416 sec partner ’s satisfaction included

Haensel et al [64]

22

25 mg 12-24 h prior to sexual activity

DB, PC, crossover

Stassberg et al [65]

34

25 mg 4-6 h prior to sexual activity

DB, PC, crossover

placebo: 2 min, clomipramine 8 min include control group: 9->11 min placebo: 52 sec, clomipramine: 229 sec include controls: 8->11 min

FLUOXETINE (SSRI) Kara et al [66]

14

20-40 mg/day

DB,PC

placebo: 30->60 sec, fluoxetine: 25->180 sec baseline: 0.9 min, fluoxetine: 9.6 min increase in ejaculation latency (p=0.007) controls: no effect

Lee et a l [67]

11

20-60 mg/day

Open label

Haensel et al [68]

40

5-10 mg/day

DB, PC, crossover

PAROXETINE (SSRI) Waldinger et al [69]

17

20-40 mg/day

DB, PC

baseline: 0.5 min, 20 mg: 7.5 min, 40 mg: 10 min. placebo no effect

Waldinger et al [70]

27

20-40 mg/day

DB, dose response

20 mg/day: 13->300 sec, 40 mg/day: 10->540 sec

McMahon and Tourma [71]

26

20 mg 3-4 h prior to sexual activity

SB, crossover

baseline: 0.3 min placebo 0.45-0.6 min paroxetine: 3.2-3.5 min

SERTRALINE (SSRI) McMahon [72]

37

50 mg/day

SB, PC, crossover

McMahon [73]

46

25-100 mg/day

Open label

baseline: 0.3 min, placebo: 0.5 min, sertraline: 3.2 min baseline: 1 min, 25 mg: 7.6 min, 50 mg:13.1 min, 100 mg: 16.4 min

Waldinger et al [74]

51

Fluoxetine 20 mg/day Fluvoxamine 200 mg/day Paroxetine 20 mg/day Sertraline 50 mg/day

DB, PC

baseline: 18 sec placebo: 29 sec fluvoxamine: 55 sec sertraline: 117 sec fluoxetine: 211 sec paroxetine: 476 sec

Kim et al [75]

36

Fluoxetine 40 mg/day Sertraline 100 mg/day Clomipramine 50 mg/day

DB, PC, crossover

baseline: 46 sec, placebo 2.3 min fluoxetine: 2.3 min sertraline: 4.3 min clomipramine: 5.8 min

COMBINED

KEY: DB - double blind; SB - single blind ; PC - placebo controlled Derived in part from: Rowland et al. [61] with permission of the author

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and antagonists, because a decrease in central 5HT would cause an increase in male rats' sexual behaviors. Probably, since MDMA has such dramatic effects in the brain, other factors may have played an important role in this experiment. GABA. The neurotransmitter gamma-aminobutric acid (GABA) occurs in the brain tissue. Two distinct types of GABA receptors are recognized: GABAA and GABAB. There is some evidence that the GABAB receptor agonists (like baclofen) inhibit sexual behavior in male rats, independently from the effects on motor systems. Efforts to discover a role for GABAA in the modulation of sexual behavior in the rat have failed so far. 4) Yohimbine. The alpha2-adrenoceptor blocking agent yohimbine has been known for its aphrodisiac properties in rats and humans. In male rat studies, it increased mounting behavior without the need for physiological levels of serum testosterone. When looking at the effects on ejaculation, a decrease in ejaculation latency, intercopulatory interval, and post-ejaculatory interval is found. d) Specific drug effects in human studies 1. MONOAMINE OXIDASE INHIBITORS. The monoamine oxidase inhibitors (MAOIs) are mainly used in the treatment of neurotic or atypical depression. These drugs increase the levels of epinephrine, norepinephrine, dopamine and serotonin. The MAOIs have been known for their sexual side effects, with an incidence up to 2040%. Delayed or inhibited ejaculation is reported for isocarbazid, phenelzine and tranylcypromine. 2. CYPROHEPTADINE It is an antihistaminic, formerly used in Cushing's disease and anorexia nervosa. It also increases serotonin levels in the brain. Several reports indicate that cyproheptadine is able to convert druginduced orgasmic failure in both men and women. 3. B ENZODIAZEPINES A number of benzodiazepines effective in treating generalized anxiety and panic attacks are also known to inhibit ejaculation in some men, presumably by enhancing gamma-aminobutyric acid (GABA). These drugs include diazepam, lorazepam, lormetazepam, temazepam, flunitrazepam, flurazepam, nitrazepam, chlordiazepoxide, and alprazolam.

4. STIMULANTS Amphetamine is a stimulating drug with affinity for different receptors in the central nervous system. It stimulates release of dopamine, inhibits monoamine oxidase and blocks the reuptake of both catecholamines and serotonin. It is reported to delay ejaculation in subjects without ejaculatory dysfunction. Cocaine is an addictive "recreational" drug and stimulates the central nervous system through blocking of monoamine transporters. Different reports confirm that delayed ejaculation appears to be the most common sexual side effect. The influences of different drugs on ejaculation are delineated in table 2 [78].

6. FUNCTIONAL DISORDERS • Seminal megavesicles Adult polycystic kidney disease has been found in association with pathological dilatation of the seminal vesicles in 6 patients [79]. TRUS and percutaneous puncture of the seminal vesicles before and after resection of the ejaculatory ducts revealed that the gross dilatation of the seminal vesicles was not caused by obstruction, but appeared to be due to atonicity (megavesicles). These ultrasonic appearances, when described previously, were incorrectly thought to be due to seminal vesicle cysts. Pathological dilatation of the seminal vesicles in the absence of obstruction has been described previously, although the aetiology remains obscure [80].

V. INVESTIGATION 1. EVALUATION OF PATIENTS WITH RAPID/PREMATURE EJACULATION a) Diagnostic criteria The diagnostic criteria for rapid or premature ejaculation have been defined as follows: • DSM-IV- PREMATURE EJACULATION 1) Persistent or recurrent ejaculation with minimal sexual stimulation before, on, or shortly after penetration and before the person wishes it. The clinician must take into account factors that

493

Table 2: Side effects of different drugs on ejaculation GROUPOFDRUGS

AGENT

EFFECT ON EJACULATION

Naproxen Methadone Morphine

Decrease/absence of ejaculation/orgasm Decrease/absence of ejaculation/orgasm Decrease/absence of ejaculation/orgasm

ANTIHYPERTENSIVES Alpha blockers

Phenoxybenzamine

Alpha and beta blockers Centrally acting

Labetolol Clonidine

Methyldopa Reserpine

Decrease/absence of ejaculation/orgasm Retrograde ejaculation Decrease/absence of ejaculation/orgasm Decrease/absence of ejaculation/orgasm Retrograde ejaculation Decrease/absence of ejaculation/orgasm Retrograde ejaculation Decrease/absence of ejaculation/orgasm Decrease/absence of ejaculation/orgasm

Bromocryptine L-DOPA Pergolide

Decrease/absence of ejaculation/orgasm Decrease & increase reported Spontaneous ejaculation

Mazindol

Spontaneous ejaculation

Methotrexate Vincristine

Decrease/absence of ejaculation/orgasm Decrease/absence of ejaculation/orgasm

Cyproterone acetate

Decrease/absence of ejaculation/orgasm

Barbiturates (all)

Decrease/absence of ejaculation/orgasm

ANALGESICS NSAID’s Opoids

Guanethidine

ANTI-PARKINSONISM AGENTS

APPETITE SUPPRESSANTS CYTOTOXICS

HORMONE ANTAGONISTS HYPNOTICS AND SEDATIVES LITHIUM PSYCHOPHARMACEUTICALS Antidepressants

Decrease/absence of ejaculation/orgasm (S)SRI’s Trazodone

See table X.1 Decrease/absence of ejaculation/orgasm Retrograde ejaculation

Anxiolytics Neuroleptics

MAOI’s Isocarboxazid Phenelzine Tranylcypromine Benzodiazepines Chlorpromazine

Phenothiazines

Fluphenazine Levomepromazine Perphenazine Pipothiazine Thioridazine

Thioxanthenes

Butyrophenones Diphenylbutylpiperidines

Trifluoperazine Chlorprotixene Thioxitene Zuclopenthixol Haloperidol Pimozide

494

Decrease/absence of ejaculation/orgasm Decrease/absence of ejaculation/orgasm Decrease/absence of ejaculation/orgasm Decrease/absence of ejaculation/orgasm Decrease/absence of ejaculation/orgasm Retrograde ejaculation Decrease/absence of ejaculation/orgasm Retrograde ejaculation Retrograde ejaculation Decrease/absence of ejaculation/orgasm Decrease/absence of ejaculation/orgasm Decrease/absence of ejaculation/orgasm Retrograde ejaculation Decrease & increase reported Decrease/absence of ejaculation/orgasm Retrograde ejaculation Spontaneous ejaculation Retrograde ejaculation Painful ejaculation Decrease/absence of ejaculation/orgasm

Table 2: Side effects of different drugs on ejaculation (ctd) GROUPOF DRUGS

AGENT

EFFECT ON EJACULATION

Baclofen

Decrease/absence of ejaculation/orgasm

Alfuzosin Phenoxybenzamine Prazosin Tamsulosin Terazosin Finasteride

Retrograde ejaculation Retrograde ejaculation Retrograde ejaculation Retrograde ejaculation Retrograde ejaculation Less ejaculatory volume

Alcohol Amphetamines Amylnitrite (poppers) Cocaine Heroin Marihuana Methadone Tobacco

Decrease/absence of ejaculation/orgasm Decrease & increase reported Increase in ejaculatory latency Decrease/absence of ejaculation/orgasm Decrease & increase reported Decrease/absence of ejaculation/orgasm Decrease/absence of ejaculation/orgasm Decrease/absence of ejaculation/orgasm

MUSCLE RELAXANTS URINARY TRACT Alpha blockers

Alpha reductase inhibitors RECREATIONALDRUGS

After; Moors-Mommers, [78]

affect duration of the excitement phase, such as age, novelty of the sexual partner or situation, and recent frequency of sexual activity. 2) The disturbance causes marked distress or interpersonal difficulty. 3) The premature ejaculation is not due exclusively to the direct effects of a substance (e.g., withdrawal from opioids).

• degree of voluntary control. The simplest dimension to assess is ejaculatory latency or duration of intercourse. The clinician inquires how long it takes for the man to reach orgasm under each of the following circumstances: with masturbation, partners hand and/or mouth stimulation, and intercourse in varying positions. As the patient answers these questions, the doctor listens for various factors that may enable reassurance to be the primary treatment. These include men with unusually high and unrealistic expectations: for instance, that intercourse should last 45 minutes! The doctor sometimes can quickly educate these men to no longer consider themselves rapid ejaculators. Reassurance can sometimes be helpful to men who are young, inexperienced, or trying too hard to please a new partner. The second major dimension to be assessed when men complain of rapid ejaculation includes the factors that affect the man's degree of voluntary control. These are generally psychosocial conditions. The doctor inquires whether the rapid ejaculation occurs under all circumstances or only with a specific partner or a specific circumstance. Selective rapid ejaculation, either specific to a partner or specific to a setting is usually acquired rapid ejaculation. In these cases, the clinician turns his attention to the life events that preceded the onset of the problem. For instance, acquired rapid ejaculation may follow a myocardial infarction or the discovery of his wife's infidelity. Acquired

• ICD-10- PREMATURE EJACULATION (ICD= INTERNATIONAL CLASSIFICATION OF DISEASES) 1) The general criteria for sexual dysfunction (F52) must be met. 2) There is an inability to delay ejaculation sufficiently to enjoy lovemaking, manifest as either of the following: • Occurrence of ejaculation before or very soon after the beginning of intercourse (if a time limit is required: before or within 15 seconds of the beginning of intercourse); • Ejaculation occurs in the absence of sufficient erection to make intercourse possible. 3) The problem is not the result of prolonged abstinence from sexual activity. b) Assessment (Decision Tree A) Rapid ejaculation is assessed along two major dimensions: • ejaculatory latency post-vaginal penetration and 495

DECISION TREE A : DECISION TREE OF INVESTIGATION AND TREATMENT OF PREMATURE EJACULATION (PE) HISTORY TAKING : PATIENT AND PARTNER - psychosocial history - somatic history - (intravaginal) ejaculatory latency time - degree of voluntary control - duration of PE

Symptom of PE ?

NO

Change diagnosis/follow-up

YES

Consider laboratory assessment e.g., psychophysiological examination electrophysiological evaluation

YES

PE secundary to erectile dysfunction or other sexual dysfunction ?

Treat primary sexual dysfunction

NO

Follow-up

Drug dependent PE ?

YES

Consider change of drug therapy

YES

Psychosexual therapy

NO Psychosocial/situational PE ? NO Follow-up Meet all DSM IV criteria ?

NO

YES

Consider laboratory assessment e.g., psychophysiological examination concomitant ED or libido dysfunction ?

YES

TREATMENT - BEHAVIORAL TECHNIQUES - stop/start - sensate focus - quiet vagina - DRUG TREATMENT (SEE TEXT) - INTEGRATED PSYCHODYNAMIC APPROACH - DESENSITIZATION - anaesthetic ointments - double condoms OR A COMBINATION OFABOVE

consider

Follow-up

496

rapid ejaculation may also mask an underlying erectile disorder. In these cases the rapid ejaculation is an adaptive response to prevent losing erections. The doctor should first proceed with the work-up and treatment for the erectile dysfunction and only treat the ejaculatory dysfunction if the symptom remains. Even when the rapid ejaculation is lifelong, the doctor needs to wonder why the man seeks help for the condition at this time. The answer is often that the stability of the marital relationship is being threatened and the man looks to the clinician for a simple face saving explanation and treatment for a more complex problem: marital deterioration. Rapid ejaculation may also be a disguise for partner sexual dysfunction. For example, a woman may have an intense sexual aversion that has kept her partner quickly ejaculating to minimize her distaste for and distress during sex. Thus clinicians need to hear about the quality of the sexual adjustment over time to ascertain the social factors that may suggest how to plan treatment.

related to orgasmic cessation are reviewed, e.g. following his wife's mastectomy: the man is afraid of hurting her and therefore only partially aroused. Societal/religious attitudes that may interfere with excitement are noted, such as the spilling of seed as a sin. Finally, questions concerning the quality of the nonsexual relationship are posed and problems explored.

3. ASSESSMENT OF HAEMOSPERMIA Haemospermia requires full investigation. Culture of expressed prostatic secretion and urine will define the nature of an infective process such as prostatitis [81]and urine cytology and serum prostate specific antigen should be assayed to exclude bladder or prostatic cancer. Ultrasound scan of the testicles and epididymes should define any local disease. TRUS will demonstrate structural abnormality in the prostate or seminal vesicles, or may show up a stone in the ejaculatory duct or even a Mullerian duct cyst. Cystoscopy is seldom helpful.

4. ASSESSMENT OF SMALL VOLUME EJACULATE (DESICION TREE B)

In summary, the assessment of rapid or premature ejaculation is done by sexual history taking. An attempt is made to ascertain the man's social circumstances, his motivations for pharmacological or psychological treatment and his partner's receptivity to such treatment. In some situations, it is best to not attempt a pharmacological therapy until social circumstances are further clarified or resolved because the patient who may ultimately have been helped by medications loses the opportunity because he or his partner could not surmount the psychosocial obstacles related to the sexual dysfunction.

If a man has difficulty with ejaculation, or has a small volume or absent ejaculate, it must first be established whether the problem is congenital or acquired. Acareful clinical history should be taken, and physical examination will establish whether the testicles and epididymes are normal, and whether the vasa are present or absent, on each side. Next, it is essential to establish whether there is retrograde or completely absent ejaculation, by examination of a deposit of urine after centrifugation. The presence of spermatozoa indicates retrograde ejaculation. These facts will allow the patient to be placed into one of several broad categories, after which more detailed evaluation can take place. Patients with ejaculatory duct obstruction usually (Decision Tree C) present with infertility. Seminal analysis may simply be reported a showing azoospermia or oligozoospermia, but the characteristic biochemical changes should be sought. There should be absence of part or the entire component of the ejaculate that comes from the vasa and seminal vesicles via the ejaculatory ducts. The volume is low (usually less than 1.5 ml), the pH is low (less than 7) and the fructose content is either low (less than 120 mg/100ml) or absent. If both vasa are palpable, a diagnosis of ejaculatory duct obstruction is very likely.

2. ASSESSMENT OF DELAYED RETARDED EJACULATION Assessment begins by reviewing the conditions under which the man is able to ejaculate, e.g. during sleep, with masturbation, with partner's hand or mouth stimulation or infrequently with varying coital positions. The course of the problem is documented, and variables that improve or worsen performance are noted, such as the need for unconventional fantasies or a lifelong need to suppress spontaneous emotional expression. Questions concerning the man's ability to relax, sustain and heighten arousal and the degree to which he can concentrate on sensations are posed. If orgasmic attainment had been possible previously, the life events/circumstances temporarily 497

DECISION TREE B : DIFFERENTIAL DIAGNOSIS OF DIMINISHED EJACULATION Presenting complaint : - little or no ejaculate

Is there orgasm ?

Anorgasmia

NO

? nocturnal emission YES

psychologist

Is there any ejaculate ?

YES

Seminal analysis ? low volume

NO

Decision tree C

? Are there sperm present in urine after orgasm

Retrograde ejaculation

YES

urologist NO

Aspermia

Decision Tree C DECISION TREE C : INVESTIGATION OF DIMINISHED EJACULATE

HISTORY - little or no ejaculate ? - infertility ? - epdidymitis ? - haemospermia ? ⇓ SEMINAL ANALYSIS - low volume ? - acid pH ? - reduced fructose ? ⇓ TRUS - distended vesicles ? - abnormal cyst ? ⇓ SEMINAL VESICULOGRAPHY Percutaneous puncture or vasography - confirms obstruction ? ⇓ TRANSURETHRAL RESECTION - volume increased ? ⇓ SEMINAL ANALYSIS - sperm count improved ? ⇓ Treatment success

No

? functional

No

? Diabetes mellitus

No

? Polycystic kidney disease

No

Redo TUR

No

Epididymo-vasostomies

498

? megavesicles

When there is absence of the vasa, it is important to establish whether the condition is unilateral or bilateral. With unilateral absence of the vas deferens, the urinary system must also be checked by ultrasound scanning, as coexisting renal anomalies may be present [82]. With bilateral absence or malformation of the vasa, it is essential to consider whether the anomaly may be part of a genetic defect associated with carriage of the potentially harmful cystic fibrosis chromosome anomaly [38].

VI. TREATMENT 1. PSYCHOLOGICAL TREATMENT FOR RAPID EJACULATION Since the early 1970's, an array of individual, conjoint, and group therapy approaches employing behavioral strategies, such as the stopstart, squeeze technique, progressive sensate focus exercises, masturbatory exercises and "quiet vagina" with the female astride, have evolved as the treatments of choice for rapid ejaculation. Behavioral treatment often begins with the man alone, having him repeatedly stimulate himself to midrange levels of excitement before pausing. After several repetitions he is permitted to ejaculate. The aim of this exercise is to help him learn intermediate levels of excitement and begin to slow down his arousal. After mastering the self-stimulation exercise the partner is asked to repeatedly bring the man to

5. ASSESSMENT OF EJACULATORY DUCT OBSTRUCTION ON IMAGING The lesion may be suspected by finding distended seminal vesicles on transrectal ultrasound scanning. However, the exact site of obstruction should be defined radiologically by vasography or percutaneous puncture of the seminal vesicles (figure 8). Subsequently, methylene blue dye may be instilled to outline the ejaculatory system so that it can be recognized after it has been entered at transurethral resection [83].

Figure 8: Vasograms showing a) Normal seminal vesicles and ejaculatory ducts, b) Mullerian duct cyst, c) Wolffian duct abnormality with absence of seminal vesicle, the duct terminating in a cystic malformation close to the prostatic urethra, d) seminal megavesicles (reproduced from the British Journal of Urology with permission).

499

high levels of excitement, initially through stimulation by her hand or mouth and later by vaginal thrusting, but stopping prior to ejaculation. This stop-start procedure allows the man's arousal to decrease and thereby delays orgasm. This behavioral sequence is repeated several times after which the man is permitted to ejaculate. Masters and Johnson [84] subsequently developed a modification of this procedure known as the squeeze technique. At the point at which stimulation is stopped, the man's glans penis is squeezed firmly but quickly by the partner which lowers arousal. Often however, this technique results in a partial loss of erection.

learnt through the use of the stop-start technique and alternating intercourse positions or thrusting movements. Finally, a cooperative, intimate and satisfying relationship is established. An integrated psychodynamic approach seeks to have the man or couple understand the hidden meaning of the rapid ejaculation, appreciate the interference of performance anxiety and, when ready, embark on a series of behavioral tasks. Clinicians need to be aware of the man or couple's need for a symptom and how rare it is to find "simple cases" of rapid ejaculation. It has been found that the impressive treatment success rates of 60% to 95% reported by Masters and Johnson [84] can not be replicated and are not sustainable. Three years after behavioral treatment, success rates dwindle to 25%. This data suggest that behavioral clinicians may have failed to recognize psychodynamic causes of the disorder or to develop long-term strategies that allow patients to maintain their initial therapeutic gains.

Sensate focus exercises are designed to allow the man to develop an awareness of his arousal level by lessening the demand characteristics of the sexual experience. In a slow, graduated fashion the man and his partner take turns giving and receiving pleasure. Initially the touching is restricted to nongenital/non breast stimulation; upon achieving ejaculatory control these areas are also pleasured. "Quiet vagina" is an extension of the stop-start maneuver to include intercourse. After successful hand stimulation the woman sits astride or lies on top of the man and, without any thrusting or rhythmic movement envelops his penis in her vagina. The aim of this exercise is to desensitize the man to the wet, warm sensations of the vagina. After the man masters the "quiet vagina" for a prolonged period of time, movement by the woman is slowly introduced. The man directs her to stop when his excitement has increased. The couple sit/lie quietly until his arousal decreases whereupon they resume the exercise. This is repeated several times before the man eventually is allowed to ejaculate.

2. PSYCHOLOGICAL TREATMENT FOR DELAYED EJACULATION Treatment efforts are guided by the assumptions underlying the contrary theoretical models of causation. Proponents of the inhibition model understand the symptom as the man's muting of his excitement and prescribe techniques to increase excitement through prolonged, intense, rough stimulation or by interpreting the man's unconscious aggressive impulses. Diametrically opposed to the inhibition model is the paradigm that considers delayed ejaculation as a failure of the man to be excited enough to achieve orgasm. Treatment efforts are aimed at having the men acknowledge their lack of both desire to have intercourse and arousal during intercourse. This model mirrors the conventional therapy for female anorgasmia focusing on decreasing demand and helping the patient focus on heightening erotic sensations.

It is crucial for the therapist to monitor the partners' needs and responses during therapy. The female partner may feel used and unimportant. This must be acknowledged while helping her to focus on the ultimate goal of pleasurable sex for both partners. Also, the therapist must monitor both patient and partner for the emergence of any resistance that will sabotage treatment.

Masters and Johnson [84] reported a low failure rate of 17.6% using a treatment combination of sensate focus, vigorous non-coital penile stimulation and modifications of intercourse technique. In another study 81% of men who were anorgasmic prior to treatment were successful in reaching orgasm through vibrator stimulation. No outcome statistics are known for treatment model that considers men insufficiently aroused.

Cognitive-behavioral treatment for this dysfunction focuses on challenging self-defeating ideas about sexuality or women while replacing them with facilitating thoughts about ejaculatory control, sexuality and intimacy. In addition, the behavioral skill of identifying the point of ejaculatory inevitability is 500

cessfully produced pregnancies by natural insemination or assisted reproductive techniques [51].

3. DRUG TREATMENTFOR RAPID EJACULATION Reducing penile skin sensitivity with the application of local anaesthetic gel can treat premature ejaculation. By keeping the cream in contact with the skin with a condom for thirty minutes, significant improvement was obtained [85]. It was, however, important to wash off the local anaesthetic prior to intercourse if diminution of vaginal sensitivity in the female partner was to be avoided [86]. Clomipramine, a tricyclic antidepressant, has been shown to produce significant delay in time to orgasm with increased satisfaction with sex life in prospective controlled trial, given in a dose of 25 mg 12 to 24 hours before inter course [64]. Fluoxetine (Prozac) given in a dose of 20 mg daily for 1 week and 40 mg daily thereafter has also been used, and produced significant benefit after 4 weeks treatment [87]. The female partners involved in the latter study subjected the effects to careful scrutiny including verification of intravaginal latency time. Retrograde ejaculation can be treated with adrenergic drugs such as ephedrine, 30 - 60 mg, or a tricyclic antidepressant with anticholinergic effects such as desipramine, 50 mg, taken 1 - 2 hours before sexual activity. One patient with azoospermia and small volume ejaculate associated with an open bladder neck and unilateral absence of the vas deferens responded well to ephedrine with normalization of the seminal analysis, and subsequently a pregnancy was produced. Alternatively, spermatozoa can be retrieved from post-orgasmic urine by centrifugation after retrograde ejaculation, resuspended and used for artificial insemination with success: a cumulative pregnancy rate as high as 72% at 6 months has been achieved [88].

5. LOSS OF EJACULATION AFTER RETROPERITONEAL LYMPH NODE DISSECTION Drug treatment for loss of ejaculation after paraaortic lymphadenectomy is not very successful [89] but electroejaculation can produce spermatozoa for insemination [90]. It is important to anticipate this complication in young men with testicular tumours who may need chemotherapy or node dissection, and arrangements should be made for sperm storage at the earliest opportunity before treatment commences. Excellent results can be obtained with artificial insemination using cryopreserved spermatozoa [56].

6. SURGICAL TREATMENT OF EJACULATORY DUCT OBSTRUCTION It is very helpful if the lesion is accurately defined preoperatively by TRUS, so that all necessary arrangements can be made in advance. The obstruction should then be defined radiologically by vasography or percutaneous puncture of the seminal vesicles, and 5 - 10 mls of 1% methylene blue dye are instilled to indicate when the ejaculatory system has been entered. The patient should be placed in the lithotomy position and suitable drapes applied to allow access to rectal examination during the procedure. After preliminary cystoscopy, the resectoscope or optical urethrotome is inserted. A Mullerian duct cyst may simply be incised, releasing a gush of fluid, but there is a tendency for the incision to heal over and it may be preferable to resect the edges or make a cruciate incision. If the ejaculatory ducts are blocked at their lower ends, it may be simpler to resect the verumontanum, commencing just above it in the prostatic urethra and drawing the loop carefully downward. The appearance of the ejaculatory ducts is characteristic and easily recognized, resembling a horse's nostrils. Pressure on the seminal vesicles will produce abundant efflux once the obstruction has been relieved.

4. SPINAL INJURIES In some paraplegic patients, application of a vibrator to the penis will lead to ejaculation; in others, electroejaculation may be necessary to produce spermatozoa that can be used for insemination. If the spinal reflex arc is intact, a hypogastric plexus stimulator will provoke ejaculation [49]. This method has the advantage that it can be used in the security of the patients' home, and repeated ejaculation can improve the quality of the semen. Alternatively, direct electroejaculation by rectal probe may be effective, but this generally requires a general anaesthetic and is done in hospital [50]. In a recent analysis of 40 paraplegic patients, 22 suc-

Analysis of results obtained with 87 patients with ejaculatory duct obstruction is summarized in Table 3 [91]. It may be seen that incision of Mullerian duct cyst was much the most successful procedure, but satisfactory results have been obtained in other patients, and have continued to be seen 501

Table 3 : Number of patients with ejaculatory duct obstruction by group, number successfully treated/number with adequate follow up in each group (from Pryor and Hendry (91)). Group

Total Number

Number with follow up

Postoperative patency

Pregnancies produced

CONGENITAL Mullerian

17

12

10

5

Wolffian

19

6

1

1

Traumatic

15

6

2

1

Infective

19

6

4

2

Tuberculous

8

Megavesicles

8

Neoplastic

1

TOTAL

87

1

31

18

1. Care should be taken to distinguish erectile dysfunction from difficulties with orgasm and ejaculation. 2. The difference between emission (deposition of semen into the posterior urethra) and ejaculation (from the urethral meatus) should be recognized. 3. The presence of retrograde ejaculation should be established early in the diagnostic work-up of patients with loss of ejaculation by appropriate examination of centrifuged urine after orgasm. 4. The afferent nervous pathways, cerebral receptor and motor areas, and efferent spinal and sympathetic nerves controlling orgasm and ejaculation should be clearly understood by physicians dealing with sexual dysfunction. 5. The facilitative role of dopamine and the inhibitory role of serotonin (5-HT) in the production of orgasm and ejaculation must be understood. 6. The effects of antidepressant and other drugs on the normal cerebral biochemical transmitters (See above : 5) should be appreciated. 7. Neurological tests to study the connections between the genitalia and the central nervous system should be more widely understood. 8. The embryology of the male genital tract, and congenital anomalies leading to ejaculatory malfunction should be familiar to all urologists. 9. Damage caused to the ejaculatory system by rectal pull-through procedures for imperforate anus should be more widely recognized by paediatric surgeons dealing with this condiotion. 10. The effects of bladderneck incision and prostatectomy on ejaculation must be explained to patients prior to surgery. 11. The possibility of ejaculatory duct obstruction should be considered in men with infertility who have had genital infection including sexually transmitted diseases, Schistosomiasis, tuberculosis and unexplained urinary infection.

1 1

VIII. RECOMMENDATIONS

10

since this study was completed. If reconstruction is not possible, sperm can be withdrawn by microscopic epididymal sperm aspiration (MESA) or percutaneously (PESA) and used for in-vitro fertilization [92]. Attempts to insert a permanent sperm reservoir gave only limited success and this treatment has now been abandoned [93].

VII. CONCLUSIONS It is clear that there is much to study and understand in disorders of orgasm and ejaculation. Experimental evidence has shone light onto the biochemical function of the brain, especially in the limbic system and hypothalamus. The side effects of drug therapy have provided insight into functional disorders, and indicated effective methods of treatment. Congenital malformations and their relationship to genetic disorders are now more clearly understood: these are matters of importance in the present era of assisted reproduction, if perpetuation of serious anomalies such as fibrocystic disease is to be avoided. Surgically induced injuries that impact upon male reproductive function are now recognized and largely preventable by careful attention to preservation of normal structures during extirpative surgery. It seems likely that in the future, these will be areas of much fruitful research. 502

12. The effects of neurological disease and spinal cord injury on sexual function should be widely understood (see section 14). 13. Nerve sparing techniques of retroperitoneal lymph node dissection should be used whenever possible. 14. Arrangements for sperm storage should be made prior to administration of chemotherapy likely to interfere with spermatogenesis or surgery that may interfere with ejaculation. 15. Rapid or premature ejaculation may be defined as inability to delay ejaculation sufficiently to enjoy lovemaking, or, alternatively, persistent or recurrent occurrence of ejaculation with minimal sexual stimulation before, on, or shortly after penetration and before the person wishes it. 16. Patients with rapid ejaculation should be fully evaluated with objective data. It is useful to measure ejaculatory latency time by stopwatch. 17. Psychosocial background to rapid ejaculation should be investigated, with involvement of the partner. 18. Societal and religious attitudes to sex should be recognized. 19. Treatment of rapid ejaculation should include behavioural therapy including the female partner. 20. Results of treatment of rapid ejaculation should be evaluated in both short and long term. 21. Drug therapy for rapid ejaculation may be given immediately prior to sexual activity (e.g. Clomipramine) or more chronically (e.g. Paroxetine). The dose schedule, effects and unwanted side effects of such therapy must be carefully monitored. 22. The volume, pH and fructose content of semen in subfertile men with oligozoospermia or azoospermia should be measured and the result noted by doctors caring for infertile couples. 23. Abnormalities in seminal volume or biochemical characteristics should be evaluated by a urologist. Transrectal ultrasound scanning is recommended as the first investigation, which may be supplemented by vasography

or percutaneous puncture of the seminal vesicles to establish the presence of ejaculatory duct obstruction. 24. Urologists should be familiar with the anatomy of the ejaculatory ducts in relation to surrounding structures and be able to relieve ejaculatory duct obstruction safely by appropriate resection. 25. Electroejaculation should be available at selected fertility centres for patients with spinal injuries or loss of ejaculation after abdominal surgery.

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22. SATO K, KIHARAK. Spinal cord segments controlling the canine vas deferens and differentiation of the primate sympathetic pathways to the vas deferens. Microsc Res Techniq 1998;42:390-7. 23. KOLBECK SC, STEERS WD. Origin of neurons supplying the vas deferens of the rat. J Urol 1993;149:91821.

39. HENDRY WF, LEVISON DA, PARKINSON MC, PARSLOW JM, ROYLE MG. Testicular obstruction: clinicopathological studies. Annals of the Royal College of Surgeons of England 1990;72:396-407. 40. WOODHOUSE CR, SNYDER HM. Testicular and Sexual Function in Adults with Prune Belly Syndrome. J Urol 1985;133:607-9.

24. LEARMONTH JR. Contribution to neurophysiology of urinary bladder in man. Brain 1931;54:147-76. 25. KIHARA K, KAKIZAKI H, DEGROAT WC. Reorganisation of the innervation of the vas deferens after sympathetic decentralisation. Am J Physiol 1996 ; 271:R1481-8.

41. HOLT B, PRYOR JP, HENDRY WF. Male infertility following surgery for imperforate anus. J Paed Surg 1995;30:1677-9. 42. HEDLUND H, EK A. Ejaculation and Sexual Function after Endoscopic Bladder Neck Incision. Br J Urol 1985;57:164-7.

26. DAIL WG. IN MAGGI CA, editors.Nervous conrol of the Urogenital System. Harwood Academic Publishers; 1993;Autonomic innervation of male reproductive genitalia. p. 69-101.

43. KELLY MJ, ROSKAMPD, LEACH GE. Transurethral incision of the prostate: a preoperative and postoperative analysis of symptoms and urodynamic findings. J Urol 1989;142:1507-9. 44. REISER C.The etiology of retrograde ejaculation and a method for insemination. Fertil Steril 1961;12:488-92.

27. KIHARA K, DEGROAT WC. Sympathetic efferent pathways projecting bilaterally to the vas deferens in the rat. Anat Rec 1997;248:291-9.

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45. EDWARDS L, POWELL C. An objective comparison of transurethral resection and bladder neck incision in the treatment of prostatic hypertrophy. J Urol 1982;128:325-7. 46. QUINLAN DM, EPSTEIN JI, CARTER BS, WALSH PC. Sexual function following radical prostatectomy: influence of preservation of neurovascular bundles. J Urol 1991;145:998-1002. 47. MCKENNA G, SCHOUSBOE M, PALTRIDGE G. Subjective change in ejaculate as symptom of infection with schistosoma haematobium in travellers. Br med J 1997;315:1000-1. 48. FLETCHER MS, HERZBERG Z, PRYOR JP. The aetiology and investigation of haemospemia. Br J Urol 1981;53:669-71. 49. BRINDLEY GS, SAUERWEIN D, HENDRY WF. Hypogastric plexus stimulators for obtaining semen from paraplegic men. Br.J.Urol. 1989;64:72-7. 50. OHL DA. Electroejaculation. Urol Clin N Am 1993;20:181-8. 51. DAHLBERG A, RUUTU M, HOVATTA O. Pregnancy results from a vibrator application, electroejaculation, and a vas aspiration programme in spinal-cord injured men. Human Reprod 1995;10:2305-7. 52. SIPSKYML.Sexual functioning in the spinal cord injury. Int J Imp Res 1998;10:S128-30. 53. TAIT D, PECKHAM MJ, HENDRY WF, GOLDSTRAW P. Post-chemotherapy surgery in advanced non-seminomatous germ-cell testicular tumours: the significance of histology with particular reference to differentiated (mature) teratoma. Br.J.Cancer 1984 ; 50:601-9. 54. HENDRY WF, A'HERN RP, HETHERINGTON JW, PECKHAM MJ, DEARNALEY DP, HORWICH A. Para-aortic lymphadenectomy after chemotheraphy for metastatic non-seminomatous germ cell tumours: prognostic value and therapeutic benefit. Br.J.Urol. 1993;71:208-13. 55. JONES DR, NORMAN AR, HORWICH A, HENDRY WF. Ejaculatory dysfunction after retroperitoneal lymphadenectomy. Eur Urol 1993;23:169-71. 56. SCAMMELLGE, WHITE N, STEDRONSKAJ, HENDRY WF, EDMONDS DK, JEFFCOATE SL. Cryopreservation of semen in men with testicular tumour or Hodgkin's disease: results of artificial insemination of their partners. Lancet 1985;2:31-2. 57. AHLENIUS S, LARSSON K. IN BEVAN P, COOLS AR, ARCHER T, editors.Behavioral pharmacology of 5-HT. Hillsdale: Lawrence Erlbaum; 1989;New aspects on the serotonergic modulation of male rat sexual behavior. p. 35-53. 58. HAENSEL SM, MOS J, OLIVIER B, SLOB AK. Sex behavior of male and female Wistar rats affected by the serotonin agonist 8-OH-DPAT. Pharmacol Biochem Behav 1991;40:221-8. 59. MOS J, MOLLET I, TOLBOOM JTBM, WALDINGER MD, OLIVIER B.Acomparison of the effects of different serotonin reuptake blockers on sexual behavior of the male rat. Eur Neuropsychopharmacol 1999;9:123-35.

60. EATON H. Clomipramine (Anafranil) in the treatment of premature ejaculation. Int Med Res 1973;1:432-4. 61. ROWLAND DL, COOPER SE, SLOB AK. The treat ment of premature ejaculation: psychological and biological strategies. Drugs of Today 1998;34:879-99. 62. SEGRAVES RT, SARAN A, MAGUIRE E. Clomipramine versus placebo in the treatment of premature ejaculation: a pilot study. [Abstract] J Sex Marit Ther 1993;19:198-200. 63. ALTHOF SE, LEVINE SB, CORTYEW, et al. A double blind crossover trial of clomipramine for rapid ejaculation in 15 couples. [Abstract] J Clin Psychiatry 1995;56:402-7. 64. HAENSEL SM, ROWLAND DL, KALLAN KTHK, SLOB AK. Clomipramine and sexual function in men with premature ejaculation and controls. J Urol 1996;156:1310-5. 65. STASSBERG DS, DE GOUVEIA BRAZAO CA, ROWLAND DL, SLOB AK. Clomipramine in the treatment of rapid (premature) ejaculation. J Sex Marit Ther 1999;25:89-101. 66. KARA H, AYDIN S, AGARGUN MY, ODABAS O, YILMAZ Y. The efficacy of fluoxetine in the treatment of premature ejaculation: a double blind placebo controlled study. J Urol 1996;156:1631-2. 67. LEE HS, SONG DH, KIM CH, CHOI HK. An open clinical trial of fluoxetine in the treatment of premature ejaculation. J Clin Psychopharmacol 1996;16:379-82. 68. HAENSELSM, KLEM TMAL, HOPWCL, SLOB AK. Fluoxetine and premature ejaculation: a double blind, crossover, placebo controlled study. J Clin Psychopharmacol 1998;18:72-7. 69. WALDINGER MD, HENGEVELD MW, ZWINDERMAN AH. Paroxetine treatment of premature ejaculation: a double blind, randomized, placebo controlled study. Am J Psychiatry 1994;151:1377-9. 70. WALDINGER MD, HENGEVELD MW, ZWINDERMAN AH. Ejaculation rerarding properties of paroxetine in patients with primary premature ejaculation: a double blind, randomized, dose response study. Br J Urol 1997;79:592-5. 71. MCMAHON CG, TOUMA K. Treatment of premature ejaculation with paroxetine hydrochloride as needed: 2 single-blind placebo controlled crossover studies. J Urol 1999;161:1826-30. 72. MCMAHON CG. Treatment of premature ejaculation with sertraline hydrochloride: a single-blind placebo controlled crossover study. J Urol 1998;159:1935-8. 73. MCMAHON CG. Treatment of premature ejaculation with sertraline hydrochloride. Int J Impot Res 1998 ; 10:181-4. 74. WALDINGER MD, HENGEVELD MW, ZWINDERMAN AH. Effect of SSRI antidepressants on ejaculation: a double-blind, randomized, placebo controlled study. J Clin Psychopharmacol 1998;18:274-81. 75. KIM SC, SEO KK. Efficacy and safely of fluoxetine, sertraline and clomipramine in patients with premature ejaculation: a double blind, placebo controlled study. J Urol 1998;159:425-7.

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76. AGMO A, PAREDES R. Opioids and sexual behaviour in the male rat. Pharmacol Biochem Behav 1988;30:1021-34.

87. KARA H, AYDIN S, AGARGUN MY, ODABAS O, YILMAZ Y. The efficacy of fluoxetine in the treatment of premature ejaculation: a double-blind placeba controlled study. J Urol 1996;156:1631-2. 88. SCAMMELL GE, STEDRONSKA-CLARK J, EDMONDS DK, HENDRY WF. Retrograde ejaculation: a successful treatment with artificial insemination. Br.J. Urol. 1989;63:198-201. 89. HENDRY WF. IN JONES WG, HARNDEN P, APPLEYARD I, editors.Germ cell tumours III. 3 ed. Oxford: Pergamon; 1994;Treatment for loss of ejaculation after para-aortic lymphadenectomy. p. 353-8. 90. OHL DA, DENIL J, BENNETT CJ, RANDOLP JF, MENGE AC, MCCABE M. Electroejaculation following retroperitoneal lymphadenectomy. J Urol 1991 ; 145:980-3.

77. DORNAN WA, KATZ JL, RICAURTE GA.The effects of repeated administration of MDMAon the expression of sexual behaviour in the male rat. Pharmacol Biochem Behav 1991;39:813-6. 78. MOORS-MOMMERS MCT. Influences of medical and recreational drugs on sexual functions. Geneesmiddelenbulletin 1994;28:53-6. 79. HENDRY WF, RICKARDS D, PRYOR JP, BAKER LRI. Seminal magavesicles with adult polycystic kidney disease. Human Reprod 1998;13:1567-9. 80. COLPI GM, CASELLA F, ZANOLLO A, BALLERINI G, BALERNA M, CAMPANAA, LANGE A. Functional voiding disturbances of the ampullo-vesicular seminal tract: a cause of male infertility. Acta Eur Fertil 1987;18:165-79. 81. DRACH GW, FAIR WR, MEARES EM, STAMEY TA. Classification of benign diseases associated with prostatic pain: prostatitis or prostatodynia? J Urol 1978 ; 120:266 82. SCHLEGELPN, SHIN D, GOLDSTEIN M. Urogenital anomalies in men with congenital absence of the vas deferens. J Urol 1996;155:1644-8. 83. HENDRY WF. Disorders of ejaculation: congenital, acquired and functional. Br J Urol 1998;82:331-41. 84. MASTERS WH, JOHNSON VE,editors.Human Sexual Inadequacy. Boston: Little Brown and Company; 1970;

91. PRYOR JP, HENDRY WF. Ejaculatory duct obstruction in subfertile males: analysis of 87 patients. Fertil.Steril. 1991;56:725-30. 92. CRAFT I, TSIRIGOTIS M. Simplified recovery, preparation and cryopreservation of testicular spermatozoa. Human Reprod 1995;10:1623-7. 93. BRINDLEY GS, SCOTT GI, HENDRY WF. Vas cannulation with implanted sperm reservoirs for obstructive azoospermia or ejaculatory failure. Br.J.Urol. 1986;58:721-3. 94. R.J. OPSOMER, PJ VAN CANGH and PM ROSSINI Motor evoked potentials in neuro-urological disorders in: Clinical applications of magnetic transcranial stimulation. M.A. Lissens (editor), Peeters Press, Leuven, Belgium 1992, Chapter 20, P 247-254.

85. BERKOVITCH M, KERESTECI AG, KOREN G. Efficacy of prilocaine-lidocaine cream in the treatment of premature ejaculation. J Urol 1995;154:1360-1.

95. ROSEN RC, LANE RM, MENZAM. Effects of SSRIs on sexual function : a critical review. J. Clin. Psychopharmacol 1999 Feb; 19(1):67-85

86. SAHIN H, BIRCAN MK. Efficacy of prilocaine-lidocaine cream in the treatment of premature ejaculation. J Urol 1996;156:1783-4.

_____________________

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Committee 14

Female Sexual Dysfunction

Chairman I. GOLDSTEIN,

Members A. G RAZIOTTIN, J. R. H EIMAN, C. JOHANNES, E. LAAN, R. L. L EVIN, K. E. M CKENNA

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CONTENTS IV. NOSOLOGY AND DIAGNOSTIC CLASSIFICATION: USE IN ASSESSING PSYCHOSEXUAL TREATMENT OF FEMALE SEXUAL DYSFUNCTION

I. EPIDEMIOLOGY OF FEMALE SEXUAL DYSFUNCTION 1. INTRODUCTION 2. METHODOLOGICAL DIFFICULTIES IN THE STUDY OF FEMALE SEXUAL DYSFUNCTION

1. INTRODUCTION

3. REVIEW OF PUBLISHED EPIDEMIOLOGIC INVESTIGATIONS OF FEMALE SEXUAL DYSFUNCTION

3. PSYCHOSEXUAL TREATMENT EFFICACY BY DIAGNOSIS

2. PSYCHOSEXUAL TREATMENT OPTIONS

V. FEMALE SEXUAL FUNCTION AND BREAST OR GYNECOLOGIC CANCER: ASSESSING THE BIOLOGICAL ISSUES

4. RISK FACTORS FOR FEMALE SEXUAL DYSFUNCTION II. ANATOMYAND PHYSIOLOGY OF SEXUALAROUSAL OF THE HUMAN FEMALE GENITAL TRACT

1. INTRODUCTION « SINE DESIDERIO MENS NIHIL INTELLIGIT» 2. FEMALE SEXUAL FUNCTION

1. INTRODUCTION VI. PHYSIOLOGIC MEASURES OF FEMALE GENITAL BLOOD FLOW

2. ANATOMY 3. P HYSIOLOGY

1. INTRODUCTION

III. CENTRAL NERVOUS SYSTEM PATHWAYS INVOLVED IN THE CONTROL OF FEMALE SEXUAL FUNCTION

2. PHYSIOLOGICAL MEASURES 3. ORGANIC ETIOLOGY 4. DIFFERENTIAL DIAGNOSIS

1. INTRODUCTION

5. FEELINGS AND STIMULI

2. O VERVIEW

6. SEX AND THE BRAIN

3. SENSORY MECHANISMS

7. PHARMACOLOGICAL INTERVENTIONS

4. SPINAL REFLEXES VII. CONCLUSIONS

5. ASCENDING SENSORY PATHWAYS 6. BRAINSTEM REGIONS 7. HYPOTHALAMUS

REFERENCES

8. FOREBRAIN

508

Female Sexual Dysfunction I. GOLDSTEIN, A. GRAZIOTTIN, J. R. H EIMAN, C. J OHANNES, E. L AAN, R. L. L EVIN, K. E. MCKENNA

The goal of the committee on Female Sexual Dysfunction was to prepare a detailed, literature-based, state-of-the-art review of current knowledge of female sexual dysfunction concer ning: epidemiology, anatomy and physiology, sexual response cycle, classification, diagnosis and treatment.

I. EPIDEMIOLOGY OF FEMALE SEXUAL DYSFUNCTION 1. INTRODUCTION The epidemiology of female sexual dysfunction (FSD) is not well understood for many reasons. Unbiased prevalence estimates from populationbased samples have been rare, and incidence estimates have been nonexistent. Most published prevalence estimates have been based on selected clinical or volunteer samples. Until the recently convened «International Consensus Development Conference on Female Sexual Dysfunction» [1], where an interdisciplinary consensus conference panel, consisting of 19 experts in female sexual dysfunction selected from 5 countries expanded female sexual dysfunctions to include both psychogenic and organic causes of desire, arousal, orgasm and sexual pain disorders, there has been a contemporary lack of standard uniformly applied definitions of FSD. Thus, there has been difficul ty in measuring FSD in non-clinical samples. Accurate estimates of prevalence and incidence are important in understanding the burden of

509

female sexual dysfunction in the community and in identifying risk factors for prevention efforts. Recognizing the distinction between prevalence and incidence is important, as each measure contains different information. Incidence is defined as the number of new cases of a condition or disease that occur during a specific time period in a population that is at risk for developing the condition [2]. Because incidence measures the transition from a non-affected (or non-diseased) to an affected state, it is a measure of risk. Preva lence measures the number of persons affected with the condition in the population at a given point in time, but does not determine when the condition developed [2]. Because the prevalence estimate contains persons who have had the condition for different lengths of time, it is not a measure of risk. Incidence estimates are useful for the identification of etiologic, or causal factors and for monitoring the efficacy of prevention programs [3]. Prevalence measures are useful for estimating the burden of a particular condition on a community. Such information is valuable for planning appropriate health services for treatment and prevention efforts. Although suspected risk factors are often evaluated in relation to the prevalence of a condition, cause can only be determined using incidence.

2. METHODOLOGICAL DIFFICULTIES IN THE STUDY OF FEMALE SEXUAL DYSFUNCTION There are a number of difficulties, discussed below, specific to the study of sexual function that contribute to the current paucity of epidemiologic knowledge in this area.

a) Definitions The first standardized method of classification of the various categories of female sexual function for use in research was published in 1980 as the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM-III) [4]. In the World Health Organization’s ICD-10 system (1992), sexual dysfunction was defined as including: «the various ways in which an individual is unable to participate in a sexual relationship as he or she would wish» [5]. Specific categories in the ICD-10 nomenclature, limited to consideration of psychiatric disorders only, included a lack or loss of sexual desire (F52.0), sexual aversion disorder (F52.1), failure of genital response (F52.2), orgasmic dysfunction (F52.3), nonorganic vaginismus (F52.5), nonorganic dyspareunia (F52.6), and excessive sexual drive (F52.7). Subsequently, in 1994, the DSM-IV defined four categories of dysfunction based on the sexual response cycle model: sexual desire disorders, sexual arousal disorders, orgasmic problems, and sexual pain disorders [6]. This DSM-IV system was also limited in that it described psychogenically-based dys functions, and was not used widely outside of psychiatry. The most contemporary definition and classification system of female sexual dysfunction resulted from an international consensus panel (1998) which employed a modified Delphi method in the development of consensus definitions and classifications and built upon the existing framework of the ICD-10 and DSM-IV [1]. Female sexual dys functions were expanded to include both psychogenic and organic causes of desire, arousal, orgasm and sexual pain disorders. An essential element of the new diagnostic system was the inclusion of a «personal distress» criterion. In particular, new definitions of sexual arousal disorder and hypoactive sexual desire disorder were developed and a new category of non-coital sexual pain disorder was added. In addition, a new sub-typing system for clinical diagnosis was devised (see table 4). There remain no «gold-standard» objective diagnostic criteria making it difficult to formulate standard operational definitions that can be applied to large, non-clinical population groups. Comparison of published studies remain problematic due to the many different ways in which

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sexual function has been defined in the past in individual studies, the different aspects of sexual function measured, and the frequent use of nonvalidated instruments. b) Assessment Epidemiological assessment of sexual dysfunction requires the use of self-reported data. Lengthy clinical assessment questionnaires and physiological measures of the female sexual response, while useful for diagnosis in a clinical or laboratory setting are not feasible for large population-based studies due to the expense, logistics, and concerns with participant burden and acceptability. Most studies have used either self-administered questionnaires or interviewer administered instruments. Self-administered instruments completed in private may be able to elicit more honest responses to sensitive questions than with a face-toface interview. These questionnaires, however, must be kept fairly short and simple because long, complicated questionnaires may lead to missing or inaccurate data. Interviewer-administered instruments can be more complex and the interviewer can probe for more detail. Respondents, however, may be reluctant to answer sensitive questions, leading to underreporting. Reporting biases due to lack of candor and comprehension, however, were negligible with interviewer-collected data in the National Health and Social Life Survey, the largest and most representative population survey to date of sexual function [7]. c) Type of population Most published research on FSD is based on samples of patients from general practice, specialty clinics, or other non-representative convenience samples such as volunteer samples or college students. Selection bias is a real consideration in these studies, as not all women experiencing sexual difficulties seek medical care, and those who do may have more severe or bothersome symptoms. Volunteer samples may be comprised of women experiencing sexual problems with unaffected women less likely to participate. Thus, prevalence estimates based on selected samples cannot be considered accurate, although such estimates may be useful for allocating resources within a particular medical care facility or for identifying trends in help-seeking behavior [3]. Glatt and coworkers [8] noted that less than half

(41%) of 104 women with persistent dyspareunia in their study had consulted a physician or health care provider for this problem. Even among women who seek medical care, sexual problems are often underreported. Practitioners may not routinely ask about sexual difficulties or patients may be reluctant to provide such information. In a survey of consecutive patients attending a general practice in the UK, although 42% of the women and 35% of the men reported some form of sexual dysfunction to the study interviewer, sexual problems were recorded in only 2% of the general practitioner notes [9]. Similarly, of 887 consecutive gynecologic outpatients in a US clinic, only 3% presented with specific sexual complaints [10]. An additional 16% admitted sexual problems following direct inquiry. In addition, availability of treatments may affect who presents to clinics. Public perception of lack of effective treatments will result in fewer affected persons seeking medical care. If a new, widely publicized treatment becomes available for a particular type of disorder, persons who may not have otherwise sought treatment may do so, leading to inflated prevalence estimates for that disorder. Another study examined the prevalence of female sexual arousal disorder in the partners’ of impotent men undergoing urologic evaluation [11]. In this report, subjects anonymously and voluntarily completed questions concerning arousal response quality during sexual activity. Female sexual arousal disorder was considered to exist if the respondent answered postively to 1 or more of 6 symptoms, present and persistent for at least 6 months during the course of the sexual relationship and adversely affecting her satisfaction. The presence of 1, 2, or 3 or more of the symptoms was considered to represent mild, moderate or severe forms of female sexual arousal disorder, respectively. Of the 268 females, 260 respondents returned complete medical and sexual data. A total of 152 (58.5%) fulfilled the criteria for female sexual arousal disorder; 22.7%, 13.8% and 22% had mild, moderate and severe forms, respectively [11].

prevalence rates can be inflated, if women with a problem tend to skip key questions or do not answer truthfully, prevalence will be underestimated. There are many factors such as age, socioeconomic status, marital status, the availability of a sexual partner, partner limitations, concurrent illnesses, and others that can affect the prevalence and incidence of FSD. Lack of adjustment for such factors may lead to distorted estimates. d) Lack of incidence data measuring risk To estimate incidence, longitudinal data are needed. To date there are no published incidence esti mates of FSD from well-designed, longitudinal, population-based samples. Two studies of women in mid-life have gathered longitudinal data on sexual functioning, The Melbourne Women’s Midlife Health study [12] and the Massachusetts Women’s Health Study II [13] which to date have published only cross-sectional results. These studies are limited to women in mid-life because the purpose of both is to examine the effects of the menopausal transition on many factors, including sexual functioning. Longitudinal data in younger populations of women initially free of sexual dysfunctions are needed to estimate the incidence and to study the natural history of FSD.

3. REVIEW OF PUBLISHED EPIDEMIOLOGIC INVESTIGATIONS OF FEMALE SEXUAL DYSFUNCTION

a) Non-population-based studies Most published studies of the prevalence of sexual dysfunctions in women were performed in clinic or other selected samples. An excellent review of earlier studies published prior to 1988 was written by Spector and Carey [3]. From this review it is apparent that the prevalence of most sexual dys functions is higher in clinical than in communi ty samples. For instance, inhibited female orgasm ranged from 18% to 76% in clinics, but only 5% to 20% in community samples [3]. Similarly up to 62% of females seeking sex therapy experience arousal disorder, while community estimates are closer to 11%.

Reliable prevalence estimates can only be obtained from well-designed population-based studies, but even the best of these can suffer from nonresponse bias, a particular problem with a sensitive topic area like FSD. If women without sexual difficulties are less likely to participate,

Table 1 summarizes more recent studies of general or specialty clinics or selected community samples. Use of different measures and time frames for symptoms makes comparison of out-

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512

comes difficult among studies. Sample sizes varied widely from 43 women in a premenstrual syndrome clinic [14] to 887 consecutive gynecology outpatients [10]. Those studies less likely to suffer from selection bias are the studies by Schien [15] with a wide age range, racial minority representation, and a detailed questonniare; Rosen [16] with a wide age range of healthy women recruited from a wellness center; and Read [9] with patients recruited from a general practice in the UK where 98% of the population is registered with a GP. The overall prevalence of dysfunction was repor ted by three studies, and ranged from 19% to 42% [9, 10, 14]. The lower estimate is based on a study that asked only two brief questions about sexual functioning without probing further as to the specific type of problem [10]. Dyspareunia was experienced by about 12% of women in two studies [14, 16], and 33% in a third. The higher estimate was from a study with a high nonresponse rate and subjects were prior participants in a study of sexually transmitted diseases, so may be an unrepresentative sample. Problems with orgasm ranged from 5% to 23% [9, 14-16]. b) Population-based studies Table 2 summarizes results regarding the prevalence of FSD from published population-based studies throughout the world. Although most studies included samples of men and women, only the results for women are presented here. Some strengths and limitations of each study are discussed below. The best information is from the large, well-designed National Health and Social Life Survey (NHSLS) [7, 17]. This was a true population-based study of a representative sample of US adults ages 18-59. Particular strengths of the study are its large sample size, minority representation (African Americans and Hispanics), excellent response rates, inclusion of a number of detailed measures of sexuality, and many other variables pertaining to demographic, health, social, and psychological characteristics. A few limitations of the study should also be noted. These include the cross-sectional design preventing measurement of incidence, inability to measure cause and effect of related factors, or risk, the inability to examine sexual dysfunction in women aged 60 and older, and the lack of adjustment for menopause status. The NHSLS found a high overall prevalence of FSD (43%) in US women ages 18-59 (Table 2).

Low desire was reported by 22%, arousal problems by 14% and sexual pain by 7% using categories similar to the DSM-IV defined by latent class analysis [17]. A prior publication from the same study [4] reported unadjusted frequencies of individual sexual dysfunction variables. About a third of women ages 18-59 reported a lack of interest in sex during the past 12 months, and a quarter of women with a partner were unable to achieve orgasm (Table 3). The prevalence of dyspareunia among women with partners was 15.5%, and trouble lubricating was experienced by about 21%. In general sexual dysfunction was more common among younger women; the one exception was trouble with lubrication [7]. Estimates of dysfunction from an older population (> 60 years) is provided by a probability sample of adults in Michigan [18]. Two thirds of 448 women were sexually inactive, 12% of married women had difficulty with intercourse and about 13% experienced pain with intercourse [18]. Activity was strongly related to marital status, with only 5.3% of non-married women being sexually active. Additional limited information from women 60 years and older is reported by Marsiglio and Donnelly [19]. In cross-sectional study of a representative sample of the US population, 49 percent of women reported no sexual activity in the past month. Women were less likely to have sex if they were older, if their partner was of poor health, and if they had low feelings of self-worth. It should be pointed out that lack of activity does not imply sexual dysfunction for older women. As shown by these two studies and others [20], lack of a partner or limitations of a partner are important reasons for lack of activity. Neither of these studies of older women included specific measures of sexual dysfunction. The other studies in Table 2 were performed in middle-aged women. The overall prevalence of sexual dysfunction was estimated at 33% in the UK [18] and 22% in Iceland [19]. Interestingly, although a third of the women in the UK had at least one operationally defined sexual dysfunction, only 10% of them thought that they had a sexual problem [21]. If few women perceive sexual dysfunction to be a problem, it may explain in part why only a portion of women seek medical attention for these conditions.

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514

NHSLF study [17], although due to the cross-sectional nature of the data, the factors identified cannot be expressed truly as risk, but as correlates of dysfunction. In contrast to men, age is inversely associated with dysfunction in women. Younger age was a significant predictor for pain during sex, lack of pleasure, and anxiety about performance [17]. Women with a lower level of education were also more likely to experience pain during sex [17]. Low desire was more likely among women who had ever experienced a sexually transmitted disease, those reporting emotional problems or stress, women with more than a 20% drop in household income from 1988-1991, and those with infrequent thoughts about sex. Arousal disorder was higher among women with a urinary tract symptom, emotional problems or stress, infrequent thoughts about sex, and a history of being sexually touched before puberty and sexually forced by a man ever. Sexual pain was increased in women with a urinary tract symptom, and emotional problems or stress, and among those reporting poor to fair health, and a 20% decrease in household income. Low physical and emotional satisfaction and low general happiness were significant correlates of all three sexual dysfunction categories: low desire, arousal disorder and sexual pain [17]. The Melbourne Women’s Midlife Health Study reported that a decline in sexual interest among mid-aged women was significantly related to the natural menopause transition, decreased well-being, decreasing employment, and increased vasomotor, cardio-pulmonary and skeletal symptoms and hormone therapy use [8]. Unpublished cross-sectional results from the Massachusetts Women’s Health Study II indicate decreased sexual desire among married women, those with psychological symptoms, current cigarette smokers, and perimenopause status [23]. Frequency of sexual intercourse was inversely related to depression, physical limitations of a partner, and smoking, but unrelated to menopause status. Pain during intercourse was related to recent vaginal dryness and recent urinary tract infection. No statistically significant correlates were found for difficulty reaching orgasm. Preliminary longitudi nal results from the MWHS II examining a change in sexual functioning over about a six-year time per-iod, in which women transitioned from pre- or perimenopause to postmenopause, indicate that

Table 3: Frequency of Female Sexual Dysfunction in women ages 18-59 from the National Health and Social Life Survey. Unadjusted prevalence of individual dysfunc tion measures SEXUAL DYSFUNCTION

ALL WOMEN, N= 1,622*

WOMEN WITH PARTNER 12 MONTHS, N= 1,486$

Lack of interest in sex

33.4

31.6

Unable to achieve orgasm

24.1

25.7

Dyspareunia

14.4

15.5

Sex not pleasurable

21.2

22.6

Anxiety about performance

11.5

12.3

Trouble lubricating

18.8

20.6

Climax too early

10.3

Not reported

* From : Laumann EO, Gagnon JH, Michaels S. The Social Organization of Sexuality : Sexual Practices in the United States. Chicago, III: University of Chicago Press; 1994, p.371 [7] $ From Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States. Prevalence and predictors. JAMA 1999, 281:537-544 (sample sizes vary from 1,475 to 1,486 depending on outcome measure) [17]

Population estimates of inhibited desire are 22% in the US [17] and 16% in Iceland [21]. Almost a third of mid-life women in Australia reported decreased sexual interest, related in part to the menopausal transition [12], and 17% of women ages 35-59 in the UK reported impaired interest. The prevalence of dyspareunia was fairly consistent across studies, ranging from 7% to 13%, except for the Icelandic study that reported a 3.1% prevalence of functional dyspareunia [22]. Orgasmic difficulties were reported by 3.5% of Icelandic women [22], 10% of Massachusetts women [13] and 16% of women in the UK [21]. A rigorous comparison of outcomes is difficult because of the different outcomes studied and the different ways in which they were measured.

4. R ISK FACTORS

FOR

FEMALE SEXUAL DYS-

FUNCTION

Limited published information is available concerning risk factors for sexual dysfunction in women. The most thorough information is from the

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decreased desire is related to increased age, increased body mass and poorer self-perceived health and higher desire to starting hormone therapy use.

2. ANATOMY a) The clitoris (Figures 1 & 2)

The study of groups of women with chronic medi cal conditions can also provide some clues as to etiology for various sexual dysfunctions. Studies of sexual dysfunction in women with diabetes, although far from being conclusive, suggest an increased prevalence of problems such as decreased lubrication and libido that may be related to duration of diabetes and presence of neuropathy [24]. Although treatment with antihypertensive agents has been associated with sexual dysfunction in men, there is little comparable research in women [24]. One study has shown a disproportionate frequency of sexual dysfunction among black and Mexican-American women who had both diabetes and hypertension [25]. There is some evidence that decreased libido and difficulties with orgasm may be related to antidepressant use in women [26]. More research is needed concerning the relation of medications and comorbidities on the occurrence of sexual dysfunction in women.

II. ANATOMY AND PHYSIOLOGY OF SEXUALAROUSAL OF THE HUMAN FEMALE GENITAL TRACT 1. INTRODUCTION The internal and external anatomical structures that comprise the female genitals are shown and listed in Figures 1 and 3-7 and further detailed in Figure 2A and B. During penile coitus certain aspects of these structures, classified as erogenous friction and pressure sites, are stimulated by the movements of the penile thrusting which are transduced by specific nerve endings [27] and relayed via the spinothalamic, spinoreticular and dorsal column systems of the spinal cord and possibly the vagus [28] to the brain where they are interpreted as sexual stimuli and converted into sexual arousal. If the stimuli are psychologically acceptable and physiologically effective they can create enough sexual excitement to activate an orgas mic response. The structure(s) of these erogenous sites and the sexual changes induced by coitus of each will be described individually. 516

Although the erogenous function of this organ has been known since antiquity [29], remarkably, the detail of its highly vascular anatomical structure is still in dispute. It is formed from the tubercle of the undifferentiated common tissue anlagen in the embryo. In the presence of androgens this develops into the penis while in their absence the clitoris is formed. Current dissections of adult female human cadavers [30] have been interpreted to indicate that the organ is a triplanar complex of erectile tissue with a midline shaft lying in the medial sagittal plane about 2-4 cm long and 1-2 cm wide which bifurcates internally into paired curved crura 5-9 cm long (attached to the under surface of the pubic symphisis) and externally is capped with a glans about 20 -30 mm long with a similar diameter. The range of external dimensions have been given by Verkauf, Von Thron & O’Brien [31]. The erectile tissue of the shaft consists of two parallel corpora cavernosa surrounded by a fibrous sheath (tunica albuginea) and the whole structure is covered by a clitoral hood formed in part by the fusion of the upper part of the two labia minora while the lower parts meet beneath the clitoris (see Figure 2 A). The clitoral cavernosal erectile tissue consists of smooth muscle and connective tissue. Tufan et al [32] utilized computer assisted histomorphometric image analysis to determine the age-associated changes in clitoral cavernosal content of smooth muscle and connective tissue. Human clitorises were obtained from fresh cadavers (age: 11 to 90 years) and from patients undergoing clitoral surgery (age: 6 months to 15 years). The percentage of clitoral cavernosal smooth muscle in age group of 6 months to 15 years was 65 ± 1.5, in 44 to 54 years was 50 ± 1.2 and in 55 to 90 years was 37 ± 1.3 (ANOVA, p=0.0001). These studies, which revealed a strong link between increase in age and decreased clitoral nerve cavernosal smooth muscle fibers, illustrate that aging women undergo histologic changes in clitoral cavernosal erectile tissue which may play an as yet undetermined pathophysiology in ageassociated female sexual dysfunction. According to O’Connell et al [30] the paired, socalled vestibular (vaginal) bulbs of erectile tissue,

P.S. = Pubic symphysis l= Clitoral glans and shaft 2 = Clitoral crura 3 = Urethral meatus 4= Periurethral glans 5 = Vaginal introitus (labia not shown) 6 = Halban's fascia 7 = Urethra 8 = G-spot 9 = Anterior fornix erotic zone 10 = Cervix 11 = Peritoneal membrane 12 = Anus

Figure 1: Highly schematic diagram of the human female genitalis. See text for explanatory details.

B

A

Figure 2 a, b: Highly schematic diagrams of the clitoral tissue complex. In Figure 2a the clitoral glans, shaft and paired crura are indicated in grey. The urethral meatus (small black dot) is shown with the urethra (dotted tube that would actually be at right angles to the page). On either side of the urethra, closely applied, are the paired vestibular or vaginal bulbs of erectile tissue. The inner and outer labia are shown together with the vaginal introitus elongated black shape) with the anus lower down. In Figure 2b the extent of the periurethral glans is displayed as the hatched area extending from the glans to the cli toris to the upper edge of the vaginal introitus. See text for details.

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Figure 3: External antomical structures which comprise the female genitals.

Figure 4: Internal antomical structures which comprise the female genitals.

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Figure 5: Autonomic and somatic innervation of the female genitals.

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Figure 6: Motor and sensory nerves innervating the external female genitalia.

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Figure 7: Arterial inflow to the external female genitalia.

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which have normally been illustrated on either side of the vagina practically as if in the labia minora, are actually closely applied anteriorly on either side of the urethra (Figure 1). In the male the corpus spongiosum is a single tubular structure of erectile tissue that ensheaths the urethra ending internally as the penile bulb and externally as the penile glans pierced by the urinary meatus. The location and extent of the female corpus spongiosum is contentious. It has been described as being the vascular tissue surrounding the female urethra, as the bilateral vestibular bulbs and as the tissue between the bladder and anterior vaginal wall (Halban’s fascia). Most authors claim that the clitoris has no spongiosus tissue. However, the extension of the corpus spongiosus tissue into the clitoris has been described by van Turnhout, Hage & van Diest [33] from their dissections and histology of the adult female cadaver. They observed that the bilateral vestibular bulbs unite ventral to the urethral orifice to form a thin strand of spongiosus erectile tissue connection (pars intermedia) that ends into the clitoris as the glans. The corpora cavernosa of the shaft do not extend into the glans.

while those in the veins and a-v anastomoses relaxed, reducing the flow to the lacunae and allowing the blood restricted in them to flow away. Despite this mechanism being published in English for over 23 years, no independent confirmation of either the mechanism or the polsters in the female arteries and veins have yet appeared. It must be regarded as a speculative working hypothesis.

Because the shaft and the glans of the clitoris have no subalbugineal layer between the erectile tissue and the tunica albuginea the organ becomes tumescent or swollen with effective sexual stimu lation but does not become erect or rigid [34]. Nevertheless, human clitoral erectile tissue has the capacity to develop drug-induced priapism which responds by detumescing following administration of alpha-adrenergic agonists [35]. The earliest attempt to characterise the possible mechanism(s) by which the crura and vestibular bulbs changed from the flaccid to the tumescent state was published first in diagrammatic form by Danesino & Martella [36] in Italian. The paper was later translated into English and republished in 1976. Their working hypothesis, based on the early mechanisms suggested for penile erection, was that during sexual excitement smooth muscle polsters («cushions») in the arteries supplying the two vestibular bodies became relaxed. Those polsters in the draining veins became contracted as did those in the a-v anastomoses (see Levin [71] for simplified diagram). This diverted blood into the lacunae, filling them and creating tumescence. For detumescence, the arterial polsters contracted

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The finding that human clitoral tissue has nitric oxide synthase (NOS) present in nerves and blood vessels [37] suggests that nitric oxide (NO) may be involved in controlling clitoral blood flow as it does in the penis. Park et al [38] have further examined the possible role for nitric oxide in the regulation of human clitoral corpus cavernosum smooth muscle contractility. In this study, cGMP and cAMP hydrolysis by phosphodiesterases were characterized in the high speed supernatant fraction (cytosol) and in partially purified preparations of human clitoral corpus cavernosum smooth muscle cells. Sildenafil was found to inhibit PDE type 5 cGMP-hydrolytic activity, in the crude extract (Ki=7 nM) and in partially purified preparations (Ki=5-7 nM) in a competitive fashion. Synthesis of cyclic nucleotides was also carried out in intact cells in culture in response to sodium nitroprusside (NO donor) and forskolin (direct adenylate cyclase activator). Intracellular cGMP was increased by 35% in presence of sildenafil (10nM) in intact cells in culture. The results of this study support a role for nitric oxide in regulation of human clitoral corpus cavernosum smooth muscle tone. b) The periurethral glans (Figure 2B) As has been described previously, the clitoris develops in the embryo from the genital tubercle of the common anlagen in the absence of androgens. However, the male glans is pierced by the urethra unlike that of the clitoral glans. Sevelly [39] suggested that there were really two glans in the female, that of the clitoris (clitoral glans) and that surrounding the urethra (female glans). The latter was renamed the periurethral glans [40] to avoid confusion and is defined as the triangular area of mucous membrane surrounding the urethral meatus from the clitoral glans to the vaginal upper rim or caruncle (Figure 2B). It is mobile and was shown to be pushed into and pulled out of the

vagina by penile thrusting during coitus [39, 40]. No studies have been undertaken on the erotic sensitivity of the periurethral glans in those women who can have orgasms from penile thrusting alone compared with those who cannot. An obvious suggestion is that the former will have a much higher erotic sensitivity than the latter. Hoch’s clinical or sexological examination of the sensitivity of the female genitalia for erotic arousal completely ignored the periurethral glans [41]. Given the complexity of the anatomy of the external female genitalia it is possible that the periurethral glans is in fact yet a further part of the corpus spongiosum of the female [33]. c) Urethra (Figure 1) The female urethra is a short conduit (approximately 3-5 cm long) running from the base of the bladder and exiting in the periurethral glans area to the outside. For nearly its entire length it is sur rounded by numerous venous/sinus channels which, according to Berkow & Amboy [42], constitute the corpus spongiosum of the urethra. This submucosal vascular tissue is physiologically important in that it contributes approximately one third of the normal urethral closing pressure [43]. It becomes further vasocongested during sexual arousal [44] converting the urinary urethra into the sexual urethra. Scattered in the lining lumenal epithelium are cells containing 5-HT (serotonin). Their function is unknown but they are thought to be chemosensing or mechanoreceptor paracrine cells [45, 46] that release the 5-HT on being stimulated by stretch or luminal chemicals. In the animal urethra, 5-HT sensitizes neural mechanisms [47]. It may be that the stretching or massage of the human female urethra by the thrusting penis during coitus causes the release of 5-HT from the urethral paracrine cells enhancing neural afferent input from the organ. d) G-spot (Figure 1) Grafenberg [44] reported that the digital stroking of the anterior vagina along the urethra, espe cially in the region of the base of the bladder, sexually aroused female subjects greatly. In a number of women this area swelled up to the size of a kidney bean and projected into the vaginal lumen. Few took any notice of this finding. The area was rediscovered and renamed the G-spot in honour of Grafenberg [48]. Other investigators could not locate a «spot» but found, rather than a 523

punctate locus, a general excitable area along the whole length of the urethra running along the anterior vaginal wall [41]. When this was stimulated manually, the sexual arousal induced was almost immediate. Alzate & Londono [49] located the erotic sensitive area in closer relation to the bladder base than the urethra while Lenck, Vanneuville, Monnet & Harmand [50] localised by ultrasound in the living subjects the underlying structure in the anterior vaginal wall that gave the erotic sensations on stimulation as the urethral sphincter confirming it by dissection in the cadaver. Other investigators have implied that the G spot/area represents that part of the urethra that contains the periglandular or paraurethral tissue, corresponding to the female equivalent of the prostate (see Zaviacic and Whipple [51] for references). These glands are present to a greater or lesser degree in about 90% of women. In some women, when stimulated sexually, a fluid secretion claimed to be dissimilar to urine or vaginal fluid can be produced which is controversially «ejaculated» from the urethra [51, 52]. Exclusion of urethrocoeles in such subjects, where urine could pool and subseqently be modified, has never been undertaken. e) Halban’s fascia (Figure 1) The space between the trigone of the bladder and the anterior part of the vaginal wall according to Minh, Smadja & Herve de Sigalony [53] and Tordjman [52] is filled with mesenchymal lamina, a fibro-elastic sheet made up of collagen, elastic and muscular fibres with a rich blood supply and a nerve supply with Krause bodies or pseudo-corpuscular nerve endings. Tordjman [52] regards this area as the homologue of the corpus spongiosum. On stimulation it becomes vasocongested and creates an erotic pleasurable response. It is obvious from Tordjman’s descriptions that he includes the G-spot in his analysis of the pleasurable response from Halban’s fascia. f) Anterior fornix erogenous zone (Figure 1) More recently Chua Chee Ann [54] has reported that in 271 women, the gentle digital stimulation of the inner half of the anterior wall of the vagina, lasting some 10-15 minutes, gave rise to a «reflex» vasocongestion of the outer half of the anterior vaginal wall with a concomittant lubricative and erotic response in 63% of the subjects. Stimulating the outer half of the anterior wall before the inner

half did not give consistant responses. The claimed vasocongestion and lubrication responses were judged subjectively and were not confirmed by objective measurements. The technique was described as inducing a «local reflex» vasodilatation that did not involve the central nervous system and that this was the reason for the rapidity and effectivenes of the stimulation. Moreover, women can be taught to undertake the stimulation for themselves, thus improving their arousal and orgasmic responses to subsequent coitus. From the descriptions of the author it appears that the digi tal technique would stimulate the urethra-G spot - Halban’s fascia complex and need not imply a new and specialised area of the anterior vagina. The concept that the stimulation created only a local reflex with no afferent input to the higher centres is impossible to verify from the described study.

phase leads to vaginal tenting and elevation of the cervix up with the anterior vagina wall. Thus penile-cervix contact should rarely occur (see Levin [59] for discussion). Ultrasound imaging of penile disposition during human coitus was illustrated in Hessel [60] and described by Riley, Lees & Riley [61]. Penile-cervix contact was not observed in the missionary or face-to-face position (the preferred position in the Western world) but Riley et al found it could occur in the rear-entry sideways and rear-(«doggie») positions.

g) Pubococcygeus muscle

a) Vaginal lubrication- basal and during sexual arousal

Kegel [55] and a number of other authors have claimed that the pubococcygeal muscle, located at the 4 and 8 o’clock points of the vagina, contain sensory and motor elements of the orgasmic response and that its stimulation gave rise to sexual pleasure and even could induce orgasm. Exercising the muscle was said to enhance both. Hoch [41], however, could not confirm these findings and reported that in the great majority of cases he examined the pubococcygeal lacked erotic sensitivity altogether.

An intriguing aspect of the cervix is that it has the second highest concentration of VIP of the fema le genitals yet no function has been ascribed to the Vipergic innervation. Its possible role in the secretion of mucus by the infolded crypts of the cervical epithelium has not been investigated.

3. PHYSIOLOGY

The vagina is a squamous epithelium devoid of glands which is surrounded by a sheath of smooth muscles set in a bed of striated pelvic muscles with an extensive blood, lymphatic and nerve supply. The latter, richer in the more distal and anterior wall areas compared to the more proximal and posterior wall parts, contain a great variety of classical and peptidergic transmitters (5HT, nor-epinephrine, acetylcholine, dopamine, VIP, NPY, GRP, TRH, CGRP, somatostatin, substance P, oxytocin, cholecystokinin (CCK) and relaxin) but the exact function of most of these whether motor or sensory or modulatory is unknown [40, 62]. The organ is a potential space with its anterior and posterior walls usually in apposition. They can be easily separated because their surfaces are normally «just moist», lubricated by a basal vaginal fluid (swabbed volume approximately 1ml). In the intermenstruum, this can consist of multiple secretions that collect finally in the vagina (peritoneal, follicular, tubal, uterine, cervical, vaginal, Bartholin’s and Skene’s glands). However, the more remote the anatomical site where the fluid is formed from the vagina, the less influence it has on the volume and ionic content of the vaginal fluid.

h) Cervix The cervix is a relatively insensitive structure with no erotogenic capabilities per se but it has been implicated by some authors as being important when jostled or buffeted by deep penile thrusting so that the uterus is pushed or rubbed against the peritoneal lining (Figure 1). This is claimed to create sexually pleasurable feelings [53, 56] but in others it creates discomfort [41]. In some women who have had their cervix/uterus removed, a significant loss in sexual arousal and orgasm by coitus occurs [57] but others have reported no differences [41]. This extreme individual variation in dysfunction may be accounted for by the extent of surgical nerve damage and loss. According to the EPOR (E = excitation, P = plateau, O = orgasm,R = resolution) human sexual response model of Masters & Johnson [58], sexual arousal in the E-

In the sexually unstimulated state, vaginal fluid has a higher K+ and lower Na+ concentration compared to plasma throughout the phases of the

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menstrual cycle [63]. The actual basal vaginal transudate that percolates through the vaginal epithelium from the plasma circulating in the capillary tufts supplying the epithelium is modified by the limited Na+ lumen-to-blood reabsorptive transport capacity of the vaginal epithelial cells [64]. This activity can be inhibited by luminal amiloride. The reabsorption of Na+ by the vaginal epithelium is presumably the ionic driving force for the reabsorption of the vaginal fluid [65] and maintains its level under basal conditions to the «just moist» condition. Autologous plasma placed in a subject’s vagina for up to 5 hours shows increased K+ and decreased Na+ concentrations indicating that the epithelium is capable of undertaking such ion transfer in vivo ( see Levin [40] for references). The basal lubrication is usually not sufficient to allow painless penile penetration and thrusting so an enhancement of the lubrication is essential for coitus. Despite many inaccurate accounts in physiology textbooks, vaginal lubrication during sexual arousal does not occur from any increased secre tion of vaginal glands (nonexistant), cervical fluid or from Bartholin’s glands. On sexual arousal the blood supply to the vaginal epithelium is rapidly increased by neural innervation via the sacral anterior nerves S2-S4 [66] and at the same time the venous drainage is probably reduced creating vasocongestion and engorgement with blood. Park et al [67] used an animal model with direct electrical stimulation of the pelvic motor nerve to quantitate the local changes in vaginal hemodynamics. They showed significant vaginal hemodynamic changes, including increased vaginal wall arterial blood inflow, vaginal wall pressure, vaginal canal length and decreased vaginal luminal pressure compared to the unstimulated state. In the vaginal epithelium, sexual arousal induces a neurogenic transudate to be created that filters through the labyrinthine pathways of the epithelium and saturates its limited Na+ reabsorptive capacity [59, 64]. It appears within seconds of succesful sexual arousal initially on the surface of the vagina as bead-like droplets which then coalesce to create a lubricative film [58] that can partially decrease the acidity of the vaginal basal fluid [68]. The smooth, slippery quality of the formed fluid is probably due to its pick up of sialoproteins coating the vaginal epithelium from the cervical secretion. The enhanced blood flow is activated by the

VIPergic innervation of the large vessels sup plying the epithelium and the transudation possi bly aided by the CGRP (calcitonin gene regula ting peptide) enhanced permeability of the capil lary tufts [62]. NPY, neuropeptide Y, a known vasoconstrictor, may be involved in constricting the venous drainage [59]. There appears to be very little NOS in the blood vessels of the premenopausal vagina and none in the postmenopausal [62]. This suggests that NO would not be a major factor influencing vaginal blood flow, unlike the situation in the penis. After orgasm or the cessation of sexual stimuli, the continuous lumen-blood transfer of Na+ by the epithelium slowly reabsorbs the excess fluid of the neurogenic transudate by osmotic drag and resets the vagina back to its just moist basal state. b) Pelvic and genital muscular activity in the basal and sexually aroused states The vagina is a tube of autonomically innervated smooth muscle (a longitudinal inner and a circular outer layer) set amidst three sets of powerful pelvic striated muscles (1, superficial- ischiocavernosus and bulbocavernosus; 2, the transverse perineii and 3, deep- the levator ani forming the pelvic diaphragm across the anterior of the pelvis of which the largest medial portion is classified as the pubococyggeus). The uterus, composed of three layers of smooth muscle, is situated in the lower pelvic part of the abdomen. The motility patterns of these organs, especially during sexual arousal to orgasm, have been studied infrequently, rarely measured and are poorly characterised [40, 58, 59, 69, 70, 71]. Their activity is usually monitored either by small luminal balloons or pressure catheters or by electrodes (needle or surface) that pick up the electromyographic activity (EMG) that increases when the muscles contract [69]. Because of the setting of the vagina, smooth muscles amongst striated, contraction of either or both will influence the pressure motility pattern obtained and the interpretation of the records often relies on the fact that at orgasm the striated motility dominates. No studies have been published that record simultaneously, but inde pendently, both the striated and the smooth muscle activity thus allowing their interaction to be better interpreted and characterised. In the basal or sexually quiescent state the striated muscle plays little or no role but the smooth

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muscle of the uterus and vagina is active especially perimenstrually when it contracts periodically to expel the uterine/vaginal contents. These uterine and vaginal contractions are normally not consciously recognised [40, 71, 72]. They only become obvious if they reach painful, spasmotic levels (dysmenorrhoeic pain). During arousal to orgasm, the few records obtained show an increasing vaginal lumenal pressure [40]. At orgasm a series of pelvic, clonic, striated muscle contractions occur at approximately 0.8 second intervals which gradually get longer and the contractions weaker [58, 69]. They can last for 5-60 seconds. These contractions are concommittant with the subjective feeling of orgasm. Voluntary contractions of the pelvic striated muscles do not give a feeling of intense pleasure but are often used to enhance arousal. Few records of the intrauterine pressure exist and those that do could well be influenced by the size of the devices used to measure the intrauterine pressure (see Levin [40] for discussion). During sexual arousal up to orgasm, individual uterine contractions may occur while at orgasm a series occurs mediated by the sym pathetic system via the hypogastric nerve. These have been implicated by some to be important in rapid sperm uptake into the uterus/fallopian tubes but this ignores the effect of vaginal tenting on cervical elevation from the ejaculated pooled semen (see previous section on cervix and Levin [59] for discussion). It has been proposed that sexual satiation in the female occurs only when the orgasmic uterine contractions are intense but there has been no quantitative studies to back up this speculation. Two studies have reported that vaginal distention induced by rapid increases in volume by inflation of luminal balloons cause i) contractions of the bulbocavernous and ischiocavernous muscles [73] and ii) an increase in the velocity of clitoral arterial blood interpreted as an increase in flow [74]. The volume increase used was between 100 to 300ml although the normal volume of the human penis is about 70 ml. Thus penile volume per se would have little effect, but penile thrusting would stretch the vaginal walls and cause the reflex actions. The enhanced clitoral flow and its engorgement and introital tightness around the penile shaft are all features suggested to enhance the pleasure of coitus for both male and female partners.

III. CENTRAL NERVOUS SYSTEM PATHWAYS INVOLVED IN THE CONTROL OF FEMALE SEXUAL FUNCTION 1. INTRODUCTION Almost nothing is known of the central nervous system (CNS) pathways controlling sexual func tion in human females. No imaging studies of neural activity during sexual arousal or orgasm in women have been reported. A few studies have correlated brain lesions with sexual dysfunction [75], but precise localization of sexual function has not been possible. Thus, almost all conclusions must be drawn from studies in animals, and to a much lesser extent, in men. Many animal studies have been performed examining the CNS control of penile erection (see review in McKenna, [76]). In contrast, the CNS control of the female genital organs has been the focus of far fewer studies. There is a large amount of literature dealing with the pathways and hormonal control of receptive behavior in female animals (reviewed in Rose, [77] and Pfaff and Schwartz-Giblin, [78]). The most studied receptive behavior is the lordosis reflex in rodents, for which the neural pathways have been significantly elucidated. Several factors make it problematic to draw conclusions about human female function from these studies. Human females do not display lordotic behavior or anything which is arguably homologous to lordosis. The pathways controlling lordosis behavior appear to be primarily involved in the expression of this behavior and not necessarily involved in the generation of sexual desire [79]. The pathways mediating sexual desire remain to be elucidated.

2. O VERVIEW Some general principles of the CNS organization of sexual function in the female can be identified. Sexual responses (eg. genital arousal and cli max) are largely the product of spinal cord reflex mechanisms. These reflexes are mediated by genital afferents, primarily from the pudendal nerve. The efferent arm of the reflexes consist of complex, coordinated somatic, sympathetic and parasympathetic activity. Thus, the reflexes in-

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volve several spinal segments. The organization of the interneurons generating the reflexes is poorly understood. Anatomical studies indicate that the interneurons are located in a column within the central portion of the spinal gray matter and extend for several segments, linking the various sensory inputs with the efferent neurons. The spinal reflex mechanisms are largely unaffected by gonadal hormones.

the medial portions of the dorsal horn and in the medial central gray matter (dorsal gray commissure) of the lumbosacral spinal cord (80; 81; 82; 83). The pudendal afferents have an almost exclusively medial distribution. Visceral pelvic afferents, on the other hand, also terminate in the lateral edge of the gray matter in the vicinity of the intermediolateral cell column, the site of the preganglionic neurons, but probably do not make synaptic contact with them.

The spinal reflex circuits are under descending control from a variety of supraspinal sites. This control is both inhibitory and excitatory. A powerful inhibitory control of spinal sexual reflexes derives from the nucleus paragigantocellularis in the rostral medulla. This site provides a tonic suppression of sexual reflexes. The inhibi tory neurotransmitter is probably serotonin. A variety of other brainstem sites have been shown to project to the relevant neurons in the spinal cord, but their functional role is unknown. Within the hypothalamus, important facilitatory roles in sexual function have been demonstrated for the medial preoptic area and the paraventricular nucleus. In the forebrain, the medial amygdala, the bed nucleus of the stria terminalis, septal nuclei, and regions of the cerebral cortex have been implicated.

Stimulation of the pudendal nerve gives rise to spinal field potentials. These were mapped in the cat. The largest field potentials and greatest number of synaptically activated neurons were found in the medial portions of the lumbosacral spinal gray [84]. Anatomical and physiological investigation in the cat also identified interneurons in the medial gray of the sacral spinal cord which responded to pelvic visceral and perineal stimulation [85]. Putative spinal interneurons related to pelvic function have been identified using the cfos technique. Strong activation of neurons often causes expression of the immediate early gene, cfos and its gene product Fos [86]. Stimulation of genital afferents resulted in labeled neurons in the medial dorsal horn, the central gray commissure and the region of the intermediolateral cell column, consistent with the distribution of pelvic sensory terminals. The distribution of interneurons was similar in males and females [87, 88, 89].

In addition to its spinal reflexive role, genital sensory information is also relayed to many of the supraspinal structures. Thus, genital stimulation is able to modify the descending control of spinal reflex mechanisms. A very strong degree of interconnection has been noted in most of the surpaspinal sites identified with sexual function. They receive inputs from a variety of higher sensory systems. Supraspinal sites are also influenced by gonadal hormones. These findings indicate that multiple factors interact at supraspinal levels to influence the excitability of spinal sexual reflexes.

Putative interneurons have also been identified by injection of neurotrophic viruses into pelvic organs. The virus is picked up by nerve terminals, retrogradely transported to the neuronal cell body, replicated and picked up by nerve terminals presynaptic to the infected neurons. In this way, a chain of functionally linked neurons can be identified [90, 91]. Following injection into the penis, clitoris or uterus, a similar finding was observed [92, 93, 94, 95]. The majority of labeled neurons in the spinal cord were located in the central gray region of the spinal cord and in the vicinity of the intermediolateral cell column. The majority of neurons were located in lumbosacral segments. Thus, several independent techniques have indicated that pelvic and sexual reflexes are dependent on spinal neurons in the central gray region of the lumbosacral segments.

3. SENSORY MECHANISMS Sensory stimuli relevant to sexual function are conveyed by afferents in the pudendal, pelvic and hypogastric nerves. The pudendal nerve conveys most of the sensory stimuli from the external genitalia and perigenital area. The pelvic and hypogastric nerves convey information from the internal pelvic organs. The afferents terminate primarily in

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4. SPINAL REFLEXES Sexual function is composed of numerous spinal level reflexes, most activated by pudendal afferents. Perhaps the best studied is the bulbocavernosus reflex. This reflex is a polysynaptic response seen in males and females elicited by low threshold pudendal sensory fibers. These activate pudendal motorneurons to contract the striated perineal muscles [80, 96, 97, 98]. This reflex is often used as a neurological test of the integrity of the pudendal nerve. Its sexual significance is unclear. However, tonic stimulation of the clitoris could lead to the development of the orgasmic platform, ie. contraction of the levator ani and circumvaginal muscles, through the mechanism of the bulbocavernosus reflex. This reflex would also lead to contraction of the external urethral sphincter, promoting urinary continence during sexual activity. In addition to the contraction of the urethral sphincter, stimulation of the clitoris and vagina leads to an inhibition of bladder activity. This reflex is mediated by pudendal nerve afferents. It leads to inhibition of pelvic nerve activity to the bladder and an increase in hypogastric nerve activity to the bladder neck, leading to detrusor inhibition and bladder neck contraction [99, 100]. The reflex mechanisms involved in sexual arousal (clitoral erection, vaginal engorgement and lubrication) have not been investigated in females. Given that these responses are mediated by the cavernous nerve, it is likely that female reflexes are similar to the cavernous nerve mediated erec tile response in males. Stimulation of the dorsal nerve of the penis (a division of the pudendal nerve) results in long latency discharges in the cavernous nerve [101] and results in increases in intracavernous pressure [102, 103]. Stimulation of the cavernous nerve in New Zealand White female rabbits resulted in increases of mean clitoral intracavernosal pressure, clitoral arterial blood inflow as well as vaginal wall arterial blood inflow, vaginal wall pressure and vaginal wall length [67]. The long latency response clearly indicates that this is a polysynaptic reflex response. The mechanisms underlying female sexual responses remain to be elucidated. Evidence indicates that sexual climax is also a spinal level reflex. Following spinal cord injury, a significant number of women are still able to experience orgasm [104]. In anesthetized, acutely spinalized female rats, genital stimulation gives rise 528

to a response which resembles climax in humans: rhythmic contractions of the striated perineal muscles and vaginal and uterine contractions [47]. It also includes strong activation of the cavernous nerve, driven by both hypogastric and pelvic nerve preganglionic activity. This response is neurologically very similar to the ejaculatory response seen in male rats.

5. ASCENDING SENSORY PATHWAYS Sexual afferents enter the spinal cord in the sacral segments. Sensory information is relayed to supraspinal sites via the spinothalamic and spi noreticular pathways. The spinothalamic pathways primarily convey the fastest fibers related to the encapsulated nerve endings of the phallus. They travel in the dorsal columns and consist primarily of fast myelinated fibers [105]. These fibers terminate in the posterolateral nucleus of the thalamus and subsequently relayed to the medial thalamus. Spinoreticular fibers tend to be slower than the spinothalamic fibers. They travel in the contralateral (and to a lesser extent ipsilateral) lateral spinal columns and terminate in brainstem reticular formation. Studies in humans have examined cortical evoked potentials following electrical stimulation of the dorsal nerve of the penis/clitoris. Evoked potentials are recorded bilaterally from cortical areas, with the highest amplitude in the midline (Cz-2) over the sensory cortex [106, 107]. This distribution is confirmation of the identification of pudendal representation deep in the midline interhemispheric fissure in humans [108)] and cats [109]. The amplitudes of cortical evoked responses are larger in men than in women [110] although slightly shorter in latency in women [111]. The smaller size in women may be related to fewer fibers innervating the clitoris relative to the penis or to the greater accessibility of stimulation of the male dorsal nerve. Studies in children (3-13 years old) revealed that the cortical evoked potentials from the phallus shorten in latency with maturation and show a narrower volley [112]. These results indicate that the nerve conduction velocity of CNS perineal senso ry pathways increases and shows a greater uni formity with maturation. However, these changes were gradual and did not show abrupt changes around puberty. No major differences were reported between boys and girls.

6. BRAINSTEM REGIONS Spinal sexual reflexes have long been known to be under descending control from brainstem sites [113] but the details of this control have not been explored until recently. One site has been identified in males as important in inhibitory control of climax-like responses. Given the high degree of similarity of this climax-like response described above between males and females, it is highly likely that this region plays a similar role in females. The nucleus paragigantocellularis projects directly to pelvic efferent neurons and interneurons in the lumbosacral spinal cord [92]. Neurons in this area are transneuronally labeled following virus injection into the penis [114] and the clitoris [93]. Lesions of this nucleus are as effective as spinal transection in suppressing a tonic inhibition of the climax-like response [92]. Most of the neurons in this region stain positively for the neurotransmitter serotonin and serotonin applied to the spinal cord inhibits spinal sexual reflexes [92]. This is a like ly candidate for mediating the high incidence of orgasmic dysfunction seen with the use of SSRI antidepressants, which elevate brain serotonin levels [116, 117]. Neurons in the nucleus paragi gantocellularis receive genital sensory informa tion in males and females [77, 118]. Several other sites have been anatomically iden tified for their projections to lumbosacral spinal cord, but their functional role in sexual response is unknown. The lumbosacral spinal cord receives strong projections from other serotonergic nuclei in the brainstem, the raphe nuclei pallidus, magnus and parapyramidal region [119, 120,121, 122]. There are also significant noradrenergic projections from the A5 catecholaminergic cell group and from locus ceruleus [123, 124]. These provide a dense innervation of pudendal motoneurons and other lumbosacral targets [125, 126]. Future research is needed to identify the functional significance of these projections. In conventional and viral tracing studies, a projection from Barrington’s nucleus in the parabrachial region of the pons to lumbosacral cord has been identified [93, 95, 119]. This region has long been known to play a role in micturition [127, 128]. It has also been implicated in pelvic contractions related to defecation and parturition [129, 130, 131, 132]. Its role in sexual responses has yet to be investigated.

In the midbrain, the periaqueductal gray is known to be an important relay center for sexually rele vant stimuli. It has extensive connections with all of the brainstem sites just discussed and has connections with many hypothalamic sites involved in sexual function [133]. Neurons in this area are labeled following viral injection into the clitoris and uterus [93, 95]. The great majority of these neurons in this region are activated during copulatory behavior [77].

7. HYPOTHALAMUS The hypothalamus is an essential site for reproduction and sexual behavior, as well as for a very large number of homeostatic and motivated behaviors [134]. The large number and complexity of these activities make it difficult to precisely define the hypothalamic role in sexual arousal and performance. The medial preoptic area has long been known to play a role in the control of male sexual behavior. Lesions of this region severely attenuate or abolish male copulatory behavior in every species tested [135]. However, medial preoptic lesions do not abolish erections caused by sleep (Schmidt, personal communication), exposure to volatile odors from estrus females [136] or masturbation [137]. Nor do medial preoptic lesions decrease sexual motivation [138]. The conclusion is that in the male, the medial preop tic relates to the animal’s ability to recognize a sexual partner. A similar conclusion may be true in the female. Lesions of the medial preoptic region in female rats resulted in greater display of lordosis, but when given the option, females avoided male partners. A tentative conclusion is that in both sexes, the medial preoptic is not directly involved in sexual motivation or performance but with mate selection. The ventromedial nucleus of the hypothalamus is critical for the expression of lordosis behavior [78]. Neurons in this region are labeled following virus injection into the uterus [95]. The role of the ventromedial nucleus in the control of genital responses has not yet been investigated. The paraventricular nucleus of the hypothala mus is a likely candidate for control of genital responses. It is known that during sexual arousal and orgasm, oxytocin from the paraventricular nucleus is secreted from the posterior pituitary into the blood stream [139, 140]. There is a direct

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projection from the paraventricular nucleus to the autonomic outflow from multiple segments as well as direct projections to pelvic autonomic and somatic efferents [141, 142, 143]. The paraventricular nucleus is extensively connected with the medial preoptic area [144]. The paraventricular nucleus was consistently labeled after pseudorabies virus injection into the clitoris and uterus [93, 95]. Neurons in the paraventricular nucleus are activated during copulation in female rats [145]. Further studies, such as stimulation studies and oxytocin pharmacological studies are needed to further characterize the sexual role in females of the paraventricular nucleus.

IV. NOSOLOGY AND DIAGNOSTIC CLASSIFICATION: USE IN ASSESSING PSYCHOSEXUAL TREATMENT OF FEMALE SEXUAL DYSFUNCTION 1. INTRODUCTION It is essential to specifically and thoroughly describe the sexual problem a woman is experiencing. There are two formal systems of diagnostic classification in general use. While a recent consensus conference panel recommended adoption of a new female sexual dysfunction diagnostic and classification system shown in table 4, based on physiological as well as psychological pathophysiologies and a «personal distress» criterion for most of the diagnostic categories, this new diagnostic and classification system in not yet in general clinical use.

8. F OREBRAIN Forebrain regions involved in female sexual function have largely been identified on the basis of Fos staining in copulatory tests and viral staining. Medial amygdala, bed nucleus of the stria terminalis and some other regions are most consistently identified [95, 146, 147, 148, 149]. The Fos labeling in these regions is strongly affected by vaginocervical stimulation during copulation. The medial amygdal is believed to be involved in the control of sexual motivation in the male [135]. Similar conclusions in the female cannot currently be drawn.

One diagnostic classification system in general use is the World Health Organization’s International Classification of Diseases (ICD-10) [5]. The other is the American Psychiatric Association’s Diagnostic and Statistical Manual (DSM-IV) [6] system. As can be seen from Table 5, the categories across the two systems are similar in certain ways. Both systems view sexual dysfunction as invol ving a combination of psychological and somatic components. Both rely heavily on the sexual res ponse cycle as proposed by Masters and Johnson [58, 153] and modified by Kaplan [154] to organize categories of desire, arousal and orgasm. The categories of pain disorders, vaginismus and dys pareunia are not part of the sexual response cycle. It should be kept in mind that the sexual response cycle is based on a conceptual framework that sees the response categories as separate and temporally ordered «phases,» though there is minimal basic research on the processes of sexual response. In men there are phase exceptions, such as orgasm with a flaccid penis or electro-ejaculation, where orgasm may not be preceded by particularly noticeable sense of genital or sexual arousal. Parallel exception in women has not been well-described in research but have some basis clinically where women not infrequently report a blending of the sense of desire and interest.

In one series of studies, intracranial stimulation of human males and females elicited subjective pleasurable response, which were described as sexual in nature [151]. An area consistently associated with this response was the septal region. Electrical stimulation or stimulation with cholinergic and adrenergic agents were effective. However, it should be noted that the subjects of these experiments were patients with severe neurological and psychiatric conditions, so interpretation of these studies is problematic. A functional imaging study in men identified cortical sites associated with visually-evoked sexual stimulation [152]. Sexual arousal was associated with an increased activity in the right insula and right inferior frontal cortex, which are two paralimbic areas relating highly processed sensory information with motivational states; and the activation of the left anteriorcingulate cortex, another paralimbic area known to control autonomic and neuroendocrine functions. No similar studies have yet been reported in women.

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Table 4: Female sexual dysfunctions as defined by the International Consensus Development Conference on Female Sexual Dysfuncffon. I. Sexual Desire Disorders IA. Hypoactive Sexual Desire Disorder Hypoactive Sexual Desire Disorder is the persistent or recurrent deficiency (or absence) of sexual fantasies/thoughts, andJor desire for, or receptivity to, sexual activity, which causes personal distress. IB. Sexual Aversion Disorder Sexual Aversion Disorder is the persistent or recurrent phobic aversion to and avoidance of sexual contact with a sexual partner, which causes personal distress. II. Sexual Arousal Disorder Sexual Arousal Disorder is the persistent or recurrent inability to attain or maintain sufficient sexual excitement, causing personal distress. It may be expressed as a lack of subjective excitement or a lack of genital (lubrication/swelling) or other somatic responses. III. OrgasmicDisorder Orgasrnic Disorder is the persistent or recurrent difficulty, delay in, or absence of attaining orgasm following sufficient sexual stimulation and arousal, which causes personal distress. IV. Sexual Pain Disorders IVA. Dyspareunia Dyspareunia is recurrent or persistent genital pain associated with sexual intercourse. IVB. Vaginismus Vaginismus is recurrent or persistent involuntary spasm of the musculature of the outer third of the vagina that interferes with vaginal penetration,which causes personal distress. IVC. Non-Coital Sexual Pain Disorder Recurrent or persistent genital pain induced by non-coital sexual stimulation. Table 5: Female dysfunctions classifications

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The two diagnostic systems differ from one another in several respects. For example, the ICD-10 has one unique category, Excessive Sexual Desire, and its sexual arousal category has a different label, Failure of Genital Response. The genital response label is actually more precise than the term Sexual Arousal Disorders since sexual arousal disorder in both systems is restricted to genital functioning and excludes loss of subjective sexual arousal. The DSM-IV’s lack of a specific category of hyperactive sexual desire is conceptually problematic and leaves a diagnostic void for individuals who are both attracted and distressed by their own high frequency of sexual desire and/or behavior. The DSM-IV specifies that the sexual problem must, «cause marked distress or interpersonal difficulty», while the ICD-10 more obliquely states that the sexual problem interferes with the person’s ability to «participate in a relationship in a way he or she would wish». Although there is some overlap in these two statements, «marked distress and interpersonal difficulty» conveys more disturbance than the more vague inability to get what one would wish for in a sexual relationship.

briefly identify comorbidity by asking whether there are also problems in each of the other major categories (sexual desire, sexual arousal, orgasm and pain). The interviewer must also ask about the degree of distress that she experiences with each category. 2. The DSM-IV offers important subcategories that are useful for diagnosis and treatment planning. They include whether the particular category is lifelong or acquired and whether it is global or situational.

Criticism about these two systems has come from two main sources. One is from the clinical theoretical position, which reminds us that these systems focus primarily on genital responses and inter course-interfering symptoms rather than a broader set of sexual activities. In addition, these diagnostic systems, in keeping with the usual medical focus, are individually as opposed to interactio nally conceptualized [155]. These «biases» may be very important for women who less often report sexual dissatisfaction focused on genital response and more often report sexual complaints based on other experience, particularly desire [7, 17]. A further criticism is that the categories either artificially isolate physical from psychological etiology or pay little attention to etiological factors in general [1]. Nevertheless, given that most clinicians do use one of these two systems, there are several guidelines that seem to increase the likelihood of getting a diagnosis that is representative of the key complaints that a woman might have. Using the DSM-IV as a basis of illustration: 1. If a woman comes in stating that she has difficulty in one of the categories, it is important to

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3. If there is more than one dysfunction, the order in which each dysfunction occurred needs to be documented. 4. The above clarification should be made in the context of a broader sexual history interview so that etiological factors might begin to be identified. The international Consensus Conference [1] raised this point as one that had been ignored by the current diagnostic systems. Particular etiological factors that are important are whether the etiology appears to be primarily physical, primarily psychological or of mixed origin. 5. Another issue to review is whether the sexual partner also has difficulties in these categories of sexual functioning. For example, if a woman reporting low arousal and anorgasmia has a male partner who ejaculates within 30 seconds of stimulation, this information significantly impacts the etiological conceptualization and the treatment plan. 6. Relationship factors, current and historic, may be important factors causing or maintaining the sexual dysfunction. Common examples are sexual or physical abuse, relationship conflict and loss of attachment. The last two items, partner sexual dysfunction and relationship factors, are not mentioned directly in either of the diagnostic systems but are considered essential in clarifying etiology and treatment needs. Precise identification of etiological factors is often difficult particularly with women. The reason is that there are few data which identify specific biologic, physiologic, anatomic and neural factors which play a role in a woman’s sexual functioning and how these factors might interact with each other and with psychological functioning.

Two diagnostic categories deserve special remarks. One is the category of Hypoactive Sexual Desire (HSD). It is clear, if useful treatments are to be recommended for hypoactive sexual desire, then a subclassification system for this diagnosis is necessary. At the present time, the only data-based subtype is HSD secondary to hormone imbalance. Other subtyping categories remain to be identified. Physiologically, one can hypothesize that some combination of adrenergic, dopaminergic and seritonergic factors may play a role [156, 157]. Psychosocially, depression (bearing in mind that depression has both biochemical and psychosocial consequences), even if adequately treated and compensated, and relationship fac tors probably play major roles [158]. The other category of dysfunction that deserves mention is Female Sexual Arousal Disorder. This has recently been acknowledged as a potentially physiologically based dysfunction with symptoms that include difficulty with gential vasoconges tion and lubrication [159]. The human data for this position are currently minimal and actively being pursued. In addition, the degree to which women’s self-report of low arousal is at all related to a lack of physiological level of arousal remains to be clarified. As can be seen from earlier work in psychophysiology, the correlation between subjective and genital response in women varies by a number of factors, but data do suggest that sexual arousal is less likely to be identified at lower levels of arousal, in the presence of less erotic stimuli, under psychological conditions of inhibition such as sexual guilt, or in a context that the woman does not identify as being parti cularly sexual [160, 161, 162].

2. PSYCHOSEXUAL TREATMENT OPTIONS There is a body of research that describes and documents the effectiveness of psychosexual individual and couples’treatments for sexual dysfunctions in women. The following comments are intended to highlight empirically supported treatments and report efficacy by diagnosis. More specific details of these studies are elsewhere described [163].

siological, psychosocial and cultural influences on sexual experience and expression. The treatment is typically delivered to either individuals or couples although some treatment has been documented to be effective in groups. Psychosexual treatment involves actively focused therapeutic interven tions in which the therapist reacts to the patient’s problems by both discussing them in session and recommending various activities to do outside of the session. Therapy of this type is usually relatively short-term (i.e., 6-14 sessions) although it is not clear what the optimum number of sessions might be for each diagnosis. b) Overview of treatment issues There have been fewer psychosexual treatment efficacy outcome studies for sexual disorders especially when compared to other mental health conditions such as anxiety and depression in which psychological and physiological factors obviously interact. The reasons for this difference have to do with the availability of funding for sex research and the fact that sexual adequacy is considered a quality of life issue that rarely threatens health in general. An important exception is the extent to which sexual problems impact enduring relationships and the stability of marriages, which themselves have complex correlations to health variables [164]. The American Psychological Association created a task force in the early 1990’s to begin to identify criteria that would define empirically supported psychotherapeutic procedures [165]. The task force identified a set of criteria and were calling a treatment either well-established or probably efficacious. Alterations to these categories have since been suggested [166]. Nevertheless for the purposes of the current description we will use the original categories because they are useful and correspond well with some parallels in clinical trial work. The more restricted category, well-established, includes the following criteria: a) group studies showing superiority to another treatment must be done by different investigators, or b) demonstrate equivalence to another established treatment with adequate statistical power, or c) a large series of well designed single case studies that

a) Treatment definitions Psychosexual treatments are those which focus on sexual symptomatology while being aware of phy-

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d) use treatment manuals and e) have clearly specified client samples. Probably efficacious categories must meet the fol lowing criteria: a) at least two studies showing treatment more effective than waiting-list control, or b) studies meeting well-established criteria except for the fact that treatment manuals were not available, or c) a small series of single case studies otherwise meeting the well-established criteria except for the group study criteria. The well-established criteria are familiar as they have a lot in common with randomized placebocontrolled clinical trial methodology in pharmacological research. However there are some distinctions between good psychotherapy research designs and randomized placebo-controlled clinical trials. In psychotherapy outcome research: 1) Placebo controls are infrequent as it is difficult to provide an ethical placebo; 2) Double-blind control conditions are not feasible, since the provider of therapy cannot be blinded to the therapy she or he is providing; 3) Until recently comparable treatments often have not been available for the treatment of sexual dysfunction; 4) There is greater variance in psychotherapy treatment delivery than in medication delivery. Psychotherapeutic treatment delivery may vary based on an array of heterogeneous qualities of patient and provider. This is one reason manuals have been recommended as a criteria of psychotherapeutic treatments. Manuals may reduce some of the variance but many providers object to them because they do not adequately account for patient differences. Thus even with manuals, individual subject and provider variance will still be an issue; 5) Many patients react to characteristics in their treatment provider which are sometimes more obvious or at issue in psychotherapeutic interactions. In the sexual dysfunction research, there also has been a problem with having very heterogeneous patient samples, combining

several dysfunctions in one category or not identifying the comorbidity that exists. Another problem with sex therapy in particular is that outcome measures have been improving but have suffered from being either too inclusive or exclusive of symptoms and having few standardized measures of sexuality and sexual satisfaction [167]. In addition to efficacy, which addresses the internal validity of a treatment, effectiveness evaluates external validity. Efficacy studies examine what goes on in actual clinical practice, without demanding such methodological constraints as randomization, controlled number of sessions and controlled content of therapy. The current opinion of clinical researchers is that efficacy is necessary to demonstrate whether the treatment has a benefit under controlled conditions, while effectiveness informs about its broader scale applications. The present review primarily summarizes the studies on efficacy. Occasionally effectiveness research is identified and discussed. It is clear that well controlled, treatment comparison or event wait-list control research on sexual dysfunction treatment is uncommon and where these designs exist statistical power is often low [163]. Though outcome measures vary considerably, the patient’s self-reports are the most common forms and are focused typically on symptom change, sexual satisfaction and occasionally relationship satisfaction.

3. PSYCHOSEXUAL TREATMENT EFFICACY DIAGNOSIS

BY

a) Sexual desire disorders There are no efficacy studies demonstrating empirically supported treatments for the Sexual Desire Disorders. There are a few effectiveness studies, however. Masters and Johnson based sex therapy methods [153] have, overall, shown positive but rather modest results for hypoactive sexual desire disorders [168, 169]. In the Hawton et al. field study of 60 British couples in which the female partner reported low desire, 56% had a positive outcome to treatment that included Masters and Johnson’s treatment methods. Similar success levels (65%) were found by Sarwer and Durlak’s [170] field study of behavioral treatments for 124 women with Hypoactive Sexual Desire Disorder.

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Success levels above 50% are noteworthy, but we do not know from these effectiveness data what the waiting-list control response might have been which would help to put these figures into perspective. b) Sexual arousal disorders Similarly, there are no empirically-supported psy chosexual treatments designed to treat Female Sexual Arousal Disorder which the DSM-IV specifically defines as the inability to attain or maintain «an adequate lubrication/swelling response of sexual excitement [5]». Few women, in fact, complain of a sexual arousal disorder in these words and researchers until recently have rarely specifically asked beyond a complaint about lubrication related to pain disorders. We thus have no idea of the prevalence of this condition, whether it is more than one condition, the precision with which women can identify degrees of genital lubrication or vasocongestion, and the extent to which women label these symptoms as problems. Anestrogenic women will note a lack of lubrication, even when subjectively sexually aroused. For this condition the administration of estrogen replacement com pounds or topical lubricants may be effective treatments. Whether these approaches would also solve a «swelling response» difficulty is not known. Current attempts to describe and document Goldstein and Berman’s [159] proposed categories of vaginal engorgement insufficiency and clitoral erectile insufficiency syndromes will be important to clarify diagnosis and treatment for female sexual arousal disorder. At the moment research from the psychophysiological lab sug gests considerable separation is possible between female genital lubrication (subjectively measured), vasocongestion (objectively measured) and a subjective sense of sexual arousal [160, 161]. Addressing treatment interventions with these findings in mind is necessary. One could make a case that sexual arousal problems in women have been treated by way of anorgasmic conditions. Indeed, orgasm dysfunction treatments focus on the woman paying attention to her physical and subjective responses during arousal and seeking more stimulation if needed [163, 171, 172]. c) Orgasmic disorders There are effective treatments for the condition of 535

orgasmic disorders. We located 17 comparison controlled studies (n = 577) and an additional 4 own control or wait-list control studies (n = 65). When diagnostics of categorization was clarified in the methods, there were more women identified as secondary (n = 244) than as primary anorgas mic (n = 198). Specific active ingredients in this treatment are unknown and there are often too few details about the treatment, but it is clear that a step-wise masturbation program in some version is successful for primary anorgasmic women though less so for secondary orgasmic women. Systematic desensitization was shown to be relatively less effective. Hurlbert and Apt [172] have successfully used the «coital alignment technique,» positioning the male partner’s body to provide more direct clitoral stimulation, so that 56% of the women increased their coital orgasmic ability. Non-controlled research has suggested that these treatments are less effective for older women [153]. There is also some suggestion that there are more complex relationship issues for secondary anorgasmia and a combination of sex therapy and relationship therapy may be indicated [173]. d) Pain disorders Vaginismus partially fulfills the probably efficacious treatment category. There are 55 women across two uncontrolled studies along with several case studies that make up the bulk of this clinical research. The difficulty in validating treatments for vaginismus is that it is a relatively rare condi tion and it can often coexist with other genital pain conditions. Also, until recently there has only been one clearly helpful treatment for this condition, preventing a good comparison treatment study. The most studied intervention is the use of a series of progressively larger dilators that the woman inserts into her vagina over a number of weeks, while also doing exercises for general relaxation as well as specific exercises to increase her control and relaxation of her pubococycegeal muscles. Often the partner is involved in learning to use the dilators, under the woman’s careful guidance, as a prelude to gradually transferring to digital and penile penetration. There are a number of clinical reports of using biofeedback to the genital area, using either anal or vaginal probe or perineal electrodes. There is a general sense that this is effective treatment for a subgroup of vaginismic women. The particular advantage to a

biofeedback procedure to the genital area is that it helps identify women who are chronically tense in the genital area. These women do not benefit from Kegel muscle exercises [55] because they are never able to relax their muscles and are unaware of this chronic tension until penetration is attempted. It would be interesting to see a comparison of sex therapy using dilators and physical therapy including genital biofeedback as well as the combined use of these two therapies.

damaged, physically and emotionally, by the many changes and challenges the woman has to face when cancer diagnosis adversely affects her life and that of her relatives [179,180]. Retrospective [181] and prospective [182, 183, 184, 185, 186] research has been carried out on the many psychosocial issues faced by the woman diagnosed with BC during this difficult transition of her life, including direction and quality of support and optimal type of psychologic intervention during BC diagnosis and treatment. The research does not address the biological issues involved in the sexual changes. This bias is probably secondary to a number of factors: the persistent gender bias in sexological research, the lack of a medicalsexologic background among the majority of researchers and research on the biological aspects of female sexuality being many years behind that of male sexuality [40].

Dyspareunia is an extremely difficult diagnosis to treat, in part because it probably needs further diagnostic subcategorization in order for effective treatments to be developed and tested. It typically has been treated with medical management and surgical interventions due to the high prevalence of organic causes though there is also a fair amount of case documentation showing psychological factors as having treatment potential. An obvious example of the latter is for the condition of vulvar vestibulitis [174, 175, 176, 177] where one study found that combining surgery and behavioral therapy was equally effective to behavior therapy alone, although none of the treatments were standardized [177]. Because pain disorders also greatly impact the partner, brief sex therapy involving both partners can be helpful in moving from a sexual interaction centered on the expectation of pain to a more normal and pleasure focused experience.

Often QOL outcomes are confused with their determinants [187]. Objective measures of QOL often include the assessment of functional status which may not correlate with a patient’s subjective impression of her life experience, e.g. sexual pain, limitations and impairment, consciously or unconsciously minimized for the relief of being alive [188]. The role of objective limitations is inadequately addressed and treated relative to the many sexual problems from which these patients suffer, especially in younger GC survivors; diagnostics and therapeutics need to be balanced between psychodynamic and physical factors.

V. FEMALE SEXUAL FUNCTION AND BREAST OR GYNECOLOGIC CANCER: ASSESSING THE BIOLOGICAL ISSUES

2. FEMALE SEXUAL FUNCTION

1. I NTRODUCTION «SINE DESIDERIO MENS NIHIL INTELLIGIT» Cancer has become much more a chronic than fatal disease. This shift in outcome has concomitantly resulted in an increased emphasis on quali ty of life (QOL), of which sexuality is a leading aspect [177, 178]. A diagnosis of breast (BC) or gynecologic (GC) cancer catapults the woman into several crises simultaneously, all different but interrelated: female sexual identity, female sexual function and sexual relationship. All three crucial and personal factors may be dramatically

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Linear models (arousal, plateau, orgasm, resolution) have been widely used since the pioneering work of Masters and Johnson [153] and Kaplan [189]. More recently, Graziottin [180,190] suggested that human sexual function can be conside red as a circuit, with four main stations: libido, arousal, orgasm, and satisfaction, including both the physical phase of resolution, with its homeostatic function of returning to baseline, and the emotional evaluation of the experience (Figure 8). Physical and emotional post-coital memories are a critical part of satisfaction, summarizing the overall subjective evaluation of each sexual experience by itself and collected over time. This model may help in understanding how positive or nega-

The interplay between estrogens and the dopami nergic system is the key process in determining the appetitive and receptive side of sexual behaviour [198, 200] which can be further excited by the peak of androgens at ovulation. Together with frequency of desire, intercourse and orgasm, these are the strongest indicators of quality of sexuality [201]. Prolactin has an inhibiting effect on libido and on the resulting neurovegetative and vascular responses, via the same dopaminergic system [198]. Small increases over normal levels may be sufficient to reduce libido, sexual arousal and vaginal lubrication [202]. Figure 8 : Human sexual function as a circuit.

tive feed-back may affect sexual function [190] and help to clarify the frequent overlapping of different sexual dysfunctions in women [191], particularly during BC and GC diagnosis and treatment. a) Libido «Libido» is a Latin word that means «desire». It has three major dimensions: biological, motiva tional-affective and cognitive [192] which have a complex interplay with both inhibition and enhancement. A useful working definition is that «sexual desire is normally an activated, unsatisfied mental state of variable intensity, created by external- via the sensory modalities- or internal stimuli- fantasy, memory, cognition...- that induces a feeling of a need or want to partake of sexual activity (usually with the object of desire) to satisfy the need» [193]. 1. B IOLOGICAL Biological roots of libido have been extensively discussed elsewhere [190,194,195]. In short, hor mones are the necessary but not sufficient factors to maintain a satisfying human libido. In women, estrogens prime the central nervous system, acting as neurotrophic and psychotrophic [196, 197, 198] factors throughout life. They prime the sensory organs, key receptors for external sexual stimuli, and secondary sex characters. Sensory organs transmit the basic information that, mixed with emotional and affective messages, contribute to the structuring of core sexual identity and self image, relevant for the personal perception of being an «object of desire» and for the direction (homo or heterosexual) of the libido itself [199].

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Progestins act as mild sedatives, through a complex mechanism that is central and, probably, peripheral: they are of inte-rest when prescribed at high dosages in hormonal treatment of advanced adenocarcinoma. Their loss after bilateral ovariectomy may lead to Female Sexual Arousal Disorder (FSAD) [203], but supplementation improves libido, arousal, assertiveness and well-being in patients with benign conditions [204, 205, 206]. Androgens have a definite excitement role in women [203] as well as in men. Hormones, in their complex interplay, seem to control the intensity of libido and sexual behaviour rather than its direction [192]. GC survivors report decrease of libido [207] and frequency of coital intercourse [208], the worst outcome reported by irradiated patients [209]. Although little attention is paid to the effect of hormones on the function and morphology of sensory organs as sexual targets and sexual determinants of libido, sensory organs are open to environmental sexual stimuli. A growing body of evidence shows that sexual hormones have a speci fic effect on smell [194, 210, 211] and taste [210]. Libido, which may be lessened by loss of estro gens secondary to menopause, may be further decreased with chemotherapy [188, 190] by an increase in smell aversion [212] and reduction of salivary secretion, particularly in young BC patients [181, 184, 211]. Skin is the organ with the largest brain representation: this may explain why touch is so important in human love and communication. Non-sexual tenderness, caresses, holding and loving behaviour seem to remained unchanged or even increased in the majority of couples after BC diagnosis and treatment, so that an average 70-80% of women with BC report an overall

good adjustment [181, 184, 185, 186]. Much less is known about the role of estrogens on hearing, despite its having a strong excitatory role for libido and arousal in women and sight, which is the most potent sexual sense in men. Subtle changes in sensory organ function and morphology could contribute to the biologic deterioration of libido with age, accelerated in many women in early postmenopausal years [213, 214], usually in cases of premature menopause [181, 215]. Loss of libido in BC patients may be secondary to a number of biologic factors such as: arousal disorders [181, 194, 216, 217, 218, 219]; pelvic floor dysfunction [220]; psychodynamic [221], motivational or relational causes [154, 215, 218, 222], sexual pain related disorders [223], orgasmic disorders [154], and physical and/or emotional sexual dissatisfaction. Loss of libido in GC patients may be secondary to: arousal disorders [190, 194 217]; pelvic floor dysfunctions [220]; sexual pain related disorders [223] including severe dyspareunia postradiotherapy and/or pain after vulvar laser CO2 [188], or vulvectomy [224] and persistent pelvic pain after GC diagnosis and treatment [188]; orgasmic disorders [154]; sexual dissatisfaction [221] and motivational or relational causes [154]. Differential diagnosis requires a careful evaluation and definition of objective criteria. BC or GC diagno sis and treatment may contribute to the complexi ty of sexual dysfunction. 2. MOTIVATIONAL-AFFECTIVE ASPECTS OF LIBIDO Human beings undertake sexual activity for procreation,“reproductive sex”, with strong biological roots, and pleasure «recreational sex», with deep relational roots [193]. The unpredictability of life is reported to be perceived as an aphrodisiac. Libido may be felt as more intense than ever, sometimes with acute transgressive needs, and increased sense of physical and emotional satisfaction. There are a host of motives [225] with a common denominator: «instrumental sex», a means to obtain conscious and/or unconscious advantages and/or to express motivations different from pleasure and/or procreation. Coitus may be used to confirm one’s identity, particularly in young patients that perceive hysteroannessiectomy and the disappearance of periods as a major wound to their female sex identity; «save the marriage»; satisfy attachment needs; rebel against destiny; overcome loneliness or boredom; show that

sexual access was still possible; obtain more attention in the relationship; satisfy masochistic needs; control the relationship and/or the partner; repair psychosexual wounds; or even for livelihood. Unfortunately, instrumental sex with its strong «defensive» nature is usually accompanied by a low physical drive and is therefore more vulnerable to dysfunctional outcomes [220] which seem more frequent in BC and GC patients. The quality of the non-sexual relationship [226, 227] and quality and intensity of transfer from past significant relationships contribute to the motivational-affective aspect of sexual desire and may help maintain the sexual relationship that is a vital part of the «personality of marriage» over the time. 3. COGNITIVE Sexual behaviour cognitively involves both wish and risk. There may be a paralysing effect when the perception of risks by a BC patient, i.e., rejection by a new partner «because of breast disfigurement» and his «fears of cancer recurrence» and/or wounded body image, or by a GC patient rejection by a new partner «because of fear of infection» after an HPV dependent intraepitelial or invasive cervical or vulvar neoplasia and/or a wounded body image [188, 201], may prevent women from engaging in sex or starting a new relationship. An enhancing effect could be perceived in those women that consciously wish to «urgently» challenge their seductiveness and enjoy sex «before the worst comes». Psychosocial variables have been well documented [177, 181-186, 188, 209, 215, 216, 228- 231]. Iatrogenic menopause, lymphedema, dyspareunia and chemotherapy seem to affect the biologic bases of libido in BC patients [179, 181, 219, 232234]. Iatrogenic menopause, with the special contribution of the loss of ovarian androgen leading to FSAD, vaginal biological damages secondary to radiotherapy and surgery leading to dyspareunia, potential mental damages of chemotherapy and vulvar damages secondary to conservative and radical treatments seem to be the major factors that may damage the biological bases of libido in GC survivors. b) Sexual arousal Libido is different from sexual arousal, a state with specific feelings usually associated with the genitals [193]. In women, arousal has three main expressions: central arousal, characterized by mental acti-

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vation leading to erotic dreams, sexual daydreams and/or voluntary sex fantasies which may activate physical genital and non genital peripheral arousal; non genital peripheral arousal, expressed by increased salivary secretion, sweating, cutaneous vasodilatation and nipple erection; and genital arousal, associated with clitoral and vestibular bulb congestion, and vaginal lubrication [40]. Arousal difficulties may be a) central, b) non genital peripheral and c) genital [40]. Estrogen and androgen loss, secondary to iatrogenic menopause, may affect these aspects of the arousal. 1. CENTRAL Biological central difficulties may be secondary to loss of sexual hormones [194, 204, 205, 235, 236], but may be worsened by depression [194, 237], anxiety [238], chronic stress and insomnia [220], which may be biologically rooted, and by estrogen and androgen deprivation [239-243]. Reduced frequency of erotic dreams, fantasies, sexual daydreams and spontaneous mental arousal are the clinical consequences of central arousal difficulties reported in BC patients and GC patients irradiated for cervical carcinoma [208, 209, 244]. 2. NON GENITAL PERIPHERAL Problems in non genital peripheral arousal may be better exemplified by «touch-impaired» disorders. Sarrel and Whitehead [245] reported 35.71% of patients described a change in touch perception suggestive of peripheral neuropathy that may lead to avoidance of skin contact during foreplay including nipple (personal unpublished data) and clitoris, interfering with sexual arousal. A chronic hypoandrogenic condition may be a cofactor in this loss of clitoral sensitivity, particularly in BC patients with reduced ovarian androgen production secondary to chemotherapy or bilateral ovariectomy. Decreased salivary secretion, secondary to chronic estrogen loss, affects 45% of normal postmenopausal women [246], affecting mostly oral intimacy and oral pleasure [194, 237]. This is all the more important in women whose coital receptivity is impaired by vaginal stenosis and fibrosis leading to severe dyspareunia. Schover [247], reports a significant decrease in the mean number of sexual acts, including oral intimacy, in the first year after treatment for cervical cancer.

3. GENITAL Without estrogen, 35 to 50% of normal postmenopausal women complained of vaginal dryness and dyspareunia [196, 214, 245]. Loss of estrogen is the primary biological cause of genital arousal difficulties in women after pre-existing arousal disorders, and may be the critical precipitating factor leading to dyspareunia in women with iatrogen ic premature menopause [248]. Preexisting arous al disorders may be worsened by the menopausal loss of estrogens leading to avoidance of intercourse. In addition to estrogen, regular and continued painless sexual activity has been found to protect against vaginal dryness [249]. Tamoxifen is the contemporary endocrine treatment most widely used in BC. It interacts with ovarian estrogen synthesis and elevates plasma estrogen levels in premenopausal women. In postmenopausal BC patients tamoxifen increases plasma levels of estrone sulfate (E1S) while plasma estradiol and free plasmatic testosterone are reduced, and increases the liver production of Sex Hormone Binding Protein (SHBG), thus further reducing the free levels of both estradiol and testosterone [250, 251]. One third of patients on tamoxifen had vaginal problems such as dryness, itching and discharge [184]. Other studies seem to confirm the negative effect of tamoxifen on sexual response [219, 252, 253]. In cases of GC, because of the direct anatomical involvement of vaginal and perivaginal vascular, nervous, connective and supportive structures, arousal is the dimension of sexual function that is more directly affected [247]. Its involvement is maximized in women treated for cervical cancer with combined surgery and radiotherapy [254257]. Radiotherapy creates a major insult to the vascular and neurological bases of the lubrication process, the elasticity of the mucosal and submucosal tissues leading to a dry, retracting, narrow and rigid «tube», instead of a wet, elastic and receptive organ. This «radiation vaginitis» may cause vaginal discharge, spontaneous and contact bleeding, besides dyspareunia, all of which may cause anxiety for the similarity to the presenting symptoms of the cervical cancer, raising threatening fears of recurrence [258, 259]. Topical and systemic estrogen replacement therapy (ERT) may improve the recovery process and is one of the critical therapeutic steps to be performed even during radiotherapy, to minimize retraction and 539

irreversible loss of vaginal elasticity [254]. Clitoral responsiveness in the arousal phase may be impaired after menopause. A chronic hypoandrogenic condition, particularly in patients who underwent bilateral ovariectomy or actinic castration, may be a co-factor in this loss of clitoral sensitivity. Clitoral arousability may be compromised in vulvar cancer, when vulvectomy is performed [224], with disruption of the excitement and resolution phase, leading to a two to threefold increase in the frequency of sexual dysfunction.

vasculature to the genitalia from direct tumor compression of the vessels [258], surgical disruption and/or vascular fibrosis from radiation therapy [177] can also interfere with sexual functioning. With persistent good libido, vascular causes might have significant clinical improvement with vasoactive drugs such as sildenafil [38]. Among GC patients, sildenafil in combination with appropriate HRT could significantly reduce dyspareu nia except in cases of hormone dependent adeno carcinoma where HRT is contraindicated.

A second biologic cause of arousal difficulties is vaginismus, either primary or, more frequently, secondary to vaginal dryness and dyspareunia with secondary defensive spasm of pubococcygeal muscle [220, 260]. It is present in all patients after vaginal radiotherapy. Secondary vaginismus may account for half the cases of postmenopausal dyspareunia.

The prospective longitudinal study of Ganz et al. [184] reported 61 and 57% of BC patients respectively had difficulty in becoming sexually aroused and lubricated. Survivors attain maximum recovery from the physical and psychological trauma of cancer treatment by one year after surgery, but a number of aspects of QOL, including rehabilitation and sexuality significantly worsen after that time, suggesting that biological factors may be responsible. According to the retrospective study of Schover et al. [181], BC women who received chemotherapy reported more vaginal dryness and dyspareunia. Overall, postmenopausal BC women were more likely to report vaginal dryness, tightness and genital pain with sexual activity.

The third most reported cause of genital arousal difficulties is urinary incontinence. Urinary dysfunction symptoms due to estrogen loss and expected with age may be increased with iatrogenic premature menopause unless appropriate hormonal replacement therapy (HRT) is prescribed. Voiding disorders are more frequent after radical hysterectomy for cervical cancer [261- 263]. Urinary incontinence may also be a complication after radical vulvectomy. Women suffering from stress incontinence secondary to disruption of pelvic floor anatomy and function, or urge incontinence secondary to detrusorial instability, may suffer from occasional loss of urine during sex and may become inhibited for fear that it would recur [264]. Appropriate diagnosis and treatment of incontinence may contribute to a renewed selfconfidence [220]. Vascular problems have recently been claimed as critical factors in female arousal problems [162]. Women who smoke, who have high levels of cholesterol which increase after the menopause, with diabetic vasculopathy and/or with severe atherosclerosis may have a significant reduction in their genital arousal and lubrication with increased vaginal dryness and dyspareunia. Vascular fac tors, specifically diabetes and hypertension, increase vulnerability to radiation damage, e.g. bladder and rectal injury, and extent of vaginal retraction [255]. A cancer related decrease in the

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Rehabilitation of the pelvic floor as an intervention is usually dismissed, as average recommen dations focus most on estrogen cream and passive dilatation of the vagina [247, 259, 265]. Through contracting, relaxing and gentle pushing the woman may gain active control of the muscle’s tonus and opening of the vagina [220]. This represents a trophic stimulus at the level of the neuromuscular plaque, helping maintain a more elastic and trophic muscle and vaginal sensitivity. Preserving a healthy vaginal space is a critical part of the recovery of the sexual function after GC diagnosis and therapy [216, 220]. Local vaginal massage may also improve vascularization and tissue elasticity, counteracting the retraction secondary to radiotherapy. Moulds or dilators are frequently recommended in clinical settings in the treatment of dyspareunia [247, 259, 265]. They should be used in conjunction with the previous procedures to allow for active control over muscle contraction and health and reduce the perception of the mould as painful and aggressive. After application of an estrogenic cream, the dilator may also contribute to reduction of vaginal retraction and stenosis

secondary to radiotherapy. Lubricants are frequently recommended to ease penetration for both partners, but the woman should be taught to relax the levator ani, increase the vaginal opening and ease penetration. Active perineal muscle contrac tions [55] after penetration may contribute to improvement of pleasure. Encouraging GC patients to be active in their recovery process increases their sense of control over the situation, reduces passivity that accompanies depression and improves the patient’s relationship with the professionals allowing for the best possible QOL.

retraction, increased connectivity and vascular and neurological damage after radiotherapy may cause dyspareunia, vaginismus and post-coital cystitis, impairing the formation of the orgasmic platform [266], due to the negative association of fear, anxiety and pain. Hypotonic conditions, leading to vaginal hypo-anesthesia, especially in patients treated with simple hysteroannessiectomy, should be rehabilitated with Kegel exercises [189, 201, 266]. Difficulty in reaching orgasm is reported in 55% of BC patients in the study by Ganz et al. [184], with a significant worsening in sexual functioning over the three year follow-up. In the Schover et al. [181] study, the ability to reach orgasm through intercourse was significantly reduced in women who received chemotherapy, although their ability to reach orgasm through non coital caressing did not differ from control women. In GC patients, difficulty in reaching coital orgasm was reported in 16.5% of patients at initial diagnosis of cervical cancer and in 60% of patients one year later [247]. Sexual function worsened significantly and the repertoire of sexual acts and number of intercourses performed decreased.

c) Orgasm Orgasm is an «altered state of consciousness», with centripetal (inward neural activity from the genitalia) and centrifugal (outward neural activity from the brain to the muscular apparatus of the genitalia) components underlying the experiential event [40]. Sensory trigger points include the clitoris and vagina, clitoral and periurethral glans, uterus, anal mucosa, and proprioceptive stimuli from the levator ani and perivaginal muscles. Non genital trigger points include nipple and sensory organs, skin first, particularly in certain regions of the body [40]. Anatomic and functional modifications of trigger points and areas may deeply affect the orgasmic potential, particularly in BC patients and GC patients after radical surgery and/or radiotherapy.

d) Sexual satisfaction

Motor orgasmic response involves an average of 3 to 8 0.8 second contractions of the «orgasmic platform», consisting of congested tissues and muscles of the pelvic floor [189, 266]. The uterus contracts some 2-4 seconds after the subjects awareness of orgasm [267]. Uterine contractions at orgasm are possibly the terminator of sexual arousal in women inducing a terminal orgasm, much like that of men [267].

Sexual satisfaction is both physical and emotional. In the physical dimension, the physiological resolution phase controls the level of physical satisfaction and is probably mediated by the oxy tocin levels [200]. In the emotional domain, satisfaction is more dependent on the quality of emo tional and physical intimacy and the overall qua lity of the relationship. The final satisfaction depends on the quality of post-coital and/or postorgasmic memories that may affect human sexual function [190] which may explain the positive or negative feed-back mechanisms that modulate the circuit of sexual function, both at the physical and emotional level [190].

Orgasmic difficulties may be the endpoint of a number of biological, motivational-affective and cognitive factors [189, 266, 220], particularly in BC survivors. They may arise from decreased sexual hormones, with secondary libido and arousal problems, vaginal and vulvar trophism including the clitoris, and pelvic floor status. Many of these aspects may be altered by surgery, chemo or radiotherapy. Hypertonic conditions, muscle

Memory of pain, particularly from dyspareunia, in strongly emotional contexts such as sexuality, is submitted to «long-term potentiation» processes [268] mediated mainly by Nerve Growth Factor (NGF), and will remain long after the resolution of the etiological cause [220, 269]. This memory or fear may cause loss of libido and arousal difficulties with reduced lubrication despite restored anatomic and/or endocrinologic conditions. This

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negative effect may be responsible for the the long term significant worsening of sexual function and satisfaction among BC survivors in studies by Ganz et al. [184], Schover et al. [181] and Dorval et al. [185, 186], who reports eight years after primary treatment, and in GC survivors noted by Schover [247] and Andersen [224] in a retrospective study of vulvar cancer patients. Pain and an overall disappointing sexual experience might also be responsible for the significantly reduced frequency and type of sex and willingness of women to initiate sex, although in both Schover’s and Andersen’s series satisfaction remains intact across time, possibly due to denial mechanisms [270] and improved emotional intimacy with the partner which acts to soften the impact of the specific sexual limits. Andersen [258] reported that while frequency of intercourse dropped one year after treatment, other sexual or affectionate behaviours remained constant. Among vulvar cancer patients a specific disruption of the physical «resolution» phase was found [224]: many patients reported «residual tension» and general sexual dissatisfaction. However, the patients’ global evaluation of their sexual life was not significantly different from that of healthy controls [224]. Women should be encouraged to continue rehabilitation training of the pelvic floor for six months after the clinical resolution of the condition, use a lubricant to ease penetration and avoid pain, help a still inadequate physical arousal, and achieve full recovery.

2. PHYSIOLOGICAL MEASURES At present, the two most widely used techniques to measure vaginal vasocongestion are vaginal photoplethysmography, first introduced in 1975 by Sinchak and Geer [275], and the oxygenation-temperature method developed by Levin and Wagner in 1977 [276] (see [277] for a more extensive review of available methods). Levin and Wagner’s device consists of a heated oxygen electrode fitted into a suction cup that is attached to the vaginal wall. The electrode is heated by an electric current to a set temperature. The amount of electrical power needed to keep the disc at this temperature can be monitored. Heat is lost from the disc mainly by conduction through the tissue and tissue fluid to the blood. Increased blood perfusion under the electrode will increase its heat loss and a greater power output will therefore be needed to maintain the electrode at the set temperature. The changes in power in milliwatts thus become an indirect measure of the changes in blood flow under the electrode, reflecting the pooling of blood in the vascular bed. The electrode also records the amount of oxygen that diffuses across the skin, reflecting transient changes in blood flow.

VI. PHYSIOLOGIC MEASURES OF FEMALE GENITAL BLOOD FLOW 1. INTRODUCTION Physiological measures for the assessment of sexual arousal in women have a relatively short history in sexology [274]. To date, knowledge of the underlying physiological mechanisms involved in female sexual arousal is scarce. Most of the real advances of the past two decades have come about mainly from the application of methods used to monitor changes in vaginal vasocongestion. These methods vary in terms of vali dity, specificity, and practical applicability.

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The vaginal photoplethysmograph is a menstrual tampon-sized device, easy to insert and sterilize, containing incandescent light, or an infrared or visible red light-emitting diode as a light source, and a photo transistor as a light detector. The light source illuminates the blood vessel plexus under the epithelium of the vaginal wall, and the photo transistor picks up the light that is backscattered from the illuminated area [278]. Two signals are usually obtained from the photo transistor. When the signal is coupled to a Direct Current amplifier, slowly developing changes in vaginal blood volume (VBV) are observed, which are thought to reflect pooling of blood in the vaginal tissue. With AC coupling, a measure of vaginal pulse ampli tude (VPA) is obtained, reflecting phasic changes in vaginal engorgement with each heart beat. The greater the blood content of the vaginal tissue, the greater the signal’s amplitude. VPA has been shown to have excellent divergent and convergent validity and is a much more sensitive and reliable measure than VBV [279]. For a representative example of VPA recording during neutral baseline and erotic film, see Figure 9.

Figure 9: A representative trace of vaginal pulse amplitude during a one-minute baseline recording and one minute of ero tic film exposure.

Each technique has its advantages and limita tions. [160]. For instance, the oxygenation-temperature measure can be calibrated in terms of absolute blood flow and is relatively free of movement artifacts. The reliability of the signal does not seem to be compromised by masturbation, clitoral vibration, and orgasm. Disadvantages are its expense, the fact that the electrode should not be applied for very long periods of recording to protect the vagina from heat damage, and that the device needs to be attached by the experimenter. The vaginal photoplethysmograph does not determine absolute levels of blood flow and is not reliable during and after orgasm [275], but surpasses the other measure with respect to practical applicability. It can be inserted by the subject herself and is well tolerated, thus diminishing the intrusiveness of the measure and allowing for long recording periods. With the right statistical design, that is a one-session within-subjects design or a placebo-controlled cross-over design in the case of pharmacological studies, the data obtained from vaginal photoplethysmography can be readily interpreted. A relatively new and promising technique is duplex ultrasonography adapted for measuring vaginal and clitoral blood flow. Several studies have used this techniques in the past including; Lavoisier et al. who reported on the use of Doppler ultrasonography to measure blood velocity in the clitoral cavernosal artery and to record changes in flow associated with intravaginal pressure changes; and Sarrel who described the use of laser Doppler velocimetry for measurement of vaginal blood flow in the evaluation of the effects of estrogen compared with estrogen-androgen treatment

in post menopausal women [280]. Such studies report that vaginal blood flow is an objective mea sure of sexual function and that laser Doppler velocimetry proved readily adaptable for measurement of vaginal blood flow. The use of Duplex Doppler ultrasonography to assess the changes in female genital hemodynamics occurs during sexual arousal. This technique provides continuous, real time imaging of anatomic, as well as vasocongestive components of the female sexual response. In addition, it records blood velocity in absolute units; centimeters per second (cm/s). Clitoral, labial (vestibular bulb), urethral, iliac, uterine and vaginal peak systolic velocity and end diastolic velocity are able to be measured using Duplex Doppler ultrasonography. The probe (12 mHz) may be used externally to measure right and left labial, urethral and clitoral cavernosal arterial blood flow velocity. A transvaginal probe may be used to measure right and left vaginal, iliac and uterine arterial blood flow. All measurements are first recorded at baseline and following sexual stimulation, with a 15-minute standardized erotic video on a 3-D surround sound headset (I.O. Display Systems and a vibrato. Visual and vibratory stimulation are maintained during the majority of the ultrasound exam, except where the vibratory stimulation interfered with certain measurements (clitoral and right and left labial blood flow velocity values). Sexual arousal results in an increased blood flow to the hypogastric-pudendal arterial bed, an important indicator of sexual arousal in women in the early stages of sexual arousal. This increased pelvic blood flow leads to increased perfusion of

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the sexual organs, specifically the vagina, clitoris and labia. Duplex Doppler ultrasonography is able to document significant increases in genital blood flow velocity to these structures with sexual stimulation. Following sexual stimulation, the phenomenon of genital tumescence is able to be adequately demonstrated on ultrasound, anatomically by increased venous pooling, and physiologically by increased end diastolic velocities in the genital arteries.

without sexual problems? The answer to this question is that we don’t know yet. Only seven studies exist to date that assessed differences in vaginal response between women with and without sexual problems, all using vaginal photoplethysmography. Three studied sexual responses to erotic stimulus materials in low arousal or nonorgasmic women [281- 283], two studies combined women with different sexual dysfunctions into one group [284, 285], one studied low desire and anorgasmic women [286], and the last study examined sexual responses of women with dyspareunia to oral sex and intercourse scenes [287]. It is difficult to compare these studies and make sense of the differential findings, because the nature of the sexual problems varied between and even within studies, different erotic stimuli were used, and studies differed with respect to the way vaginal responses were measured (using either VPA or VBV or both) and analyzed.

Practical applicability of measuring blood flow in the genital arteries before and after sexual stimulation is not a trivial issue. Studies measuring sexual responses in the vagina are limited as it is, with its restriction to solo sexual activities and its contrived context [161, 277]. So it seems crucial to use a measure and a procedure that most women would be willing to undergo, respecting a woman’s privacy, allowing her to become sexually aroused in the laboratory. Balancing validity and applicability concerns, we feel that at present, vaginal photoplethysmography is the method of choice.

The Meston and Gorzalka [286] study was the first to compare different diagnostic categories, thus making the important step toward differentiating patterns according to the presenting sexual problem. Wouda et al [287] were the first to study vaginal responses of women with sexual problems to sexual stimuli differing in content. Eighteen women with dyspareunia participated. In this study, a neutral baseline period was followed by an erotic scene depicting fellatio and cunnilingus. Then the women were subjected to a return-tobaseline period followed by a cunnilingus scene and an intercourse scene. There were no differences in VPA between the women with dyspareunia and a control group of women without sexual problems in the first four phases of the experiment. But during the intercourse scene responses of the control group further increased while in the dyspareunia group responses declined. There were no differences in subjectively reported sexual arousal to the last scene. These results suggest a number of things. First, differences in vaginal vasocongestion response may be highly situa tion- or stimulus specific. Only during the intercourse scene VPA was significantly lower in the clinical group. Second, genital measures and sub jective feelings did not correspond.

3. ORGANIC ETIOLOGY Recently, investigators interested in the pathophysiology of female sexual dysfunction have proposed that in some women, female sexual arousal problems are associated with vascular and clitoral erectile insufficiency [67]. These authors suggest that future management strategies for women with sexual arousal problems should be aimed at assessing vasculogenic sexual dysfunction, especially if these women are postmenopausal. Of course, it is highly unlikely that organic factors in female sexual dysfunction are absent. We therefore believe that (psycho)physiological assessment should be more routinely implemented as a diagnostic tool in post- as well as premenopausal women. We nevertheless have to be careful not to oversimplify and take any vascular irregularity as the organic factor causing the sexual difficulties. As will be outlined below, even in postmenopausal women reduced vaginal vasocongestion is not always indicative of sexual dysfunction.

4. DIFFERENTIAL DIAGNOSIS 5. FEELINGS AND STIMULI

How well do the available vaginal vasocongestion measures differentiate between women with and

A large number of studies have addressed the cri-

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tical issue of subjective feelings and physiologic responses. In some studies positive correlations between VPA or VBV and subjective feelings of sexual arousal were reported, but the majority fai led to find a relationship between genital and subjective sexual arousal [274, 288]. This issue seems to be unique for women. In men without sexual problems correlations between penile circumference change and subjective report are usually fairly high [274]. In recent years we studied this phenomenon more closely. We consistently found VPA to occur fairly automatically in response to an explicit erotic stimulus such as erotic film [288]. That is, vaginal vasocongestion increases within seconds after the onset of the stimulus (cf. Figure 4), without most women being aware of this happening, even when the stimulus is negatively evaluated or induces little or no feelings of sexual arousal. Women do not simply attend to genital changes when assessing their subjective feeling state. Their subjective experience of sexual arousal is determined both by feedback from their genitals (which becomes more important as genital arousal increases) and by the intensity and appraisal of the sexual stimulus. Therefore, genital measures should always be used concurrent with subjective measures of sexual arousal.

gesting that inadequate erotic stimulation may be more important in sexual arousal disorders than a vasculogenic dysfunction related to menopause [67]. This study demonstrates that depending on whether one measures VPA without or with sexual stimulation, one could either decide for or against organic factors contributing to arousal problems. Furthermore, these findings again point to the importance of measuring genital function in a sexually stimulated state, and to devise physiological measures that generate valid data in a situation that allows women to become sexually stimulated.

6. SEX AND THE BRAIN

These findings suggest an important role for the sexual stimulus in psychophysiological studies. Not only is blood flow directly dependent upon the intensity of the sexual stimulus, subjective feelings depend on the intensity and appraisal of the sexual stimulus as well. And what is intense in terms of blood flow may differ from what is intense in terms of subjective sexual arousal. In order to meaningfully compare clinical groups within and between labs, some level of standardi zation with respect to the type of erotic stimulus seems essential. Finally, measuring vaginal vasocongestion in the absence of a sexual stimulus may lead to false conclusions. For instance, a recent study demonstrated an estrogen related difference in VPA between premenopausal and untreated postmenopausal women during initial baseline, before any erotic stimulation had taken place [202]. During subsequent erotic stimulation however, this difference in VPA between groups disappeared, sug-

The recent focus of the medical literature on the peripheral components of sexual response, i.e. erection and vaginal vasocongestion, ignores the fact that genital response is dependent on commands from the central nervous system [76]. For instance, the importance of stimulus features and the apparent dissociation between genital and subjective response suggest a significant contribution of central processes to sexual arousal. The amygdala play a crucial role in mediating between multi-sensory inputs and their emotional and motivational significance [289]. These influences are modulated by prefrontal processes where stimulus features are matched with memories of previous experience [290]. There is evidence that the amygdala are directly linked with autonomic motor output, implying an automatic pathway between sensory input and response. In addition, there is a second pathway through projections from the amygdala to the medio-dorsal thalamic nucleus, and from there to the prefrontal cortex. This pathway eventually enables subjective awareness of sexual excitement and (conscious) sexual action. The dissociation between genital and subjective measures of sexual excitement may thus be explained by the overriding influence of central, possibly prefrontal, processing. Whether there is a gender difference in neural processing that may explain the difference in association between genital and subjective sexual response for women and men could become clear in future functional brain imaging studies.

7. PHARMACOLOGICAL INTERVENTIONS Given the above observations, what would be the minimal requirements for a psychophysiological 545

laboratory study designed to test the efficacy of a pharmacological agent? First and foremost, genital responses should be measured under sexual stimulus conditions, because they determine the intensity of both VPAand subjective sexual arousal. By now we know quite well which stimuli yield, on average, the highest levels of VPA in functional women, without causing movement artifacts [288]. This means we can reliably predict and control VPA levels by means of the sexual stimuli that are presented. Another quite obvious reason for measuring VPA to a sexual stimulus is that the new generation of vasoactive drugs (e.g.. sildenafil) work under sexual conditions only. Second, a physiological measure is needed and we have argued that VPA is the best measure that is now available, even though it is far from perfect. Such a measure is essential simply to prove that the pharmacological agent indeed enhances blood content in the vaginal wall during sexual stimulation relative to placebo. And third, it is necessary to assess subjective sexual arousal concurrently, preferrably in a variety of ways, because subjective sexual arousal is not only dependent upon VPAintensity but also on the evaluation of the sexual stimulus.

skills. We would predict that a pharmacological agent would add little to sexual arousal when someone rates his or her partner low in sexual attractivity and sexual skills.

VII. CONCLUSIONS Female sexual dysfunction is a common condition, with population estimates ranging from 22% to 43% [17, 21, 22]. Population estimates of the prevalence of dyspareunia, a sexual dysfunction that causes many women to seek medical attention, ranges from 3% to 15%; estimates from clinic or other selected samples are generally higher (12% to 33%). Epidemiologists, clinicians, therapists, and physiologists should work together to formulate standard definitions that can be applied to large population groups to obtain reliable and valid estimates of the prevalence and incidence of various types of female sexual dysfunction in the community. In this way, the true burden of these disorders can be established. Little is known about risk factors for female sexual dysfunction or changes over the life span (natural history). Longitudinal data from representative samples are needed for this. A thorough epidemiologic examination of suspected risk factors for well-defined categories of sexual dysfunction can provide help in identifying etiologic factors, an important first step in planning treatment and prevention efforts. There remain large gaps in our understanding of the central nervous control of female sexual function. This problem is especially acute with regard to higher centers. Most of the animal work relates to receptive behavior in female animals and very little on the control of genital responses. There is considerably more research on these issues in males. It is likely that there will be significant homology between males and females in the control of sexual function. However, significant differences may also be present, especially in forebrain regions. Therefore, it is unwise to assume a complete correspondence between the male and female and to try to construct a neural wiring diagram of the female based largely on research in the male. Obviously, there is a tremendous need for more research in this area.

Evidently, it is relatively easy to control for the sexual stimulus in the laboratory. It is far more difficult to control sexual stimulation in the real world. We will finish by speculating a bit on ways in which to assess the quality and intensity of sexual stimulation outside the laboratory, again in the case of a study designed to test the efficacy of a pharmacological agent. What seems of importance is knowing to what extent the sexual stimulation is adequate for the subject who takes the drug. You need to get some grip on the quality and intensity of the sexual stimulation. This is quite difficult, because in theory anything that has positive sexual meaning for an individual can be sexually stimulating. By way of example, let us limit ourselves to relationship factors. A partner’s sexual attractivity seems related to relationship duration. We know that in long term relationships, habituation occurs [291]. Possibly, in a new relationship a partner’s looks are more important than his or her sexual skills, such as timing, intensity of stimulation, and so on. In ongoing relationships sexual skills probably become increasingly important. So we need to try and measure both partner-attractivity and partner-

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Breast and gynecologic cancer may affect female sexual function, female sexual response and couple relationship in a complex way, involving both psychosocial and biological factors. The overall quality of life of BC survivors is positive in an average of 70 - 80% of cases, except in the areas of sexual function and satisfaction [181, 184-186, 219]. GC survivors, on average, show a 50% reduction of sexual activity, both in quantity and physical satisfaction. There may be a subgroup of cancer survivors whose quality of life is more seriously affected by the cancer treatment [224, 247, 269, 272]. Moreover, sex hormones contribute to the biological femininity, the basic biology of sexual function and the biological signals, leading to sexual attraction and affective bonding that reverberates in the couple relationship. Their action in human female sexuality is strongly context-dependent [273].

action of new pharmacological agents, but also enable us to better differentiate responders from non-responders.

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268. SVENDSEN F., TJOLSEN A. & HOLE K. (1997): LTPof spinal A beta and C fibre evoked responses after electrical sciatic nerve stimulation. Neuroreport 8 (17): 3427-3430. 269. GRAZIOTTIN A. (1997): Aspetti psicoemotivi del dolore. In Graziottin A e Di Benedetto P (a cura di), Piacere e Dolore. Atti Sesto Meeting della Sezione di Riabilitazione Perineale della Societe Italiana di Medicina Fisica e Riabilitazione (Simfer), Libreria Goliardica Editrice, p.223-228; Maggio. 270. GABBARD G.O. (1995): Psichiatria psicodinamica. Masson Ed., Milano. 271. CHOO Y.C. (1982): Invasive squamous carcinoma of the vulva in young patients. Gynecol. Oncol. 13: 158164.

286. MESTON C.M. & GORZALKA B.B. (1996): Differential effects of sympathetic activation on sexual arousal in sexually dysfunctional and functional women. J Abnor. Psychol. 105: 582-591.

272. PLOCH E. (1987): Hormonal repalcement therapy in patients after cervical cancer treatment. Gynecol. Oncology 26: 169-177.

287. WOUDA J.C., HARTMAN P.M., BAKKER R.M., BAKKER I.O., Van De WIEL H.B.M., WEIJMAR SCHULTZ W.C.M. (1998): Vaginal plethysmography in women with dyspareunia. J. Sex. Res. 5: 141-147. 288. LAAN E. & EVERAERD W. (1995): Determinants of female sexual arousal: Psychophysiological theory and data. Ann. Rev. Sex. Res. 6: 32-76. 289. DIXON A.F. (1998): Primate Sexuality: Comparative Studies of the Prosimians, Monkeys, Apes, and Human Beings. Oxford University Press, New York. 290. FUSTER J.M. (1997): The Prefrontal Cortex, 3rd ed. Lippincott-Raven Publishers, Philadelphia.

273. ALFONSON C., COHEN M.A., LEVIN M., SIMON K. et al. (1997): Sexual dysfunction in cancer patients: a collaborative psychooncology project. Int. J. Mental Health 26(1): 90-98. 274. ROSEN R.C. & BECK J.G. (1988): Patterns of sexual arousal: Psychophysiological processes and clinical applications. The Guilford Press, New York. 275. SINTCHAK G. & GEER J.H. (1975): A vaginal pho toplethysmograph system. Psychophysiology 12: 113115.

291. EVERAERD W. & LAAN E. (1995): Desire for passion: Energetics of sexual response. J. Sex. Mar. Ther. 21: 255-263.

276. LEVIN R.J . & WAGNER G. (1977): Haemodynamic changes of the human vagina during sexual arousal assessed by a heated oxygen electrode. J. Physiol.75: 23P-24P.

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Committee 15

Priapism

Chairman W. S TACKL,

Members P. BONDIL, R. CARTMILL, D. K NOLL, E.S. PESCATORI

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CONTENTS

I. INTRODUCTION

IV. MEDICAL TREATMENT 1. VENOUS OR LOW-FLOW OR ISCHEMIC PRIAPISM

II. CLASSIFICATION

2. ARTERIAL OR HIGH-FLOW OR NON-

1. VENOUS OR LOW-FLOW OR ISCHEMIC PRIAPISM

ISCHEMIC PRIAPISM 3. RECURRENT PRIAPISM/PROLONGED ERECTION

2. ARTERIAL OR HIGH-FLOW OR NONISCHEMIC PRIAPISM 3. RECURRENT PRIAPISM

V SURGICAL TREATMENT III DIAGNOSIS REFERENCES

1. HISTORY 2. EXAMINATION 3. INVESTIGATIONS

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Priapism W. STACKL, P. BONDIL, R. C ARTMILL, D. K NOLL, E.S. P ESCATORI

detumescence mechanism leading to an obstruction of venous outflow (Fig. 2). Rarely, initial impairment of venous outflow results from an obstruction of cavernous drainage outside of the cavernous bodies. Any penile and / or perineal compression whatever its origin (inflammation, infection, tumor, trauma...) of the pericavernous veins may slow down the cavernous venous outflow and potentially induces a veno-occlusive priapism during the occurrence of a physiological erection (nocturnal...).

I. INTRODUCTION Priapism is an involuntary, non physiologic, usually painful prolonged erection that does not result from sexual desire. The corpus spongiosum and glans are not affected. It is not relieved by ejaculation and may ironically result in impotence. Priapism is a rare condition that can occur in any age. In younger patients sickle cell disease is the most common cause, whereas in older men most priapism is due to intracavernous injection of vasoactive drugs [1].

However the most frequent initial impairment occurs within the corpora cavernosa by two main mechanisms: • Hematological changes of cavernous blood

II. CLASSIFICATION

Physiologically, during the rigidity phase, the cavernous venous outflow is reduced because anatomically the cavernous body acts like a kind of funnel for the venous outflow. If the viscosity of the intracavernous blood increases, the cavernous drainage will decrease at the same time. Thus, any disease increasing the blood hyperviscosity may provoke a veno-occlusive priapism by slowing down the cavernous venous outflow. The contraction of the smooth erectile tissue draining off the blood of the corpora cavernosa is present but inefficient.

Priapism may be defined as a pathological erection provoked by hemodynamic anomalies (Fig. 1) [2]. These anomalies may arise from several origins involving either the arterial or above all venoocclusive component. Thus, priapism is commonly classified as venous (low-flow or ischemic) and arterial (non-ischemic, high-flow). This hemodynamic definition eliminates the false priapisms, in particular, many of the malignant priapisms (the ”erection” is a priapistic appearance only due to an infiltration of penile tissue by the cancer without any hemodynamic anomalies).

The most typical cause is sickle cell anemia. The increase of the viscosity of the intracavernous blood results from the clotting of the intracavernous blood sickle red cells [3]. Hematological malignancies with hypercellularity (especially leukemia and thrombocytemia) and hyperlipidic parenteral nutrition are the main causes inducing priapism by the same mechanism [4].

1. VENOUS OR LOW-FLOW OR ISCHEMIC PRIAPISM a) Pathophysiology Venous priapism reflects a failure of the cavernous

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• Pathologic prolonged relaxation of cavernous smooth muscle

seriousness is directly correlated to both the severity of the obstruction and the duration of corpora cavernosa drainage blockage, themselves related to the priapistic etiology. In fact, the cavernous venous outflow blockage may be temporary or definitive, partial or complete. These changes depend on two parameters: Etiology of the priapism: In the case of ”hematological” priapism there is still a little venous outflow explaining a better prognosis. For this reason, the hematological priapism is often less dangerous. For example, the sickle cell priapism is often characterized by the occurrence of previous prolonged erections resolving frequently and spontaneously. Delay of developoment: The main danger of the low-flow priapism is the potential occurrence of an acute ischemia of cavernous bodies. For this major reason, it is a real urological emergency. It has been demonstrated in prolonged pharmacological erections that a cavernous hypoxia (mainly acidosis) begins after 4 hours and increases over 24 hours. With time, pO2 and pH of the trapped blood decrease reaching levels close to anoxia (p02 0-10 mmHg) and severe acidosis (pH about 6.6). Penile pain is a significant clinical symptom of tissue hypoxia [6]. Thus, a vicious physiopathological circle (Fig. 3) occurs self-maintaining the priapism that become autonomous. The hypoxia as well as the acidosis cause loss of the contractility of the cavernous smooth muscle impairing the venous stasis. At the

The vascular lacunar spaces cannot be emptied because the re-contraction of the cavernous smooth muscle tissue is absent preventing the de-activation of the veno-occlusive mechanism necessary for the drainage of blood from the cavernous bodies. Physiologically, it has been demonstrated that the erectile smooth muscle tissue recontraction is under both local (neuronal and endothelial) and spinal or central control. So, any impairment of the contractile ability of the smooth muscle cavernous tissue leads to a temporary or definitive ”paralysis” [2]. These muscular ”paralyses” resulting from several causes still are not completely understood. The most typical cause is the prolonged erection induced by intracavernous erectogenic drugs. Overdosage of the drug saturates the smooth myorelaxant receptors provoking a persistent smooth myorelaxation. The duration of the blockage depends on both the saturation of drug receptor and the drug’s pharmacological half-life. This smooth muscle paralysis likely results from several causes acting at the level of the erectile peripheral and central nervous centers either by stimulation of inductor centers or by inhibition of inhibitor centers whatever be the pathological stimulation (drug, hormonal, tumor, inflammation...) [5]. Venous priapism is the most common form of priapism and also the most dangerous because it is a real acute ischemia of the cavernous bodies. Its

Figure 1: Priapism hemodynamic definition

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Figure 2: Pathophysiology venous priapism, mechanisms of cavenous detumescence anomalies

Figure 3 : Pathophysiological mechanisms self-maintaining the venous priapism

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as idiopathic. The physiopathologic mechanisms of priapism allow to differentiate priapisms related either to hematological changes or to ”pathologic prolonged relaxation” of cavernous smooth muscle. However, the precise etiological diagnosis is still often difficult for three reasons:

Table 1: Main causes of venous priapism 1. HEMATOLOGICALCAUSES HEMATOLOGIC DISORDERS

sickle cell disease thrombocythemia leukemia erythrocytosis thalassemia fat emboli

IATROGENIC

hyperlipidic parenteral nutrition

MISCELLANEOUS

inflammation, infection, metabolic causes...

1) a ”trial-like” investigation is necessary, 2) a multifactorial etiology is a frequent condition for the initiation of priapism, exactly as for erectile insufficiency. Thus, the association of alcohol abuse, use of drugs and hemorrheological abnormal conditions are often present in patients suffering from priapism. The addition of these favoring factors appears as a stimulation factor.

2. PATHOLOGIC PROLONGED RELAXATION OF CAVERNOUS SMOOTH MUSLE DRUGS

3) many priapisms still must be classified as idiopathic in the absence of evident cause.

anticoagulant antihypertensive antidepressant psychotrophic androgen (testosterone) erectogenic (intracavernous injections and oral) alphablocker parasympathometics cocaine, alcohol

NEUROLOGIC DISORDERS

spinal cord lesions cauda equina compression autonomic neuropathy spinal stenosis

INFECTION OR TOSIX

rabies, scorpion sting,

• Causes of hematological priapism: Any pathological condition inducing a blood hyperviscosity may induce a venous priapism. The most classical and frequent cause in the world is sickle-cell disorder particularly in children. The most affected are the patients with homozygous forms who present in about 40 % of cases with previous recurrent prolonged erection phases lasting 2 to 6 hours. Hypercellularity conditions (as leukemia, thrombocytemia, thalassemia, erythrocytosis) fat emboli or hyperlipidic parenteral nutrition are other causes of hematological priapism.

malaria 3. IDIOPATHIC

• Causes of pathologic prolonged relaxation of cavernous smooth muscle: Presently, it is difficult to classify precisely the causes of this type of priapism. Many classical causes as neurological, iatrogenic, neoplastic, infectious, toxic, medications may induce this type of priapism by (spinal and / or central) stimulation of erectogenic centers and / or inhibition of antierectogenic centers. The most frequently accused drugs are antidepressants, antipsychotics (as clozapine), tranquilizers, antianxiety agents, psychotropics (as chlorpromazine), alpha-adrenergic blockers (as prazosin) and recreational drugs (as cocaine or alcohol) [7].

same time, histological changes occur with first edema of cavernous tissue, then after the 24th hour, necrosis of cavernous smooth muscle cells leading to a fibrosis responsible for impotence. For these reasons, after the 24th hour, the risk of autonomisation of the priapism becomes major even if the pathological stimulation stops. b) Causes Since the first report of a priapism by Callaway in 1824, a long list of its causes has been developed (Table 1). In the past many cases of priapism were classified

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The recent progress in our understanding of physiology has shown that any drug having the following pharmacological effect(s): alpha-adrenergic blockade, serotoninergic agonist, dopamine agonist, para-sympathetic agonist, may induce a priapism by central and / or peripheral action.

The frequently observed delayed clinical onset, following the offending event, has been hypothesized to be due to immediate vasospasm and platelet aggregation at the site of cavernosal artery laceration. During subsequent nocturnal or sexual erections, dilatation and stretching of the arterial wall might displace the unorganized clot and thus allow direct bleeding into the lacunar spaces, with the creation of a cavernosinusoidal fistula [8].

The most frequent and demonstrative the priapism is that induced by erectogenic drug used either by intracavernous (papaverine chlorydrate, prostaglandine E1, moxisylite, phentolamine...) or less often by oral route (trazodone, testosterone, sildenafil...). In most of the cases, the priapism results from an over-dosage or inadequate consideration of contraindications. Hormones as testosterone or gonadotropin-releasing hormone have also been incriminated, likely owing to their erectogenic action. The mechanisms of anticoagulants (heparin, coumarin) are still little known.

The perpetuation of the priapistic state has been proposed to rely on the generated shear stress from the continuous high inflow state that would release endothelium-derived factors, as nitric oxide and prostacyclin. These substances would act both by dilating the lacerated cavernosal artery and inhibiting platelet aggregation [8]. Few cases of high-flow priapism without evidence of cavernosal artery laceration, often developing after veno-occlusive low flow priapism refractory to conventional treatments, have been reported [6, 12-15]. This high-flow state characteristically responds to pudendal artery embolization. It has been recently proposed that these cases may represent either a variant of traumatic high flow priapism, or the pathophysiology of recurrent idiopathic priapism. According to the latter hypothesis, patients with veno-occlusive priapism in whom conservative treatment fail, should be considered in the differential diagnosis with high flow states [15], besides with recurrent low flow priapism as a sequel a of priapism [16].

Very likely, the blockage of the cavernous smooth muscle sponge may result from different origins (neurological, metabolic, inflammatory, traumatic...). For example, neurological conditions as lumbar stenosis, spinal cord injury or herniated discs probably either enhance the release of erection-inducing neurotransmitters from the parasympathetic nerves or interfere with tonic discharge from the sympathetic nervous system.

2. ARTERIAL OR HIGH-FLOW OR NONISCHEMIC PRIAPISM • Pathophysiology

3. RECURRENT PRIAPISM

Following a traumatic (or surgically induced) defect in the integrity of the cavernous artery, unregulated arterial inflow bypasses the protective, high resistant helicine arteries and enters the lacunar spaces directly. The lacunar spaces distend, but compression of the subtunical venous plexus against the tunica albuginea is incomplete, due to the absence of neurological stimulation. Therefore corporal venous outflow is not restricted, thereby preventing pooling of lacunar blood, obstruction of arterial inflow, ischemia, and pain to occuring. The net hemodynamic result is a high inflow, high outflow prolonged penile erection [8 -11].

Recurrent, chronic intermittent or stuttering priapism is defined as multiple, brief (less than 3 hour) episodes several times a week for 4 weeks or more. It is a rare condition that occurs often in patients with sickle trait of disease. Its mechanism is still unknown [17]. It is necessary to look for hemorrheological anomalies or pharmacological side-effect of drugs. Dysfunction of spinal or central mechanism are also likely partially responsible. This phenomenon has received almost no attention in the literature. Neither the prevalence, the ultimate outcome, nor its conversion rate to low-flow priapism is know.

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b) Trauma

III DIAGNOSIS

Trauma to the perineum is generally the cause of a high flow priapism. The traumatic event characteristically consists in a straddle injury producing perineal pain and hematoma: cavernous artery laceration results in fact from the crush-like injury between the object striking the perineum and the ischiopubic ramus. Less frequently intracavernosal self-injection needle injury and penile trauma have been reported. Of note, high flow priapism has been a frequent complication of early penile revascularization procedures, where the inferior epigastric artery was directly anastomosed to a window in the tunica albuginea [8, 10,13].

It is extremely important to distinguish low-flow priapism from high-flow. This is achieved by:

1. H ISTORY a) Drugs Drug use would account for up to 80 % of the incidents of priapism. Oral medication for hypertension, anti-depressant, anti-coagulants would be the main oral therapies associated with priapism [19, 44]. The anti-hypertensives probably cause priapism because of the alpha adrenergic blocking function. This may cause some relaxation of the smooth muscle of the cavernous tissue although this would not be the major route by which smooth muscle relaxation is normally achieved for normal erectile function [6].

c) Time factor The length of time of the priapism is important when low flow priapism is suspected. The ischemia of low flow priapism will cause replacement of intracavernosal smooth muscle with collagen tissue. This pathological change is directly related to the severity of erectile dysfunction [6]. d) Pain

Tricyclic anti-depressants are probably associated with priapism through an alpha-adrenergic blocking function acting peripherally. The phenothiazines may act centrally blocking the D1 receptor or again as an alphagrenergic blocking effect within the cavernous tissue [18].

Low-flow priapism is generally painful and therefore is a feature of the history to help establish the diagnosis. e) Quality of previous erection

Anticoagulants commonly used to maintain shunts in dialysis units provide a recognized source of priapism. The mechanism of the priapism is not known but certainly the use of low dose heparin has been recognized as an associated factor with the incidence of priapism [19].

This clearly has some prognostic importance in predicting the likely quality of erections following treatment of the presenting priapism. f) Malignancy

Social drugs (legal and illegal) have also been associated with priapism. Alcohol, marijuana and cocaine have all been associated with priapism. Again the mechanism of the priapism is not clear [6].

While this is a rare cause of priapism, primary tumors of the urethra and penis or metastatic tumors can cause obstruction of the venous outflow from the cavernous tissue and therefore establish a mechanism for low-flow priapism [21]. g) Hemoglobin abnormalities

The most common cause of prolonged erections is the use of intracavernosal injection therapy for erectile dysfunction. The incidence of prolonged erection is dose related as well as related to the specific agent injected. The problem is uncommon with prostaglandin injection but certainly is well recognized using papaverine and phentolamine. Such agents should be used with care when used for diagnostic purposes or when being injected into a patient suspected of psychogenic or neurogenic erectile dysfunction [20].

The importance of such abnormalities will vary in different parts of the world where there is a racial prejudice disposition to abnormalities such as sickle cell anemia and thalassemia. Sickle cell anemia is the most common cause of pediatric priapism. Hematological disorders all predispose to a low flow priapism. The hematological disorder causes white cell or platelet sludging in the sinusoids. Recurrent episodes of priapism have also been described in patients with hematological disorders.

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h) Metabolic diseases

Color-doppler ultrasonography has recently emerged as the mainstay diagnostic evaluation of high flow priapism, confining the role of selective internal pudendal arteriography to arterial priapism treatment, by means of selective embolization [11]. Arteriography shows a typical unilateral cavernous artery blush, consistent with extravasation of contrast material from the lacerated cavernous artery deep into the cavernosal erectile tissue (Fig. 5).

This is a rare cause of priapism but metabolic diseases associated or described in association with priapism include amyloidosis, gout, diabetes, nephrotic syndrome and renal failure [7].

2. EXAMINATION The degree of rigidity of the penis is important in differentiating high and low-flow priapism [12]. In general a low-flow priapism causes a hard erection but a normal corpus spongiosum so that the glans penis remains soft except in very rare cases of tricorporal priapism [22]. Tenderness and loss of elasticity of the penis are further points supporting the diagnosis of a low-flow priapism. In high-flow priapism the clinical picture is characterized by a spectrum of persistent erectile status, that ranges from tumescence to full erection, although the most common finding is a partial erection. If the erection is partial, it can be improved with sexual or manual stimulation, but it seldom reaches full rigidity. Invariably, the erection is painless and the glans is soft.

When compared to selective internal pudendal arteriography, color-doppler ultrasonography exhibits a 100 % sensitivity and a 73 % specificity [11]. Considering the unlikelihood that doppler ultrasound may record turbulence in the absence of block inflow through the lacerated cavernous artery, ultrasonography appears more accurate than arteriography in predicting arterial priapism [11].

3. INVESTIGATIONS a) Cavernosal blood Most important is the aspiration of cavernosal blood with blood gas analysis (if available). Dark hypoxic blood (p02 <30 mmHg and pCo2 >70 mmHg) suggests low flow and bright red, normal blood gases respectively suggests high-flow priapism [23]. b) Color doppler ultrasonography

Figure 4: Color-Doppler imaging in a patient with highflow priapism demonstrates the site of lesion

Doppler ultrasonography at 3 and 9 o’clock position detects strong pulsation of the cavernosal arteries [8], suggesting high-flow priapism (Fig. 4). The color-doppler probe must be placed in the perineum, i.e. in the typical location of the cavernous artery laceration. In the rare cases of laceration at the shaft level, the probe should be placed along the pendulous penis. The characteristic finding of color-doppler is the detection of a focal, pseudoaneurysmatic area of high flow turbulence, along the affected cavernous artery. The above findings of doppler ultrasound, corporal aspiration and blood gas analysis do not strictly rule out veno-occlusive priapism, as they are commonly found early in prolonged erections following intracavernosal pharmacological injections.

Figure 5: Selective internal pudendal arteriogram shows intracorporal contrast material extravasation arising from deep penile artery.

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Moreover, in the rare cases of high flow priapism without cavernosinusoidal fistula, color-doppler ultrasonography can detect the high flow states of the cavernosal arteries [15], where arteriography cannot. Color-doppler is presently the gold-standard also of follow-up, where it has been shown to be superior to clinical examination in detecting recurrence of the arteriosinusoidal fistula [11]. Moreover, after treatment by embolization with absorbable substances, color-doppler can document cavernosal artery recanalization, with return of antegrade flow. Further advantages of color-doppler over pudendal arteriography are given by absence of invasivity, easy repeatability, wide availability, and cost-effectiveness.

Table 2: Proven methods of using alpha adrenergic agents DRUG

PREPARATION

METHOD OFUSE

PHENYLEPHRINE (INJECTION)

10 mg = 1ml + 9 ml saline

Inject 0.2-0.4ml

or 6 mg = 0.6 ml + 30 ml Saline (-> 1 ml = 200 µg)

Inject 1 ml

ETILEFRINE (INJECTION)

10 mg = 1 ml + 9 ml Saline

Inject 2 ml

NOREPINEPHRINE (IRRIGATION)

1 ml 1:1000 in 1000 ml Saline

Aspirate, Inject 25 ml of solution

or 2 ml 1:1000 in 500 ml 5 % Dextrose

Inject 5 ml

IV. MEDICAL TREATMENT The injections may be repeated every 5 minutes up to a maximum number of 10 doses. During this treatment the blood pressure,pulse and detumescence of the penis should be monitored.

Prior to any therapy for priapism a detailed, informed consent that includes the fact that impotence is a known sequela of priapism regardless of treatment, read to the patient is mandatory with the patient or one of his relatives signing it with appropriate witness. Since approximately 50 % of patients develop some degree of erectile failure (regardless of the duration of priapism or mode of therapy [24], meticulous attention to this matter can prevent unnecessary medicolegal litigation.

Relative contraindications are heart block and bradycardia. Epinephrine, Norepinephrine and Metaraminol all have significant alpha 1 systemic activity and may cause hypertensive crises and pulmonary edema. Metaraminol has been responsible for two deaths and one case of necrosis of penile skin [7]. The effectiveness of oral drugs such as Terbutaline and Pseudoephedrine remains uncertain [25, 26].

1. VENOUS OR LOW-FLOW OR ISCHEMIC PRIAPISM

2. ARTERIAL OR HIGH-FLOW OR NONISCHEMIC PRIAPISM

Low-flow priapism should be treated urgently if normal erectile function is to be maintained. Initial treatment is to aspirate blood from the cavernous tissue ideally to achieve total detumescence. This can be aided by irrigating the cavernosal tissue with normal saline. This process should be repeated if the priapism recurs after initial aspiration/ irrigation. Failure to achieve persisting detumescence after the second treatment is an indication for using injected medication [12].

Ice packs and compression are the most conservative measure addressing arterial high flow priapism. They infrequently allow resolution of the priapistic state, but, being noninvasive, are nonetheless reasonable as initial attempts [10]. It has been recently reported that color-doppler guided compression, by ultrasound probe, of the flow in the pseudoaneurysm can achieve complete thrombosis of the pseudoaneurysmal cavity, with resulting detumescence [27, 28].

An alpha-adrenergic agent suitably diluted should be injected following the aspiration. Available agents differ around the world. Proven methods of using alpha-adrenergic agents are listed in table 2:

Intracavernosal blood aspirations and cavernosal irrigations with alpha-adrenoreceptor agonists,

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while highly effective in low flow priapism, reportedly induce only transient detumescence in cases of arterial priapism [9, 11, 13, 16]. These approaches, described in detail under treatments of the veno-occlusive forms, are all aimed, in fact, chiefly at improving corporal venous outflow, that in the high flow forms is already not restricted. The vasoconstriction, and the inhibition of shearstress induced nitric oxide (NO) relaxing effects, have therefore only a temporary effect on the damaged cavernosal artery, and accordingly cannot be recommended.

re be informed that watchful waiting is also an option, as outlined, below. • Watchful waiting. Transcatheter embolization of the bleeding artery, although presently the treatment of choice, carries nonetheless few drawbacks. A 66 % rate of recurrent arterial priapism, together with cases of permanent cavernous artery occlusion and persistent impotence [11], and one case of perineal abscess with persistent impotence [30], have been reported. At the same time, it should be noted that spontaneous healing of the injured vessel has been occasionally reported [10], and that non treated patients have retained partial and sometimes satisfactory sexual potency for years, despite the persistent painless erection [11]. Watchful waiting can therefore be included in the treatment approaches to high flow arterial priapism [10, 11], and thoroughly discussed with the patient, while considering that the best chances of successful treatment with transcatheter embolization by means of absorbable material, are within a month after the cavernous artery lesion.

• Selective internal pudendal arteriography with transcatheter temporary embolization by means of absorbable material (autologous clot ±gelatine sponge particals) of the bleeding artery [29] is presently the treatment of choice [8, 11], allowing an excellent rate of resolution (100 %) with immediate detumescence of the erect penis, and of restoration of erectile potency (86 %) [11] (Table 3). Table 3: Commonly used embolizing agents TEMPORORAY

PERMANENT

EMBOLIZATION

EMBOLIZATION

Autologous clot (lasting few hours)

Polyvinylic alcohol particles

Gelatine sponges (lasting 3-7 days)

i. Ivalon ™

i. Gellfoam ™

Surgical ligation of the neoarterial inflow source was the treatment of choice when high flow priapism, resulting from direct anastomosis of inferior epigastric artery to the tunica albuginea, occurred in early penile revascularization procedures. Internal pudendal artery ligation, and resection/ligation of lacerated cavernosal artery, has also been performed in posttraumatic arterial priapism [6, 10]. In such procedures the vascular pseudocapsule formed around the site of ruptured cavernous artery provides an important anatomical landmark for intraoperative localization [10]. This surgical approach is effective in resolving the priapistic state, but the permanent obliteration of the cavernous artery determinates an unacceptably high rate of postoperative impotence.

ii. Contour ™

ii. Spongostan ™

Acrilic glues

iii. Spongel ™

Ethanol

Should the cavernosinusoidal fistula recur, this procedure can be repeated. Temporary embolization nonetheless should be performed soon after the traumatic episode, ideally within a month, as endothelization of the cavernosinusoidal fistula may jeopardize fistula repair and closure, at absorbable material dissolution. In the event of fistula endothelization, the option of permanent embolization with non-absorbable agents may be considered, with the awareness that this approach carries with it the risk of irreversible changes in the erectile function, should the residual arterial supply of the contralateral cavernosal vessel not be adequate to allow rigidity. Patients should therefo-

Corporospongiosal shunting procedures are not indicated, since, again, the corporeal blood outflow is already adequate in arterial priapism [10].

3. RECURRENT PRIAPISM/PROLONGED ERECTION Initial management should be undertaken as soon as possible after presentation. A prolonged erection following intracavernosal injection therapy should

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be treated at 4 hours if the erection is persisting [31, 32]. Initial management would be to encourage exercise and use a cold shower. This should be followed by oral Pseudoephedrine 120 mg [25] but if this simple measure fails treatment should be as described for a spontaneous low flow priapism. The effectiveness of oral therapy to gain detumescence is approximately 30 % of pharmacologically induced priapism patients. Oral Terbutaline is not recommended in patients suffering diabetes, hypertension, hyperthyroidism or epilepsy [25].

to be considered in cases of nonischemic, highflow priapism. Surgery should be undertaken as soon as possible if priapism persists or recurs after initial successful medical treatment to prevent ultrastructural damage to the cavernous endothelium and smooth muscle, which could lead to erectile dysfunction [7]. Surgical intervention is indicated in ischemic priapism of more than 36 hours duration [1, 6]. Inherent in all shunt procedures is the concept that they are temporary with spontaneous closure occurring in the majority of cases once normal venous drainage patterns have been re-established. If after successful shunting, impotence persists secondary to veno-occlusive dysfunction a cavernosogram should be performed to look for continued shunt patency that can be surgically closed.

Conventional medical therapy of priapism secondary to sickle cell anemia has relied on a combination of hydration, analgesia and hypertransfusion [3]. The goal of intravenous fluid therapy is to inhibit sickling by decreasing tonicity and improving circulation. A fluid rate of three times maintenance is recommended. Blood transfusions and partial exchange transfusions are used to increase hemoglobin levels above 10 mg/dl and to decrease hemoglobin S to less than 30 %. Priapism in sickle cell anemia in the pediatric population should be treated medically if possible because of the high recurrence rate and because shunting procedure under general anesthesia in this age group are associated with an increased risk of cardiac and respiratory complications, which occasionally can be lethal [3, 33].

The simplest shunt between to corpus spongiosum and the corpora cavernosa was first described by Ebbehoj [37] and later modified by Winter [38]. These procedures are now one of the ”first line” shunt treatments used throughout the world. Following corporal irrigation, under local anesthesia using Ebberhoj’s technique, a narrow-blade scalpel is inserted through the glans dorsal to the meatus, avoiding the urethra, through the tunica albuginea and into the corpora cavernosa (Fig. 6).

Treatment of priapism with intracavernous injections of small amounts of alpha-agonists have been successful even in children. Intracavernous autoinjection of phenyllephrine has been recommended for early therapy in recurrent priapism [16]. Additionally, six patients with sickle cell anemia were treated with oral phenylpropanolamine, which reduced the frequency and duration of recurrences [34]. Antisickling agents, including diltiazem, a calcium-channel blocker, and pentoxifylline, a vasodilator and membrance liquidifier, may eventually play a preventative or therapeutic role in the management of sickle cell anemiainduced priapism [35, 36].

V SURGICAL TREATMENT Surgical shunting procedures should be considered if the presumptive diagnosis is ischemic priapism and if the medical therapy for ischemic priapism had failed. These shunting procedures are not

Figure 6: The distal end of the corporal body is pierced through the glans with a No. 11 blade. Both corpora caver nosa can be punctured using the same incision site on the glans. If a larger shunt is necessary the blade can be turned along its longitudinal axis.

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Multiple incisions are made by rotating the scalpel blade 90 degrees in each tunica albuginea of each corporal body to create multiple fistulas. The same entry site on the glans is used for all incisions. Winter’s procedure uses a Travenol Trucut biopsy needle to remove cores of tunica albuginea to create fistulous communications between the corpora cavernosa and the glans penis. During both proce dures the penis is mechanically compressed to remove all dark old blood and replace it with bright red blood. The glandular defect is closed with a figure of eight absorbable suture. The patient is instructed to squeeze and ”milk” the penis every few minutes. The procedure(s) can be done at the bedside and repeated in a few hours if needed.

blished by squeezing the penis, the openings are joined by two half-circles of running 5-0 absorbable suture (Fig. 7). Care is taken not to incise the urethra. If one shunt does not result in detumescence, a contralateral one can be performed but at a slightly different level to avoid tension on the suture line and to prevent stricture formation. No compression dressing is necessary. Along with Quackle’s procedure, the saphenous vein-corpus cavernosum shunt was described by Grayhack in 1964 [41]. A longitudinal ventral penile skin incision is made, exposing the tunica albuginea of the corpus cavernosum. Another incision is made medial to the ipsilateral femoral artery 3 to 4 cm below the inguinal ligament. The saphenous vein is exposed for 10 to 12 cm and detached proximally so it is long enough to reach the base of the penis. This isolated segment should maintain its attachment to the femoral vein. The saphenous vein is passed through a bluntly dissected subcutaneous tunnel connecting the thigh incision with the penile incision. An ellipse of the tunica, approximately 11/2 times the size of the lumen of the saphenous vein is excised. The corpus is irrigated to obtain bright red blood and an end-to-side anastomosis is created between the spatulated saphenous vein and corpus cavernosum using a 5-0 nonabsorbable suture (Fig. 8).

Another method of creating a glans-cavernosum shunt is the Al Ghorab procedure [39]. This procedure done under direct vision creates larger shunts. The glans is incised semicircularly on the dorsum at the coronal level and the tips of the distal corpora cavernosa are exposed. A circular core of tissue 5 mm in diameter is excised from each corpora to create a cavernous-glandular shunt. The penis is squeezed until bright red blood is seen and the glans is resutured to the penis with absorbable suture. It is crucially important not to damage the dorsal neurovascular bundle to prevent hypoaesthesia of the glans and distal penis. Intermittent compression with a pediatric blood pressure cuff can be applied to the penis for the first 24 hours post-operatively.

One of the major dilemmas of treating priapism is the frequent recurrence after intervention. Before any surgical procedure for priapism can be considered successful, the intracorporeal blood pressure must remain lower than 40 mmHg for more than 10 minutes. If the pressure rises above 40 mmHg after several minutes, recurrence is likely and larger shunts are needed. Severe edema and induration of the corpora frequently are observed for several days after shunting. The best way to differentiate post-operative edema from recurrence is to measure intracavernous blood gases. Normal values indicate tissue edema rather than recurrent priapism.

If a corporal-glandular shunt is not successful, the next simplest and highly successful procedure is the construction of a formal shunt or communication between the cavernosa and spongiosal systems. The principle is to utilize the thickest portion of the corpus spongiosum to avoid a urethral fistula and this implies performing the shunt as proximally as possible. The prototype of this procedure was described by Quackles in 1964 [40]. This procedure is performed in an operating room usually utilizing general anesthesia. The skin incision may be perineal, transverse scrotal or penoscrotal. Following the skin incision, the corpus spongiosum and the corpus cavernosum are isolated for a distance of at least 3 cm. A Foley catheter is utilized to help localize the urethra. Windows of tissue of approximately 1 cm are removed from both structures and once bright red corporal bleeding is esta-

Circular compressive dressings should be avoided. After a shunting procedure, the dorsal veins and the corpus spongiosum temporarily become the major drainage routes. These types of dressings may compromise the venous return, trigger recurrence, or even cause necrosis of the penile skin and glans penis. To prevent infection of ischemic

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Figure 8: Cavernososaphenous shunt: The saphenous vein is divided, drawn through a skin tunnel and anastomosed using a 5-0 arterial suture. Care must be taken to avoid kin king of the vein.

Figure 7: Cavernosospongiosum shunt

Figure 9: Management of priapism : algorithm

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tissue, perioperative antibiotics are recommended. Urethral catheters should be removed as soon as possible and avoided in cavernosum-spongiosum shunt procedures.

intracaverneuses de drogues dans les dyserections. Leur interet clinique a propos de 100 cas. J Urol (Paris); 1987; 93: 547 – 548.

Complications associates with surgical shunting for ischemic priapism are unusual. Early complication includes recurrence of priapism, bleeding, infection, skin necrosis, abscess, cellulitis, gangrene, urethral damage, urethro-cutaneous or urethrocavernous fistulas, urethral stricture and pulmonary embolism [7]. Late complications include fibrosis of vascular spaces and failure of venous shunt to close spontaneously leading to erectile dysfunction. Corporal fibrosis and scarring may be extensive and not permit intracavernosal pharmacological injections or penile vacuum devices, to be effective therapies. In these patients the implantation of a penile prothesis, either semirigid rods or an inflatable device remains the only treatment option available to allow for sexual function [42, 43]. Penile implants should not be implanted into the patient at the initial hospitalization of surgical shunting procedures. The patient should be given a time period to see if he will have return of any penile activity and should be given the options of penile vacuum device or penile injection prior to determining if the prosthesis should be inserted. If implants are placed at the same time of the initial shunting procedures, distal erosion through the tunica would be very risky while the risk of infection would be very high secondary to this device being implanted in poorly vascularized tissue.

6.

HAURI D, SPYCHER M, BRÜHLMANN W: Erection and priapism: A new physiopathological concept. Urol Int; 1983; 38: 138 – 145.

7.

STACKL W, MEE SL: Priapism. In Krane RJ, Siroky MB, Fitzpatrick JM (ads): Clinical Urology; JB Lippincott Company, Philadelphia; 1994; 1245 – 1258.

8.

WITT MA, GOLDSTEIN I, SAENZ DE TEJADA, GREENFIELD A, KRANE RK: Traumatic laceration of intracavernosal arteries: the pathophysiology of nonischemic, high-flow, arterial priapism. J Urol; 1990; 143: 129 – 132.

9.

RICCIARDI RJ, BHATT GM, CYNAMON J, BAKAL CW, MELMAN A: Delayed high-flow priapism: pathophysiology and management. J Urol; 1993; 149: 119 – 121.

10. BROCK G, BREZAJ, LUE TF, TANAGHO EA: Highflow priapism: a spectrum of disease. J Urol; 1993; 150: 968 – 971. 11. HAKIM LS, KULAKSIZOGLU H, MULLIGAN R, GREENFIELD A, GOLDSTEIN I: Evolving concepts in the diagonsis and treatment of arterial high-flow priapism. J Urol; 1996; 155: 541 – 548. 12. LUE TF, HELLSTROM WJG, MCANINCH JW, TANAGHO EA: Priapism: a refined approach to diagnosis and treatment. J Urol; 1986; 136: 104 – 108. 13. STEERS WD, SELBY JB Jr: Use of methylene blue and selective embolization of the pudendal artery for highflow priapism refractory to medical and surgical treatments. J Urol; 1991; 146: 1361 – 1363. 14. RAMOS CE, PARK JS, RITCHEYML, BENSON GS: High-flow priapism associated with sickle cell disease. J Urol; 1995; 153: 1619 – 1621

Management strategy is summarized by the algorithm Fig. 9

15. SEFTEL AD, HAAS CA, BROWN SL; HERBENER TE, SANDS M, LIPUMA J: High-flow priapism complicating veno-occlusive priapism: pathophysiology of recurrent idiopathic priapism?. J Urol; 1998; 159: 1300 –1301.

REFERENCES

16. LEVINE JF, SAENZ DE TEJADA I, PAYTON TR, GOLDSTEIN I: Recurrent prolonged erections and priapism as a sequela of priapism: pathophysiology and management. J Urol; 1991; 145: 764 – 767.

1.

WINTER CC, MCDOWELL G: Experience with 105 patients with priapism: Update review of all aspects. J. Urol; 1988; 140: 980 – 983.

2.

BONDIL P: Aspects physiopathologiques du priapisme: maladie ou symptome?. J. Urol; 1990 (Paris): 96: 115 – 118.

17. SERJEANT GR, DE CEULAER K, MAUDE GH: Stilboestrol and stuttering priapism in homozygous sickle cell disease. Lancet; 1985; 2: 1274 – 1276.

3.

TARRY WF, DUCKETT JW, SNYDER HM: Urological complications of sickle cell disease in a pediatric population. J. Urol; 1987; 138: 592 – 594.

4.

EKSTRÖM B, OLSSON AM: Priapism in patients treated with total parenteral nutrition. Br J Urol; 1987; 59: 170 – 171.

18. THAVUNDAYIL JX, HAMBALEK R, KIN NM: Prolonged penile erections induced by hydroxyzine: possible mechanism of action. Neuropsychobiology; 1994; 30: 4-6.

5.

19. ADJIMAN S, FAVA P, BITKER MO: Heparin-induced priapism: a more serious prognosis. Ann Urol; 1988; 22: 125 – 126.

BONDIL P, RIGOT JM, MAZEMAN E: Les injections

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20. JÜNEMANN KP, ALKEN P: Pharmacotherapy of erectile dysfunction: a review. Int J Impotence Res; 1989; 1: 71 – 93.

function: a model for ischemic priapism. J Urol; 1994; 151: 259 – 262. 33. SEELER RA: Intensive transfusion therapy for priapism in boys with sickle cell anemia. J Urol; 1973; 110 : 360– 363.

21. PUPPO P, PERACHINO M, RICCIOTTI G, VITALIA: Malignant priapism due to a huge renal carcinoma. Eur Urol; 1992; 21: 169 – 171.

34. 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.

22. SHARPSTEEN JR JR, POWARS D, JOHNSON C: Multisystem damage associated with tricorporal priapism in sicke cell disease. Am J Med; 1993; 94: 289 – 295. 23. LUE TF, MCANNINCH JW. PRIAPISM: IN: TANAGHO EA, LUE TF, MCCLURE RD, eds. Contemporary management of imptence and infertility. Baltimore, Hong Kong, London, Sidney, Williams and Wilkins; 1988: 201 – 210.

35. WEINTRAUB M, ONUNZU M: Inhibition of in vitro sickling by diltiazem. Clin Pharmacol Ther; 1984; 35: 281 – 282. 36. AMBRUS JL, MEKY N, STADLER S, SILLS RH, GASTPAR H, RAPOSA T: Studies on the vasoocclusive crisis of sickle cell disease. IV Mechanism of action of pentoxifylline (Trental). J Med.; 1988; 19: 67 – 72.

24. MELMAN A: Impotence secondary to priapism. In Current Urologic Therapy. Edited by Joseph Kaufman. Philadelphia: WB Sanders co: 1994; 1245 – 1258.

37. EBBEHOJ J: A new operation for priapism. Cand J Plast Reconstr Surg; 1975; 8: 241 – 242.

25. LOWE FC, JAROW JP: Placebo-controlled Study of oral Terbutaline and Pseudoephedrine in management of Prostaglandin E1-induced prolonged erection. Urology; 1993; 42: 51 – 54.

38. WINTER CC: Priapism cured by creation of fistulas between glans penis and corpora cavernosa. J Urol; 1978; 119: 227 – 228.

26. GOVIER FE, JONSSON E, KRAMER LEVIEN D: Oral Terbutaline for treatment of priapism. J Urol; 1994; 151: 877 – 879.

39. ERCOLE CJJ, PONTES JE, PIERCE JM: Changing surgical soncents in the treatment of priapism. J Urol; 1981; 125: 210 – 211.

27. MABJEESH NH, CHEMESH D, ABRAMOWITZ HB: Posttraumatic high-flow priapism: successful management using duplex guided compression. J. Urol; 1999; 161: 215 – 216.

40. QUACKLES R: Cure d’un cas de priapisme par anastomose cavernospongieuse. Acta Urol Belg; 1964; 32: 5 – 13. 41. GRAYHACK JT, MCCULLOGH W, O’CONNOR VJ JR, TRIPPEl O: Venous bypass to control priapism. Invest Urol; 1964; 1: 509 – 513.

28. BASTUBAMD, SAENZ DE TEJADAI, DINLENI CZ, SARAZEN A, KRANE RJ, GOLDSTEIN I: Arterial priapism: diagnosis and long term follow up. J Urol; 1994; 151: 1231 – 1237.

42. PRYOR JP: Management of priapism. Current Opinion in Urology; 1994; 4: 343 – 345.

29. WEAR JB JR, CRUMMYAB, MUNSON BO: A new approach to the treatment of priapism. J Urol; 1976; 117: 252 – 254.

43. KNOLLLD: Use of penile prostetic implants in patients with penile fibrosis. Urol Clin North Amer; WB Saunders 22 (4); 1995; 857 – 863.

30. SANDOCK DS, SEFTEL AD, HERBENER TE, GOLDSTEIN I; Green field AJ: Perineal abscess after embolization for high-flow priapism. Urology; 1996; 48: 308 – 311.

44. BANOS JE, BOSCH F, FARRE M. Drug-induced priapism: Its etiology, incidence and treatment. Medical toxicology 1989;4:46.

31. BRODERICK GA, HARKAWAY R: Pharmacologic erection: time dependent changes in the corporal environment. Int J Impot Res; 1994; 6: 9 – 16. 32. BRODERICK GA, GORDON D, HYPOLITE J, LEVIN RM: Anoxia and corporal smooth muscle dys-

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Committee 16

Socio-Cultural, Educational and Ethical Aspects of Erectile Dysfunction

Chairman A. MORALES

Members H. CHOI, A. GIAMI, C. GINGELL, B. JOHNSTON, W. PASINI, L. VELA-RODRIGUEZ, C. SAMKANGE, A. SCHMIDT, F. UGARTE, G. WILLIAMS

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CONTENTS

PREAMBLE

II. EDUCATIONAL AND ETHICAL ASPECTS

I. SOCIO-CULTURAL CONSIDERATIONS

1. INTRODUCTION

2. MATERIALS AND METHODS 1. INTRODUCTION

3. FINDINGS

2. METHODS

4. DISCUSION

3. FINDINGS

5. PUBLIC EDUCATION 6. RECOMMENDATIONS

4. DISCUSSION 5. RECOMMENDATIONS

REFERENCES

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Socio-Cultural, Educational and Ethical Aspects of Erectile Dysfunction A. MORALES, H. CHOI, A. GIAMI, C. GINGELL, B. JOHNSTON, W. PASINI, L. VELA-RODRIGUEZ, C. SAMKANGE, A. SCHMIDT, F. UGARTE, G. WILLIAMS

PREAMBLE The First Consultation on Erectile Dysfunction initially included two separate committees: Sociocultural Aspects and Ethics and Education. Subsequent consideration resulted in the amalgamation of the works of the two committees. This was an appropriate decision when consideration is given to the heterogeneity in cultural and professional backgrounds of the Committee’s membership that, unavoidably resulted in divergent points of view. This report comprises two separate sections, each one addressing, independently, specific aspects related to male erectile dysfunction (ED)

Figure 1: United Nations projections of the world population from the end to the 21st. century to the middle of the 22nd.

I. SOCIO-CULTURAL CONSIDERATIONS 1. INTRODUCTION Over the last 50 years the world population has increased rapidly. Just 25 years ago there were 4 billions humans while the number is projected to double to more than 8 billions by the year 2025 (Figure 1). More important, however, is the phenomenon of the aging of humanity. Figure 2 shows the projections from the United Nations [1] for the old (>65 years) and old-old (> 85 years) population between 1950 and 2050. These demographic changes are very relevant in the context of the socio-cultural aspects of ED. It is well recognized that ED is not the result of aging but associated with many conditions (i.e. diabetes, atherosclero-

Figure 2: The United Nations estimate a significant decline in the under 15 year-old population in the period 19502050. The older population (>65 years) will continue to increase during the same period. The effects of aging in sexual function will translate in an increasing demands for services by an aging humanity.

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sis) frequently developing in aging men. The extent of the health issues related to aging have not been defined completely but, population projections clearly indicate that health problems related specifically with aging will increase significantly over the next 25 years.

2. METHODS The Committee found a scarcity of valid documentation on the subjects assigned to it. Due to financial and temporal constraints, a properly designed and validated population survey was not considered feasible. The Committee is fully aware of the limitations of an opinion survey and wishes to emphasize that the results shown here only represent a majority view of the Committee members and the literature, as indicated in the text.

The overwhelming majority of investigators have reported the mean age of patients consulting for ED to be about 55 years. At this stage in life there is a conjunction of conditions which alone or in combination may be responsible or may contribute to the establishment or perpetuation of erectile difficulties. Health care professionals in general, and urologists in particular, need to look at the middle age and elderly man as person with more than a specific complaint such as lower urinary tract obstructive symptoms, but at other manifestations of aging (loss of libido, tiredness, depression). It is imperative that quality of life issues are proactively sought out. In this context, adequate sexual function is an important item in many societies. As indicated in the section on Ethics and Education, there is a dismal performance by medical and nursing schools curricula throughout the world in sexual education. The majority of the world population has very limited factual information on sexual health issues and, almost universally, government agencies either ignore the topic or neglect it in favor of, what is perceived, as more important health concerns. However, a recent publication (2) reporting one the few populationbased assessments of sexual dysfunction in 50 years indicated that “sexual dysfunction remains a largely uninvestigated yet significant health problem”. Unfortunately, the perception by government agencies [3] and the public is that sexual dysfunctions in general and ED specifically are not particularly important health issues. The problem is further complicated by the cost of currently available treatments and their limited availability to all sectors of a community.

The Committee members responded to a short survey related to socio-cultural issues with the answers specifically focused on the region of the responder. The survey provided the basis for further discussion at the three preparatory meetings and a consensus for the submisson of the written report. This material was supplemented by comments from opinion leaders strategically located around the world because many distinctive regions (i.e. Middle-East, Asia-Pacific) had limited or no representation on the Committee. It was also deemed necessary to perform a limited review of the literature. For purposes of reporting and due to the socio-cultural diversity, greatly magnified in the area of ED, it was considered appropriate to divided the world following the geographical distribution of the 5 regional societies with a mandate to promote the investigation and treatment of ED and who are affiliates of the International Society for Impotence Research (ISIR): 1. Society for the Study on Impotence (United States and Canada); 2. Sociedad Latinoamericana de Impotencia (all Ibero-American countries from Mexico to Argentina); 3. Asia-Pacific Society for Impotence Research; 4. European Society for Impotence Research and 5. African Society for Impotence Research. It is clear that within these very large regions there are enormous social and cultural differences. Therefore, the Committee, chose information available from 2 or 3 representative countries in the region in assessing the socio-cultural aspects of the whole region and by a review of the pertinent literature. The Committee relied primarily on the voluminous International Encyclopedia of Sexuality.

The complexity of socio-cultural aspects of ED are clearly illustrated in the findings of high incidence of psychological and social causes of the condition among young men and men in the lower economic stratus [2]. These, are the ones with the less ability to attract the interest of health authorities, particularly in issues of sexual dysfunction.

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3. FINDINGS

most societies, it is clear that the perception of its importance is changing. Figure 3 shows that, according to the responders, in the majority of societies the public considers it a medical problem but only a small minority discusses it freely while a larger proportion considers the topic banned from open discussion. It was anticipated and reiterated by the survey that no one would consider ED at the same level of relevance as other common medical conditions (i.e. cancer, cardio-vascular disease). On the other hand, it is evident that the population is not indifferent to the issues related to ED (Figure 4). The responses indicate that, in most regions, the public is aware of ED as a common condition but either has limited knowledge or gives it a low priority in favor of more pressing health issues. These findings are consistent with attitude of the health authorities (Figure 5): a large proportion of them ignore ED or recognizes it as a health issue; but, like the constituency they serve, do not take a proactive attitude towards its treatment. No one felt that these authorities are interested in supporting investigation and treatment of ED. In regions with a relatively homogeneous religious orientation, it is evident that ED has not caught the interest of the religious leadership (Figure 6). The last 3 questions of the survey focused on the medical aspects of ED. Most patients affected by erectile problems initially seek a variety of treatments ranging from non-medical healers to conventional medical advice; the survey did not ask if the healers use non-medical methods, but it was assumed that this was the case (Figure 7). The low profile of the medical profession in the treatment of ED is confirmed by the limited number of scientific societies actively involved in promoting increased knowledge and understanding of ED. The largest proportion (67%) indicated that such societies either do not exist or if present they were largely ineffective (Figure 8). The absence or irrelevance of medical societies in the field of ED are a faithful reflection of the feelings and attitudes of health authorities and health professionals. Figure 9 indicates that the majority of health professionals feel that the issue of male sexual dysfunction is either irrelevant or should take a low priority position in favor of more important health problems. In this regard, the appearance of easy to use, effective, safe and readily available treatments (e.g. sildenafil) has created new sociomedical dimensions which have not yet been

a) The committee There are evident divergent and, occasionally conflicting perceptions on ED among health care professionals. Medical sociology and medical anthropology make a clear distinction between disease and illness. Disease represents the condition as it is defined as perceived by physicians and scientists, while illness represents it as it is perceived by the sufferer and defined and perceived by common sense and lay knowledge [4]. This view is eminently applicable to the concept of ED and provides an explanation for the misunderstandings that can, and frequently develop between the patient and the health provider. The potential for patient-health provider difficulties can be further magnified in trans-cultural situations within the same social universe. The differences among concepts have a profound effects in communication between health professionals and their clients. The currently predominant approach for the management of a man complaining of impotence (a term still firmly grounded in sociology and anthropology) follows the medical model in which a set of investigations and treatments are carried out. The model is presented in several previous chapters of this volume. Taken to its therapeutic extreme (insertion of a penile prosthesis), this approach would invariably result in “success”: resolution of the man’s inability to accomplish vaginal penetration. What this approach does not answer is the patient’s feelings of humiliation, loss of self-esteem, shame, marital discord and so on. As it will be discussed below, the medical model is frequently successful in resolving the erectile problems. The constellation of other issues associated with the condition are not so easily solvable. There are enormous socioeconomic, cultural, educational and professional difficulties that need to be addressed in order to provide adequate global care to the couple affected by sexual inadequacy. The Committee is not optimistic about a resolution of those issues in the forseeable future, even in advanced societies. b) Results of a survey The survey completed by the Committee and other individuals working in the field showed different insights among various regions of the world. Although ED is a topic not openly discussed in

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Figure 3: At the end of the millenium the topic of ED is most often a guarded secret. Attitudes in this regard, however, are changing due, in part to the availability of simple and effective treatments.

Figure 4: The public does not consider ED an important condition. This is an interesting dichotomy since the demand for information on the topic is large. As expected, other health concerns (cancer, cardiovascular) are considered more significant.

Figure 5: Health authorities appear to be overwhelmed with other issues and devote little attention to the topic of ED.

Figure 6: Similarly to health authorities, the different religious leaderships tend to ignore the relevance and impact of ED in every day’s life.

Figure 7: Almost universally, friends and relatives are initially consulted by those affected with ED. Traditional medicine is the preferred approach in less advanced societies. A combination of allopathic and traditional approaches is used in most regions of the world.

Figure 8: Most medical communities consider ED as a low priority among the medical conditions. The relevance and impact of ED in the quality of life has been underestimated by health professionals.

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1 NORTH AMERICA. This region probably offers the most abundant cultural diversity and a large number of publications on sexuality. It has long been recognized that sexual dysfunctions cover the entire range regardless of the racial or cultural origin of the patients. Very recently an encyclopedic publication proclaiming to promote “understanding our (American) sexual values and behavior” covered a large number of aspects of human sexuality. It correctly indicated that most of the “research has been conducted with samples of white, middle-class clients”. It further indicated that minority groups generally lack either the confidence or the financial resources to seek therapy [6]. To complicate matters, therapy generally is offered by Anglo-American professionals. Therefore, culturally appropriate counseling and therapy appears to be largely inaccessible for minority groups in the American scene. Slowinski and Stayton [7] lament on the “medicalization” of sex therapy. This medicalization is also lamented by Francoeur [8] who specifically refers to the use of phosphodiesterase inhibitors in the treatment of ED. These points of view by authors with the same professional background are somewhat difficult to reconcile: they believe that sexual counseling demands socio-cultural sensitivity but they also recognize that such therapists are very scarce. The counter-point of these views, of course, is that therapy of ED is in most cases, primarily a medical problem, affordably and successfully treated by medical means [9, 10]. In addition, ED is culturally generic [11]. It appears that the so called “medicalization” of sex therapy is not only unavoidable but desirable [1]. This in no way implies that the resolution of erectile difficulties would in every instance overcome marital or emotional problems. Germane to this point is a recent Canadian study which showed that the vast majority of patients seeking treatment for ED are not interested in counseling nor are their partners willing to participate in it [12]. This observation is relevant because the refusal to accept counseling was not related to financial issues since the group of patients in the study all had access to free counseling but not to medical treatment: despite the cost, patients were only interested in recovering their ability for vaginal penetration (the study was conducted in the pre-sildenafil era). Evidently this is a fairly common universal occurrence as “professionals can become fixated on this (the penis)

Figure 9: The limited interest by health care providers is reflected in the scarcity and ineffectiveness of professional societies dealing with sexual inadequacy.

settled and are incompletely understood. Suffice it to say that medicine is currently faced with a new situation in which the therapy of “real” disease is in tension with the availability of increasing number of highly successful treatments that are perceived as simply aimed at improving quality of life. Pharmacological management of ED falls in the gray zone between the treatment of a medical condition and the enhancement of quality of life. c) The literature As mentioned before, the population projections clearly point to an aging of all societies in a global pattern. It is evident, therefore, that over the next 25 years there will be an increased demand for services related to sexual dysfunction which is clearly related to the aging process, although not its unavoidable consequence [5]. The literature is remarkably sparse in the specific area of sociocultural aspects of erectile dysfunction. A PubMed search found < 30 articles on the subject and the majority were irrelevant to the objectives set out by the Committee. On the other hand, there is a very voluminous body of literature on the topic of general sexuality, sexual behaviors including prostitution, homosexuality and paraphilias. The basic and clinical sciences dealing specifically with ED currently enjoy a great deal of attention, not so the socio-cultural aspects. This appears to be a fairly universal situation and no region in particular is an exception, although changing trends are becoming apparent. In other words, publishing on ED is a rapidly expanding field, particularly on its physiological mechanisms and diagnostic and therapeutic aspects but with very little research available on trans-cultural issues. 579

organ as their patients and forget that it has a multiplicity of connections within the man’s mind and body- and, indeed, outside it” [13]. The study, however, did not address ethno-cultural issues. Many of the American situations can be easily accommodated into a Canadian context and vice versa. There are however, cultural and social differences: the American society has been likened to a melting pot of cultural diversity in which cultures are rapidly assimilated. A cultural mosaic best described the Canadian situation where different cultures form part of the whole but maintain a clear identity. Despite these possible differences, it is difficult to identify significant cultural differences among the causes or the results to therapy of ED in North America regardless of social or cultural background. In both countries numerous studies have been conducted on ethno-cultural variations of sexual attitudes and behaviors. The Committee was unable to identify any studies on differences in the specific area of ED. Whether this simply reflects the view that, from the purely medical point of view, there are no relevant sociocultural issues remains to be investigated.

based on myths, rituals and magic. This cultural dichotomy is repeated with only small differences among the various societies of the region. At the northern end of the area (Mexico) there is a similar situation although the isolation of rural and native societies is much less marked than in Central American and other South American Countries like Colombia, Peru and Venezuela. In all these countries there are two sources of cultural values: the European Catholic influence and the native beliefs that existed in the region prior to the European colonization. They co-exist to the present. Factual, physiologically based concepts about ED have become popularized only very recently, primarily through the lay media. Contemporary treatment is available to only a limited segment of society. There is still a pervading reluctance for men to seek medical advice for erectile problems. 3 ASIA-PACIFIC According to Hatano and Shimazaki [15] ED is the most common of the sexual dysfunctions reported in Japan. As in other countries in the region, the topic is not discussed freely but the availability of new therapies has created pressure to a more open discussion of ED. In a long chapter devoted to sexuality in China [16], the Encyclopedia devotes only a short paragraph to sexual dysfunction. It only indicates that “20 percent of China’s adult male population” suffers from sexual dysfunction but fails to mention the incidence of ED. In India, in addition to well developed understanding and practice of Western-type concepts on ED, there are also specific Hindu and Moslem beliefs. The Ayurvedic medicine is still widely practiced not only in the sub-continent but also by Indian expatriates [17]. It is interesting that practitioners of Ayurvedic and Unani medicine (in a behavior similar to some of their Western counterparts) make exaggerated claims on treatments based on modern medical approaches. These claims are advertised in the popular press [18].

2 IBERO-AMERICA Argentina appears to be a microcosm of the urban centers in the region. Although the public is interested in knowing more about available treatments for ED, until recently there was very limited expertise available. “When people come for advise on sexual problems -like frigidity, impotence, fast ejaculation, painful sex, sex during pregnancy, sex among the aging, etc.- gynecologists, obstetricians, urologists and general practitioners find that they all are confused” [14]. The same author, however, indicates that evaluation of dysfunctions such as impotence and premature ejaculation follow the approach of Masters and Johnson and Singer-Kaplan and complains that “unfortunately few urologists and gynecologists are informed or prepared to assist in these type of problems". These views are not shared by urologists in the region which enjoys active research and modern diagnostic and therapeutic practices in dealing with ED. In neighboring Brazil a very similar condition exists in the larger cities where there is abundant reliable information, modern treatment and research on ED. However, the situation among aboriginals is completely different where much of the understanding and treatment of male sexual dysfunction is

4 EUROPE Although distinct European societies are very easily identifiable, it is extremely difficult to establish ethno-cultural variations in the region when addressing the issues of ED. As advanced societies, the Europeans enjoy a great deal of sophistication in the understanding of the pathophysiology of erectile problems and as a consequence

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5 AFRICA AND THE MIDDLE EAST

maintain a leadership position on its treatment. European societies rely primarily on a medical focus for treatment of ED. Modern treatments are readily available. The International Encyclopedia of Sexuality (p. 516), in dealing with sexual dysfunctions in Germany, speculates that in the eastern part of the country “men suffer in particular from mental problems connected with sexual competence, sexual performance, their own attractiveness, and frustration in love and sex”. There is no mention at all of ED and no references are provided for these opinions. The same Encyclopedia in dealing with The Netherlands simply puts forward unsupported views regarding the acceptability of treatment by Dutch men (p. 956). The comments for Spain in the same publication are equally unhelpful when searching for the areas of interest to this Committee. It is likely that the opinions provided for the United Kingdom are applicable to the rest of western Europe: British society appears to be having a reemergence of sexual awareness. After a very conservative attitude towards sex in the first half of the century, there was an awakening in the 1960s…. One area where this has become particularly evident is male erectile disorder, for which a proliferation of treatment centers, both within the health service and in the private sector has developed” [19]. Preliminary information from a French survey on sexology as a profession indicates that 60% of sexologists are physicians [20]. This survey also indicates that, most commonly, French sexologists employ various approaches of psychotherapy (including sexotherapy, behavioral, cognitive, psychodynamic and medical relaxation). However, on occasion psychotherapy is used together with pharmacotherapy. A French working party on the treatments of ED concluded that “In all cases the degree of ED as it is experienced by the subject results from his suffering and is not directly dependent on the etiology. The evaluation of the degree of severity is grounded on the evaluation of the subjective suffering felt by the subject and eventually by his partner”[21]. In a more general way, the results of the Committee’s survey is confirmed by a survey on diagnostic attitudes and treatments of impotence that was carried out in six European countries. It concluded that there was a lack of interest regarding ED among health care professionals [22].

This region offers impossible tasks in an attempt to summarize the socio-cultural aspects of ED. The differences between countries in the region are enormous. For instance, in Ghana where polygyny was desirable and currently socially accepted, ED is seen with suspicion and is socially frowned upon. On the other hand, Ankomah [23] reports that infertility takes priority on sexual problems. Probably its management applies equally to ED: “Traditional healers in Ghana, while conceding the superiority of Western biomedical medicine for certain diseases insists that infertility and sexually transmitted diseases are more effectively treated by traditional than modern medicine. The secret and highly confidential nature of their practice makes traditional medicine men, herbalists, Mallams, fetish priests, and others the main source of treatment”. At the other end of the spectrum in Israel ED is seen more from the European or North American perspective. In Iran, it is reported by Drew : “Counseling in all marital matters is strictly a family affair. There is strong taboo against discussing family problems of any kind with a non-family member… Iran is thus not very fertile ground for any kind of psychotherapy” [24]. Whether this unsupported opinion applies to ED, could not be determined reliably by the Committee. The Committee felt that South Africa is worth noting because its diversity in socio-cultural groups. In this country there is an interesting coexistence of so-called third, second and first world socio-cultural conditions. In many ways, therefore, South Africa is representative of the issues related to erectile dysfunction in other parts of the world. In rural areas wives and children perform a great deal of work. The males exhibit a high sexual drive and performance. ED in these communities is, primarily related to the inability to achieve multiple orgasms per night. The majority of cases of impotence are treated by traditional healers with herbal preparations. Primary care physicians treat them with androgens and vitamins. In more advanced, “second world” areas, extensive changes have been introduced by Christian missionaries and other immigrants. In these societies, ED is rarely discussed openly and is considered only of procreative importance. Here, again a good number are treated, inappropriately, by traditional healers or by primary care physicians with vitamins and androgens. In the

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a more scientific approach. In reality, there are no major surprises when the different views were compiled or through discussions at the 3 separate meetings of the Committee members (unfortunately, not all members were pressent at all meetings). It was felt that the public perception of ED is that, for the most part, it does not constitute a major health concern. While a small number (20%) felt that the topic was kept under wraps in their social environment, the large majority (65%) estimated that ED is simply not discussed openly. This is somewhat surprising in western societies where there has been an overwhelming amount of discussion in the spoken and written press. Notably none of the responders felt that sexual dysfunctions are perceived as a topic to be discussed as freely as any other medical conditions (e.g. heart disease, diabetes). A large number of responders (> 70%) indicated public apathy in regard to ED. This opinion may be based on the situation prior to the public accessibility to effective, non-invasive therapy for erectile problems. The massive exposure of large sectors of the population to the newer medical treatments has, undoubtedly created an increased awareness, particularly in men at or beyond middle age. Of particular interest to the committee was the position of the regional health authorities in regard to ED. As anticipated, it was felt that the vast majority simply ignores its prevalence and effect on the quality of life. Equally important was the finding that when the condition is not ignored, the same authorities remain inactive in the promotion of preventive and curative measures for it. A cited example was the labeling of cigarette packages: all sort of adverse health effects have been printed in such products for years. Only recently and in a few areas, has ED been named as a significant consequence of cigarette smoking. It was felt that this type of warning would be particularly effective in the younger population who is the most susceptible to initiate the habit and to respond to a threat of diminution in sexual capacity. In areas with limited religious diversity, religious authorities, for the most part, are oblivious of the condition. Only a small minority takes a proactive attitude and promote discussion of sexual issues. In several regions there is such a variety of beliefs that the religious influence on ED could not be reliably determined.

most advanced areas where “first world” conditions prevail, ED is still considered mostly of psychogenic origin and treated with androgens. However, the availability of better treatments has resulted in a proliferation of “male clinics” which prescribed intracavernosal injections. Very few are equiped to treat their complications or to provide integrated therapy for the couple. A few psychiatrists and family physicians have developed an interest in sexual dysfunction and practice as sexologists. These physicians tend to deal with the problem mostly in terms of psychogenicity. Urologist are more eclectic in their approach to the problem but it is predominantly pharmacotherapeutic in nature. The males are usually treated without considering the influence on the couple’s relationship.

4. DISCUSSION The Committee recognizes that cultural background exerts enormous influence in the way a man discusses his sexual function. We further recognize that there are other important factors in an individual’s personality and beliefs system. They include levels of education and economic class [25]. In addition, we feel that it is important to emphasize that any profession, including medicine, may operate as a culture and, here again, socio-cultural influences may affect health professionals attitudes in terms of both their own backgrounds and the backgrounds of the people they interact with [26]. The work of the Committee was severely impaired by the lack of reliable information about regional social views on erectile dysfunction. The literature search disclosed a very limited number (< 30) of articles specifically dealing with socio-cultural aspects of ED. The voluminous International Encyclopedia of Sexuality was equally disappointing in this regard. In it, an unspecified selection process, only 32 countries were considered. Among the numerous authors there is a scarcity of physicians and few, if any, urologists or pharmacologists. This translates to a serious bias when dealing with male sexual dysfunctions: the authors simply ignore them, focus mostly on emotional aspects and counseling or lament the “medicalization” of therapy. The report of this Commitee, therefore, is primarily based on the views of the Committee members as well as reports from regional opinion leaders. Again, the financial and temporal limitations, obviously, did not permit an extensive survey with 582

In order to establish, not only the degree of interest by the community in ED but also the input from the health care providers, the questionnaire asked about the availability of lay (i.e. support groups) or professional (i.e. “impotence” societies) organizations dealing with ED. In most regions (80%) such societies do not exist and where they do, are perceived as ineffective. This finding was curious and worth noting. The International Society for Impotence Research (ISIR) has regional affiliated societies that cover the globe. It is evident that its membership remains, primarily, limited to individuals with specific interest in the field of erectile function at an academic level and its activities do not percolate to either the public or health care providers in general.

such groups exist at a local level, the Committee was able to identify only one with a national mandate: The Impotence Association of the United Kingdom. This group publishes a simple review of the causes and treatment of ED that are not much different than many other educational materials on the subject. However, this publication contains a very notable and crucial difference: on the back page there are listed (with addresses and telephone numbers) 4 large groups that offer counseling and advice (e.g.: Sexual and Personal Relationships of People with a Disability (SPOD), 286 Camden Road, London, Tel. 016078851. Tuesday to Thursday 10:30 am to 1:30 pm, Wednesday 1:30 to 4:30 pm). This type of organizations are of enormous value to a population reluctant to approach physicians and other health professionals with a problem related to a sexual inadequacy.

Notable exceptions to the observations mentioned above exist. In Europe for example the European Society for Impotence Research (ESIR) has produced a "Patient's Guide to a Common Medical Problem: Impotence" and "A Physicians Guide to the Management of Erectile Dysfunction"; both publications are simple and practical but not available in all languages. The recent "Man's Guide to Sexual Health" booklet produced by South African psychiatrist Bernard Levinson and published by the Erectile Dysfunction Advisory Council (EDAC) is also very practical and culturally generic but, at the time of writing exists only in the English version. Most of these educational materials are developed by knowledgeable health professionals and with the support but without interference from industry. This important point is further elaborated on in the section on Education and Ethics. Similar publications (and a great deal of duplication) exist in all regions surveyed although their quality is inconsistent. The importance of dealing appropriately with ethnic, cultural and even gender sensitivities in these materials cannot be over-emphasized.

An important cultural issue refers to who is providing the primary care for patients with ED. Not surprisingly a significant number (20%) of patients seek advice from friends and other nonmedical people to assist with simple remedies. While the same number attend a medical professional regarding his condition, another 10% seeks non-medical but “professional” advice from shamans, herbalists and other similar persons. While most (44%) seek help from all these sources. Such an approach is what one would expect for a nonlife threatening condition such as ED. It is likely also that the placebo effects from herbs and incantations are significant and will perpetuate the tendency, in many cultures, to rely on traditional remedies. Other factors of importance in this regard are the low cost and accessibility of nonallopathic treatments. The Committee determined that there are very large social, economic and cultural discrepancies among the various regions of the world and among segments of the population within the same region. In most areas the public simply lacks the financial resources to obtain appropriate care for ED. The problem is compounded further by an acute absence of a cadre of properly trained health providers capable of dealing with the condition in a knowledgeable and sensitive manner. This unsatisfactory situation can be solved only when an educated public and trained professionals create

Much less successful have been the health professionals or the public itself in organizing support groups for men/couples affected by ED. The Committee fully recognizes that trans-cultural motivations and connotations associated with ED are quite different than, for example, a subject such as prostate cancer where support groups are numerous. ED in most of the world remains an intensively private matter. Although it is likely than many

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2. Health authorities should promote sexual health as an important factor in the overall quality of life. This should take place by educating not only the public but also health professionals.

the demand and deliver the expertise for adequate management of sexual dysfunctions. Resolution of such matters is, obviously, complex and not forthcoming due to very pressing health issues and the major socio-economic discrepancies facing the world today.

3. It is important to increase the public awareness about the large prevalence of ED in all regions of the world. Health authorities and medical organizations need to provide guidance on the material made available to the public.

The final area explored by the Committee was the perceived interest by the regional medical community on issues related to ED. The overwhelming position was that ED is either irrelevant or quite insignificant in relation to other more pressing health issues. This is an understandable position that correlates well with the one expressed in relation to the health authorities. Undoubtedly, health authorities and providers will preferentially direct their energies, budgets and interest to conditions threatening life, associated with serious physical sequelae or enjoying an effecting lobbying force. ED does not score very high here.

4. There is an obvious need, in most countries, for the creation of lay support groups with and interest in dealing with sexual (both male and female) issues. 5. Pertinent scientific societies, when appropriate, should promote high standards of clinical practice, research and education in the field of ED.

The Committee felt that socio-economic issues did not fall into its mandate and purposely avoid addressing them. There are enormous discrepancies not only among countries but also between health agencies and authorities within the same country. In addition, the rapid development on therapeutics for ED present a rapidly shifting view of “clinical, equity and cost-effective grounds” [27]. On the other hand, the Committee felt encouraged by the vigorous debate in Great Britain on the funding of all treatments for ED regardless if the patients are considered “deserving” or “undeserving” of such treatment [28]. This sort of debate and interest by government agencies is an example for societies in other countries.

6. With deep respect to religious and cultural sensitivities the topic of sexuality in general and ED in particular needs to be addressed at all levels of medical practice. 7. Regardless of socio-economic status, in most regions of the world the medicalization of sexuality is a reality. In the specific area of ED it is not only unavoidable but desirable. Although most cases of ED have a multifactorial etiology, organic factors are frequently identified. They can be treated promptly, inexpensively and effectively by pharmacological means. 8. The Committee, however, is fully aware that a "penocentrically" oriented approach has its own drawbacks. Serious emotional and psychological issues may be overlooked. In addition, the treatment of the purely erectile problem, although successful, in most cases results in the emergence of new patient’s and couple’s issues that would interfere with a fulfilling sexual relationship. Whenever feasible, the investigation and treatment of ED should be comprehensive and viewed as “a couple problem”.

5. RECOMMENDATIONS The Committee believes that the statement of the Director General of the WHO fits well in the management of ED. She wrote that “prevailing cultural values have to be observed if appropriate policies are to be developed. Indeed health cannot be dissociated from cultural, social processes or economic forces – all are interrelated” [29]. With this in mind, we agreed on the following culturally generic recommendations: 1. ED needs to be recognized globally as a significant health concern and not as a life style issue.

9. The therapy of sexual dysfunction in general and of ED in particular must be sensitive to ethno-cultural issues

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2. MATERIALS AND METHODS

II. EDUCATIONAL AND ETHICAL ASPECTS

The Committee was charged with a global assessment of issues on ethics and education concerning exclusively the field of erectile dysfunction (ED). For this purpose, members of the Committee and other health care professionals in leadership positions, provided information regarding educational and ethical aspects of ED in their individual regions. Their opinions were tabulated and the results supplemented with information available from government and non-government agencies. This approach provided a wide geographical picture of the topics of interest which were then divided as follows: 1. Public Education 2. Professional Education 3. Professional Ethics 4. Industrial Ethics

1. INTRODUCTION There are few, if any, fields in human health that have been ignored for longer than erectile dysfunction (ED). Similarly, in few has progress been so rapid in elucidating the physiology of the erectile mechanisms as well as the causes and treatment of ED. Thus, at the basic level, we have evolved, in less than 30 years, from the erroneous concept of “pollsters” as the system to trap blood in the corpus cavernosum to our current understanding of the molecular mechanisms of penile physiology [30]. Clinically, the opinion [31] that “With few exceptions, the causes of impotence in the male are psychic, i.e. based on guilt, anxiety, jealousy, or frigidity on the part of the wife”, has been drastically revised as scientifically and politically incorrect. Therapeutically, in the short span of 15 years, the sub-specialty has expanded from no options or only the possibility of an implant to safe and effective oral medications. The speed of progress has been astonishing.

The Committee is fully aware of a multitude of other very relevant ethical issues in the treatment of ED. However, they appear of secondary importance to the specifics of ED or are too vast and complex to be explored within the limited mandate of the Committee. These include the concepts of confidentiality, informed consent, respect for personal values of the patient. Interested parties are referred to the early work of Macklin [32].

However, the rapid pace of discovery on all aspects of penile physiopathology has not kept abreast with the dissemination of this wealth of knowledge outside a relatively small group of interested health professionals, most commonly urologists. The gap in the information network is rooted in a variety of factors which include:

In regards to education pertinent to ED, we concentrated our efforts in establishing: 1) the adequacy of public and professional education in the field of erectile function

a) the accelerating rate of breakthroughs;

2) the availability and effectiveness of educational material specifically dealing with the topic of ED.

b) the lack of sexual education at the graduate and undergraduate levels for health professionals;

The Committee focused on 3 ethical issues: 1) the appropriateness of the information provided by industry to health care professionals and to the public. 2) conflict of interests that may exist between industry and physicians in the diagnosis and treatment of ED. 3) ethical concerns regarding false advertising and questionable practices by health care providers (both as individuals ans as government and nongovernment coporations) in the diagnosis and treatment of ED were gleaned from the literature and from information from scientific societies.

c) inability and lack of interest by government and non-government health agencies to invest resources in the field of sexual dysfunction; d) reluctance of the lay press to deal with issues of sexual health in a serious manner; e) a pervading belief, at all levels of society, that sexual health issues are of minor importance; f) deeply rooted socio-cultural convictions that prevent open discussion of issues in this area and g) misinformation provided by ignorant and/or dishonest parties.

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that the average consultation time is 12 minutes which does not give much time for assessment or counseling of erectile problems.

3. FINDINGS a) Public education. The majority of responders (55%) felt that the amount of sexual education among the people of their region of concern was inadequate. Over onethird indicated that in their region sexual education to the public was non existent, while just over 10% found it to be adequate (Figure 10). The sexual education material was found to be quantitatively and qualitatively inadequate by 55% of responders, non-existent by 11% and adequate by 33% (Figure 11). Traditional publications (booklets and pamphlets) were selected by the majority (66%), as the most effective educational material for the public (Figure 12) while audio-visual aids were most appropriate in the view of a third of the responders. Public lectures were the medium of choice for only a minority of responders (11%) and no one indicated electronic media as first or second choice in regard to acceptability and effectiveness.

Another important professional group is nursing. Nurses are close to patients, can be effective advocates of patients within the health care system and are well placed to discuss the patient’s physical problems and partner relationships. It was felt that nurse educators involved in primary and community care nurse training are a fundamental target audience for educational programs. In addition, nurses are capable of sharing the load with primary care physicians. The Committee believes that family physicians, nurses and clinical psychologist in their formative years should be targeted for enhanced training and understanding of human sexuality in general and sexual dysfunction specifically. In this regard, it is important to reiterate the interdependence of the various fields of expertise which should be able to work in a harmonious and effective way. The opinions regarding the information provided by industry were mixed. It was recognized that before medical therapy became available there was very limited dissemination of information by industry. A trickle began with the appearance of invasive pharmacotherapy and now there is an avalanche of information as a result of the availability of new oral drugs. Comments regarding the efforts by large companies in providing education in ED were generally positive. Various correspondents noted the sensationalistic, frequently erroneous and derogatory comments by the lay media which may have resulted in a negative view of medical intervention by patients suffering with ED. It was felt that, on many occasions, industry has to battle with an unjustifiably negative media. On the other hand, concern was expressed about the large amount of information, from clinical studies, that has been collected by industry but has not yet been published. There is a suspicion that industry may have delayed publication of information that could adversely affect their marketing position. Regarding conflicts of interest between physicians and industry, a variety of views were expressed. They ranged from the inappropriateness of stock ownership to lectures and workshops in which the benefits of one product were extolled without proper balance and exposure to alternative products.

b) Sexual education and health care professionals. There was a consensus among responders regarding the inadequacy of sex education for health professionals (physicians and nurses). In addition, the amount and quality of material available for sexual education was reported to be adequate by only one-third of the responders (Figure 13) . A large majority of responder (77%) indicated that the needs for sexual education in their region are best satisfied by enhanced exposure to the topic at the undergraduate and post-graduate level. The remaining gave as first option the availability of conferences and workshops. When asked to provide a second priority for their country or region, traditional publications (books, professional journals), audiovisual aids and improved curricula were given equal value (Figure 14). Of particular interest are the views of the World Organization of National Colleges and Academies of Family and General Practice (WONCA). Family physicians are the point of entry in most health care systems and they have the most intimate knowledge of the social, family and medical history of these patients. At the same time they have received little or no training in ED during their under and post-graduate years. It was pointed out

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Figure 10: The inadequacy of sexual education is a universal phenomenon. Even advanced and wealthy societies experience it. Figure 11: Although a great deal of educational material is available for the public, much of it is inadequate in quality. Self-serving, inaccurate information is quite prevalent throughout the world. Health authorities and professional organizations have been impotent in eliminating the flow of inaccurate, self-serving or plainly false and misleading advertising.

Figure 12: Booklets and audio-visual materials are considered the most effective means to disseminate educational material for the public.

Figure 13: The quantity and quality of educational material for health professionals is deficient in most regions. Only recently, and mostly though industry support, there has been an increase in the amount and quality of available material both printed, electronic and in the form of courses and lectures.

Figure 14: Professional education is best accomplished at the undergraduate level with changes in curricula. These changes need to emphasize the impact of ED in the quality of life and the need to consider ED as a significant medical condition. For practicing health professionals, re-enforcement of those concepts is best accomplished by either workshops or standard printed material.

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Traditional educational material (booklets and videos) appear to be more effective. As the electronic communications become more accessible they may turn out to be equally effective. However, this does not appear to be the case at the moment.

Behavior of health workers in the area of ED is felt to offer an enormous potential for ethical conflict and controversy. Again, the opinions are varied. It was pointed out that at one end there is the honest but misinformed clinician who may over-investigate or the equally honest but ignorant one who may treat without proper assessment of the patient. At the other end, more serious, and bordering on the criminal, is the behavior of some health care workers (it was remarked that physicians do not have exclusivity on unethical practices) where false advertising and exaggerated claims are rampant. Equally serious and widespread is the practice of inappropriate, experimental or unproved expensive treatments (i.e. surgery for penile elongation).

The interest of medical organizations in promoting sexual health has grestly increased in the last few years. The American Foundation for Urological Diseases (AFUD) started in 1998 the Impotence Awareness Month (October) and the ESIR has established help lines in several European countries. Similar organizations are developing in Latin America, Africa and the Asia Pacific region. This developments are a welcomed addition to the educational aspects of ED. The availability of information easy to obtain in a nonthreatening situation is important for a public that generally perceives ED has a terribly embarrasing topic to discuss openly.

4. DISCUSION An early WHO document [33] stated that “Sexual health is the integration of the somatic, emotional, intellectual and social aspects of sexual being, in ways that are positively enriching and that enhance personality, communication and love. Fundamental to this concept are the right to sexual information (the underlying is ours) and the right to pleasure.” There is no qualm with this statement but, at this juncture it should be emphasized that all humans have a right to factual and accurate sexual information. The most vexing educational issue for the Committee was dealing with the inaccurate and self-promoting material that is widely disseminated to the public and health professionals. Although this is not a phenomenon occurring exclusively in the field of ED, it is particularly evident here with the recent availability of relatively simple diagnostic and therapeutic alternatives.

Currently there is a proliferation of publications on ED. It appears that every manufacturer of products for the treatment of the condition develops an urge to publish information similar to the one from the competitors but with a slant on their specific product or area of interest. Every regional professional organization appears to be possessed by the same informational urge. It would be desirable to have a more centralized informational office with a great deal of credibility providing guidance and approval of the educational material. Naturally, publications and information in general require a great deal of cultural sensitivity as well as understanding of the financial limitations experienced by the society to which such recommendations are aimed to.

5. PUBLIC EDUCATION

The commercial launching of sildenafil (Viagra) was one of the major media events of 1998. Internationally the press created a variety of images about ED and its new simpler orl treatment. On many occasions, the importance of the primary objective of treatment (to restore normal sexual activity) was grossly distorted by the media which presented Viagra as «the pill for happiness». The media also frequently and erroneously indicated that the drug was an effective aphrodisiac. This image, together with the strident and unjustified display of safety concerns interfered with the proper physician-patient dialogue and the adequacy of treatment.

Although an increasing amount of educational material is available to increase public awareness and understanding of the issues related to ED, the material is not widely disseminated. Most of the educational information is factual and of good quality. However, most of the publications are sponsored by industry and the potential for ethical conflict is always present. In this regard the availability of regional societies with a mandate to revise the accuracy of the information passed to the public is of outmost importance. A relationship between the health authorities and professional societies is an obvious way to maintain and enhance public education in the field of ED. 588

6. Insist that all educational publications on ED, including those sponsored exclusively by industrial concerns, adhere to scientific and ethical guidelines accepted by major scientific agencies and professional associations.

The Committee feels that medical and nursing schools are largely ignoring the importance of a significant condition such as ED. In many regions with health problems of an enormous magnitude the consequences of ED appear to be secondary. The Committee agreed with this assessment but at the same time feels that ED needs to be considered a significant condition that universally affects the quality of life and that demands more consideration in the formation of health professionals.

7. Denounce in their publications cases of misleading and false advertising. The Committee recognizes that the above recommendations represent continued work and cannot be carried out by groups working sporadically. The membership of a group with the mandate listed above requires, in addition to a multidisciplinary representation, cultural sensitivity as well as a balanced international representation.

6. RECOMMENDATIONS Increase awareness of the public on all aspects of ED and better education of health professionals will translate in an improvement in the treatment of the condition. The WHO is in a privileged position to develop a propitious environment for an improvement in the prevention, assessment and treatment of ED. The Committee feels that health organizations such as the WHO and professional organizations such as the the International Society for Impotence Research should:

REFERENCES For an extensive opinion on the medicalization of sexuality (not necessarily ED), the reader is referred to Tiefer L. The Medicalization of Sexuality: conceptual, normative and professional issues. Ann Rev Sex Res 7:252,1996.

1. Promote the development of recommendations and guidelines, particularly on the investigation and treatment of ED. This would increase public confidence on modern, efficacious, safe and affordable therapies for ED. 2. Recognize that the development of guidelines is usually a time consuming process, therefore, international bodies should establish a Committee for the development of Position Statements in areas that demand prompt and decisive action (false claims, unproven methods) to prevent emotional, physical and financial injury to sufferers of erectile problems. 3. Promote better understanding of the issues related to ED by national health agencies and authorities. 4. Heighten awareness by regional health authorities as well as educational leaders on the need to increase teaching of sexual health issues in general and ED in particular at the undergraduate level. 5. Disseminate widely factual, balanced and truthful information regarding the causes, investigation and treatment of ED.

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United Nations Department of Economic and Social Information and Policy Analysis. Population Division. World Population Prospects: the 1994 Revision. United Nations, New York. Document 145, 1995.

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LAUMANN EO, PAIK A, ROSEN RC. Sexual dysfunction in the United States. Prevalence and predictors. JAMA 1999;281:537-541.

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BEECHAM L. UK issues guidance to doctors on Viagra. BMJ 1999; 318:279-281.

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KLEINMAN A. Patients and healers in the context of culture. University of California Press. Berkley, 1980.

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FELDMAN HA, GOLDSTEIN I, HARTZICHRISTOU DG, KRANE RB, MCKINLEY JB. Impotence and its medical and psychosocial correlates. J Urol 1996; 151:54-59.

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Sexuality in America. P Barthalow-Koch, DL Weis (eds) Continuum, New York. 1998:292.

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SLOWINSKI J, STAYTON WR. Sexual dysfunctins counsling and therapies: recent developments. In RT Francoeur (ed) “International Encyclopedia of Sexuality”. Continuum, New York: Continuum 1998:16301631.

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FRANCOEUR RT. Male erectile problems. In P Bartthalow-Kochs, DL Weiss “Sexuality in America”. P Bartthalow-Kochs and DL Weiss. , New York: Continuum. 1998: 293-301.

9.

PORST H. Injectable drugs: advantages and drawbacks. In Morales A (ed) “Erectile Dysfunction. Issues in Cur-

rent Pharmacotherapy”. London: Martin Dunitz, 1998:157-187.

puissance en Europe: resultats d’ une enquete sur les attitudes diagnostiques et therapeutques dans six pays. Revue Europeenne de Sexologie Medicale 6:19-32.

10. ZAGAJA GP, MHOON DA, BRENDLER CB. Evaluation of response to sildenafil (Viagra) after radical prostatectomy using a confidential mail survey. J. Urol 1999;161-155. 11.

23. ANKOMAH A. GHANA. In The International Encyclopedia of Sexuality. RT Francoeur, ed. Continuum, New York. 518-546, 1998. 24. DREW PE. Iran. In the RT Francoeur “International Encyclopedia of Sexuality”. (ed) New York: Continuum 1998;621-648.

CELA. Prevalence and associated risk factors of erectile dysfunction in Colombia, Ecuador and Venezuela. Presented at the 1st Consultation on Erectil Dysfunction. Paris July, 1999.

25. JOHNSON TM, HARDT EJ, KLEINMAN A. Cultural factors in the medical interview. In: Lipkin M, Jr, Putnam Sm, Lazare A, eds. The Medical Interview: Clnical Care, Education and Research. Springer-Verlag, New York. 1995:153-162.

12. SURRIDGE DHC, LEE J, MORALES A., HEATON JPW. Penile rigidity may supersede partner and counseling issues. J Urol 1998; 159:29. 13. GREGOIRE A. Male 1999;318:245-247.

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26. NOVACK DH, SCHUMAN AL, CLARK W. Calibrating the physician: personal awareness and effective patient care. JAMA 1997; 282:502-509.

14. KAMENETZKY S. Argentina. In Francoeur RT “The International Encyclopedia of Sexuality”( ed) New York: Continuum. 1998: 763-842.

27. CHISOLM J. Viagra: a botched test case for rationing. BMJ 1999:318:273-274.

15. HATANO Y, SHIMAZAKI T. Japan. In Francoeur RT (ed) “The International Encyclopedia of Sexuality”. New York: Continuum 1998: 763-842.

28. POWNALL M. UK consultation rejects restriction of impotence treatment funding. BMJ 1999;318:892.

16. RUAN F, LAU MO. China. In Francoeur RT “the International Encyclopedia of Sexuality” (ed) New York: Continuum 1998: 345-399.

29. BRUNDTLAND GH. Challenges and opportunities of ageing in a New World. The Agung Male 1998; 1:229233.

17. PETRAK J, KEANE F. Cultural beliefs and the treatment of sexual dysfunction: an overview. Sexual Dysfunction 1998;1:13-17.

30. SERELS S, DAY NS, WEN YP, GIRALDI SW, MELMAN A, CHRIST GJ: Molecular studies of human conexin 43 expression in isolated corporal tissue strips and cultured corporal smooth muscle cells. Int J Impotence Res 1998;10:135-143.

18. BHUGRA D, DE SILVA P. Sexual dysfunction across cultures. Int Rev Psychiatry 1993;5:243-252.

31. SMITH DR: Impotence. In General Urology. Philadelphia: Lang Medical Publications. 6th Edition 1966: 405407.

19. WYLIE KR. Sexual Dysfunctions counseling and therapies. In The International Encyclopedia of Sexuality. RT Francoeur, ed. Continuum, New York. Pp 1363-1354, 1998.

32. MACKLIN R. Sex Therapy and Sex Research. Ethical Perspectives. Encyclopedia of Bioethics. Chicago:MacMillan. 1978: 1556-1559.

20. GIAMI A (personal communication) To be presented to the International Academy of Sex Research. Stony Brook, New York, June, 1999.

33. WHO Report No. 572. Education and Treatment in Human Sexuality: The Training of Health Professionals. 1975.

21. GIAMI A, PIETRI L. (in press) Rapport du Group de Travail sur le Traitements de l’impuissance. Paris. 22. BUVAT J, PORTO R, CARUSO S. BORRAS VALLS JJ, WAGNER G, RILEY AJ, PAHLA A. (1997) L’im-

___________________

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Committee 17

Neurological Disorders: Erectile and Ejaculatory Dysfunction

Chairman P.O. LUNDBERG

Members N.L. BRACKETT, P. DENYS, E. CHARTIER-KASTLER, J. SØNKSEN, D. B. V ODUSEK

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CONTENTS

E. ERECTILE AND EJACULATORY DYSFUNCTION IN SPINAL CORD DISORDERS.

A. THE NEUROANATOMY AND NEUROPHYSIOLOGY OF ERECTION, EJACULATION AND ORGASM.

F. ADVERSE SEXUAL REACTIONS FROM PRESCRIPTION DRUGS

B. SEXUAL CASE HISTORY IN NEUROLOGICAL DISORDERS. CLINICAL AND LABORATORY INVESTIGATIONS.

G. TREATMENT OF NEUROGENIC ERECTILE DYSFUNCTION

C.SEXUAL DYSFUNCTION IN BRAIN DISORDERS INCLUDING MULTIPLE SCLEROSIS

H. TREATMENT OF EJACULATORY DYSFUNCTION IN MEN WITH NEUROLOGICAL DISORDERS

D. SEXUAL DYSFUNCTION IN AMYOTROPHIC LATERAL SCLEROSIS, POLYNEUROPATHIES AND MUSCLE DYSTROPHIES.

I. OVERALL CONCLUSIONS AND RECOMMENDATIONS

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Neurological Disorders: Erectile and Ejaculatory Dysfunction P.O. LUNDBERG N.L. BRACKETT, P. DENYS, E. C HARTIER-KASTLER, J. S ØNKSEN, D. B. V ODUSEK

A. THE NEUROANATOMY AND NEUROPHYSIOLOGY OF ERECTION, EJACULATION AND ORGASM.

II. HYPOTHALAMUS (Fig. 2)

I. CEREBRAL CORTEX (Fig. 1) Both thalamic and cortical areas receive sensory input from the genitalia, and sexual feelings may be elicited when such areas are stimulated. In the primary sensory cortex, localised in the parasagittal region of the brain, there is a centre for sensory input from the genitalia. This conclusion is based mainly on observations from a limited number of cases of parasagittal tumours. The rhinen cephalon, including the limbic cortex, is of importance for sexual behavior, but also for sexual desire. Lesions of the frontal lobes, the baso-medial part in particular, may lead to loss of social control, which may also influence sexual behaviour. In a recent PET-study [1] where regional cerebral blood flow was measured in eight male subjects during visually evoked sexual arousal, the following observations were made. The inferior temporal cortex (a visual association region) was activated on both sides. The right insula and right inferior frontal cortex (regions processing sensory information and motivational state) and the left anterior cingulate cortex (involved in neuroendocrine function) were also activated. In the future we can hope for many more imaging studies of the functional anatomy of the human brain during sexual activity. For clinical data about sexuality and the cerebral cortex, see Lundberg [2].

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In studies using retrograde labelling with pseudorabies virus in the rat, most of the labelling from the corpus cavernosum at the level of the diencephalon was found only in the hypothalmus - the paraventricular nucleus, the tuber cinereum, the medial preoptic area and the dorsal hypothalamic area [3]. The neurons from the paraventricular nucleus are known to project to thoracic and lumbosacral nuclei concerned with erection. Hypothalmo-spinal projections are localised in the dorsolateral funiculus [4]. The hypothalamus is the part of the human brain directly controlling the gonadotropin functions of the pituitary. In such a way both the prenatal and pubertal development of the genital organs is regulated. It is well established that in the basal hypothalamus there is a centre for sexual desire. Animal experiments have shown that tissue levels of sex steroid hormones (testosterone, dihydrotestosterone and estradiol) in the hypothalamus affect desire. Destruction of this centre by surgery [5] or by a tumour [6] leads to loss of sexual desire. Animal experiments have proven a dopaminergic stimulating and a serotoninergic inhibiting mechanism within the hypothalamus controlling sexual desire. Aseries of observations on human beings supports the existence of similar mechanisms in man [7]. Sexually dimorphic nuclei are localised in the anterior hypothalamus - preoptic region. Their importance in humans is largely unknown but they may play a role in regulating sexual motivation and performance [89].

From the Ciba collection with permission

ACG : Anterior Central Gyrus AG : Angular Gyrus CS : Central Sulcus (fissure of Rolando) FP : Frontal pole FS : Fissure of sylvius IFG : Inferior frontal gyrus IPG : Inferior parietal gyrus IPS : IInter-perietal sulcus ITG : Inferior temporal gyrus LOG : Lateral occipital gyrus MFG : Middle frontal gyrus

MTG : Middle temporal gyrus MTS : Middle temporal sulcus O : Operculum OP : Occipital pole PCG : Posterior central gyrus PCS : Pre-central sulcus POCS : Post central sulcus

SFG SMG SPG STG

: : : :

Superior frontal gyrus Supra marginal gyrus Superior parietal gyrus Superior temporal gyrus

STS : Superior temporal sulcus TP : Temporal pole

Figure 1: Cerebral cortex

t uc

d ue Aq From the Ciba collection with permission

Figure 2: Hypothalanus

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level of the fifth lumbar vertebral body and sacral promontory between the common iliac arteries. It divides caudally into the right and the left hypogastric nerves. Within the pelvis these nerves become the inferior hypogastric plexuses. This plexus is joined on each side by the pelvic nerves, also called the nervi erigentes. The inferior hypogastric plexus is lateral to the rectum, seminal vesicle, prostate and the posterior part of the urinary bladder. The internal iliac vessels are lateral to this plexus.

III. BRAINSTEM AND SPINAL CORD (Fig. 3 &4) In studies using retrograde labelling in the rat, most of the labelling from corpus cavernosum at the level of the brainstem was found in the pons and medulla oblongata [3]. Projections from the brainstem raphe nuclei descend through in the lateral funiculus. The nucleus paragigantocellularis was shown to have a majority of serotoninergic neurons projecting to the spinal cord and provided tonic inhibition of sexual reflexes in the rat [10]. Efferent nerve impulses are conveyed from the brain stem through the spinal cord mainly via the paraependymal tract.

Most of the sympathetic nerve fibres are conveyed through the hypogastric nerves and the parasympathetic fibres through the pelvic nerves. However, these plexuses contain numerous small ganglia with nerve cells.

Clinical observations support a theory that the cervical spinal cord is of special importance for ejaculation [11]. At low thoracic level (spinal cord segments Th10 - L2) there is a centre for emission and ejaculation. The impulses are conveyed via the sympathetic nervous system. Cerebral (psychogenic) erection is also effected through the sympathetic nervous system as well as inhibition of erection in a stress situation.

Pregangionic efferent sympathetic fibres originate in the lower three thorasic and the upper two lumbar spinal segments. Preganglionic parasympathetic nerve fibres originate in the second to forth sacral spinal cord segments. The vesical plexus is the anterior part of the inferior hypogastric plexus. Branches from here also supply the seminal vesicles and the deferent ducts [13]. There are many neurons among the nerve fibres in the vesical muscular wall [14]. The parasympathetic preganglionic efferent fibres are mainly motor in function and stimulate the detrusor muscles as well as inhibit the internal bladder sphincter. The efferent sympathetic nerve fibres are also mainly motor in function but have the opposite effect to the parasympathetic efferent fibres. The sympathetic nerve fibres also have a vasomotor function.

At the sacral level (S2-4) there is a centre with a parasympathetic nerve outflow. These nerves regulate reflex erection and changes in blood flow in the genital area. Also entering the sacral level are sensory nerve impulses from the sex organs via both parasympathetic and somatic nerves. In the sacral spinal cord there is a nucleus called Onuf´s nucleus [12]. The upper pole of this nucleus lies at rostral S1/midcaudal S1 and the nucleus varies in length between 4 and 7 mm. There is a high density of neurons at the cranial and caudal ends but no distinct segmentation. This nucleus is comprised of alpha-motor neurons to the pelvic floor muscles. These nerve cells have special pathophysiological properties. In this nucleus there are also nerve cells belonging to the parasympathetic nervous system.

The prostate plexus comes from the lower part of the inferior hypogastric plexus. It supplies the prostate, the seminal vesicles, the ejaculatory ducts and the prostatic urethra. It also contains many neurons.

V. EXTERNAL GENITALIA AND PELVIC FLOOR (Fig. 6)

IV. RETROPERITONEAL SPACE (Fig. 5)

From the front of the prostatic plexus there are two set of nerves on each side: the lesser and the greater cavernous nerves. The nerve fibres travel along the posterolateral aspect of the seminal vesicle and prostate within the lateral pelvic fascia

The superior hypogastric plexus is localised retroperitoneally anterior to the aortic bifurcation at the

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3

FI : Inter-peduncular Fossa CP : Cerebral Peduncle AS : Aqueduct of Sylvius LQ : Lamina Quadri-gemina CPV4 : Choroid Plexus of 4th Ventricle AMV : Anterior Medullary Velum F : Fastigium

Figure 3: Brainstem

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C1 Cervical Plexus

Brachial Plexus C8

Dura Mater Spinalis

T12 Conus Medullaris L1 Iliohypogastric N. Ilio-Inguinal N. Genitofemoral N. Cauda Equina Lumbar Plexus Femoral N. Communication between lumbar and sacral plexuses Filum Terminale Sacral Plexus Superior Gluteal N. Inferior Gluteal N. Filum durae Matris Spinalis Coccygeal N. Pudendal N.

From the Ciba collection with permission

Sciatic N. Posterior Cutaneous N. of Thigh

Figure 4: Spinal Cord

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White and gray rami communicantes

2nd Lumbar sympathetic ganglion Aortic Plexus Inferior mesenteric ganglion

Gray ramus communicans

Inferior mesenteric artery and plexus

Hypogastric plexus

Superior hemorrhoidal artery and plexus Right pelvic plexus

Lumbo-sacral plexus

Vesical plexus

Pelvic nerves (nervi erigentes), sacral parasympathetic

Rectal plexus Prostatic plexus Cavernous plexus

Pudendal nerve (somatic)

Corpus penis

From the Ciba collection with permission

Figure 5: Retroperitoneal space

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T10

Great splanchnic nerve T11

Celiac ganglion Lesser splanchnic nerve T12

Superior mesenteric ganglion

Least splanchnic nerve L1

Aortico-renal ganglion L2

Intermesenteric nerves (aortic plexus)

L3

Internal spermatic artery and plexus

Inferior mesenteric ganglion

L4

Key Sympathetic preganglionics

Sympathetic postganglionics

Internal spermatic artery and plexus

Parasympathetic postganglionics

Hypogastric plexus

Parasympathetic preganglionics S1

S1

Afferents and somatic nerves

VAS S2

Sacral plexus

S2

S3

Pelvic nerve (nervus erigens)

S3

S4

Sacral plexus

S4

S5

S5

Pudendal nerve Pelvic nerve (nervus erigens)

Dorsal nerve of penis Vas deferens

Pelvic plexus Epididymis Vesical plexus

Prostatic plexus

Testis

Cavernous plexus From the Ciba collection with permission

Figure 6: External genitalia

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quite near the rectum [15] and then accompany the membranous urethra through the genitourinary diaphragm. These fibres are located on the lateral aspect of the membranous urethra and ascend gradually to the 1 and 11 o´clock position in the proximal bulbous urethra [16]. The lesser cavernous nerve goes into the proximal part of the penis to supply the erectile tissue of the corpus spongiosus and the penile urethra. The greater cavernous nerve proceeds on the dorsum of the penis near the dorsal vein and artery and supplies mainly the cavernous bodies. The nerves follow the arteries all the way and innervate the helicine arteries and the erectile tissue. The nerves of the corpora cavernosa have anatomical characteristics different from other nerves. The intracavernous nerves are located in fibrous tunnels into which numerous fibrous bundles establish attachments. These bundles are part of a fibrous network. They are supposed to prevent compression of the intracavernous nerves during erection [17]. Also the penile veins are under neurogenic control [18].

there are rather large nerve endings which resemble onions, with thick lamellae and a central nerve fibre. These nerve endings respond to deep pressure and vigorous movement. The nerve impulses are conveyed through thick, myelinated nerve fibres to the cortex at a very high velocity (100 m/sec). The last two types of nerve endings are thus localised within or near cavernous tissues. The type of signal going to the brain via the spinal cord is influenced by the amount of engorgement of cavernous tissues. Touch may thus be experien ced as just touch or as sexual stimuli depending upon the degree of engorgement. Motor innervation of the pelvic floor muscles as well as the ischiocavernosus and bulbocavernosus muscles is conveyed through pudendal nerve branches from below. However, there is also a motor innervation of the pelvic floor muscles directly from the sacral plexus.

VII. THE SEXUAL RESPONSE CYCLE FROM THE NERVOUS SYSTEM POINT OF VIEW

VI. PERIPHERAL SENSORY MECHANISMS

There are several mechanisms through which erection can be achieved and maintained [19]. Psychogenic stimuli from the brain are at least in part conveyed through the sympathetic nervous system and the hypogastric nerves. This explains why certain paraplegics with lesions to the cauda and conus that preserve thoracolumbar segments may still have erections. Somatic sensory affe rents deliver information on tactile stimuli mainly from the genital region via the pudendal nerve. After synapsing in the sacral spinal cord the efferent arm of this arc travels via the pelvic nerves producing vasodilatation and giving erection. Continued parasympathetic activity maintains the erection [20]. Contraction of some striated pelvic floor muscles, the ischiocavernosus muscles in particular, brought about through the pudendal nerve, are also of importance for maintaining erection. For detail concerning animal experiments on the physiology of erection, see Andersson & Wagner [21].

The sensory input from the glans penis and the skin covering the penis is conveyed mainly through the dorsal penile nerve on both sides. The dorsal penile nerves are branches of the pudendal nerve. There is also a sensory input from the root of the penis to the ilioinguinal nerve. There are three types of nerve endings in the penile area that can record exteroception. The most superficial layer of skin/mucosa contains free nerve endings which record pain. Through very thin nerve fibres the impulses from these nerve endings are conveyed via somatic peripheral nerves, and then within the spinal cord, at velocities of 1-2 m/sec. Beneath the skin and mucosal layer the so-called genital nerve corpuscles are localised. These nerve endings look like balls of yarn and have a central “nucleus”. Different types of stimuli can regulate these nerve corpuscles so that the cortical response changes. They react both for pressure and movement and the impulses are conveyed via medium-thick, myelinated nerve fibres with a relative high velocity (40-60 m/sec) to the cerebral cortex. Finally, along the nerves and tendons surrounding the cavernous bodies,

For detail of the vascular mechanisms brought about by the nervous system as well as about transmitters, see other parts of this volume. 600

The sympathetic nervous system also conveys nerve fibres causing inhibition of erection. These nerve fibres produce vasoconstriction. This inhibition is considered part of the flight-alarm reaction of the body and probably plays an important role in psychogenic erectile dysfunction.

2. DETAILED HISTORY RELATED TO SEXUAL DYSFUNCTION

Continued sexual stimulation triggers seminal emission through the sympathetic nervous system already activated during the arousal phase [22]. Ejaculation is effected by an integrated sympa thetic outflow from the Th11- L2 segments The sympathetic nerves cause smooth muscle contractions in the seminal vesicles, the prostate and the ejaculatory duct [14]. The components of the seminal fluid are delivered into the posterior urethra. Sympathetic nervous activity also causes contraction of the internal bladder sphincter during ejaculation to prevent retrograde ejaculation. The ejaculation proper, the expulsion of semen through the urethra, is then brought about through contractions of the striated pelvic floor muscles, the bulbocavernosus muscle in particular. These muscles are under control of somatic fibres arising from the pudendal nerve (S2-4). The CNS mechanisms behind emission are not very well known. Psychogenic factors are of great importance, both as facilitators and inhibitors.

B. SEXUAL CASE HISTORY IN NEUROLOGICAL DISORDERS. CLINICAL AND LABORATORY INVESTIGATIONS.

I. CASE HISTORY IN PATIENTS WITH SEXUAL DYSFUNCTION AND NEUROLOGICAL DISORDERS 1. GENERAL ASPECTS From the general medical point of view the case history should include a survey of the patient´s medical history, particularly concerning cardio vascular, endocrine, psychological and psychia tric disturbances, neurological disorders, disor ders of the sex organs, prior trauma and surgical procedures, the use of prescription drugs, smo king and alcohol habits, and possible drug abuse. 601

From the sexological point of view the case history should define the patient´s sexual expectations, needs and behavior and should identify sexual problems as well as misconceptions. Psychological factors are often involved as an emotional reaction to sexual dysfunction or as a consequence of a socially or physically disabling disease. The dependence and the lack of acceptance of the disease by the patient or the partner, feelings of unattractiveness or reduced self-esteem also play a relevant role. It is usually important also to interview the partner if the patient has one, and to evaluate the quality of marital/partner relationship. Thus, it is important to clarify the nature and the characteristics of sexual dysfunction, to disclose the underlying (and possibly treatable) organic cause and to evidence the existence of psychological factors.

3. DETAILS OF THE CASE HISTORY OF PARTICULAR NEUROLOGICAL INTEREST: As always in neurology, temporal aspects are very important. Has the problem been there all the time, or did it have an onset at a particular point in time? Was the development rapid or slow, the course chronic or episodic? 1. The patient should be asked about sexual desi re. Is there a spontaneous desire, a lack of desire but a wish to have a desire or a total sexual uninterest? Is the desire evoked by specific visual, tactile or emotional stimuli? Is the desire partner-dependent or not? 2. Sensory aspects of sexual function should be elucidated. The patient should describe sensory experiences of sexual arousal in different areas of the body. Present or past disturbances of sensitivity in the region corresponding to the sacral segments is of particular interest as well as pain during sexual arousal or intercourse and pelvic or superficial dyspareunia. 3. Descriptions of erections are important. Does the patient have nocturnal erections, morning erections, erections evoked by visual, auditory or psychogenic stimuli and erections evoked or enhanced by genital stimulation? What is the quality of penile tumescence? Is there a premature loss of erection during sexual intercourse? Does the patient have episodes of priapism or painful nocturnal erections?

4. Ejaculation should be described. Does the patient have premature or retarded ejacula tion, or even absence of ejaculation? Is the ejaculation dribbling, i. e. is semen passing through the urethra without contractions of pelvic floor muscles? Retrograde ejaculation means ejaculation into the bladder with presence of spermatozoa in urine. The term emission refers to peristalsis of the ductus deferens with propulsion of semen from the epidydimis, and smooth muscle contractions in the ampulla, prostate and seminal vesicles resulting in collection of seminal fluid in the posterior urethra. Aspermia means lack of emission of semen [1]. Both lack of emission and retrograde ejaculation can be described as «dry ejaculation». Spontaneous ejaculations may also occur or ejaculations may be painful. The fertility history should be investigated. 5. The the capacity to achieve an orgasm and also the quality of orgasmic sensations and experiences should be analyzed. An orgasm may be unhedonic, i. e. without pleasurable sensations. The patient may have orgasms without ejaculations or ejaculations without orgasms. In sexology, one often talks about the orgasmic phase. Kaplan [2] has simplified the sexual response model into three phases: the phase of Desi re, the phase of Excitement and the phase of Orgasm. (DEO) (Table 1). Thus, the orgasm can be defined as the sum of all physiological events that happen in the body during the sexual climax and how the individual experiences this. Others define the orgasm in men as just the feeling of pleasure accompanying ejaculation. However, the word orgasm should never be used to describe the ejaculation itself, i. e., the forceful expulsion of semen from the penis. Unfortunately, in the literature the terms orgasm and ejaculation are often Table 1: Sexual response model 1.

PHASE OF DESIRE Sexual stimulation

2.

PHASE OF EXCITEMENT Erection Further sexual stimulation

3.

PHASE OF ORGASM Emission Ejaculation Orgasm

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poorely defined which makes the interpretation of data difficult. Further details about case history can be found in Fugl-Meyer et al [3]. Formal questionnaires can be used to obtain standardized information. An often used form is the «Brief Male Sexual Function Inventory for Urology» [4]. It has been suggested that this protocol is helpful in studies of treatment efficacy in patients with erectile disorders, but not practical for everyday assessment of patient with sexual dysfunction [5].

II. THE CLINICAL EXAMINATION OF THE NEUROLOGICAL PATIENT WITH SEXUAL DYSFUNCTION 1. GENERAL CLINICAL EXAMINATION Sexual development, body height and weight, changes in pigmentation and body hair and the presence of galactorrhea are looked for. Inspection of external genitalia for any pathology, evaluation of the size of the testes (normal 15-25 ml) and the prostate gland is performed. Palpation of peripheral pulses (arms, legs, penis), auscultation of the heart, and blood pressure measurement is mandatory.

2. NEUROLOGICAL EXAMINATION A standard neurological examination including assessment of mental state should reveal any signs of an underlying neurological disease. Such an examination will always be somewhat tailored to the particular patient´s data obtained from the history. In addition, particular care will be given to inspection of lower back (for naevus, hypertricosis, sinus etc.) and the feet (for deformity, muscle atrophy). Special attention should be paid to the nervous function of sacral segments. The bulbocavernosus muscles can be palpated, and tested for voluntary contraction («move the penis»), and reflex contraction. Anal sphincter and levator ani tone, volunta ry and reflex contraction can be examined. In addition to standard reflexes, the cremasteric reflex (testing the L1 segment), and the bulbocavernosus and external anal reflex (testing the S2 to S4-5 segments) should be tested [6]. The bulbocavernosus reflex is tested by squeezing the glans and observing (or palpating) contraction of the anal sphincter

or the bulbocavernosus muscle. The external anal reflex is tested by repetitive pricking (or a scratch) delivered to perianal skin (on both sides!) and observing for anal sphincter contraction. Skin sensitivity is tested for touch and pain perception in the perineum, perianally and on the genitals in addition to testing other dermatomes. Particular laboratory tests (usually classified as neurophysiological) are direct extensions of clinical examination of the nervous function. Thus, a controversial reflex response can be recorded with greater sensitivity electromyographically; perineal sensation can be quantified using special devices and algorithms (see below).

cost screening tests for nocturnal penile expansion have been proposed, but their validity is questionable [9]. Continuous monitoring of nocturnal penile tumescence and rigidity can be obtained by a rigidometer during normal sleeping conditions at home [10], and also during daytime napping [11] or in the awake sexually stimulated examinee [12]. The screening tests for nocturnal penile tumescence have been classified as promising in distinguishing psychogenic from other causes of erectile dysfunction, but insufficient on their own to arrive at such a conclusion. However, home measurements with the rigidometer have been classified as a promising screening in establishing presence and quality of erections. The nocturnal penile tumescence measurement in the sleep laboratory has been proposed to be reliable in distinguishing psychogenic from other causes [13].

3. INVESTIGATIONS Generally speaking, the investigations will be performed to objectively assess sexual function, and then to address the questions of etiology. In few centers and in very selected males with erectile dysfunction, spontaneous and physiologically induced erections are examined; the capacity to obtain pharmacological erection is evaluated routinely in many centers. Other segments of sexual function (i. e., ejaculation) are, as a rule, not directly evaluated. If retrograde ejaculation is suspected, the bladder neck (internal urethral sphincter) function may be assessed by videourodynamics. Basic blood and urine tests are commonly recommended for any patient with erectile or ejaculatory dysfunction. In some patients, further investigations are performed to evaluate the neurogenic, vascular, endocrinologic and other possible etiologic factors, but always in view of therapeutic and prognostic considerations.

b) Investigation of erectile capacity

a) Investigation of erectile function Although valuable data will be obtained by history, objective evaluation of erection is considered the gold standard to determine its quality. Spontaneous and physiologically induced erection can be studied with a variety of techniques. The sponta neous nocturnal penile tumescence and rigidity can be measured in the sleep laboratory using mercury strain gauges (measuring penile expansion), visual inspection and measuring the buckling force (for assessment of rigidity), and polygraphic confirmation of sleep phases; such a procedure is considered as the most accurate for determining erectile function [7-8]. Various low

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In addition for the need to study spontaneous or physiologically induced erections (to verify history data and distinguish psychogenic from organic dysfunction), the great advancement in diagnostics of erectile failure came with the introduction of pharmacologically induced erections. Given that no major vascular problem is present (particularly no significant venous incompetence) an intracorporeal injection of a vasoactive substan ce (papaverine; combination of papaverine and phentolamine; prostaglandin E1) will lead to an erection, thus strengthening the suspicion of neurogenic or psychogenic etiology of erectile dysfunction [14]. The combination with self-stimulation is considered to increase the test sensitivity [15]. Intracorporeal injection of vasoactive agents has been proposed as an established diagnostic tool in patients undergoing assessment for possible neurogenic erectile dysfunction, and if performed by experienced physicians, is considered to be safe and have an acceptable complication rate [13]. c) Investigation of nervous system function clinical neurophysiological and other methods In patients with erectile (and occasionally ejaculatory) dysfunction and (suspected) neurologic disorder, a diagnosis of involvement of neural and muscular structures related to sexual function may be strengthened, refined and documented by neuro-

physiologic tests. There are several different methods, and they may be classified according to the neuroanatomic subsystem whose function they test. Motor (somatic and autonomic), and sensory (somatosensory and viscerosensory) tests may be distinguished (Table 2). Most of the tests are electrophysiological, but quantitative sensory testing and testing lower urinary tract and anorectal function (as indices of sacral autonomic function) can be conveniently discussed under the same heading.

18]. Even more informative on nervous control of erection should be tests evaluating thin fiber function, i.e. testing for penile thermal sensation [19]. Electromyography (EMG) may be used to demonstrate activation patterns of striated muscles -within the sexual response - kinesiological EMG; as for instance demonstrating the pattern of perineal muscle activity during ejaculation [20]. EMG however, is mainly used to differentiate normal from denervated (reinnervated) muscle. Concentric needle EMG (Figure 7-8) can identify changes due to recent denervation, and changes due to reinnervation, and is considered the method of choice to diagnose lower motor neuron involvement in the lower sacral myotomes (i. e., in pelvic floor, bulbocavernosus and sphincter muscles). Apart from diagnosing traumatic and compressive lesions this may be particularly helpful for strengthening a diagnosis of multiple system atrophy (Figure 4) in which erectile dysfunction can precede other symptoms [21]. Different tests involving stimulation and recording of somatosensory and motor evoked responses, and sacral reflexes, reflect the function of defined parts of the motor and sensory nervous system (Figure 9). These tests measure conduction through nervous pathways and are sensitive to demyelinization, but not to axonal lesions (which predominate in clinical practice). Tests have been proposed to assess the lumbosacral sympathetic system (the sympathetic skin responses) and penile smooth muscle (the corpus cavernosum EMG). Details of methodology and findings are discussed elsewhere [22-23].

In addition to clinical testing for sensation, special devices and algorithms can be used for quantifying sensory perception on the genital organs. Measuring vibratory perception (biothesiometry/ vibrametry) on the penis has been found to correlate with results of electrodiagnostic testing [16]. The vibration sense threshold in the penis (glans and shaft) is in the neurologically healthy man similar to that of the feet [17]. The test is considered promising in evaluating penile sensation [13, Table 2: Tests of nervous system function SOMATIC SENSORY TESTS • Quantitative sensory testing • Dorsal penile nerve neurography • Pudendal somatosensory evoked potentials (SEP) • Vibrametry REFLEX LATENCIES • Bulbocavernosus reflex • Anal reflex VISCERAL SENSORY TESTING • SEPto proximal urethra/bladder neck stimulation

Neurophysiological tests provide a safe means of detecting nerve or muscle pathology and may refine the diagnosis of nervous system involvement. In a recent review [22] of such testing for patients with incontinence (i.e., another group of patients with possible involvement of the sacral nervous system and/or its suprasegmental connections) it has been suggested that tests should be considered in selected patients with suspected or known involvement of the peripheral nervous system (i.e. of the sacral reflex arc). In these patients, concen tric needle EMG of pelvic floor muscles and recording of the bulbocavernosus reflex have been classified as optional, and all other tests as investigational. The review further suggested that testing in patients with suspected central nervous system involvement would rarely reveal abnorma-

• Testing bladder sensitivity • Sacral reflex to proximal urethra/bladder neck stimulation SOMATIC MOTOR TESTS • Electromyography • Pudendal motor latency • Motor evoked potentials (MEP) (above mentioned reflexes also test the motor part of the reflex arc). AUTONOMIC TESTS • Sympathetic skin response • Penile (corpus cavernosum) EMG • Neurocardial tests • Cystometry • Anorectal manometry

604

Figure 7: Concentric needle EMG recording from right bulbocavernosus muscle of a 49years old male. Pathological spontaneous activi ty (runs of positive sharp waves) is shown.

Figure 8: Concentric needle EMG recording from the external anal sphincter from the same patient as in Fig. 7. A polyphasic motor unit potential of prolonged duration is shown. Ove rall, the percentage of polyphasic potentials was 50%. The happily married and otherwise healthy man presented with a one year history of progressive erectile dysfunction, which became complete (no erections on attempted intercourse, mastur bation; no morning erections). He recently became aware of slight gait insecurity. Signs of mild cerebellar ataxia and bilateral Babinski signs were present on examination, neuroima ging was negative. A diagnosis of possible Mul tiple system atrophy was given. The diagnosis was supportod by development of slight parkin sonism and urge incontinence at follow up alter six months.

Figure 9: Different tests involving stimulation and recording of somatosensory and motor evoked responses, and sacral reflexes, reflect the function of defined parts of the motor and sensory nervous system (Figure 9).

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lities not already verified by clinical examination; in such patients the recording of pudendal soma tosensory evoked potentials was classified as optional Although it was initially hoped that neurophysiologic tests would discriminate between neurogenic and non-neurogenic erectile dysfunction the correlation of test results and erectile function has been generally poor. In order to diagnose erectile dysfunction in a particular patient as neurogenic an abnormal test result should be correlated to erectile failure in absence of any additional factors which might cause the problem. But abnormalities in neurophysiologic tests (EMG, evoked potentials) have been found in patients with good erections, and absent erections in a patient with abnormal test results can still be at least partially due to other (non-neurogenic) factors. The neurophysiologic tests can only be expected to correlate with the underlying neuromuscular pathology. Even their correlation to “simple” nerve and muscle function is not straightforward, and therefore very strong correlation to any “complex” function (such as erection) cannot be expected. This is not only because most established methods test somatic elements of the sacral neuromuscular system, but also because most of the diagnosed lesions are only partial. Partial lesions may not necessarily lead directly to obvious dysfunction. To summarize, neurophysiological tests have a particular sensitivity and specificity for diagnosing a neuromuscular lesion (and even that is not well explored in literature) but not in any general way to diagnose sexual dysfunction. Also, neurophysiologic tests cannot in and of themselves define erectile dysfunction as neurogenic [13]. However, measurement of dorsal penile nerve conduction, the bulbocavernosus reflex, and pudendal SEP have been suggested as promising tools in evaluating patients with suspected neurogenic erectile dysfunction [13]. This may be particularly true if tests are selectively applied in well defined patient groups. The presence of the bulbocavernosus reflex, for instance, has been reported to correlate highly with presence of reflex erection in a group of spinal cord injured patients [24]. Tests measuring penile autonomic innervation and smooth muscle function would be of particular diagnostic value, but their validity is controversial (for corpus cavernosum EMG) or the clinical experience still scarce (for perineal sympathetic skin response). Arecent report

found correlation of psychogenic erection and sympathetic skin responses in the perineum in spinal cord injured patients [24]. Cystometry, other urodynamic tests, and anorectal function tests may strengthen the suspicion of sacral autonomic dysfunction [25]. After delineating as much as possible the presence of a neurological deficit by clinical and laboratory examination, further investigations (neuroradiological, cerebrospinal fluid etc) necessary to diagnose the neurological disorder are performed.

4. LABORATORY INVESTIGATION OF BLOOD AND URINE Basic laboratory data (including sedimentation rate, blood cell count, fasting blood sugar, serum lipids, urinanalysis) as well as serum parameters screening for hepatic, kidney and thyroid function should be obtained in every patient suspected to suffer from organic sexual dysfunction. What hormone to be studied is dependent on the circumstances (sex, age, onset of symptoms). Prolactin and testosterone levels in blood should be investigated whenever a hypothalamo-pituitary-gonadal insufficiency is suspected.

5. INVESTIGATION OF VASCULAR FUNCTION If intracorporeal injection testing of penile tumescence has strengthened a suspicion of vascular etiology in the male patient with erectile dysfunction, further investigations may be contemplated, and as a rule are performed by urologists. Penile blood pressure can be measured using a simple Doppler method and then related to the arm blood pressure. Vascular competence can be measured by angiography, color ultra-sonography and dynamic cavernosography. It has been stressed that the purpose of testing should always be defined: pharmacotesting may be sufficient for the majority of patients, and the invasive tests reserved for those in whom surgery is contemplated [26].

6. A DIAGNOSTIC ALGORITHM (Figure 10) It has to be acknowledged that the diagnostic procedure to establish an erectile dysfunction in a particular patient as neurogenic has at this stage of our knowledge mostly some relevance for defining the neurological disease, disorder or trauma of which ED is one of the symptoms -, but not yet much influence on choosing a particular treatment

606

607

option. In offering an algorithm for diagnostic decisions in patients with ED of possible neurogenic origin, the fact should be stressed that treatment may be instituted at any stage of assessment as it will be little influenced by detailed diagnosis. Nevertheless, many patients and their physicians will desire a better knowledge of the underlying pathophysiology of ED; furthermore such knowledge may be of prognostic value. The suggested algorithm (Figure 10) may serve as a basis for insights how further diagnostic tests - which at present are classified as investigational, and therefore not included - could further improve the definition of the neuromuscular lesion underlying the ED, and how further subgroups of patients might be evaluated. Its is to be expected that better defined neurological diagnosis of patients with possible neurogenic ED may prove more relevant in the future, when treatment options tailored to particular subgroups of ED will become available. Futhermore, a better diagnostic definition of patient subgroups may be important in research projects on pathophysiology of sexual dysfunction, and on the effect of different treatment options in well defined subgroups of neurological patients. A simplified algorithm is shown in Table 3.

III. CONCLUSIONS AND RECOMMENDATIONS

Taking a careful case history, performing at least a focused neurological examination, including the lumbosacral segments, complemented in very selected patients (particularly those with suspected peripheral nervous system involvement) by neuro-physiological tests, should - in addition to other indicated investigations - be considered in patients seeking medical advice because of a sexual disability.

C. SEXUAL DYSFUNCTION IN BRAIN DISORDERS INCLUDING MULTIPLE SCLEROSIS I. SEXUAL DYSFUNCTION IN PATIENTS WITH HYPOTHALAMOPITUITARY DISORDERS

Table 3: Erectile dysfunction and suspicion of a neurologi cal disorder 1.

Spinal cord injury : Remit to Spinal Cord Injury Center

2.

Other known neurological disorder : Consult with neurologist treating patient

3.

Case history and/or result of neurological examination indicates central nervous system disorder : a) Try to make a diagnosis b) Then : Try oral drugs such as sildenafil at first

4.

Case history and/or result of neurological examination indicates peripheral nervous system disorder : a) Try to make a diagnosis b) Then : Try ICI with prostaglandin E 1 at first

5.

No known neurological disorder present nor anything in case history nor in examination indication nervous system disorder : Proceed according to general principles

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Decreased or absent sexual desire is the cardi nal symptom in males with hypothalamo-pitui tary disorders. In most cases this is the first symptom to appear. However, males rarely seek medical advice when experiencing a loss of sexual desire. Hence, the diagnosis is usually postponed in men until some other symptoms appear and it may be as long as a decade after the onset of the sexual problem before any further symptom of a pituitary tumour develops. Threefourths of hypothalamo-pituitary cases report decreased or absent sexual desire at the time of diagnosis. The figures are higher for those with larger tumours extending into the suprasellar region than for those with intrasellar tumours. A highly significant correlation has been found between low serum testosterone levels and a decrease in desire [1]. Usually the patients also have an erectile failure. However, because of reduced sexual interest, the erectile failure is less problematic to the patient. Decreased sexual desire is

also the first symptom in most men with smaller pituitary tumours and hyperprolactinaemia [2].

after their stroke were normal in 45%, and impaired in 55% of patients [12]. Orgasmic dysfunction after stroke was reported in 2/3 of men [8]. Sexual problems in post-stroke patients are usually explained in terms of lack of coping. Diminished sexual contact for post-stroke patients is primarily due to the patient´s overwhelming fears of inadequacy. Other psychological factors have also been suggested. Cognitive impairment may disturb the sexual part of a relationship. Sexual problems are more often seen in cases with aphasia [13]. In some studies the prevalence of major sexual dysfunction (decrease in libido and in frequency of intercourse) was significantly greater after right than after left hemisphere stroke in male patients with unilateral stroke [14-15]. Other studies did not confirm this observation [8,16]. Lesions in the non-dominant hemisphere and the parietal lobe in particular were more often associated with a decline of desire. General hemihypoaesthesia is associated with decreased sexual ability probably due to loss of erogenous zones.

Most of the time a hypothalamo-pituitary dysfunction is caused by a pituitary adenoma. There are also less common types of tumours in this region of the brain such as craniopharyngiomas, meningiomas, optic gliomas, hypothalamic hamartomas and metastasis [3]. Furthermore, there are many non-tumour disorders of hypothalamo-pituitary dysfunction with loss of sexual desire and impotence as cardinal symptoms [4]. There are also a lot of other causes of secondary hypogonadism (see committee 7). Thus, in a CT/MRI study of 164 impotent men with low serum testosterone values significant pathology of the hypothalamo-pituitary region was found in only 11 patients [5].

II. SEXUAL DYSFUNCTION IN PATIENTS WITH BRAIN INJURIES Disability and cognitive impairment occur rather often after a traumatic brain injury. Sexual impairment is not rare either as a consequence of the cerebral lesion or as a consequence of psychological factors. Both decreased and increased sexual desire may be seen as well as impotence and retarded ejaculation [6-7]. Lesions of the frontal and temporal lobe seem to result more often in sexual problems than do lesions of the parieto-occipital part of the brain. Bilateral lesions of the anterior temporal regions may result in the so-called Klüver-Bucy syndrome where pansexuality is a prevailing symptom. Pansexuality refers to sexual drive that is directed not only towards humans but also towards animals and inanimate objects.

IV. SEXUAL DYSFUNCTION IN PATIENTS WITH EPILEPSY Numerous symptoms of sexual dysfunction can be seen in epileptic patients, during the interictal period or in relation to seizures. a) Interictal phenomena. Many male epileptic patients suffer from loss of sexual desire, reduced sexual activity, and/or inhibited sexual arousal [17-20]. The figure varies in different studies and is generally higher than those observed in the control population, with some exceptions. Inability to maintain erection, more rarely ejaculatory dysfunction, decreased satisfaction with sexual life, reduced sexual fantasies, dreams and initiatives, are reported in patients with complex partial epilepsy and mesiobasal temporal spike focus [21-22]. Sexual interest seems to be more reduced in patients with right compared to left temporal lobe epilepsy. Life satisfaction and sexuality are higher in patients who are seizure-free compared to non-seizure-free. Prior surgery for epilepsy does not seem to be a causal factor [23]. Hypersexual behaviour exists only in a few reported cases [24]. Social and psychological factors may also play an important role.

III. STROKE AND SEXUAL DYSFUNCTION About 3/4 of stroke patients who were sexually active before the stroke, report an abrupt and permanent decrease in coital frequency. The feeling of an overall change in sexual life is reported more frequently by male patients. The majority (5065%) have erectile dysfunction after a stroke [811]. In one study nocturnal erections two months

609

b) Seizures and sexual dysfunction Epilepsy and sexual behaviour may be connected in many ways. For example, sexual activity can pro voke an epileptic attack, sexual phenomena may be a part of an epileptic seizure, and the epileptic patient may display changes in sexual behaviour. Hyperventilation is weIl-known to provoke generalised epileptic seizures. Most individuals hyperventilate during sexual intercourse. Thus, it is not uncommon for sexual activity to provoke an epileptic fit. Certain types of sexual behavior can trigger a partial epileptic attack by stimulating particular cortical areas of the brain. Sexual fantasies as well as genital stimuli (masturbation) or orgasm may trigger reflex epilepsy. Only few such cases have been published but the problem is probably not reported very often by the patients if not explicitly asked for. If an epileptic seizure is generated from a genital sensory cortical area, sensations in the genital organs may be experienced as a partial epileptic fit [25]. Motor symptoms such as erection and ejaculation or the sensory experience of an orgasm may occur during an epileptic fit. Such events may be experienced by the patients as sexual or as nonsexual. Pelvic sexual movements, as a part of epileptic automatisms, or compulsive masturbation in front of other people may occur during or after a seizure. In addition to sensory phenomena, other sexual phenomena may occur during an epileptic seizure in patients with complex partial epilepsy, most often in patients with temporal lobe lesions [26]. Sexual automatisms may also occur with frontal lobe lesions. They are very uncommon in primary generalised epilepsy of the grand mal or petit mal type. Deviate sexual behaviour such as exhibitionism, fetishism, frotteurism, sadomasochism, transvestism, and violent sexual behavior or pansexual behavior is sometimes displayed by the epileptic patient. Only a small number of cases have been reported but the fact that the behaviour in question may occur episodically and sometimes disappears after treatment speaks in favour of a causal connection between the behaviour and the epilepsy or the cerebral lesion behind it. In most cases there were partial complex epileptic seizures and lesions in one or both temporal lobes. Sometimes

the deviate behavior correlated with continuous epileptic discharges in the EEG (psychomotor status). For further details about sexual phenomena in epileptic patients, see Lundberg [4]. c) Antiepileptic drugs and sexual function It should be noticed that antiepileptic drugs, especially the older types (phenytoin, phenobarbital, primidone and carbamazepine), may influence both sexual desire and performance [27]. Patients on phenytoin or carbamazepine monotherapy as well as those on polytherapy had a significantly lower free androgen index than controls [28]. In this study it was also found that those patients receiving anti-epileptic drugs embraced a stricter sexual morality and expressed greater satisfaction with their marriages then untreated patients with epilepsy.

V. SEXUAL DYSFUNCTION IN PARKINSON´S DISEASE AND OTHER MOVEMENT DISORDERS Decrease in sexual desire is common in Parkin son´s disease. Symptoms of sexual dysfunction are also frequent in their partners [29]. Erectile dysfunction during sexual intercourse occurs in half of the males [30-31] and nocturnal and morning erections are usually absent. Many males are also unable to ejaculate and to achieve an orgasm. During sexual arousal tremor is often enhanced which makes sexual activity more difficult. Muscle rigidity and akinesia may also contribute to difficulties in performance of sexual activities. Patients with Parkinson´s disease are often depres sed and have a tendency to isolate themselves from other people. The mechanisms behind sexual dysfunction in parkinsonian patients is not very well understood. To some extent it may be a similar mechanism as with other chronic disorders, such as arthritis [32]. But studies of bladder and bowel function have demonstrated a high frequency of bladder detru sor hyperreflexia and paradoxical contractions of the striated sphincter muscles during defecation, suggesting that specific autonomic nervous system involvement may exist in these patients [33-34].

610

It is interesting to note that decrease of sexual desire is not directly coupled to the severity of the disease. Treatment with dopaminergic compounds may result in an apparent increase, or rather a normalisation, of sexual desire without corresponding improvement of the movement disorder. Thus, increase in desire has been reported as an adverse reaction to dopaminergic drugs.

flow [45]. Problems with ejaculation are also very frequent, 35-60 % have been reported [41, 43-44]. Decreased desire also occurs, but this problem has not been studied to a large extent. Occasionally, increased sexual desire can constitute a problem. Sexual dysfunction correlates with bladder and bowel dysfunction and mildly with motor and sensory dysfunction in the lower extremities [42, 46-47]. The correlation is poor with disability, clinical course and disease duration. Depression and cognitive impairment may play an important role. Anorgasmia has been correlated with MRI brain stem and pyramidal abnormalities as well as with total area of lesions on MRI [48].

The situation is quite different in Huntington´s disease (HD). Fertility is increased among these patients: those of the family who are going to develop the disease have more children than those who do not. Increased sexual activity is seen in around 10% of the patients with HD, not seldom in combination with mania or hypomania. Habitual promiscuity and marital infidelity may be symptoms of onset in HD. However, HD patients may have difficulty in getting sexually aroused. Paraphilias such as sexual aggression, exhibitionism and pedophilia have been reported in HD patients [35].

Symptoms related to MS, such as fatigue, muscle contractions in the lower limbs, urinary disturbances and the use of aids to manage incontinence and paroxysmal motor and sensory disturbances triggered by sexual intercourse can indirectly exert a negative effect on sex life as well as social and physical changes. A comprehensive review on sexuality and MS has recently been published [49]

Disorders of sexual inhibition and some kind of pansexuality, e.g. copulation with non-living objects are not infrequent in Tourette´s syndrome [36-37]. Increased sexual activity is also reported in patients with Wilson´s disease [38]. Impotence is almost universal among patients with multiple system atrophy, both of the striato-nigral type and the olivo-ponto-cerebellar type [39]. It may be the presenting symptom.

VII. CONCLUSIONS Sexual disabilities such as erectile dysfunction and disturbances of ejaculation and orgasm are very common among patients with disorders of the central nervous system. Examples of such disorders of great importance are sequelae after brain injuries, stroke, Parkinson´s disease, multiple sclerosis and epilepsy. In brain disorders and after brain injuries sexual desire may also be reduced and behavioral disturbances may occur.

VI. SEXUAL DYSFUNCTION IN MULTIPLE SCLEROSIS Changes in sexual function are rare at the onset of the disease but become very common during the evolution of the disease. Impotence is the most notable sexual dysfunction in men with multiple sclerosis. Figures given in the literature vary between 35 and 80% [40-44]. There are no indications of insufficient arterial inflow or venous out-

Sexual disabilities may be the presenting symptom or one of the early symptoms of a neurological disorder.

611

paramalignant manifestations. Such is also the case in Guillain-Barré syndrome. In a study of 341 consecutive impotent patients, neurophysiological evaluation for polyneuropathy revealed the presence of polyneuropathy in 38 % of the diabetic cases and in 10 % of the other impotent cases [9].

D. SEXUAL DYSFUNCTION IN AMYOTROPHIC LATERAL SCLEROSIS, POLYNEUROPATHIES AND MUSCLE DYSTROPHIES

Since amyotrophic lateral sclerosis is a rapidly progressive paralytic disease leading to an almost total paralysis of the whole body including respiratory muscles, severe sexual problems might be expected. However, the neurones of Onuf´s nucleus in the sacral spinal cord innervating the pelvic floor muscles are spared and the patients do not have sensory or autonomic symptoms. Thus, the patients usually have no difficulty with urination and defecation, and normal sexual functions are the rule in males [1]. Despite the fact that severe paralysis of all voluntary movements eventually make intercourse impossible, erection and eja culation is possible through partner masturbation and the sensation of orgasm may be experienced as normal. In Kennedy´s syndrome (X-linked bulbospinal muscular atrophy) gynecomastia is common, and testicular atrophy, decreased libido and impotence may occur [2]. In certain types of progressive muscular dystrophies, the Becker type in particular, hypogonadism in combination with disturbances of potency and reduction of libido have been described [3]. Early onset of the neuromuscular disease, together with rapid disease progression results in constricted psychosocial and psychosexual development and in severe limitations on sexual activity [4].

For a further description of sexual dysfunction in diabetic polyneuropathy the reader is referred to the Chapter on Endocrine and Metabolic Aspects in this volume as well as to recent reviews [1011]. In addition to the neuropathies described above, there are also a number of hereditary metabolic polyneuropathies. Very little has been written about sexual dysfunction in these types of polyneuropathies. However, based on physiological data both impotence, retarded or retrograde ejaculation and difficulty in reaching the orgasm phase are to be expected. Thus, impotence and ejaculation problems have been observed in patients with hereditary sensory neuropathy [12], CharcotMarie-Tooth syndrome [13], adrenomyeloneuropathy [14-15], Refsum´s disease [16] and primary amyloidotic polyneuropathy [17-20]. The adrenoleukodystrophies represent a group of impotent patients of particular interest since this is a fatal disease [14]. On the other hand, in a study of patients with hereditary motor and sensory neuropathy (HMSN) motor pudendal nerve involvement was reported but the patients did not have any signs of erectile dysfunction [21].

CONCLUSIONS

Autonomic dysfunction, including erectile dysfunction, is a common complication in peripheral neuropathies [5]. Polyneuropathies resulting in such complications include those due to infectious agents, chemical toxins [6], prescription or street drugs, vitamin deficiency (Vitamin B1 [7], Vitamin B12 [8]) as well as parainfectious or

Erectile dysfunction is very common among patients with polyneuropathies, diabetic polyneuropathy in particular. This is also the case in the large group of genetic neurological disorders. However, here our knowledge is insufficient.

612

rience that SCI men may more easily accept their motor deficits than their sexual problems [3]. Some of these patients even indicate that, if they had the choice, they would rather regain their sexual life than their motor function [6]; erectile dysfunction as well as ejaculatory dysfunction are frustrating conditions.

E. ERECTILE AND EJACULATORY DYSFUNCTION IN SPINAL CORD DISORDERS.

I. INTRODUCTION II. PATHOPHYSIOLOGICAL PHASES FOLLOWING SPINAL CORD INJURIES

In this review concerning spinal cord disorders no distinction is made between individuals with nontraumatic spinal cord or cauda equina lesions (including congenital spina bifida, sequelae after transverse myelitis, spinal cord tumours, prolapsed discs etc.) and traumatic spinal cord injuries as they have similar erectile and ejaculatory dysfunctions [1-3], however, the traumatic group constitutes the majority of the spinal cord lesioned population.

Following a sudden and complete spinal cord transsection, three disorders of function become evident [10]: 1) all voluntary movement below the level of lesion is immediately and permanently lost; 2) all sensations below the level of lesion are abolished; and

Traumatic spinal cord injury (SCI) is a devastating medical condition. In an instant of time, an ablebodied individual experiences extreme changes in body functions, including paralysis and loss of sensation below the level of lesion, loss of normal urinary bladder and bowel functions, and erectile as well as ejaculatory dysfunction. Another function that is usually lost in SCI men is the ability to procreate naturally [1,3].

3) reflex function in all segments of the isolated spinal cord is completely lost (spinal shock). Less complete lesions of the spinal cord may result in little or no spinal shock, and the same is true for lesions that develop slowly. Guttmann [11] distinguished between three phases in the pathophysiology of the sexual organs: spinal shock, reflex return, and readjustment.

For several decades it has been a widespread belief that individuals with SCI are permanently and completely impotent and infertile. Fortunately, many investigations demonstrate that this is not true [2,3]. Comarr & Vigue [4] stated that health professionals had been guilty of perpetuating the myth that disabled individuals are asexual, and according to Anderson & Cole [5] many people harbor the belief that a body with some degree of paralysis or deformity is unable to engage in sexual intercourse at all.

a) Spinal shock The spinal shock phase lasts from a few hours to several weeks, during which there is a complete or almost complete suppression of the reflex activity below the level of the cord lesion. The male genital reflexes (reflex penile erection, bulbocavernosus and cremaster reflexes) are abolished or profoundly depressed. The erectile and ejaculatory functions are abolished. In complete lesions, the penis may become enlarged and semierected, which is a result of a passive engorgement of the corpora cavernosa due to the paralytic vasodilation following the interruption of the vasoconstrictor fibers in the antero-lateral tracts of the spinal cord [11]. The spinal shock stage is believed to be due to the sudden interruption of the suprasegmental descending fiber systems that keep the spinal motor neurons in a continuous state of subliminal depolarization (ready to respond) [10].

Sexual dysfunction following SCI has fortunately attracted considerable attention from therapists in the field, perhaps, because many people affected by SCI are young, active, and otherwise healthy [6]. Modern rehabilitation techniques have given them much greater life expectancy [7-9] and considerably greater mobility. Preoccupation with future sexual performance occurs early and is quite prominent in the mind of persons with SCI [6]. Even when considerable, it is a common expe-

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The period of spinal shock is the main reason that it usually is impossible to predict the sexual function, including return of erection and ejaculation, in SCI males within the first weeks after injury.

tance [12, 14, 17-37]. Several previous reviews and studies [24,38-44] have stressed the difficulty in interpreting the various results due to methodological factors. These include variability in subject selection and data collection (for instance, information may be obtained by mailed questionnaire or by personal interview), poorly described diagnostic criteria for determining the level and extent of the SCI, failure to identify variables such as years of age and duration of SCI, general health status, possible surgical intervention such as external sphincter resection, previous sexual experience, and opportunity for sexual activity. However, the most important factor may be that the validity of the retrospective reports obtained from men with SCI is not known. Thus, Kennedy & Over [43] found that among SCI men who were studied with straingauge measurement of penile tumescence when exposed to erotic material, several who had anticipated having an erection failed to do so, whereas others demonstrated penile tumescence during erotic stimulation despite claiming loss of the capacity for psychogenic erection.

b) Return of reflexes When spinal shock subsides, reflex activity and spasticity may appear in the lower extremities, and urinary bladder and bowel function may become reflexogenic. In upper motor neuron lesions, the erection reflex becomes one of the components of the autonomic functions of the isolated cord, taking part in the “mass response”. In fact, it may appear, independent of cerebral participation, before the reflex responses of the skeletal muscles are fully developed. Tactile stimuli of varying type and intensity, including stimuli of the penis, result in erection [11]. c) Re-adjustment Sexual re-adjustment after SCI is very dependent on the particular person’s wishes, experience, and sexual habits in pre-SCI life, whether this applies to love play or actual methods of intercourse. It may also, to a great extent depend on the cooperation and helpfulness of their partner [11]. Siösteen et al [12] found that sexual readjustment after injury was closely and positively correlated to a young age at injury and willingness to experiment with alternative sexual expressions. Physical and social independence and a high mood level were further positive determinants of sexual adaptation after injury.

Tsuji et al [24] reported a very low frequency of successful intercourse as seen in Table 4, but this was due to the fact that the majority of the SCI men did not have the opportunity to test their sexual ability. In contrast, Jackson [29] found that 15 out of 20 SCI males engaged successfully in intercourse. The possible influence of the type and level of lesion is illustrated with the figures in Table 5 from Bors & Comarr’s study [14]. In general it has been experienced [38] that the frequency of erection is higher among SCI men with incomplete than with complete lesions, with upper than with lower motor neuron lesions (refering to injuries that do or do not preserve S2-S4), and with high rather than low levels of SCI. In a recent study [45] it was noted that normal erectile function was maintained in men with incomplete but not with complete spinal cord lesions. However, as pointed out by Comarr [26] although knowledge about completeness and upper/lower motor neuron lesion enables a general prognosis, it does not necessarily provide an accurate prognosis for future sexual function in the individual. Siösteen et al [12] found that the neurological level and completeness of injury showed no significant correlation with sexual function.

III. ERECTILE DYSFUNCTION Erectile dysfunction is defined as the inability to achieve and maintain an erection sufficient for satisfactory sexual performance [13]. The neurological level and completeness of the spinal cord lesion varies considerably, but in general more than half of all SCI men are unable to achieve erections that permit successful sexual intercourse [14]. However, at least three types of erections in SCI men have been described in the literature including reflexogenic, psychogenic and mixed erections [15,16]. Table 4 shows an overview of the percentage of men with SCI reporting erection (any type) and successful intercourse without therapeutic assis614

Table 4: Percentage of men with spinal cord injury reporting erec tion (any type) and successful sexual intercourse without therapeu tic assistance. REFERENCE Munro et al 1948 [17]

NO. OF MEN

ERECTION %

SUCCESSFUL coitus %

84

74

-

Bors 1948 (cited in ref.14)

157

87

33

Talbot 1949 [18]

200

64

-

Bors et al 1950 [19]

34

88

-

Kuhn 1950 [20]

29

86

-

Talbot 1955 [21

208

69

23

Zeitlin et al 1957 [22]

100

86

26

Bors & Comarr 1960 [14]

529

81

50

Money 1960 [23]

14

79

-

Tsuji et al 1961 [24]

638

54

5

46

73

-

Hohmann 1966 [25]

25

72

-

Comarr 1970 [26]

150

82

38

-

Jochheim & Wahle 1970 [27] Wahle & Jochheim 1970 [28]

48

58

-

Jackson 1972 [29]

20

85

75

Piera 1973 [30]

100

79

-

Fitzpatrick 1974 [31]

14

86

21

Comarr & Vigue 1978 [32]

153

90

-

Morley et al 1979 [33]

18

83

-

Uyttendaele et al 1979 [34]

18

78

-

Taylor & Coolican 1988 [35]

16

81

69

Slot et al 1989 [36]

38

95

-

Zasler & Katz 1989 [37]

20

70

-

Siösteen et al 1990 [12]

60

83

64

Total Range Median

2,719 54%-95% 80%

5%-75% 36%

Table 5: Effects of completeness and upper versus lower motor neuron lesion on erection, ejaculation and successful sexual intercourse TYPE OF LESION

NO

ERECTION

EJACULATION

SUCC

Compl upper

287

93 %

5%

53 %

Incompl upper

123

99 %

32 %

63 %

Compl lower

109

26 %

18 %

23 %

Incompl lower

10

90 %

70 %

80 %

(After Bors & Comar 1960) [14]

615

INTERCOURSE

Table 5 shows figures from Bors & Comarr’s study [14] illustrating the influence of the type and level of lesion on the capability of ejacula tion. The frequency of ejaculation is generally considered to be higher among SCI men with incomplete than with complete lesions and with lower motor neuron than upper motor neuron lesions, respectively.

IV. EJACULATORY DYSFUNCTION The ability to ejaculate by masturbation or by sexual intercourse is impaired in the majority of men with SCI and, consequently, pregnancies caused by SCI men without medical intervention are rare [1,3,21,46]. The low incidence of fertility can not be completely attributed to ejaculatory dysfunction because semen obtained from SCI men by methods of assisted ejaculation is of poor quality [47-58].

Table 6: The percentage of men with spinal cord injury reporting ejaculation without therapeutic assistance.

REFERENCE

The impact of loss of the ability to proceate is amplified by the demographics of SCI from USA [9]. In this country there are approximately 10,000 new SCI cases per year. Eighty-two percent occur in males. About 80% of new SCI men are 40 years of age or younger. Table 6 shows the reported frequencies of ejaculation in SCI men without therapeutic assistance. Considerations concerning methodological factors, similar to those mentioned about erectile dysfunction, must be made when comparing the literature results of ejaculatory capability [24,38,4042,44]. An additional problem is to determine what an ejaculation actually is, which can be confounded by individual patients perception of ejaculation. For example, in some studies dribbling emission has been included, but not in other studies [59]. Another difficulty in determining the frequency of ejaculation after SCI is the possibility of retrograde ejaculation especially following transurethral resection of the urinary bladder neck or the prostate [60].

NUMBER OF MEN

EJACULATION %

Munro et al 1948 [17]

84

10

Bors 1948 (cited in ref. 14)

157

20

Talbot 1949 [18]

200

10

Bors et al 1950 [19]

34

15

Kuhn 1950 [20]

25

8

Talbot 1955 [21]

208

15

Zeitlin et al 1957 [22]

100

3

Bors & Comarr 1960 [14]

529

15

Money 1960 [23]

14

0

Tsuji et al 1961 [24]

638

9

46

14

Hohmann 1966 [25]

-

25

12

Comarr 1970 [26]

150

11

Jochheim & Wahle 1970 [27]

Despite these objections it is interesting to note that the studies from 1948 to 1970 report ejaculation frequencies between 0 and 20%, while those from 1972 to 1990 all show frequencies between 27 and 52% (table 6). These findings may reflect some differences in the populations studied, including the number of men with incomplete lesions. Also other external reasons, such as changing attitudes in the surrounding society towards a more permissive and open view of sexuality and disability, supported and encouraged by patients’organisations and the media may be important in this respect as well [12]. However, this can also imply that some of these reported ejaculations have been induced, for example, by the use of penile vibratory stimulation at home [30].

Wahle & Jochheim 1970 [28] 48

8

Jackson 1972 [29]

20

35

Piera 1973 [30]

101

27

Fitzpatrick 1974 [31]

14

42

Morley et al 1979 [33]

18

33

Uyttendaele et al 1979 [34]

18

33

Slot et al 1989 [36]

38

45

Siösteen et al 1990 [12

60

52

Total

2,527

0%-52% (median 15%)

V. CONCLUSIONS The majority of men with SCI can obtain some type of erection but, in general, less than half of all SCI men are able to achieve erections that permit successful sexual intercourse. Only a minority of SCI men have the ability to ejaculate during sexual intercourse. 616

number of cases of decreased libido was of the same magnitude (2.9 to 5.4) for all these groups, indicating a similar mechanism. Alpha-adrenoreceptor blocking agents as well as alpha-and betaadrenoreceptor blocking agents and guanidine derivatives were associated not only with erectile dysfunction but also with ejaculation failure. Alpha-methyldopa has been reported to cause suppression of ejaculation [10] Furthermore, pria pism was reported with the alpha-adrenoreceptor blocking agents (such as prazosin).

F. ADVERSE SEXUAL REACTIONS FROM PRESCRIPTION DRUGS

I. INTRODUCTION The emergence of genito-urinary symptoms with antidepressant treatment was already pointed out by Simpson et al in 1965 [1]. Since then a number of review articles on adverse reactions affecting sexual function from prescription drugs have appeared [2-6]. However, most of these have been based on case reports. Relatively few clinical drug trials have sexual dysfunction included in the side effect check lists. Also, the mechanisms behind the drug actions in those cases are not very well known.

III. ANTIDEPRESSANT DRUGS If the sexual response cycle is divided into three phases, then 30% of the more than 5.000 reports (both sexes) concerning antidepressant drugs related to the phase of desire, 30 % to the phase of excitement and 40 % to the phase of orgasm [9]. For the non-selective monoamine reuptake inhibitors, erectile dysfunction and problems with ejaculation were the most abundant, whereas problems with desire were less important. Problems with ejaculation and orgasm were much more fre quently reported for the group of selective serotonin reuptake inhibitors (SSRIs) than for the group of non-selective monoamine reuptake inhibitors. The most frequent adverse reaction with SSRIs concerned ejaculation and orgasm in males, whereas problems with erectile dysfunction were less often reported. Trazodone was the drug with the highest number of priapism reports among all drugs.

Another way to get information about sexual adverse reactions is to use the WHO data base of suspected adverse sexual reactions from prescription drugs. This data base contained (1968 to October 1997) 1.7 million reports about adverse reactions of drugs in 49 countries from all over the world. Adverse sexual reactions were described in approximately 1 % of the reports [7-9]. From these reports two types of drugs can be distinguished as the most important: the antihypertensive drugs and neuro-psychopharmacological drugs, antidepressant drugs in particular.

II. ANTIHYPERTENSIVE DRUGS The greatest number of reports concerned antihy pertensive drugs [7-8]. All classes of these drugs were represented. The different drugs seem to have few pharmacological effects in common other than lowering blood preasure, hence, the erectile dysfunction could be vascular. However, since decrease in libido was also reported with these drugs, the effect may be partly central. Another possibility for decreased sexual desire is a psychological feed-back mechanism: loss of erection provides less sexual stimulation. The quotient number of cases of erectile dysfunction over the

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Decreased desire and erectile dysfunction are typical symptoms of depression. Therefore, it is difficult to determine in each case what symptoms are caused by the depression itself and what may be an adverse drug reaction. It is also difficult to estimate the incidence of sexual dysfunction in patients taking antidepressant drugs. Most data regarding non-selective monoamine reuptake inhibitors were from a time when these problems were not given much respect. The SSRIs belong to a more recent generation of antidepressant drugs and therefore reports of sexual dysfunction or adverse drug reactions may be increased because they are more common and accepted. If a particular drug is followed during its post marketing period, the frequency of reported adverse sexual drug

reactions may vary immensely, for example, with fluoxetine, reports varied from 2% - 75% [11]. If only spontaneous reports were counted, the incidence of sexual adverse reactions during treatment with SSRIs was much lower (14 %) than if direct questions were asked (58%) [12].

do [7]. L-DOPA has such a pronounced positive effect on sexual function that it has been used in treatment [17-18]. Antipsychotic drugs with alpha-adrenoreceptor blocking properties, chlorpromazine, thioridazine, haloperidol and clozapine in particular, are reported to give either impotence or priapism as adverse reactions and also ejaculation failure and changes of quality of orgasm [2-4, 7]. Increase or decrease in sexual desire and erectile dysfunction may also occur. The mechanisms are largely unknown, but there is a suspiscion that they could be related to the increase in plasma prolactin levels that is commonly seen with these types of drugs [19]. Thioridazine, belonging to a group of antipsychotic drugs that rarely causes extrapyramidal side effects, can also lead to painful, retrograde, or spontaneous ejaculations [4, 20].

Ejaculatory problems are seldom reported as symptoms of depression, nor are anorgasmia or priapism. In the study of Lundberg & Biriell [9] on adverse effects of antidepressant drugs, orgasm and ejaculation were impaired to a greater extent than erection. Reports on adverse drug reaction reports do not usually allow a critical analysis of the distinction between “ejaculation” and “orgasm” in each male patient. The ejaculatory process is as mentioned earlier very complex. Probably the most important effect of the nonselective monoamine re-uptake inhibitors is an alpha-receptor blockade of emission.

Another main group of drugs causing erectile dysfunction are the histamine-2-receptor antagonists, cimetidine in particular. These drugs are also reported to cause decreased libido and gynaecomastia. The mechanism is at least partly an estrogenic/antiandrogenic effects of the drugs in question [21].

Priapism after trazodone is a very typical sexual adverse reaction from this drug. The mechanism for this is thought to be interference with the sympathetic control of detumescence due to alphaadrenoreceptor blocking properties of the drug [13].

From animal experiments we know that the GABA agonist baclofen can block penile reflexes on a spinal level [22]. Erectile dysfunction in men who were receiving intrathecal baclofen by an implantable pump has been reported [23] as well as anejaculation. Oral baclofen can sometimes result in increase in sexual desire [24].

To be able to compare different drugs one needs controlled studies comparing therapeutic doses of the drugs in question with a proper analysis of any possible sexual side effects. Few such studies exist. Harrison et al [14] compared imipramine and phenelzine and found a high incidence of adverse sexual reactions. Both amitriptyline and mianserin significantly decreased the amplitude and total duration of nocturnal erections [15]. Feiger et al [16] studied nonpsychotic patients with major depression treated with sertraline or with nefazodone. 78 % of the men taking sertraline and 59 % of those taking nefazodone reported delayed ejaculation. 15 % of the men taking sertraline and 52 % of the men taking nefazodone, reported premature ejaculation.

V. CONCLUSIONS AND RECOMMENDATIONS Sexual adverse reactions have been reported not only with the use of many prescription drugs acting on the nervous system but also with many other groups of drugs, such as antihypertensive drugs and drugs acting on the endocrine system. It is therefore advisably to enquire all patients with sexual problems about actual use of prescription drugs.

IV. OTHER TYPES OF DRUGS Dopaminergic drugs (L-dopa, bromocriptine, selegiline) represent the only group where the number of reports with increased libido was greater than the number of reports with decreased libi-

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G. TREATMENT OF NEUROGENIC ERECTILE DYSFUNCTION

III. INTRACAVERNOUS INJECTION THERAPY 1. INTRACAVERNOUS INJECTION OF PAPAVERINE Since the first report by Virag [8] in 1982, papaverine has been used extensively in the treatment of erectile dysfunction in spinal cord injured men especially in the USA[9]. Seven studies, focusing on the efficacy of papaverine for erectile dysfunction in spinal cord injury, have been published [8, 10-15] and one for multiple sclerosis [1]. All of them are open trials with the number of patients ranging from 12 [16] to 101 [13]. The dosage of papaverine did not relate statistically to the level or extent of injury [15, 17]. All the authors reported efficacy around 90%. In this population doses were lower than in vascular diseases and erection lasted longer and was of better quality [14]. In a study in which the dose started at 3 mg and was increased weekly, [17] 56% of the patients used doses of 12 mg or less. Priapism and prolonged erection were the most common acute complica tions but were obviously related to the dosage used in the protocols. Beretta [10] found 31% of patients reported priapism with 30 mg of papaverine and other studies reported 7% with priapism when the dose was progressively increased [1, 1415, 17]. Tunical scarring is a long term treatment complication and affects from 2% to 8% of patients after 6 months of treatment. Little is known about the long term efficacy in this population.

I. INTRODUCTION Recent advances in the knowledge of physiology, pharmacology and haemodynamics of erection have led to the development of new treatments by transcutaneous, oral, intracavernous or transurethral therapies. All such drugs are now available for neurologically impaired patients. The majority of publications have focused on spinal cord injured patients except for one on multiple sclerosis patients [1]. In general, the spinal cord injured population is young, and probably exempt from vascular diseases, and this becomes important when considering dose ranging studies and risk of priapism. However in the majority of studies very little is said about the level of the lesion, whether it is complete or incomplete or whether reflexogenic erections may be obtained.

II. VACUUM THERAPY Vacuum constriction devices have been used since 1917. Initially the results were excellent, with adequate rigidity for penetration reported in 90% [2,3-5] of the patients with neurogenic erectile dysfunction (ED). Satisfaction of the partners was also initially high (70%). After six months of treatment, despite an increase in sexual activity, only 41% of the patients were satisfied with the device [3].Similar results have been reported by Heller [4]. In this study the most common complaint was premature loss of rigidity and difficulty in placing and removing the constriction bands. The most common complications were bruises, petechiae, and skin oedema. Severe complications such as penile gangrene, severe erosion and cellulitis were reported and were associated with prolonged constriction band wearing [6, 7].

2. I NTRACAVERNOUS PROSTAGLANDIN E1 Prostaglandin E1 is used worldwide for self injection therapy in ED. An extensive review [18] of the literature on PGE1 and also on papaverine and a papaverine-phentolamine mixture showed a efficacy rate of more than 70% in patients with ED. Complications such as priapism were lower with prostaglandin (0.25%) than with papaverine (6.5%) or a papaverine-phentolamine mixture (6.3%). Furthermore the risk of local long term complications was lower with prostaglandin (0.8%) than with papaverine (5.7%) or a papaverine-phentolamine mixture (12.4%).

619

In the setting of neurogenic ED, Hirsh [19] reported that the mean dosage for efficacy was 6.2 mg for spinal cord injured patients and 8.2 mg for multiple sclerosis patients or discogenic diseases. In a long term study 40% of the patients dropped out the treatment. This is comparable to the rate of a non selective population of patients with ED [20]. No priapism or local complication was observed in this population [19] with a mean follow-up of 28 months. No patients discontinued treatment because of pain. This could be explained by the loss of sensations in contrast to the general population in which 50% of men reported pain [21, 22]. Similar results in terms of efficacy have been reported by Tang [23]. In this population of 15 spinal cord injured patients, only two with incomplete lesions complained of pain at the site of injection.

IV. TRANSDERMAL THERAPIES Because of the well known complications of intracavernous injections such as corporeal fibrosis or priapism, local non invasive therapy seems to be attractive. This is particularly true in a population of young patients in which it will be used for several decades. Claes reported [26] the use of trans dermal nitroglycerin for non specific erectile dysfunction with complications such as local pain and vasodilatory headache, orthostatic hypotension and dizziness. In a group of 17 patients [27] who had a good response with intracavernous papaverine, Transiderm-Nitro plaster (10 mg/24 h) on the penis was tested. The plaster was placed 1 or 2 hours and a penile shaft was placed 10 minutes before removal. An initial test was positive in 12 patients with 5 having a complete and 7 having a partial response. These 12 patients tried at home. It appeared that 5 patients obtained an erection sufficient for vaginal penetration. In this group the initial response was complete in four. Secondly the dose of papaverine required for efficacy in this group was low (between 5-15 mg). The only side effect was headache in 50% of the patients in the home study. It seems that this treatment was safe, efficient, with minor side-effects. In another group of 28 spinal cord injured men an open randomized cross over trial [28] compared the efficacy of an intracavernous injection of papaverine versus transdermal nitroglycerin. The initial dose of papaverine was 10 mg. The nitroglycerin patch was 5 mg/24 h. A rubber band was kept on the penis for 1 hour with the patch. 93% of the patients who received papaverine showed a complete response and 61% with the nitroglycerin patch. This difference was statistically significant. No significant difference was found between spastic and flaccid patients. The only complication with nitroglycerin was mild headache in 21% of the patients. This study demonstrated that a patch of nitroglycerin can improve erectile dysfunction in spinal cord injured patients. The better results obtained in the second study [28] can be explained by the use of a rubber band for one hour, despite a lower dosage of nitroglycerin. Chancelor [29] demonstrated that topical administration of minoxidil 2% on the glans did not improve the

3. MOXISYLYTE Moxisylyte is an alpha-blocking agent. Efficacy and tolerance have been sudied in a double blind study against a placebo [24]. In 12 spinal cord injured patients all the parameters such as rigidity, abdominal penile angle, and lenght were improved significantly by moxisylyte. But no significant differences were found between the three doses of 10, 20 and 30 mg. Full rigidity was acheived in 7 patients and for 2, partial rigidity sufficient for vaginal intromission was achieved. Neither priapism nor hypotension occured in this laboratory assessment. Despite these encouraging results no long term study in neurogenic ED with intracavernous moxisylyte has been reported.

4. M IXTURE Different protocols combining papaverine with phentolamine have been reported to be effective for the treatment of neurogenic ED [1, 11, 12, 1416]. Unfortunately all the protocols were different regarding doses of papaverine or phentolamine. There is no double blind controlled study comparing the efficacy of papaverine alone or papaverine plus phentolamine in this population of patients. Moreover no comparison of papaverine and PGE1 has been performed in this population as in arteriogenic impotence [25] where the superiority of PGE1 has been suggested.

620

erectile dysfunction in terms of rigidity in comparison with papaverine or a vacuum device.

Sildenafil was well tolerated with a low discontinuation rate due to adverse events (3%). The median proportion of succesful attemps at intercourse was 55% versus 0% for placebo.

Safe and effective local treatment is highly desirable, however topical agents are likely to be delivered via general circulation. The superiority of local administration on the skin of the penis versus another place on the body has not been demonstrated. Placebo controlled studies are needed.

VI. INTRAURETHRAL THERAPY Intraurethral therapy seems to be effective in the treatment of ED [11, 33, 34]. No specific double blind studies focusing on neurogenic ED has yet been reported.

V. ORAL THERAPY Since 1997 sildenafil has been avaliable for the treatment of erectile dysfunction. Only two studies have focused on its efficacy in a population with neurogenic aetiology of erectile dysfunction [30]. Sildenafil is an active selective inhibitor of cGMPspecific phosphodiesterase type 5. Sildenafil improves erection significantly in able bodied patients [31] with no known organic cause. 27 spinal cord injured patients were randomized in a double blind placebo controlled study to receive 50 mg of sildenafil or placebo [30]. After 28 days, improvement of erection was found in 75% of the sildenafil group and 7% in the placebo group. Furthermore a significant improvement in satisfaction with their sex life was reported by the patients under sildenafil. Suprisingly in a sexual function questionnaire and patient questionnaire, only a global satisfaction was improved significantly. Frequency of erection lasting long enough, frequency of erections hard enough for sex, frequency of stimulated erections and frequency of waking erections showed an improvement but without statistical significance. It probably means that 50 mg is not high enough in this population of patients to improve more than a global satisfaction. Another placebo-controlled, 20 weeks, double-blind, flexible-dose, two way crossover sudy was undertaken to evaluate the efficacy and safety of sildenafil in a large population (178) of spinal cord injured men [32]. At the entry 151 patients were reported to have reflexogenic or psychogenic erections and 27 had no residual erectile function. The proportion of patients classified with complete or incomplete lesions were similar in the two groups. 83% of the patients reported improvement in erections and 80% improved the ability ro have sexual intercourse. All those results were stastically significant when compared to placebo.

VII. PENILE PROSTHESIS Penile prostheses are one of surgical treatments for impotence. They have been described over the last 50 years and improvements have been made on prostheses devices and on implantation techniques. General indications have been summarized by Shabsigh in a recent editorial [35] for patients with severe dysfunction or organ failure who do not respond to any pharmacotherapy. Neurogenic patients represent a special group since their complications may be related to the etiology of erectile dysfunction, and because penile prostheses are indicated not only for sexual intercourse but also for appliance maintenance (condoms catheters). That is why, as for other treatments, spinal cord injured patients represent the most documented population for penile prostheses implantation in neurogenic erectile dysfunction. The prostheses can be malleable (semirigid) or inflatable (semi-flexible or flexible). The choice is made by the patient and the physician after specific information is exchanged. Inflatable prostheses require manual dexterity from the patient himself or from his partner who must also be informed. They allow a flacid penis when not inflated which is more practical for everyday life. The choice is guided by indications specially for neurological patients. The maintenance of external appliances and/or treatment of penile skin laceration is best treated by a semirigid prosthesis avoiding ventral flexion of the penis. Most of the reports in the literature are about this type of penile prosthesis. The first important report on inflatable prosthesis was made by Scott [36], and

621

concerned 245 patients during a five year multicenter experience. Seventeen were spinal cord injured patients and no comments have been given regarding specific complications or indications. Since this first report, inflatable prostheses are not so much indicated for this type of patients (between 2 to 6% [37-40]. Among a paraplegic population 31% received a flexible or semi-flexible prosthesis and the others (143/209) had a semirigid one [41].

retrospective methodology in all of them require that readers critically evaluate the rates. An attempt was made by Jarow [46] to describe risk factors for penile prostheses. 24 of the 157 procedures that he described were done on spinal cord injured patients and no prosthesis became infected in this group. The factors that seem of high risk for complications are revisions including associated reconstruction of the penis or a previous surgery for penile implant. Penile prosthesis may be used in diabetic patients [38, 46] but this group seems to be at higher risk [47].

It is important to distinguish between the use of a penile prosthesis for the enhancement of a small retrectable penis versus the enhancement of a normally-sized penis for the purpose of improving sexual function. Primary contraindication for implants is the loss of condom catheters in patients with a small retractable penis [41, 44]. Infection rate in such patients has been considered to be important,with the rates ranging from 2% [43], to 5.6% [41] or 10% [44].

As it was reported by Green in 1986 [48] and is still true today, this is not a procedure to be recommended indiscriminately to every patient who requests it. If an urologic indication is present, careful information must be given to the patient to avoid failure of the prosthesis due to lack of local care of the penis and prosthesis (skin ulcers, use of vacuum device, permanent urethral catheter). In terms of sexual satisfaction, levels of satisfactory sexual intercourse and of subjective improvement have not been carefully analysed because of the lack of good standardized methodology and validated questionnaires in this population.

A consensus has to be reached with regards to meticulous preoperative skin preparation, prophylactic antibiotics, careful choice of type and size of prosthesis, which depend on indication and motivation of the patient. The heterogeneity of different patient populations, and the retrospective studies with non comparable implantation protocols, makes this a difficult comparison. Despite this fact, use of penile implants in patients with a neuropathic bladder can be recommended to allow condom catheter maintenance. It has also been reported to be useful to facilitate intermittent self cathetrisation by lengthening and straightening the penis for selected patients.

VIII. CONCLUSIONS There exsists an arsenal of specific methods, medical as well as surgical, for treatment of erectile dysfunction that can be used also in the neurologic patient. These include testosterone substitution, vacuum therapy, intracavernous injection of prostaglandin E1, papaverine or moxisylyte, transdermal or intraurethral application of different drugs, oral administration of phosphodiesterase inhibitors, and penile prosthesis.

Other complications include penile prosthesis extrusion leading to explantation and prosthesis failure (reported to be 6.7% [41], 8% [43], and 16.7% [45]). The lack of homogeneity in preoperative protocols among various studies and the

622

depends on the patient’s ability to respond to methods of assisted ejaculation and on the quantity and quality of sperm obtained in the ejaculate. With surgical methods, the assisted reproductive technology (ART) of intracytoplasmic sperm injection (ICSI) will probably be required, due to the low numbers of sperm obtained with these methods. Assisted ejaculation methods generally result in higher numbers of sperm,thus allowing for more ART options (see Assisted Conception, page 630).

H. TREATMENT OF EJACULATORY DYSFUNCTION IN MEN WITH NEUROLOGICAL DISORDERS

I. INTRODUCTION Disorders of the central nervous system that may lead to ejaculatory dysfunction include: spinal cord injury, multiple sclerosis, transverse myelitis, cerebrovascular accidents, and damage resulting from excision of central nervous system neoplasms. Disorders of the peripheral nervous sys tem that may lead to ejaculatory dysfunction include: cauda equina injuries, retroperitoneal lymph node dissection (RPLND), pelvic and colo rectal surgery, and diabetes mellitus. In addition, congenital disorders, most notably, myelomeningocele, may lead to ejaculatory dysfunction. In this part of the text, rapid ejaculation will not be discussed. Treatment options for neurogenic anejaculation depend on the origin of the disorder. Diabetes mellitus, RPLND, and some pharmacologic agents [13], may render the patient effectively «sympathectomized» leading to failure of seminal emission, or to retrograde ejaculation. These patients may respond with varying degrees of success to management with sympathomimetic pharmacologic agents such as imipramine, phenylpropanolamine, pseudophedrine, or ephedrine [4-6]. If these measures fail to produce any ejaculation (antegrade or retrograde), then other procedures are indicated such as electroejaculation (EEJ) [7], or surgical sperm retrieval from testis, epididymis, or vas deferens [8-12]. If retrograde ejaculation persists, however, sperm retrieval from the bladder is usually all that is necessary. Such «sympathectomized» patients are usually poor candidates for the assisted ejaculation procedure of penile vibratory stimulation (PVS) since they lack the intact sympathetic innervation necessary for seminal emission.

The majority of reports on treatments for neurogenic anejaculation have focused on men with spinal cord injury, presumably because they comprise the largest proportion of neurogenic anejaculators. Thus, the majority of literature reviewed in this report, with respect to techniques, results, etc., will be from studies of men with spinal cord injury. To retrieve semen from men with neurogenic anejaculation, the methods most commonly used are PVS or EEJ [7,13,14]. In PVS, a vibrator is placed against the penis and mechanical stimulation is delivered to induce ejaculation. In EEJ, a probe containing electrodes is placed into the rectum and electrical stimulation is delivered to cause the release of semen. The term “electroejaculation” is a misnomer. Semen usually drips from the penis rather than being forcefully expelled as is typically seen during a PVS-induced or during a natural ejaculation. “Electroemission” is a more accurate term, however, this chapter will use the term “electroejaculation” since it is a conventional term in widespread use throughout the world. To retrieve semen from a man with neurogenic anejaculation, it is recommended that EEJ be used only if PVS fails. The basis for this recommendation is that PVS is less invasive, is preferred more by patients [15] and results in better semen quality than EEJ [15,16].

II. PATIENT SELECTION 1. PENILE VIBRATORY STIMULATION Almost any man with spinal cord injury, regardless of level of injury, is a candidate for PVS although certain medical conditions are relatively contraindicated [13]. (Men with peripheral innervation dysfunction may also be given a trial of

Treatment options for other conditions of neuropathic anejaculation include assisted ejaculation or surgical sperm retrieval. The choice of treatment

623

PVS although few will be found to respond). Severe inflammation or irritation of the glans penis, which sometimes occurs in patients who wear condom catheters, is a relative contraindication because PVS may lead to further skin abrasion. PVS should not be administered to patients with untreated hypertension or cardiac disease, as PVS may cause an increase in blood pressure. In patients with a penile prosthesis, PVS must be applied with care, as the pressure of the vibrator may push the glans onto the distal end of the prosthesis. An additional contraindication is the patient´s inability to comprehend instructions about the procedure.

2. ELECTROEJACULATION The above contraindications apply for EEJ, with the exception that patients with a penile prosthesis or irritation of the penile skin are of less concern with EEJ than with PVS. Additional contraindi cations for EEJ are the presence of a cardiac pacemaker, and rectal pathology other than simple hemorrhoids noted on anoscopic or sigmoidoscopic exam. As a note of caution, patients with recent spinal cord injuries (i.e. less than 24 months) may not respond readily to PVS or EEJ. Often their ejaculatory response becomes apparent only after 9-24 months.

III. PREPARATION OF PATIENTS 1. O RIENTATION AND MEDICAL HISTORY Prior to the first trial of PVS or EEJ, it is advisable that the patient be oriented to the procedure and to the potential responses he may experience. In men with spinal cord injury a complete medical history should be taken with special attention to autonomic dysreflexia and attempts at ejaculation since spinal cord injury, and the neurological level of injury assessed

2. BLADDER PREPARATION Once the patient is safely positioned on an examination table, blood pressure medication is given if necessary (see Management of Autonomic Dysreflexia). Next, the bladder is prepared in patients likely to have retrograde ejaculation, and/or in patients likely to ejaculate urine along with semen.

624

(These features will not be known until the patient´s ejaculation history is established). To prepare the bladder, first empty the bladder by catheterization, then instill 25-50 ml sperm washing buffer into the bladder[16]. The bladder should be prepared immediately (no more than 10 minutes) prior to PVS or EEJ, to minimize accumulation of urine. In addition to these measures, some centers recommend restricting fluids for 8 hours prior to the ejaculation procedure, or recommend alkalinizing the urine with the administration of oral alkalinizing agents such as sodium bicarbonate. For patients whose bladders are managed with suprapubic catheters, the following may be done before a trial of PVS or EEJ. First, lavage the bladder with aliquots of normal saline until no sediment is seen in the fluid. Then lavage again once or twice with the sperm washing medium of your choice. Finally, leave 25-50 ml of sperm washing medium in the bladder. The suprapubic tube is clamped during the procedure. A collection cup should be held at the meatus since the suprapubic tube does not preclude antegrade ejaculation.

3. MANAGEMENT OF AUTONOMIC DYSREFLEXIA Patients with injuries at T6 or above are prone to autonomic dysreflexia, which is an exaggerated sympathetic response to an afferent stimulus. Common symptoms include high blood pressure, sweating, chills, and headache, which if not managed properly, can lead to dangerously high blood pressure levels [17]. Autonomic dysreflexia can occur suddenly by any irritating stimulus introduced to the body below the level of injury, such as an overfull bladder or impacted bowel. In some patients, PVS or EEJ can cause autonomic dysreflexia, but with proper medication, symptoms can be safely managed or avoided altogether [18,19]. Patients at risk (i.e., any patient with an injury T6 or higher, or any patient with a history of autonomic dysreflexia) should be given between 10 and 40 mg of nifedipine, sublingually, 15 minutes prior to PVS or EEJ. A standard protocol is to start with 20 mg of nifedipine, then increase or decrease the dose on subsequent trials based on the patients response [13,14]. In patients with a very labile blood pressure, 0.4 mg nitroglycerin, sublingually may be given in addition to nifedipine. In

these patients, the procedure should be started within 30 seconds of nitroglycerine administration. During the procedure, blood pressure should be monitored every minute, preferably with an automatic blood pressure cuff.

2. VIBRATOR PLACEMENT AND TIMING (FIG. 13) The patient may be positioned in a supine or in a reclining position. The vibrator should be placed on the glans of the penis, either the dorsum or frenulum. The condition of the penile skin in contact with the vibrator should be constantly monitored by the operator. In order to monitor the penile skin during PVS, the following protocol is recommended. Apply PVS for 5 minutes, then stop for one minute and inspect the penile skin. Repeat this step for up to two more times for a total of 15 minutes of PVS. Stop PVS if the penile skin bleeds or becomes edematous, if the patient’s blood pressure rises to a dangerous level, if the patient requests, or if ejaculation occurs. For general safety, the PVS procedure should not last longer than 15 minutes.

In a study of 211 men with spinal cord injury ranging between C3-L3, 41% required nifedipine for autonomic dysreflexia, and in all but three, the level of injury was T8 or higher. Of those who received nifedipine, 17.2% also required nitroglycerin during at least one trial [13].

4. P ERSONNEL It is recommend that 2-3 professionals be present during PVS or EEJ, depending on the complexity of the case. One professional administers the PVS or EEJ, one collects the semen, and a third attends to the patients´s symptoms, if necessary. In simple cases of PVS, only one professional may be necessary, as for example, in the case of a patient who can hold the vibrator or the specimen cup during PVS, and who does not get autonomic dysreflexia or severe spasticity during ejaculation.

3. SOMATIC RESPONSES DURING PVS A series of somatic responses are typically observed during PVS in men with spinal cord injury [13,14,20]. These include: contraction of the abdominal muscles, followed in frequency of occurrence by spasticity below the level of injury, knee flexion, hip flexion and abduction of the thighs. During PVS, periurethral contractions can be felt on most of the trials in which ejaculation occurs. However, these somatic responses are not predictive of ejaculation with PVS. On many trials, there are somatic responses but no antegrade or retrograde ejaculation. A lack of somatic responses, however, is usually predictive of no ejaculation [13]. It is possible for ejaculation to occur without erection, therefore, erection is not a good predictor of ejaculation. In patients who can ejaculate with PVS, the majority will have an antegrade ejaculate, and some will also have a retrograde ejaculate. If no antegrade ejaculate is observed, the best indicators of a retrograde ejaculate are a cumulative building of somatic responses, contraction of the bulbocavernosus muscles, and an increase in blood pressure.

IV. PVS PROCEDURE 1. VIBRATOR SELECTION Vibrators have been designed specifically for ejaculation of men with spinal cord injury (FERTI CARE® clinic or FERTI CARE® personal, Multicept,Denmark). These vibrators have the capability of delivering an amplitude of 2.5 mm when pressed against the penis, and this amplitude has been found to significantly increase ejaculatory success rate compared to lower amplitudes [13,20]. For the purposes of this paper, such vibrators will be referred to as “high amplitude vibrators” (Fig.11). Other commercially available devices, while not specifically designed for ejaculation of men with spinal cord injury, may be used for this purpose. Typically called “massagers” in the United States, such devices are marketed to the general public for relief of muscle strain. Most of these massagers deliver an unloaded amplitude of 1.6 mm or less (Fig. 12). Any type of vibrator may be perceived as painful when applied to the penis of men with some degree of intact sensation.

4. USE OF PHYSOSTIGMINE To facilitate ejaculation in men with spinal cord injury, the anticholinesterase, physostigmine, has been used alone and in combination with masturbation or PVS [21-24]. Physostigmine is generally administered subcutaneously following pretreat-

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Figure 11: The FERTI CARE® clinic (left) and the FERTI CARE® personal (right) vibrators (Multicept, Denmark) are medical devices that have been engineered specifically for ejaculation of men with spinal cord injury. They can deliver an amplitude of 2.5 mm when pressed against the penis. In men with spinal cord injury, this amplitude results in a higher ejaculatory success rate compared with lower amplitudes.

Figure 12: While not specifically made for ejaculation of men with spinal cord injury, a wide variety of devices may be used to deliver penile vibratory stimulation. Typically called massagers in the United States, these devices are sold 'off-the-shelf in drug stores or department stores. They are marketed to the general public for use in muscle massage. Those shown in the picture deliver an amplitude of 1.6 mm or less, and are not as effective for inducing ejaculation in men with spinal cord injury as are the high-amplitude vibrators shown in Figure 11. The advantage of these vibrators is that they are usually less expensive and easier to obtain than high-amplitude vibrators.

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Figure 13: During PVS, the vibrator may be placed on the dorsum or the renulum (shown here) of the glans penis. The penile skin should be monitored during PVS to avoid edema or bleeding.

EEJ was originally developed to retrieve semen from farm animals for selective breeding [25]. Later, a variety of rectal probes were developed to harvest semen from a variety of endangered species [26,27]. In the mid 1980’s, EEJ equipment was modified, and became commercially available for use in humans [7,28]. Although the exact neural mechanism by which this method works is not understood, an intact ejaculatory reflex is not necessary, and thus EEJ is suitable for any patient with neurogenic anejaculation.

ment with N-butylhyoscine to reduce the common side effect of nausea. Criteria for selecting patients for treatment with physostigmine has not been established and currently seems to be guided by clinician preference (personal communications).

5. FAILURE WITH PVS In men with spinal cord injury, if there is no ejaculation with a high amplitude vibrator, a trial with two vibrators may be attempted, with one vibrator placed on the dorsum and one on the frenulum of the penis. Signs of autonomic dysreflexia should be monitored closely when using two vibrators. If no ejaculation occurs after three trials of PVS with one or two high amplitude vibrators, the case should be considered an ejaculatory failure and referred for EEJ. Exceptions are patients injured two years or less. Ejaculation with PVS may occur once their injury has matured. In non-spinal cord injured patients, failure with one trial or pain on application of the vibrator is an indicator for no further attempts.

For EEJ, the patient is placed in the lateral decubitus position (Fig. 14 a , b). The bladder is prepared for retrograde ejaculation, which is common with EEJ. An anoscopy or sigmoidoscopy should be performed prior to introducing the probe, to rule out pre-existing rectal conditions. A probe of appropriate diameter is selected. Considerations are the volume and sensitivity of the patient´s rectum, as well as the amount of current required to obtain semen from the individual. The EEJ procedure is usually performed with a low level of electrical baseline current of 50 to 100 milliamperes which is maintained between stimulation peaks. In a recent study it was shown that during EEJ, the external urinary sphincter contracts during electrical stimulation [29]. Therefore, the common practice of a continuous electrical baseline may be counter-productive, since it may lead to a relative

V. EEJ PROCEDURE In the method of EEJ, a probe containing electrodes is placed into the patient´s rectum and direct current is delivered to cause the release of semen.

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Figure 14 a : Electroejaculation equipment.

A

B b: Electroejaculation should be used when PVS fails. A probe is placed in the rectum (shown here in sagittal view) and electricity, delivered via electrodes aimed ventrally, results in the release of semen. Ejaculatory success rate is higher with EEJ compared to PVS, however, PVS results in better semen quality, is less invasive, and is prederred more by patients.

increase of external sphincter tone, and an increase in the retrograde ejaculation fraction. It is suggested that it may be optimal to completely discontinue electrical stimulation during seminal emission leading to an increase in the percentage of sperm ejaculated in the antegrade direction. As with PVS, it is important to monitor for symptoms of autonomic dysreflexia during EEJ.

mise a significant amount of the intercostal musculature. In the typical patient, a series of these somatic responses will occur prior to emission. In some patients, somatic responses occur with no accompanying emission. In these instances, the current may be abruptly turned off, at which point the patient will then have prolonged extensor spasms of the lower extremities. Semen will often drip out of the penis at this point. If none is seen, a second course of electrical stimulation may be given.

1. SOMATIC RESPONSES DURING EEJ During EEJ in men with spinal cord injury, typical somatic responses, in the order in which they appear, include: tightening of the abdominal and intercostal muscles below the level of injury, abduction of the thighs, tightening of the paraspinatis muscles with back arching, and finally, penile erection[30]. As a note of caution, patients may complain of tightness of the chest and difficulty breathing if their injury is high enough to compro-

2. ANESTHESIA DURING EEJ Non-spinal cord injured men or spinal cord injured men with enough sensation to feel pain or discomfort may require intravenous sedation or general anesthesia for EEJ. Generally, such measures are necessary in fewer than 10% of the SCI group.

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rates ranging from 21% to 91% depending on type of equipment used and patient selection [20,3135]. To address this variability, a large scale study of 653 trials of PVS in 211 patients was performed. [13] Success rate was dependent on level of injury. For example, when patients were grouped by level of injury (C3-7, T1-5, T6-10, and T11L3), the success rate of ejaculation with a high amplitude vibrator was 66%, 54%, 41% and 36%, respectively. Completeness of injury, as measured by the University of Miami Neurospinal Index [36] was not predictive of ejaculatory success. Ejaculation was quick and reliable, since most men who ejaculated did so on 100% of trials, and within two minutes of stimulation onset. The effectiveness of the high amplitude vibrator has been verified in other studies which showed about 80% success rate of antegrade ejaculation with spinal cord lesions above T10 [20, 37].

VI. WHEN TO CHECK FOR A RETROGRADE EJACULATE 1. PVS TRIALS At the conclusion of a PVS trial, a decision must be made about the necessity of urinary catheterization to check for a retrograde ejaculate. Generally, post-procedure urinary catheterization should be done on any trial in which somatic responses but no antegrade ejaculate occurred. On trials in which an antegrade ejaculate occurred, a retrograde ejaculate should be checked: on a patient´s first visit (to establish the volume); if the volume of antegrade ejaculate is low (<0.5 cc); if the sperm count is unexpectedly low (i.e., significantly lower than previous trials). It is not necessary to perform urinary catheterization if recent trials of PVS have resulted in no retrograde ejaculation, or if the amount of motile sperm in the antegrade specimen is sufficient for an intended assisted conception procedure.

There has been no definitive study to determine the interval between ejaculations that optimizes ejaculatory success rate with PVS. In general, experience indicates that an interval of one week or longer results in a higher success rate of ejaculation than shorter intervals. There have been studies to investigate if repeated ejaculation with PVS results in improved semen quality in men with spinal cord injury, with some studies finding improvement [34,35] and others not[38].

2. EEJ TRIALS At the end of EEJ, whether or not antegrade semen has been obtained, the bladder should be catheterized and lavaged since retrograde ejaculation is very common with EEJ. The exceptions are patients with an established history of no retrograde ejaculation, if sufficient antegrade semen is obtained for an intended assisted conception procedure, or if urinary catheterization is contraindicated.

With the method of EEJ, recent studies have shown that semen can be retrieved in 85% to 100% of men with SCI [7,28,38-41]. As discussed previously, the success rate may be lower in patients injured less than two years.

3. RETRIEVAL OF RETROGRADE EJACULATES To check for a retrograde ejaculate, the bladder contents may be retrieved by first catheterizing the bladder and emptying by gravity. Then, another 25-50 ml of sperm washing medium is used to lavage the bladder to extract any residues of ejaculate that may have fallen to the floor of the bladder and were thus not captured easily during the initial draining.

2. SEMEN QUALITY In summarizing the literature, the most important points about semen quality in men with spinal cord injury are: generally, sperm concentration is normal to high, but sperm motility is abnormally low [28,39,42-44]; most of the immotile sperm are dead [45,46]; sperm of spinal cord injured men lose motility faster than sperm from normal men [47]; semen quality is better with PVS compared to EEJ, even in the same patient [15,16]; semen quality is better in antegrade versus retrograde specimens [15,16,45,48]; there is little difference in semen quality with high versus low amplitude stimulation [13].

VII. RESULTS WITH PVS AND EEJ 1. EJACULATION SUCCESS RATES There have been various reports of the efficacy of PVS in men with SCI, with ejaculation success

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The reason for impaired semen quality in spinal cord injured men is unknown, but evidence suggests that factors in the seminal plasma contribute to this condition. For example, seminal plasma from spinal cord injured men inhibits sperm motility from normal men [49]. Additionally, different concentrations of biochemical substances are found in the semen of men with spinal cord injury compared to that of normal men. These substances include prostate specific antigen [50,51], somatostatin [52], reactive oxygen species [53], fructose [54], and others [55]. The most compelling evidence is that the motility of sperm obtained from the vas deferens of men with spinal cord injury is much higher (and in many cases, normal) compared to the motility found in these same men’s ejaculates [56].

with male factor infertility due to spinal cord injury or other neurogenic disorders. Individual centers have reported their pregnancy success rates using various forms of ART in couples with a spinal cord injured male partner [43,59-65]. The success rates are similar to those obtained in the general population, and it appears that for any given number of motile sperm, those obtained from men with spinal cord injury offer the same potential for fertilization and pregnancy as those of noninjured men. As with the general population, the decision of what type of ART to use should be governed by the number of motile sperm obtainable, and the ease of obtaining them. Other factors that influence the selection of an ART include female factors, whether the couple can financially afford the procedure, how quickly they want children, and the couple´s emotional stability in dealing with possible conception failures. Also to be considered is the frequent request from couples (based on our experience) that the most simple methods be used, particularly methods that require less pharmacologic manipulation and less invasiveness to the female partner. Of further consideration in choosing an ART is the coordination of the semen retrieval procedure with the insemination procedure. If there is a significant gap between these two procedures, (for example, if the two centers performing these procedures are located a significant distance from each other) couples may have to rely on a frozen semen specimen, collected at some earlier time, for the insemination procedure.

VIII. OTHER METHODS OF SPERM RETRIVAL If assisted ejaculation procedures yield insufficient motile and/or viable sperm for ART, including ICSI, other procedures of sperm retrieval are indicated. The patient should be evaluated (as if he had no neurologic dysfunction) for obstructive versus nonobstructive causes of the problem. Transrectal ultrasonographic evaluation should be performed before any other invasive procedure [57]. A testicular biopsy may provide useful information [58]. Sperm may be obtained from the testicle by needle aspiration, core needle biopsy, or open biopsy. Sperm from the epididymis and vas deferens may be aspirated using microsurgical techniques [812]. Since most of the neurogenic anejaculators do not have ductal obstruction, percutaneous aspiration of the epididymis may be fruitless. All of these techniques have the potential of yielding adequate numbers of motile/viable sperm for ICSI. The choice of technique is often up to the preference of the surgeon and the embryologist who will process the sperm.

No standard algorithm has been established for recommending ART to couples with male factor infertility due to neurogenic anejacualtion. Some centers report successful pregnancies in couples using home insemination, with the semen collected by PVS and introduced intravaginally [62]. The criteria for recommending more advanced ART, such as intrauterine insemination, in vitro fertilization, gamete intrafallopian transfer, the use of ICSI, and the use of stimulation or monitoring protocols for the female, have not been standardized for these couples, and to date seem to follow a particular center´s trend for treating other etiologies of male infertility. The evaluation of a large series of patients is needed to establish standard treatment protocols for couples with male factor infertility secondary to spinal cord injury.

IX. ASSISTED CONCEPTION The same assisted reproduction techniques (ART) used to treat male-factor infertility in the general population may be used to assist couples 630

tion/extraction techniques which essentially commit the patient only to ICSI, and are themselves more expensive than assisted ejaculation. As technology and pregnancy rates improve and costs come down, this philosophy may need to be reevaluated.

X. USE OF PVS FOR SEXUAL PLEASURE No studies have established guidelines for the use of home PVS for sexual pleasure in patients with neurogenic anejaculation. Some self-reports of its use by men with spinal cord injury have appeared in lay magazines written primarily for the disabled population, such as New Mobility, or on websites devoted to topics of sexual activity in persons with disability [66,67]. Anecdotally, many of our patients have reported on the use of PVS as part of their sexual activity. Although they do not achieve the same orgasmic responses they achieved prior to their injury/disorder, they nevertheless report a sense of pleasure and well-being at being able to achieve ejaculation during sexual activity with their partner. Clinicians counseling patients in the use of PVS for unsupervised use at home should do so with great caution, since approximately 40% of all patients with spinal cord injury experience autonomic dysreflexia with this method (see Management of Autonomic Dysreflexia [H-III-3] and Patient Selection [H-II]).

Some economic considerations are relevant specifically for patients with spinal cord injury. 1. PVS should be attempted before EEJ, especially in patients with injuries above T10. PVS is less invasive to the patient and results in better semen quality compared to EEJ [15,16] and may offer the less expensive option (relative to other ARTs) of home insemination in selected couples in whom the male has a reasonable amount of motile sperm and is at low risk for autonomic dysreflexia, and in whom the female partner is young and health.[62]. 2. In patients who require EEJ, general anesthesia is not necessary in the majority of cases, and should thus be avoided unless EEJ is too painful for the patient. 3. Since there is a controversy over the use of repeated ejaculation for improving semen quality, this method should not be routinely advocated.

XI. ECONOMIC CONSIDERATIONS

4. There is no evidence to support the notion that sperm cryospreserved shortly after injury offers a better chance of fertilization and pregnancy (when thawed) than fresh sperm collected years after injury. This information should be offered to patients considering cryopreservation of their sperm.

In choosing treatment options for ejaculatory dysfunction in men with neurogenic disorders, economic considerations may be important, depending on the health care system in which the patient is treated. Generally, the more sophisticated ARTs are the most expensive. For example, in the United States, ICSI ranges between $12,000 and $15,000, while intrauterine insemination ranges between $600 and $800. In Denmark, the prices are about 20% lower than those for the United States, but a couple may have to wait for up to two years to for treatment. While these considerations may not apply to patients in whom full medical benefits are provided by their health care system, a similar hierarchy in cost borne by the system may have to be considered. For this reason, we advocate attempts at assisted ejaculation, combining the motile /viable sperm from the antegrade and retrograde fractions for use in the more simple ARTs, before committing to the various surgical sperm aspira-

XII. CONCLUSIONS 1. Treatments for neurogenic anejaculation for the purpose of assisting conception depend on the etiology of the disorder, and may include sympathomimetic agents, assisted ejaculation procedures, orsperm retrieval by surgical removal from the testis, epididymis, or vas deferens. 2. The same assisted reproductive technologies used to treat male factor infertility in the general population may be used to assist couples with male factor infertility due to

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neurogenic anejaculation. Pregnancy success rates appear to be similar to those obtained in the general male factor infertile population.

injured patients who are at risk for autonomic dysreflexia. 2. Practitioners attempting to manage couples for ART should be familiar with the type of semen quality usually obtained from men with neurogenic anejaculation, and how it may differ from normal semen. They should be familiar with how to retrieve and utilize sperm from a retrograde ejaculate.

3. Depending on the health care system where the patient is treated, economic considerations may be of importance when selecting treatments for anejaculation and when selecting ARTs.

3. PVS should be used as the first line of treatment for ejaculatory dysfunction of men with spinal cord injury, due to its safety, efficacy, and reliability, and low investment of time and money. Compared to EEJ, PVS is less invasive, is preferred more by patients, and results in better semen quality. If PVS fails, patients should be referred for EEJ.

XIII. RECOMMENDATIONS 1. Practitioners treating patients with neurogenic ejaculatory dysfunction should be familiar with the management of such patients, especially the management of spinal cord

I. OVERALL CONCLUSIONS AND RECOMMENDATIONS

I. OVERALL CONCLUSIONS

II. OVERALL RECOMMENDATIONS

1. Sexual disabilities such as erectile dysfunction and disturbances of ejaculation and orgasm are very common among patients with neurological disorders or patients suffering from sequelea from injuries, spinal cord injuries in particular. In brain disorders and after brain injuries sexual desire may also be reduced and behavioral disturbances may occur. Sexual adverse reactions have been reported with the use of many prescription drugs acting on the nervous system.

1. DIAGNOSIS Taking a more careful case history, performing at least a focused neurological examination, including the lumbosacral segments, complemented in very selected patients (particularly those with suspected peripheral nervous system involvement) by neuro-physiological tests, should - in addition to other indicated investigations - be considered in patients seeking medical advice because of a sexual disability.

2. TREATMENT

2. Sexual disabilities may be the presenting symptom or one of the early symptoms of a neurological disorder.

1. The first step of the counselling is to open the mind of the patient to the existence of sexual disabilities in cases of his type. The second step is to give the patient proper information about sexual issues in this particular type of disorder/injury. A number of specific suggestions, such as practical informations about positions and stimulation techniques and technical aids and devices could be given.

3. All neurological patients should have the opportunity of sexual counselling. The majority of them, even those with complete spinal cord injuries, can be treated for erectile and ejaculatory dysfunction.

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2 The next step is to use the arsenal of specific treatments available, medical as well as surgical, for treatment of erectile dysfunction and ejaculatory dysfunction. These include testosterone substitution, vacuum therapy, intracavernous injection of prostaglandin E1, papaverine or moxisylyte, transdermal or intraurethral application of different drugs, oral administration of phosphodiesterase inhibitors, and penile prosthesis. Treatment of bladder dysfunction and spasticity as well as autonomic dysreflexia in SCI is also important.

important central nervous system areas and their connections. It is expected that further research (probably involving also functional neuroimaging) will reveal and better delineate relevant areas in the central nervous system relevant to psychogenic, reflex, and sleep erections, orgasm and ejaculation. 2. At present the diagnosis of neurogenic ED can usually only be inferred as possible or probable on the grounds of association with particular neurologic diseases or neuroanatomic lesions. Better data on association of particular neurologic conditions/diseases with ED as well as a better correlation of sexual dysfunction with localised lesions (the diagnosis of which is much improved by modern diagnostic methods) are expected to improve the diagnostic accuracy.

3 In spinal cord injuries semen can be retrieved by use of assisted ejaculation methods such as penile vibratory stimulation (PVS) or rectal probe electroejaculation (EEJ). PVS should be used first due to its safety, reliability and low investment in time and money. It also results in better semen quality. If PVS fails, the patient should be referred to a specialist center for EEJ. So far there are no treatments to normalise semen quality in men with spinal cord injury.

3. Clinical neurophysiological tests to assess the function of the sacral parasympathetic system and the penile smooth muscles are as yet controversial. Further research is expected to clarify the validity, sensitivity and specificity of corpus cavernosum EMG. Generally, the place of clinical neurophysiological tests to help establish certain neurological diseases associated with early and possibly isolated neurogenic ED (e.g. multiple system atrophy) or better define the functional neuroanatomic deficits caused by lesions (for instance in spinal cord involvement) should be better defined. 4. a. Advanced possibilities for diagnosis should help in more precise definition of neurologic patient populations, thusmaking studies of effectiveness of particular therapies more discriminant.

4. In the neurological patient, it is important to treat sexual, bladder, bowel and fertility problems with a global view of the patient. Different disciplines need to be better informed and to collaborate both in diagnostics and treatment of patients with complex sacral dysfunctions. 5. Greater efforts must be aimed at educating the medical profession about the nature and treatment of sexual disability problems in general, and in neurological patients in particular. This education should especially be aimed at support personnel, such as nurses, occupational therapists, and physical therapists, who spend more time with the patient and are thus more likely to be the recipients of the patient’s questions.

b. Studies are needed to better define optimal algorithms for investigation of different neurological patient populations with erectile and ejaculatory dysfunction. c. Studies are needed to better define optimal algorithms for investigation of patients with isolated ED, suspected to be organic (neurogenic), and whether investigations are relevant to make an early diagnosis of some neurologic diseases /conditions possible (MSA, MS and so on).

III. SUGGESTIONS FOR FUTURE RESEARCH 1. Detailed knowledge of neurocontrol of erection, orgasm, and ejaculation is as yet rudimentary, particularly as regards functionally

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5. a. Detailed information on the applicability and efficacy of different therapies for ED in different and better defined neurologic patient populations is as yet unknown. Long-term follow-up and costefficiency as well as quality of life assessment is expected to give us better data for a rational choice of individual therapies in particular patient populations.

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F. ADVERSE SEXUAL REACTIONS FROM PRESCRIPTION DRUGS 1.

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BUFFUM J:Pharmacosexology: The effects of drugs on sexual function. A review. J Psychoactive Drugs 1982;14:5-44.

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BUFFUM J: Prescription drugs and sexual function. Psychiatr Med 1992;10:181-198.

18. HYYPPÄ MT, FALCK SC, RINNE UK: Is L-DOPA an aphrodisiac in patients with Parkinson´s disease?. In Sandler M, Gessa GL(eds): “Sexual Behavior:Pharmacology an Biochemistry.” New York:Raven Press 1975:315-327.

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21. GALBRAITH RA, MICHNOVICS JJ: The effects of cimetidine on the oxidative metabolism of estradiol New Engl J Med 1989;321:269-274.

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10. KIMURA Y, TADANO T, URANO S, YONEZAWAA, WATANABE A, WATANABE H, KISARA K: On suppression of ejaculation with alpha-methyldopa. Andrologia 1984;16:118-123.

24. LUNDBERG PO: Data from WHO-data base on Adverse Drug Reactions.

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impotence in spinal cord injury patients. Paraplegia 1993;31:675-677.

G. TREATMENT OF NEUROGENIC ERECTILE DYSFUNCTION

14. LLOYD L, RICHARDS J: Intracavernous Pharmacotherapy for management of erectile dysfunction in spinal cord injury. Paraplegia 1989;27:457-464.

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KIRKEBYH, PETERSEN T, POULSEN E: Pharmacologically induced erection in patients with multiple sclerosis. Scand J Urol Nephrol 1988;22:241-244.

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4.

HELLER L, KEREN O, ALONI R, DAVIDOFF G: An open trial of vacuum penile tumescence: constriction therapy for neurological impotence. Paraplegia 1992;30:550-553.

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ZASTLER N, KATZ P: Synergist erection system in the management of impotence secondary to spinal cord injury. Arch Phys Med Rehabil 1989;70:712-716.

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19. HIRSH I, SMITH R, CHANCELLOR M, BAGLEYD, CARSELLO J, STASS W: Use of intracavernous injection of prostaglandin E1 for neuropathic erectile dysfunction. Paraplegia1994;32:661-664.

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15. SIDI A, CAMERON J, DYSTRA D, REINBERG Y, LANGE P: Vasoactive intracavernous pharmacotherapy for the treatment of erectile impotence in men with spinal cord injury. J Urol 1987;138:539-542.

20. LUNDBERG L, OLSSON J, KIHL B: Long term experience of self injection therapy with prostaglandin E1 for erectile dysfunction. Scand J Urol Nephrol 1996;30:395-397. 21. BECHARAA, CASABÉ A, CHELIZ G, ROMANO S, REY H, Fedotovitch N: Comparative study of papaverine plus phentolamine versus prostaglandin E1 in erectile dysfunction. J Urol 1997;157:2132-2134. 22. LINET O, OGRING F: Efficacy and safety of intracavernosal alprostadil in men with erectile dysfunction. New Engl J Med 1996;334:873-877. 23. TANG S, CHU N, WONG M. Intracavernous injection of prostaglandin E1 in spinal cord injured patients with erectile dysfunction. A preliminary report. Paraplegia 1995;33:731-733.

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COSTAP, SARRAZIN B, BRESSOLE F, COLSON M, BONDIL F, SAUDUBRAY F: Efficiency and side effects of intracavernous injections of moxisylyte in impotent patients: a dose finding study versus placebo. J Urol 1993;149:301-305.

25. LEE L, STEVENSON W, SZASZ G: Prostaglandin E1 versus phentolamine/papaverine for the treatment of erectile impotence: a double blind comparison. J Urol 1989;141:549-550.

12. EARLE CM, KEAGH EJ, KER JK, CHERRY DJ, TULLOCH AG, LORD DJ: The role of intracavernosal vasoactive agents to overcome impotence due to spinal cord injury. Paraplegia 1992;30:273-276.

26. CLAES H, BAERT L. Transcutaneous nitroglycerin therapy in the treatment of impotence. Int J Impot Res 1989;1:71-93.

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29. CHANCELLOR M, RIVAS D, PANZER D, FREEDMANN W: Prospective comparison of topical minoxidil to vacuum constriction device and intracorporeal papaverine injection in treatment of erectile dysfunction due to spinal cord injury. Urology 1994;43:365-369.

43. PERKASH I, KABALIN J, LENNON S, WOLFE V: Use of penile prostheses to maintain external condom catheter drainage in spinal cord injury patients. Paraplegia 1992;30:327-32.

30. DERRY FA, DINSMORE WW, FRASER M, GARDNER BP, GLASS CA, MAYTON MC, SMITH MD: Efficacy and safety of oral sildenafil (Viagra) in men with erectile dysfunction caused by spinal cord injury. Neurology 1998;51:1629-1633.

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48. GREEN B, SLOAN S: Penile prostheses in spinal cord injured patients: combined psychosexual counselling and surgical regimen. Paraplegia 1986;24:167-172.

H. TREATMENT OF EJACULATORY DYSFUNCTION IN MEN WITH NEUROLOGICAL DISORDERS

34. WILLIAMS G, ABBOU CC, AMAR ET, DESVAUX P, FLAM TA, LYCKLAMAA, MIJEHOLT GA, LYNCH SF, MORGAN RJ, MULLER SC, PORST H, PRYOR JP, RYAN P, WITZSCH UK, HALLMM, PLACE VA, SPIVACK AP, TODD LK, GESUNDHEIT N: Efficacy and safety of transurethral alprostadil therapy in men with erectile dysfunction. Br J Urol1998;81:889-894. 35. SHASBIGH R: Penile prostheses toward the end of millenium. J Urol 1998;159:819. 36. SCOTT F, BYRD G, KARAKAN I, OLSSON P, BEUTLER L, ATTIA S: Erectile impotence with an inplantable, inflatable prosthesis. Five years of clinical experience. JAMA1979;241:2609-2612. 37. ROSSI D, AYUSO D, RATTIER C, BLADOU F, HERMANOWITZ M, SERMENT G: Clinical experience with 80 inflatable penile prosthesis. Eur Urol 1997;31:335-338.

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38. GARBER B: Inflatable prosthesis: result of 150 cases. Br J Urol 1996;78:933-935. 39. MAC LAREN R, BARRETT D: Patient and partner satisfaction with the AMS 700 penile prosthesis. J Urol 1992;147:62-65.

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20. SØNKSEN J, BIERING-SØRENSEN F, KRISTENSEN JK: Ejaculation induced by penile vibratory stimulation in men with spinal cord injuries. The importance of the vibratory amplitude. Paraplegia 1994;32:651-660.

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SU LM, PALERMO GD, GOLDSTEIN M, VEECK LL, ROSENWAKS Z, SCHLEGEL PN: Testicular sperm extraction with intracytoplasmic sperm injection for nonobstructive azoospermia: testicular histology can predict success of sperm retrieval. J Urol 1999;161:112116.

21. CHAPELLE PA, ROBY-BRAMI A, YAKOVLEFF A, BUSSEL B: Neurological correlations of ejaculation and testicular size in men with a complete spinal cord section. J Neurol Neurosurg Psychiatry 1988;51:197202.

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11. OSTAD M, LIOTTA D, YE Z, SCHLEGEL PN: Testicular sperm extraction for nonobstructive azoospermia: results of a multibiopsy approach with optimized tissue dispersion. Urol 1998;52:692-696.

25. DZUIK PJ, GRAHAM EF, DONREK JD, MARION GB, PETERSEN WE: Some observations in collection of semen from bulls, goats, boars and rams by electrical stimulation. Vet Med 1954;49:455-460. 26. SEAGER SW, WILDT DE, PLATZ C: Semen collection by electroejaculation and artificial vagina in over 100 species of animals. Proc 9th Int Cong An Reprod and AI 1980;571-576.

12. SHIN D, PALERMO GD, GOLDSTEIN M, ROSENWAKS Z, SCHLEGEL PN: Indications for corticosteroids prior to epididymal sperm retrieval.Int J Fertil Women Med 1998;43:165-170. 13. BRACKETTNL, FERRELLSM, ABALLATC, AMADOR MJ, PADRON OF, SØNKSEN J, LYNNE CM: An analysis of 653 trials of penile vibratory stimulation on men with spinal cord injury. J Urol 1998;159:19311934.

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14. OHL DA, SØNKSEN J: Penile vibratory stimulation and electroejaculation. In Hellstrom WJG (ed): “Male Infertility and Sexual Dysfunction”. New York: Springer-Verlag New York, Inc., 1997: 219-229.

29. SØNKSEN J, OHL DA, WEDEMYER G: Physiological events during penile ejaculation and electroejaculation in men with spinal cord injuries. J Urol 199;161:343.

15. OHL DA, SØNKSEN J, MENGE AC, MCCABE M, KELLER LM: Electroejaculation versus vibratory stimulation in spinal cord injured men: sperm quality and patient preference. J Urol 1997;157:2147-2149.

30. BRACKETT NL, NASH MS, LYNNE CM: Male fertility following spinal cord injury: facts and fiction. Phys Ther 1996;76:1221-1231.

16. BRACKETT NL, PADRON OF, LYNNE CM: Semen quality of spinal cord injured men is better when obtained by vibratory stimulation versus electroejaculation. J Urol 1997;157:151-157.

31. SARKARATI M, ROSSIER AB, FAM BA: Experience in vibratory and electro-ejaculation techniques in spinal cord injury patients: a preliminary report. J Urol 1987;138:59-62.

17. TROP CS, BENNETT C: The evaluation of autonomic dysreflexia. Semin Urol 1992;10:95-101.

32. SZASZ G, CARPENTER C: Clinical observations in vibratory stimulation of the penis of men with spinal cord injury. Arch Sex Behav 1989;18:461-474.

18. VERVOORT SM, DONOVAN WH, DYKSTRA DD, SYERS P: Increased current delivery and sperm collection using nifedipine during electroejaculation in men with high spinal cord injuries. Arch Phys Med Rehabil 1988;69:595-597.

33. BRINDLEY GS: The fertility of men with spinal injuries. Paraplegia 1984;22:337-348. 34. BERETTA G, CHELO E, ZANOLLO A: Reproductive aspects in spinal cord injured males. Paraplegia 1989;27:113-118.

19. STEINBERGER RE, OHL DA, BENNETT CJ, MCCABE M,.WANG SC: Nifedipine pretreatment for autonomic dysreflexia during electroejaculation. Urol 1990;36:228-231.

35. SIÖSTEEN A, FORSSMAN L, STEEN Y, SULLIVAN

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48. HIRSCH IH, SEDOR J, JEYENDRAN RS, STAAS WE: The relative distribution of viable sperm in the antegrade and retrograde portions of ejaculates obtained after electrostimulation. Fertil Steril 1992;57:399-401.

36. KLOSE KJ, GREEN BA, SMITH RS, ADKINS RH, MACDONALD AM: University of Miami Neuro-Spinal Index (UMNI): a Quantitative Method for Determining Spinal Cord Function. Paraplegia 1980;18:331334.

49. BRACKETT NL, DAVI RC, PADRON OF, LYNNE CM: Seminal plasma of spinal cord injured men inhibits sperm motility of normal men. J Urol 1996;155:16321635. 50. BRASSØ K, SØNKSEN J, SOMMER P, ODUM L, BIERING-SØRENSEN F, IVERSEN P,.KRISTENSEN JK: Seminal plasma PSA in spinal cord injured men: a preliminary report. Spinal Cord 1998;36:771-773.

37. OHL DA, MENGE AC, SØNKSEN J: Penile vibratory stimulation in spinal cord injured men: optimized vibration parameters and prognostic factors. Arch Phys Med Rehab 1996;77:903-905. 38. SØNKSEN J, OHL DA, GIWERCMAN A, BIERINGSØRENSEN F, SKAKKEBAEK NE, KRISTENSEN JK: Effect of repeated ejaculation on semen quality in spinal cord injured men. J Urol 1999;161:1163-1165.

51. LYNNE CM, ABALLATC, WANG TJ, RITTENHOUSE HG, FERRELL SM, BRACKETT NL: Serum and seminal plasma prostate specific antigen (PSA) levels are different in young spinal cord injured men compared to normal controls. J Urol 1999;(in press)

39. BRACKETT NL, LYNNE CM, WEIZMAN MS, BLOCH WE, ABAE M: Endocrine profiles and semen quality of spinal cord injured men. J Urol 1994;151:114119.

52. ODUM L, SØNKSEN J, BIERING-SØRENSEN F: Seminal somatostatin in men with spinal cord injury. Paraplegia 1995;33:374-376. 53. PADRON OF, BRACKETT NL, SHARMA RK, LYNNE CM, THOMAS AJ, JR, AGARWALA: Seminal reactive oxygen species and sperm motility and morphology in men with spinal cord injury. J Urol 1997;67:1115-1120.

40. LINSENMEYER TA, PERKASH I: Infertility in men with spinal cord injury. Arch Phys Med Rehabil 1991;72:747-754. 41. MARTIN DE, WARNER H, CRENSHAW TL, CRENSHAW RT, SHAPIRO CE, PERKASH I: Initiation of erection and semen release by rectal probe electrostimulation (RPE). J Urol 1983;129:637-642.

54. GREEN JT, ABALLA TC, FERRELL SM, LYNNE CM, BRACKETT NL: Seminal fructose is decreased in ejaculates from men with spinal cord injury. Fertil Steril 1998;70:S200.

42. BRACKETT NL, LYNNE CM, WEIZMAN MS, BLOCH WE, PADRON OF: Scrotal and oral temperatures are not related to semen quality or serum gonadotropin levels in spinal cord-injured men. J Androl 1994;15:614-619.

55. HIRSCH IH, JEYENDRAN RS, SEDOR J, ROSECRANS RR, STAAS WE:Biochemical analysis of electroejaculates in spinal cord injured men: comparison to normal ejaculates. J Urol 1991;145:73-76.

43. BRACKETT NL, ABAE M, PADRON OF, LYNNE CM: Treatment by assisted conception of severe male factor infertility due to spinal cord injury or other neurological impairment. J Assist Reprod Genet 1995; 12: 210-216.

56. BRACKETT NL, FERRELL SM, ABALLA TC, LYNNE CM: Sperm motility from the vas deferens of spinal cord injured (SCI) men is higher than from their ejaculates. J Urol 1998;159 Suppl:266. 57. MEACHAM RB, DROSE JA: Evaluation and treatment of ejaculatory duct obstruction in the infertile male. Chapter 12 in Hellstrom WJG (ed): “Male Infertility and Sexual Dysfunction”. New York: Springer, 1997;189200.

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59. BRINSDEN PR, AVERY SM, MARCUS S, MACNAMEE MC: Transrectal electroejaculation combined with in-vitro fertilization: effective treatment of anejaculatory infertility due to spinal cord injury. Hum Reprod 1997;12:2687-2692.

47. BRACKETT NL, SANTA-CRUZ C, LYNNE CM: Sperm from spinal cord injured men lose motility faster than sperm from normal men: The effect is exacerbated at body compared to room temperature. J Urol 1997;157:2150-2153.

60. HULTLING C, ROSENLUND B, LEVI R, FRIDSTROM M, SJÖBLOM P, HILLENSJÖ T: Assisted ejaculation and in-vitro fertilization in the treatment of

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64. CHUNG PH, PALERMO G, SCHLEGEL PN, VEECK LL, EID JF, ROSENWAKS Z: The use of intracytoplasmic sperm injection with electroejaculates from anejaculatory men. Hum Reprod 1998;13:1854-1858.

61. CHUNG PH, YEKO TR, MAYER JC, SANFORD EJ, MAROULIS GB:Assisted fertility using electroejaculation in men with spinal cord injury—a review of literature. Fertil Steril 1995;64:1-9.

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62. SØNKSEN J, SOMMER P, BIERING-SØRENSEN F, ZIEBE S, LINDHARD A, LOFT A, ANDERSEN AN, KRISTENSEN JK: Pregnancy after assisted ejaculation procedures in men with spinal cord injury. Arch Phys Med Rehab 1997;78:1059-1061.

66. Arkansas Spinal Cord Commission. Vibrator technique for ejaculation: one person’s experience. http://www.spinalcord.uab.edu/docs/ark018.htm. 67. TEPPER, M. Sexual health in persons with disabilities. http://www.sexualhealth.com.

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________________________

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646

Committee 18

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

Chairman R. ROSEN

Members A. BENNETT, D. FERGUSON, M. HIRSCH, H. PADMA-NATHAN, M. WYLLIE

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CONTENTS

I. INTRODUCTION

V. PROTOCOL DESIGN AND IMPLEMENTATION

II. RATIONALE AND DESIGN OF CLINICAL TRIALS

1. BACKGROUND OF THE STUDY 2. STUDY OBJECTIVES 3. DESIGN OF THE STUDY 4. ADMINISTRATIVE CONSIDERATIONS

1. P HASE I 2. P HASE II 3. PHASE III 4. P HASE IV 5. DRUG INTERACTION STUDIES

VI. DATAANALYSIS AND REPORTING OF RESULTS

III. STUDY POPULATIONS VII. ETHICALAND CLINICAL ISSUES IN ERECTILE DYSFUNCTION RESEARCH

1. GENERAL PRINCIPLES 2. DEFINING THE DISEASE STATE AND PATIENT POPULATION 3. BALANCE BETWEEN “OPENNESS” OF THE ENTRY CRITERIA AND PATIENT SAFETY

VIII. FINAL RECOMMENDATIONS FOR CLINICAL TRIAL DESIGN AND OUTCOMES ASSESSMENT

IV. OUTCOME ASSESSMENTS REFERENCES

1. PHYSIOLOGICAL MEASURES 2. SELF-REPORT MEASURES 3. DAILY DIARY AND EVENT LOGS 4. PARTNER ASSESSMENTS 5. QUALITY OF LIFE AND TREATMENT SATISFACTION

APPENDIX A APPENDIX B APPENDIX C

6. ADVERSE EVENT MONITORING

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Standards for Clinical Trials in Erectile Dysfunction: Research Designs and Outcomes Assessment R. ROSEN, A. BENNETT, D. F ERGUSON, M. H IRSCH, H. PADMA-NATHAN, M. W YLLIE

A major goal of the chapter is to review current standards of practice in the design and conduct of clinical trials. Many of these standards represent general principles in the design of clinical trials, although specific issues in the evaluation of new agents for ED are addressed. These include the use of objective (physiological) versus self-report (questionnaire) measures of sexual function, reports of the sexual partner, global patient and physician assessments, and the use of disease-specific quality of life measures. The advantages and disadvantages of each of these assessment approaches are considered. Although much of the focus in recent years has been on the development of new oral agents (e.g. sildenafil, oral phentolamine, sublingual apomorphine), similar standards of research must be applied in the evaluation of other drug delivery systems or mechanical devices for the treatment of erectile dysfunction.

I. INTRODUCTION Clinical trials of erectile dysfunction (ED) have proliferated in the past decade, as a wide range of injectable, transurethral and oral agents have become available. Critical to the development of these new treatments has been the design, conduct and interpretation of clinical trials in selected patient groups. Along with the development of novel agents for the treatment of ED, a plethora of new outcome measures and assessment tools have been developed. These new measurement approaches have allowed for more precise and reliable assessment of erectile function in research and clinical settings. In addition, the use of valid and reliable outcome assessments in the context of a wellcontrolled clinical trial is the sine qua non for regulatory approval of any new clinical agent. In this chapter we focus on the design and conduct of clinical trials in ED, including a review of the design and methodology of Phase I, II, III, and IV clinical trials. In particular, we consider such issues as the choice of study design, duration and timing of the trial, selection of clinical or non-cli nical populations to be studied, outcome assess ments or response variables to be measured, and statistical analyses to be employed. The use of parallel-design, crossover-design, and combination clinical trial designs is reviewed. The chapter also presents practical guidelines in the development of clinical protocols for new drug evaluation, the role of ethical and clinical issues in the conduct of clinical trials, and guidelines for the preparation of research reports and publications. 649

Summary points: • This chapter focuses on the design and conduct of clinical trials for erectile dys function. Issues such as the choice of study design and methodology, selection of the study population, and outcome variables to be measured are considered in depth. • The development of new agents for treat ment of ED has been associated with advances in clinical trial methodology, parti cularly the development of new outcome measures for assessing sexual functioning and quality of life. The use of validated and reliable outcome measures is a necessary component in all clinical trials.

dicted threshold efficacy dose in man. Should this be well tolerated, additional doses will usually be evaluated at dose increments of 2x to 3x. Signs of poor toleration or reaching a pre-determined dose level will normally conclude this stage of development. Where possible, these studies are accompanied by concomitant assays of plasma drug levels.

II. RATIONALE AND DESIGN OF CLINICAL TRIALS The process of development and/or regulatory approval for new treatments for ED can be broken down into several discrete phases. This process is usually described as occurring in four phases (Phases I, II, III, and IV), each of which is described in detail below. Beyond the immediate goal of attaining regulatory approval, clinical trials are also intended to be predictive of the likely risk/benefit outcomes when the drug or device enters widespread clinical use.

To ensure that tolerability is not affected by administration of subsequent doses of the drug, mul tiple dose studies should be undertaken. The frequency of dosing will depend on the predicted dosing regimen of the novel agent. Again, plasma drug levels should be monitored provided that the basic assessment of drug tolerability is not compromised. Formal pharmacokinetic and drug metabolism studies are usually initiated following single and multiple dose tolerability studies. It is important to ensure that there is no dose-dependent tissue drug accumulation, and that the metabolic path way and potential for major drug interactions are known. Limited efficacy information can be obtained from Phase I clinical pharmacology studies in healthy volunteers that may expedite dose selection and the overall drug development process. In recent years, surrogate endpoints have been used increasingly in phase I trials for this purpose. For example, this type of study is now used routinely in BPH/LUTS drug development, where the efficacy of novel alpha-blockers is determined by a reduction in response to the alpha agonist, phenylephrine [1]. A similar model could potentially be developed for dose selection of novel pharmaco logical agents for ED, based upon specific mechanisms of actions of these drugs (e.g. PDE5 inhibition, alpha-adrenergic blockade). Finally, it is sometimes worthwhile to undertake phase I studies in specific populations. For example, studies in women or the “supra-elderly” may be undertaken during phase I if these populations are likely to be further studied during phase II or III clinical trials.

1. P HASE I These studies represent the first exposure in man of the novel agent or device and are typically conducted in healthy individuals. Unless there is a particular need at this stage, women of child-bearing age are generally excluded. The full range of phase I studies potentially relevant to ED is shown in Table 1. Initial studies in volunteers typically involve administration of a single dose of the new agent. The first dose is selected on the basis of acute and chronic animal studies and, if available, data from human liver metabolism in vitro. The initial dose selected may be 30-100 times lower than the preTable 1: Phase 1 Drug Development in Healthy Volun teers S TUDY T YPE

RATIONALE

Single dose

Assessment of tolerability after single dose administration

Multiple dose

Asssessment of tolerability over likely dosing period

Pharmacokinetics

Assess if pre-clinical studies are predictive of kinetics and metabolites.

Clinical pharmacology

Indirect assessment of efficacy. Ensure adequate pharmacodynamic/Pharmacokinetic relationships.

Special populations

Women and/or “supraelderly” May display different tolerability/Pharmacokinetics.

2. PHASE II Efficacy assessment is formally begun in phase II. Outcome assessments during this phase typically involve a mixture of objective measures (e.g. Rigiscan) or self-report measures (e.g., daily dia-

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ries, IIEF) and are likely to be similar to those used in the more extensive phase III studies (see below). The primary objective of phase II effica cy studies is dose-setting, i.e., the identification of an effective dose range to be evaluated in phase III. The range of doses in phase II studies are usually more limited than in phase I, since the maximum tolerability of the drug has been established. A starting dose of 5-10% of the maximum tolerated dose may be initially employed. Additional information on drug tolerability is also obtained during this stage of clinical development, allowing calculations of potential benefit/risk ratio. Crossover designs, in which each patient serves as his own control, are often used in phase II trials. The major advantage of this design is the availa bility of within-subject comparisons and the associated reduction in patient variability and increased statistical power - a feature that may inadvertently result in a bias towards positive outcomes. As such, this design is generally favored in early stage clinical studies (phase I and II). Other potential problems are the likelihood of carryover effects from one treatment phase to the next and susceptibility to patient drop-outs. These problems may be exacerbated if three or more treatment arms are included in the study design. Despite these limitations, crossover designs are frequent ly preferred in early phase II dose setting studies. Phase II studies may involve evaluations in spe -

cial populations. The high degree of comorbid hypertension and diabetes associated with ED [2] may warrant early stage characterization of the potential cardiac or metabolic effects of novel ED agents in these patient groups. Additionally, drug interaction studies may be undertaken during this phase (see below).

3. PHASE III Prior to regulatory approval, it is necessary to conduct two or more large-scale (“pivotal”) outcome studies in appropriately selected patient groups. Phase III trials are usually designed as multi-center, randomized, prospective studies with two or more doses of the study drug and a doubleblind placebo control condition. Parallel designs are typically employed in this phase. In the simplest parallel design study, patients are randomly assigned to two or more parallel treatment arms for the duration of the study period (usually 12-16 weeks). Each patient is exposed to one treatment condition only, and comparisons are made between treatment groups at various time points. Treatment-induced changes are assessed by analysis of between-group differences following treatment. Results can also be analyzed relative to changes in baseline. Baseline assessments are necessary to ensure that the treatment groups are equivalent prior to randomization. Mixed parallel-crossover designs have also been used in Phase III trials with novel ED agents (See Figure 1). Figure 1: A combination parallel-crossover design. This design was used in recent phase III trials of sub lingual apomorphine for erectile dysfunction. Patients were randomly assigned to one of three treatment arms (2 mg, 4 mg, 6mg apomorphi ne SL). Within each treatment arm, each patient received active drug or double-blind placebo for an initial 4-week treatment period. Following a brief washout period (24-72 hours), patients received the alternative drug or placebo condition during the second 4-week treatment period. The design is completely counter balanced and minimal car ryover effects were observed.

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The parallel treatment phase, usually double-blind, is frequently preceded by a single-blind placebo or “no treatment” run-in phase to establish a reprodu cible baseline prior to randomization. This run-in period can also be used to screen out patients who are most susceptible to placebo effects. Following this stage, patients are assigned to the double-blind, randomized phase of the study. A comparison drug or treatment may be included, although these are not essential or required for initial regulatory approval. All phase III studies should be prospective and placebo-controlled, defining in advance inclusion and exclusion cri teria and the baseline characteristics of the popu lation. Primary and secondary study endpoints should be clearly specified, as well as key safety parameters. Phase III studies are typically powered for the primary efficacy endpoints. The duration of treatment may range from several weeks to 6 months or more, although longer duration trials may be difficult to complete due to subject attrition. A minimum duration of 8 weeks of treat ment is generally recommended. Most phase III trials of ED include an open-label extension phase during which additional safety data is collected. Open-label extension phases may last from 6 months to 2 years or more.

4. P HASE IV Phase IV studies are undertaken either during the registration process or subsequent to approval. One component involves “post marketing sur veillance” studies designed to provide long-term tracking of patients on active drug and thereby expand the safety database. Special population studies may also be conducted during this phase. In general, phase IV studies are designed to increase understanding of the overall treatment profile in the target population(s). These studies may not include all of the controls (e.g., placeboblinding and baseline assessment) utilized in phase II/III. On the other hand, comparator agents and special population groups are more likely to be included in the trial design during this phase. Increasingly, the healthcare environment requires outcome assessment in long-term studies to generate data on the potential effect of treatment on healthcare economics. At the earliest, these studies would be conducted in phase IV.

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5. DRUG INTERACTION STUDIES Many patients with ED are likely to be receiving drug therapy for associated co-morbidities (e.g. diabetes, hypertension, hypercholesterolemia) or unrelated disorders (e.g. asthma, gastric ulcer). Although it is neither practicable or necessary to determine the impact of a novel agent for ED on every potential drug taken by the patient, certain key drug interactions should be examined. The interaction studies fall into two major categories: pharmacokinetic and pharmacodynamic interactions. Pharmacokinetic drug interaction studies are designed to evaluate acute effects of the new agent on the plasma levels of other drugs (e.g. antihypertensives, anticholesterolemics) being concomitantly administered. Specific drug interaction studies may be required should the novel agent be known to be an inducer or inhibitor of cytochro me-dependent liver metabolizing systems. Equally important is the potential for pharmaco dynamic interactions. Of particular relevance is the potential of novel ED agents to impact positively or negatively on the efficacy of agents taken to control comorbidities such as hypertension, hyperlipidemia or diabetes. An alteration in blood pressure control in a patient with controlled hypertension, or endocrine control in a diabetic patient would be undesirable features, and should be carefully evaluated during early phase I or phase II studies. In addition, specific pharmacodynamic interactions relevant to the mechanism of action, e.g. PDE-5/nitrate interactions in angina patients should be carefully assessed. Summary Points: • The process of new drug or device develop ment is categorized into 4 stages. Stage 1 studies are usually performed in healthy volunteers to evaluate pharmacokinetic properties and tolerability of new drugs. Phase II studies provide initial efficacy and dose ranging assessment. Phase III studies are large-scale, prospective (“pivotal”) stu dies of efficacy and safety. Finally, phase IV studies are post-approval or special popula tion studies.

A second underlying principle in defining the study population is that the disease state under investigation must be well characterized and well defined. In order for the results of controlled clinical trials to be easily interpreted by practitioners, it is critical that the entrance criteria clearly define a patient population with well-recognized disease manifestations. Although practitioners of clinical medicine are not limited by the boundaries of a particular disease category when they treat patients in the real world, the clinical trial investigator should attempt to control these boundaries relatively strictly. The investigator tries to achieve this by meticulously defining the particular disease manifestations, using particular signs and symptoms, and considering symptom severity and duration. Careful patient selection using unam biguous inclusion and exclusion criteria should be sufficient to delineate a study population that is easily recognized by all those who assess the study results.

• Among the available research designs, cros sover designs are usually employed in Phase II studies. This design has the advantage of controlling for subject variability and pro vides increased statistical power. Parallel or combination parallel-crossover designs are preferred in Phase III or IV studies. Phase III studies should always be double-blinded and placebo controlled with careful assess ment of baseline functioning prior to rando mization. The minimum duration of treat ment is usually 12-16 weeks in these studies. • Drug interaction studies are important in evaluating possible phamacokinetic and pharmacodynamic interactions between ED agents and other drugs used in the treatment of common comorbidities, such as hyperten sion, hyperlipidemia and diabetes. Possible interactions with other cardiovascular drugs (e.g. nitrates) are of special concern.

III. STUDY POPULATIONS 1. GENERAL PRINCIPLES All clinical trials require a precise definition of which patients are eligible for inclusion and which patients are not eligible. The most important underlying principal guiding this definition is that the study population should represent the overall patient population for whom the treatment under investigation is inten ded. If the study population is truly representative of the intended treatment population, then the results of a well-designed controlled trial are likely to predict the “real-world” effect. On the contrary, if the study population is too narrowly defined, then the trial results may not generalize to the broader population. Therefore, when conducting “pivotal” phase III trials, it is important for the investigator to define a group of patients that will be as representative as possible of the intended patient population at large. The investigator accomplishes this by taking into account such factors as patient age, overall health status, concomitant medications, and the severity and duration of the disorder. All of these considerations apply in the selection of patients for clinical trials of ED.

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A third principle is that a logical and reaso nable balance must be struck between the safe ty of the enrolled patients and the “openness” of the entrance criteria. Specifically, the trial population should be sufficiently broad to represent the larger group of patients who may eventually benefit from treatment, although it should not be so broad so as to include patients who are clearly at direct high risk of injury from the study treatment or procedures. Such balance requires skillful selection of entrance criteria which comes only with a sound understanding of the disease process, experience in the management of such patients, and knowledge of the conduct of clinical trials. A corollary of this principle is that exclusion criteria should be sufficiently strict so as to adequately define the study population and to safeguard the enrolled population, but should not be so strict as to significantly impair the ability of the investigator to recruit the necessary numbers of patients. Specific study population issues in erectile dys function: Representative patient population: The phase III study population should include patients with erectile dysfunction of varying etiologies and severities. Such patients will include those with diabetes, atherosclerosis, hypertension, hyperlipi-

demia, neurologic disorders, genitourinary disorders, appropriately treated endocrinopathies and depression, tobacco use, and various psychologic etiologies. The practice of attempting to divide the population into “organic” and “psychoge nic” etiologies appears to create artificial and unrealistic subgroups. Such a division may serve to reduce the overall applicability of results. Alternatively, it may be argued that “too much” heterogenity of disease can increase inter-patient variability and may mask or obscure an underlying treatment effect that would have been observed in a more homogeneous population. Regarding disease severity, the phase III study population should provide a representative mixture of the various degrees of severity of erectile dysfunction, as assessed by well-validated and sensitive instruments. It may be argued that the inclusion of milder forms of disease could make the demonstration of a treatment effect more difficult. In addition, it is also possible that patients with more severe forms of disease may be more resistant to treatment. Nevertheless, the principle of generalizability seems to carry sufficient weight that it currently appears reasonable to include the broadest possible range of etiologies and severities in the “pivotal studies”. On the other hand, it also appears reasonable, at this time, to study certain sub-groups of patients in smaller, “special population” trials. These trials may include patients with more severe dysfunctional states, patients who have undergone radical prostatectomy, and patients with spinal-cord injury. It may even be reasonable to perform separate studies in diabetics or depressed patients. Proponents of special population studies argue that patient-related variability is reduced and that the likelihood of obtaining a significant treatment effect is increased. In addition, individual study reports may be easier to interpret. Regardless, such studies are capable of providing important support for the pivotal trials.

2. DEFINING THE DISEASE STATE AND PATIENT POPULATION a) Inclusion criteria Phase III studies in erectile dysfunction are typically conducted in adult males, 18 years of age and older. There are usually no upper age limitations. In most circumstances, males are heterosexual and 654

have a stable, monogamous relationship with a willing partner. The partner must agree to participate in the trial. The patient must complain specifically of “erectile dysfunction”; that is, a consistent difficulty in achieving and/or maintaining an erection sufficient for sexual intercourse. In general, the dysfunctional state must negatively impact on the enjoyment or satisfaction with the overall sexual experience. The duration of dysfunction is variable in different trials, but in general, the problem should be described as a “consistent” one rather than a “transient” one. Currently, it appears that a duration of at least 3 months is a generally accepted, minimum period of disease, although it may be argued that both shorter and longer duration of dysfunction also constitute true “erectile dysfunction”. Enrolled patients must be willing to provide informed consent and must be willing and able to participate in all necessary and pre-specified study procedures. In some trials, inclusion is limited to patients with “mild to moderate erectile dysfunction”, as assessed by standardized instruments such as the International Index of Erectile Function (IIEF) (See Appendix B). In the design of some trials, patients who succeed “too often” during a pre-specified run-in period (e.g. >75% successful attempts) are excluded from additional study participation. b) Exclusion criteria In general, exclusion criteria are used to strictly define the study population and to provide safeguards against enrolling patients who are at inhe rent high risk from study participation. In studies of agents for the treatment of erectile dysfunction, it has been customary to exclude certain patient groups. These are shown in Table 2 (following page). In some trials, exclusion criteria have been employed which provide safeguards for a particu larly susceptible group of patients from exposure to a particular physiologic response associated with the treatment. Such exclusion criteria are often dependent on the proposed mechanism of action of the drug. For example, in trials of potent vasodilator agents, patients with orthostatic hypotension may be excluded. In trials of the phosphodiesterase inhibitor, sildenafil, patients using nitrate therapy are excluded due to the drug’s enhancement of the systemic vasodilating effect of nitrates.

Table 2: Patients Typically Excluded from Clinical Trials of ED

3. BALANCE BETWEEN “OPENNESS” OF THE ENTRY CRITERIA AND PATIENT SAFETY

1. Patients with untreated hypogonadism.

In examining some of these exclusion criteria, it becomes clear that there is a degree of conflict between maintaining the safety of those in the trials and studying the treatment in a broadly representative patient population. For example, patients with extensive cardiovascular disease may not be appropriate candidates for controlled clinical trials for safety reasons, yet such patients may become candidates for treatment once therapy becomes widely available. As an overview of this problem, it appears reasonable to state that entry criteria should allow the broadest pool of patients that reasonable safety allows. The rapid development of therapies for erectile dysfunction may help us to better manage this conflict in the near future.

2. Patients with penile deformities such as Peyronie’s plaques; patients with penile implants; and patients with predispositions to priapism, such as those with sickle cell disease, blood dyscrasias and multiple myeloma. 3. Patients with significant baseline liver dysfunction, such as those with baseline SGOT or SGPT > 3 times the upper limit of normal. 4. Patients with significant baseline renal dysfunction, such as those with serum creatinine values greater than 2.5 mg/dl, those on dialysis, and those who are status post renal transplant. 5. Patients with a history of HIV infection. 6. Patients with drug, alcohol or substance abuse within 6 months of study initiation.

Summary Points: • In general, the study population in clinical trials of ED should be broadly representati ve of the overall patient population. Inclu sion criteria should define the patient’s condition as clearly as possible, and should provide minimal duration and severity crite ria. Exclusion criteria should be sufficiently strict so as to adequately define the study population and to safeguard the enrolled population.

7. Patients who have participated in another study for the treatment of ED within 30 days of study initiation. 8. Patients who have partners who are nursing, who are pregnant, or who wish to become pregnant during the course of the study. 9. Patients who are unable to provide informed consent. 10. Patients with uncontrolled psychiatric disorders, such as psychosis, manic as is depressive disorders or chronic depression.

• Special population studies may also be of value in assessing the safety or efficacy of new treatments in selected sub-populations. These studies provide valuable complemen tary data to the main pivotal trials.

11. Patients with uncontrolled diabetes mellitus, as evidenced by elevated hemoglobin A1c levels. In addition, patients in whom sexual activity itself may be a risk for cardiovascular events have been excluded from these trials. The specific exclusion criteria that have been employed to remove such patients from the study population have included:

IV. OUTCOME ASSESSMENTS

1. Patients with unstable angina. 2. Patients with a history of myocardial infarction within 6 months of study initiation.

4. Patients who have suffered a stroke within 6 months of study initiation.

The outcome of clinical trials in erectile dysfunction should only be assessed by validated and sensitive instruments which can be used to measure changes due to treatment from baseline to a predetermined follow-up period. Historically, studies on ED have suffered from the following:

5. Patients with uncontrolled hypertension, for example, those with systolic blood pressures above 170 mm Hg or diastolic blood pressures >100 mm Hg.

1. Outcomes reported by verbal interactions with the patient and not by a standardized, written questionnaire.

3. Patients with a history of life-threatening cardiac arrhythmia within 6 months of study initiation.

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2. Follow-up periods of short or indeterminate length. 3. Pre-treatment and post-treatment clinical status poorly defined. 4. Quality of life and sexual status questionnaires not used. 5. Partner verification infrequently used. For the safety and effectiveness of a drug/device to be measured and compared to existing thera py, both pre-treatment and post-treatment assess ments must be standardized and broadly accepted by the research community. Response variables are the endpoints or outcomes to be measured during the course of a clinical trial. In principle, one or two response variables should be selected in advance as the primary endpoints of the trial, although in practice several response variables are usually reported. In these situations, special care needs to be taken to correct statistical ly for the number of comparisons made, and possible interrelationships between the response variables of interest. The choice of primary end points in a clinical trial is essential, and response variables should be clearly defined and justified prior to initiation of the trial. In the absence of standardized outcome measures, comparison of results from one ED trial to another should be viewed with considerable caution. Among the response variables most frequently used in trials of ED are physiological measures of penile rigidity or tumescence (e.g. Rigiscan), patient-based questionnaires or diary reports of sexual function (e.g. IIEF, SEP), partner assessments, and global ratings of clinical improvement. Each of these measures has certain advantages and disadvantages.

determined force to each loop every 3 minutes initially, and at 30 sec intervals when an increase of >10 mm at the base is detected. Penile rigidity is expressed as a function of displacement when the loop is tightened around the penis, and rigidity is defined in terms of penile stiffness as determined by cross-sectional response to radial compression [7]. Although the technique was developed originally for home monitoring of NPT, Rigiscan recording has been used extensively for real-time assessment of penile tumescence and rigidity in response to pharmacological or visual sexual stimulation (VSS). For example, in-office Rigiscan measures of penile rigidity were reported as a primary endpoint in a pivotal dose-finding study of intracavernosal alprostadil for ED [8]. Rigiscan changes in response to VSS (Fig. 3) have similarly been reported in trials of sildenafil [9] and sublingual apomorphine [10]. Several potential limitations have been identi fied, the most significant of which is the assumption of equivalence between radial and axial rigidity. Although there is limited evidence for this assumption, at least one study compared measurements of axial and radial rigidity at constant corporal pressures [11]. Axial and radial rigidity were found to be functionally related, and both measures were moderately correlated with intracavernous pressure. In a comparison of Rigiscan with sleep laboratory measures of tumescence and rigidity, Licht et al. [12] reported that a base

1. P HYSIOLOGICAL MEASURES Several methods for objective measurement of penile rigidity and engorgement have been described [3-5], the most widely used of which is the Rigiscan system (Timm Medical Systems) (See Figure 2). This method was first described by Bradley and Timm [6], who recommended use of the device in the home setting for monitoring of nocturnal penile tumescence and rigidity (NPTR). The device is attached to the patient’s inner thigh, with two loops placed around the base and tip of the penis proximal to the coronal sulcus. Measures of radial rigidity are obtained by application of a pre-

Figure 2: The Rigiscan device (Timm Medical Systems) for continuous monitoring of penile tumescence and rigidity. The device can be used for overnight recording of noctur nal penile tumescence and rigidity (NPTR) or for provoca tive testing of responses to visual sexual stimulation (VSS).

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Figure 3: Sample Rigiscan tracing from a provocative testing session with VSS. The onset of stimulation is indicated by the double vertical lines. The patient achieved near-maximal rigidity for most of the testing session.

rigidity of 55% or more predicted functional erection with a sensitivity of 85% and specificity of 91%. Other investigators have reported that tip rigidity of 70% for greater than 5 minutes provides the best cutoff for diagnostic classification [13]. Additional limitations of the device include lack of adequate standardization of normal values, limited time sampling of tumescence and rigidity, inflexibility of the accompanying software, and potential intrusiveness of the device for some patients. Despite these limitations, Rigiscan recording plays an important role as an objective and quantifiable measure of erectile response.

assessment is a major disadvantage of these approaches in clinical trials of ED. Finally, the erectiometer provides a crude measure of both rigidity and tumescence (circumference change). This device consists of a 2 cm wide felt band with a sliding collar fastened to one end. The felt band expands with tumescence, but requires a force of about 250 grams to initiate expansion. In this way, the device provides a combined assessment of both circumference and rigidity changes [16]. It has been used to differentiate response patterns in clinical studies with normal and sexually dysfunctional men [23-24], although the erectiometer provides less sensitivity and reliability than either the Rigiscan or mercury strain gauge devices [24].

Other physiological measures of penile tumescence and rigidity include volumetric and straingauge plethysmography [14,15], and the erectiometer [16]. Volumetric plethysmography provides a highly sensitive measure of penile engorgement, which has been used extensively in studies of sexual preference or paraphilias [17-19]. However, the measurement apparatus is obtrusive and inconvenient to use, and provides no information on penile rigidity. Similarly, mercury-in-rubber and electromechanical strain-gauges provide sensitive measures of penile circumference change and have been widely used in laboratory studies of sexual arousal [20-22]. Again, the lack of rigidity

2. S ELF-REPORT MEASURES Self-report measures of sexual function are divided into three major categories: self-administered questionnaires, daily diaries or event logs, and structured interviews. Each of these approaches has been used in recent clinical trials, although the primary emphasis in most validation studies has been on self-administered questionnaires (SAQ’s). These measures have the potential advantage of providing standardized and relative-

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ly cost-efficient assessment of current and past sexual functioning. Patient burden is generally low, and some measures have been designed specifically for use in multicenter, clinical trials [2526]. Only one structured interview method has been evaluated to date [27]. At present, the most widely used measures are as follows.

(internal consistency and test-retest reliability) in both clinical and nonclinical samples. Discriminant and concurrent validity are adequate. Sensitivity and specificity (treatment responsiveness) are excellent, as has been demonstrated in recent clinical trials [30,31]. The IIEF is available in more than 30 languages, and has been widely adopted as the “gold standard” instrument for efficacy assessment in clinical trials of ED.

a) The International Index of Erectile Function (IIEF)

Major advantages of the IIEF are its relative brevity and ease of use, inclusion of multiple domains of sexual function, and strong psychometric profile. Aggregate scores on the Erectile Function (EF) domain are recommended for use as a primary endpoint in large-scale pivotal trials of ED. Baseline scores on this domain are also useful for stratifying patients according to disease severity, or as a potential baseline covariate. Potential disadvantages of the measure are the limited assessment of other domains of sexual function (e.g. sexual desire, orgasmic function) and restricted time frame (four weeks). At present, the IIEF is widely used as an international standard in both clinical and research assessment of male erectile function. It is highly recommended for use in clinical trials of ED.

The International Index of Erectile Function (IIEF) was designed and developed specifically for assessment of sexual function in clinical trials [26] (See Appendix B for sample questionnaire). The IIEF has been extensively validated and widely used as a measure of efficacy in clinical trials of ED agents. The instrument consists of 15 items and assesses sexual functioning in five domains: erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction (See Figure 4). Average scores are calculated in each of the major domains, and a simple severity algorithm is available for clinical interpretation of scores on the erectile function domain [28]. A brief, 5-item version of the test has also been shown to be useful for screening of patients in clinical settings [29]. Psychometric validation has demonstrated a high degree of reliability

b) The Brief Male Sexual Function Inventory (BMSFI) This is an 11-item, questionnaire scale which assesses several components of male sexual function, including sexual drive, erection, ejaculation, sexual problems, and overall satisfaction [25]. Major advantages of this scale are: (a) a relatively high degree of internal consistency and test-retest reliability, (b) adequate discriminant validity for three of the domains (erectile function, problems, overall satisfaction), and (c) ease of use. Potential disadvantages are the restricted evaluation of erectile and orgasmic function, and lack of evidence concerning sensitivity or treatment responsiveness. The scale has had limited use in large-scale clinical trials of ED. c) The Center for Marital and Sexual Health Questionnaire (CMSH-SFQ) This brief 18-item, self-report questionnaire assesses current sexual function in the areas of erection, orgasm, desire and satisfaction [32]. Initial psychometric assessment of the instrument has been performed, although data regarding sensitivi-

Figure 4: IIEFDomain scores in untreated and treated ED patients compared to age-matched controls. The 5 domains of sexual function are shown (EF, OF, SD, IS, OS), with near-normalization across each of the domains with silde nafil treatment. (Adapted from Dinsmore et al., Urol 1999; 53: 800-805).

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ty and specificity are lacking. In this study, the measure showed adequate reliability and construct validity. It has had minimal use to date in clinical trials of ED.

faction [35]. Further studies are needed to eva luate the sensitivity and reliability of partner ratings in comparison to patient ratings of erec tile function.

d) The Derogatis Sexual Function Inventory (DSFI)

A partner version of the SEP scale is also available (See Figure 6). This measure has not been psychometrically validated to date.

The DSFI is a comprehensive, multidimensional measure of male and female sexual function [33]. The complete DSFI scale consists of 245 items, requiring 40-60 minutes to complete. Ten domains of sexual function are assessed, including information, experience, drive, attitudes, psychological symptoms, affects, gender role definition, fantasy, body image, and sexual satisfaction, in addition to a global sexual satisfaction index. The test has been psychometrically validated, and has been widely used in studies of normal and dysfunctional individuals. Its major drawbacks are the excessive length and complexity of the instru ment, which make it generally unsuitable for use in clinical trials.

3. DAILY DIARY AND EVENT LOGS Daily diaries or sexual event logs are alternative measures of sexual function that may be used to complement the use of structured questionnaires, such as the IIEF. Event logs or daily diaries typically include assessment of variables such as intercourse frequency and satisfaction, quality of erection, and medication use. The Sexual Encounter Profile (SEP) is a 6-item event log which has recently been used in a number of large-scale clinical trials (See Figure 5). In a preliminary validation study, a high degree of correlation was observed between erection and intercourse satisfaction ratings on the SEP and IIEF measures in patients with mild to moderate degrees of ED [34].

4. PARTNER ASSESSMENTS Partner assessments of sexual function may be of value in corroborating the patient’s efficacy assessment and are generally favored by regula tory agencies for inclusion in clinical trials. Although no standardized or accepted measure of partner ratings exists, one recent study used a brief adaptation of the BMSFI for assessment of partner responses. In this study, a high degree of correlation was observed between patient and partner ratings of erectile function and intercourse satis-

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5. QUALITY OF LIFE AND TREATMENT SATISFACTION Quality of life measures, such as physical functioning, mood state, and overall life satisfaction are routinely used in large-scale clinical trials of cardiovascular disease, cancer and other chronic illnesses [36-38]. Recent clinical trials of ED have included quality of life and patient satisfaction measures as secondary endpoints. Although these measures provide a potentially broader understanding of treatment effects, several limitations and problems are evident. First, most quality of life scales are designed for use in medically ill patients, whose disease or treatment has a noticeable impact on physical or psychological functioning. Although ED patients in the general population may have deficits in some areas [39], clinical trials of ED typically exclude patients with major medical or psychiatric disease. Additionally, most domains of quality of life assessment, such as physical functioning, cognitive performance, and global health perceptions, are unlikely to be affected by the symptoms of ED or its treatment. In response to the need for a more “disease-speci fic” approach, two new instruments for quality of life assessment in ED trials have been developed. Wagner et al. [40] report the development of a 19item scale (QOL-MED), based on semi-structured interviews with a representative sample of ED patients. This measure has a high degree of reproducibility and internal consistency, but has received little validation in ED patients or controls. More recently, Fugl-Meyer et al. [39] have described the use of a brief, 8-item life satisfaction checklist for specific quality of life assessment in ED trials (See Figure 7). This measure was found to differentiate between ED patients and controls on several dimensions. Significant improvements on two scale dimensions (sexual life and overall life satisfaction) were found following successful treatment with prostaglandin E1 injections. This

Figure 5: The Sexual Encounter Profile (SEP). This sexual event log measure is widely used in clinical trials of ED. SEXUAL ENCOUNTER PROFILE (SEP) Date of Sexual Encounter _________/_______/_______ (month/day/year) Time of Sexual Encounter ________________________ 1. Were you able to achieve at least some erection (some enlargement of the penis)? If yes, place 1 in the box and CONTINUE. If no, place 0 in the box and STOP.

[ ]

2. Were you able to insert your penis into your partner’s vagina? If yes, place 1 in the box. If no, place 0 in the box.

[ ]

3. Did your erection last long enough for you to have successful intercourse? If yes, place 1 in the box. If no, place 0 in the box.

[ ]

4. Were you satisfied with the hardness of your erection? If yes, place 1 in the box. If no, place 0 in the box.

[ ]

5. Were you satisfied overall with this sexual experience? If yes, place 1 in the box. If no, place 0 in the box.

[ ]

Figure 6: The Partner Sexual Encounter Profile (PSEP). This is a partner version of the sexual event log measure used by male patients in clinical trials of ED. PARTNER SEXUAL ENCOUNTER PROFILE (PSEP) Date of Sexual Encounter _________/_______/_______ (month/day/year) Time of Sexual Encounter ________________________ 1. Was your partner able to achieve at least some erection (some enlargement of the penis? If yes, place 1 in the box. If no, place 0 in the box.

[ ]

2. Was your partner able to insert his penis into your vagina? If yes, place 1 in the box. If no, place 0 in the box.

[ ]

3. Were you satisfied overall with this sexual experience? If yes, place 1 in the box. If no, place 0 in the box.

[ ]

Figure 7: The Fugl-Meyer Life Satisfaction Scale. This simple measure of life satisfaction has been used for assessing quality of life outcomes in epidemiological and clinical studies of ED (From: Fugl-Meyer AR et al., Intl J Impot Res 9:141-148, 1997.) FUGL-MEYER LIFE SATISFACTION SCALE How satisfactory are these different aspects of your life? 1 = Very dissatisfying 2 = Dissatisfying 3 = Rather dissatisfying

4 = Rather satisfying 5 = Satisfying 6 = Very Satisfying

Life as a whole is …………………………………

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My sexual life is ………………………………….

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My partnership relation is ………………………..

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My contacts with friends and acquaintances are…

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My vocational situation is…………………………

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My leisure situation is …………………………….

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My financial situation is …………………………..

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measure provides a broad assessment of quality of life dimensions of potential interest in ED patients and may be of value in future clinical trials.

ted over several stages, ranging from Phase I safety and toxicology studies in humans and animals, to large-scale, Phase III trials during which multiple adverse events are monitored and evaluated. Post-marketing surveillance studies provide additional data on side effects associated with longterm use of the drug or device. Although most pharmacological agents are extensively evaluated prior to and following regulatory approval, several issues and concerns in adverse event monitoring in ED trials are worth noting.

A treatment satisfaction measure (Erectile Dys function Inventory of Treatment Satisfaction – EDITS) has also recently been described [41] (Appendix C). This measure assesses patient and partner ratings of treatment satisfaction across several domains of treatment efficacy. The measure has had limited psychometric validation and has been used in recent clinical trials with sildenafil.

First, the means by which adverse events are ascertained can influence the frequency and type of reports obtained. Checklist or interview approaches each have certain advantages and disadvantages. Symptom checklists (see Figure 8) have the major advantage of allowing standar-

6. ADVERSE EVENT MONITORING An important consideration in clinical trials of ED is the monitoring and reporting of adverse events. Evaluation of adverse events is typically conducFigure 8: Adverse Events – Definitions and Description

ADVERSE EVENTS All adverse events are to be investigated as to: DEGREE OF INTENSITY

DESCRIPTION

MILD

Awareness of signs and symptoms; easily tolerated

MODERATE

Discomfort sufficient to interfere, but not prevent daily activity

SEVERE

Unable to carry out usual activity

• Seriousness (whether or not the adverse event is fatal or life-threatening, is persistent or permanently disabling, requires or prolongs inpatient hospitalization, or is a congenital anomaly, or is medically significant) or unexpected (not listed in the Investigators Brochure). • Action taken (whether or not the adverse event caused the subject/patient to be discontinued from the study). • Causal relationship to test medication, to be graded as follows: DEGREE

DESCRIPTION

DEFINITELY

There is evidence of exposure to the test medication, for example, reliable history or acceptable compliance assessment; the temporal sequence of the AE onset relative to the medication is reasonable; the AE is most likely to be explained by the treatment than by another cause; the challenge is positive; rechallenge (if feasible) is positive; the AE shows a pattern consistent with previous knowledge of the treatment.

PROBABLY

There is evidence of exposure to the test medication; the temporal sequence of the AE onset relative to medication administration is reasonable; the AE is more likely explained by the treatment than by another cause; the challenge (if performed) is positive.

POSSIBLY

There is evidence of exposure to the test medication; the temporal sequence of the AE relative to the medication administration is reasonable; the AE could have been due to another equally likely cause; the challenge (if performed) is positive.

PROBABLY NOT

There is evidence of exposure to the treatment; there is another more likely cause of the AE; the challenge (if performed) is negative or ambiguous; rechallenge (if performed) is negative or ambiguous.

DEFINITELY NOT

The subject/patient did not receive the treatment; or temporal sequence of the AE onset relative to administration of the test medication is not reasonable; or there is another obvious cause of the AE.

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dization of reporting between and within trials, whereas interview methods encourage more indepth assessment and recording of unanticipated adverse events. Some trials use a combination of these approaches. The number of patients and duration of the trial can have a significant impact on the frequency of adverse events reported. Since sample size is invariably calculated on the basis of estimated changes in the primary efficacy parameter, most trials lack adequate power for reliably assessing the frequency of adverse events, particularly in the area of low frequency, but potentially serious adverse events (e.g. MI). A related problem is the relatively high rate of adverse events often observed in placebo control groups, which could be related to the age and health status of the patients, or the influence of placebo effects. Long-term follow up studies of ED treatment are relatively rare, although such trials are obviously important for adequate safety assessment.

• Adverse event monitoring is a critical aspect of safety evaluation for new drugs or devices for ED. Several methods are available for monito ring of adverse events, including symptom checklists and patient interview methods. Long-term monitoring of adverse events is essential in evaluating the long-term safety of new treatments for ED.

V. PROTOCOL DESIGN AND IMPLEMENTATION

With the advent of a wide range of treatment options for ED, it might be anticipated that safety issues and reporting of adverse events will assume even greater significance in the years to come. Regulatory agencies are likely to place increasing emphasis on adverse event reporting since ED is regarded as neither life-threatening nor a serious medical condition. Pharmaceutical companies are also tending to pay greater attention to safety issues in an attempt to differentiate their product from those of competitors. A positive effect of these trends is that clinical trials of ED are including increasingly larger number of patients for longer periods of time (e.g. 1-2 years). Summary Points: • Safety and efficacy endpoints should be clearly identified in advance. A variety of outcome measures are available for assessing efficacy, including physiological (e.g. Rigiscan) and questionnaire measures (e.g. IIEF). Daily diary and event log measures are used for assessing frequency and adequacy of sexual performance, and partner assessments provide valuable corroborating data. Patient satisfac tion and disease-specific quality of life mea sures have recently been developed. Several complementary outcome measures are recom mended in large-scale clinical trials of ED.

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The conduct of each clinical trial should be based on a well-designed and carefully implemented study protocol. The study protocol serves as a written agreement between the investigator, the research participant and the scientific community. It includes the goals and objectives of the trial, research design and methodology, plans for data analysis, and overall organization of the trial. Each of these sections should be described in detail, with supplemental data or procedural information contained in a protocol appendix or manual of procedures. The study protocol should be fully deve loped prior to the initiation of the trial and should remain essentially unchanged, except for minor updates or amendments during the course of the trial. The protocol should be agreed to in writing by each investigator and should be made available to all study personnel and others involved in the conduct of the trial. A copy of the study protocol and informed consent statement should also be submitted to the Institutional Review Board and appropriate regulatory agency prior to initiation of the trial. The study protocol should be organized as follows:

1. BACKGROUND OF THE STUDY This section should provide a concise overview of the epidemiology and clinical significance of the problem, alternative approaches to treatment, and proposed mechanism or site of action of the treatment under study. The need for a new therapeutic agent or device should be addressed, as well as the potential advantages or disadvantages of the study intervention. Also included in this section is a review of previous animal safety or toxicology studies, in addition to any available data in humans.

procedures should be described in detail. The description should include full details regarding: (i) the design to be employed (e.g., crossover, parallel), (ii) blinding procedures (e.g., singleblind, double-blind), (iii) type of treatment control (e.g. placebo, standard treatment), (iv) number and sequencing of treatment periods, (v) method of randomization (e.g., complete, stratified randomization), (vi) pre-treatment or baseline assessment (e.g. single-blind, open run-in), (vii) treatment interventions, (viii) and management of dropouts (e.g. with or without replacement). Full details of the patient population should be provided (inclusion, exclusion criteria) and the study endpoints (primary, secondary) should be clearly defined. Detailed plans for data collection and analysis should be included (See Section VI). Procedures for interim analysis and termination of the study should also be clearly specified. In addition to a written description, all study procedures and visits should be summarized in the form of a flow-sheet or summary table , as illustrated in Figure 9.

2. STUDY OBJECTIVES Each of the study objectives should be stated clear ly in advance. Primary and secondary questions (e.g. effects on quality-of-life or partner relationship) should be delineated, as well as the response variables to be measured in addressing each of these questions. Any planned sub-group analyses (e.g. older vs. younger patients, diabetics vs. non-diabetics) should be specified in advance. The safety objectives of the study and adverse event monitoring plans should also be described in this section. Although multiple objectives are possible, care should be taken not to overcomplicate the study design or conduct of the trial. This can result in excessive patient burden, diminished quality of data collection and “data dredging” in the analysis of results. Typically, statistical penalties are applied when multiple comparisons are made (See Section VI).

3. D ESIGN OF THE STUDY This section comprises the main body of the protocol, and all aspects of the study design and

Figure 9: Sample study flow sheet from a phase III trial of ED. The flow sheet shows all of the study procedures to be conduc ted over 5 study visits. SAMPLE STUDYFLOW SHEET Schedule of Events Activity

V1

Informed consent

X

Sex history

X

Medical and medication history

X

Physical examination

X

Height and weight

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ECG

V2

V3

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Clinical laboratory tests 1

X

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IIEF

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Dispense medication 1

X

Dispense diaries (SEP)

X

X

Collect medication 1

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Collect and review diaries

X

Begin washout period

X

X

End washout period

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Dispense medication 2

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Collect medication 2

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Monitor adverse events

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Monitor use of concomitant medications

X

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1 Hematology, serum chemistry, and urinalysis

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The methods and procedures section should provide detailed information for each study visit, specifying all study procedures to be performed, the response variables to be recorded at each visit, and the proper order or sequencing of study procedures and data collection. Standardized laborato ry procedures (e.g. ECG, blood sampling) should be employed unless otherwise specified. Detailed instructions are especially important for in-hospital recording of erectile responses (e.g. Rigiscan/VSS protocols), in order to optimize the quality of recording and to ensure standardization of data collection across sites. These instructions may be contained in a protocol appendix or manual of procedures. The use of concomitant medications should be carefully monitored throughout the study and instructions provided for the recording and management of adverse events (e.g. serious vs. non-serious; treatment related vs. treatment unrelated). Clear criteria should be provided for withdrawal of patients from the study or for study discontinuation. Periodic reviews of the study by an independent safety committee or monitoring board are frequently used in other clinical trial areas (e.g. cancer, cardiovascular disease), although these are less common in clinical trials of ED. The role of the safety committee should be clearly specified, if relevant. Finally, this section of the protocol should contain a clear description of the study materials. The test article (e.g., drug tablet, solution) should be described in terms of its physical and chemical properties, formulation and packaging. The stability of the formulation and specific requirements for storage and handling should be included. Information on dosage and administration of both active medication and control (e.g. placebo) is necessary, including unit dose, frequency of dosing, patient instructions and labeling. The protocol should also specify the investigator’s responsibilities in recording the receipt, dispensing and return of the study medications.

4. ADMINISTRATIVE CONSIDERATIONS Issues related to the protection of subjects’rights, monitoring and documentation of the study conduct, maintenance and retention of study records, and publication policies are all covered in detail in this section. A clear description should be provided of the level of patient confidentiality

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to be observed. Access to the study records by the sponsor, Institutional Review Board, regulatory agency or others should be clearly specified. Also, the terms of confidentiality between the sponsor and the investigator should be defined. A separate section should be addressed to the role of the Institutional Review Board and the procedures to be followed in obtaining informed consent. A copy of the actual informed consent statement should be included as an appendix to the protocol. A sample protocol outline for a clinical trial in ED is shown in Appendix A. Summary Points: • The study protocol is a written agreement between the investigator, the research subject and the scien tific community. It includes the goals and objec tives of the study, research design and methodolo gy, plans for data analysis, and overall organiza tion of the trial. The study protocol should be fully developed and agreed upon prior to initiation of the trial. • Essential features of the protocol include the back ground, study objectives, design and methods, and administrative considerations. Each of these sec tions should be completed in a clear and detailed fashion, with the entire protocol being reviewed by the sponsor, the Institutional Review Board and the relevant regulatory agency. • Investigators should adhere to the study protocol as closely as possible throughout the conduct of the trial. Procedures should be specified in advance for monitoring of the trial, and for maintenance and retention of all study documents. Publication plans and policies should also be clearly specified.

VI. DATAANALYSIS AND REPORTING OF RESULTS A variety of data analytic methods have been employed in recent clinical ED trials. Although a detailed discussion of these methods is beyond the scope of this chapter, some general comments and recommendations can be made. To a large degree, the type of statistical model employed depends upon the nature of the research design (e.g. parallel, between-group vs. counterbalanced, crossover design) and the response variables being analyzed (e.g. continuous vs. dichotomous variables).

Given the large number of statistical issues and data analysis considerations, it is essential that a qualified biostatistician be involved in the design and analysis of all clinical trials in ED.

sexual intercourse at least once during the study period. It could be argued that this definition is overly-liberal, and not in keeping with the usual clinical criteria for successful treatment.

Sample power should be calculated in advance, using the best available estimates of the means and variances of the primary efficacy variables, and anticipated changes associated with treatment. Sample power for phase III trials is traditionally based on estimates of efficacy, not safety. In this respect, studies may not be adequately powered for detection of low-frequency safety problems. Standard formulae are available for the computation of sample power for a clinical trial [42].

Unfortunately, normative population data are lac king to establish response criteria for adequate sexual performance at each age group. In the absence of such data, continued disagreement on the definition of a treatment responder is likely. One approach to the problem is to report several measures of treatment efficacy, including both quantitative (e.g. number of successful intercourse attempts) and qualitative (e.g. global satisfaction) indices. This allows for a more comprehensive assessment of the magnitude and consistency of treatment effects.

All subjects randomized to treatment or control conditions should be included in an “intentionto-treat” analysis, in which data from dropouts or withdrawals are included in the final analysis of treatment outcome. This general rule should not be applied to the assessment of adverse events, however, where it may be preferable to report the frequency of side effects only among those who actually received the treatment [43]. Covariate adjustments or stratification techniques can be used to control for differences between the study groups in baseline levels of functioning or demo graphic characteristics (e.g. age, duration of illness), although covariance analysis should be performed only when specific statistical assumptions are met [44,45]. As noted above, a limited number of sub-group analyses may be conducted, paying careful attention to the potential lack of power and possibility of Type II errors associated with these analyses [43]. Assessing the magnitude of treatment effects is a potentially thorny issue, which involves both statistical and clinical considerations. Effect size calculations can be used to provide a statistical estimate of the magnitude of treatment effects, although this approach has not been used to any significant degree in clinical trials of ED. Rather, most investigators report the magnitude of treat ment effects in terms of percentages of respon ders in the active compared to control groups. Such comparisons involve prior definition of a response threshold or cutoff, which may be subject to criticism. For example, in a multi-center trial of transurethral alprostadil [46], a treatment responder was defined as any individual who completed

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Finally, meta-analysis is a potentially powerful statistical technique for assessing the direction and magnitude of treatment effects over several independent trials [47,48]. First, the method requires careful selection of trials for inclusion in the analysis, based upon pre-determined criteria for assessing methodological adequacy (i.e. randomization, double-blinding). Results from all eligible trials are standardized and combined according to strict statistical rules. An odds ratio or relative risk analysis is then performed on the resulting data. Relatively few meta-analyses have been used in the analysis of clinical trial data in ED, although this technique offers considerable promise for addressing certain issues. As the number of clinical trials of ED increases, it is anticipated that meta-analy tic studies will play an increasingly important role in the future. Several points should be closely attended to in the final report preparation and publication of all clinical trials in ED. These are briefly as follows: 1. Authors should be selected for inclusion based solely on their contributions to the study design, conduct, analysis and write-up. Individuals who have not participated substantially in one or more of these aspects of the study should not be listed as authors on the final publication. 2. Full disclosure and acknowledgement should be made of the source of funding for the study. Additionally, potential conflicts of interest for each of the study authors or investigators should be clearly acknowledged.

3. A complete description of the study methods and procedures is essential, including a detailed description of the inclusion and exclusion criteria, patient selection and screening procedures, efficacy and safety assessments, and treatment protocol. A table of visits and procedures should be included.

VII. ETHICALAND CLINICAL ISSUES IN ERECTILE DYSFUNCTION RESEARCH

4. Complete reporting of all statistical procedures and data analyses is necessary. The final report should clearly indicate negative, as well as positive findings in the study. Statistical corrections should be made when multiple analyses are reported. When possible, effect size calculations should be included. 5. Potential limitations and weaknesses of the study should be carefully considered in the Discussion. This section of the report should also consider the clinical implications of the study and relevance of the findings to the broader development of the field. Summary Points: • Due to the number of statistical and data ana lysis issues, a qualified biostatistician should be involved in the design and analysis of all clini cal trials in ED. Specific issues include the cal culation of sample power for the trial, type of statistical model and design to be employed, use of covariate or sub-group analyses, and calcu lation of effect sizes. • Although most ED trials report the number of treatment responders following treatment, disagreement exists at present concerning the criteria and appropriate definition of a treat ment responder. • Meta-analysis is a potentially valuable statisti cal procedure which will undoubtedly play an increasingly important role in the clinical lite rature on ED. • Key considerations in the preparation and publication of clinical trial data have been identified. These include criteria for author ship, disclosure of financial support and conflicts of interest, and complete reporting of the study methods and findings. The limitations and weaknesses of the study should also be clearly identified.

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Ethical issues in clinical trials of ED include those related to (1) informed consent, (2) patient confidentiality, (3) patient safety, and (4) trial design issues, such as randomization and the use of placebo treatments. In each of these areas, it is essential that the trial be conducted according to the highest standards of ethical and clinical conduct. Patient rights and protections in human research have been fully delineated in the International Ethical Guidelines for Biomedical Research Involving Human Subjects (World Medical Association Declaration of Helsinki [49]). This declaration emphasizes that the health of the patient is the primary concern of all physicians including those involved in clinical research. The purpose of biomedical research is to impact and improve on clinical practice. It is possible in a clinical trial to address important public and societal health concerns, without compromising the health of the individual. The potential benefits, hazards and risks of a novel intervention or therapy in sexual medicine must be carefully weighed against the advantages of the best available therapeutic alternatives. Ethical principles of the Declaration of Helsinki are especially relevant in the study of “quality of life” disorders such as erectile dys function. Specific principles are as follows: 1. Erectile dysfunction research should conform to the generally accepted scientific principles outlined in this chapter, and should be based on prior laboratory and animal experimentation, as well as a thorough background knowledge of the scientific literature. 2. The design and conduct of any experimental procedure in this field involving human subjects should be formulated in protocols that are reviewed by an independent (of the investigator and the sponsor) bio-ethical committee, such as an accredited Institutional Review Board (IRB). This committee must be constituted in accordance with the laws and regulations of the country or region in which the research is conducted. 3. Erectile dysfunction trials should only be conducted by scientifically qualified indivi duals under the supervision of a clinically com petent medical person(s).

4. There must be a balance between the objectives of the study and its value to the public, and the protection of patient’s rights and safety. In quality of life disorders, such as erectile dysfunction or other male or female sexual dysfunctions, the risks to the patient must inherently be exceedingly low. In any study, each potential subject must be adequately informed of the aims, methods, anticipated benefits and potential hazards of the study and any potential discom fort or risk it may entail. The employment of randomization and placebo-controls must be made clear to the subject prior to participation. The patient should be informed that he/she is at liberty to abstain from participation in the study, and that he/she is free to withdraw his or her consent to participation at any time. The refusal of a patient to participate in a study must never interfere with the physician-patient relation ship. 5. Informed consent is a dynamic process that is ongoing as a study evolves and data is accumulated and analyzed. The physician, or an appropriately delegated representative, must obtain the subject’s freely given informed consent, preferably in writing. Sexual dysfunction research does not ethically permit the involvement of minors or those that are mentally incompetent. Therefore the issue of consent from a legal guardian is not strictly relevant to this topic. 6. The right of the patient to safeguard his priva cy or anonymity must be respected at all times. With increasing availability of electronic data retrieval, the topic of patient confidentiality has become a major concern in many countries, with specific legislation being developed to protect medical records confidentiality. The pro tection of personally-identifiable health infor mation is especially relevant in the area of sexual dysfunction, considering the emotional overtones and social stigma associated with these disorders. 7. The findings of clinical trials in ED should be published in peer-review literature, as well as being made publicly available following regu latory review. The broad and general utilization of any new medical intervention or therapy for ED should be preceded by proper scientific scrutiny, such as provided by the editorial board of an appropriate peer-review journal.

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The ultimate objective of clinical trials in erectile dysfunction, as in any new field of medical research, is to impact upon the clinical care of the patient. As such, the design of research protocols, patient inclusion/exclusion criteria, and endpoint assessments should all have maximum relevance to the practicing clinician. The trial design should ideally be simple and straightforward, with broad inclusion of patients that mimic the clinical arena. The endpoints measured and reported should be readily translated into clinically meaningful terms (e.g. percentage of successful intercourse attempts). Although objective measurement via Rigiscan or other laboratory devices can provide valuable data, the most relevant information for the practicing clinician is that provided by selfreport measures such as the IIEF. Additionally, global efficacy and satisfaction measures, as well as quality of life assessments are valuable to the practicing clinician in determining the ultimate “real world” value of a new intervention or therapy in clinical practice. Clinical research is a dynamic enterprise; as new interventions and therapies are introduced, they should be tested not only against the rigors of an experimental control or placebo group, but also evaluated in the context of current clinical practice. Summary Points: • Clinical trials in ED should always be conducted in accordance with the highest ethical and clini cal standards, as specified in the Helsinki Decla ration. • All clinical trials should be subject to the appro val of an independent review board (Institutional Review Board), which is constituted according to the laws and regulations of the host country. • There must be a careful balance between the potential benefits and risks to the individual patient. Patients must be fully informed about the nature of the study, and any potential risks or discomforts involved. Consent should always be freely given without compromising the patient’s access to healthcare or further research involve ment. Confidentiality must be protected to the fullest extent permitted by the law. • The findings from clinical research in ED should be made available in a form that is practically and clinically useful. The ultimate goal of clini cal research is to impact positively on the clinical care of the patient.

5. Adverse events should be carefully monitored via symptom checklists or structured patient interviews. Adverse events should be classified according to severity, and should be judged as treatment-related or treatment-unrelated by the investigator. Longterm monitoring of adverse events is critically important in assessing the overall safety of new treatment agents.

VIII. FINAL RECOMMENDATIONS FOR CLINICAL TRIAL DESIGN AND OUTCOMES ASSESSMENT Clinical trials in erectile dysfunction should be conducted according to the highest standards of trial design and should make use of the best available outcomes measures. Based upon the information presented and issues considered in this chapter, the following general recommendations can be made:

6. A detailed study protocol should be developed and agreed upon by the sponsor, the investigator, the institutional review board, and the relevant regulatory agencies prior to initiation of the study. The study protocol should include a complete description of the background and study objectives, design and methods, plans for data analysis and overall organization of the trial. All aspects of the protocol should be strictly adhered to in the conduct of the study.

1. Novel drugs or devices for treatment of ED should be systematically evaluated through a comprehensive series of phase I through IV clinical trials. Beginning with tolerability assessments of single and multiple drug dosages, these studies should carefully evaluate the overall safety and efficacy of any new agent before regulatory approval is granted and the treatment enters widespread clinical use. 2. Among the available clinical trial designs, crossover designs are generally recommended in early phase I or II studies. Parallel or combination parallel-crossover designs are preferred in phase III or IV trials. Posttreatment changes should always be compared to baseline assessments of erectile function prior to treatment.

7. A qualified biostatistician should be involved in the design and analysis of all clinical trials in ED. A lack of agreement exists currently regarding the definition of a treatment responder and few studies have reported effect size calculations. Similarly, meta-analytic procedures have been used infrequently to date. All findings in clinical trials of ED should be accurately reported, and investigators should make full disclosure regarding financial relationships with the study sponsor and funding of the study.

3. Study populations in clinical trials of ED should be broadly representative of the overall patient population. Inclusion criteria should define the patient’s condition clearly, including minimal duration and severity of disease. Exclusion criteria should provide adequate safeguards against unnecessary risk of drug exposure in the study population. Special population studies are recommended to evaluate drug efficacy and safety in selected sub-populations (e.g. diabetic patients, spinal cord injury).

8. All clinical trials should be conducted in accordance with standards of Good Clinical Practice, and in accordance with ethical principles concerning human subjects as specified in the Helsinki Declaration. All clinical trials should also be approved and monitored by an accredited human rights committee (Institutional Review Board). Patients must be fully informed about the nature of the study and the potential risks or hazards involved. Confidentiality should be protected to the fullest extent permitted by the law. Finally, the findings from clinical research should be disseminated in a form that is clinically useful to practicing physicians, patients and society at large.

4. Efficacy and safety endpoints should be specified in advance. Recommended efficacy endpoints include self-report questionnaires (e.g. IIEF), patient and partner diaries (e.g. SEP), and objective measures of erectile function (e.g. Rigiscan). Patient satisfaction or disease-specific quality of life measures are recommended as secondary endpoints in phase III or IV clinical trials.

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rison of two penile measures of erotic arousal. Behav Res Ther 12:355-359, 1974.

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9.

16. SLOB AK, BLOM JH, VAN DER WERFF JJ: Erection problems in medical practice: Differential diagnosis with a relatively simple method. J Urol 143:46-50, 1990.

18. FREUND K, LANGEVIN R: Bisexuality in homosexual pedophilia. Arch Sex Behav 5:415-423, 1976. 19. FREUND K, CHAN S, COULTHARD R. Phallometric diagnosis with ‘ R R: Male sexual arousal across five modes of erotic stimulation. Arch Sex Behav 17:131143, 1988. 23. ROWLAND DL, SLOB AK: Vibrotactile stimulation enhances sexual response in sexually functional men: A study using concomitant measures of erection. Arch Sex Behav 21:387-400, 1992. 24. ROWLAND DL, DEN OUDEN AH, SLOB AK: The use of vibrotactile stimulation for determining sexual potency in the laboratory in men with erectile problems: Methodological considerations. Int J Impot Res 6:153161, 1994. 25. O’LEARY MP, FOWLER FJ, LENDERKING WR, BARBER B, SAGNIER PP, GUESS HA: A brief male sexual function inventory for urology. Urol 46:697-706, 1995. 26. ROSEN RC, RILEYA, WAGNER G, OSTERLOH IH, KIRKPATRICK J, MISHRAA: The International Index of Erectile Function (IIEF): A multidimensional scale for assessment of erectile dysfunction. Urol 49:822-830, 1997. 27. DEROGATIS LR: The Derogatis Interview for Sexual Functioning (DISF/DISF-R): An introductory report. J Sex Mar Ther 1997; 23:291-296. 28. CAPPELLERI JC, ROSEN RC, SMITH MD, MISHRA A, OSTERLOH IH:A diagnostic evaluation of the Erectile Function domain of the International Index of Erectile Function (IIEF). Urol 1999; 54:346-351.

BOOLEL M, GEPI-ATTEE S, GINGELL JC, ALLEN MJ: Sildenafil, a novel effective oral therapy for male erectile dysfunction. Br J Urol 1996;78:257-261.

10. HEATON JPW, MORALES A, ADAMS MA et al: Recovery of erectile function by the oral administration of apomorphine. Urology 45:200-206,1995. 11.

29. ROSEN RC, CAPPELLERI JC, SMITH MD, LIPSKY J, PENABM: Development and evaluation of an abridged 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Intl J Impot Res (In Press).

FROHIB DA, GOLDSTEIN I, PAYTON TR, PADMANATHAN H, KRANE RJ: Characterization of penile erectile states using external computer-based monitoring. J Biomech Eng 109:110, 1987.

30. GOLDSTEIN I, LUE TF, PADMA-NATHAN H, ROSEN RC, STEERS WD, WICKER PA: Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med 1998; 338:1397-1404.

12. LICHT MR, LEWIS RW, WOLLAN PC, HARRIS CD: Comparison of Rigiscan and sleep laboratory nocturnal penile tumescence in the diagnosis or organic impotence. J Urol 154: 1740-1743, 1995.

31. DINSMORE WW, HODGES M, HARGREAVES C, OSTERLOH IH, SMITH MD, ROSEN RC: Sildenafil citrate (Viagra) in erectile dysfunction: near normalization in men with broad-spectrum erectile dysfunction compared with age-matched healthy control subjects. Urol 1999; 53:800-805.

13. BENETAE, REHMAN J, HOLCOMB RG, MELMAN A: The correlation between the Rigiscan plus software and the final diagnosis in the evaluation of erectile dysfunction. J Urol 156:1947-1950, 1996. 14. ROSEN RC, KEEFE FJ: The measurement of human penile tumescence. Psychophysiol 15:366-376, 1978.

32. CORTYEW, ALTHOF SE, KURIT DM: The reliability and validity of a sexual functioning questionnaire. J Sex Mar Ther 22:27-34, 1996.

15. FREUND K, LANGEVIN R, BARLOWDH: A compa-

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33. DEROGATIS LR, MELISARATOS N: The DSFI: A multidimensional measure of sexual functioning. J Sex Mar Ther 5:244-281, 1979.

APPENDIX A

34. ROSEN RC: Sexual function assessment in the male: physiological and self-report measures. Intl J Impot Res 1998; 10 Suppl 2:S59-S63.

SAMPLE PROTOCOL OUTLINE

35. MATHIAS SD, O’LEARY MP, HENNING JM, PASTA DJ, FROMM S, ROSEN RC: A comparison of patient and partner responses to a brief sexual function questionnnaire. J Urol (In Press). 36. AARONSON NK: Quality of life: What is it? How should it be measured? Oncology 2:69-74, 1988. 37. GILL TM, FEINSTEIN AR: A critical appraisal of the quality of quality-of-life measurements. JAMA 272:619-626, 1994. 38. GUYATT GH, FEENY DH, PATRICK DL: Measuring health-related quality of life. Ann Intern Med 118:622629, 1993. 39. FUGL-MEYER AR, LODNERT G, BRANHOLM I-B, FUGL-MEYER KS: On life satisfaction in male erectile dysfunction. Intl J Impot Res 9:141-148, 1997. 40. WAGNER TH, PATRICK DL, MCKENNA P, FROESE PS: Cross-cultural development of a quality of life measure for men with erectile difficulties. Qual Life Res 5:443-449, 1996. 41. ALTHOF SE, CORTY EW, LEVINE SB, LEVINE F, BURNETT AL, MCVARY K, STECHER V, SEFTEL AD: EDITS: Development of questionnaires for evaluating satisfaction with treatments for erectile dysfunction. Urol 1999; 53:793-799. 42. DAY SJ, GRAHAM DF: Sample size estimation for comparing two or more treatment groups in clinical trials. Stat Med 1991; 10:33-43. 43. COLLINS R, PETO R, GRAY R, PARISH S: Largescale randomized evidence: trials and overviews. In: Weatherall DJ, Ledingham JGG, Warrell DA (Eds). Oxford Textbook of Medicine (3rd ed), Oxford: Oxford University Press, 1996. 44. BEACH ML, MEIER P: Choosing covariates in the analysis of clinical trials. Controlled Clin Trials 10:161S175S, 1989. 45. CANNER PL:Covariate adjustment of treatment effects in clinical trials. Controlled Clin Trials 12:359-366, 1991. 46. PADMA-NATHAN H, HELLSTROM WJG, KAISER, FE et al.: Treatment of men with erectile dysfunction with transurethral alprostadil. N Engl J Med 1997; 336:1-7. 47. CHALMERS TC, LEVIN H, SACKS HS et al: Metaanalysis of clinical trials as a scientific disclipline. Stat Med 6:315-326, 1987. 48. DEMETS DL: Methods for combining randomized clinical trials: strengths and limitations. Stat Med 6:341348, 1987. 49. CIOMS/ WHO: International ethical guidelines for biomedical research involving human subjects. Geneva, 1993.

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COVER PAGE TABLE OF CONTENTS BACKGROUND OF THE STUDY References STUDY OBJECTIVES STUDY DESIGN PATIENT SELECTION Inclusion Criteria Exclusion Criteria STUDY METHODS Visit 1 (Screening) Visit 2 Visit 3 Clinical Laboratory Tests Concomitant Medications Withdrawal Criteria Handling of Withdrawals Study Discontinuation ADVERSE EVENTS Definitions Serious Adverse Events Medical Monitor Antidote STATISTICAL ANALYSIS Safety Variables Efficacy Variables Primary Secondary Baseline Measurements Statistical Analysis Plan Sample Size Randomization MATERIALS Test Article Dosage and Administration Test Article Accountability ADMINISTRATIVE CONSIDERATIONS Confidentiality Institutional Review Board Informed Consent Monitoring Case Report Forms Study Record Retention Publications INVESTIGATOR’S STATEMENT APPENDIX 1: S CHEDULE OF EVENTS APPENDIX 2: I NTERNATIONAL INDEX OF ERECTILE FUNCTION (IIEF)

1 2 3 6 9 9 10 10 11 12 12 13 14 15 16 16 17 17 18 18 18 19 20 20 20 21 21 21 22 22 24 24 24 24 24 24 25 25 25 26 27 27 28 29 30 31

APPENDIX B INTERNATIONAL INDEX OF ERECTILE FUNCTION These questions ask about the effects your erection problems have had on your sex life. Please answer the following questions as honestly and clearly as possible. In answering these questions, try to base your answers on how you currently are without any treatment. The following definitions apply: • sexual activity includes 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.• ejaculate: the ejection of semen from the penis (or the feeling of this) 1. Over the last month, how often were you able to get an erection during sexual activity? Please check one box only a. [ ] No sexual activity b. [ ] Almost always or always c. [ ] Most times (much more than half the time) d. [ ] Sometimes (about half the time) e. [ ] A few times (much less than half the time) f. [ ] Almost never or never 2. Over the last month, when you had erections with sexual stimulation, how often were your erections hard enough for penetration? Please check one box only a. [ ] No sexual stimulation b. [ ] Almost always or always c. [ ] Most times (much more than half the time) d. [ ] Sometimes (about half the time) e. [ ] A few times (much less than half the time) f. [ ] Almost never or never The next three questions will ask about the erections you may have had during sexual intercourse. 3. Over the last month, when you attempted sexual intercourse, how often were you able to penetrate (enter) your partner? Please check one box only a. [ ] Did not attempt intercourse b. [ ] Almost always or always c. [ ] Most times (much more than half the time) d. [ ] Sometimes (about half the time) e. [ ] A few times (much less than half the time) f. [ ] Almost never or never 671

4. Over the last month, during sexual intercourse, how often were you able to maintain your erection after you had penetrated (entered) your partner? Please check one box only a. [ ] Did not attempt intercourse b. [ ] Almost always or always c. [ ] Most times (much more than half the time) d. [ ] Sometimes (about half the time) e. [ ] A few times (much less than half the time) f. [ ] Almost never or never

5. Over the last month, during sexual intercourse, how difficult was it to maintain your erection to completion of intercourse? Please check one box only a. [ ] Did not attempt intercourse b. [ ] Extremely difficult c. [ ] Very difficult d. [ ] Difficult e. [ ] Slightly difficult f. [ ] Not difficult

6. Over the last month, how many times have you attempted sexual intercourse? Please check one box only a. [ ] No attempts b. [ ] 1-2 attempts c. [ ] 3-4 attempts d. [ ] 5-6 attempts e. [ ] 7-10 attempts f. [ ] 11+ attempts

7. Over the last month, when you attempted sexual intercourse how often was it satisfactory for you? Please check one box only a. [ ] Did not attempt intercourse b. [ ] Almost always or always c. [ ] Most times (much more than half the time) d. [ ] Sometimes (about half the time) e. [ ] A few times (much less than half the time) f. [ ] Almost never or never

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8. Over the last month, how much have you enjoyed sexual intercourse? Please check one box only a. [ ] No intercourse b. [ ] Very highly enjoyable c. [ ] Highly enjoyable d. [ ] Fairly enjoyable e. [ ] Not very enjoyable f. [ ] No enjoyment

9. Over the last month, when you had sexual stimulation or intercourse how often did you ejaculate? Please check one box only a. [ ] No sexual stimulation/intercourse b. [ ] Almost always or always c. [ ] Most times (much more than half the time) d. [ ] Sometimes (about half the time) e. [ ] A few times (much less than half the time) f. [ ] Almost never or never

10. Over the last month, when you had sexual stimulation or intercourse how often did you have the feeling of orgasm (with or without ejaculation)? Please check one box only a. [ ] No sexual stimulation/intercourse b. [ ] Almost always or always c. [ ] Most times (much more than half the time) d. [ ] Sometimes (about half the time) e. [ ] A few times (much less than half the time) f. [ ] Almost never or never

The next two questions ask about sexual desire. Let’s define sexual desire as a feeling that may inclu de wanting to have a sexual experience (for example masturbation or intercourse), thinking about having sex, or feeling frustrated due to lack of sex. 11. Over the last month, how often have you felt sexual desire? Please check one box only a. [ ] Almost always or always b. [ ] Most times (much more than half the time) c. [ ] Sometimes (about half the time) d. [ ] A few times (much less than half the time) e. [ ] Almost never or never

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12. Over the last month, how would you rate your level of sexual desire? Please check one box only a. [ ] Very high b. [ ] High c. [ ] Moderate d. [ ] Low e. [ ] Very low or none at all

13. Over the last month, how satisfied have you been with your overall sex life? Please check one box only a. [ ] Very satisfied b. [ ] Moderately satisfied c. [ ] About equally satisfied and dissatisfied d. [ ] Moderately dissatisfied e. [ ] Very dissatisfied

14. Over the last month, how satisfied have you been with your sexual relationship with your partner? Please check one box only a. [ ] Very satisfied b. [ ] Moderately satisfied c. [ ] About equally satisfied and dissatisfied d. [ ] Moderately dissatisfied e. [ ] Very dissatisfied

15. Over the last month, how do you rate your confidence that you can get and keep your erection? Please check one box only a. [ ] Very high b. [ ] High c. [ ] Moderate d. [ ] Low e. [ ] Very low

Source: Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A: The International Index of Erectile Function (IIEF): A multidimensional scale for assessment of erectile dysfunction. Urol 49:822830, 1997.

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APPENDIX C The EDITS: Erectile Dysfunction Inventory of Treatment Satisfaction Patient Version STANLEY E. ALTHOF, PH.D. & E RIC W. CORTY, PH.D. For permission to use this questionnaire, contact Dr. Althof at: Center for Marital & Sexual Health 23230 Chagrin Boulevard, Suite 350 Beachwood, Ohio 44122-5402 Phone: (216) 831-2900 Fax: (216) 831-4306

Name or ID number: __________________________________

Date: ____________________

What treatment method are you currently using? ____________________________ The questions in this inventory ask about a sensitive topic, your sexual life with your wife or partner as well as your attitude towards and expectations from the treatment method you are using to help with your erection problem. Please answer the questions as honestly and candidly as you can. If any questions or terms are unclear, please ask for clarification.

1. Overall, how satisfied are you with this treatment? a. Very satisfied b. Somewhat satisfied c. Neither satisfied nor dissatisfied d. Somewhat dissatisfied e. Very dissatisfied

2. During the past four weeks, to what degree has the treatment met your expectations? a. Completely b. Considerably c. Half way d. A little e. Not at all

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3. How likely are you to continue using this treatment? a. Very likely b. Moderately likely c. Neither likely nor unlikely d. Moderately unlikely e. Very unlikely

4. During the past four weeks, how easy was it for you to use this treatment? a. Very easy b. Moderately easy c. Neither easy nor difficult d. Moderately difficult e. Very difficult

5. During the past four weeks, how satisfied have you been with how quickly the treatment works? a. Very satisfied b. Somewhat satisfied c. Neither satisfied nor dissatisfied d. Somewhat dissatisfied e. Very dissatisfied

6. During the past four weeks, how satisfied have you been with how long the treatment lasts? a. Very satisfied b. Somewhat satisfied c. Neither satisfied nor dissatisfied d. Somewhat dissatisfied e. Very dissatisfied

7. How confident has this treatment made you feel about your ability to engage in sexual activity? a. Very confident b. Somewhat confident c. It has had no impact d. Somewhat less confident e. Very much less confident

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8. Overall, how satisfied do you believe your partner is with the effects of this treatment? a. Very satisfied b. Somewhat satisfied c. Neither satisfied nor dissatisfied d. Somewhat dissatisfied e. Very dissatisfied

9. How does your partner feel about your continuing to use this treatment? a. My partner absolutely wants me to continue b. My partner generally prefers me to continue c. My partner has no opinion d. My partner generally prefers me to stop e. My partner absolutely wants me to stop

10. How natural did the process of achieving an erection feel when you used this treatment over the past four weeks? a. Very natural b. Somewhat natural c. Neither natural nor unnatural d. Somewhat unnatural e. Very unnatural

11. Compared to before you had an erection problem how would you rate the naturalness of your erection when you used this treatment over the past four weeks in terms of hardness? a. A lot harder than before I had an erection problem b. Somewhat harder than before I had an erection problem c. The same hardness as before I had an erection problem d. Somewhat less hard than before I had an erection problem e. A lot less hard than before I had an erection problem

Source: Althof SE, Corty EW, Levine SB, Levine F, Burnett AL, McVary K, Stecher V, Seftel AD: EDITS: Development of questionnaires for evaluating satisfaction with treatments for erectile dysfunction. Urol 1999; 53:793-799.

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Imaging Atlas

DIMITRIOS G. HATZICHRISTOU

679

CONTENTS

INTRODUCTION

VI. ARTERIOVENOUS FISTULA

I. ANATOMICAL CONSIDERATIONS

VII. PRIAPISM

II. NOCTURNAL PENILE TUMESCENCE AND RIGIDITY TEST (NPTR)

VIII. PEYRONIE’S DISEASE

IX. PENILE FRACTURE III. PROLACTINOMA X. PENILE PROSTHESIS IV. NEUROPHYSIOLOGIC TESTING XI. FEMALE SEXUAL FUNCTION AND DYSFUNCTION

V. VASCULAR TESTING

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Imaging Atlas DIMITRIOS G. HATZICHRISTOU,

Despite numerous controversies in the field, several methodologies have been described to assess erectile mechanism integrity. Nowadays, diagnostic work-up has been minimized and specific diagnostic procedures are included in the evaluation of small subgroups of patients with erectile dysfunction (ED). Although, the imaging techniques do not constitute a critical aspect, directing patients’ management strategy in common clini cal practice, the images help to understand the mechanisms involved in erectile function and the pathophysiology of ED. Without such knowledge efficient patients’ management seems questionable. The purpose, therefore, of the present atlas is to be used as an educational document, helpful for a better understanding of the pathophysiology of ED, as well as for teaching purposes. Selected images and diagnostic procedures tracings were included.

INTRODUCTION Male erectile dysfunction has been considered for many decades a psychologic condition, mainly due to the lack of methodology to reproduce in a clinical setting the physiologic events of an erection. The introduction of pharmacologic erections led to the development of numerous diagnostic procedures, as it was possible for the first time to induce and maintain an erection, independently of sexual stimulation. After a decade of debate, it was recognized that diagnostic procedures for impotence may take place exclusively in the dynamic state, after intracavernosal administration of vasoactive agents. Moreover, taking into consideration that vasculogenic impotence is the main organic cause of erectile dysfunction, pharmacologic erections became the cornerstone in the hemodynamic evaluation of patients with arterial insufficiency and/or corporal veno-occlusive dysfunction.

This atlas was made possible through the contributions of ED experts worldwide, who generously offered the products of long lasting dedicated clinical research in the field.

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I. ANATOMICAL CONSIDERATIONS

A

Figure 1: Topographic anatomy of a male and a female body befo re sexual intercourse. This unique MRI shows a male and a fema le body together, while the associated schematic drawing, offers further information on the anatomy of the genitourinary organs before intromission. a) Sagittal MRI sequences showing a male and a female body before intromission. 1. female, a. female bladder, c. female pubis. 2. male, b. male bladder, d. male pubis. b) Drawing showing the position of the couple. 1. pubococcygeal line, 2. vaginal axis, 3. levator ani. A. Faix, MD, Department of Urology and JF Lapray, MD, A. Mau bon, MD. Department of Radiology, Clinique Beausoleil, Montpel lier, France

B

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I. ANATOMICAL CONSIDERATIONS

A

Figure 2: MRI and drawing after insertion of the semi-erect penis into the vagina, while the female bladder is full. Anatomical changes include modification of the vaginal axis, moderated translocation of the uterus upwards and backwards and raising of the bladder neck and the urethra. a) 1. Glans penis, 2. Crus of the corpora cavernosa, 3. Female bladder. b) 1. Penis and vagina axis, 2. Fornix, 3. Uterus, 4. Pubococygeal line, 5. Pubis angle, 6. Bladder neck. A. Faix, MD, Department of Urology and JF Lapray, MD, A. Mau bon, MD. Department of Radiology, Clinique Beausoleil, Montpel lier, France.

B

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P

A

Figure 3 : MRI and drawing demonstrating anatomical changes when the penis is inserted into the vagina, while the female blad der is empty. a) MRI shows that the glans penis is in contact with the anterior cul-de-sac, while the bladder is pushed forwards and upwards. 1. Glans penis, 2. Female bladder, 3. Fornix, 4. Uterus, 5. Per ineum. b) Schematic drawing demonstrates the modification of vaginal axis, the translocation of the uterus, while the bladder neck and posterior bladder wall have been pushed upwards and forwards. A. Faix, MD, Department of Urology and JF Lapray, MD, A. Mau bon, MD. Department of Radiology, Clinique Beausoleil, Montpel lier, France.

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B

I. ANATOMICAL CONSIDERATIONS (Ctd)

Figure 4 : Transverse sections of a nor mal penis. The penis includes the 2 cor pora cavernosa and the corpus spongiosum (Figure 4a). The corpora consist of trabecular smooth muscle and connecti ve tissue and are engloved in the tunica albuginea (Figure 4b: T: trabecular smooth muscle, C: cavernous space, *:tunica albuginea). The structure of the corpora cavernosa is of particular importance in that, unlike skeletal load carrying, penile rigidity is asserted through soft tissue. Corporal structural changes, such as decrease in the amount of trabecular smooth muscle and increase in the amount of collagen or changes in the fibers of collagen and elastin, as occur with aging and disea se, result in increased tissue stiffness, reduced capacitance and corporal venoocclusive dysfunction.

A

E. Meuleman, Department of Urology, University Hospital Nijmegen , The Netherlands

B

685

II. NOCTURNAL PENILE TUMESCENCE AND RIGIDITY TEST (NPTR)

A

B

C

Figure 5a-c : Penile rigidity represents the main characteristic of a functional erection. NPTR, using the Rigiscan® device, beca me the most popular method to differentiate organic from psychogenic impotence, based on the assumption that psychological factors do not influence this form of erectile activity. In 3 consecutive night recordings of a 23-year-old, healthy, potent volun teer, several erectile episodes of adequate rigidity and duration were recorded; the results were reproduced, when the test was repeated twice. D.G. Hatzichristou, MD, Department of Urology, Aristotle University of Thessaloniki, Greece

686

II. NOCTURNAL PENILE TUMESCENCE AND RIGIDITY TEST (NPTR) (Ctd)

A

B

C

Figure 6a-c : NPTR is based on the assumption that patients with psychogenic impotence would be expected to exhibit a normal pattern of nocturnal erections, while patients with organic impotence will show impaired or absent erectile activity. In a 3-night recording (a,b,c) of a 46 year old male, with a 15-year history of diabetes mellitus and 8-year history of erectile dysfunction, abnormal NPTR patterns were recorded; few erectile episodes, of inadequate rigidity and duration were noted. D.G. Hatzichristou, MD, Department of Urology, Aristotle University of Thessaloniki, Greece

687

III. PROLACTINOMA

Figure 7: Brain MRI after gadolinium injection showing a pituitary microadenoma (6mm diameter). Serum testostero ne was 3.2mg/ml (normal values >2.5 ng/ml) and serum prolactin 130ng/ml (normal values <15ng/ml). J. Buvat, MD and A. Lemaire, MD, Centre ETPARP, Lille, France

Figure 8 : Brain MRI demonstrating a pituitary adeno ma after gadolinium injection. The 35-year old man was complaining of decreased libido and erectile dysfunction. He was treated with intracavernosal injection therapy for a year, without any previous diagnostic work-up. Hormo nal profile revealed hyperprolactinemia, which led to the diagnosis and treatment of the main disease (surgical excision of the adenoma). After surgery, restoration of erectile function was reported by the patient. D.G. Hatzichristou, MD, Department of Urology, Aristotle University of Thessaloniki, Greece

688

IV. NEUROPHYSIOLOGIC TESTING

B

A

Figure 9: Pudendal evoked potentials: normal and abnormal findings. a) Pudendal evoked potential recorded and the average superimposed twice in response to stimulation of the dorsal nerve of the penis. Recordings were made from electrodes placed over FZ and CZ-2cms using the conventional system scalp measurement for EEG recording. b) Absent pudendal evoked potential recorded from a patient with a cauda equina lesion. This patient had perineal sensory loss, as well as erectile dysfunction. C. Fowler, MD, Department of Uro-Neurology, The National Hospital for Neurology and Neurosurgery, London, United Kingdom

B

A

Figure 10: Normal and abnormal bulbocavernosus reflex recordings. a) Bulbocavernosus reflex recording from the striated muscle of the urethral sphincter in response to stimulation of the dorsal nerve of the penis. The first response occurs at 35m/s. Poor sweeps in step display are superimposed. b) Delayed bulbocavernosus reflex at 60m/s recorded from a man with a spinal angioma and erectile failure. C. Fowler, MD, Department of Uro-Neurology, The National Hospital for Neurology and Neurosurgery, London, United Kingdom

689

V. VASCULAR TESTING

Figure 11: Normal power doppler ultrasonography, sho wing the cavernosal and the helicine arteries. F. Montorsi, MD, Department of Urology, San Raffaele Hos pital, Milan, Italy

A

B

Figure 12: Power doppler ultrasonography in a young healthy volunteer, at the phase of full (a) and rigid (b) erection. When intracorporal pressure reaches values close to the cavernosal artery pressure, flow in the helicine arteries diminishes (a), while during rigid erection the arterial flow is interrupted (b). K. Hatzimouratidis, Department of Urology, 401 General Military Hospital, Athens, Greece

Figure 13: Duplex ultrasonography showing dorsal to cavernous collaterals, which may be an important source of inflow in the aging patient. Sacrifice of these intra-arterial connections, for example during Peyronie’s surgery, may cause postoperative erectile dysfunction. G. A. Broderick, MD, Department of Urology, Mayo Clinic, Jacksonville Florida, USA

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V. VASCULAR TESTING (Ctd)

Figure 14: Duplex ultrasonography showing cavernous venoocclusive dysfunction: excellent arterial flows with peak systo lic velocity > 30 cm/sec, while resistance index is < 0.9. G. A. Broderick, MD, Department of Urology, Mayo Clinic, Jacksonville Florida, USA

Figure 15: Duplex ultrasonography showing severe cavernous arterial insufficiency, with peak systolic velocity < 20 cm/sec G. A. Broderick, MD, Department of Urology, Mayo Clinic, Jacksonville Florida, USA

A

B

Figure 16: Power doppler ultrasonography allows not only better imaging of the cavernosal arteries, but also demonstration of the helicine arteries pathology. a) cavernosal artery insufficiency and b) helicine arteries deficiency. F. Montorsi, MD, Department of Urology, San Raffaele Hospital, Milan, Italy

691

V. VASCULAR TESTING (Ctd)

A

B

C Figure 17: Pharmacocavernosometry is a more invasive test, which allows to study the hemodynamics of the erectile mechanism in details. a) intracavernosal pressure and circumference increase slowly after intracavernosal injection of vasoactive agents; such res ponse may be either to incomplete smooth muscle relaxation due to anxiety, or due to arterial insuficiency. b) normal flow-to-maintain values (<3ml/min), detected at intracavernosal pressures of 60, 90, 120, 150mmHg. Such findings are associated with normal veno-occlusive mechanism. c) intracavernosal pressure decay, from an initial value of 150mmHg to a value of 56mmHg, during a 30 secs period. Drop in intracavernosal pressure more than 45mmHg within 30secs is associated with cavernosal veno-occlusive dysfunction. D.G. Hatzichristou, MD, Department of Urology, Aristotle University of Thessaloniki, Greece and I. Goldstein, MD, Department of Urology, Boston University Medical Center, Boston, USA

Figure 18: Normal pharmacocavernosography, showing absence of contrast media outside the two corporal bodies. I. Goldstein and R. Munarriz, Department of Urology, Bos ton University Medical Center, Boston, USA.

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V. VASCULAR TESTING (Ctd)

Figure 19: Abnormal pharmacocavernosography of a bicy clist, showing proximal crural leak, due to blunt perineal trauma. I. Goldstein and R. Munarriz, Department of Urology, Boston University Medical Center, Boston, USA.

B

A Figure 20: Spongiography, after contrast media injection in the glans penis. a) the media is inserted through the glans penis to the deep dorsal vein and the corpus spongiosum. b) through the glans penis (arrow), the media is inserted in the corpora cavernosa (*), demonstrating communication between the corpus spongiosum and the corpora cavernosa. Such images explain the mechanism of action of intraurethraly administe red agents. Y. Vardi, MD and A. Engel, MD, Neuro-Urology Unit and Department of Radiology, Ranbam Medical Center, Haifa, Israel

Figure 21: Normal selective internal pudendal arteriogra phy, showing both dorsal and cavernosal arteries. Y. Vardi, MD and A. Engel, MD, Neuro-Urology Unit and Department of Radiology, Ranbam Medical Center, Haifa, Israel

693

V. VASCULAR TESTING (Ctd)

Figure 22: Selective internal pudendal arteriogram showing accesory pudendal artery which originates from the obturator artery. Injury of this vessel during radical retropubic prosta tectomy can lead to vasculogenic impotence. I. Goldstein and R. Munarriz, Department of Urology, Boston University Medical Center, Boston, USA.

Figure 23: Selective internal pudendal arteriogram showing proximal occlusion of the cavernosal artery and normal dorsal artery with distal cavernosal branch I. Goldstein and R. Munarriz, Department of Urology, Boston University Medical Center, Boston, USA

A

B

Figure 24: Penile post-revascularization arteriogram. a) flush arteriogram showing origin of inferior epigastric artery and anastomosis to the dorsal penile artery. b) inferior epigastric artery to dorsal artery anastomosis. I. Goldstein and R. Munarriz, Department of Urology, Boston University Medical Center, Boston, USA.

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V. VASCULAR TESTING (Ctd)

B

A

C

Figure 25: Inferior epigastric artery anastomosed to an isolated deep dorsal vein segment. Selective arteriography of the inferior epigastric artery preoperatively (a), postoperative conventional (b) and digital substractive (c) arteriogram showing patent anasto mosis Y. Vardi, MD and A. Engel, MD, Neuro-Urology Unit and Department of Radiology, Ranbam Medical Center, Haifa, Israel

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V. VASCULAR TESTING (Ctd)

Figure 26: Duplex ultrasonography showing patent anasto mosis. E. Meuleman, MD, Department of Urology, University Hospi tal Nijmegen, The Netherlands

B A

Figure 27: The goal of an anastomosis of the inferior epigastric artery to an isolated deep dorsal vein segment is to achieve retro grade flow through the emmisary veins to the corpora cavernosa. Whether this is possible remains uncertain. a) intraoperative arteriogram showing filling of the deep dorsal penile vein. The contrast medium runs through the corpus spon giosum collaterals without filling the corpora cavernosa. b) postoperative superselective magnetic ressonance angiography with catheter tip in inferior epigastric artery: contrast medium runs through arterialized deep dorsal vein into infrapubic venous plexus. M. Sohn, MD, Department of Urology, Markus-Krankenhaus, Frankfurt, Germany.

696

V. VASCULAR TESTING (Ctd)

D

C

c) high flow signal intensity in the arterialized deep dorsal vein. d) gadolinium-enhanced MR 20 secs later: strong enhance ment of the corpus spongiosum, without enhancement of the corpora cavernosa. e) histology of corpus cavernosum in HE-staining: vein valves in emissary vein obstructing retrograde inflow from the arterialized deep dorsal vein to the corpus cavernosum.

E

697

V. VASCULAR TESTING (Ctd)

Figure 28: Selective penile arteriography in a patient with glans hyperemia, after anastomosis of the inferior epigastric artery to an isolated deep dorsal vein segment. Y. Vardi, MD and A. Engel, MD, Neuro-Urology Unit and Department of Radiology, Ranbam Medical Center, Haifa, Israel

A

B

Figure 29: Erection penogram after audiovisual sexual stimulation. 99mTechnetium (99m Tc) was injected in the antecubital vein and papaverine intracavernosally. A computerized gamma camera was used to calculate penile blood flow. a) normal penogram, b) penogram demonstrating corporeal veno-occlusive dysfunction H. K. Choi, MD, Department of Urology, Yonsei University College of Medicine, Seoul, Korea.

Figure 30: Schematic drawing demonstrating the 3 factors affecting penile rigidity: intracavernosal pressure, penile geo metry and mechanical properties of the corpora cavernosa and the tunica albuginea. Impotence, defined as absence of ade quate rigidity for vaginal penetration, may therefore be not exclusively due to decreased arterial inflow or increased venous outflow (the two determinants of intracavernosal pres sure), but also due to geometric or tissue mechanical factors, as well as due to any combination of these factors (A, B, C, D). Such data help to explain the frustration and confusion clini cians have experienced, when attempting to correlate erectile potency exclusively based on hemodynamic findings. D.G. Hatzichristou, Department of Urology, Aristotle Universi ty of Thessaloniki, Greece

698

VI. ARTERIOVENOUS FISTULA

A

B

C

D

Figure 31: A case of arteriovenous fistula after transurethral surgery. A 60 year-old male with a bulbar urethral stricture: a): urethrogram), developed urethral hemorrhage following uneventful optical urethrotomy, that could not be stopped with conservative methods. Perineal ultrasonography showed an arteriovenous fistula b), which was confirmed by a selective angiogram (c and d). Angiographic embolization failed e). Open surgical suture-ligation was successful. R. Shabsigh, MD, Department of Urology, Columbia Universi ty, New York, USA.

E

699

VII. PRIAPISM

Figure 32: Penile duplex ultrasonography demonstrating arte riolacunar fistula in a patient with arterial, high-flow pria pism after blunt perineal trauma. I. Goldstein and R. Munarriz, Department of Urology, Boston University Medical Center, Boston, USA

A

B

Figure 33: Digital substractive internal pudental arteriography in a patient with arterial priapism (a), treated with embolization of the internal pudental artery (b). S. Glina, MD, Department of Urology, Instituto H. Ellis, Sao Paolo, Brazil

Figure 34: A case of arterial priapism in an 11-year-old boy. Three weeks prior to admission, the young patient fell on his bicycle, causing a direct trauma to the perineum. a) colour duplex ultrasonography shows increased flow in the right cavernous body and the development of the arteriolacu nar fistula. A. Kolbenstvedt, M.D., Ph.D., B. Smevik, M.D., Department of Radiology and H. Hedlund, MD, PhD, Department of Urology, National Hospital (Rikshospitalet), Oslo, Norway.

700

VII. PRIAPISM (Ctd)

Figure 34: b) pelvic arteriography shows widened right puden tal artery (straight arrow) and posttraumatic fistula (curved arrow) between the right cavernosal artery and the right cavernous body.

Figure 34: c) distal branches of right pudendal artery after embolization by particles of a size 250-355 microns. Detumes cence was achieved and the boy was discharged from the hos pital the next day.

B

A

Figure 35: A patient with veno-occlusive priapism treated surgically with the Al Ghorab technique. Post-shunt penile duplex ultrasonography: a) large filling defects in the distal corpora cavernosa-tunica albuginea consistent with shunt procedure. b) longitudinal view showing distal corporal-tunical defect. I. Goldstein and R. Munarriz, Department of Urology, Boston University Medical Center, Boston, USA.

701

VIII. PEYRONIE’S DISEASE

Figure 36: Excessive tissue scarring in the corpora caverno sa, associated with Peyronie’s disease. E. Meuleman, Department of Urology, University Hospital Nij megen, The Netherlands

Figure 37: Preoperative staging of Peyronie’s disease should include a penile blood flow study to define relationship of plaques to vessels and assess erectile hemodynamics. G. A. Broderick, MD, Department of Urology, Mayo Clinic, Jacksonville Florida, USA

B

A

Figure 38: Cavernosographies of patients with Peyronie’s disease. a) distal circumferencial plaque with site specific leak. b) mild dorsal penile angulation with distal site specific leak I. Goldstein and R. Munariz, Department of Urology, Boston University Medical Center, Boston, USA

702

IX. PENILE FRACTURE

A

B Figure 39: MRI of a 23-year-old male, one day post-penile trauma during sexual intercourse. The penile MRI (a and b) shows small defect in the tunica albuginea of the left corpus cavernosum, with a very small hematoma. The patient was treated conservatively and three months later he was potent with no curvature. R. Shabsigh, MD, Department of Urology, Columbia University, New York, USA

703

X. PENILE PROSTHESIS

A

Figure 40: X-ray showing a penile pros thesis a) deflated and b) inflated. I. Moncada, MD, Department of Urology, Hospital General Universitario Gregorio Maranon, Madrid, Spain.

B

704

X. PENILE PROSTHESIS (Ctd) Figure 41: Pelvic CT in a patient with an inflatable 3-piece penile implant, showing the prosthesis reservoir intraabdomi nally. Y. Vardi,MD and A. Engel, MD, Neuro-Urology Unit and Department of Radiology, Rambam Medical Center, Haifa, Israel

B Figure 42: Penile MRI showing an implanted penile prosthe sis. a) axial and b) sagittal view. I. Moncada, MD, Department of Urology, Hospital General Universitario Gregorio Maranon, Madrid, Spain

A

A

B

Figure 43: MRI showing S-shaped deformity and buckling (a and b) of penile implants. Such deformities caused by inappropriate introperative corpora length measurements and had as consequence post-implantation penile pain. I. Moncada, MD, Department of Urology, Hospital General Universitario Gregorio Maranon, Madrid, Spain

705

XI. FEMALE SEXUAL FUNCTION AND DYSFUNCTION

A

B

C

D

Figure 44: Several studies have shown that the pelvic floor is a muscular structure, pierced by the lower urinary, genital and distal intestinal tract. This structure is a functional unit , therefore any pathology may be associated with voiding, sexual, genital and defe catory dysfunction. Anatomical and imaging studies have given valuable information regarding the function of the pelvic floor muscles. The figures are part of a study on the role of levator ani in the continence mechanism of women. The same structure may be implicated in female sexual dysfunction, such as vaginismus. Moreover, such sophisticated technique may be valuable tool in female sexual function research. The figure includes MRI images of young healthy volunteers in the transverse plane, corresponded to gross transverse sections a). MRI are taken with the pelvic floor muscles relaxed b) and contracted c). The substraction between the two images shows in dark the location of maximum pelvic floor displacement due to contraction (d). C.E. Constantinou, PhD, Department of Urology, Stanford University Medical Center, Stanford, California, USA.

706

XI. FEMALE SEXUAL FUNCTION AND DYSFUNCTION (Ctd)

Figure 45: Duplex ultrasonography in a female pre- and postsexual stimulation, showing increased arterial inflow after sexual arousal. I. Goldstein and R. Munarriz, Department of Urology, Boston University Medical Center, Boston, USA.

Figure 47: Duplex ultrasonography of the clitoris in a 45-year old woman with sexual arousal disorder. Sagittal scan of the cavernosal artery after audio-visual sexual stimulation sho wed PSV 26cm/sec and EDV 11cm/sec. K. Park, MD, Department of Urology, Chonnam National Uni versity School of Medicine, South Korea

Figure 46: Duplex ultrasonography of the clitoris in a 28-year old, healthy female volunteer. Sagital scan of the cavernosal arte ry after audio-visual sexual stimulation showed PSV 48cm/sec and EDV 20cm/sec. K. Park, MD, Department of Urology, Chonnam National Univer sity School of Medicine, South Korea

Figure 48: Duplex ultrasonography of the clitoris in a 53-year old, post-menopausal woman with sexual arousal disorder. Sagittal scan of the cavernosal artery after audio-visual sexual stimulation showed PSV 19cm/sec and EDV 8cm/sec. K. Park, MD, Department of Urology, Chonnam National Uni versity School of Medicine, South Korea

707

708

2000 Co-Sponsored by World Health Organisation (WHO) International Consultation on Urological Diseases (ICUD) Société Internationale d’Urologie (SIU) * In collaboration with American Urological Association (AUA) European Association of Urology (EAU) African Society of Impotence Research (ASIR) Asia Pacific Society for Impotence Research (APSIR) Confederaçion Americana de Urologia (CAU) European Society for Impotence Research (ESIR) International Academy of Sex Research (IASR) International Society for Impotence Research (ISIR) Société d’Andrologie de Langue Française (SALF) Sociedad Latino Americana para el estudio de la Impotencia (SLAI) Society for Study of Impotence (SSI) World Association of Sexology (WAS)

Recommendations of the 1st International Consultation on Erectile Dysfunction Jardin A., Wagner G., Khoury S., Giuliano F., Goldstein I., Padma-Nathan H., Rosen R., Andersson K.E., Becher E., Hendry B., Jonas U., Kim Y.C., Krane R., Lewis R., Lue T., Lundberg P.O., Mc Aninch J., Melman A., Meuleman E., Morales A., Navratil H., Sáenz de Tejada I., Schmidt A., Shabsigh R., Stackl W., Tan H.M., Teloken C., Tiefer L., Virag R. «There exists fundamental rights for the individual, including the right to sexual health and a capacity to enjoy and control sexual and reproductive behavior in accordance with a social personal ethic - freedom from fear, shame, guilt, false beliefs and other factors inhibiting sexual response and impairing sexual relationships - freedom from organic disorders, disease and deficiencies that interfere with sexual and reproductive function. » WHO 1994

INTRODUCTION The 1st International Consultation on Erectile Dysfunction was convened from July 1-3 1999 in Paris, France . Its mission was to develop recommendations for the diagnostic evaluation and management of erectile dysfunction. The recommendations are based on a thorough review of the available literature and the subjective opinion of recognized global experts serving on eighteen focused committees. The individual committee reports were developed and peer-reviewed by open presentation and comments. Each committee also provided focused recommendations. Final recommendations were then refined by a working group and discussed by the Scientific Committee, consisting of the Chairmen of each committee and representatives of the associations sponsoring the Consultation. These recommendations, published in 1999, will be periodically re-evaluated in the light of clinical experience and progress within the field.

711

CONTENTS A. DEFINITION OF ERECTILE DYSFUNCTION B. THE KEY TO THE DIAGNOSIS AND EVALUATION OF ERECTILE DYSFUNCTION (Algorithm A) I. HIGHLY RECOMMENDED EVALUATION AND TESTS 1.COMPREHENSIVE SEXUAL, MEDICAL AND PSYCHO-SOCIAL HISTORY a) Medical and Sexual History b) Erectile Dysfunction Intensity and Impact Scales

2. FOCUSED PHYSICAL EXAMINATION II. RECOMMENDED DIAGNOSTIC TESTS 1. FASTING GLUCOSE OR GLYCOSYLATED HAEMOGLOBIN (HBA1C) AND LIPID PROFILE 2. EVALUATION OF THE HYPOTHALAMIC-PITUITARY-GONADAL AXIS WITH A TESTOSTERONE ASSAY III. OPTIONAL DIAGNOSTIC TESTS 1. PSYCHOLOGICAL AND/OR PSYCHIATRIC CONSULTATION 2. LABORATORY INVESTIGATIONS: (Serum prolactin, LH, TSH, CBC, Urinalysis) IV. SPECIALIZED EVALUATION AND DIAGNOSTIC TESTS 1. IN DEPTH PSYCHOSEXUAL AND RELATIONSHIP EVALUATION 2. PSYCHIATRIC EVALUATION 3. NOCTURNAL PENILE TUMESCENCE AND RIGIDITY (NPTR) ASSESSMENT 4. VASCULAR DIAGNOSTICS 5. SPECIALIZED ENDOCRINOLOGICAL TESTING 6. NEURO-PHYSIOLOGICAL TESTING V. CONCLUSION

C. THE KEY TO THE TREATMENT OF ERECTILE DYSFUNCTION (ALgorithm B) I. ALTER MODIFIABLE RISK FACTORS OR CAUSE 1. LIFESTYLE AND PSYCHOSOCIAL FACTORS 2. SEXUAL TECHNIQUE AND INFORMATION 3. PRESCRIPTION OR NON-PRESCRIPTION DRUG USE 4. HORMONE REPLACEMENT THERAPY II. DIRECT TREATMENT INTERVENTIONS FOR ERECTILE DYSFUNCTION 1. SEXUAL COUNSELLING AND EDUCATION 2. ORAL AGENTS a) Sildenafil b) Apomorphine c) Phentolamine d) Other drugs

3. LOCAL THERAPIES a) Intracavernosal Injection Therapy b) Intraurethral Therapy c) Vacuum Constriction Devices

4. SURGICAL THERAPY a) Vascular Surgery b) Penile implants

III. REASSESSMENT AND FOLLOW-UP GENERAL CONCLUSION

712

A. Definition of Erectile Dysfunction

collaborating specialists should possess a broad knowledge about human sexuality. In the case of erectile dysfunction, problems may be lifelong or acquired, global or situational. Adequate attention to these details during the history will educate the often uninformed patient regarding the complex nature of sexuality, and prepare him to understand treatment and outcome realities.

The term «erectile dysfunction» is widely used to refer to the consistent or recurrent inability of a man to attain and/or maintain a penile erection sufficient for sexual performance. «Erectile dysfunction» is now used in preference to the more traditional terms, «impotence» or «male impotence». These earlier terms were replaced due to their lack of specificity and pejorative connotations for the patient.

Patient and partner expectations, needs and priorities will be significantly influenced by cultural, social, ethnic, religious and national/regional perspectives. The rational selection of therapy by patients is only possible following appropriate education, including information about sexuality and all treatments for erectile dysfunction. Although not always possible on the first visit, every effort should be made to involve the patient’s primary sexual partner early in the therapeutic process.

Erectile dysfunction is a disorder and a symptom based on the patient’s complaints. Objective testing (or partner reports) may be used to support the diagnosis of erectile dysfunction, but these measures cannot substitute for the patient’s selfreport in defining the disorder or establishing the diagnosis. The necessary reliance on patient reports implies that cultural factors and patient-physician communication will be important determinants in defining, diagnosing and evaluating the disorder.

Erectile dysfunction with its abbreviation ED is a worldwide accepted term. Although there are some acceptable synonyms for ED e.g. erectile insufficiency or failure or impairment, ED refers to the specific inability to achieve or sustain a penile erection, and should not be applied to penile curvatures, La Peyronie’s disease, spontaneous or drug-induced prolonged erections and painful erections.

Consistency is a part of the definition of erectile dysfunction. Erectile difficulties must be reported to occur on a consistent or recurrent basis in order to qualify for the diagnosis of erectile dysfunction. At present, a 3-month minimum duration is generally accepted for establishment of the diagnosis. In some instances of trauma or surgically-induced erectile dysfunction (e.g. post-prostatectomy), the diagnosis may be given prior to 3 months.

ED must also be distinguished from other sexual disorders in the male such as premature ejaculation, anorgasmia and lack of desire, although ED may occur concurrently with these other sexual disorders.

Erectile dysfunction may occur regardless of the postpubertal age and there are many aetiologic profiles in erectile dysfunction. It is noteworthy that erectile dysfunction might not be the primary complaint and/or may be associated with other sexual problems.

In contrast to most other medical conditions, the various treatments for ED have to be considered in the context of traditions, ethnicity and socio-economic conditions and also the patient’s and partner’s preference, expectations and psychological status.

Sexuality, including erection, is a complex biopsychosocial process. The treating physician and

713

B. The Key to the Diagnosis and Evaluation of Erectile Dysfunction (Algorithm A) The cornerstone of clinical assessment of all men with ED is an initial diagnostic work-up and evaluation. This evaluation should be performed by a physician knowledgeable in male sexual function and dysfunction with sensitivity toward cultural, ethnic and religious factors. It is anticipated that most men with ED will first be evaluated by a primary care physician. Basic knowledge of human sexuality as well as anatomy and physiology of male sexual function are essential. A multidisciplinary approach may be required. Although a male with ED may be referred for psychosexual therapy, the medical treatment including pharmacological and surgical therapies for ED require the involvement of a physician.

The diagnostic tests utilized in the assessment of the patient with ED may be stratified as: u Highly recommended test: is a test that should be done on every patient u Recommended test: test of proven value in the evaluation of most patients. Its use is strongly encouraged during initial evaluation u Optional test: test of proven value in the evaluation of specific patient profiles, with use left to the clinical judgment of the treating physician in general practice u Specialized test : test of value in selected patient profiles in specialized settings. The rationale for testing and the potential impact of a positive test must be explained to the patient (e.g. an abnormal fasting glucose result may lead to the diagnosis of diabetes).

I. HIGHLY RECOMMENDED EVALUATION AND TESTS

1.

• smoking • chronic medical illness: - hypertension - diabetes mellitus - renal or hepatic dysfunction - atherosclerosis and cardiovascular risk factors including hyperlipidaemia • pelvic/perineal/penile trauma and surgery • medications/recreational drug use • pelvic radiotherapy • neurological disease • endocrine disease • psychiatric illness • current psychological state (Table 2): with special attention to symptoms of depression (Table 3), altered self-esteem and coping skills, past and present partner relationships (given the interpersonal context of sexual problems), past and present sexual practices, history of sexual trauma/abuse, history of somatization, hypochondriasis, history of obsession related to sexual function, job and social position satisfaction, economic position, educational attainment.

COMPREHENSIVE SEXUAL, MEDICAL AND PSYCHOSOCIAL HISTORY

a) Medical and sexual history The medical and sexual history (Table 1 gives a sample of sexual history questions in everyday practice) are the most important elements in the evaluation of ED. Such a history should be obtained by a patient -physician dialogue in all men presenting with complaints consistent with ED. The essential components of this history should include an assessment of the following: • erectile insufficiency (onset, duration, progression, severity of the problem (see Table 4), evidence of ED as it relates to sex with a partner, nocturnal/morning erections, self-stimulatory and visual erotic-induced erections) • altered sexual desire • ejaculation • orgasm • sexually induced genital pain • partner sexual function • lifestyle factors 714

DIAGNOSTIC AID : SAMPLE QUESTIONS Table 1: Sample Sexual History Questions:

Table 2: Sample Psychosocial Assessment Questions:

•

•

"Do you suffer from depression or other mood problems?"

•

"Have you seen a psychiatrist or other mental health professional in recent years? If yes, please describe the circumstances and outcome"

"Many men of your age start to experience sexual difficulties, if you have such a problem, I would be happy to discuss this further"

•

" Could you describe your sexual problem?"

•

"When did your erection problems begin?" "Please describe the circumstances".

•

"How are your relationships with family members and other important people in your life?"

•

"Tell me about your sexual life and satisfaction in the past"

•

"Do you have any difficulties in your work situation, if applicable?"

•

"How are your erections that you achieve with masturbation or those that occur with sleep or upon awakening early in the morning ?" (The discussion of masturbation is a sensitive issue that is often influenced by cultural and religious perspectives.)

•

"How is your current relationship with your partner? How was it in the past?"

•

"Were you ever the victim of sexual abuse (e.g. forced to have sex)? If yes, what effect did this have on you then or now?"

•

"Is your economic situation contributing to significant stress in your life?"

•

"How strong is your desire for sex, now and in the past?"

•

"Do you have difficulties with ejaculating too fast or too slow, either now or in the past?"

•

"Do you know whether your partner was satisfied with your sexual life together? Would it be helpful for me to talk with your partner about your sexual life and situation?"

Table 3: A 2-question scale for depression

•

•

"What has been your partner’s reaction to your sexual problem and does your partner want to resume sexual intercourse now?"

•

During the past month have you often been bothered by feeling down, depressed or hopeless?

•

During the past month have you often been bothered by little interest or pleasure doing things? Source : Whooley M.A., Avins A.L., Miranda J., Browner W.S. Case-finding instruments for depression. Two questions are as good as many. J. Gen. Intern. Med. 1997; 12: 439-445

"What has been the effect of your sexual difficulties on your overall lifestyle?"

715

Brief symptom scales and quality of life measures* can assist the practitioner or clinical researcher in obtaining clinically-relevant data in a standardized and cost-efficient manner. These instruments can also be used in patient follow-up to document some aspects of clinical outcome. Despite these advantages, symptom scales should not be used as a substitute for physical examination or medical history of the patient. These latter procedures are the sine qua non for clinical care of the patient with ED. The substitution of a questionnaire may not address the specific religious, cultural, educational and economic factors of the individual patient.

b) Erectile dysfunction intensity and impact scales Symptom intensity and impact scales are used for several purposes: • to aid clinicians in recognizing, diagnosing and evaluating the disorder, • to permit patients to acknowledge the problem in routine office settings, and • to assist researchers in the collection of epidemiological and clinical trial data. Brief symptom scales also assist clinicians in classifying the severity of the disorder and its impact on the patient. The use of a brief, self-administered questionnaire is particularly recommended for assessment of ED symptom intensity and impact. The following scales are proposed for this purpose:

Particular attention should be paid to:

•

Patient expectations

A critical aspect of assessment is the identification of patient needs, expectations, priorities and treatment preferences which may be significantly influenced by such factors as cultural, social, ethnic and religious perspectives. Patient education is also important in fostering a therapeutic relationship, facilitating patient-physician communication and enhancing patient compliance.

˚ 5-item Intensity Scale (Table 4) The 5-item ED Intensity item is based on extensive research and clinical experience, including publication in recent years of several well-validated questionnaire measures of sexual function. The 5 items in this scale characterize the ability to achieve and maintain erection. These items have high test-retest reliability and have been validated linguistically in more than 30 languages. The items have been selected from the International Index of Erectile Function (Rosen et al., Urology, 1997-49:822-830), a 15-item questionnaire measure of male sexual function developed for use in clinical trials of ED. An aggregate score of the 5-item scale can be calculated, and used to classify the severity of the disorder

• Partner involvement Although not always possible on the first visit, efforts should be made to involve the patient’s partner early in the process. The partner’s presence may be influenced by cultural and social preferences as well as individual patient needs and preferences.

2.

FOCUSED PHYSICAL EXAMINATION

A focused physical examination should be performed on every patient with ED. This examination should include: • assessment of body habitus (secondary sexual characteristics) • assessment of the cardiovascular, neurological and genito-urinary system focusing on penile, testicular and rectal exam. Blood pressure and heart rate should be measured if not assessed in the previous 3-6 months. The physical examination may corroborate aspects of the medical history and may occasionally reveal unsuspected physical findings (e.g. penile plaques, atrophic testes, suspicion of prostate cancer).

˚ Single item ED Impact scale (Table 4) The single-item impact scale is adapted from a similar scale widely used in Benign Prostate Hyperplasia, and which has been shown to be a sensitive and reliable index of subjective distress. It has also been included in a well-validated quality of life scale for ED*. The single-item impact scale provides a quantitative index of subjective distress or bother associated with the disorder (ED impact scale). This score should be recorded separately from the aggregate symptom score of the first 5 items (ED intensity scale).

716

*There exists a validated quality of life scale for ED by Fugl-Meyer et al., Int J Impot Res., 1997-9:141-148.

Table 4: ED Intensity and Impact Scales

ERECTILE DYSFUNCTION 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 OF ASSESSMENT :

Almost never A few times Sometimes or never (much less than (about half half the time) the time) 1. HOW OFTEN WERE YOU ABLE TO GET AN ERECTION DURING SEXUAL ACTIVITY?

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

1

2

3

4

5

1

2

3

4

5

1

2

3

4

5

1

2

3

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

Extremely difficult

Very difficult

4

5

Difficult

Slightly difficult

3

4

Not difficult

5. DURING SEXUAL INTERCOURSE, HOW DIFFICULT 1

WAS IT TO MAINTAIN YOUR ERECTION TO COMPLETION OF INTERCOURSE?

2

5

ED Intensity Score : • Instructions for 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.

ERECTILE DYSFUNCTION IMPACT SCALE VERY DISSATISFIED

RATHER 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

717

4

5

II. RECOMMENDED 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.

2.

TOSTERONE ASSAY

Although controversy exists as to the relative value of the various testosterone assays (total, free or bioavailable), strong consensus exists that at least one of these assays should be performed particularly in case of low sexual desire and of testes of diminished size. Although it might be argued that testosterone testing is associated with a low positive yield, in the group of men with ED secondary to hypogonadism, it might represent a potentially reversible form of ED.

These tests include the following focused laboratory tests:

1.

EVALUATION OF THE HYPOTHALAMICPITUITARY-GONADAL AXIS WITH A TES-

FASTING GLUCOSE OR GLYCOSYLATED HAEMOGLOBIN (HBA1C) AND LIPID PROFILE,

if not available within the previous 12 months, are of clinical utility to rule out diabetes mellitus and hyperlipidemia.

III. OPTIONAL DIAGNOSTIC TESTS

1.

PSYCHOLOGICAL AND/OR PSYCHIA-

2.

TRIC CONSULTATION

(if available) for thorough sexual and psychosocial history

LABORATORY INVESTIGATIONS:

• Serum prolactin, LH • Thyroid stimulating hormone (TSH) • Complete blood count (CBC) if not available during the last 6 months • Urinalysis (dip-stick or microscopic)

IV. SPECIALIZED EVALUATION AND DIAGNOSTIC TESTS While the majority of patients with ED can be managed within the primary care setting by a physician educated in male sexual dysfunction, specific circumstances may dictate the need for referral for specialized testing and/or treatment (Table 5). Before considering specialized evaluation and

diagnostic testing, the physician should consider whether the patient’s case profile meets the indications for specialist referral. The physician must also consider the ability of his clinic facility to provide and support specific hormonal, vascular, neurologic and psychological testing.

Table 5: Specific Indications for Referral and/or Treatment 1. Patient requests referral for specfic testing or treatment. 2. Patient requiring vascular, neurological or cardiologic evaluation 3. Young patient with pelvic, perineal or penile surgery or trauma who may be a candidate for reconstructive vascular surgery. 4. Patient with La Peyronie’s disease and/or a significant penile bend or deformity that might require surgical correction.

5. Patient with refractory depression, bipolar disorder, psychosis or history of sexual abuse or trauma and those patients with complicated psychiatric or psychosexual disorder as well as those with complex relationship issues. 6. Patient with a complicated endocrinopathy including complicated diabetes mellitus 7. Patient with treatment failures who may be a candidate for intracavernosal injection therapy or penile implant surgery.

718

1.

IN DEPTH PSYCHOSEXUAL AND RELATIONSHIP EVALUATION

2.

PSYCHIATRIC EVALUATION

3.

NOCTURNAL PENILE TUMESCENCE AND RIGIDITY (NPTR) ASSESSMENT

4.

VASCULAR DIAGNOSTICS

5.

S PECIALIZED

ENDOCRINOLOGICAL

TESTING

- Thyroid function studies - Hypothalamic-pituitary-gonadal function studies - MRI sella turcica

6.

NEURO-PHYSIOLOGICAL TESTING

- Vibrometry - Bulbocavernosus reflex latency - Cavernosal EMG - Somatosensory evoked potential testing - Pudendal and sphincter EMG

- In office penile injection pharmacotesting - Penile Doppler ultrasound - Dynamic infusion pharmacocavernosometry and pharmacocavernosography - Penile arteriography - CT and MR imaging (to evaluate trauma and infection) - Nuclear imaging

V. CONCLUSION The first step in the management of the patient with ED is to facilitate the patient’s and partner’s (if available) understanding of the condition and the results of the diagnostic assessment and to identify the patient’s and partner’s needs, expectations, priorities and preferences.

The identification and recognition of medical and psychological factors associated with ED in the individual patient, must be emphasized.

SUMMARY DIAGNOSIS AND EVALUATION OF ERECTILE DYSFUNCTION I. HIGHLY RECOMMENDED EVALUATION AND TESTS

III. OPTIONAL DIAGNOSTIC TESTS

1. COMPREHENSIVE SEXUAL, MEDICAL AND PSYCHO-SOCIAL HISTORY

1. PSYCHOLOGIC AND/OR PSYCHIATRIC

a) Medical and Sexual History b) Erectile Dysfunction Intensity and Impact Scales

2. LABORATORY INVESTIGATIONS (Serum prolactin, LH, TSH, CBC, Urinalysis)

CONSULTATION

2. FOCUSED PHYSICAL EXAMINATION

IV. SPECIALIZED EVALUATION AND DIAGNOSTIC TESTS

II. RECOMMENDED

1. IN DEPTH PSYCHOSEXUAL AND RELATIONSHIP EVALUATION

1. FASTING GLUCOSE OR GLYCOSYLATED HEMOGLOBIN (HBA1C) AND LIPID PROFILE

2. PSYCHIATRIC EVALUATION 3. NOCTURNAL PENILE TUMESCENCE AND RIGIDITY (NPTR) ASSESSMENT 4. VASCULAR DIAGNOSTICS 5. SPECIALIZED ENDOCRINOLOGIC TESTING 6. NEURO-PHYSIOLOGIC TESTING

2. EVALUATION OF THE HYPOTHALAMICPITUITARY-GONADAL AXIS WITH A TESTOSTERONE ASSAY.

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C. The Key to the Treatment of Erectile Dysfunction (Algorithm B) The selection of therapy is strongly influenced by personal, cultural, ethnic, religious and economic (affordability) factors.

may therefore vary among individuals, among persons from different cultural or religious backgrounds, or among persons with varying socioeconomic backgrounds.

The presentation and stratification of therapies

I. ALTER MODIFIABLE RISK FACTORS OR CAUSES Prior to direct intervention, good medical practice recognizes the value of altering modifiable risk factors. Although frequently insufficient to reverse ED completely, this step may be of great value in selected patients. Although the quantitative benefits of altering modifiable risk factors or causes, particularly when associated with the need to modify behavior, are not documented, good clinical practice mandates attention to these issues either prior to, or along with, direct therapies as a key to treating ED. These potentially modifiable risk factors and causes include the following:

1.

LIFESTYLE

4.

for hormonal abnormalities (e.g. hypogonadism, hyperprolactinemia) Hormone replacement therapy is appropriate in the presence of a documented deficiency (e.g. androgen deficiency and hypogonadism). However, adequate replacement may not necessarily improve ED and thus one may need to consider direct intervention therapy even in this patient population. The issue of androgen replacement therapy is complicated. There is a statistical decline of testosterone levels, particularly free testosterone, in ageing men. While this fall is only moderate, ageing men show clinical signs of hypogonadism (loss of muscle mass/strength, reduction in bone mass and an increase in visceral fat). Testosterone replacement or supplement therapy may improve bone mass, muscle mass, strength and frequently nocturnal erections as well in this age group. However, the effects on sexual function, mood and cognition are less clear, but may be meaningful in certain men. The identification of that segment of the ageing male population that might possibly benefit from androgen supplementation remains unclear. Questions still remain regarding the magnitude and longevity of these potential beneficial effects.

AND PSYCHOSOCIAL FAC-

TORS

Lifestyle factors such as cigarette smoking, alcoholism, substance abuse, may require priority management specific to the particular issue. Psychosocial factors include relationship issues e.g. partner conflict, sexual misinformation, limited sexual practices and also depression

2.

SEXUAL TECHNIQUE AND INFORMATION

This includes lack of awareness of psychological impact on sexual function, information about normal age-related changes, need for partner foreplay and lubrication.

3.

HORMONE REPLACEMENT THERAPY

PRESCRIPTION OR NON-PRESCRIP-

More importantly, the long-term risks of androgen therapy in this age group are not really known, especially in the areas of cardiovascular and prostate diseases. It has been known that testosterone in general should be employed as replacement therapy. Despite increasing evidence that patients with subnormal or borderline normal levels of testosterone could be considered as candidates for testosterone treatment, until more information is available testosterone and androgens in general should not be recommended as supplement therapy.

TION DRUG USE

Most commonly used antihypertensives, psychotropic drugs including antidepressants and anti-psychotics, as well as anti-arrhythmics and antiandrogens and steroids. Alterations in drug dosages or classes may be of significant benefit in selected patients, but this should be coordinated with the primary physician managing, for example, the patient’s hypertension or depression. 720

II. DIRECT TREATMENT INTERVENTIONS FOR ERECTILE DYSFUNCTION The patient and his partner (if available) should be informed about all of the available and acceptable treatment options applicable to his clinical condition and the related benefits, risks, and costs of each modality. The development of ED can significantly affect the quality of life, but it is not a life-threatening disease. Consequently, it is reasonable to discuss the benefits, risks, and costs of the available treatment strategies with the patient and have the patient actively participate in the choice of therapy (shared decision-making). There is a documented correlation between cardiovascular disease and ED. In a significant number of patients ED is a sign of vascular desease An important issue prior to the institution of any therapy and the subsequent resumption of sexual activity is the patient’s overall cardiovascular condition. Is this patient able to resume the exercise of sexual activity? If not, priority cardiovascular assessment and intervention may be appropriate. The partner’s sexual function if possible should be considered prior to initiating therapy. The vast majority of patients will need to consider direct treatment options for ED. Only those pharmacological treatments that have been thoroughly tested in randomized clinical trials, with subsequent publication of results in peer-reviewed literature, should be considered for general use. Long-term follow-up of all treatment options must be performed to demonstrate durability and continued efficacy and safety, as well as patient and partner acceptability. Additionally, new treatment options that enter the arena will need to meet not only the above efficacy and safety criteria but should also be compared to available therapies for cost-effectiveness. The treatment selected by a patient will be influenced not only by issues such as efficacy and safety, but also by the patient’s cultural, religious and economic background. Additionally, such factors as: 1. the mechanism of action: peripheral vs central, inducer vs enhancer and 2. ease of administration 3. invasiveness 4. reversibility 5. cost 6. legal regulatory approval and availability

may all critically influence the individual patient’s selection of therapy. As previously mentioned, affordability is a prime factor worldwide in influencing patient acceptance and utilization of a specific therapy for ED. ˚ The use of the internet to prescribe therapies for ED is to be condemned since it fails to meet the need for direct physician-patient contact in the assessment of all patients presenting with this complaint.

1.

SEXUAL COUNSELLING AND EDUCATION

Sexual counselling and education (sex therapy, psychosexual therapy or marital therapy) for individuals or couples address specific psychological or interpersonal factors such as relationship distress, sexual performance concerns, dysfunctional communication patterns and comorbid sexual conditions that are likely to impact sexual functioning. Modified sex therapy may serve as an adjunct to the other direct therapies for ED to address psychological reactions to these medical or surgical therapies which may be perceived as temporary, unnatural or unacceptable by the patient and/or partner. The advantages of psychosexual therapy include its noninvasive nature and broad applicability. The disadvantages of psychosexual therapy include its variable efficacy in the treatment of ED, cost acceptability by the patient or the couple and availability of qualified providers.

2.

ORAL AGENTS

When indicated, oral therapies will probably become the first-line treatment for the majority of patients because of potential benefits and lack of invasiveness. Historically, oral medications such as yohimbine have been utilized empirically without the support of rigorous clinical trial data on efficacy and safety. Oral therapies may act: • centrally as dopaminergic agonists • both centrally and peripherally as alpha adrenergic blockers or • peripherally as phosphodiesterase 5 (PDE 5) inhibitors or nitric oxide (NO) precursors • as an inducer or as an enhancer 721

adverse effect is nausea, which has been reported as usually mild at lower dosages (2 mg and 4 mg). Other adverse effects are dizziness, sweating, somnolence, yawning and rarely syncopy. It is under review at the time of writing.

a) Sildenafil Sildenafil, a selective inhibitor of phosphodiesterase type 5 (PDE 5), has been approved in many countries for the treatment of ED. PDE-5 is the enzyme responsible for the breakdown of the intracellular second messenger of NO i.e. cyclic guanosine monophosphate (cGMP). PDE 5 is the predominant isoform of phosphodiesterases found in the corporal smooth muscle. Sexual stimulation is necessary to initate NO release within the corpora, accordingly sildenafil is ineffective in the abscence of sexual stimulation. In clinical trials, sildenafil has shown broad spectrum efficacy in a majority of patients regardless of the underlying aetiology of ED, the baseline severity of ED or the age of the patient. Recent studies in patients with specific disorders such as diabetes mellitus, hypertension, spinal cord injury, multiple sclerosis and depression have also shown sildenafil to be effective. It is important to stress that the co-administration of nitrates and sildenafil is strictly contraindicated. Severe hypotension may ensue following this combination. Side-effects include transient headache, flushing, dyspepsia, nasal stuffiness and transient altered colour-vision (due to PDE 6 inhibition). Although there was no difference in CV mortality compared to placebo in the controlled trials presented for registration, a number of deaths have been reported in association with sildenafil usage in post marketing reporting but the specific relationship to the drug is uncertain. In several of these cases, nitrates and sildenafil were administered concomitantly against the prescribing information. In general, sildenafil when prescribed appropriately has demonstrated broad efficacy and an acceptable safety profile.

c) Phentolamine Phentolamine is an alpha-adrenergic blocking agent with both central and peripheral activity. In placebo controlled studies, phentolamine mesylate has been found to have modest efficacy in patients with mild-to-moderate ED. Adverse events includes dizziness, nasal stuffiness and tachycardia which is generally well tolerated at the 40 mg dose. It is under review at the time of writing. d) Other drugs Other drugs under investigation include: • IC 351 is a more pharmacologically selective and longer acting PDE-5 inhibitor, the clinical significance of which remains under investigation in clinical trials • melanotan II an alpha-MSH analogue and • the combination of L-arginine and yohimbine. In the future, combination oral therapy may be employed and potentially demonstrate additive or synergistic actions (e.g. theoretically sildenafil and apomorphine). Because of the possible additive effects of combination therapy (e.g. hypotension), clinical trials must be first performed to evaluate not only efficacy but also safety. The advantages of oral drug therapies include broad patient acceptance, ease of administration and relative efficacy. The disadvantages include specific contraindications such as the concomitant use of nitrates with respect to sildenafil, the relatively high cost and lack of long-term use follow-up data.

3.

b) Apomorphine

LOCAL THERAPIES

Local therapies include intracavernosal injection therapy, intraurethral therapy and vacuum device therapy. Patients who fail oral drug therapy, who have contraindications to specific oral drugs or who experience adverse events with oral drugs might consider these local therapies. Additionally, individual preferences may direct a patient to consider local therapies prior to, or as an alternative to, an oral drug therapy.

Apomorphine is a dopaminergic agonist acting on the central nervous system. It was initially administered subcutaneously, however intolerable adverse events prompted the development of a sublingual pill. Apomorphine has shown efficacy in placebo-controlled fixed and dose escalation studies. In responders erectile activity is usually experienced within 20 minutes. Its principal

722

gical therapies or who have specific contra-indications to these therapies. VCDs apply a negative pressure to the pendulous penis, thus drawing blood into the penis, which is then retained by application of an elastic band at the base of the penis. The side-effects associated with VCD therapy include penile pain, penile numbness, bruising and retarded ejaculation. The advantages of VCD therapy include its nonpharmacological nature, on-demand use, lack of contraindications and cost. The disadvantages of VCD therapy include their cumbersome utilization and minor local sideeffects.

a) Intracavernosal injection therapy Intracavernosal injection therapy is a well established medical therapy for ED. The delivery, by penile injection, of agents that directly relax corporal smooth muscle such as papaverine, phentolamine or more recently alprostadil (prostaglandin E1) is associated with broad efficacy and relative safety. • Alprostadil is widely approved worldwide as alprostadil sterile powder or alfadex. • Combinations of agents have established efficacy and safety based upon common usage. Injection therapy with alprostadil or a combination of drugs is effective in a large majority of patients, although discontinuation rates are usually high. The side-effects associated with injection therapy are primarily local and include pain, priapism and scar tissue formation over time. This therapy is contraindicated in patients with sickle cell anaemia and with other conditions that predispose to priapism. The advantages of penile injection therapy include broad efficacy, relative safety and rapid onset of action. The disadvantages include invasive local administration and relatively high cost.

4.

SURGICAL THERAPY

a) Vascular surgery Microvascular arterial bypass and venous ligation surgery may achieve the goal of increasing arterial inflow and decreasing venous outflow. Certain young patients with vascular insufficiency may be candidates for surgical cure or improvement of ED. These patients must be evaluated by specialized testing and should be treated by an experienced surgeon.

b) Intraurethral therapy The intraurethral application of alprostadil is an alternative to injection therapy. Intraurethral therapy is associated with significanlty less efficacy than direct injection of alprostadil. The efficacy may be increased by using an elastic band placed at the base of the penis. The associated side-effects include pain as well as systemic hypotension. The advantages of intraurethral therapy include its less invasive nature. The disadvantages include local as well as systemic side-effects, relatively high cost and partner-related vaginal irritation.

b) Penile implants The final treatment option for ED is the surgical implantation of a malleable or inflatable penile prosthesis. This option is highly invasive and irreversible and should therefore be reserved for select cases failing other treatment modalities. However, under unique and uncommon circumstances, a penile implant could be selected as a primary option. When properly selected, penile prostheses may be associated with high rates of patient satisfaction. Penile implant surgery is uncommonly associated with prosthesis infection, but such cases usually require explantation and may result in severe scarring and penile deformity.

Transdermal penile delivery of vasoactive drugs is currently under investigation at the time of writing. c) Vacuum constriction devices

The advantages of penile prosthesis implantation include relative efficacy and a «long-term solution». The disadvantages of penile prostheses include irreversibility, invasiveness, surgical complications and mechanical failure.

Vacuum constriction devices (VCDs) are widely available including over-the-counter (without prescription) in some countries. They are of appeal to a group of men not interested in pharmacolo-

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III. REASSESSMENT AND FOLLOW-UP Reassessment and follow-up should be conducted at regular intervals for every patient receiving treatment for ED. The goals of follow-up include:

3. Patients may change medication regimens, either for ED or a concomitant medical disorder. The possibility of adverse drug reactions or drug interaction effects with oral medication for ED should be carefully monitored.

1. The need for dose titration or substitution of another treatment intervention should be considered at each treatment follow-up visit. Patients may change treatment preferences, seek new information, or wish to re-evaluate their current treatment choices.

4. General medical and psychosocial reassessment should be performed at regular intervals, depending upon the patient’s health, physical and psychosocial needs. Follow-up also provides an additional opportunity for patient education.

2. Patient communication. Patients may have concerns regarding treatment administration, other sexual dysfunctions (e.g. premature ejaculation), partner issues (e.g. anorgasmia) or lifestyle factors (e.g. emotional stress).

GENERAL CONCLUSION experts in the field. They are rational and stepwise with respect to diagnostic and treatment interventions. These recommendations recognize and respect the influence of cultural, ethnic, religious and individual patient and partner perspectives and, in general, attempt to ensure broad global applicability and appeal.

The field of sexual health medicine is rapidly evolving. The consensus opinions expressed in this 1st International Consultation will require updating with the rapid developement in: - basic and clinical sciences - culture/race/ ethnic specific epidemiology - new drugs in all classes - gene therapy - prevention strategies. These International recommendations for the key to resolving ED (algorithms A and B) have been based on a thorough review of the literature and the opinions of recognized worldwide

The diagnosis and treatment of ED by Internet or any other electronic or otherwise distant interaction between patient and physician which prevents direct one-on-one assessment and examination is strongly discouraged.

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