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.

GEBHARD PH, JOHNSON AB: “The Kinsey Data: Marginal Tabulations of the 1938-1963 Interviews Conducted by the Institute for Sex Research”, Philadelphia: WB Saunders, 1979, 125.

9.

DIOKNO AC, BROWN MB, HERZOG AR: Sexual Function in the Elderly. Arch Intern Med 1990, 150:197-200.

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.

REFERENCES 1.

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

2.

BOYLE P: Epidemiology of Erectile Dysfunction. In Carson C, Kirby R, and Goldstein I (eds), “Textbook of Erectile Dysfunction”, Oxford: Ibis Medical Media, 1999: 15-24.

3.

4.

16. FUGL-MEYER AR AND SJOGREN FUGL-MEYER K: Sexual Disabilities, Problems and Satisfaction in 1874 Year Old Swedes. Scand J Sexol 1999, 2:79-105. 17. BEJIN A: Epidemiologie de l’ejaculation prematuree et de son cumul avec la dysfonction erectile. Andrologie 1999,9:211-225. 18. SHIRAI M, TAKANAMA M, TANAKA T, MATSUMASHI M, MAKI A, NIURA K AND ANDO K: A Stochastic Survey of Impotence Population in Japan. Impotence 1987, 2:67.

SPECTOR IPAND CAREY MP: Incidence and Prevalence of the Sexual Dysfunctions: A Critical Review of the Empirical Literature. Arch Soc Behavior 1990, 19: 389-407.

19. CHEW KK, EARLE CM, STUCKEY BGA, JAMROZIK K AND KEOGH EJ.: Erectile Dysfunction in General Medical Practice: Prevalence and Clinical Correlates. Int J Impotence Res (submitted).

KINSEY AC, POMEROY WB, AND MARTIN CE: Sexual Behavior in the Human Male. Philadelphia: WB Saunders, 1948.

5.

LAUMANN EO, GAGNON JH, MICHAEL RT, MICHAELS S: “The Social Organization of Sexuality. Sexual Practices in the United States”, Chicago: University of Chicago Press, 1994.

6.

FELDMAN HA, GOLDSTEIN I, HATZICHRISTOU DG, KRANE RJ AND MCKINALY JB. Impotence and its Medical and Psychosocial Correlates: Results of the Massachusetts Male Aging Study. J Urol 1994, 151:5461.

20. JOHANNES CB, ARAUJO AB, FELDMAN HA, DERBY CA, KLEINMAN KP, MCKINLAY JB: Incidence of Erectile Dysfunction in Men Ages 40-69: Longitudinal Results from the Massachusetts Male Aging Study. Submitted. 21. AYTAC IA, MCKINLAY JB, KRANE RJ: The Likely Worldwide Increase in Erectile Dysfunction between 1995 and 2025 and Some Possible Policy Consequences. BJU International 1999, 84:50-56. 22. WEI M, MACERA CA, DAVIS DR, HORNUNG CA,

48

NANKIN HR, BLAIR SN: Total Cholesterol and High Density Lipoprotein Cholesterol as Important Predictors of Erectile Dysfunction. Am J Epidemiol 1994, 140:930-937.

NELSON CJ, NELSON AE, KINLAW WD, BEYER HS, NUTTAL FQ, SHAFER RB: Impotence in Medical Clinic Outpatients. JAMA1983, 249:1736-1740. 37. BARRETT-CONNOR E, KHAW K-T, YEN SSC: A Prospective Study of Dehydroepiandrosterone Sulfate. New Eng J Med 1986, 315:1519-1524.

23. CLOGG CC: LATENTCLASS MODELS. IN ARMINGER G, CLOGG, CC, SOBELME (eds) “Handbook of Statistical Modeling for the Social and Behavioral Sciences”, New York: Plenum Press, 1995.

38.

24. MCCUTCHEON AL: “Latent Class Analysis”, California: Sage Publications, 1987.

39. MILLS TM, LEWIS RW: The Role of Androgens in the Erectile Response: A 1999 Perspective. Mol Urol 1999, 3:75-80.

25. UEBERSAX JS, GROVE WM: Latent Class Analysis of Diagnostic Agreement. Stat Med 1990, 9:559-572. 26. YOUNG MA: Evaluating Diagnostic Criteria: A Latent Class Paradigm. J Psychiatr Res 1983, 17:25-296.

40. BURRIS AS, BANKS SM, CARTER CS, DAVIDSON JM, SHERINS RJ: A Long-Term, Prospective Study of the Physiologic and Behavioral Effects of Hormone Replacement in Untreated Hypogonadal Men. J Androl 1992, 13:297-304.

27. YOUNG MA, TANNER MA, MELTZER HY: Operational Definitions of Schizophrenia: What Do They Identify? J Nerv Ment Dis 1982, 170:443-447.

41. CARANI C. SCUTERI A, MARRAMA P, BANCROFT J: The Effects of Testosterone Administration and Visual Erotic Stimuli on Nocturnal Penile Tumescence in Normal Men. Horm Behavior 1990, 24:435-441.

28. EATON WW, MCCUTCHEON AL, DRYMAN A, SORENSON A: Latent Class Analysis of Anxiety and Depression. Sociol Methods Res 1989, 18: 104-125. 29. KOHLMAN R, FORMANN AK: Using Latent Class Analysis Models to Analyze Response Patterns in Epidemiological Mail Surveys. In Rost J, Langeheine R (eds) “Applications of Latent Trait and Latent Class Models in the Social Sciences”, Munster: Waxmann 1997, 345-351.

42. HORITA J, KUMAMOTOY: Study on Nocturnal Penile Tumescence (NPT) in Healthy Males: Study on the Relationship Between the Serum Free Testosterone Level and NPT. Jap J Urol 1994, 85:1511-1520. 43. CARANI C, GRANATAAR, BANCROFTJ, MARRAMA P: The Effects of Testosterone Replacement on Nocturnal Penile Tumescence and Rigidity and Erectile Response to Visual Erotic Stimuli in Hypogonadal Men. Psychoneuroendocrinol 1995, 20:743-753.

30. KWAN M, GREENLEAF WJ, MANN J, CRAPO L, DAVIDSON JM: The Nature of Androgen Action on Male Sexuality: A Combined Laboratory-Self-Report Study on Hypogonadal Men. J Clin Endo and Met 1983, 57:557-562.

44. CARANI C, GRANATA AR, FUSTINI MF, MARRAMAP: Prolactin and Testosterone: Their Role in Male Sexual Function. Int J Androl 1996, 19:48-54.

31. NICKEL JC, MORALES A, CONDRA M, FENEMORE J, SURRIDGE DH: Endocrine Dysfunction in Impotence: Incidence, Significance, and Cost-Effective Screening. J Urol 1984, 132:40-43.

45. GRANATA AR, ROCHIRA V, LERCHL A, MARRA MA P, CARANI C: Relationship Between Sleep-Related Erections and Testosterone Levels in Men. J Androl 1997, 18:522-527.

32. GRAY A, FELDMAN HA, MCKINLEY JB, LONGCOPE C: Age, Disease and Changing Sex Hormone Levels in Middle-Aged Men: Results of the Massacusetts Male Aging Study. J Clin Endo and Met 1991, 73:1016-1105.

46. TENOVER JL: The Male Climacteric: Fact or Fiction? In “Erectile Dysfunction: Issues in Current Pharmacotherapy”, Morales A (ed) London: Martin Dunitz, 1998, 39-48.

33. FOSTER RS, MULCAHY N, CALLAGHAN JT, CRABTREE R, BRASHEAR D: Role of Serum Prolactin Determination in Evaluation of Impotent Patients. Urology 1990, 36:499-501.

47. BHASIN S: Issues in Testosterone Replacement in the Elderly Male: Testosterone Biology In Meuleman E, Lysklama a Nijeholt A, Vanderschueren D. (eds) “The 8th World Meeting on Impotence Research”, Bologna: Allen Dunitz, 1998, 105-110.

34. KORENMAN SG, MORLEY JE, MOORADIAN AD, DAVIS SS, KAISER FE, SILVER AJ, VIOSCA SP, GARZA D: Secondary Hypogonadism in Older Men: Its Relation to Impotence. J Clin Endo and Met 1990, 71:963-969. 35.

GREENSTEIN A, PLYMATE SR, KATZ PG: Visually Stimulated Erection in Castrated Men. J Urol 1995, 153:650-652.

48. MORALES A: “Androgens, Sexual Endocrinophathies and their Treatment in Erectile Dysfunction: Issues in Current Pharmacotherapy”, Morales A. (ed) London: Allen Dunitz, 1998, 141-155.

SPARK RR, WHITE RA, CONNOLLY PB: Impotence Is Not Always Psychogenic: Newer Insights into the Hypothalmic-Pituitary-Gonadal Dysfunction. JAMA 1980, 243:750-756.

49. MULLIGAN T, SCHMITT B: Testosterone for Erectile Failure. J Int Med 1993, 8:517-521. 50. CONDRA M, SURRIDGE DH, MORALES A, FENEMORE J, OWEN JA: Prevalence and Significance of

36. SLAG MF, MORLEY JR, ELSON MK, TRENCE DL,

49

Tobacco Smoking in Impotence. 27:495-498.

Urology 1986,

MARINO G, FERRI, SANTUCI A: Endothelin-1 in Diabetic and Non-Diabetic Men with Erectile Dysfunction. J Urol 1997, 158:1770-1774.

51. MIKHAILIDIS DP AND JEREMY JY: Smoking and Erectile Impotence. Int Angiology 1993, 12:297-298.

65. VARDI Y, SPRECHER E, KANTER Y, LIVNE PM, HEMLI JA, YARNITSKYD: Polyneuropathy in Impotence. Int J Imp Research 1996, 8:65-68.

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.

66. KOLLER WC, VETERE-OVERFIELD B, WILLIAMSON A, BUSENBARK K, NASH J, PARRISH D: Sexual Function in Parkinson’s Disease. Clin Neuropharmacol 1990, 13:461-463.

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.

55. GUAY A AND HEATLEY G: Cessation of Smoking Produces Rapid Improvement in Erectile Function. J Androl (21st Annual Meeting Program) 1996, Abst 68,p39.

70. STAERMAN F, GUIRAUD P, COEURDACIER P, MENARD D, EDAN G, LOBELB: Value of Nocturnal Penile Tumescence and Rigidity (NPTR) Recording in Impotence Patients with Multiple Sclerosis. Int J Imp Research 1996, 8:241-245.

56. GLINA S, REICHLET AC, PUECH LEAO P, MARCONDES DOS REIS JMS: Impact of Cigarette Smoking on Papaverine-Induced Erection. J Urol 1988, 140:523-524.

71. LILIUS HG, VALTONEN EJ, AND WIKSTROM J: Sexual Problems in Patients Suffering From Multiple Sclerosis. J Chron Dis 1976, 29:643-647.

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.

72. VAS CJ: Sexual Impotence and Some Autonomic Disturbances in Men with Multiple Sclerosis. Acta Neurol Scand 1969, 45:166-182.

59. HATZICHRISTOU DG, SEFTEL A, SAENZ DE TEJADA I: Sexual Dysfunction in Diabetes and Other Autonomic Neuropathies. In Singer C, and Weiner WJ (eds), “Sexual Dysfunction: A Neuro-Medical Approach” Armonk: Futura Publishing Company, 1994: 167198.

73.

BETTS CD, JONES SJ, FOWLER CG, FOWLER CJ: Erectile Dysfunction in Multiple Sclerosis. Associated Neurological Deficits, and Treatment of the Condition. Brain 1994, 117:1303-1310.

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.

79. FLETCHER EC, MARTIN RJ: Sexual Dysfunction and Erectile Impotence in Chronic Obstructive Pulmonary Disease. Chest 1982, 81:413-421.

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.

91. GOLDSTEIN I, FELDMAN MI, DECKERS PJ, BABAYAN RK, KRANE RJ: Radiation-Associated Impotence: A Clinical Study of its Mechanism. JAMA 1984, 251:903-910.

83. OAKS WWAND MOYER JH: Sex and Hypertension. Med Aspects Hum Sexual 1972, 6:128-137. 84. MULLER SC, EL DAMANHOURY H, RUTH J, LUE TF: Hypertension and Impotence. Eur Urol 1991, 19:2934.

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

85. LUNDBERG PO, BIRIELL C: Impotence – The Drug Risk Factor. Int J Imp Research 1993, 5:237-239.

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

86. MEINHARDT W, KROPMAN RF, VERMEIJ P, LYCKLAMA A NIJEHOLT AAB, ZWARTENDIJK J: The Influence of Medication on Erectile Function. Int J Imp Research 1997, 9:17-26.

94. DERBY CA, MOHR B, GOLDSTEIN I, FELDMAN HA, JOHANNES CB, MCKINLAY JB: Modifiable Risk Factors and Erectile Dysfunction: Can Life-Style Changes Modify Risk? J Urol (submitted)

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-

REFERENCES

63

1.

FELDMAN, H.A., GOLDSTEIN, I., HATZICHRISOU, D.G., et al: Impotence and its medical and psychological correlates: results of the Massachusetts male aging study. J. Urol., 151: 54, 1994.

2.

NIH Consensus Development Panel on Impotence.

Impotence. JAMA; 270:83-90, 1993. 3.

4.

11.

SLAG, M.F., MORLEY, J.E., ELSON, M.K., et al: Impotence in medical clinic outpatients. JAMA, 249:1736, 1983.

XI. ACKNOWLEDGEMENTS

MULLIGAN, T., RETCHIN, S.M., CHINCHILLI, V.M., & BETTINGER, C.B.: The role of aging and chronic disease in sexual dysfunction. JAGS, 36: 520524, 1988.

5.

SHABSIGH, R.: Editorial: Impotence on the rise as a urologic subspecialty. J. Urol., 155: 924-925, 1996.

6.

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.

MORELAND, R.B. Is There a Role of Hypoxema in Penile Fibrosis? Int. J Impotence Res. 10: 113-120, 1998.

11.

MUNARRIZ, R.M., YAN, Q.R., NEHRA, A., UDELSON, D. AND GOLDSTEIN, I. Blunt trauma: the pathophysiology of hemodynamic injury leading to erectile dysfunction. J. Urol. 153: 1831-1840, 1995.

12.

BENET, A.E. AND MELMAN, A. The epidemiology of erectile dysfunction. Urol. Clin. N. Am. 22: 699-709, 1995.

13.

HSU, G.-L., BROCK, G.B., MARTINEZ-PIÑEIRO, L., NUNES, L., VON HEYDEN, B. AND LUE, T.F. The three-dimensional structure of the tunica albuginea: anatomical and structural levels. Int. J. Impoten. Res. 4: 117-132, 1992.

14.

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.

15.

BROCK, G., HSU, G.-L., NUNES, L., VON HEYDEN, B. AND LUE, T.F. The anatomy of the tunica albuginea in the normal penis and in Peyronie’s disease. J. Urol. 157: 276-281, 1997.

16.

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.

17.

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: 437442, 1993.

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.

18.

7.

SATTAR, A.A., SALPIGIDES, G., VANDERHAEGHEN, J.J., SCHULMAN, C.C. AND WESPES, E. Cavernous oxygen tension and smooth muscle fibers: relation and function. J. Urol. 154:1736-1739, 1995.

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.

19.

8.

TARHAN F, KUYUMCUOGLU U, KOLSUZ A, ÖZGÜL A, CANGÜVEN Ö. Cavernous oxygen tension in patients with erectile dysfunction. Int. J. Impot. Res. 9: 149-153, 1997.

CHRIST, G.J. The penis as a vascular organ. The importance of corporal smooth muscle tone in the control of erection. Urol Clin North Am. 22 (4): 727, 1995.

20.

HEDLUND, H., ANDERSSON, K-E. Comparison of responses to drugs acting on adrenoceptors and muscarinic receptors in human isolated corpus cavrnosum and cavernous artery. J Auton Pharmacol. 5: 81, 1985.

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].

REFERENCES 1.

WESSELLS, H., LUE, T.F. AND MCANINCH, J.W. Penile length in the flaccid and erect states: guidelines for penile augmentation. J. Urol. 156: 995-997, 1996.

2.

SCHONFIELD, W.A. Primary and secondary sexual characteristics. Study of their development in males from birth through maturity with biometrtic study of penis and testes. Am. J. Dis. Child. 63: 535-549, 1943.

3.

ANDERSSON, K.-E. AND WAGNER, G. Physiology of erection. Physiol. Rev. 75: 191-236, 1995.

4.

SHETTY, S.D. AND FARAH, R.N., “Anatomy of erectile function.” in Textbook of Erectile Dysfunction, Carson, C.C.Kirby, R. and Goldstein, I., editors, (ISIS Medical Media, Oxford, 1999), pp25-30.

5.

NITAHARA, K.S. AND LUE, T.F., “Microscopic anatomy of the penis.” in Textbook of Erectile Dysfunction, Carson, C.C.Kirby, R. and Goldstein, I., editors, (ISIS Medical Media, Oxford, 1999), pp31-42.

6.

9.

NEHRA, A., GOLDSTEIN, I., PABBY, A., NUGENT, M., HUANG, Y.-H., DE LAS MORENAS, A., KRANE,

94

21. SAENZ DE TEJADA, I., KIM, N. LAGAN, I., KRANE, R. J., AND GOLDSTEIN, I. Modulation of adrenergic activity in penile corpus cavernosum. J Urol. 142: 1117, 1989.

33.

MONCADA, S. The L-arginine-nitric oxide pathway. The 1991 Ulf von Euler Lecture. Acta Physiol Scand. 145: 201, 1992.

34.

22. TRAISH AM, NETSUWAN N, DALEY JT, PADMANATHAN H, GOLDSTEIN I, SAENZ DE TEJADA I. A heterogeneous population of alpha 1 adrenergic receptors mediates contraction of human corpus cavernosum smooth muscle to norepinephrine. J. Urol: 153: 222, 1995.

MONCADA, S., PALMER, R.M.J., HIGGS, E.A. Biosynthesis of nitric oxide from L-arginine. Biochem Pharmacol. 38: 1709, 1989.

35.

23. SAENZ DE TEJADA I, MOROUKIAN P, TESSIER J, KIM JJ, GOLDSTEIN I, FROHRIB D. The trabecular smooth muscle modulates the capacitor function of the penis. Studies on a rabbit model. Am J Physiol 260 (Heart and Cir. Physiol 29): H1590, 1991.

IGNARRO, L.J., BUSH, P.A., BUGA, G.M., WOOD, K.S., FUKOTO, J.M. RAJFER, J. Nitric oxide and cyclic GMP formation upon electrical stimulation cause relaxation of corpus cavernosum smooth muscle. Biochem. Biophys. Res. Commun. 170: 843, 1990.

36.

KIM N, AZADZOI KM, GOLDSTEIN I, SAENZ DE TEJADA I. A nitric oxide-like factor mediates nonadrenergic noncholinergic neurogenic relaxation of penile smooth muscle. J Clin Invest, 88: 112, 1991.

37.

HOLMQUIST, F., ANDERSSON, K-E., HEDLUND, H. Characterization of inhibitory neurotransmission in the isolated corpus cavernosum from the rabbit and man. J Physiol. Lond. 449: 295, 1992.

38.

SIMONSEN U, PRIETO D, SAENZ DE TEJADA I, GARCIA-SACRISTAN A. Involvement of nitric oxide in non-adrenergic non-cholinergic neurotransmission of horse deep penile arteries: Role of charybdotoxin-sensitive K+-channels. Br J Pharmacol. 116, 2582, 1995.

26. INOUE K., YANAGISAWA M, KIMURA S, KASUYA Y, MIYAUCHI T, GOTO K, MASAKI T. The human endothelin family: three structurally and pharmacologically distict isopeptides predicted by three separate genes. Proc Natl Acad Sci USA. 86: 2863, 1989.

39.

BURNETT, A.L., TILLMAN, S.L., CHANG, T.S:K., EPSTEIN, J.I., LOWENSTEIN, C.J., BREDT, D.S., SNYDER, S.H., WALSH, P.C. Immunohistochemical localization of nitric oxide synthase in the autonomic innervation of the human penis. J Urol. 150: 73, 1993.

27. SAENZ DE TEJADA I, CARSON MP, DE LAS MORENAS A, GOLDSTEIN I, TRAISH AM. ENDOTHELIN: Localization, synthesis, activity and receptor types in the human penile corpus cavernosum. Am J Physiol 261(Heart Circ. Physiol. 30) H1078, 1991.

40.

KEAST, J.R. A possible neural source of nitric oxide in the rat penis. Neurosci Lett. 143: 69, 1992.

41.

28. HOLMQUIST F, ANDERSSON K-E, HEDLUND H. Actions of endothelin on isolated corpus cavernosum from rabbit and man. Acta Physiol Scand.139: 113, 1990.

HOLMQUIST, F., STIEF, C.G., JONAS, U., ANDERSSON, K-E. Effects of the nitric oxide synthase inhibitor NG-nitro-L-arginine on the erectile response to cavernous nerve stimulation in the rabbit. Acta Physiol. Scand. 143: 299, 1991.

42.

29. CHRIST, G.J. LERNER, S.E., KIM, D.C., MELMAN, A. Endothelin-1 as a putative modulator of erectile dysfunction: I. Characteristics of contraction of isolated corporal tissue strips. J Urol. 153: 1998, 1995.

BURNETT , A.L. LOWENSTEIN, C.J., BREDT, D.S., CHANG, T.S.K., SNYDER, S.H. Nitric oxide: a physiologic mediator of penile erection. Science. 257: 401, 1992.

43.

PORST, H. Prostaglandin E1 and the nitric oxide donor lisidomine for erectile failure: a diagnostic comparative study of 40 patients. J Urol. 149: 1280, 1993.

44.

WANG, R., DOMER, F.R., SIKKA, S.C., KADOWITZ, P.J., HELLSTROM, W.J.G. Nitric oxide mediates penile erectionin cats. J Urol. 151: 234, 1994.

45.

HELLSTROM, W.J.G., MONGA, M., WANG, R., DOMER, F.R., KADOWITZ, P.J., ROBERTS, J.A. Penile erection in the primate: induction with nitric oxide donors. J Urol. 151: 1723, 1994.

46.

LARSEN, J.J., OTTESEN, B., FAHRENKRUG, J., FAHRENKRUG, L., Vasoactive intestinal polypeptide (VIP) in the male genito-urinary tract, concentration and moter effect. Invest. Urol. 19: 211, 1981.

24. HATZICHRISTOU DG, SAENZ DE TEJADA I, KUPFERMAN S, NAMBURI S, PESCATORI ES, UDELSON D, GOLDSTEIN I. In vivo assessment of trabecular smooth muscle tone, its application in pharmacocavernosometry and analysis of intracavernous pressure determinants. J Urol, 153: 1126,1995. 25. FOURNIER, G.R., JUNEMANN, K-P., LUE, T.F., TANAGHO, E.A. Mechanisms of veno-occlusion during canine penile erection: An anatomic demonstration. J Urol. 137: 163, 1987.

30. CHRIST, G.J., MAAYANI, S., VALCIC, M., MELMAN, A. Pharmacological studies of human erectile tissue: Characteristic of spontaneous contractions and alteration in a-adrenoceptor responsiveness with age and disease in isolated tissues. Br J Pharmacol. 101: 375, 1990. 31. AZADZOI KM, KIM N, BROWN ML, GOLDSTEIN I, COHEN RA, SAENZ DE TEJADA I. Modulation of penile corpus cavernosum smooth muscle tone by endothelium-derived nitric oxide and cyclooxygenase products. J Urol, 147: 220, 1992. 32. MONCADA, S., PALMER, R.M.J., HIGGS, E.A. Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev. 43: 109, 1991.

95

DE TEJADA I. Prostanoid production in rabbit corpus cavernosum: I. Regulation by oxygen tension. J Urol 155: 1482, 1996.

47. LARSSON, L.I., FAHRENKRUG, J., SCHAFFALITZKY DE MUCKADELL, O.B. Ocurrence of nerves containing vasoactive intestinal polypeptide immunoreactivity in the male genital tract. Life Sci. 21: 503, 1977.

61.

ABICHT JH. TESTING THE AUTONOMIC SYSTEM. IN: JONAS U, THON WF, STIEF CG, editors. Erectile dysfunction. Berlin: Springer Verlag, 1991;187194.

62.

ABOSEIF S, SHINOHARA K, BORIRAKCHANYAVAT S, DEIRMENJIAN J, CARROLL PR. The effect of cryosurgical ablation of the prostate on erectile function. Br. J. Urol., 1997; 80:918-922.

50. EHMKE, H., JUNEMANN, K-P., MAYER, B.KUMMER, W.Nitric oxide synthase and vasoactive intestinal polypeptide colocalization in neurons innervating the human penile circulation. Int J Impotence Res. 7:147, 1995.

63.

CAETANO DB, FARIAS DS, DE AZEVEDO FILHO HC, SPINELLI C. Disturbances of sexual potency in patients with basilar impression and Arnold-Chiari malformation. J. Neurol. Neuros. & Psych., 1975;38:598600.

51. DHABUWALA, C.B., RAMAKRISHNA, C,V., ANDERSON, G.F. Beta adrenergic receptors in human cavernous tissue. J Urol. 133: 721, 1985.

64.

CAHN D, MELMAN A, VALCIC M, CHRIST GJ. FORSKOLIN - a promising new adjunct to intracavernous pharmacotherapy. J. Urol., 1996;155:1789-1794.

52. CARATI, C.J., GOLDIE, R.G., WARTON, A., HENRY, P.J., KEOGH, E.J. Pharmacology of the erectile tissue of the canine penis. Pharmacol. Res. Commun. 17: 951, 1985.

65.

CARRIER S, ZVARA P, NUNES L, KOUR NW, REHMAN J, LUE TF. Regeneration of nitric oxide synthasecontaining nerves after cavernous nerve neurotomy in the rat. J. Urol. 1995;153:1722-1727.

53. HEDLUND, H., ANDERSSON, K-E. Comparison of the responses to drugs acting on adrenoceptors and muscarinic receptors i human isolated corpus cavernosum and cavernous artery. J Autonomic Pharmacol. 5:81, 1985.

66.

CHRIST GJ, MELMAN A. The application of gene therapy to the treatment of erectile dysfunction. Int. J. Imp. Res., 1998;10:111-112.

67.

ADSAN O, OZTURK B, CETINKAYA M, KULACOGLU S, MEMIS A, GUNER E. The value of cavernous body biopsy in evaluating of impotent men. Archivio Italiano di Urologia, Andrologia, 1997; 69:151-153.

68.

ALI ST, SHAIKH RN, SIDDIQI A. HIV-1 associated neuropathies in males; impotence and penile electrodiagnosis. Acta Neurologica Belgica, 1994;94:194-199.

69.

AMELAR RD, DUBIN L. Impotence in the low-back syndrome. JAMA, 1971;216:520.

70.

AUTIERI MV, MELMAN A, CHRIST GJ. Identification of a down-regulated mRNA transcript in corpus cavernosum from diabetic patients with erectile dysfunction. Int. J. Imp. Res., 1996;8:69-73.

71.

BECK RO, BETTS CD, FOWLER CJ. Genitourinary dysfunction in multiple system atrophy: clinical features and treatment in 62 cases. J. Urol., 1994;151:13361341.

72.

BETTS CD, JONES SJ, FOWLER CG, FOWLER CJ. Erectile dysfunction in multiple sclerosis. Associated neurological and neurophysiological deficits, and treatment of the condition. Brain, 1994;117(Pt6):1303-10.

73.

BORS E, COMARR AE. Neurological Urology. University Park Press: Baltimore, 1971.

74.

BRIEN SE, HEATON JPW, ADAMS MA. Interactions between apomorphine and sildenafil: evidence for normalization of erections during hyperadrenergic stimulation. J. Urol., 1999;161:219 Abstract.

75.

COSTABILE RA, SPEVAK M, FISHMAN IJ,

48. HEDLUND, H., ANDERSSON, K-E. Effects of some peptides on isolated human penile erectile tissue and cavernous artery. Acta Physiol Scand. 124: 413, 1985. 49. OTTESEN, B., WAGNER, G., VIRAG, R, FAHRENKRUG, J. Penile erection: Possible role for vasoactive intestinal polypeptide as a neurotransmitter. Br. Med J, 288:9, 1984.

54. CHRIST, GJ. BRINK, PR., BROOK, S., NEY, P. PGE1induced alterations in maxi-K+-channel activity in cultured human corporal smooth muscle cells. J. Urol. 155: 678A (abstract# 1468), 1996. 55. GUPTA S, MORELAND RB, MUNARRIZ R, DALEY J, GOLDSTEIN I, SAENZ DE TEJADA I. Possible role of Na+-K+ ATPase in the regulation of human .corpus cavernosum smooth muscle contractility by nitric oxide. Br J Pharmacol. 116: 2201, 1995. 56. SAENZ DE TEJADA, I., BLANCO, R., GOLDSTEIN, I., AZADZOI, K., DE LAS MORENAS, A., KRANE, R.J. AND COHEN, R.A.: Cholinergic neurotransmission in human corpus cavernsosum. I. Responses of isolated tissue. Am J. Physiol. (Heart Circ. Physiol 23) H459, l988. 57. MORELAND RB, TRAISH A, MCMILLIN, SMITH B, GOLDSTEIN I, SAENZ DE TEJADA I. PG E1 suppresses the induction of collagen synthesis by transforming growth factor-ß1 in human corpus cavernosum smooth muscle. J. Urol : 153: 826, 1995. 58. MOLDERINGS, G.J., GOTHERT, M, VAN AHLEN, H., PORST, H. Modulation of noradrenaline release in human corpus cavernosum by presynaptic prostaglandin receptors. Int J Impotence Res. 4: 19, 1992. 59. SIMONSEN, ULF. Personal Communication 60. DALEY JT, BROWN ML, WATKINS MT, TRAISH AM, HUANG YUE-HUA, MORELAND RB, SAENZ

96

90.

AZADZOI, K.M., GOLDSTEIN, I., SIROKY, M.B., TRAISH, A.M., KRANE, R.J., SAENZ DE TEJADA, I. Mechanisms of ischaemia-induces cavernosal smooth muscle relaxation impairment in a rabbit model of vasculogenic erectile dysfunction. J. Urol. 160: 2216, 1998.

91.

AZADZOI, K. M., KRANE, R.J., SAENZ DE TEJADA, I., GOLDSTEIN, I., SIROKY, M.B. Relative roles of cyclooxygenase and nitric oxide synthase pathways in ischaemia-induced increased contraction of cavernosal smooth muscle. J. Urol. 161:1324, 1999.

92.

SUN, C-W., ALONSO-GALICIA, M., TAHERI, M.R., FALCK, J.R., HARDER, D.R., ROMAN, R.J. Nitric oxide-20-hydroxyeicosatetraenoic acid interaction in the regulation of K+ channel activity and vascular tone in renal arterioles. Circ. Res. 83:1069, 1998.

93.

SIMONSEN, U., EHRNROOTH, E., GERDES, L.U., FÆRGEMANN, O., BUCH, J., ANDREASEN, F., AND MULVANY, M.J. The functional properties in vitro of small arteries from rabbits fed an atherogenic diet for 12 weeks. Clin. Sci. 80:119, 1991.

94.

SIMONSEN, U., NYBORG, N.C.B., AND MULVANY, M.J. Is endothelial function in small arteries altered by hypercholesterolemia or atherosclerosis ? In Resistance arteries, structure and function. Ed. M.J. Mulvany et al. Elsevier Science Publishers; 1991: p. 329-332.

83. LERICHE, R. Des obliterations artérielles hautes comme cause dúne insuffisance circulatoire des membres inférieurs. Bull Soc. Chirurgie 49: 1404, 1923.

95.

84. FORSBERG, L., HEDERSTRÖM, E, OLSSON, A.M. Severe arterial insufficiency in impotence confirmed with an improved angiographic technique: The impact of smoking and some other etiologic factors. Eur. Urol. 16:357, 1989.

KUGIYAMA, K., KERNS, S.A., MORRISETT, J.D., ROBERTS, R. HENRY, P.D. Impairment of endothelium-dependent arterial relaxation by lysolecithin in modified low-density lipoproteins. Nature 344: 160, 1990.

96.

85. ROSEN, M.P., GREENFIELD, A.J., WALKER, T.G., GRANT, P., GUBEN, J.K., DUBROW, J., BETTMAN, M.A., GOLDSTEIN, I. Arteriogenic impotence: findings in 195 impotent men examined with selective internal pudendal angiography. Young investigators award. Radiology 174: 1043, 1990.

AHN, T.Y., COMEZ-CORONADO, D.G., MARTINEZ, V., CUEVAS, P., GOLDSTEIN, I., SAENZ DE TEJADA, I. Enhanced contractility of rabbit corpus cavernosum smooth muscle by oxidized low density lipoproteins. Int. J. Impot. Res. 11: 9, 1999.

97.

MORITA, R., MORIMOTO, S., KOH, E., FUKUO, K., KIM, S., ITOH, K., TANIGUCHI, K et al. Low density lipoprotein and apoprotein B induce increases in inositol triphosphate and cytosolic free calcium via pertussis toxin-sensitive GTP-binindg protein in vascular smooth muscle cells. Biochem. Internat. 18:647, 1989.

98.

AZADZOI, K.M., SAENZ DE TEJADA, I. Hypercholesterolemia impairs endothelium-dependent relaxation of rabbit corpus cavernosum smooth muscle. J. Urol. 146:238, 1991.

99.

KIM, S.C., KIM, I.K., SEO, K.K., BAEK, K.J., LEE, M.Y. Involvement of superoxide radical in the impaired endothelium-dependent relaxation of cavernous smooth muscle in hypercholesterolemic rabbits. Urol. Res. 25:341, 1997.

GOVIER FE, HELLSTROM WJ, SHABSIGN R, et al. Efficacy and safety of transurethral alprostadil in patients with erectile dysfunction following radical prostatectomy. J.Urol., 1998;160:1325-1328. 76. COURTOIS FJ, MACDOUGALL JC, SACHS BD. Erectile mechanism in paraplegia. Phys. Behav., 1993;53:721-726. 77. LUE, T.; Impotence after radical pelvic surgery: physiology and management. Urol. Int, 46: 259, 1991. 78. QUINLAN, D.M., EPSTEIN, J.I., CARTER, B.S., WALSH, P.C.: Sexual function following radical prostatectomy: influence of preservation of neurovascular bundles. J. Urol, 145: 998, 1991. 79. LEACH, G.E.: Potency evaluated after radical retropubic prostatectomy. Clin. Perp., 5: 1, 1992. 80. WABREK, A. J., BURCHELL, R. C.: Male sexual dysfunction associated with coronary artery disease. Arch. Sexual Behav., 9:69, 1980. 81. SHABSIGH, R., FISHMAN, I. J., SCHUM, C.: Cigarette smoking and other vascular risk factors in vasculogenic impotence. Urology, 39:227,1991. 82. RUBEN, A., BABBOTT, D.: Impotence in diabetes mellitus. JAMA, 168:498,1958.

86. KAUFMAN, J.M., HATZICHRISTOU, D.G., MULHALL, J.P., FITCH, W.P., GOLDSTEIN, I. Impotence and chronic renal failure: A study of the hemodynamic pathophysiology. J. Urol. 151: 612, 1994. 87. AZADZOI, K.M., GOLDSTEIN, I. Erectile dysfunction due to atherosclerotic vascular disease: the development of and animal model. J. Urol. 147:1675, 1992. 88. AZADZOI, K.M., GOLDSTEIN, I., SIROKY , M.B. Relationship between cavernosal ischaemia and corporal veno-occlusive dysfunction in an animal model. J. Urol. 157:1011, 1997.

100. VERBEUREN, T.J., JORDAENS, F.H., ZONNEKEYN, L.L., VANHOVE, C.E., COENS, M-C., HERMAN, A.G. Effect of hypercholesterolemia on vascular reactivity in the rabbit. I. Endothelium-dependent and endothelium-independent contractions and relaxations in isolated arteries of control and hypercholesterolemic rabbits. Circ. Res. 58:522, 1986.

89. NEHRA, A., AZADZOI, MORELAND, R.B., PABBY, A., SIRO´KY, M.B., KRANE, R.J., GOLDSTEIN, I., UDELSON, D. Cavernosal expandabillity is an erectile tissue mechanical property which predicts trabecular histology in an animal model of vasculogenic erectile dysfunction. J. Urol. 159:2229, 1998.

97

113. MCCULLOCH DK, CAMPBELL IW, WU FC, PRESCOTT RJ, Clarke BF. The prevalence of diabetic impotence. Diabetologia, 18: 279-283, 1980.

101. SIMONSEN, U., EHRNROOTH, E., PRIETO, D., GERDES, U., NYBORG, N.C.B. & MULVANY, M.J. Vascular responses of rabbit small arteries either exposed to 12 weeks high plasma cholesterol in vivo or low density lipoprotein in vitro are unchanged. Eur. J. Pharmacol. 183 (4):1330, 1990.

114. MCCULLOCH DK, YOUNG RJ, PRESCOTT RJ, CAMPBELL IW, CLARKE BF. The natural history of impotence in diabetic men. Diabetologia, 26: 437-440, 1984.

102. KIM, J.H., KLYACHKIN, M.L., SVENDSEN, E., DAVIES, M.G., HAGEN, P.O., CARSON, C.C. Experimental hypercholesterolemia in rabbits induces cavernosal atherosclerosis with endothelial and smooth muscle cell dysfunction. J. Urol. 151:198, 1994.

115. DUNSMUIR WD, HOLMES SAV. The aetiology and management of erectile, ejaculatory and fertility problems in men with daibetes mellitus. Diabetic medicine, 13:700-708, 1996.

103. JOHN, S., SCLAICH, M., LANGENFELD, M., WEIHPRECHT, H., SCHMITZ, G., WEIDINGER, G., SCHMIEDER, R.E. Increased bioavailability of nitric oxide after lipid-lowering therapy in hypercholesterolmic patients. A randomized, placebo-controlled, doubleblind study. Circulation 98:211, 1998.

116. HERMAN A, ADAR R, RUBINSTEIN Z. Vascular lesions associated with impotence in diabetic and nondiabetic arterial occlusive disease. Daibetes, 27: 975981, 1978. 117. KARACAN I, SALIS PJ, WARE JC, DERVENT B, WILLIAMS RL, SCOTT FB, ATTIA SL, BEUTLER LE. Nocturnal penile tumescence and diagnosis in diabetic impotence. Am J Psychiatry, 135: 191-196, 1978.

104. MACMAHON, S., CUTLER, J.A., FURBERG, C.D. et al. The effects of drug treatment for hypertension on morbidity and mortality from cardiovscular disease: a review of randomized controlled trials. Progr. Cardiovascl. Dis. 29(suppl. 1):99, 1986.

118. VIRAG R, BOUILLY P, FRYDMAN D. Is impotence an arterial disorder. Lancet, 1:181-184, 1985. 119. BEMELMANS BLH, MEULEMAN EJH, DOESBURG WH, NOTERMANS LH, DEBRUYNE FMJ. Erectile function in diabetic men: the neurological factor revisited. J Urol, 151: 884-889, 1994.

105. MULVANY, M.J. Peripheral vasculature in essential hypertension. Clin. Exp. Pharmacol. Physiol. 23 (suppl. 1): S6, 1996. 106. LÜSCHER, T.F.. Endothelial vasoactive substance and cardiovascular disease. S Karger Publisher AG, Basel, 1988, 1-1333.

120. WANG CJ, SHEN SY, WU CC, HUANG CH, CHIANG CP. Penile blood flow study in diabetic impotence. Urol Internat, 50: 209-212, 1993.

107. TADDEI, S., VIRDIS, A., GHIADONI, L., SALVETTI, A. Endothelial dysfunction in hypertension: Fact or fancy ? J. Cardiovascl. Pharmacol. 32(suppl. 3): S41, 1998.

121. MERSDORF A, GOLDSMITH PC, DIEDERICHS W, PADULA CA, LUE TF, FISHMAN IJ, TANAGHO EA, Ultrastructural changes in impotent penile tissue: a comparison of 65 patients. J Urol, 145: 749-758, 1991.

108. KELM, M., PREIK, M., HAFNER, D.J., STRAUER, B.E. Evidence for a multifactorial process involved in the impaired flow response to nitric oxide in hypertensive patients with endothelial dysfunction. Hypertension 27(part 1):346, 1996.

122. SAENZ DE TEJADA I, GOLDSTEIN I, AZADZOI K, KRANE RJ, COHEN RA. Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence. New Engl J Med, 320: 1025-1030, 1989.

109. DENG, L-Y, LI, J-S., SCHIFFRIN, E.L. Endotheliumdependent relaxation of small arteries from essential hypertensive patients: mechanisms and comparison with normotensive subjects and with responses of vessels from spontaneously hypertensive rats. Clin. Sci. 88:611, 1995.

123. PICKARD RS, KING P, ZAR MA, POWELL PH. Corpus cavernosal relaxation in impotent men. Br J Urol, 74: 485- 491, 1994. 124. KNISPEL HH, GOESSL C, BECKMANN R. Nitric oxide mediates relaxation in rabbit and human corpus cavernosum smooth muscle. Urol Res, 20: 253-257, 1992.

110. THYBO, N.K., MULVANY, M.J., JASTRUP, B., NIELSEN, H., AALKJAER, C. Some pharmacological and elastic characteristics of isolated subcutanous small arteries from patients with essential hypertension. J. Hyperten. 14: 993, 1996.

125. KNISPEL HH, GOESSL C, BECKMANN R. Effects of papaverine and prostaglandin E1 on corpus cavernosum smooth muscle of arteriogenically and diabetically impotent men. Europ Urol, 26: 35-39, 1994.

111. KOLDNY RC, KAHN CB, GOLDSTEIN HH, BARNETT DM. Sexual function in diabetic men. Diabetes, 23: 306-309, 1973.

126. PICKARD RS, POWELL PH, ZAR MA. Nitric oxide and cyclic GMP formation following relaxant nerve stimulation in isolated human corpus cavernosum. Br J Urol, 75: 516-522, 1995.

112. FELDMAN HA, GOLDSTEIN I, HATZICHRISTOU DG, KRANE RJ, MCKINLAY JB. Impotence and its medical and psychosocial correlates: results of the massachusetts male aging study. J Urol, 151: 54-61, 1994.

127. SEFTEL AD, VAZIN ND, NI Z, RAZMJOUEI K, FOGARTY J, HAMPEL N, POLAK J, WANG RZ,

98

FERGUSON K, BLOCK C, HAAS C. Advanced glycation end products in human penis: elevation in diabetic tissue, site of deposition and possible effect through iNOS or eNOS. Urology 50:1016-1026, 1997.

139. STEHOUWER CDA, LAMBERT J, DONKER AJM, VAN HINSBERGH VWM. Endothelial dysfunction and pathogenesis of diabetic angiopathy. Cardiovascular research, 34:55-68, 1997.

128. CHRIST GJ, SCHWARTZ CB, STONE BA, PARKER M, JANIS M, GONDRE M, VALCIC M, MELMAN A. Kinetic characteristics of ? 1-adrenergic contrcations in human corpus cavernosum smooth muscle. Am J Physiol, 263: H15-H19, 1992.

140. CINES DB, POLLAK ES, BUCK CA, LOSCALZO J, ZIMMERMAN GA, MCEVER RP, POBER JS, WICK TM, KONKLE BA, SCHWARTZ BS, BARNATHAN ES, MCCRAE KR, HUG BA, SCMIDT A-M, STERN DM. Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood, 91: 3527-3561, 1998.

129. MILLER MA, MORGAN RJ, THOMPSON CS, MIKHAILIDIS DP, JEREMY JY. Adenylate and guanylate cyclase activity in the penis and aorta of the diabetic rat: an in vitro study. Br J Urol, 74: 106-111, 1995.

141. SOBREVIA L, MANN GE. Dysfunction of the endothelial nitric oxide signalling pathway in diabetes and hyperglycaemia. Experimental Physiology, 82: 423452,1997.

130. JEREMY JY, THOMPSON CS, MIKHAILIDIS DP, DANDONA P. Experimental diabetes mellitus inhibits prostacyclin synthesis by the rat penis: pathological implications. Diabetologia, 28: 365-368, 1995.

142. TOOKE JE. Peripheral microvascular disease in diabetes. Diabetes research and clinical practice, 30 Suppl: S61-S65, 1996.

131. SULLIVAN ME, BELL CR, DASHWOOD MR, MILLER MA, THOMPSON CS, MIKHAILIDIS DP, MORGAN RJ. Autoradiographic localization of nitric oxide synthase binding sites in normal and diabetic rat corpus cavernosum. Europ Urol, 30: 506-511, 1996.

143. POSTON L, TAYLOR PD. Endothelium-mediated vascular function in insulin-dependent diabetes mellitus. Clinical Science, 88: 245-255, 1995. 144. TOOKE JE. Microvascular dysfunction in human diabetes. Diabetes, 44: 721-726, 1995.

132. ELABBADY AA, GAGNON C, HASSOUNA MM, BEGIN LR, ELHILALI MM. Diabetes mellitus increases nitric oxide synthase in penises but not in major pelvic ganglia of rats. Br J Urol, 76: 196202,1995.

145. CARSON, C.C.: Impotence and chronic renal failure. In: Impotence:: Diagnosis and management of erectile dysfunction. Eds:: A.H. Bennett. Philadelphia. W.B. Saunders Co., chapter 8, p: 124, 1994.

133. ABDEL-BAKY TM, HUYNH H, BEGIN LR, BROCK GB. Free radical scavengers and insulin improve erection in diabetic rats by regulating the expression of penile nitric oxide synthase. Internat J Impot Res, 10 (suppl 3): S19, 1998.

146. LUE, T.: Physiology of erection and pathophysiology of impotence. In: Campbell´s Urology. Sixth edition. Philadelphia: W.B. Saunders Co., chapter 16, p: 728, 1992. 147. LEONARD, P.L., NICKEL, C.J., MORALES, A.: Hyperprolactinemia and impotence: Why, when and how to investigate. J. Urol., 142: 992, 1989.

134. EL-SAKKA AI, LIN C-S, CHUI RM, DAHIYA R, LUE TF. Effects of diabetes on nitric oxide synthase and growth factor genes and protein expression in an animal model. Internat J Impot Res, 10 (suppl 3): S43, 1998.

148. STIEF, C.G., BAHREN, W., SCHERB, W. AND GALL, H. Primary erectile dysfunction. J. Urol. 141: 315319,1989.

135. SULLIVAN M, THOMPSON CS, MIKHAILIDES DP, MORGAN RJ, ANGELINI GD, JEREMY JY. Differential alterations of prostacyclin, cyclic AMP and cyclic GMP formation in the corpus cavernosum of the diabetic rabbit. Br J Urol, 82: 578-584, 1998.

149. ABOSEIF, S.R., BASKIN, L.S., YEN, T.S. AND LUE, T.F. Congenital defect in sinusoidal smooth muscles: a cause of organic impotence. J. Urol 148:58-60, 1992. 150. MONTAGUE, D.K., LAKIN, M.M., ANGERMEIER, K.W. AND LAMMERT, G.K. Primary erectile dysfunction in a man with congenital isolation of the corpora cavernosa. Urology 46:114-116, 1995.

136. 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 pathogenis of erectile dysfunction. J Urol, 158: 1966-1972, 1997.

151. MATTER, L.E., MAILEMARIAM, S., HUCH, R.A., HAURI, D. AND SULSER, T. Primary erectile dysfunction in combination with congenital malformation of the cavernous bodies. Urol. Int. 60:175-177,1998.

137. MINHAS S, EARDLEY I, MORRISON J. The effect of hyperglycaemia on corpus cavernosal and smooth muscle function. Proceedings of 2nd Meeting of European Society of Impotence Research, Madrid, Abstracts 63 and 68, 1997.

152. CHUBB, C. AND HENRY, L. Impotence induced by a single gene mutation. Biol. Reprod. 36:557-561, 1987. 153. JEREMY, J.Y. AND MIKHAILIDIS, D.P. Cigarette smoking and erectile dysfunction. J. R. Soc. Health 118:151-155,1998.

138. YILDIRIM S, AYAN S, SRAIOGLU Y, GULTEKIN Y, BUTUNER C. The effects of long-term oral administration of L-arginine on the erectile response of rabbits with alloxan-induced diabetes. Br J Urol, 83: 679-685, 1999.

154. ARAUJO AB, DURANTE R, FELDMAN HA, GOLDSTEIN I, MCKINLAY JB. The relationship between

99

JM, SIRGO MA, PLACHETKA JR. Comparative tolerability of labetalol versus propranolol, atenolol, pindolol, metoprolol, and nadolol. J Clin Hypertens 1986 Sep;2(3):285-93.

depressive symptoms and male erectile dysfunction: cross-sectional results from the Massachusetts Male Aging Study. Psychosom. Med. 60:458-465, 1998. 155. LAUMANN, E.O., PAIK, A. AND ROSEN, R.C. Sexual dysfunction in the United States. Prevalence and predictors. J.A.M.A. 281:537-544, 1999.

170. BROEKMAN CP, HAENSEL SM, VAN DE VEN LL, SLOB AK, Bisoprolol and hypertension: effects on sexual functioning in men. J Sex Marital Ther 1992 Winter;18(4):325-31.

156. SUTHERLAND, R.S., KOGAN, B.A., BASKIN, L.S., MEVORACH, R.A., CONTE, F., KAPLAN, S.L. AND GRUMBACH, M.M. The effect of prepubertal androgen exposure on adult penile length. J. Urol. 156:783787, 1996.

171. KAPLAN SA, REIS RB, KOHN IJ, SHABSIGH R, TE AE, Combination therapy using oral alpha-blockers and intracavernosal injection in men with erectile dysfunction. Urology 1998 Nov;52(5):739-43.

157. BASKIN, L.S., SUTHERLAND, R.S., DISANDRO, M.J., HAYWARD, S.W., LIPSCHULTZ, J. AND CUNHA, G.R. The effect of testosterone on androgen receptors and human penile growth. J. Urol. 158:11131118, 1997.

172. ABRAMOWICZ M. Drugs that can cause sexual dysfunction. Med.Lett. 1987;29:65-70.

158. MILLS T.M., REILLY C.M., LEWIS R.W. Androgens and penile erection: a review. J. Androl. 17:633-638, 1996.

174. ZORGNIOTTI AW, ROSSMAN B, CLAIRE M, Possible role of chronic use of nasal vasoconstrictors in impotence..Urology 1987 Dec;30(6):594.

159. BASKIN, H.J. Endocrinologic evaluation of impotence. South. Med. J. 82:446-449, 1989.

175. HOGAN, M.J., WALLIN, J.D., BAER, R.M. Antihypertensive therapy and male sexual dysfunction. Psychosomatics 1980; 21:234-237.

173. JARA J, MONCADA I, BUENO G, HERNANDEZ C. Intracavernous methoxamine in the treatment of priapism. Int J Impot Res 1998 Dec;10(4):257-9.

160. WORTSMAN, J., ROSNER, W. AND DUFAU, M.L. Abnormal testicular function in men with hypothyroidism. Am. J. Med. 82:207-212, 1987.

176. HONG CV, CHIANG BN, KU J Et al. Calcium antagonists stimulate sperm motility in ejaculated human semen. Br J Clin Pharmacol 1985;19:45-9.

161. MCNEIL, L.W., MCKEE, L.C., LORBER, D. AND RABIN, D. The endocrine manifestations of hemochromatosis. Am. J. Med. Sci. 285:7-13, 1983.

177. GRIMM RH JR, GRANDITS GA, PRINEAS RJ, MCDONALD RH, LEWIS CE, FLACK JM, YUNIS C, SVENDSEN K, LIEBSON PR, ELMER PJ. Long-term effects on sexual function of five antihypertensive drugs and nutritional hygienic treatment in hypertensive men and women. Treatment of Mild Hypertension Study. Hypertension 1997 Jan;29(1 Pt 1):8-14.

162. FRANKS, S., JACOBS, H.S., MARTIN, N. AND NABARRO, D. Hyperprolactinemia and impotence. Clin. Endocrinol. 8:277-287, 1978. 163. BULPITT CJ, BEEVERS DG, BUTLER A, COLES EC, HUNT D, MUNRO-FAURE AD, NEWSON RB, O'RIODAN PW, PETRIE JC, RAJAGOPALAN B, et al. The effects of anti-hypertensive drugs on sexual function in men and women: a report from the DHSS Hypertension Care Computing Project (DHCCP). J Hum Hypertens 1989 Feb;3(1):53-6.

178. ANDERSSON K-E. Clinical pharmacology of potassium channel openers. Pharmacol Toxicol 1992;70:24454. 179. GIRALDI A, WAGNER G. Effects of pinacidil upon penile erectile tissue, in vitro and in vivo. Pharmacol Toxicol 1990;67:235-8.

164. MCCARRON DA, Diuretic therapy for mild hypertension: the "real" cost of treatment. Am J Cardiol 1984 Jan 27;53(3):9A-11ª.

180. SULLIVAN G, LUKOFF D. Sexual side effects of antipsychotic medication: evaluation and interventions. Hosp Community Psychiatry 1990; 41 (11): 1238-41.

165. CHANG SW, FINE R, SIEGEL D, CHESNEY M, BLACK D, HULLEY SB, The impact of diuretic therapy on reported sexual function. Arch Intern Med 1991 Dec;151(12):2402-8.

181. SMITH PJ, TALBERT RL. Sexual dysfunction with antihypertensive and antipsychotic agents. Clin Pharm 1986;5:373-84. 182. SEGRAVES RT. Antidepressant-induced sexual dysfunction. J Clin Psychiatry 1998;59 Suppl 4:48-54.

166. CROOG, S.H. et al. Sexual symptoms in hypertensive patients. A clinical trial of antihypertensive medications. Archives of Internal Medicine. 1988.148:788-794.

183. MCWAINE DE, PROCCI WR. Drug-induced sexual dysfunction. Med Toxicol Adverse Drug Exp 1988;3:289-306.

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

100

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.

202. GUPTA S, SALIMPOUR P, SAENZ DE TEJADA I, DALEY J, GHOLAMI S, DALLER M, KRANE RJ,

216. LEVINE LA, GERBER GS. Acute vasospasm of penile

101

223. VALIMAKI M, SALASPURO M, HARKONEN M, YLIKAHRI R. Liver damage and sex hormones in chronic male alcoholics. Clin Endocrinol (Oxf) 1982; 17: 469-77.

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.

224. MIRIN SM, MEYER RE, MENDELSON JH, ELLINGBOE J. Opiate use and sexual function. Am J Psychiatry 1980;137:909-15.

218. MILLER NS, GOLD MS. The human sexual response and alcohol and drugs. J Subst Abuse Treatm 1988;5:171-7.

225. CICERO TJ, BELL RD, WIEST WG, ALLISON JH, POLAKOSKI K, ROBINS E. Function of the male sex organs in heroin and methadone users. N Engl J Med 1975;292:882-7.

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.

228. DEAMER RL, Thompson JF. The role of medications in geriatric sexual function. Clin Geriatr Med 1991;7:95111.

222. JENSEN SB, GLUUD C. Sexual dysfunction in men with alcoholic liver cirrhosis. A comparative study. Liver 1985;5:94-100.

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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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ponse. 1st ed Boston: Little, Brown & co 1966.

V. PSYCHOLOGICAL OR PSYCHIATRIC EVALUATION

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SPARK RF, WHITE RA, CONNOLLY PB. Impotence is not always psychogenic. JAMA1980;243:750-755.

11

BASKIN HJ. Endocrinologic evaluation of impotence. South Med J 1989;82:446-449.

12

LEONARD MP, NICKEL CJ, MORALES A. Hyperprolactinaemia and impotence. Why, when and how to investigate. J Urol 1989;142:142.

13

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.

REFERENCES 1

LUE TF: Impotence: A patient's goal directed approach to treatment. World J Urol 1990;8:67.

2

SPECKENS AEM, HENGEVELD MW, LYCKLAMA A NIJEHOLT, HEMERT VAN AM, HAWTON KE. Discrimination between psychogenic and organic erectile dysfunction J Psychsom Res 1993;37:135-145.

3

MCMAHON C. Isir satellite symposium 'Goal directed approach of erectile dysfunction'. World meeting on Impotence research, Amsterdam, august 24-28, 1998.

4

BANCROFT J. Assessing people with sexual problems. In: Human sexuality and its problems. Second edition. Churchill Livingstone, Edinburgh 1989, pp 412-455.

21

MORALES A, JOHNSTON B, HEATON JWP, CLARK A. Oral androgens in the treatment of hypogonadal impotent men. J Urol 1994;152:1115.

5

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. Urology 1997 ; 49:822-830.

22

HELL K, WERNZE H. Drug induced changes in prolactin secretion: clinical implications. Med Toxicol 1988;3:463-498.

23

GOVIER FE, MCCLURE RD, LEVIEN DK. Endocrine screening for sexual dysfunction using free testosterone determinations. J Urol 1996;156:405-408.

24

GREENBLATT RB, OETTINGER M, BOHLER CSS. Estrogen - androgen levels in ageing men and women: therapeutic considerations. J Am Geriatr Soc 1976;24:173.

25

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.

26

LUE TF, TANAGHO EA: Physiology of erection and pharmacological management of impotence. J Urol 1987;137:829.

6

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. Urology 1999;53:793-799.

7

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.

8

Diagnosis and treatment of Erectile Dysfunction: a step by step plan. ISBN 90-5139-119-6.

9

MASTERS WH, JOHNSON VE,In: Human Sexual res-

134

27

NIH Consensus Development Panel on Impotence. Jama. 1993;270(1):83-90.

28

PADMA NATHAN H, AZADZOI K. BLANCO R. Development of an animal model of atherosclerotic impotence. Surg Forum 1986;37:640.

29

QUERAL, LA, WHITEHOUSE, WMJR. FLINN WR. Pelvic hemodymics after aorto-iliac reconstruction. Surgery 1979;86:799.

30

WESPES E, SCHULMAN C: Venous impotence: Pathophysiology, diagnosis and treatment. J Urol 1993;149:1238.

31

CAMPOS DE CARVALHO AC, ROY C, MORENO AP, et al: Gap junction formed of connexin 43 are found between smooth muscle cells of human corpus cavernosum. J Urol 1993;149:1568.

32

MORENO AP, CAMPOS DE CARVALHO AC, CHRISTGJ,et al: Cap junctions between human corpus cavernosum smooth muscle cells: Gating properties and unitary conductance. Am J Physiol 1993;264:80.

33

CHRIST GJ, STONE B, MELMAN A: Age-dependent alternations in the efficacy of phenylephrine-induced contractions in vascular smooth muscle isolated from the corpus cavernosum of impotent men. Can J Physiol Pharmacol 199169:909.

42

CORMIO L, NISEN H, SELVAGGI FP, RUUTU M. A positive erection test does not rule out arteriogenic erectile dysfunction. J Urol 1996;156:1628-1630.

43

MONTAGUE DK, LAKIN MM: False diagnoses of venous leak impotence. J Urol 1992;148:148.

44

PESCATORI ES, HATZICHRISTOU DC, NAMBURI S, et al: A positive intracavernous injection test implies normal veno-occlusive but not necessarily normal arterial function: A hemodynamic study [see comments]. J Urol 1994;151:1209.

45

LEVINE FJ, GREENFIELD AJ, GOLDSTEIN I. Arteriographically determined occlusive disease within the hypogastric-cavernous bed in impotent patients following blunt perineal and pelvic trauma. J Urol 1990;144:1147-1153.

46

KRANE RJ, GOLDSTEIN I, SAENZ DE TEJADA I: Medical progress. Impotence. N Engl J Med 1989 ; 321:1648.

47

BENSON DF, SEFTEL AD, KRANE RJ, et al: The hemodynamic pathophysiology of impotence following blunt trauma to the erect penis. J Urol 1992;143:1171.

48

DONACUTTI CF, LUE TF. The combined intracavernous injection and stimulation test: Diagnostic accuracy. J Urol 1992;148:61.

34

SAENZ DE TEJADA I, GOLDSTEIN I, AZADZOI KM, et al: Impaired neurogenic and endotheliumdependent relaxation of human penile smooth muscle from diabetic men with impotence. N Engl J Med 1989; 320:1025.

49

ROWLAND DL,DEN OUDEN AH, SLOB AK The use of vobrotactile stimulation for determining sexual potency in the laboratory in men with erectile problems: methodological considerations. Int J Impotence Res 1994;6:153.

35

VANDER VEN PFM, WEI AY, JAP PHK, VANDERLEE HAL, DEBRUYNE FMJ, MEULEMAN EJH. Increased expression of a 68-kDa protein in the corpus cavernosum of some men with erectile dysfunction. J Androl 1995;16:242-247.

50

ROWLAND DL, SLOB AK: Vibrotactile stimulation enhances sexual response in sexually functional men: A study using concomitant measures of erection. Arch Sex Behav 1992;21:387.

51

VRUGGINK PA, DIEMONT WL, DEBRUYNE FM, MEULEMAN EJH. Enhanced pharmacological testing in patients with erectile dysfunction. J Androl 1995;16:163-168.

52

JANSSEN E, EVERAERD W, VAN LUNSEN RH, et al: Visual stimulation facilitates penile responses to vibration in men with and without erectile disorder. J Consult Clin Psychol 1994:62:1222.

53

LANIGAN D, ROOBOTTOM C, CHOA RG. A modified papaverine test and the use of venous constriction in erectile dysfunction. Int J impotence Res 1993;5:119.

54

BEMELMANS BL, MEULEMAN EJ, DOESBURG WH, et al: Erectile dysfunction in diabetic men: The neurological factor revisited. J Urol 1994;151:884.

55

KAUFMAN JM, HATZICHRISTOU DC, MULHALL JP, et al: Impotence and chronic renal failure: Astudy of the hemodynamic pathophysiology. J Urol 1994; 151 : 612.

56

WANG CJ, SHEN SY, WU CC, et al: Penile blood flow study in diabetic impotence. Urol Int 1993;50:209.

57

VIRAG R. Intracavernous injection of papaverine for erectile failure. Lancet 2 1982;938.

36

PERSSON C, DIEDERICHS W, LUE TF, et al: Correlation of altered penile ultrastructure with clinical arterial evaluation. J Urol 1989;142:1462.

37

HAYASHI K, TAKAMIZAMA K, NAKAMURA T, et al: Effects of elastase on the stiffness and elastic properties of arterial walls in cholesterol-fed rabbits. Atheroscierosis 1980;35:259.

38

MEULEMAN EJ, BEMELMANS BL, VAN ASTEN WN, et al: The value of combined papaverine testing and duplexscanning in men with erectile dysfunction. Int J Impotence Res 1990;2:87.

39

40

41

BEMELMANS BL, MEULEMAN EJ, DOESBURG WH, et al: Erectile dysfunction in diabetic men: The neurological factor revisited. J Urol 1994;151:884. KAUFMAN JM, HATZICHRISTOU DC, MULHALL JP, et al: Impotence and chronic renal failure: A study of the hemodynamic pathophysiology. J Urol 1994 ; 151 : 612. WANG CJ, SHEN SY, WU CC, et al: Penile blood flow study in diabetic impotence. Urol Int 1993;50:209.

135

58

WESPES E, DELCOUR C, RONDEUX C, et al: Erectile angle: objective criterion to evaluate the papaverine test in impotence. J Urol 1987;138:1171.

59

BUVAT J, BUVATHERBAUTM, DEHAENE JL, et al: Is intracavernous injection of papaverine a reliable screening test for vascular impotence? J Urol 1986;135:476.

60

MEULEMAN EJ, BEMELMANS BL, DOESBURG WH, et al: Penile pharmacological duplex ultrasonography: a dose-effect study comparing papaverine, papaverine/phentolamine and prostaglandin E1. J Urol 1992;148: 63.

61

LOMAS GM, JAROW JP: Risk factors for papaverineinduced priapism. J Urol 1994;147:1280.

62

PORST H: Diagnostic use and side-effects of vaso-active drugs: A report on over 2100 patients with erectile failure [abstract]. Int J Impotence Res 1990;2(suppl 2):222.

63

PORST H: Prostaglandin El and the nitric oxide donor linsidomine for erectile failure: A diagnostic comparative study of 40 patients. J Urol 1993;149:1280.

64

JÜNEMANN KP, ALKEN P: Pharmacotherapy of ED: A review. Int J Impot Res 1989;1:71.

65

LEE B, SIKKA S, RANDRUP ER, et al: Standardization of penile bloodflow parameters in normal men using intracavernous prostaglandin El and visual sexual stimulation. J Urol 1992;149:49.

66

67

68

NI G, MENCHINI FABRIS GF, RIGATTI P, PIZZINI G, MIANI A. Functional anatomy of cavernous helicine arterioles in potent subjects. J Urol 1998;158:808810. 73

SARTECHI LM, MONTORSI F, MENCHINI FABRIS F, GUAZZONI G, LENCIONI R, RIGATTI P. Cavernous arterial and arteriolar circulation in patients with erectile dysfunction: a power Doppler study. J Urol 1998;159:428-432.

74

CHIOU RK, ALBERTS GL, POMEROYBD, ANDRESON JC, CARLSON LK, ANDERSON JR, WOBIG RK. Study of cavernosal arterial anatomy using color and power Doppler sonography: impact on hemodynamic parameter measurement. J Urol 1999;162:358-360.

75

MELLINGER BC, FRIED JT, VAUGHN ED: Papaverine-induced penile blood flow acceleration in impotent men measured by duplexscanning. J Urol , 1990 ; 144 : 827.

76

KNISPEL HH, ANDRESEN R: Color-coded duplex sonography in impotence: significance of different flow parameters in patients and controls. Eur Urol 1992;21:22.

77

MEULEMAN EJ, BEMELMANS BL, VAN ASTEN WN, et al: Assessment of penile bloodflow by duplex ultrasonography in 44 men with normal erectile potency in different phases of erection. J Urol 1992;147:51.

78

BONGAERTS AH, DE KORTE PJ, DELAERE KP, et al: Erectile dysfunction: timing of spectral waveform analysis in the assessment of the function of the cavernosal arteries. Eur J Radiol 1992;15:140.

MONTORSI F, GUAZZONI G, BARBIERI L, FERINI-STRAMBI L, IANNACCONE S, CALORI G, NAVA L, RIGATTI P, PIZZINI G, MIANI A. genital plus adiovisual sexual stimulation following intracavernous vasoactive injection versus re-dosing for erectile dysfunction - results of a prospective study. J Urol 1998;159:113-115.

79

BRODERICK GA, ARGER PA. Penile bloodflow study: age specific reference ranges. J Urol 1994 ; 151 (5) :a371.

80

MONTORSI F, GUAZZONI G, CESTARI A, RIGATTI P. The role of audiovisual sexual stimulation in the evaluation of the impotent man. In: Erectile Dysfunction. Issues in current Pharmacotherapy. Ed: Morales A. Martin Dunitz Editors. London, 1998.

KROPMAN RF, SCHIPPER J, VAN OOSTAYEN JA , et al: The value of increased end diastolic velocity during penile duplex sonography in relation to pathological venous leakage in erectile dysfunction. J Urol 1992;148:314.

81

BRODERICK GA, ARGER P. Doppler ultrasonography: noninvasive assessment of penile anatomy and function. Sem Roentgen 1993;28:43.

MERCKX LA, DE BRUYNE RM, GOES E, et al: The value of dynamic color duplex scanning in the diagnosis of venogenic impotence. J Urol 1992;148:318.

82

PETROU S, LEWIS RW: Management of corporal venoocclusive dysfunction. Urol Int 1992;49:48.

69

VALJI K, BOOKSTEIN JJ: Diagnosis of arteriogenic impotence: Efficacy of duplex sonography as a screening tool. AJR Am J Roentgenol 1993;160:65.

83

70

BENSON CB, ARUNY JE, VICKERS MAJ: Correlation of duplex sonography with arteriography in patients with erectile dysfunction. Am J Roentgenol 1993;160:71.

SAENZ DE TEJADA I, MOROUKIAN P, TESSIER J, et al: Trabecular smooth muscle modulates the capacitor function of the penis. Studies on a rabbit model. Am J Physiol 1991;260:1590.

84

HATZICHRISTOU DG, SAENZ DE TEJADAI, KUPFERMAN S et al. In vivo assessment of trabecular smooth muscle tone, its application in pharmacocavernosometry and analysis of intracavernous pressure determinants. J urol 1995;153:1126-1135.

85

UDELSON D, HATZICHRISTOU D, SAENZ DE TEJADA I, et al: A new methodology of pharmacocavernosometry which enables hemodynamic analysis

71

72

LUE TF, HRICAK H, MARICH KW, et al: Vasculogenic impotence evaluated by high-resolution ultrasonography and pulsed Doppler analysis. Radiology 1985;155:777. MONTORSI F, SARTESCHI M, MAGA T, GUAZZO-

136

under conditions of known corporal smooth muscle relaxation. Int J Impotence Res 1994;6(suppl l):A17.

function. Issues in current pharmacotherapy. Ed: Morales A.Martin Dunitz LTd 1998, London.

86

MEULEMAN EJH, DIEMONT WL. Investigation of erectile dysfunction. Urol Clin N America 1995;22(4):803-819.

101

RIGISCAN:Ambulatory Rigidity and tumescence system document No 750-156-0486. Dacomed Corporation, Minneapolis, Minnesota.

87

GINESTIE JF, ROMIEUX A: Radiological exploration of impotence. The Hague, Martinus Nijhoff Medical Division, 1978.

102

88

GOLDSTEIN I, KRANE RJ, GREENFIELD AJ, et al: Vascular diseases of the penis: Impotence and priapism. In Pollack HM (ed): Clinical Urography, Philadelphia, WB Saunders, 1989, p 2231.

ALLEN RP, SMOLEVJK, ENGELRM, et al. Comparison of Rigiscan and formal nocturnal penile tumescence testing in the evaluation of erectile rigidity. J Urol 1993;149:1265-8.

103

HATZICHRISTOU DG, HATZIMOURATIDIS K, IOANNIDES E, YANNAKOYORGOS K, DIMITRIADIS G, KALINDERIS A. Nocturnal penile tumescence and rigidity monitoring in young potent volunteers: reproducibility, evaluation criteria and the effect of sexual intercourse. j urol 1998;159:19211926.

89

WAHL SI, RUBIN MB, BAKAL CW. Radiologic evaluation of penile arterial anatomy in arteriogenic impotence. Int J Impotence Res 1997;9:93-97.

90

LEVINE FJ, GOLDSTEIN I: Vascular reconstructive surgery in the management of erectile dysfunction. Int J Impot Res 1990;2:59.

104

91

YEH SH, LIU RS, CHEN KK, et al: Diagnosis of venous leakage by 133Xe corporeal clearance after intravenous injection of prostaglandin El in poorly responding patients. Nucl Med Commun 1992;13:28.

MEULEMAN EJH, LYCKLAMA A NIJEHOLT AAG, SLOB A et al. Effects of IC351 on erectile response to visual sexual stimulation. J Urol 1999;161:212 (abstract 814).

105

DIEMONTWL, MEULEMAN EJH. Neurological testing in erectile dysfunction. J Androl 1997;18:345-350.

106

FOWLER CJ. The neurology of male sexual dysfunction and its investigation by clinical neurophysiological methods. Br J urol 1998;81:785-795.

107

ANDERSSON KE, WAGNER G. Physiology of penile erection. Physiol Rev 1995;75:191-236.

108

GIULIANO FA, RAMPIN 0, BENOIT G, JARDIN A. Neural control of penile erection. Urol Clin North Am 1995;22:747-766.

109

VODUSEK DB, RAVNIK OBLAK M, BLAK C. Pudendal versus limb nerve electrophysiological abnormalities in diabetics with erectile dysfunction. Int J Impotence Res 1993;5:37-42.

110

VARDI Y, YARNITSKY D, SIMRI W, HONIGMAN S, HEMLI J. Bulbocavernosus reflex reflex latency evaluation of diabetic impotence. Int J Impotence Res 1992;4:175-178.

111

BEMELMANS BLH, MEULEMAN EJH, ANTEN BWM, DOESBURG WH, VAN KERREBROECK PEVA, DEBRUYNE FMJ. Penile sensory disorders in erectile dysfunction. Results of a comprehensive neuro-urophysiological diagnostic work-up in 123 patients. J urol 1991;146:777-782.

112

BREDA G, XAUSA D, GUINTA A, TAMAI A, SILVESTRE P, GHERARDI L. Nomogram for penile biothesiometry. Eur Urol 1991;20:67-69.

113

PADMA NATHAN, LEVINE F. Vibratory testing of the penis (abstract). J Urol 1987;137:201A.

114

BEMELMANS BL, HENDRIKX LB, KOLDEWIJN EL, LEMMENS WA, DEBRUYNE FMJ, MEULEMAN EJH. Comparison of biothesiometry and neurourophysiological investigations for the clinical evaluation of patients with erectile dysfunction. J Urol 1995;153:1483-1486.

92

ZUCKIER LS, STROBEr MD: Nuclear medicine in problems of fertility and impotence. Semin Nucl Med 1992;22:122.

93

GRECH P, DAVE S, CUNNINGHAM DA, et al: Combined papaverine test and radionuclide penis blood flow in impotence: method and preliminary results. Br J Urol 1992;69:408.

94

SIRAJ QH, BOMANJI J, AHMED M: The effect of intracavernosal haemodilution on the radionuclide quantification of penile vascular changes during pharmacologically induced penile erections. Nucl Med Commun 1992;13:547.

95

MIRALDI F, NELSON AD, JONES WT, et al: A dual radioisotope technique for the evaluation of penile blood flow during tumescence [see comments]. J Nucl Med 1992;33:41.

96

KARACAN I, HURCH CJ, WILLIAMS RL. Some characteristics of nocturnal penile tumescence in elderly males. J Gerontol 1972;27:39.

97

GIESBERS AA, BRUINS JL, KRAMER AE, et al: New methods in the diagnosis of impotence: Rigiscan penile tumescence and rigidity monitoring and diagnostic papaverine hydrochloride injection. World J Urol 1987;5:173.

98

SCHIAVI RC, SCHREINER-ENGEL P, MANDELI J, SCHANZER H, COHEN E. Healthy ageing and male sexual function. Amer J Psychchiatr 1990;147:766.

99

SCHIAVI RC: The role of the sleep laboratory in the evaluation of male erectile dysfunction. Mt Sinai J Med 1994;61:161.

100

EL-SAKKAAI, LUE TF .A rational approach to investigation of sexually dysfunctional man.In: Erectile dys-

137

115

BRAVENBOER B, VAN DAM PS, HOP J, VD STEENHOVEN J, ERKELENS DW. Thermal thresholt testing for the assessment of small fibre dysfunction: normal values and reproducibility. Diabet Med 1992;9:546-549.

116

LOW P. Evaluation and management of clinical autonomic disorders. Boston: Little Brown. 1993.

117

CAMPESE VM, PROCEI VR, LEVITAN D, ROMOFF MS, GOLDSTEIN DA, MASSRY SG. Autonomous nervous system dysfunction and impotence in uremia. Am J Nephrol 1982;2:140-143.

118

119

BUVAT J, LEMAIRE A. Endocrine screening in 1,022 men with erectile dyfunction : Clinical significance and cost-effective strategy. J. Urol. 1997; 158:17641767.

129

BASKIN HJ. Endocrinologic evaluation of impotence. South Med. J. 1989; 82:446-449. ABOSEIF SR, LUE TF. Hemodynamics of penile erection. Urol Clin. North. Am. 1988; 15: 1-7.

131

STIEF CG, DJAMILIAN M, ANTON P, DEREISE W, ALTHOFF EP, JONAS U. Single potential analysis of cavernous electrical activity in impotent patients: a possible diagnostic method for autonomic cavernous dysfunction and cavernous smooth muscle degeneration. J Urol 1991;146:771-776.

BRODERICK GA, LUE TF. The penile bloodflow study : evaluation of vasculogenic impotence in: JONAS U, THON WF, STIEF CG. Erectile dysfunction. Berlin, Heidelberg, New York, Springer Verlag, 1991.

132

SHABSIGH R, FISHMAN IJ, SHOTTLAND Y et al. Comparison of penile duplex ultrasonography with nocturnal penile tumescence monitoring for the evaluation of erectile impotence. J. Urol. 1990; 143-924.

133

BENSON CB, VICKERS MA. Sexual impotence caused by vascular disease : diagnosis with duplex sonography. AJR 1989; 153:1149.

134

QUAM JP, KING BFR, JAMES EM et al.Duplex and color doppler sonographic evaluation of vasculogenic impotence. AJR 1989; 153:1141.

135

TRUSS M, DJAMILIAN M, TAN H et al. Single potential analysis of cavernous electrical activity. Four years experience in more than 500 patients with erectile dysfunction. Eur Urol 1993;24:358-365.

MCMAHON CG, KALEY J. Correlation of duplex ultrasonography, PBI, DICC and angiography in the diagnosis of impotence. Int. J. Impotence Res.1994; 6(1) : A322.

136

ERTEKIN C, ERTEKIN N, MUTLU S, ALMIS A, AKCAM A. Skin potentials recorded from the extremities and genital region in normal and impotent subjects. Acta Neurol Scand 1987;76:28-36.

NARODA T, YAMANAKA M, MATSUSHITA K et al. Evaluation of resistance index in the cavernous artery with color doppler ultrasonography for venogenic impotence. Int. J. Impotence Res. 1994; 6 (1): D62.

137

ERTEKIN C, ALMIS S, ERTEKIN N. Sympathetic skin potentials and bulbocavernosus reflex in patients with chronic alcoholism and impotence. Eur Neurol 1990;30:334-337.

O’CARROLLR, SHAPIROC, BANCROFT J. Androgens, behavior and nocturnal erections in hypogonadal men: The effect of varying the replacement dose.Clin Endocrinol 1985; 23: 527-37

138

RUBIN HB, HENSON DE, FALVO RE, HIGH RW. The relationship between men’s endogenous levels of testosterine and their penile responses to erotic stimuli. Behav Res Ther 1979; 17:305-12

139

LANGE JD, BROWN WA, WINCZE J, ZWICK W. Serum testosterone concentration and penile tumescence changes in men. Horm. Bech 1980; 14:267-70.

121

YARNITSKY D, SPRECHER E, BARILAN Y, VARDI Y. Corpus cavernosum electromyogram: spontaneous and evoked electric activities. J Urol 1995;153:653-654.

124

128

130

MERCKX L, DE ZBRUYNE R, KEUPPENS F. Electromyography of cavernous smooth muscle during flaccidity: evaluation of technique and normal values. Br J Urol 1993;72:353-358.

123

SHABSIGH R, KLEIN LT, SEIDMAN S, KAPLAN SA, LEHRHOFF BJ, RITTER JS. Increased incidence of depressive symptoms in men with erectile dysfunction. Urology 1998;52 :848-852.

WAGNER G, GERSTENBERG T, LEVIN RJ. Electric activity of the corpus cavernosum during flaccidity and erection of the human penis: a neew diagnostic method? J Urol 1989;142:723-725.

120

122

127

125

Mc CULLOCH DK, CAMPBELLIW, WU FC, PRESCOTT RJ. The prevalence of diabetic impotence. Diabetologia. 1980; 18:11; 279-283.

126

MEULEMAN EJH, VAN BERKEL JTHH, RABSZTYN P, DAMEN L, SILDENAFIN (Viagra) voor de behandeling van erectiestoornissen. Ned Tijdschr Geneeskkd 1998; 142:2337-41.

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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.

1.

VIRAG, R.: Intracavernous injection of papaverine for erectile failure, Lancet ii: 938, 1982.

2.

STEERS, W.D.: Neural control of penile erection. Semin. Urol. 8: 866, 1990.

3.

DE GROAT, W.C. AND BOOTH, A.M.: Neural control of penile erection. In: The Autonomic Nervous System. Vol. 6, Chapter 13, Nervous Control of the Urogenital System, edited by C A Maggi, Harwood Academic Publishers, London, UK, p465, 1993.

4.

ANDERSSON, K.-E, AND WAGNER, G.: Physiology of penile erection. Physiol. Rev. 75: 191, 1995.

5.

ARGIOLAS, A. AND MELIS M.R.: Neuromodulation of penile erection: an overview of the role of neurotransmitters and neuropeptides. Prog. Neurobiol. 47: 235, 1995.

6.

GIULIANO, F.A. RAMPIN, O., BENOIT, G. AND JARDIN, A.: Neural control of penile erection, Urol. Clin. North Am. 22:747, 1995.

7.

ANDERSSON, K.-E.: Pharmacology of lower urinary tract smooth muscles and penile erectile tissues. Pharmacol. Rev. 45: 254, 1993.

8.

GIULIANO, F.A., RAMPIN, O., BENOIT, G. AND JARDIN A.: The peripheral pharmacology of erection, Progres en Urologie 7:24, 1997.

9.

SACHS, B.D. AND BARFIELD, R.J.: Functional analysis of masculine copulatory behavior in the rat. In : Advances in the study of behavior, vol. 7. Academic Press, New-York. p.91, 1976

10. MEISEL, R.L. AND SACHS, B.D.: The physiology of male sexual behavior. In: The Physiology of Reproduction. Edited by E. Knobil and J. Neill. New-York: Raven Press, 2nd edition. Chapt. 35, pp.3, 1994. 11. HART, B.L.: Hormones, spinal reflexes and sexual behaviour. In: Hutchinson JB. ed. Biological determinants of sexual behaviour. Chichester: John Wiley & Sons. Chapt. 10, p.319, 1978. 12. SACHS, B.D., AKASOFU. K., CITRON, J.H., DANIELS, S.B., NATOLI, J.H.: Noncontact stimulation from estrous females evokes penile erection in rats. Physiol. Behav. 55. 1073, 1994. 13. SACHS, B.D.: Erection evoked in male rats by airborne scent from estrous females. Physiol. Behav. 62: 921, 1997. 14. ARGIOLAS, A. AND MELIS, M.R.: 1995. Neuromo dulation of penile erection : an overview of the role of neurotransmitters and neuropeptides. Prog. Neurobiol. 47: 235, 1995. 15. MELIS, M.R. AND ARGIOLAS, A.: Dopamine and sexual behavior. Neurosci. Biobehav. Rev. 19: 19, 1995. 16. BARALDI, M., BENASSI-BENELLI, A. AND LOLLI,

184

M.: Penile erection in rats after fenfluramine administration. Riv. Farmacol. Ther. 8: 375, 1977.

30. BECKETT, S.D., HUDSON, S., WALKER, D.F., REYNOLDS, T.M. AND VACHON, R.I.: Blood pressures and penile muscle activity in the stallion during coitus. Am. J. Physiol. 225: 1072, 1973.

17. BENASSI-BENELLI, A., FERRARI, F. AND PELLEGRINI QUARANTOTTI, B.: Penile erection induced by apomorphine and N-n-propyl-norapomorphine in rats. Arch. Int. Pharmacodyn. Ther. 241: 128, 1979.

31. PUROHIT, R.C. AND BECKETT, S.D.: Penile pressures and muscle activity associated with erection and ejaculation in the dog. Am. J. Physiol. 231: 1343, 1976.

18. BERENDSEN, H.H.G., JENCK, F. AND BROEKKAMP, C.L.E.: Involvement of 5-HT1C receptors in drug-induced penile erections in rats. Psychopharmacology 101: 57, 1990.

32. SACHS, B.D.: Role of striated penile muscles in penile reflexes, copulation, and induction of pregnancy in the rat. J. Reprod. Fertil. 66: 433, 1982.

19. GOWER, A.J., BERENDSEN, H.H.G., PRONCEN, M.M. AND BROEKKAMP, C.L.E.: The yawning-penile erection syndrome as a model for putative dopamine autoreceptor activity. Eur. J Pharmacol. 103: 81, 1984.

33. HART, B.L. AND MELESE-D'HOSPITAL, P.Y.: Penile mechanisms and the role of the striated penile muscles in penile reflexes, Physiol. Behav. 31: 807, 1983.

20. MAEDA, N., MATSUOKA, N. AND YAMAGUCHI, I.: Septohippocampal cholinergic pathway and penile erections induced by dopaminergic and cholinergic stimulants. Brain Res. 537: 163, 1990.

34. HOLMES, G.M, CHAPPLE, W.D., LEIPHEIMER, R.E. AND SACHS, B.D.: Electromyographic analysis of male rat perineal muscles during copulation and reflexive erections. Physiol. Behav. 49: 1235, 1991.

21. MAEDA, N., MATSUOKA, N. AND YAMAGUCHI, I.: Possible involvement of the septo-hippocampal cholinergic and raphe-hippocampal serotonergic activations in the penile erection induced by fenfluramine in rats. Brain Res. 652: 181, 1994.

35. SCHMIDT, M.H., VALATX, J.L., SAKAI, K., DEBILLY, G. AND JOUVET, M.: Corpus spongiosum penis pressure and perineal muscle activity during reflexive erections in the rat. Am. J. Physiol. 269: R904, 1995.

22. SZELE, F.G., MURPHY, D.L. AND GARRICK, N.A.: Effects of fenfluramine, m-chlorophenylpiperazine, and other serotonin-related agonists and antagonists on penile erection in non-human primates. Life Sci. 43: 1297, 1988.

36. BERNABÉ, J., RAMPIN, O., SACHS, B.D. AND GIULIANO, F.: Intracavernous pressure during erection in rats: an integrative approach based on telemetric recording. Am. J. Physiol. 276: R441, 1999. 37. MELIS, M.R., SUCCU, S., MAURI, A. AND ARGIOLAS, A.: Nitric oxide production is increased in the paraventricular nucleus of the hypothalamus of male rats during non-contact penile erections and copulation. Eur. J. Neurosci. 10: 1968, 1998.

23. MILLAN, M.J., PEGLION, J.L., LAVIELLE, G. AND PERRIN-MONNEYRON, S.: 5-HT2C receptors mediate penile erections in rats : actions of novel and selective agonists and antagonists. Eur. J. Pharmacol. 325: 9, 1997.

38. ROUSSEL, B., PUJOL, J.F. AND JOUVET, M.:Effects of lesions in the pontine tegmentum on the sleep stages in the rat. Arch. Ital.Biol. 114: 188, 1976.

24. DUA, S. AND MCLEAN, P.D.: Localization for penile erection in medial frontal lobe. Am J Physiol. 207: 1425, 1964.

39. SACHS, B.D. AND GARINELLO, L.D.: Hypothetical pacemaker regulating penile reflexes in rats: evidence from transection of spinal cord and dorsal penile nerves. J. Comp. Physiol. Psychol. 94: 530, 1980.

25. MACLEAN, P.D. AND PLOOG, D.W.: Cerebral representation of penile erection. J. Neurophysiol. 25: 29, 1962.

40. MARSON, L., LIST, M.S. AND MCKENNA, K.E.: Lesions of the nucleus paragigantocellularis alter ex copula penile reflexes. Brain Res. 592: 187 1992.

26. MACLEAN, P.D., DENNISTON, R.H. AND DUA, S.: Further studies on cerebral representation of penile erection: caudal thalamus, midbrain, and pons. J. Neurophysiol. 26: 273, 1963.

41. MARSON, L. AND MCKENNA, K.E.: A role for 5hydroxytryptamine in descending inhibition of spinal sexual reflexes. Exp. Brain Res. 88: 313, 1992.

27. COURTOIS, F.J. AND MACDOUGALL, J.C.: Higher CNS control of penile responses in rats: The effect of hypothalamic stimulation. Physiol. Behav. 44: 165, 1988.

42. MATSUMOTO, T., KONDO, Y., SACHS, B.D. AND YAMANOUCHI, K.: Effects of p-chlorophenylalanine on reflexive and noncontact penile erections in male rats. Physiol. Behav. 61: 165, 1997.

28. HUSTON, J.:Yawning and penile erection induced in rats by cortical spreading depression. Nature 232: 274, 1971.

43. KONDO, Y., SACHS, B.D. AND SAKUMA, Y.: Importance of the medial amygdala in rat penile erection evoked by remote stimuli from estrous females. Behav. Brain. Res. 91: 215, 1998.

29. KURTZ, R.G. AND SANTOS, R.: Supraspinal influences on the penile reflexes of the male rat: a comparison of the effects of copulation, spinal transection and cortical spreading depression. Horm. Behav. 12: 73, 1979.

44. LIU, Y.C., SACHS, B.D. AND SALAMONE, J.D.: Sexual behavior in male rats after radiofrequency or

185

dopamine-depleting lesions in nucleus accumbens. Pharmacol. Biochem. Behav. 60: 585, 1998.

58. HONDA, C.N.: Visceral and somatic afferent convergence onto neurons near the central canal in the sacral spinal cord of the cat. J. Neurophysiol. 53: 1059, 1985.

45. LIU, Y.C., SALAMONE, J.D. AND SACHS, B.D.: Lesions in medial preoptic area and bed nucleus of stria terminalis : differential effects on copulatory behavior and noncontact erection in male rats. J. Neurosci. 17: 5245, 1997.

59. JOHNSON, R.D.: Physiology of single spinal cord sensory neurons responding to penile stimulation in the rat. Soc. Neurosci. Abstr. 15: 756, 1989 60. RAMPIN, O., GOUGIS, S., GIULIANO, F. AND ROUSSEAU, J.P.: Spinal Fos labeling and penile erection elicited by stimulation of the dorsal nerve of the penis in the rat. Am. J. Physiol. 272: R1425, 1997.

46. LIU, Y.C., SALAMONE, J.D. AND SACHS, B.D.: Impaired sexual response after lesions of the paraventricular nucleus of the hypothalamus in male rats. Behav. Neurosci. 111: 1361, 1997.

61. NUNEZ, R., GROSS, G.H. AND SACHS, B.D.: Origin and projections of rat dorsal penile nerve: possible direct projections to autonomic and somatic neurons by primary afferents of nonmuscle origin, J. Comp. Neurol. 247: 417, 1986.

47. DAIL, W.G., WALTON, G. AND OLMSTED, M.P.: Penile erection in the rat: stimulation of the hypogastric nerve elicits increases in penile pressure after chronic interruption of the sacral parasympathetic outflow, J. Auton. Nerv. Syst. 28: 251, 1989.

62. HUBSCHER, C.H. AND JOHNSON, R.D.: Responses of medullary reticular formation neurons to input from the male genitalia. J. Neurophysiol 76: 2474, 1996.

48. BECKETT, S.D., REYNOLDS, T.M., HUDSON, R.S. AND HOLLEY, R.S.: Serial angiography of the crus penis of the goat during erection. Biol. Reprod. 7: 365, 1972.

63. MALLICK, H.N., MANCHANDA, S.K. AND MOHAN KUMAR, V.: Sensory modulation of the medial preoptic area neuronal activity by dorsal penile nerve stimulation in rats, J. Urol. 151: 759, 1994.

49. CARATI, C.J., CREED, K.E. AND KEOGH, E.J.: Vascular changes during penile erection in the dog. J. Physiol. 400: 75, 1988.

64. YANAGIMOTO, M., HONDA, K., GOTO, Y. AND NEGORO, H.: Afferents originating from the dorsal penile nerve excite oxytocin cells in the hypothalamic paraventricular nucleus of the rat. Brain Res. 733: 292, 1995.

50. ANDERSSON, P.O., BLOOM, S.R. AND MELLANDER, S.: Haemodynamics of pelvic nerve induced penile erection in the dog: possible mediation by vasoactive intestinal polypeptide. J. Physiol. 350: 209, 1984. 51. LUE, T.F., TAKAMURA, T., SCHMIDT, R.A., PALUBINKAS, A.J. and Tanagho, E.A.: Hemodynamics of erection in the monkey, J. Urol. 130: 1237, 1983.

65. CHEN, K.K., CHAN, J.Y.H., CHANG, L.S., CHEN, M.T. AND CHAN, S.H.H.: Elicitation of penile erection following activation of the hippocampal formation in the rat. Neurosci. Lett. 141: 218, 1992.

52. LUE, T.F., TAKAMURA, T., UMRAIYA, M., SCHMIDT, R.A. AND TANAGHO, E.A.: Hemodynamics of canine corpora cavernosa during erection. Urology 24: 347, 1984.

66. CHEN, K.K., CHAN, S.H., CHANG, L.S. AND CHAN, J.Y.: Participation of paraventricular nucleus of hypothalamus in central regulation of penile erection in the rat. J. Urol. 158: 238, 1997.

53. AZADZOI, K.M., VLACHIOTIS, J., PONTARI, M. AND SIROKY, M.B.: Hemodynamics of penile erection: III. Measurement of deep intracavernosal ansd subtunical blood flow and oxygen tension. J. Urol. 153: 521, 1995.

67. MARSON, L. AND MCKENNA, K.E.: Stimulation of the hypothalamus initiates the urethrogenital reflex in male rats. Brain Res. 638: 103, 1994.

54. STEERS, W.D., MALLORY, B. AND DEGROAT, W.C.: Electrophysiological study of neural activity in penile nerve of the rat, Am. J. Physiol. 254: R989, 1988.

68. GIULIANO, F., BERNABÉ, J., BROWN, K., DROUPY, S., BENOIT, G. AND RAMPIN, O.: Erectile response to hypothalamic stimulation in rats : role of peripheral nerves. Am. J. Physiol. 273, R1990, 1997.

55. MCKENNA, K.E. AND NADELHAFT, I.: The pudendo-pudendal reflex in male and female rats. J. Autonom. Nerv. Syst. 27: 67, 1989.

69. ANDERSSON, K.-E. AND STIEF, C.G.: Neurotransmission and the contraction and relaxation of penile erectile tissues. World J. Urol. 15: 14, 1997.

56. PESCATORI, E.S., CALABRO, A., ARTIBANI, W., PAGANO, F., TRIBAN, C. AND ITALIANO, G.: Electrical stimulation of the dorsal nerve of the penis evokes reflex tonic erections of the penile body and reflex ejaculatory responses in the spinal rat, J. Urol. 149: 627, 1993.

70. SCHRODER, H.D.: Organization of the motoneurons innervating the pelvic muscles of the male rat, J. Comp. Neurol. 192: 567, 1980. 71. MCKENNA, K.E. AND NADELHAFT, I.: The organization of the pudendal nerve in the male and female rat, J. Comp. Neurol. 248: 532, 1986.

57. RAMPIN, O., GIULIANO, F., DOMPEYR, P. AND ROUSSEAU, J.P.: Physiological evidence of neural pathways involved in reflexogenic penile erection in the rat. Neurosci. Lett. 180: 138, 1994.

72. CARD, J.P.: Alpha herpesvirus replication and assembly in the rodent CNS. In: Viral vectors, Tools for the analysis and genetic manipulation of the nervous sys-

186

tem. Eds Kaplitt MG and Loewy AD. Academic Press, Orlando, p. 319, 1995.

85. 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, 1992.

73. UGOLINI, G.: Transneuronal tracing with alpha-herpesviruses: a review of the methodology. In: Viral vectors, Tools for the analysis and genetic manipulation of the nervous system. Eds Kaplitt MG and Loewy AD. Academic Press, Orlando, p. 319, 1995.

86. MAGEE, T., FUENTES, A.M., GARBAN, H., RAJAVASHISTH, T., MARQUEZ, D., RODRIGUEZ, J.A., RAJFER, J. AND GONZALEZ-CADAVID, N.: Cloning of a novel neuronal nitric oxide synthase expressed in penis and lower urinary tract. Biochem. Biophys. Res. Comm. 226: 145, 1996.

74. MARSON, L., PLATT, K.B. AND MCKENNA, K.E.: Central nervous system innervation of the penis as revealed by the transneuronal transport of pseudorabies virus. Neuroscience 55: 263, 1993.

87. GARBAN, H., VERNET, D., FREEDMAN, A., RAJFER, J. AND GONZALEZ-CADAVID, N.: Effect of aging on nitric oxide-mediated penile erection in rats. Am. J. Physiol. 268: H467, 1995a.

75. MARSON, L. AND MCKENNA, K.E.: CNS cell groups involved in the control of the ischiocavernosus and bulbospongiosus muscles: a transneuronal tracing study using pseudorabies virus. J. Comp. Neurol. 374: 161, 1996.

88. GARBAN, H., MARQUEZ, D., CAI, L., RAJFER, J. AND GONZALEZ-CADAVID, N.: 1995b. Restoration of normal adult penile erectile response in aged rats by long-term treatment with androgens. Biol. Reprod. 53: 1365, 1995b.

76. SJÖSTRAND, N.O. AND KLINGE, E.: Nitric oxide and the neural regulation of the penis. In : Nitric oxide in the nervous system. Academic Press, N.Y. Chapt.13, p. 281, 1995.

89. VERNET, D., CAI, L., GARBAN, H., BABBITT, M.L., MURRAY, F.T., RAJFER, J. AND GONZALEZCADAVID, N.F.: Reduction of penile nitric oxide synthase in diabetic BB/WORdp [Type I] and BBZ/WORdp [Type II] rats with erectile dysfunction. Endocrinology 136: 5709, 1995.

77. BOWMAN, A. AND GILLESPIE, J.S.: Neurogenic vasodilatation in isolated bovine and canine penile arteries. J. Physiol. 341: 603, 1983. 78. GILLESPIE, J.S., LIU, X. AND MARTIN, W.: The neurotransmitter of the non-adrenergic non-cholinergic inhibitory nerves to smooth muscle of the genital system. In: Nitric oxide from L-arginine: a bioregulatory system. S. Moncada and E.A. Higgs eds. Elsevier Science Publishers, Amsterdam. Chapt 17, p.147, 1990.

90. GIULIANO, F., RAMPIN, O. AND MCKENNA, K.E.: Animal models used in the study of erectile dysfunction. In: Textbook of erectile dysfunction. Eds Carson CC, Kirby RS, Goldstein I. ISIS Medical Media, Oxford. Chapter 5, p.43, 1999.

79. IGNARRO, L.J., BUSH, P.A., BUGA, G.M., WOOD, K.S., FUKOTO, J.M. AND RAJFER, J.: Nitric oxide and cyclic GMPformation upon electrical field stimulation cause relaxation of corpus cavernosum smooth muscle. Biochem. Biophys. Res. Commun. 170: 843, 1990.

91. HART, B.L., HAUGEN, C.M. AND PETERSON, D.M.: Effects of medial preoptic –anterior thalamic lesions on mating behavior of male cats. Brain Res. 54: 177, 1973. 92. PERACHIO, A.A., MARR, L.D. AND ALEXANDER, M.: Sexual behavior in male rhesus monkeys elicited by electrical stimulation of the preoptic and hypothalamic areas. Brain Res. 177: 127, 1979.

80. HOLMQUIST, F., HEDLUND, H. AND ANDERSSON, K.-E.: L-NG-nitroarginine inhibits non-adrenergic, non- cholinergic relaxation of human isolated corpus cavernosum. Acta Physiol. Scand. 141: 441, 1991.

93. MALSBURY, C.W. : Facilitation of male rat copulatory behavior by electrical stimulation of the medial preoptic area. Physiol. Behav. 7: 797, 1971.

81. HOLMQUIST, F., HEDLUND, H. AND ANDERSSON KE.: Characterization of inhibitory neurotransmission in the isolated corpus cavernosum from rabbit and man. J. Physiol. 449: 295, 1992.

94. MERARI, A AND GINTON, A. : Characteristics of exaggerated sexual behavior induced by electrical stimulation of the medical preoptic area in the male rats. Brain Res. 86: 97, 1975.

82. KIM, N.N., AZADZOI, K.M., GOLDSTEIN, I. AND SAENZ DE TEJADA, I.: A nitric oxide-like factor mediates nonadrenergic noncholinergic neurogenic relaxation of penile corpus cavernosum smooth muscle. J. Clin. Invest. 88: 112, 1991.

95. MACLEAN, P.D AND PLOOG, D.W. : Cerebral representation of penile erection. J. Neurophysiol. 25: 29, 1962.

83. KNISPEL, H.H., GOESSL, C. AND BECKMAN, R.: Basal and acetylcholine stimulated nitric oxide formation mediates relaxation of rabbit cavernous smooth muscle. J. Urol. 146: 1429, 1991.

96. MELIS, M.R., ARGIOLAS, A. AND GESSA, G.L. : Oxytocin-induced penile erection and yawning: site of action in the brain. Brain Res. 398: 259, 1986.

84. KNISPEL, H.H., GOESSL, C. AND BECKMAN, R.: Nitric oxide mediates neurogenic relaxation induced in rabbit cavernous smooth muscle by electric field stimulation. Urology 40: 471, 1992.

97. ARGIOLAS, A., MELIS, M.R., MAURI, A. AND GESSA, G.L. : Paraventricular nucleus lesion prevents yawning and penile erection induced by apomorphine and oxytocin, but not ACTH. Brain Res. 421: 349, 1987.

187

98. CHEN, K.K., CHAN, S.H.H., CHANG, L.S. AND CHAN, J.Y.H. : Participation of paraventricular nucleus of hypothalamus in central regulation of penile erection in the rat. J. Urol. 158: 238, 1997.

113. SAPER, C.B., LOEWY, A.D., SWANSON, L.W. AND COWAN, W.M. : Direct hypothalamo-autonomic connections. Brain Res. 117: 305, 1976. 114. HOSOYA, T. : The distribution of spinal projection neurons in the hypothalamus of the rat, studied with the HRP method. Exp. Brain Res. 40: 79, 1980.

99. CHEN, K.K., CHAN, J.Y.H., CHANG, L.S., CHEN, M.T. AND CHAN, S.H.H. : Elicitation of penile erection following activation of the hippocampal formation in the rat. Neurosci. Lett. 141: 218, 1992.

115. LUITEN, P.G.M., TER HORST, G.J., KARST, H. AND STEFFENS, A.B. : The course of paraventricular hypothalamic efferents to autonomic structures in medulla and spinal cord. Brain Res. 329: 374, 1985.

100. MELIS, M.R., STANCAMPIANO, R. AND ARGIOLAS, A. : Hippocampal oxytocin mediates apomorphine-induced penile erection and yawning. Pharmacol. Biochem. Behav. 42: 61, 1992.

116. SWANSON, L.W. : An autoradiographic study of the efferent connections of the preoptic region in the rat. J. Comp. Neurol. 167: 227, 1976.

101. KLUVER, H. AND BUCY, P.C. : Preliminary analysis of the functions of the temporal lobes in monkeys. Arch. Neurol. Psychiat. 42: 979, 1939.

117. COLLINS, W.F. III, ERICHSEN, J.T. AND ROSE, R.D. : Pudendal motor and premotor neurons in the male rat: A WGA transneuronal study. J. Comp. Neurol. 308: 28, 1991.

102. TERZIAN, H. AND ORE, G.D. : Syndrome of Kluver and Bucy reproduced in man by bilateral removal of the temporal lobes. Neurology 5: 373, 1955.

118. MARSON, L., PLATT, K.B. AND MCKENNA, K.E. : CNS innervation of the penis as revealed by the transneuronal transport of pseudorabies virus. Neuroscience 55: 263, 1993.

103. MARSON, L. AND MCKENNA, K.E. : The identification of a brainstem site controlling spinal sexual reflexes in male rats. Brain Res. 515: 303, 1990. 104. YELLS, D.P., HENDRICKS, S.E. AND PRENDERGAST, M.A. : Lesions of the nucleus paragigantocellularis: Effects on mating behavior in male rats. Brain Res. 596: 73, 1992.

119. KUYPERS, H.G.J.M. AND UGOLINI, G. : Viruses as transneuronal tracers. TINS 13: 71, 1990.

105. MARSON, L., LIST, M.S. AND MCKENNA, K.E. : Lesions of the nucleus paragigantocellularis alter ex copula penile reflexes. Brain Res. 592: 187, 1992.

120. BAUM, M.J. AND EVERITT, B.J. : Increased expression of c-fs in the medial preoptic area after mating in male rats: Role of afferent inputs from the medial amygdala and midbrain central tegmental field. Neuroscience 50: 627, 1992.

106. SWANSON, L.W. AND SAWCHENKO, P.E. : Paraventricular nucleus: a site for the integration of neuroendocrine and autonomic mechanisms. Neuroendocrinology 31: 410, 1980.

121. RAMPIN, O., GOUGIS, S., GIULIANO, F. AND ROUSSEAU, J.P. : Spinal Fos labeling and penile erection elicited by stimulation of dorsal nerve of the rat penis. Am. J. Physiol. 272: R1425, 1997.

107. WAGNER, C.K. AND CLEMENS, L.G. : Projections of the paraventricular nucleus of the hypothalamus to the sexually dimorphic lumbosacral region of the spinal cord. Brain Res. 539: 254, 1991.

122. BITRAN, D. AND HULL, E.M. : Pharmacological analysis of male rat sexual behavior. Neurosci. Biobehav. Rev. 11: 365, 1987. 123. STEINBUSCH, H.: Distribution of serotonin-immunoreactivity in the central nervous system of the ratcell bodies and terminals. Neuroscience. 6: 557, 1981.

108. WAGNER, C.K., SISK, C.L. AND CLEMENS, L.G. : Neurons in the paraventricular nucleus of the hypothalamus that project to the sexually dimorphic lower lumbar spinal cord concentrate 3H-estradiol in the male rat. J. Neuroendocrinol. 5: 545, 1993.

124. FISCHETTE, C.T., B. NOCK AND RENNER, K.: Effects of 5,7-dihydroxytryptamine on serotonin 1 and 2 receptors throughout the rat central nervous system using quantitative autoradiography. Brain Res. 421: 263, 1987.

109. SACHS, B.D. : Role of striated penile muscles in penile reflexes, copulation, and induction of pregnancy in the rat. J. Reprod. Fertil. 66: 433, 1982.

125. MONROE, P.J. AND SMITH, D.J.: Characterization of multiple 5-[3H]hydroxytryptamine binding sites in the rat spinal cord tissue. J. Neurochem. 41: 349, 1983.

110. SCHMIDT, M.H., SCHMIDT, H.S. : The ischiocavernosus and bulbospongiosus muscles in mammalian penile rigidity. Sleep 16: 171, 1993. 111. DE GROAT, W.C. AND STEERS, W.D. : Neuroanatomy and neurophysiology of penile erection. In: Contemporary Management of Impotence and Infertility. Edited by EA Tanagho, TF Lue, RD McClure. Baltimore: Williams & Wilkins, p 3, 1988.

126. TANG, Y., RAMPIN, O., CALAS, A., FACCHINET TI, P. AND GIULIANO, F.: Oxytocinergic and serotonergic innervation of identified lumbosacral nuclei controlling penile erection in the male rat. Neuroscience 82: 241, 1998.

112. GIULIANO, F., RAMPIN, O., BERNABE, J. AND ROUSSEAU, J.P. : Neural control of penile erection in the rat. J. Auton. Nerv. Syst. 55: 36, 1995.

127. KONDO, Y., YAMANOUCHI, K. AND ARAI, Y.: pChlorophenylalanine facilitates copulatory behavior in

188

septal lesioned but not in preoptic lesioned male rats. J. Neuroendocrinol. 5: 629, 1993.

141. HAWTHORN, J., ANG, V.TAND J.S. JENKINS, J.S.: Effects of lesions in the hypothalamic paraventricular, supraoptic and suprachiasmatic nuclei on vasopressin and oxytocin in rat brain and spinal cord. Brain Res. 346: 51, 1985.

128. MCINTOSH, T.K. AND BARFIELD, R.J.: Brain monoaminergic control of male reproductive behavior. I. Serotonin and the postejaculatory period. Behav. Brain Res. 12: 255, 1984.

142. SKAGERBERG, G., BJÖRKLUND, A., LINDVALL, O. AND SCHMIDT, R.H.: Origin and termination of the diencephalo-spinal dopamine system in the rat. Brain Res. Bull. 9: 237, 1982.

129. AHLENIUS, S., LARSSON, K., SVENSSON, L., HJORTH, S., CARLSSON, A., LINDBERG, P., WIKSTRÖM, H. AND SANCHEZ, D.: Effects of a new type of 5-HT receptor agonist on male rat sexual behavior. Pharmacol. Biochem. Behav. 15: 785, 1981.

143. SKAGERBERG,G. AND LINDVALL, O.: Organization of diencephalic dopamine neurons projecting to the spinal cord of the rat. Brain Res. 342: 340, 1985.

130. SVENSSON, L. AND HANSEN, S.: Spinal monoaminergic modulation of masculine copulatory behavior in the rat. Brain Res. 302: 315, 1984.

144. PEHEK, E.A., THOMPSON, J.T., EATON, R.C. AND HULL, E.M. : Apomorphine and haloperidol, but not domperidone, affect penile responses in rats. Pharmacol. Biochem. Behav. 31: 201, 1988.

131. MELIS, M.R. AND ARGIOLAS, A.: Role of central nitric oxide in the control of penile erection and yawning. Prog. Neuropsychopharmacol. Biol. Psychiatry. 21: 899, 1997.

145. BAZZETT, T.J., EATON, R,C., THOMPSON, J.T., MARKOWSKI, V.P., LUMLEY, L.A. AND HULL, E.M.: Dose dependent D2 effects on genital reflexes after MPOA injections of quinelorane and apomorphine. Life Sci. 48: 2309, 1991.

132. BENASSI-BENELLI, A., FERRARI, F. AND PELLEGRINI QUARRANTOTTI, B.: Penile erection induced by apomorphine and N-n-propyl-norapomorphine in rats. Arch. Int. Pharmacodyn. 242: 241, 1979.

146. WARNER, R.K., THOMPSON, J.T., MARKOWSKI, V.P., LOUCKS, J.A., BAZZETT, T.J., EATON, R,C. AND HULL, E.M.: Microinjection of the dopamine antagonist cis-flupenthixol into the MPOA impairs copulation, penile reflexes and sexual motivation in male rats. Brain Res. 540: 177, 1991.

133. BJÖRKLUND, A., LINDVALL, O. AND NOBIN, A.: Evidence of an incertohypothalamic dopamine neuron system in the rat. Brain Res. 89: 29, 1975. 134. HULL, E.M., EATON, R.C., MARKOWSKI, V.P., MOSES, J., LUMLEY, L.A. AND LOUCKS, J.A.: Opposite influence of medial preoptic D1 and D2 receptors on genital reflexes: implications for copulation. Life Sci. 51: 1705, 1992.

147. PEHEK, E.A., THOMPSON, J.T. AND HULL., E.M.: The effects of intrathecal administration of the dopamine agonist apomorphine on penile reflexes and copulation in the male rat. Psychopharmacology. 99: 304, 1989.

135. MELIS, M.R., ARGIOLAS, A. AND GESSA, G.L.: Apomorphine-induced penile erection and yawning: site of action in the brain. Brain Res. 415: 98, 1987.

148. PEHEK, E.A., THOMPSON, J.T. AND HULL, E.M.: The effects of intracranial administration of the dopamine agonist apomorphine on penile reflexes and seminal emission in the rat. Brain Res. 500: 325, 1989.

136. BUIJS, R.M.: Intra- and extrahypothalamic vasopressin and oxytocin pathways in the rat. Cell Tissue Res. 192: 423, 1992.

149. CLARK, J.T.: Central alpha-2-adrenoceptors modulate male rat sexual activity (Abstract). Endocrinology 122 Suppl.: 315, 1988 150. CLARK, J.T., SMITH, E.R. AND DAVIDSON, J.M.: Evidence for the modulation of sexual behavior by alpha-adrenoceptors in male rats. Neuroendocrinology. 41: 36, 1985. 151. BURNETT, A.L.: Oral pharmacotherapy for erectile dysfunction: current perspectives. Urology 54: 392, 1999. 152. MELIS, M.R., STANCAMPIANO, R. AND ARGIOLAS, A.: Penile erection and yawning induced by paraventricular NMDA injection in male rats are mediated by oxytocin. Pharmac. Biochem. Behav. 48: 203, 1994.

137. LINDVALL, O., BJÖRKLUND, A. AND SKAGERBERG, G.: Selective histochemical demonstation of dopamine terminal systems in rat di- and telencephalon: new evidence for dopaminergic innervation of hypothalamic neurosecretory nuclei. Brain Res. 306: 19, 1984. 138. ARGIOLAS, A., MELIS, M.R. AND GESSA, G.L.: d(CH2)5Tyr(Me)-Orn8-vasotocin, a potent oxytocin antagonist, antagonizes penile erection and yawning induced by oxytocin and apomorphine, but not by ACTH (1-24). Eur. J. Pharmacol. 134: 221, 1987a. 139. MELIS, M.R., ARGIOLAS, A. AND GESSA, G.L.: Evidence that apomorphine induces penile erection and yawning by releasing oxytocin in the central nervous system. Eur. J. Pharmacol. 164: 565, 1989.

153. ARGIOLAS, A.: Nitric oxide is a central mediator of penile erection. Neuropharmacology. 33: 1339, 1994. 154. MELIS, M.R., STANCAMPIANO, R. AND ARGIOLAS, A.: Nitric oxide synthase inhibitors prevent Nmethyl-D-aspartic acid-induced penile erection and yawning in male rats. Neurosci. Lett. 179: 9, 1994.

140. LANG, R.E., HEIL, J., GANTEN, D., HERMAN, K., RASCHER, W. AND UNGER, TH.: Effect of lesions in the paraventricular nucleus of the hypothalamus on vasopressin and oxytocin content in the brainstem and spinal cord of rat. Brain Res. 260: 326, 1983

189

155. MELIS, M.R., SUCCU, S., IANNUCCI, U. AND ARGIOLAS, A.: N-methyl-D-aspartic acid-induced penile erection and yawning: role of hypothalamic paraventricular nitric oxide. Eur. J. Pharmacol. 328: 115, 1997.

and oxytocin, but not ACTH 1-24. Brain Res. 421: 349, 1987. 169. THEODOSIS, D.T.: Oxytocin-immunoreactive terminals synapse on oxytocinergic neurons in the supraoptic nuclei. Nature (Lond.) 313: 682, 1985.

156. SNYDER, S.H.: Nitric oxide: First in a new class of neuro-transmitters? Science. 257: 494, 1992.

170. ARGIOLAS, A., MELIS, M.R., STANCAMPIANO, R. AND GESSA, G.L.: Oxytocin-induced penile erection and yawning: role of calcium and prostaglandins. Pharmacol. Biochem. Behav. 35: 601, 1990.

157. SUCCU, S., SPANO, M.S., MELIS, M.R. AND ARGIOLAS, A.: Different effects of omega-conotoxin on penile erection, yawning and paraventricular nitric oxide in male rats. Eur. J. Pharmacol. 359: 19, 1998.

171. STANCAMPIANO, R., MELIS, M.R. AND ARGIOLAS, A.: Apomorphine- and oxytocin-induced penile erection and yawning in male rats: effect of pertussis toxin. Brain Res. Bull. 28: 315, 1992.

158. ELEKES, I., PATTHY, T., LANG, T. AND PALKOVITS, M.: Concentrations of GABA and glycine in discrete brain nuclei. Stress-induced changes in the levels of inhibitory amino acids. Neuropharmacology. 25: 703, 1986.

172. MELIS, M.R. AND ARGIOLAS, A.: Nitric oxide synthase inhibitors prevent apomorphine- and oxytocininduced penile erection and yawning in male rats. Brain Res. Bull. 32: 71, 1993.

159. BOWERY, N.G., HUDSON, A.L. AND PRICE, G.W.: GABAA and GABAB receptor site distribution in the rat cental nervous system. Neuroscience. 20: 365, 1987.

173. MELIS, M.R., STANCAMPIANO, R. AND ARGIOLAS, A.: Prevention by NG-nitro-L-arginine methyl ester or apomorphine- and oxytocin-induced penile erection and yawning: site of action in the brain. Pharmacol. Biochem. Behav. 48: 799, 1994.

160. Magoul,R., Oteniente, B., Geffard, M. and Calas, A.: Anatomical distribuion and ultrastructural organization of the GABAergic system in the rat spinal cord. An immunocytochemical study using anti-GABA antibodies. Neuroscience. 20: 1001, 1987.

174. YANAGIMOTO, M., HONDA, K., GOTO, Y. AND NEGORO, H.: Afferents originating from the dorsal penile nerve excite oxytocin cells in the hypothalamic paraventricular nucleus of the rat. Brain Res. 733: 292, 1996.

161. FERNANDEZ-GUASTI, A., LARSSON, K. AND BEYER, C.: GABAergic control of masculine sexual behavior. Pharmacol Biochem. Behav. 24: 1065, 1986.

175. BERTOLINI, A., GESSA, G.L. AND FERRARI, W.: Penile erection and ejaculation: A central effect of ACTH-like peptides in mammals. In: Sexual Behavior - Pharmacology and Biochemistry, edited by M. Sand ler and G.L. Gessa. New York: Raven Press, p. 247, 1975.

162. FERNANDEZ-GUASTI, A., LARSSON, K. AND BEYER, C.: Comparison of the effects of different isomers of bicuculline infused in the preoptic area on male rat sexual behavior. Experientia 41: 1414, 1985. 163. CARMICHAEL, M.S., HUMBERT, R., DIXON, J., PALMISANO, G., GREENLEAF, W. AND DAVIDSON, J.M.: Plasma oxytocin increases in the human sexual response. J. Clin. Endocrinol. Metab. 64: 27, 1987.

176. MAINS, R.E., EIPPERS, B.A. AND LING, N.: Common precursor to the corticotropins and endorphins. Proc. Nat. Acad. Sci. U.S.A. 74: 3014, 1977. 177. FERRARI, W., GESSA, G.L. AND VARGIU, L.: Behavioural effects induced by intracisternally injected ACTH and MSH. Am. NYAcad. Sci. 104: 330, 1963.

164. MURPHY, M.R., SECKL, J.R., BURTON, S., CHECKLEY, S.A. AND LIGHTMAN, S.L.: Changes in oxytocin and vasopressin secretion during sexual activity in men. J. Clin. Endocrinol. Metab. 65: 738, 1987.

178. POGGIOLI, R., ARLETTI, R., BENELLI, A., CAVAZZUTI, E. AND BERTOLINI, A.: Diabetic rats are unresponsive to the penile erection-inducing effect of intracerebroventricularly injected adrenocorticotropin. Neuropeptides. 32: 151, 1998.

165. ARGIOLAS, A., MELIS, M.R. AND GESSA G.L.: Oxytocin: a potent inducer of penile erection and yawning in male rats. Eur. J. Pharmacol. 130: 265, 1986.

179. ARGIOLAS, A., MELIS, M.R., STANCAMPIANO, R. AND GESSA, G.L.: 4-Conotoxin prevents apomorphine and oxytocin-induced penile erection and yawning in male rats. Pharmac. Biochem. Behav. 37: 253, 1990

166. ARGIOLAS, A.: Oxytocin stimulation of penile erection. Pharmacology, site, and mechanism of action. Ann. NYAcad. Sci. 652: 194, 1992.

180. MELIS, M.R., STANCAMPIANO, R. AND ARGIOLAS, A.: Effect of excitatory amino acid receptor antagonists on apomorphine-, oxytocin- and ACTHinduced penile erection and yawning in male rats. Eur. J. Pharmacol. 20: 43, 1992.

167. MELIS, M.R., SUCCU, S. AND ARGIOLAS, A.: Prevention by morphine of N-methyl-D-aspartic acidinduced penile erection and yawning: involvement of nitric oxide. Brain Res. Bull. 44: 689, 1997. 168. ARGIOLAS, A., MELIS, M.R., MAURI, A. AND GESSA, G.L.: Paraventricular nucleus lesion prevents yawning and penile erection induced by apomorphine

181. ARGIOLAS, A. AND MELIS., M.R.: Neuromodulaiton of penile erection: an overview of the role of neu-

190

rotransmitters and neuropeptides. Prog. Neurobiol. 47: 235, 1995.

195. HEDLUND, P., ALM. P., ANDERSSON, K.-E.: NO synthase in cholinergic nerves and NO-induced relaxation in the rat isolated corpus cavernosum. Br. J. Pharmacol. 127:349, 1999.

182. CUSHMAN, P.: Sexual behavior in heroin addiction and methadone maintenance. NY State J. Med. 72: 1261, 1972.

196. LEVIN, R.M. AND WEIN, A.J.: Adrenergic alphareceptors outnumber beta-receptors in human penile corpus cavernosum. Invest. Urol. 18: 225, 1980.

183. CROWLEY, T.J. AND SIMPSON, A.: Methadone dose and human sexual behavior. Int. J. Addict. 31:285, 1978.

197. COSTA, P., SOULIE-VASSAL, M.L., SARRAZIN, B., REBILLARD, X., NAVRATIL, H. AND BALI, J.P.: Adrenergic receptors on smooth muscle cells isolated from human penile corpus cavernosum. J. Urol. 150: 859, 1993.

184. MCINTOSH, T.K, VALLANO, M.L. AND BARFIELD, R.J.: Effects of morphine, -endorphin and naloxone on catecholamine levels and sexual behavior in the male rat. Pharmacol. Biochem. Behav. 13: 435, 1980. 185. PFAUS, J.G. AND GORZALKA, B.B.: Opioids and sexual behaviour. Neurosci. Biobehav. Rev. 11: 1, 1987.

198. REILLY, C.M., STOPPER, V.S. AND MILLS, T.: Androgens modulate the a-adrenergic responsiveness of vascular smooth muscle in the corpus cavernosum. J. Androl. 18: 26, 1997.

186. HUGHES, A.M., EVERITT, B.J. AND HERBERT, J.: Selective effects of beta-endorphin infused into the hypothalamus, preoptic area and bed nucleus of the stria terminalis on the sexual and ingestive behavior of male rats. Neuroscience. 23: 1063, 1987.

199. TRAISH, A.M., MORELAND, R.B., HUANG, Y.H. AND GOLDSTEIN, I.: Expression of functional alpha2-adrenergic receptor subtypes in human copus cavernosum and in cultured trabecular smooth muscle cells. Recept. Signal Transduc. 7:55, 1997.

187. MELIS, M.R., STANCAMPIANO, R., GESSA, G.L. and Argiolas, A.: Prevention by morphine of apomorphine- and oxytocin-induced penile erection: Site of action in the brain. Neuropsychopharmacology. 6: 17, 1992.

200. TRAISH, A., NETSUWAN, N., DALEY, J., PADMAN-NATHAN, H., GOLDSTEIN, I. AND SAENZ DE TEJADA, I.: A heterogenous population of a1 adrenergic receptors mediates contraction of human corpus cavernosum smooth muscle to norepinephrine. J. Urol. 153: 222, 1995.

188. MELIS, M.R., SUCCU., S., IANNUCCI, U. AND ARGIOLAs, A.: Prevention by morphine of apomorphine- and oxytocin-induced penile erection and yawning: involvement of nitric oxide. Naunyn Schmiedebergs Arch. Pharmacol. 355: 595, 1997.

201. SIMONSEN, U., PRIETO, D., HERNANDEZ, M., SAENZ DE TEJADA, I. AND GARCÍASACRISTÁN, A.: Adrenoceptor-mediated regulation of the contractility in horse penile resistance arteries. J. Vasc. Res. 34: 90, 1997.

189. POGGIOLI, R., VERGONI, A.V., GUILIANI, D., MARRAMA, D., RASORI, E. AND BERTOLINI, A.: Brain acetylcholine is involved in the ACTH-induced syndrome in rats. Neurosci. Res. Com. 8: 102, 1991.

202. HIEBLE, J.P., BYLUND, D.B., CLARKE, D.E., EIKENBURG, D.C., LANGER, S.Z., LEFKOWITZ, R.J., MINNEMAN, K.P. AND RUFFOLO, JR. R.R.: International Union of Pharmacology X. Recommendation for nomenclature of a1-adrenoceptors: consensus update. Pharmacol. Rev. 47: 267, 1995

190. MELIS, M.R., SUCCU, S., IANNUCCI, U. AND ARGIOLAS, A.: Oxytocin increases nitric oxide production in the paraventricular nucleus of the hypothalamus of male rats: correlation with penile erection and yawning. Regul. Pept. 69: 105, 1997.

203. PRICE, D.T., SCHWINN, D.A., KIM, J.H., CARSON III, C.C, CARON, M.G. AND LEFKOWITZ, R.J.: Alpha1 adrenergic receptor subtype mRNAexpression in human corpus cavernosum. J. Urol. 149: 285A(abstract 287), 1993.

191. BREDT, D.S., HWANG, P.M.. AND SNYDER, S.H.: Localization of nitric oxide synthase indicating a neural role for nitric oxide. Nature 347: 768, 1990.

204. TRAISH, A., GUPTA, S., TOSELLI, P., SAENZ DE TEJADA, I., GOLDSTEIN, I. AND MORELAND, R.B.: Identification of a1 -adrenergic receptor subtypes in human corpus cavernous tissue and in cultured trabecular smooth muscle cells. Receptor 5: 145, 1996.

192. MELIS, M.R. AND ARGIOLAS, A.: Nitric oxide donors induce penile erection and yawning when injected in the central nervous system of male rats. Eur. J. Pharmacol. 294: 1, 1995. 193. SATO, Y., HORITA, H., KUROHATA, T., ADACHI, H. AND TSUKAMOTO, T.: Effect of the nitric oxide level in the medial preoptic area on male copulatory behavior in rats. Am. J. Physiol.. 274: R243, 1998. 194. LUNDBERG, J.M.: Pharmacology of cotransmission in the autonomic nervous system: integrative aspects on amines, neuropeptides, adenosine triphosphate, amino acids and nitric oxide. Pharmacol. Rev. 48:113, 1996

205. DAUSSE, J.P., LERICHE, A. AND YABLONSKY, F.: Patterns of messenger RNA expression for alpha1adrenoceptor subtypes in human corpus cavernosum. J. Urol. 160: 597, 1998. 206. MURAMATSU, I., OHMURA, T., HASHIMOTO, S. AND OSHITA, M.: Functional subclassification of vascular a1-adrenoceptors. Pharmacol Commun 6: 23, 1995.

191

207. DAVIS, B., CHAPPLE, C. AND CHESS-WILLIAMS, R.: The α1L-adrenoceptor mediates contraction in human erectile tissue. Eur. Urol. 35(suppl 2): 102 (abstract 406), 1999.

220. ARI, G., VARDI, Y., HOFFMAN, A. AND FINBERG, J.P.: Possible role for endothelins in penile erection. Eur. J. Pharmacol. 307: 69, 1996. 221. FRANCAVILLA, S., PROPERZI, G., BELLINI, C., MARINO, G., FERRI. C. AND SANTUCCI, A.: Endothelin-1 in diabetic and nondiabetic men with erectile dysfunction. J. Urol. 158: 1770, 1997.

208. MOLDERINGS, G.J., GÖTHERT, M., VAN AHLEN, H. AND PORST, H.: Noradrenaline release in human corpus cavernosum and its modulation via presynaptic alpha 2-adrenoceptors. Fundam. Clin. Pharmacol, 3: 497, 1989. 209. SIMONSEN, U., PRIETO, D., HERNANDEZ, M., SAENZ DE TEJADA, I. AND GARCÍASACRISTÁN, A.: Prejunctional alpha 2-adrenoceptors inhibit nitrergic neurotransmission in horse penile resistance arteries. J. Urol. 157: 2356, 1997b.

222. KIFOR, I., WILLIAMS, G.H., VICKERS, M.A., SULLIVAN, M.P., JODBERT, P. AND DLUHY, R.G.: Tissue angiotensin II as a modulator of erectile function. I. Angiotensin peptide content, secretion and effects in the corpus cavernosum. J. Urol. 157: 1920, 1997. 223. COMITER, C.V., SULLIVAN, M.P., YALLA, S.V. AND KIFOR, I.: Effect of angiotensin II on corpus cavernosum smooth muscle in relation to notric oxide environment: in vitro studies in canines. Int. J. Impot. Res. 9: 135, 1997.

210. RUBANYI, G.M. AND POLOKOFF, M.A.: Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. Physiol. Rev. 46: 325, 1994. 211. SAENZ DE TEJADA, I., CARSON, M.P., DE LAS MORENAS, A., GOLDSTEIN, I. AND TRAISH, A.M.: Endothelin: localization, synthesis, activity, and receptor types in human penile corpus cavernosum. Am. J. Physiol. 261: H1078, 1991. 212. HOLMQUIST, F., ANDERSSON, K.-E. AND HEDLUND, H.: Actions of endothelin on isolated corpus cavernosum from rabbit and man. Acta Physiol. Scand. 139: 113, 1990.

224. PARK, J.K., KIM, S.Z., KIM, S.H., PARK, Y.K. AND CHO, K.W.: Renin angiotensin system in rabbit corpus cavernosum: functional characterization of angiotensin II receptors. J. Urol. 158: 653, 1997 225. TRAISH, A.M., PALMER, M.S., GOLDSTEIN, I. AND MORELAND, R.B.: Expression of functional muscarinic acetylcholine receptor subtypes in human corpus cavernosum and in cultured smooth muscle cells. Receptor 5: 159, 1995.

213. HOLMQUIST, F., KIRKEBY, H.J., LARSSON, B., FORMAN, A. AND ANDERSSON, K.-E.: Functional effects, binding sites and immunolocalization of endothelin-1 in isolated penile tissues from man and rabbit. J. Pharmacol. Exp. Ther. 261: 795, 1992.

226. TOSELLI, P., MORELAND, R. AND TRAISH, A.M.: Detection of m2 muscarinic acetylcholine receptor mRNA in human corpus cavernosum by in-situ hybridization. Life Sci 55: 621, 1994.

214. CHRIST, G.J., LERNER, S.E., KIM, D.C. AND MELMAN, A.: Endothelin-1 as a putative modulator of erectile dysfunction: I. Characteristics of contraction of isolated corporal tissue strips. J. Urol. 153: 1998, 1995. 215. BELL, C.R.W., SULLIVAN, M.E., DASHWOOD, M.R., MUDDLE, J.R. AND MORGAN, R.J.: The density and distribution of endothelin 1 and endothelin receptor subtypes in normal and diabetic rat corpus cavernosum. Br. J. Urol. 76: 203, 1995.

227. KLINGE, E. AND SJÖSTRAND, N.O.: Suppression of the excitatory adrenergic neurotransmission; a possible role of cholinergic nerves in the retractor penis muscle. Acta Physiol. Scand. 100: 368, 1977. 228. BURNETT, A.L.: Nitric oxide in the penis: physiology and pathology. J. Urol. 157: 320, 1997. 229. ALM, P., LARSSON, B., EKBLAD, E., SUNDLER, F. AND ANDERSSON, K.-E.: Immunohistochemical localization of peripheral nitric oxide synthase-containing nerves using antibodies raised against synthesized C- and N-terminal fragments of a cloned enzyme from rat brain. Acta Physiol. Scand. 148: 421, 1993.

216. PARKKISENNIEMI, U.-M. AND KLINGE, E.: Functional characterization of endothelin receptors in the bovine retractor penis and penile artery. Pharmacol. Toxicol. 79: 73, 1996. 217. HOLMQUIST, F., PERSSON, K., GARCIA-PASCUAL, A. AND ANDERSSON, K.-E.: Phospholipase C activation by endothelin-1 and noradrenaline in isolated penile erectile tissue from rabbit. J. Urol. 147: 1632, 1992. 218. KIM, D.C., GONDRE, C.M. AND CHRIST, G.J.: Endothelin-1-induced modulation of contractile responses elicited by an alpha 1-adrenergic agonist on human corpus cavernosum smooth cells. Int. J. Impot. Res. 8: 17, 1996.

230. 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, 1992. 231. BURNETT, A.L., TILLMAN, S.L., CHANG, T.S.K., EPSTEIN, J.I., LOWENSTEIN, C.J., BREDT, D.S., SNYDER, S.H. AND WALSH, P.C.: Immunohistochemical localization of nitric oxide synthase in the autonomic innervation of the human penis. J. Urol. 150: 73, 1993.

219. ZHAO, W. AND CHRIST, G.J.: Endothelin-1 as a putative modulator of erectile dysfuncton. II. Calcium mobilization in cultured human corporal smooth muscle cells. J. Urol. 154: 1571, 1995.

232. BURNETT, A.L., NELSON, R.J., CALVIN, D.C., LIU, J.X., DEMAS, G.E., KLEIN, S.L., KRIEGSFELD PFEIFER, L.J., DAWSON, V.L., DAWSON,

192

T.M. AND SNYDER, S.H.: Nitric oxide-dependent penile erection in mice lacking neuronal nitric oxide synthase. Mol. Med. 2: 288, 1996.

NISHI, Y., TSURUO, Y. AND ISHIMURA, K.: Coexistence of nitric oxide synthase, tyrosin hydroxylase and vasoactive intestinal polypeptide in human penile tissue- a triple histochemical and immunohistochemical study. J. Urol. 153: 530, 1995.

233. DAIL, W.G., BARBA, V., LEYBA, L. AND GALINDO, R.: Neural and endothelial nitric oxide synthase activity in rat penile erectile tissue. Cell Tissue Res. 282: 109, 1995.

244. TAMURA, M., KAGAWA, S., TSURUO, Y., ISHIMURA, K., KIMURA, K. AND KAWANISHI, Y.: Localization of NADPH diaphorase and vasoactive intestinal polypeptide-containing neurons in the efferent pathway to the rat corpus cavernosum. Eur. Urol. 32: 100, 1997.

234. HUANG, P.L., DAWSON, T.M., BREDT, D.S., SNYDER, S.H. AND FISHMAN, M.C.: Targeted disruption of the neuronal nitric oxide synthase gene. Cell 75: 1273, 1993. 235.

245. VANHATALO, S., KLINGE, E., SJÖSTRAND, N.O. AND SOINILA, S.: Nitric oxide-synthesizing neurons originating at several different levels innervate rat penis. Neuroscience 75: 891, 1996.

BLOCH, W., KLOTZ, T., SEDLACZEK, P., ZUMBE, J., ENGELMANN, U. AND ADDICKS, K.: Evidence for the involvement of endothelial nitric oxide synthase from smooth muscle cells in the erectile function of the human corpus cavernosum. Urol. Res. 26: 128, 1998.

246. DAIL, W.G., GALINDO, R., LEYBA, L. AND BARBA, V.: Denervation-induced changes in perineu ronal plexuses in the major pelvic ganglion of the rat: immunohistochemistry for vasoactive intestinal polypeptide and tyrosine hydroxylase and histochemistry for NADPH-diaphorase. Cell Tiss. Res. 287: 315, 1997.

236. ELIASSON, M.J., BLACKSHAW, S., SCHELL, M.J. AND SNYDER, S.H.: Neuronal nitric oxide synthase alternatively spliced forms: prominent functional localizations in the brain. Proc. Natl. Acad. Sci. U S A 94: 3396, 1997.

247. SCHIRAR, A., CHANG, C. AND ROUSSEAU, J.P.: Localization of androgen receptor in nitric oxide synthase- and vasoactive intestinal peptide-containing neurons of the major pelivic ganglion innervating the rat penis. J. Neuroendocrinol. 9 :141, 1997.

237. PFEIFER, A., KLATT, P., MASSBERG, S., NY, L., SAUSBIER, M., HIRNEISS, C., WANG, G.-X., KORTH, M., ASZÓDI, A., ANDERSSON, K.-E., KROMBACH, F., MAYERHOFER, A., RUTH, P., FÄSSLER, R. AND HOFMANN, F.: Defective smooth muscle regulation in cGMP kinase I-deficient mice. EMBO J. 17: 3045, 1998.

248. ARVIDSSON, U., RIEDL, M., ELDE, R. AND MEISTER, B.: Vesicular acetylcholine transporter (VAChT) protein: a novel and unique marker for cholinergic neurons in the central and peripheral nervous systems. J. Comp. Neurol. 378: 454, 1997.

238. HEDLUND, P., ASZODI, A., FÄSSLER, R., ANDERSSON, K.-E., PFEIFER, A. AND HOFMANN, F.: Erectile dysfunction in cGMP-dependent protein kinase 1-deficient mice. J. Urol. 161Supplement: 216 (abstract 827).

249. FAHRENKRUG, J.: Transmitter role of vasoactive intestinal peptide. Pharmacol. Toxicol. 72: 354, 1993. 250. CHAKDER, S. AND RATTAN, S.: Involvement of cAMPand cGMP in relaxation of internal anal sphincter by neural stimulation, VIP, and NO. Am. J. Physiol. 264: G702, 1993.

239. DAIL, W.G.: Autonomic innervation of male reproductive genitalia. In: The Autonomic Nervous System. Vol. 6, Chapter 3, Nervous Control of the Urogenital System, ed by CAMaggi. Harwood Academic Publishers, London, UK, p 69, 1993.

251. MILLER, M.A., MORGAN, R.J., THOMPSON, C.S., MIKHAILIDIS, D.P. AND JEREMY, J.Y.: Effects of papaverine and vasointestinal polypeptide on penile and vascular cAMP and cGMP in control and diabetic animals: an in vitro study. Int. J. Impot. Res. 7: 91, 1995.

240. EHMKE, H., JUNEMANN, K.P., MAYER, B. AND KUMMER, W.: Nitric oxide synthase and vasoactive intestinal polypeptide colocalization in neurons innervating the human penile circulation. Int. J. Impot. Res. 7: 147, 1995.

252. MAHER, E., BACHOO, M., ELABBADY, A.A., POLOSA, C., BEGIN, L.R., COLLIER, B., ELHILALI, M.M. AND HASSOUNA, M.M .: Vasoactive intestinal peptide and impotence in experimental diabetes mellitus. Br. J. Urol. 77: 271, 1996

241. HEDLUND, P., ALM, P., EKSTRÖM, P., FAHRENKRUG, J., HANNIBAL, J., HEDLUND, H., LARSSON, B. AND ANDERSSON, K.-E.: Pituitary adenylate cyclase-activating polypeptide, helospectin, and vasoactive intestinal polypeptide in human corpus cavernosum. Br. J. Pharmacol. 116: 2258, 1995.

253. GU, J., POLAK, J.M., LAZARIDES, M., MORGAN, R., PRYOR, J.P., MARANGOS, P.J., BLANK, M.A. AND BLOOM, S.R.: Decrease of vasoactive intestinal polypeptide (VIP) in the penises from impotent men. Lancet ii: 315, 1984.

242. HEDLUND, P., LARSSON, B., ALM, P. AND ANDERSSON, K.-E.: Distribution and function of nitric oxide-containing nerves in canine corpus cavernosum and spongiosum. Acta Physiol. Scand. 155: 445, 1995.

254. LINCOLN, J., CROWE, R., BLACKLEY, P.F., PRYOR, J.P., LUMLEY, J.S.P. AND BURNSTOCK, G.: Changes in the VIPergic, cholinergic and adrener-

243. TAMURA, M., KAGAWA, S., KIMURA, K., KAWA-

193

gic innervation of human penile tissue in diabetic and non-diabetic impotent males. J. Urol. 137: 1053, 1987.

B. AND ANDERSSON, K.-E.: Localization and effects of pituitary adenylate cyclase-activating polypeptide (PACAP) in human penile erectile tissues. Acta Physiol. Scand. 150: 103, 1994.

255. HABERMAN, J., VALCIC, M., CHRIST, G. AND MELMAN, A.: Vasoactive intestinal polypeptide and norepinephrine concentration in the corpora cavernosa of impotent men. Int. J. Impotence Res. 3: 21, 1991.

267. GERSTENBERG, T.C., METZ, P., OTTESEN, B. AND FAHRENKRUG, J.: Intracavernous self-injection with vasoactive intestinal polypeptide and phentolamine in the management of erectile failure. J. Urol. 147: 1277, 1992.

256. ADAIKAN, P.G., KOTTEGODA, S.R. AND RATNAM, SS.: Is vasoactive intestinal polypeptide the principal transmitter involved in human penile erection? J. Urol. 135: 638, 1986.

268. 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.

257. PICKARD, R.S., POWELL, P.H. AND ZAR, M.A.: Evidence against vasoactive intestinal polypeptide as the relaxant neurotransmitter in human cavernosal smooth muscle. Br. J. Pharmacol. 108: 497, 1993.

269. MILLER, M.A.W., MORGAN, R.J., THOMPSON, C.S., MIKHAILIDIS, D.P. AND JEREMY, J.Y.: Effects of papaverine and vasointestinal polypeptide on penile and vascular cAMPand cGMPin control and diabetic animals: an in vitro study. Int. J. Impot. Res. 7: 91, 1995.

258. KIM, Y.C., KIM, J.H., DAVIES, M.G., HAGEN, P.O. AND CARSON, C.C.: Modulation of vasoactive intestinal polypeptide (VIP)-mediated relaxation by nitric oxide and prostanoids in the rabbit corpus cavernosum. J. Urol. 153: 807, 1995.

270. PORST, H.: A rational for prostaglandin E1 in erectile failure: a survey of worldwide experience. J. Urol. 155: 802, 1996.

259. HAYASHIDA, H., OKAMURA, T., TOMOYOSHI, T. AND TODA, N.: Neurogenic nitric oxide mediates relaxation of canine corpus cavernosum. J. Urol. 155: 1122, 1996.

271. DALEY, J.T., BROWN, M.L., WATKINS, M.T., TRAISH, A.M., HUANG, Y.-H., MORELAND, R.B. AND SAENZ DE TEJADA, I.: Prostanoid production in rabbit corpus cavernosum: I. Regulation by oxygen tension. J. Urol. 155: 1482, 1996.

260. HEMPELMANN, R.G., PAPADOPOULOS, I AND HERZIG, S.: Non-synergistic relaxant effects of vasoactive intestinal polypeptide and SIN-1 in human isolated cavernous artery and corpus cavernosum. Eur. J. Pharmacol. 276: 277, 1995.

272. DALEY, J.T., WATKINS, M.T., BROWN, M.L., MARTINEZ, V., CUEVAS, P. AND SAENZ DE TEJADA, I.: Prostanoid production in rabbit corpus cavernosum: II. Inhibition by oxidative stress. J. Urol. 156: 1169, 1996.

261. SUH, J.K., MUN, K.H., CHO, C.K., SHIN, H.C., KIM, Y.S. AND PARK, T.C.: Effect of vasoactive intestinal peptide and acetylcholine on penile erection in the rat in vivo. Int. J. Impot. Res. 7: 111, 1995.

273. COLEMAN, R.A., SMITH, W.L. AND NARUMIYA, S.: International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes. Pharmacol. Rev. 46: 205, 1994.

262. YIANGOU, Y., CHRISTOFIDES, N.D., GU, J., BLANK, M.A., POLAK, J.M. AND BLOOM, S.R.: Peptide histidine methionine (PHM) and the human male genitalia. Neuropeptides 6: 133, 1985. 263. KIRKEBY, H.J., FAHRENKRUG, J., HOLMQUIST, F. AND OTTESEN, B.: Vasoactive intestinal polypeptide (VIP) and peptide histidine methionine (PHM) in human penile corpus cavernosum tissue and circumflex veins: localization and in vitro effects. Eur. J. Clin. Invest. 22: 24, 1992.

274. PIERCE, K.L., GIL, D.W., WOODWARD, D.F., REGAN, J.W.: Cloning of human prostanoid receptors. Trends Pharmacol. Sci. 16: 253, 1995. 275. MORELAND, R.B., TRAISH, A., MCMILLAN, M.A., SMITH, B., GOLDSTEIN, I. AND SAENZ DE TEJADA, I.: PGE1 suppresses the induction of collagen synthesis by transforming growth factor-ß1 in human corpus cavernosum smooth muscle. J. Urol. 153: 826, 1995.

264. HAUSER-KRONBERGER, C., HACKER, G.W., GRAF, A.-H., MACK, D., SUNDLER, F., DIETZE, O. AND FRICK, J.: Neuropeptides in the human penis: an immunohistochemical study. J. Androl. 15: 510, 1994a.

276. KITAMURA, K., KANGAWA, K., KAWAMOTO, M., ICHIKI, Y., NAKAMURA, S., MATSUO, H. AND ETO, T.: Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem. Biophys. Res. Commun. 92: 553, 1993.

265. HAUSER-KRONBERGER, C., HACKER, G.W., MACK, D., DIETZE, O., ARIMURA, A., SUNDLER, F. AND FRICK, J.: Pituitary adenylate cyclases activating peptide (PACAP), helospectin, peptide histidine methionine (PHM) and vasoactive intestinal polypeptide (VIP) in the human penis: an immunocytochemical evaluation on the occurrence of VIP-related peptides. Cell Vision 1: 319, 1994.

277. CHAMPION, H.C., WANG, R., HELLSTROM, W.J.G.AND KADOWITZ, P.J.: Nociceptin, a novel endogenous ligand for the ORL1 receptor, has potent erectile activity in the cat. Am. J. Physiol. 273: E214, 1997.

266. HEDLUND, P., ALM, P., HEDLUND, H., LARSSON,

194

278. CHAMPION, H.C., WANG, R., SANTIAGO, J.A., MURPHY, W.A., COY, D.H., KADOWITZ, P.J. AND HELLSTROM, W.J.G.: Comparison of responses to adrenomedullin and calcitonin gene-related peptide in the feline erection model. J. Androl. 18: 513, 1997.

terization of ATP-sensitive potassium channels in human corporal smooth muscle cells. Int. J. Impot. Res. 11: 179, 1999. 291. CHRIST, G.J., VALCIC, M., MAAYANI, S. AND MELMAN, A.: Kinetic studies of contraction in human erectile tissue (HET) and rabbit aortic rings in vitro: Modulation by papaverine and the dihydropyridine analog nifedipine. Int. J. Impot. Res. 1: 1, 1989.

279. CHAMPION, H.C., WANG, R., SHENASSA, B.B., MURPHY, W.A., COY, D.H., HELLSTROM, W.J.G. AND KADOWITZ, P.J.: Adrenomedullin induces penile erection in the cat. Eur J Pharmacol 319: 71, 1997.

292. CHRIST, G.J., MAAYANI, S. AND MELMAN, A.: Pharmacological studies of human erectile tissue: Characteristics of spontaneous contractions and alterations in a-adrenoceptor responsiveness with age and disease in isolated tissues. Br. J. Pharmacol. 101: 375, 1990.

280. STIEF, C.G., BENARD, F., BOSCH, R.J.L.H., ABOSEIF, S.R., LUE, T. AND TANAGHO, E. A.: possible role for calcitonin-gene-related peptide in the regulation of the smooth muscle tone of the bladder and penis. J. Urol. 143: 392, 1990.

293. CHRIST, G.J., STONE, B.S. AND MELMAN, A.: Age-dependent alterations in the efficacy of phenylephrine-induced contractions in vascular smooth muscle isolated from the corpus cavernosum of impotent men. Can. J. Physiol. Pharmacol. 69: 909, 1991.

281. STIEF, C.G., WETTERAUER, U., SCHAEBSDAU, F. AND JONAS, U.: Calcitonin-gene-related peptide: A possible role in human penile erection and its therapeutical application in impotent patients. J. Urol. 146: 1010, 1991.

294. CHRIST, G.J., VALCIC, M., GONDRE, C.M., PARKER, M., JANIS, M., SCHWARTZ, K., STONE, B.A. AND MELMAN, A.: Kinetic characteristics of a1adrenergic contractions in human corpus cavernosum smooth muscle. Am. J. Physiol. 263: H15, 1992.

282. TRUSS, M.C., BECKER, A.J. AND THON, W.F.: Intracavernous calcitonin gene-related peptide plus prostaglandin E1: possible alternative to penile implants in selected patients, Eur. Urol. 26: 40, 1994.

295. CHRIST, G.J., MORENO, A.P., MELMAN, A.P. AND SPRAY, D.C.: Gap junction-mediated intercellular diffusion of Ca2+ in cultured human corporal smooth muscle cells. Am. J. Physiol. 263: C373, 1992.

283. HENDERSON, G. AND MCKNIGHT, A.T.: The orphan opioid receptor and its endogenous ligand nociceptin/orphanin FQ. Trends Pharmacol. Sci. 18: 293, 1997.

296. NOACK, T. AND NOACK, P.: Multiple types of ion channels in cavernous smooth muscle. World J. Urol. 15: 45, 1997.

284. CHRIST, G.J.: The “syncytial tissue triad”: A model for understanding how gap junctions participate in the local control of penile erection. World J. Urol. 13: 36, 1997.

297. CHRIST, G.J., BRINK, P.R., MELMAN, A. AND SPRAY, D.C.: The role of gap junctions and ion channels in the modulation of electrical and chemical signals in human corpus cavernosum smooth muscle. Int. J. Impotence. Res. 5: 77, 1993

285. CHRIST, G.J., RICHARDS, S. AND WINKLER, A.: Integrative erectile biology: The role of signal transduction and cell-to-cell communication in coordinating corporal smooth muscle tone and penile erection. Int. J. Impotence Res. 9: 1, 1997.

298. ZHAO, W. AND CHRIST, G.J.: Endothelin-1 as a putative modulator of erectile dysfunction. II. Calcium mobilization in cultured human corporal smooth muscle cells. J. Urol., 154: 1571, 1995.

286. RAMANAN, S.V., BRINK, P.R. AND CHRIST, G.J.: Neuronal innervation, Intracellular signal transduction and intercellular coupling: A model for syncytial tissue responses in the steady state. J. Theor. Biol., 193: 69, 1998.

299. STAERMAN, F., MELMAN, A. AND CHRIST, G.J.: On the putative mechanistic basis for intraoperative propofol-induced penile erections. Int. J. Impotence Res., 9: 1, 1997.

287. CHRIST, G.J. The “syncytial tissue triad”: The mechanistic basis for integrative tissue physiology. Einstein Quarterly J. Biol. Med. 15: 179, 1998.

300. FAN, S.F., CHRIST, G.J., MELMAN, A. AND BRINK, P.R.: A stretch-sensitive Cl- channel in human corpus cavernosal myocytes. Int. J. Impot. Res. 11: 1, 1999.

288. FAN, S.-F., BRINK, P.R., MELMAN, A. AND CHRIST, G.J.: An analysis of the Maxi-K+(KCa) channel in cultured human corporal smooth muscle cells. J. Urol. 153: 818, 1995.

301. CAMPOS DE CARVALHO, A.C., MORENO, A.P., CHRIST, G.J., MELMAN, A. ROY, C., HERTZBERG, E.L. AND SPRAY, D.C.: Gap junctions formed of connexin43 interconnect smooth muscle cells of the human corpus cavernosum. J. Urol. 149: 1568, 1993

289. LEE, S.W., WANG, H.Z., ZHAO, W., NEY, P., BRINK, P.R. AND CHRIST, G.J.: Prostaglandin E1 activates the large-conductance KCa channel in human corporal smooth muscle cells. Int. J. Impot. Res. 11: 189, 1999.

302. MORENO, A.P., CAMPOS DE CARVALHO, A.C., CHRIST, G.J. AND SPRAY, D.C.: Gap junctional communication between human corpus cavernosum

290. LEE, S.W., WANG, H.Z. AND CHRIST, G.J.: Charac-

195

smooth muscle cells in culture: Gating behavior and single channel events. Am. J. Physiol., 264: C80, 1993.

HURWITZ , M.Y., KEMP, B.E. AND MEANS, A.R.: Regulatory and structural motifs of chicken gizzard myosin light chain kinase. Proc. Natl. Acad. Sci. U S A 87: 2284, 1990.

303. CHRIST, G.J.: The penis as a vascular organ: The importance of corporal smooth muscle tone in the control of erection. Urol. Clin. N. Am., 22: 727, 1995.

317. SYBERTZ, E.J., DESIDERIO, D.M., TETZLOFF, G. AND CHIU, P.J. Phorbol dibutyrate contractions in rabbit aorta: calcium dependence and sensitivity to

304. BRINK, P.R., RAMANAN, S.V. AND CHRIST, G.J.: Human connexin43 gap junction channel gating: evidence for mode shifts and/or heterogeneity. Am. J. Physiol. 271: C321, 1996.

318. ITOH, H., SHIMOMURA, A., OKUBO, S., ICHIKAWA, K., ITO, M., KONISHI, T. AND NAKANO, T.: Inhibition of myosin light chain phosphatase during Ca(2+)-independent vasocontraction. Am. J. Physiol. 265: C1319, 1993.

305. CHRIST, G.J. AND BRINK, P.R.: Analysis of the presence and physiological relevance of subconducting states of Connexin43-derived gap junction channels in cultured human corporal vascular smooth muscle cells. Circ. Res. 84: 797, 1999.

319. BEAVO, J.A.: Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol. Rev. 75: 725, 1995.

306. CHRIST, G.J., BRINK, P.R. AND RAMANAN, S.V.: Dynamic gap junctional communication: A delimiting model for tissue responses. Biophys. J. 67: 1335, 1994.

320. POLSON, J.B. AND STRADA, S.J.: Cyclic nucleotide phosphodiesterases and vascular smooth muscle. Annu. Rev. Pharmacol. Toxicol. 36: 403, 1996.

307. CHRIST, G.J., SPRAY, D.C., MOORE, L.K., ELSABBAN, M.E. AND BRINK, P.R.: Gap junctions in vascular tissues: Evaluating the role of intercellular communication to the modulation of vasomotor tone. Circ. Res. 79: 631, 1996.

321. DOUSA, TP.: Cyclic-3',5'-nucleotide phosphodiesterase isozymes in cell biology and pathophysiology of the kidney. Kidney Int. 55: 29, 1999. 322. TAHER, A., STIEF, C.G., RAIDA, M., JONAS ,U. AND FORSSMANN, W.G.: Cyclic nucleotide phosphodiesterase activity in human cavernous smooth muscle and the effect of various selective inhibitors. Int J Impot Res 4Suppl 2: P11, 1992

308. REHMAN, J., CHRIST, G.J., MELMAN, A. AND FLEISCHMANN, J.: Intracavernous pressure responses to physical and electrical stimulation of the cavernous nerve in rats. Urology 51: 640, 1998. 309. CHRIST, G.J., REHMAN, J., DAY, N., SALKOFF, L., VALCIC, M., MELMAN, A. AND GELIEBTER, J.: Intracorporal injection of hSlo cDNA in rats produces physiologically relevant alterations in penile function. Am. J. Physiol. 275: H600, 1998.

323. STIEF, C.G., TAHER, A., TRUSS, M., ÜCKERT, S., MEYER, M., SCHULZ-KNAPPE, P., FORSSMANN, W.F AND JONAS, U.: Die Phosphodiesterase-Isoenzyme des humanen Corpus Cavernosum Penis und deren funtionelle Bedeutung. Akt. Urol. 26Suppl I: 58, 1995

310. KURIYAMA, H., KITAMURA, K., ITOH, T. AND INOUE, R.: Physiological features of visceral smooth muscle cells, with special reference to receptors and ion channels. Physiol. Rev. 78: 811, 1998.

324. STIEF, C.G., KÜTHE, A., ÜCKERT, S., BRODERICK, G.A. AND JONAS, U.: Phosphodiesterases in human cavernous smooth muscle: expression and possible clinical significance. 1999, in press

311. BERRIDGE, M.J. AND IRVINE, R.F.: Inositol trisphosphate, a novel second messenger in cellular signal transduction. Nature 312: 315, 1984.

313. SOMLYO, A.P. AND SOMLYO, A.V.: Signal transduction and regulation in smooth muscle. Nature 372: 231, 1994.

325. BALLARD, S.A., GINGELL, C.J., TANG, K., TURNER, L.A., PRICE, M.E. AND NAYLOR A.M..: Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes. J. Urol. 159: 2164, 1998. 326. BALLARD, S.A., TURNER, L.A. AND NAYLOR, A.M.: Sildenafil, a potent selective inhibitor of type 5 phosphodiesterase enhances nitric oxide-dependent relaxation of rabbit corpus cavernosum (abstr). Br J Pharmacol 118: 153P, 1996.

314. KARAKI, H., OZAKI, H., HORI, M., MITSUISAITO, M., AMANO, K., HARADA, K., MIYAMOTO, S., NAKAZAWA, H., WON, K.J. AND SATO, K.: Calcium movements, distribution, and functions in smooth muscle. Pharmacol. Rev. 49: 157, 1997.

327. KÜTHE, A., STIEF, C.G., MÄGERT, H.-J., ÜCKERT, S., FORSSMANN, W.-G. AND JONAS, U.: Molecular biological characterisation of phosphodiesterases 3 and 5 in human corpus cavernosum penis Eur. Urol. 35(suppl 2): 102 (abstract 405), 1999a.

312. FERRIS, C.D. AND SNYDER, S.H.: IP3 receptors. Ligand-activated calcium channels in multiple forms. Adv Second Messenger Phosphoprotein Res 26: 95, 1992.

328. STIEF, C.G., ÜCKERT, S., BECKER, A.J., TRUSS, M.C. AND JONAS, U.: The effect of the specific phosphodiesterase (PDE) inhibitors on human and rabbit cavernous tissue in vitro and in vivo. J. Urol. 159: 1390, 1998.

315. CHACKO, S. AND LONGHURST, P.A.: Regulation of actomyosin and contraction in smooth muscle. World J. Urol. 12: 292, 1994. 316. OLSON, N.J., PEARSON, R.B., NEEDLEMAN, D.S.,

196

329. BALLARD, S.A., GINGELL, C.J., TANG, K., TURNER, L.A., PRICE, M.E. AND NAYLOR, A,M.: Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes. J. Urol. 159: 2164, 1998.

341. WESPES, E., GOES, P.M., SCHIFFMANN, S., DEPIERREUX, M., VANDERHAEGHEN, J.J. AND SCHULMAN, C.C.: Computerized analysis of smooth muscle fibers in potent and impotent patients. J. Urol. 146: 1015, 1991. 342. MORELAND, R.B.: Is there a role of hypoxemia in penile fibrosis: a viewpoint presented to the Society for the Study of Impotence. Int. J. Impotence Res. 10: 113, 1998.

330. BOOLELL, M., ALLEN, M.J., BALLARD, S.A., GEPI-ATTEE, S., MUIRHEAD, G.J., NAYLOR A.M., OSTERLOH, I.H. AND GINGELL, C.: Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int. J. Impot. Res. 8: 47, 1996.

343. ANDERSON, W.F.: Human gene therapy. Science 256: 808, 1992. 344. MILLER, A.D.: Human gene therapy comes of age. Nature 357: 455, 1992.

331. BOOLELL, M., GEPI-ATTEE, S., GINGELL, J.C. AND ALLEN ,M.J.: Sildenafil, a novel oral therapy for male erectile dysfunction. Br. J. Urol. 78: 257, 1996.

345. CRYSTAL, R.G.: Transfer of genes to humans: Early lessons and obstacles to success. Science 270: 404, 1995.

332. TANG, K., TURNER, L.A., BALLARD, S.A. AND NAYLOR, A.M.: Effects of a novel phosphodiesterase type 5 inhibitor, sildenafil, on methacholine induced relaxation of isolated rabbit corpus cavernosum (abstr). Br. J. Pharmacol., 118: 154P, 1996.

346. ROEMER, K. AND FRIEDMANN, T.: Concepts and strategies for human gene therapy. Eur. J. Biochem. 208: 211, 1992.

333. CHUANG, A.T., STRAUSS, J.D., MURPHY, R.A. AND STEERS W.D.: Sildenafil, a type-5 cGMP phosphodiesterase inhibitor, specifically amplifies endogenous cGMP-dependent relaxation in rabbit corpus cavernosum smooth muscle in vitro. J. Urol. 160: 257, 1998.

347. ROWEN, L., MAHAIRAS, G. AND HOOD, L.: Sequencing the human genome. Science. 278: 605, 1997. 348. NABEL, E.G., PLAUTZ, G. AND NABEL, G.J.: Sitespecific gene expression in vivo by direct gene transfer into the arterial wall. Science 249: 1285, 1990.

334. CARTER, A.J., BALLARD, S.A. AND NAYLOR, A.M.: Effect of the selective phosphodiesterase type 5 inhibitor sildenafil on erectile function in the anesthetized dog. J. Urol. 160: 242, 1998.

349. BENNETT, M.J., NANTZ, M.H., BALASUBRAMANIAM, R.P., GRUENERT, D.C. AND MALONE. R.W.: Cholesterol enhances cationic liposome-mediated DNA transfection of human respiratory epithelial cells. Biosci. Rep. 15 :47, 1995.

335. JEREMY, J.Y., BALLARD, S.A., NAYLOR, A.M., MILLER, M.A.W. AND ANGELINI, G.D.: Effects of sildenafil, a type-5 cGMP phosphodiesterase inhibitor, and papaverine on cyclic GMP and cyclic AMP levels in the rabbit corpus cavernosum in vitro. Br. J. Urol. 79: 958, 1997.

350. CHANG, M.W., BARR, E., LU, M.M., BARTON, K. AND LEIDEN, J.:Adenovirus-mediated over- expression of the cyclin/cyclin-dependent kinase inhibitor, p21 inhibits vascular smooth muscle cell proliferation and neointima formation in the rat carotid artery model of balloon angioplasty. J. Clin. Invest. 96: 2260, 1995.

336. KENDREW, J.: ED. The encyclopedia of molecular biology. Blackwell Science, Oxford, England, p.664, 1994 337. LUE, T.F. AND DAHIYA, R: Molecular biology of erectile function and dysfunction. Mol. Urol. 1: 55, 1997.

351. FINKEL, T. AND EPSTEIN, S.E. Gene therapy for vascular disease. FASEB Journal 9: 843, 1995. 352. KASS-EISLER, A., FALCK-PEDERSEN, E., ALVIRA, M., RIVERA, J., BUTTRICK, P.M., WITTENBERG, B.A., CIPRIANI, L. AND LEINWAND, L.A.: Quantitative determination of adenovirus-mediated gene delivery to rat cardiac myocytes in vitro and in vivo. Proc. Natl. Acad. Sci. 90:11498, 1993.

338. AUTIERI, M.V., MELMAN, A. AND CHRIST, G.J.: Identification of a down-regulated mRNAtranscript in corpus cavernosum from diabetic patients with erectile dysfunction. Int. J. Impotence Res. 8: 69, 1996. 339. SERELS, S., DAY, N.S., WEN, Y.P., GIRALDI, A., LEE, S.W., MELMAN, A. AND CHRIST, G.J.: Molecular studies of connexin43 (Cx43) expression in isolated corporal tissue strips and cultured corporal smooth muscle cells. Int. J. Impotence Res. 10: 1, 1998.

353. KASS-EISLER, A. AND LEINWAND, L.A.: DNAand adenovirus-mediated gene transfer into cardiac muscle. Methods Cell Biol. 52: 423, 1997. 354. SCHULICK, A.H., NEWMAN, K.D., VIRMANI, R., DICHEK, D.A.: In vivo gene transfer into injured carotid arteries. Circulation 91: 2407, 1995.

340. NEHRA, A., GOLDSTEIN, I., PABBY, A., NUGENT, M., HUANG, Y.H., DE LAS MORENAS, A., KRANE, 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, 1996

355. HANANIA, E.G., KAVANAGH, J., HORTOBAGYI, G., GILES, R.E., CHAMPLIN, R. AND DIESSEROTH, A.B.: Recent advances in the application of gene therapy to human disease. Am. J. Med. 99: 537, 1995.

197

356. WESSELS, H. AND WILLIAMS, S.K.: Endothelial cell transplantation into the corpus cavernosum: Basis for efficient gene therapy for erectile dysfunction. J. Urol. 159: 92, 1998.

366. BURCHARDT, M., BURCHARDT, T., CHEN, M-W, SHABSIGH, A., DE LA TAILLE, A., BUTTYAN, R. AND SHABSIGH, R.: Expression of messenger ribonucleic acid splice variants for vascular endothelial growth factor in the penis of adult rats and humans. Biol. Reprod. 60: 398, 1999.

357. WESSELS, H. & WILLIAMS, S.K.: Transplantation of microvessel endothelial cells into the corpus cavernosum: Applications for gene therapy. Int. J. Impotence Res.10: S7, 1998.

367. MOELLING, K.: Naked DNA- the poor man’s gene therapy? Gene Therapy. 5: 573, 1998.

358. BALLINGAND, J.-L. AND CANNON, P.J.: Nitric oxide synthases and cardiac muscle. Arterioscler. Thromb. Vasc. Biol. 17: 1846, 1997.

368. JÜNEMANN. K.-P. AND ALKEN, P.: Pharmacotherapy of erectile dysfunction: a review, Int. J. Impot. Res. 1:71, 1989.

359. HUARD, J., TIRNEY, S., MATTES, C.E., WATANABE, T., OZAWA, H., YOSHIMURA, N., MORENO, J., BIRDER, L.A., KANAI, A.J., DE GROAT, W.C., TZENG, E., KIBBE, M., HIERHOLZER, C., GELLER, D.A., SIMMONS, R.L., BILLIAR, T.R. AND CHANCELLOR, M.B.: Nitric oxide synthase (NOS) therapy for erectile dysfunction; comparison between plasmid, adenovirus, and adenovirus-transduced myoblast vectors. J. Urol. 159: 90 (abstract 342), 1998.

369. JÜNEMANN, K.-P.: Pharmacotherapy of impotence: where are we going? In: World Book of Impotence, ed. by T.F. Lue, Smith-Gordon and Company Limited, London, p181, 1992. 370. GREGOIRE, A.; New treatments for erectile impotence, Br. J. Psychiat. 160: 315, 1992. 371. LINET, O.I. AND OGRINC, F.G.: Efficacy and safety of intracavernosal alprostadil in men with erectile dysfunction, N. Eng. J. Med. 334: 873, 1996.

360. BIRDER, L., KANAI, J., TIRNEY, S., HUARD, J., MATTES, C.E., OZAWA, O., JUNG, S.Y., TZENG, E., KIBBE, M., HIERHOLZER, C., SIMMONS, R.L., BILIAR, T.R., DE GROAT, W.C. AND CHANCELLOR, M.B.: Direct measurement of basal nitric oxide release with a porphyrinic microsensor following inducible nitric oxide synthase gene therapy. J. Urol. 159: 95 (abstract 364), 1998.

372. PORST, H.: A rational for prostaglandin E1 in erectile failure: a survey of worldwide experience, J. Urol. 155: 802, 1996. 373. ANDERSSON, K.-E.: Pharmacology of erection: agents which initiate and terminate erection, Sexuality and Disability 12: 53, 1994. 374. KIRKEBY, H.-J., FORMAN, A. AND ANDERSSON, K.-E.: Comparison of the papaverine effects on isolated human penile circumflex veins and corpus cavernosum, Int. J. Impot. Res. 2: 49, 1990.

361. GARBAN, H., MARQUEZ, D., MAGEE, T., MOODY, J., RAJAVASHISTH, T., RODRIGUEZ, J.A., HUNG, A., VERNET, D., RAJFER, J. AND GONZALEZ-CADAVID, N.F.: Cloning of rat and human inducible penile nitric oxide synthase. Application for gene therapy of erectile dysfunction. Biol. Reprod. 56: 954, 1997.

375. JUENEMANN, K.-P., LUE, T.F., FOURNIER, JR. G.R. AND TANAGHO, E.A.: Hemodynamics of papaverine- and phentolamine-induced penile erection, J. Urol. 136: 158, 1986.

362. MELMAN, A. AND GINGLE, J.C.: The epidemiology and pathophysiology of erectile dysfunction. J. Urology. 161: 5, 1999.

376. DELCOUR, C., WESPES, E., VANDENBOSCH, G., SCHULMAN, C.C. AND STRUYVEN, J.: The effect of papaverine on arterial and venous hemodynamics of erection, J. Urol. 138: 187, 1987.

363. MCCOBB, D.P., FOWLER, N.L., FEATHERSTONE, T., LINGLE, C.J., SAITO, M., KRAUSE, J.E. AND SALKOFF, L.: Human calcium-activated potassium channel gene expressed in vascular smooth muscle. Am. J. Physiol. 269: H 767, 1995.

377. TRAISH, A., GUPTA, S., GALLANT, C., HUANG, Y.H- AND GOLDSTEIN I.: Phentolamine mesylate relaxes penile corpus cavernosum tissue by adrenergic and non-adrenergic mechanisms. Int. J. Impot. Res. 10: 215, 1998

364. SMITH, W.L. MELMAN, A., SATO, Y., DAY, N.S., VALCIC, M., SCLAFANI, T., REHMAN, J., BAKAL, R. & CHRIST, G.J.: Gene therapy with hSlo naked DNA preserves erectile capacity following 12- 16 weeks of experimental diabetes in rats. Accepted. Keystone Symposium: “Molecular and cellular biology of gene therapy”, January 14-20th, 1999, Salt Lake City, UT.

378. WESPES, E., RONDEUX, C., SCHULMAN, C.C.: Effect of phentolamine on venous return in human erection, Br. J. Urol. 63: 95, 1989. 379. IMHOF, P.R., GARNIER, B. AND BRUNNER, L.: Human pharmacology of orally administered phentolamine. In: Phentolamine in Heart Failure and Other Cardiac Disorders. Proceedings of an International Workshop London, November 1975. Ed SH Taylor, LA Gould, Hans Huber Publishers, 11-22, 1975.

365. REHMAN, J., CHENVEN, E., BRINK, P.R., GRINE, B., WALCOTT, B., MELMAN, A. AND CHRIST, G.J.: Diminished neurogenic-, but not pharmacologicinduced intracavernous pressure responses in the 3 month streptozotocin (STZ)-diabetic rat. Am. J. Physiol., 272: H1960, 1997.

380. HAKENBERG, O., WETTERAUER, U., KOPPERMANN, U. , LÜHMANN, R.: Systemic pharmacoki-

198

netics of papaverine and phentolamine: comparison of intravenous and intracavernous application, Int. J. Impot. Res. 2(Supplement 2): 247, 1990.

SIGH, R. AND TAM, P.Y. .: Treatment of men with erectile dysfunction with transurethral alprostadi. N. Engl. J. Med. 336: 1, 1997.

381. ZORGNIOTTI, A.W. AND LEFLEUR, R.S.: Autoinjection of the corpus cavernosum with a vasoactive drug combination for vasculogenic impotence, J. Urol. 133: 39, 1985.

393. HATZINGER, M., JUNEMANN, P., WOESTE, M., CAWELLO, T., ALBRECHT, D. AND ALKEN, P.: Pilot study on systemic plasma concentrations of prostaglandin E1, 15-keto PGE0 and PGE0 after intravenos injection in patients with chronic erectile dysfunction. J. Urol. 153: 367A, 1995.

382. GERSTENBERG, T.C., METZ, P., OTTESEN, B. AND FAHRENKRUG, J.: Intracavernous self-injection with vasoactive intestinal polypeptide and phentolamine in the management of erectile failure. J. Urol. 147: 1277, 1992. 383. MARQUER, C. AND BRESSOLLE, F.: Moxisylyte: a review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic use in impotence. Fundam. Clin. Pharmacol. 12: 377, 1998.

394. TRAISH, A.M., MORELAND, R.B., GALLANT, C., HUANG, Y.H. AND GOLDSTEIN. I.: G-protein-coupled receptor agonists augment adenylyl cyclase activity induced by forskolin in human corpus cavernosum smooth muscle cells. Recept. Signal Transduct. 7: 121, 1997.

384. IMAGAWA, A., KIMURA, K., KAWANISHI, Y.AND TAMURA, M .: Effect of moxisylyte hydrochloride on isolated human penile corpus cavernosum tissue, Life Sci. 44: 619, 1989.

395. MOLDERINGS, G.J., VAN AHLEN, H. AND GÖTHERT, M .: Modulation of noradrenaline release in human corpus cavernosum by presynaptic prostaglandin receptors, Int. J. Impot. Res. 4: 19, 1992.

385. BRINDLEY, G.S. Pilot experiments on the actions of drugs injected into the human corpus cavernosum penis, Br. J. Pharmacol. 87: 495, 1986.

396. PALMER, L.S., VALCIC, M., GIRALDI, A.M., WAGNER, G. AND CHRIST, G.J.: Characterization of cyclic AMP accumulation in cultured human corpus cavernosum smooth muscle cells. J. Urol. 152: 1308, 1994.

386. BUVAT, J., LEMAIRE, A., BUVAT-HERBAUT, M. AND MARCOLIN, G.: Safety of intracavernous injections using an alpha-blocking agent. J. Urol. 141:1364, 1989.

397. LIN, J.S.-N., LIN, J.-M., JOU, Y.-C. AND CHENG, J.T.: Role of cyclic adenosine monophosphate in prostaglandin E1-induced penile erection in rabbits. Eur. Urol. 28: 259, 1995.

387. BUVAT, J., BUVAT-HERBAUT, M., LEMAIRE, A. AND MARCILIN, G.: Reduced rate of fibrotic nodules in the cavernous bodies following auto-intracavernous injections of moxisylyte compared to papaverine. Int. J. Impot. Res. 3: 123, 1991.

398. CAHN, D., MELMAN, A., VALCIC, M. AND CHRIST, G.J.: FORSKOLIN: A promising new adjunct to intracavernous pharmacotherapy. J. Urol. 155: 1789, 1996.

388. ARVIS, G., RIVET, G., SCHWENT, B.: Utilisation prolongée de chlorhydrate de moxisylyte (Icavex®) en auto-injections intra-caverneuses dans le traitement de l´impuissance. J. Urol. (Paris) 102: 151, 1996.

399. GLOUB, M., ZIA, P. AND MASTSUNO, M.:Metabolism of prostaglandins A and E1 in man. J. Clin. Invest. 56: 1404, 1975.

389. BUVAT, J., LEMAIRE, A., BUVAT-HERBAUT, M.: Intracavernous pharmacotherapy: comparison of moxisylyte and prostaglandin E1. Int. J. Impot. Res. 8: 41, 1996.

400. MULHALL, J.P., DALLER, M., TRAISH, A.M., GUPTA, S., PARK, K., SALIMPOUR, P., PAYTON, T.R., KRANE, R.J. AND GOLDSTEIN, I.: Intracavernosal forskolin: role in management of vasculogenic impotence resistant to standard 3-agent pharmacotherapy. J. Urol. 158: 1752, 1997.

390. DE TEJADA, I.S., GARVEY, D.S., SCHROEDER, J.D., SHELEKHIN, T., LETTS, L.G., FERNANDEZ, A., CUEVAS, B., GABANCHO, S., MARTINEZ, V., ANGULO, J., TROCHA, M., MAREK, P., CUEVAS, P. AND TAM, S.W.: Design and evaluation of nitrosy lated alpha-adrenergic receptor antagonists as potential agents for the treatment of impotence. J. Pharmacol. Exp. Ther. 290: 121, 1999.

401. LAURENZA, A., ROBBINS, J.D. AND SEAMON, K.B.: Interaction of aminoalkylcarbamates of forskolin with adenylyl cyclase: synthesis of an iodinated derivative of forskolin with high affinity for adenylyl cyclase. Mol. Pharmacol. 41: 360, 1992.

391. HELLSTROM, W.J.G., BENNETT, A.H., GESUNDHEIT, N., KAISER, F.E., LUE, T.F., PADMANATHAN, H., PETERSON, C.A., TAM, P.Y., TODD, L.K., VARADY, J.C.AND PLACE, V.A.: A doubleblind, placebo-controlled evaluation of the erectile response to transurethral alprostadil. Urology 48: 851, 1996.

402. ANDERSSON, K.-E. AND STIEF, C.G.: Neurotransmission, contraction and relaxation of penile erectile tissues, World J. Urol. 15: 14, 1997. 403. WAGNER, G.AND GERSTENBERG, T.: Vasoactive intestinal peptide facilitates normal erection. In Proceedings of the Sixth Biennal International Symposium for Corpus Cavernosum Revascularization and the Third Biennal World Meeting on Impotence. Boston, Massachusetts, October 6-9, 146, 1988.

392. PADMA-NATHAN, H., HELLSTROM, W.J.G., KAISER, F.E., LABASKY, R.F., LUE, T.F., NOLTEN, W.E., NORWOOD, P.C., PETERSON, C.A., SHAB-

199

404. ADAIKAN, P.G., KOTTEGODA, S.R. AND RATNAM, S.S.: Is vasoactive intestinal polypeptide the principal transmitter involved in human penile erection? J. Urol. 135: 638, 1986.

417. FEELISCH. M.: Cellular and non-cellular metabolism of organic nitrates to nitric oxide: involvement of enzymic and non-enzymic pathways. In: The Biology of Nitric Oxide. I Physiological and Clinical Aspects. S Moncada, MA Marletta, JB Hibbs Jr, EA Higgs (eds) Portland Press Proceedings, 13-17, 1992.

405. 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.

418. ROSENKRANZ, B., WINKELMANN, B.R. AND PARNHAM, M.J.: Clinical pharmacokinetics of molsidomine. Clin Pharmacokinet 30: 372, 1996.

406. ROY, J.B., PETRONE, R.L. AND SAID, S.:A clinical trial of intracavernous vasoactive intestinal peptide to induce penile erection. J. Urol. 143: 302, 1990.

419. REDEN, J,: Molsidomine. Blood Vessels 27: 282, 1990.

407. GERSTENBERG, T.C., METZ, P., OTTESEN, B. AND FAHRENKRUG, J.: Intracavernous self-injection with vasoactive intestinal polypeptide and phentolamine in the management of erectile failure. J. Urol. 147: 1277, 1992.

420. WILDGRUBE, H.J., OSTROWSKI, J., CHAMBERLAIN, J., GÄRTNER, W.AND STOCKHAUSEN, H.: 3-morpholinosydnonimine in healthy volunteers. Arzneim. Forsch. (Drug Res) 36: 1129, 1986. 421. STIEF, C.G., HOLMQUIST, F., ALLHOFF, E.P., ANDERSSON, K.-E. AND JONAS, U.: Preliminary report on the effect of the nitric oxide (NO) donor SIN1 on human cavernous tissue in vivo, World J. Urol. 9: 237, 1991.

408. 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. 409. PALMER, J.B.D., CUSS, F.M., WARREN, J.B., BLANK,M., BLOOM, S.R. AND BARNES, P.J.: Effect of infused vasoactive intestinal peptide on airway function in normal subjects. Thorax 41: 663, 1986.

422. STIEF, C.G., HOLMQUIST, F., DJAMILIAN, M., KRAH, H., ANDERSSON, K.-E. AND JONAS, U.: (1992) Preliminary results with the nitric oxide donor linsidomine chlorhydrate in the treatment of human erectile dysfunction. J. Urol. 148: 1437, 1992.

410. KREJS, G.J.: Effect of vasoactive intestinal peptide in man. Ann. N. Y. Acad. Sci. 527: 501, 1988.

423. TRUSS, M.C., BECKER, A.J., DJAMILIAN, M.H., STIEF, C.G. AND JONAS, U.: Role of the nitric oxide donor linsidomine chlorhydrate (SIN-1) in the diagnosis and treatment of erectile dysfunction. Urology 44: 553, 1994.

411. STIEF, C.G., BENARD, F., BOSCH, R.J.L.H., ABOSEIF , S.R., LUE, T. AND TANAGHO, E.A. : A possible role for calcitonin-gene-related peptide in the regulation of the smooth muscle tone of the bladder and penis. J. Urol. 143: 392, 1990.

424. PORST, H.: Prostaglandin E1 and the nitric oxide donor linsidomine for erectile failure for erectile failure: a diagnostic comparative study of 40 patients. J. Urol. 149: 1280, 1993.

412. CROSSMAN, D., MCEWAN, J., MACDERMOT, J., MACINTYRE. I, DOLLERY C.T.: Human calcitonin gene-related peptide activates adenylate cyclase and releases prostacyclin from human umbilical vein endothelial cells. Br. J. Pharmacol. 92: 695, 1987.

425. WEGNER, H.E.H., KNISPEL, H.H., KLÄN, R., MEIER, T. AND MILLER, K.: Prostaglandin E1 versus linsidomine chlorhydrate in erectile dysfunction. Urol. Int. 53:214, 1994.

413. PERSSON, K., GARCIA-PASCUAL. A. AND ANDERSSON, K.-E .: Differences in the actions of calcitonin gene-related peptide (CGRP) in pig detrusor and vesical arterial smooth muscle. Acta Physiol. Scand. 143: 45, 1991.

426. MARTINEZ-PINEIRO, L., LOPEZ-TELLO, J., ALONSO DORREGO, J.M., CISNEROS, J., CUERVO, E. AND MARTINEZ-PINEIRO, J.A.: Preliminary results of a comparative study with intracavernous sodium nitroprusside and prostaglandin E1 in patients with erectile dysfunction. J Urol 153: 1487, 1995.

414. ALARANTA, S., UUSITALO, H., HAUTAMÄKI, A.M. AND KLINGE, E.: Calcitonin gene-related peptide: immunohistochemical localization in, and effects on, the bovine penile artery. Int. J. Impot. Res. 3: 49, 1991.

427. TARHAN, F., KUYUMCUOGLU, U., KOLSUZ, A., OZGUL, A. AND CANGUVEN, O.: Effect of intracavernosal sodium nitroprusside in impotence. Urol. Int. 56: 211, 1996.

415. STIEF, C.G., WETTERAUER, U., SCHAEBSDAU, F. AND JONAS, U.: Calcitonin-gene-related peptide: A possible role in human penile erection and its therapeutical application in impotent patients. J. Urol. 146: 1010, 1991.

428. HEATON, J.P.W. Synthetic nitrovasodilators are effective, in vitro, in relaxing penile tissue from impotent men: the findings and their implications. Can. J. Physiol. Pharmacol. 67:78, 1989.

416. TRUSS, M.C., BECKER, A.J. AND THON, W.F.: Intracavernous calcitonin gene-related peptide plus prostaglandin E1: possible alternative to penile implants in selected patients. Eur. Urol. 26: 40, 1994.

429. TALLEY, J.D. AND CRAWLEY, I.S.: Transdermal nitrate, penile erection and spousal headache. Ann. Intern. Med. 103: 804, 1985.

200

430. OWEN, J.A., SAUNDERS, F., HARRIS, C., FENEMORE, J., REID, K., SURRIDGE, D., CONDRA, M. AND MORALES, A.: (1989) Topical nitroglycerin: a potential treatment for impotence. J. Urol. 141: 546, 1989.

444. GWINUP, G.: Oral phentolamine in non-specific erectile insufficency, Ann. Intern. Med. 109: 162, 1988. 445. ZORGNIOTTI, A.W.: ”On demand” erection with oral prparations for impotence: 3-(N-(2-imidazoline2ylmethyl)-p-toluidinol) phenol mesylate, Int. J. Impot. Res 4(Supplement2):A99, 1992.

431. CLAES, H- AND BAERT, L.: (1989) Transcutaneous nitroglycerin therapy in the treatment of impotence. Urol. Int 44: 309, 1989.

446. BECKER, A.J., STIEF, C.G., MACHTENS, S., SCHULTHEISS, D., HARTMANN, U., TRUSS, M.C. AND JONAS, U.: Oral phentolamine as treatment for erectile dysfunction. J. Urol. 159: 1214, 1998.

432. MEYHOFF, H.H., ROSENKILDE, P., BØDKER. A.: Non-invasive management of impotence with transcutaneous nitroglycerin, Br. J. Urol. 69: 88, 1992.

447. GOLDBERG, M.R. AND ROBERTSON, D.: Yohimbine: a pharmacological probe for study of the a2-adrenoceptor, Pharmacol. Rev. 35: 143, 1983.

433. SØNKSEN, J. AND BIERING SØRENSEN, F.: Transcutaneous nitroglycerin in the treatment of erectile dysfunction in spinal cord injured, Paraplegia 30: 554, 1992.

448. DANJOU, P., ALEXANDRE, L., WAROT, D., LACOMBLEZ, L. AND PUECH, A.J.:Assessment of erectogenic properties of apomorphine and yohimbine in man. Br. J. Clin. Pharmacol. 26: 733, 1988.

434. RENGANATHAN, R., SURANJAN, B. AND KURIEN, T.: Comparison of transdermal nitroglycerin and intracavernous injection of papaverine in the treatment of erectile dysfunction in patients with spinal cord injuries, Spinal Cord 35: 99, 1997.

449. MONTORSI, F., STRAMBI, L.F., GUAZZONI, G., GALLI, L., BARBIERI, L., RIGATTI, P., PIZZINI, G. AND MIANI, A.: Effect of yohimbine-trazodone on psychogenic impotence: a randomized, doubleblind, placebo-controlled study. Urology 44:732, 1994.

435. STEERS, W.D.:Viagra--after one year. Urology 54: 12, 1999. 436. ZUSMAN, R.M., MORALES, A., GLASSER, D.B. AND OSTERLOH, I.H.: Overall cardiovascular profile of sildenafil citrate. Am. J. Cardiol. 83:35C, 1999.

450. JACOBSEN, F.M.: Fluoxetin-induced sexual dysfunction and an open trial of yohimbine. J. Clin. Psychiatry 53: 119, 1992.

437. CONTI, C.R., PEPINE, C.J.AND SWEENEY, M.; Efficacy and safety of sildenafil citrate in the treatment of erectile dysfunction in patients with ischemic heart disease. Am. J. Cardiol. 83: 29C, 1999.

451. CHARNEY, D.S. AND HENINGER, G.R.: Alpha2adrenergic and opiate receptor blockade. Arch. Gen. Psychiatry 43: 1037, 1986.

438. MEULEMAN, E., LYCKLAMA À NIJEHOLT, G., SLOB, K., ROELEVELD, N., DAMEN, L., DE BRAZAO, D., PADMA-NATHAN, H. AND ROSEN, R.: Effects of IC351 on erectile response to visual sexual stimulation. J. Urol. 161: Supplement 212 (abstract 814), 1999.

452. MORALES, A., CONDRA, M. AND OWEN, J.A.: Is yohimbine effective in the treatment of organic impotence? Results of a controlled trial, J. Urol. 137: 1168, 1987. 453. REID, K., MORALES, A., HARRIS, C., SURRIDGE, D.H. CONDRA, M. AND OWEN J.: Double-blind trial of yohimbine in treatment of psychogenic impotence, Lancet i: 421, 1987.

439. PADMA-NATHAN, H., BENNETT, A.H., GESUNDHEIT, N. et al.: Treatment of erectile dysfunction by the medicated urethral system for erection (MUSE), J. Urol. 153: 473A, 1995.

454. RILEY, A.J., GOODMAN, R.E., KELLETT, J.M. AND ORR R.: Double blind trial of yohimbine hydrochloride in the treatment of erection inadequacy. Sexual and Marital Therapy 4:17-26, 1989.

440. BENEVIDES, M.D., PARIVAR, K., VICK, R.N., PATEL, M.P. AND CARSON, C.C.: Intracavernosal (IC) injection of a potassium channel opener to treat erectile dysfunction. J. Urol. 161Supplement:: 212 (abstract 812), 1999.

455. SUSSET, J.G., TESSIER, C.D., WINCZE, J., BANSAL, S., MALHOTRA, C. AND SCHWACHA, M.G.: Effect of yohimbine hydrochloride on erectile impotence: a double-blind study. J. Urol. 141: 1360, 1989.

441. ANDERSSON, K.-E.:Clinical pharmacology of potassium channel openers, Pharmacol. Toxicol. 70:244, 1992.

456. TURCHI, P., CANALE, D., DUCCI, M., NANNIPERI, E., SERAFINI, M.F. AND MENCHINI FABRIS, G.F.: The transdermal route in the treatment of male sexual impotence: preliminary data on the use of yohimbine, Int. J. Impot. Res. 4: 45, 1992.

442. MCCALL, J.M., AIKEN, J.W., CHIDESTER, C.G., DUCHARME, D.W. AND WENDLING, M.G.: Pyrimidine and triazine 3-oxide sulfates: a new family of vasodilators, J. Med. Chem. 26: 1791, 1983.

457. KUNELIUS, P., HÄKKINEN, J. AND LUKKARINEN, O.: Is high-dose yohimbine hydrochloride effective in the treatment of mixed-type impotence? A prospective, randomized, controlled double-blind crossover study. Urology 49:441, 1997.

443. CAVALLINI, G.: Minoxidil versus nitroglycerin: a prospective double-blind controlled trial in transcutanous erection facilitation for organic impotence, J. Urol. 146: 50, 1991.

201

458. VOGT, H.-J., BRANDL, P. AND KOCKOTT, G.: Double-blind, placebo-controlled safety and efficacy trial with yohimbine hydrochloride in the treatment of nonorganic erectile dysfunction. Int. J. Impot. Res. 9: 155, 1997.

473. LAL, S., ACKMAN, D., THAVUNDAYIL, J.X., KIELY, M. AND ETIENNE, P.: Effect of apomorphine, a dopamine receptor agonist, on penile tumescence in normal subjects. Progr. Neuro-Psychopharmacol. Biol. Psychiat. 8: 695, 1984. 474. LAL, S., LARYEA, E., THAVUNDAYIL, J.X., NAIR, N.P., NEGRETE, J., ACKMAN, D., BLUNDELL, P. AND GARDINER, R.J : Apomorphine-induced penile tumescence in impotent patients-preliminary findings. Progr. Neuro-Psychopharmacol. Biol. Psychiat. 11: 235, 1987.

459. OWEN, J.A., NAKATSU, S.L., FENEMORE, J., CONDRA, M., SURRIDGE, D.H.C. AND MORALES, A. : The pharmacokinetics of yohimbine in man. Eur. J. Clin. Pharmacol. 32:577, 1987. 460. GALITZKY, J., RIVIÈRE, D. AND TRAN, M.A.: Pharmacodynamic effects of chronic yohimbine treatment in healthy volunteers. Eur. J. Clin. Pharmacol. 39: 447, 1990. 461. CHARNEY, D.S., HENINGER, G.R. AND STERNBERG, D.E.: Assessment of alpha2-adrenergic autoregulator function in humans: effects of oral yohimbine, Life Sci. 30: 2033, 1982. 462. CHARNEY, D.S., HENINGER, G.R. AND REDMOND, JR, D.E.: Yohimbine induced anxiety and increased noradrenergic function in humans: effects of diazepam and clonidine. Life Sci, 33:19, 1983.

475. LAL, S., LARYEA, E., THAVUNDAYIL, J.X., NAIR, N.P., NEGRETE, J., ACKMAN ,D., BLUNDELL, P. AND GARDINER, R.J.: Apomorphine: clinical studies on erectile impotence and yawning. Progr. NeuroPsychopharmacol. Biol. Psychiat. 13: 329, 1989. 476. VOGEL, H.P. AND SCHIFFTER, R.: Hypersexuality a complication of dopaminergic therapy in Parkinson´s disease. Pharmacopsychiat. 16: 107, 1983. 477. ZARRINDAST, M.-R., SHOKRAVI, S. AND SAMINI, M.: Opposite influences of dopaminergic receptor subtypes on penile erection. Gen. Pharmacol. 23: 671, 1992. 478. POMERANTZ, S.M.: Quinelorane (LY 163502), a D2 dopamine receptor agonist, acts centrally to facilitate penile erections of male rhesus monkeys. Pharmacol. Biochem. Behav. 39:123, 1991. 479. JULIEN, E. AND OVER, R.:Male sexual arousal with repeated exposure to erotic stimuli. Arch. Sexual Behavior 13: 211, 1984. 480. SEGRAVES, R.T., BARI, M., SEGRAVES, K. AND SPIRNA, P.: Effect of apomorphine on penile tumescence in men with psychogenic impotence. J. Urol. 145: 1174, 1991.

463. PRICE, L.H., CHARNEY, D.S. AND HENINGER, G.R.: Three cases of manic symptoms following yohimbine administration. Am. J. Psychiatr. 141: 1267, 1984. 464. PARR, D.: Sexual aspects of drug abuse in narcotic addicts. Br. J. Addict. 71: 261, 1976. 465. CROWLEY,T.J. AND SIMPSON, A.: Methadone dose and human sexual behavior. Int. J. Addict. 13: 285, 1978. 466. FABBRI, A., JANNINI, E.A., GNESSI, L., MORETTI, C., ULISSE, S., FRANZESE, A., LAZZARI, R., FRAIOLI, F., FRAJESE, G. AND ISIDORI, A.: Endorphins in male impotence: evidence for naltrexone stimulation ef erectile activity in patient therapy, Psychoneuroendocrinology. 14: 103, 1989. 467. GOLDSTEIN, A. AND HANSTEEN, R.W.: Evidence against involvement of endorphine in sexual arousal and orgasm in man. Arch. Gen. Psychiatr. 34: 1179, 1977. 468. GOLDSTEIN, J.A.: Erectile function and naltrexone. Ann Intern Med 105: 99, 1986. 469. VAN AHLEN, H., PIECHOTA, H.J., KIAS, H.J, BRENNEMANN, W. AND KLINGMULLER, D.: Opiate antagonist in erectile dysfunction: a possible new treatment option? Results of a pilot study with naltrexone. Eur. Urol. 28: 246, 1995. 470. FOREMAN, M..M. AND HALL, J.L.: Effects of D2 dopaminergic receptor stimulation on male rat sexual behavior. J. Neural. Transm. 68: 153, 1987. 471. MOGILNIKA, E. AND KLIMEK, V.: (1977) Drugs affecting dopamine neurons and yawning behaviour. Pharmacol. Biochem. Behav. 31: 303, 1977. 472. BENASSI- BENELLI, A., FERRARI, F. AND PELLEGRINI-QUARANTOTTI, B.: Penile erection induced by apomorphine and N-n-propylnorapomorphine in rats. Arch. Int. Psychodyn. Ther. 242: 241, 1979.

481. HEATON, J.P.W., MORALES, A., ADAMS, M.A., JOHNSTON, B. AND EL-RASHIDY, R.: Recovery of erectile function by the oral administration of apomorphine Urology 45: 200, 1995. 482. PADMA-NATHAN, H., AUERBACH, S., LEWIS, R., LEWAND, M. AND PERDOK, R.: Efficacy and safety of apomorphine SL vs placebo for meale erectile dysfunction (MED). J. Urol. 161Supplement: 214 (abstract 821), 1999. 483. LEWIS, R., AGRE, K., FROMM S. AND RUFF, D. Efficacy of apomorphine SL vs placebo for erectile dysfunction in patinets with hypertension. J. Urol. 161Supplement: 214 (abstract 821), 1999. 484. GEORGOTAS, A., FORSELL, T.L., MANN, J.J., KIM, M.. AND GERSHON, S.: Trazodone hydrochloride: a wide spectrum antidepressant with a unique pharmacological profile. A review of its neurochemical effects, pharmacology, clinical efficacy, and toxicology. Pharmacotherapy 2: 255, 1982. 485. MONSMA, F.J., SHEN, Y. AND WARD, R.P.: Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs. Mol. Pharmacol. 43: 320, 1993.

202

486. STEERS ,W.D. AND DE GROAT, W.C.: Effects of mclorophenylpiperazine on penile and bladder function in rats. Am. J. Physiol. 257: R1441, 1989.

490. LANCE, R.L., ALBO, M., COSTABILE, R.A,. AND STEERS, W.D.: Oral trazodone as empirical therapy for erectile dysfunction: a retrospective review. Urology 46: 117, 1995.

487. BLANCO, R. AND AZADZOI, K.M.: Characterization of trazodone-associated priapism. J. Urol. 136: 203A, 1987

491. MEINHARDT, W., SCHMITZ, P.I.M., KROPMAN, R.F., DE LA FUENTE, R.B., LYCKLAMA A NIJEHOLT, A.A. AND ZWARTENDIJK, J.: Trazodone, a double blind trial for treatment of erectile dysfunction. Int. J. Impot. Res. 9: 163, 1997.

488. SAENZ DE TEJADA, I , WARE, J.C., BLANCO, R., PITTARD, J.T., NADIG, P.W., AZADZOI, K.M., KRANE, R.J. AND GOLDSTEIN, I: Pathophysiology of prolonged penile erection associated with trazodone use. J. Urol. 145: 60, 1991. 489. AZADZOI, K.M., PAYTON, T., KRANE, R.J. AND GOLDSTEIN, I.: Effects of intracavernosal trazodone hydrochloride: animal and human studies. J. Urol. 144: 1277, 1990.

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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.

2.

DAVIES T F, GOMEZ-PAN A, WATSON M J, MOUNT JOY C Q, HANKER J P, BESSER G M, HALL R. Reduced gonadotropin response to releasinghormone after chronic administration to impotent men. Clin. Endocrinol. 1977; 6 : 213-218.

3.

5.

PIRKE K M, KOCKOTT G, ALDENHOFF J, BESINGER U, FEIL W. Pituitary gonadal system function in patients with erectile impotence and premature ejaculation. Arch. Sex. Behav. 1979 ; 8 : 41-48.

6.

RACEY P A, ANSARI M A, ROWE P H, GLOVER T D. Testosterone in impotent men. J. Endocrinol. 1973 ; 59 : 23-29.

7.

BUVAT-HERBAUT M, BUVAT J, DANCOINE F, LEMAIRE A, MARCOLIN G. Serum bioavailable testosterone is decreased in 39% and serum free testosterone in 28% of the impotent patients who have normal serum total testosterone . Proceedings of the 3rd biennal world meeting on impotence. Boston, I988: 67.

8.

FORTI G, POZZAGLI M, CALABRESI E, FIORELLI G, SERIO M. Radioimmunoassay of plasma testosterone. J. Clin. Endocrinol. Metab. 1974 ; 3 : 5-17.

9.

RABOCH J, MELLAN J, STARKAL. Plasma testosterone in male patients with sexual dysfunction. Arch. Sex. Behav. 1975 ; 4 : 541-545.

11. BENKERT O, HOLSBOER F. Sexual dysfunction in male patients. Biological indices and classification. In Libbey J (ed): “Psychopharmacology of sexual disorders. Biological psychiatry. New prospects” London: N° 4, 1985: 133-144. 12. SPARK R F, WHITE R.A, CONNOLLY P.B. Impotence is not always psychogenic. Newer insights into hypothalamic-pituitary gonadal dysfunction. J.A.M.A. 1980 ; 243 : 750-755. 13. NICKEL J C, MORALES A, CONDRAM, FENEMORE J, SURRIDGE D.H. Endocrine dysfunction in impotence : incidence, significance and cost-effective screening. J.Urol. 1984 ; 132: 40-43.

REFERENCES ANSARI J M A. A study of 65 impotent males. J. Psychiat. 1975 ; 127 : 337-341.

LEGROS J J, MORMONTC, SERVAIS J A.A psychoneuroendocrinological study of erectle " psychogenic impotence " : a comparison between normal patients and patients with abnormal reaction to glucose tolerance test. In Academic press(ed) “Clinical psychoendocrinology in reproduction” Academic press: New York, 1978: 301-319.

10. VILLANI C, ARAGONA C, POZZI V, TAMBURELLO A, FELICIOTTI M. Plasma prolactin, FSH, LH and testosterone in 71 patients with sexual disturbance. In Carenza L, Pancheri P, Zichella L (eds): “Clinical psychoendocrinology in reproduction” London: Academic press, 1978 ; 21 : 457-464.

2. SUBSEQUENT FOLLOW UP (EVERY 6 MONTHS FOR 2 YEARS THEN ANNUALLY) Continuous monitoring of clinical symptoms and adverse effects of medication. Laboratory tests consist of urinalysis and complete blood cell counts, as well as DRE and PSA for prostate evaluation.

1.

4.

14. KEOGH E J, CARATI C J, EARLE C M, WISNIEWSKI Z S,LORD D J,Glancy J J et al. Diagnosis and medical treatment of erectile dysfunction. In Dennerstein L, Fraser J (eds): “Hormone and behaviour” Amsterdam: Elsevier Science, 1986: 406-415. 15. MAATMAN T J, MONTAGUE D K. Routine endocrine screening in impotence. Urology 1986 ; 27 : 499-502. 16. KROPMAN R F, VERDIJK R, LYCKLAMA A, NIJOHLT A.A.B, ROEFSEMA F. Routine endocrine screening in impotence : signifiance and cost effectiveness. Int. J. Impot. Res. 1991 ; 3 : 87-94.

LAWRENCE D M, SAWYER G I M. Plasma testosterone and testosterone binding-affinities in men with impotence, oligospermia and hypogonadism. Brit. Med. J. 1974 ; 1 : 349-351.

233

17. JOHNSON A R, JAROW J P. Is routine endocrine testing of impotent men necessary ? J. Urol. 1992 ; 147 : 1542-1543.

30. BUVAT J .Neurotransmetteurs cérébraux et contrôle du comportement sexuel masculin. Andrologie. 1996 ; 6 : 184-199.

18. BUVAT J, LEMAIRE A. Endocrine screening in 1022 men with erectile dysfunction : clinical significance and cost-effective strategy. J. Urol. 1997 ; 158 : 1764-1767.

31. CARANI C, GRANATA AR, FUSTINI MF, MARRAMA P. Prolactin and testosterone: their role in male sexual function. Int. J. Androl. 1996 ;19:48-54. 32. GRANATA AR, ROCHIRA V, LERCHL A, MARRA MA P, CARANI C. Relationship between sleep-related erections and testosterone levels in men. J. Androl. 1997;18 :522-527.

19. BUVAT J, LEMAIRE A, RATAJCZYK J. Role des hormones dans les dysfonctions sexuelles, l’homosexualité, le transsexualisme et les comportements sexuels deviants : Consequences diagnostiques et therapeutiques. Contracept. Fertil. Sex. 1996 ; 24 : 834-846.

33. SALMINIES S, KOCKOTTG, PIRKE KM, VOGTHJ, SCHILL WB. Effects of testosterone replacement on sexual behavior in hypogonadal men. Arch. Sex. Behav. 1982 ; 11 : 345-353.

20. KORENMAN S G, MORLEY JE, MOORADIAN AD, DAVIS SS, KAISER FE, SILVER AJ, VIOSCA SP, GARZAD. Secondary hypogonadism in older men : its relation to impotence. J. Clin. Endocrinol. Metab. 1990; 71 : 963-969.

34. BUENA F, SWERDLOFF R, STEINER B.S., LUCHMANSINGH P, PETERSON M.A., PANDIAN M.R., GALMARINI M, BHASIN S. Sexual function does not change when serum testosterone levels are pharmacologically varied within the normal male range. Fertil. Steril. 1993 ; 59 : 1118-1123.

21. ROUSSEAU L, DUPONT A, LABRIE F, COUTURE M. Sexuality changes in prostate cancer patients receiving antihormonal therapy combining the antiandrogen flutamide with medical (LHRH agonist) or surgical castration. Arch. Sex. Behav. 1988 ; 17 : 87-98.

35. WHO (World Health Organization). Task Force on Psychosocial Research in Family Planning . Hormonal contraception for men : acceptability and effects on sexuality. Studies in Family Planning 1982; 13 : 328342.

22. THIBAUT F, CORDIER B, KUHN J.M. Modulation médicamenteuse de la libido et de l’activité sexuelle. Annales d’Endocrinologie. 1994 ; 55 : 229-233.

36. ANDERSON RA., BANCROFT J, WU FCW. The effects of exogenous testosterone on sexuality and mood of normal men. J. Clin. Endocrinol. Metab. 1992 ; 75 : 1503-1507.

23. BAGATELLE C, HEIMAN JR, RIVIER RE, BREMMER WJ. Effects of endogenous testosterone and estradiol an sexual behaviour in normal young men. J. Clin. Endocrinol. Metab. 1994 ; 78 : 711-716.

37. O’CARROLL R, BANCROFT J. Testosterone therapy for low sexual interest and erectile dysfunction in men : a controlled study. Br. J. Psych. 1984 ; 145 : 146-151.

24. CARANI C, ZINI D, BALDINI A, DELLA CASA L, GHIZZANI A, MARRAMA P. Testosterone and prolactin : behavioural and psychophysiological approaches in men. In Bancroft J (ed): “The pharmacology of sexual function and dysfunction.” Amsterdam: Esteve Foundation Symposia, Vol 6. Excepta Medica,. Elsevier science, 1995 ; 145-150.

38. BUVAT J, BUVAT-HERBAUT M, LEMAIRE A. Human chorionic gonadotropin treatment of non organic erectile failure and lack of sexual desire : a doubleblind study. Urology. 1987 ; 30 : 216-219. 39. EVERITTB.J. Neuroendocrine mechanisms underlying appetitive and consummatory elements of masculine sexual behaviour. In Bancroft J(ed): “The pharmacology of sexual function and dysfunction.” Amsterdam: Esteve Foundation Symposia, Vol 6. Excepta Medica,. Elsevier science, 1995 ; 15-31.

25. ROSEN RC. Pharmacological effects on Nocturnal Penile Tumescence (NPT). In Bancroft J (ed): “The pharmacology of sexual function and dysfunction.” Amsterdam: Esteve Foundation Symposia, Vol 6. Excepta Medica,. Elsevier science, 1995 ; 277-287. 26. BURRIS AS, BANKS SM, CARTER CS, DAVIDSON JM, SHERINS RJ. A long term prospective study of the physiology and behavioural effects of hormone replacement in untreated hypogonadal men. J. Androl. 1992 ; 13 : 297-304.

40. BAUM MJ. Reassessing the role of medial preoptic area / anterior hypothalamic neurons in appetitive aspects of masculine sexual behavior. In Bancroft J(ed): “The pharmacology of sexual function and dysfunction.” Amsterdam: Esteve Foundation Symposia, Vol 6. Excepta Medica,. Elsevier science, 1995 ; 133-139.

27. COOPER AJ, LOSZTYN S, RUSSEL NC, CERNOVSKY Z. Medroxyprogesterone acetate, Nocturnal Penile Tumescence, laboratory arousal, and sexual acting out in a male with schizophrenia. Arch. Sex. Behav. 1990 ; 19 : 361-372.

41. CLARK JT. Sexual arousal and performance are modulated by adrenergic-neuropeptide-steroid interaction. In Bancroft J(ed): “The pharmacology of sexual function and dysfunction.” Amsterdam: Esteve Foundation Symposia, Vol 6. Excepta Medica,. Elsevier science, 1995 ; 55-68.

28. LANGE JD, BROWN WA, WINCZE J.P, ZWICK W. Serum testosterone concentration and penile tumescence changes in men. Horm. Behav. 1980 ; 14 : 267-270.

42. PUY L, MACLUSKY NJ, BECKER L, KARSAN N, TRACHTENBERG J, BROWN TJ.Immunocytochemical detection of androgen receptor in human temporal

29. BANCROFT J. Sexual desire and the brain. Sex. Marit. Ther. 1988 ; 3 : 11-27.

234

cortex characterization and application of polyclonal androgen receptor antibodies in frozen and paraffinembedded tissues. J. Steroid. Biochem. Mol. Biol. 1995;55:197-209.

terone, Action, Deficiency ,Substitution.” 2nd Ed. Berlin: Springer 1998: 437-471. 57. MEIKLE AW, BISHOP T, STRINGHAM JD, WEST DW. Quantitating genetic and non genetic factors to determine sex steroid variations in normal male twins. Metabolism 1986;35:1090-1095.

43. HART BL. Effects of testosterone propionate and dihydrotestosterone on penile morphology and sexual reflexes in spinal male rats. Horm. Behav. 1973; 4 : 239246.

58. VERMEULEN A, KAUFMAN JM. Role of the hypothalamo-pituitary function in hypoandrogenism of healthy aging. J.Clin.Endocrinol.Metab. 1992;74:1226ZA1226C.

44. BREEDLOVE SM, ARNOLD AP. Hormone accumulation in a sexually dimorphic motor nucleus of the rat spinal cord. Science. 1980 ; 210 : 564-566. 45. DAIL WG, EVAN AP, EASON HR. The major pelvic ganglion in the pelvic plexus of the male rat : a histochemical and ultrastructural study. Cell Tissue Res. 1975 ; 159 : 49-62.

59. DESLYPERE JP, KAUFMAN JM, VERMEULEN T, VOGELAERS D, VANDALEM JL, VERMEULEN A. Influence of age on pulsatile luteinizing hormone release and responsiveness of the gonadotrophs to sex hormone feedback. J.Clin.Endocrinol.Metab.1987;64:6873.

46. MELVIN JE, HAMILLRW. The major pelvic ganglion: androgen control of post-natal development. J. Neurosci. 1987 ; 7 : 1607-1612.

60. WINTERS J, SHERINS RJ, TROEN P. The gonadotropin suppressive activity of androgens is increased in elderly men. Metabolism 1984;33:1052-1059.

47. GIULIANO F, RAMPIN O, SCHIRAR A, JARDIN A, ROUSSEAU JP. Autonomic control of penile erection: modulation by testosterone in the rat. J. Neuroendocrinol. 1993 ; 5 : 677-683.

61. WINTERS SJ, ATKINSON L, Testoderm Study Group. Serum LH concentrations in hypogonadal men during transdermal testosteone replacement through scrotal skin: further evidence that aging enhances testosterone negative feed back. Clin.Endocrinol.1997;47:317-322.

48. MILLS TM, STOPPER VS, WIEDMEIER VT. Effects of castration and androgen replacements on the hemodynamics of penile erection in the rat. Biol. Reprod. 1994 ; 51 : 234-238. 49. REILLY CM, LEWIS RW, STOPPER VS, MILLS TM. Androgenic maintenance of the rat erectile response via a non-nitric-oxide-dependent pathway. J. Androl. 1997;18:588-594. 50. REILLY CM, ZAMORANO P, STOPPER VS, MILLS TM. Androgenic regulation of NO availability in rat penile erection. J. Androl. 1997;18:110-115.

62. RAJFER JK, NAMKUN PC, PETRAPH. Identfication, partial characterization of age associated changes in a cytoplasmatic androgen receptor in the rat penis. J.Ster.Biochem. 1980;13:1489-1492. 63. GONZALES-CADAVIT NF, SWERDLOFF RS, LEMMI CAE, RAJFER J. Expression of androgen receptor gene in rat penile tissue and cells during sexual maturation. Endocrinology 1991;129:1671-1678. 64. ZIRKIN BR, CHEN H, LUO L. Leydig cell steroidogenesis in aging rats. Exp. Gerontol. 1997; 32:529-537.

51. TENOVER JL. Testosterone and the aging male. J. Androl. 1997;18:103-106.

65. KORENMAN SG, MORLEY JE, MOORADIAN AD, DAVIS SS, KAISER, FE, SILVER AJ, VIOSCA SP, GARZAD. Secondary hypogonadism in older men: its relation to impotence. J. Clin. Endocrinol. Metab. 1990;71:963-969.

52. PEARSON UJD, BLACKMAN MR, METTER EJ, WACLAWIW Z, CARTER HB, HERMAN JM. Effect of age and cigarette smoking on longitudinal changes in androgens and SHBG in healthy males. 77th Ann.Meet.Endocrin.Soc.(Bethesda) pp 322 abstr. 12129.

66. FELDMAN HA, GOLDSTEIN I, HATZICHRISTOU, DG, KRANE RJ, MCKINLAY JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J. Urol. 1994;151:54-61.

53. MORLEY JE, KAISER FE, PERRY HM, PATICK P, MORLEY PM, STAUBER PM, VELLAS B, BAUMGARTNER RM, GARRY PJ. Longitudinal changes in testosterone, luteinizing hormone and follicle stimulating hormone in healthy old men. Metabolism 1997;46:410-413.

67. DAVIDSON JM, CHEN JJ, CRAPO L, GRAY GD, GREENLEAF WJ, CATANIA JA. Hormonal changes and sexual function in aging men. J. Clin. Endocrinol. Metab. 1983;57:71-74. 68. FINKLE AL, MOYERS TG, TOBENKIN MI, KARG SJ. Sexual potency and aging males. JAMA 1959 ; 170:1391-1393.

54. VERMEULEN A, KAUFMAN JM, GIAGULLI VA. Influence of some biologocal indices on sex hormone binding globulin and androgen levels in aging and obese males. J.Clin.Endocrinol.Metab. 1996;81;1921-1927.

69. KINSEYAC, POMEROY WB, MARTIN CF. “Sexual Behavior in the Human Male.” Philadelphia: Saunders, 1948.

55. VERMEULEN A, KAUFMAN JM. Ageing of the hypothalamo-pituitary-testicular axis in men. Horm. Res. 1995;43:25-28. 56. KAUFMAN JM, VERMEULEN A. Androgens in Male Senescence. In: Nieschlag E, Behre HM (eds): “Testos-

70. MARTIN CE. Factors affecting sexual function in 60 79 year old married males. Arch. Sex. Behav. 1981;10:399-420.

235

71. PFEIFFER E, VERWOERDT A, WANG HS. Sexual behavior in aged men and women. Arch. Gen. Psychiatry 1968;19:753-758.

Experimental evidence for endothelium dependent relaxation and neuronal nitric oxide in corpus cavernosum. Yonsei Med. J. 1994; 35:308-313.

72. VERMEULEN A, RUBENS R, VERDONCK L. Testosterone secretion and metabolism in male senescence. J. Clin. Endocrinol. Metab. 1972;34:730-734.

88. ITALIANO G, PETRELLI L, MARIN A, et al. Ultrastructural analysis of the cavernous and dorsal penile nerves in experimental diabetes. Int. J. Impot. Res. 1993; 5:149-160.

73. MINHAS S, EARDLEY I. DIABETIC IMPOTENCE. IN CARSON CC, KIRBY RS, GOLDSTEIN I (eds): “Textbook of Erectile Dysfunction.” Oxford: Isis Medical Publishers, 1998: 531-540.

89. FRANCAVILLA S, PROPERZI G, BELLINI C, et al. Endothelin-1 in diabetic and nondiabetic men with erectile dysfunction. J. Urol. 1997;158:1770-1774.

74. MCCULLOCH DK, YOUNG RJ, PRESCOTT RJ et al. The natural history of impotence in diabetic men. Diabetologia 1984; 26:437-440.

90. KAISER FE. Sexuality and impotence in the aging man. Clin. Geriatr. Med. 1991;7:63-74. 91. ROSS R. The pathogenesis of atherosclerosis: a perspective for the 1990’s. Nature 1993; 362:801-818.

75. NALIBOFF BD, ROSENTHAL M. Effects of age on complications in adult onset diabetes. J. Geriatr. Soc. 1989; 37:838-842. 76. KLEIN R, KLEIN BE, LEE KE, et al. Prevalence of self-reported erectile dysfunction in people with long term IDBM. Diabetes Care 1996; 19:135-141.

92. HUTCHISON SJ, SUDHIR K, CHOU TM, et al. Testosterone worsens endothelial dysfunction associated with hypercholesterolemia and environmental tobacco smoke exposure in male rabbit aorta. J. Am. Col.Cardiol. 1997;29:800-807.

77. HAKIM LS, GOLDSTEIN I. Diabetic sexual dysfunction. Endocrinol. Metab. Clin. North Am. 1996; 25:379400.

93. SHARRETAR. Invasive versus non-invasive studies of risk factors and atherosclerosis. Circulation. 1993;87:1148-1158.

78. AZADZOI AM, DE TEJADA IS. Diabetes mellitus impairs neurogenic and endothelium dependent relaxation of rabbit corpus cavernosum smooth muscle. J. Urol. 1992;148:1587-1591.

94. KIM JH, KLYACHKIN ML, SVENDSEN E et al. Experimental hypercholesterolemia in rabbits induces cavernosal atherosclerosis with endothelial and smooth muscle dysfunction. J. Urol. 1994;151:198- 205.

79. DAVIES MG, KIM JH, KLYACHKIN ML et al. Diabetes mellitus and experimental vein graph structure and function. J Vasc. Surg. 1994;19:1031-1043.

95. KIM JH, DAVIES MG, KIM YC, HAGEN PO, CARSONCC. Dietary supplementation with the nitric oxide precursor. L-Arginine: the effects of corpus cavernosum contraction in the hypercholesterolemic rabbit. J. Urol. 1994;151:493A.

80. GUPTA S, MORELAND RE, PABBYA,et al. Diabetes induced structural changes in the rabbit corpus cavernosum. Int. J. Impot. Res.1996; 8:136(D55).

96. THORNE S, MULLEN MJ, CLARKSON P, et al. Early endothelial dysfunction in adults at risk from atherosclerosis: different responses to L-Arginine. J. Am. Col. Cardiol. 1998;32:110-116.

81. DE TEJADA IS, GOLDSTEIN I. Diabetic penile neuropathy. Urol. Clin. North Am. 1998;15:17-22. 82. WAGNER G, GERSTENBERG T, LEVIN RJ. Electrical activity of the corpus cavernosum during flacidity and erection of the human penis: a new diagnostic method. J. Urol. 1989; 142:723-725.

97. DAVIES MG, BARBER E, DALEAN H, HAGEN PO. L-Arginine supplementation improves venous endothelial cell but not smooth muscle cell dysfunction induced by prolonged diet induced hypercholesterolemia J. Invest. Surg. 1996; 9:415-422.

83. MURRAY FT, WYSS HU, THOMAS RG, et al. Gonadal dysfunction in diabetic men with organic impotence. J. Clin. Endocrinol. Metab.1987;65:127-135.

98. CLARKSON P, ADAMS MR, POWE AJ, et al. Oral LArginine improves endothelium dependent dilation in hypercholesterolemic young adults. J. Clin. Invest. 1996; 97:1989-1994.

84. DUNSMUIR WD, HOLMES SA. The etiology and management of erectile ejaculatory and fertility problems in men with diabetes mellitus. Diabetic Med.1996;13:700-708.

99. JORGE PA, OSAKI MR, DEALMEIDA E. Rapid reversal of endothelial dysfunction and hypercholesterolemic rabbits treated with Simvastatin and Pravastatin. Clin. Exp. Pharmacol. Physiol. 1997;24:948-953.

85. VEVES A, WEBSTER L, CHEN TF, et al. Aetiopathogenesis and management of impotence in diabetic males: four years experience from a combined clinic. Diabetic Med. 1995; 12:77-82. 86. BANCROFTJ, GUTIERREZ P. Erectile dysfunction in men with and without diabetes mellitus: a comparative study. Diabetic Med. 1996; 13:84-89.

100. SCHWARZACHER SP, HUTCHISON S, CHOU TM, et al. Antioxidant diet preserves endothelium dependent vasodilation in resistance arteries of hypocholesterolemic rabbits exposed to an environmental tobacco smoke. J. Cardiovasc. Pharmacol. 1998;31:649-653.

87. KIM YC, DAVIES MG, HAGEN PO, CARSON CC.

101. VAN HORN L, KAVEY RE: Diet and cardiovascular

236

disease prevention: What works. Ann. Behav. Med. 1997;19:197-212.

117. PROCCI WR, MARTIN DJ. Effect of maintenance hemodialysis on male sexual performance. J. Nerv Ment. Dis. 1985; 173:366-372.

102. GRUNDY SM: Cholesterol management in patients with heart disease. Postgrad. Med. 1997; 102:81-90.

118. LAWRENCE IG, PRICE DE HOWLETT TA, HARRIS KP, FEEHALLY J, WALLS J. Correcting impotence in the male dialysisi patient: experience with testosterone replacement and vacuum tumescence therapy. Am. J. Kidney Dis. 1998; 31:13-19.

103. MULLIGAN T, KATZ PG. Why aged men become impotent. Arch. Intern. Med. 1989;149:365-376. 104. GLASS AR, SWERDLOFF RS, BRAY GA, DAHMS WT,ATKINSON RL. Low serum testosterone and sex hormone-binding globulin in massively obese men. J. Clin. Endocrinol. Metab. 1977; 45:1211-1219.

119. KIDD GS, GLASS AR, VIGERSKY RA. The hypothalamic-pituitary-testicular axis in thyrotoxicosis. J. Clin. Endrinol. Metab. 1979; 48:798-802.

105. STRAIN GW, ZUMOFF B, KREAM J, STRAIN JJ, DEUCHER R, ROSENFELD RS, LEVIN J, FUKUSHIMA DK. Mild hypogonadotropic hypogonadism in obese men. Metabolism 1982; 31:871-875.

120. WORSTMAN J, ROSNER W, DUFAU ML. Abnormal testicular function in men with primary hypothyroidism. Am. J. Med. 1987;82:207-212. 121. MOLITCH ME. Prolactin; In, Melmed S (ed): “The Pituitary.” Cambridge:Blackwell, l995: 136-186.

106. SCHNEIDER G, KIRSCHNER MA, BERKOWITZ R, ERTELNH. Increased estrogen production in obese men. J. Clin. Endocrinol. Metab. 1979; 48:633- 638.

122. BOULOUX PMG, WASS JAH. Endocrinology. In Kirby RS, Carson CC, Webster GD(eds): “Impotence: Diagnosis and management of male erectile dysfunction” Oxford: Butterworth-Heinemann Ltd, 1991: 4454.

107. STANIK S, DORNFELD LP, MAXWELLMH, VIOSCASP, KORENMAN SG. The effect of weight loss on reproductive hormones in obese men. J. Clin. Endocrinol. Metab. 1981;53:828- 832.

123. SATO F, AOKI H, NAKAMURA K, TAGUCHI M, AOKI T, YASUDA N. Suppressive effects of chronic hyperprolactinemia on penile erection and yawning following administration of apomorphine to pituitarytransplanted rats. J. Androl. 1997;18:21-25.

108. RODGER RS, FLETCHER K, DEWAR J et al. Prevalence and pathogenesis of impotence in 100 uremic men. Uremia Invest. 1984-85; 8:89-96. 109. LIM VS, FANG VS. Gonadal dysfunction in uremic men. A study of the hypothalamo-pituitary-testicular axis before and after renal transplantation. Am. J. Med. 1975; 58: 655-662.

124. CARTER N, TYSON JE, TOLI G, VAN VLIET S, FAIMAN R, FRIESEN HG. Prolactin secreting tumors and hypogonadism in 22 men. N.E.J.M. 1978:299:847-852.

110. HANDELSMAN DJ, DONG Q. Hypothalamo-pituitary gonadal axis in chronic renal failure. Endocrinol. Metab. Clin. North Am. 1993; 22:145-161.

125. SWERDLOFF RS, WANG C. Influence of pituitary disease on sexual development and functioning. Psychother. Psychosom. 1998; 67:173-180.

111. COPPOLAA, CUOMO G. Pituitary-testicular evaluation in patients with chronic renal insufficiency in hemodialysis treatment. Minerva Med. 1990; 81:461464.

126. LEONARD MP, NICKEL CJ AND MORALES A. Hyperprolactinemia and impotence: why, when and how to investigate. J. Urol. 1989; 42:992-994. 127. MASTERS LA. Sex and aging. Expectations and reality Hosp. Pract. 1986;15:175-198.

112. WEIZMAN R, WEIZMAN A, LEVI J et al. Sexual dysfunction associated with hyperprolactinemia in males and females undergoing hemodialysis. Psychosom. Med. 1983; 45:259-269.

128. MCKINLAY JD, FELDMAN HA. Age related variations in sexual activity and interest in normal men. Results of the Massachussets Male Aging Study. In: Rossi AJ (ed): “Sexuality across life course.” Chicago: The University of Chicago Press, 1994:231-286.

113. GURA V, WEIZMAN A, MAOZ B, ZEVIN D, BENDAVID M. Hyperprolactinemia: a possible cause of sexual impotence in male patients undergoing chronic hemodialysis. Nephron 1980; 26:53-54.

129. MARTIN CE. Factors affecting sexual functioning in 60-79 year old married males. Arch.Sex.Behav. 1981;10:399-420.

114. KAUFMAN JM, HATZICHRISTOU DG, MULHALL JP, FITCH WP, GOSDSTEIN I. Impotence and chronic renal failure: a study of the hemodynamic pathophysiology. J. Urol. 1994; 151: 612-618.

130. FORBES GB, REINA JC. Adult lean body mass declines with age. Some longitudinal observations. Metabolism 1970;19:653-663.

115. WALTZER WC. Sexual and reproductive function in men treated with hemodialysisi and renal transplantation. J. Urol. 1981: 126:713- 716.

131. SHIMOKATA HA, TOBIN JD, MULLER DC, ELAHI D, COON RJ, ANDRES R. Studies on the distribution of body fat- 1. Effect of age, sex and obesity . J. Gerontol. Med. Sci. 1989;44:M66-M73.

116. NGHIEM D, CORRY R, PICON-MENDEZ G et al. Factors influencing male sexual impotence after renal transplantation. Urology 1983; 21:49-52.

132. MÄRIN P, HOLMÄNG S, JÖNNSON L, SJÖSTRÖM

237

L, KVISTB, HOLM G, BJÖRNTORP P.The effects of testosterone treatment on body composition and metabolism in middle aged men. Int. J. Obesity 1992 ; 16:991-997.

Vermeulen A(eds): “Androgens and the ageing male.” New York: Parthenon Publishing Group, 1997: 205211. 146. FRICK J, JUNGWIRTH A, ROVAN E.Androgens and the prostate. In: Nieschlag E, Behre HM (eds): “Testosterone, Action, Deficiency ,Substitution.” 2nd Ed. Berlin: Springer 1998: 259-292.

133. KATZNELSON L, FINKELSTEIN JS, SCHÖNFIELD AA, ROSENTHAL DI, ANDERSEN EJ, KLIBANSKI A. Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. J. Clin. Endocrinol. Metab. 1996;81:4358-4363.

147. ALEXANDERSEN P, HEARBO J, CHRISTIANSEN C. The relationship of natural androgens to coronary heart desease in males: a review. Atherosclerosis 1996;125:1-13.

134. GREENDALE G, EDELSTEIN S, BARRETTCONNOR E. Endogenous sex steroids and bone mineral density: The Rancho Bernardo Study. J. Bone Mineral Res. 1977,12:1833-1843.

148. BAGATELL CJ, BREMNER WJ. Androgens and progestogen effects on plasma lipids. Prog. Cardiovasc. Dis. 1995;38:2355-2371.

135. CHRISTIANSEN K. Behavioural correlates of testosterone. in: Nieschlag E, Behre HM (eds): “Testosterone, Action, Deficiency, Substitution.” 2nd Ed. Berlin: Springer, 1998: 107-142.

149. PHILLIPS GB, PINKERNELL RH, JING TY. The association of hypotestosteronemia with coronary artery disease. Arterioscler. Thromb. 1994;14:701-706.

136. KIM YC. Testosterone supplementation in the aging male. Int. J. Impot. Res. 1999 (in Press).

150. ZMUDA JM, THOMPSON PD, DICKINSON R, BAUSSERMAN LL. Testosterone decreases lipoprotein(a) in men. Am. J. Cardiol. 1996;77:1244-1247.

137. WHEELER MJ: The determination of bio-available testosterone. Ann. Clin. Biochem. 1995; 32: 345-357.

151. BARRETT-CONNOR E, KHAW KS. Endogenous sex hormones and cardiovascular disease in men: a prospective population based study. Circulation 1988 ; 78:539-545.

138. ROSNER W. Errors in the measurement of plasma testosterone. J. Clin. Endocrinol. Metab. 1997;82:20142015.

152. HAFFNER LM. Androgens in relation to cardiovascular disease and insulin resistance in aging men. In: Oddens BJ, Vermeulen A(eds): “Androgens and the ageing male.” New York: Parthenon Publishing Group, 1997: 65-93.

139. VERMEULEN A, LIEVE V, KAUFMAN JM. Critical evaluation of single methods for the estimation of tfree testosterone in serum. J .C l i n . Endocrinol. Metab. 1999 (In press). 140. VELDHUIS JD, URBAN RJ, LIZARRALDE G, JOHNSON ML, IRANMANESH A. Attenuation of lutenizing hormone secretory burst amplitude as a proximate basis for the hypoandrogenism of healthy aging in men. J. Clin. Endocrinol. Metab. 1992: 75: 5258.

153. HERMAN MR, ROBINSON JTC, MCCREDIE J, ADAMS MR, BOYER MJ, CELERMAJER DS. Androgen deprivation is associated with enhanced endothelin dependent dilatation in adult men. Arterioscler. Thromb. Vasc. Biol. 1997;17:2004-2005. 154. POLDERMAN KH, STEHOUWER CDA, VAN DE KAMP GJ, DEKKER GA, VERHEUGT FWA, GOOREN LJG. Influence of sex hormones on plasma endothelin levels. Ann. Int. Med. 1993;118:429-432.

141. MORALES A, BAIN J, RUIJS A, CHAPDELAINE A, Tremblay RR. Clinical practice guideline for screening and monitoring male patients receiving testosterone supplementation therapy. Int. J. Impot. Res. 1996; 8: 95-97.

155. GLAZER G. Atherogenic effects of anabolic steoids on serum lipids. Steroids 1991;151:1925-1933.

142. TENOVER J. Effects of androgen administration in the ageing male. In: Oddens BJ, Vermeulen A(eds): “Androgens and the ageing male.” New York: Parthenon Publishing Group, 1997: 191-204.

156. GUAYAT, BANSAL S, HODGE MB. Possible hypothalamic impotence : male counterpart to hypothalamic amenorrrhea ? Urology 1991 ; 38 : 317-322. 157. KRENTZ L E, ROSE R M, JENNINGS R. Suppression of plasma testosterone levels and psychological stress. Arch. Gen. Psychiatry 1972 ; 26 : 279-281.

143. BAGATELL CJ, BREMNER WJ. The effects of aging and testosterone on lipids and cardiovascular risk. J. Clin. Endocrinol. Metab. 1998; 83: 3340-3341.

158. BUVAT J. Hormones et comportement sexuel de l’homme : données physiologiques et physiopathologiques. Contracept. Fertil. Sex. 1996 ; 24 : 767-778.

144. MARIN P, LONN L, ANDERSSON B, ODEN B, OLBE L, BENGTSSON B-A, BJORNTORP P. Assimilation of triglycerides in subcutaneous and intraabdominal adipose tissue in vivo in men: effects of testosterone . J. Clin. Endocrinol. Metab. 1996; 81: 10181022.

159. FOX C, ISMAILA, LOVE D, KIRKHAM K, LORAI NE J. Studies on the relationship between plasma testosterone level and sexual activity. J. Endocrinol. 1972; 52 : 51-54.

145. GOOREN LJG, GILTAY EJ. Risks associated with long-term androgen supplementation. In: Oddens BJ,

160. ROWE P H, RACEY PA , LINCOLIN GA, ELL-

238

WOOD M, LEHANE J, SHENTON JC. The temporal relationship between the secretion of luteinizing hormone and testosterone in men. Endocrinology 1975 ; 64 : 17-26.

175. MORALES A, JOHNSTON B, HEATON JPW, LUNDIE M. Testosterone supplementation for hypogonadal impotence : assessment of biochemical measures and therapeutic outcomes. J. Urol. 1997 ; 157 : 849-854.

161. BRECHER J. Sex , stress and health. Int. J. Health Serv. 1977 ; 7 : 89-101.

176. GUAY A T, BANSALS,HEATLEY G J. Effect of raising endogenous testosterone levels in impotent men with secondary hypogonadism : double blind placebocontrolled trial with clomifene citrate. J. Clin. Endocrinol. Metab. 1995 ; 80 : 3546-3552.

162. ROWLAND DL, HEIMAN JR, GLADUE BA, HATCH JP, DOERING CH, WEILER SJ. Endocrine psychological and genital response to sexual arousal in men. Psychoneuroendocrinol. 1987 ; 12 : 149-158.

177. NANKIN H R ,LIN T, OSTERMAN J. Chronic testosterone cypionate therapy in secondary impotence. Fertil. Steril. 1986 ; 46 : 300-307.

163. VERMEULEN A. The aging of the endocrine system and its clinical consequences. The Aging Male 1998; 1(suppl 1): 1.

178. BENKERT O, WITT W, ADAM W, LEITZ A. Effects of testosterone undecanoate on sexual potency and the hypothalamic-pituitary-gonadal axis of impotent males. Arch. Sex. Behav. 1979 ; 8 : 471-480.

164. TENOVER JS. Effect of testosterone supplementation in the aging male. J. Clin. Endocrinol. Metab. 1992; 75: 1092-1098.

179. MOSS H B, PANZAK G L, TARTER R E. Sexual functionning of male anabolic steroid abusers. Arch. Sex. Behav. 1993, 22, 1-12.

165. MORALES A. Androgen supplementation in practice: the treatment of erectile dysfunction associated with hypotestosteronemia. In: Oddens BJ, Vermeulen A(eds): “Androgens and the ageing male.” New York: Parthenon Publishing Group, 1997: 233-245.

180. BURNS-COX N, GINGELLJC: Erectile dysfunction: Endocrinological therapies, risks and benefits of treatment. In Carson CC, Kirby RS, Goldstein I (eds): “Textbook of Erectile Dysfunction.” Oxford: Isis Medical Publishers, 1998: 327-344.

166. ROY AK, VELLANOWETH RL, DHEN S, SUPAKAR PC, JUNG MH, SONG CS, CHATTERJEE B. The evolutionary tangle of aging, sex, and reproduction and an experimental approach to its mollecular dissection. Exp. Gerontol. 1996; 31: 83-94.

181. MATSUMOTO AM: Clinical use and abuse of androgens and Anti-Androgens. In: Becker KL(ed.): “Principles and Practice of Endocrinology and Metabolism” 2nd Ed, Philadelphia: JD Lippincott, 1995: 1110-1119.

167. SUPAKAR PC, ROYAK. Role of transcription factors in the age-dependent regulation of the androgen receptor gene in rat liver. Biol. Signals 1996; 5: 170-179.

182. BHASIN S, STORER TW, BERMAN N, et.al.: The effects of supraphysiologic doses of testosterone on muscle size and strength in men. N.E. J.M. 1996: 335:1-8.

168. DAVIDSON J M, CAMARGO C A, SMITH E R. Effects of androgen on sexual behavior in hypogonadal men. J. Clin. Endocrinol. Metab. 1979 ; 48 : 935-941.

183. LIGNIERES B: Transdermal testosterone treatment of andropause. Ann. Med. 1993; 25:235-41.

169. KWAN M, GREENLEAF W J, MANN J, CRAPO L, DAVIDSON J M. The nature of androgen action on male sexuality : a combined laboratory-self-report study on hypogonadal men. J. Clin. Endocrinol. Metab. 1983 ; 57 : 557-562.

184. DICKERMAN RD, MCCONATHY WJ, ZACHARIAH NY. Testosterone, sex hormone-binding globulin, lipoproteins, and vascular disease risk. J. Cardiovasc. Risk 1997;4:363-366. 185. KRAUSS DJ, TAUB HA, LANTIGA LJ. Risks of blood volume changes in hypogonadal men treated with testosterone enanthate for erectile impotence. J. Urol. 1991; 146:1566-1570.

170. BURRIS A S, BANKS S.M, CARTER C.S, DAVIDSON J.M, SHERINS R.J. A long term prospective study of the physiologic and behavioural effects of hormone replacement in untreated hypogonadal men. J. Androl. 1992 ; 13 : 297-304.

186. EVENS RPAMERSON AB. Androgens and erythropoiesis J. Clin. Pharmacol. 1974; 14:94-101.

171. MULLIGAN T , SCHMIDT B. Testosterone and erectile failure. J. Gen. Int. Med. 1993 ; 8 : 517-521.

187. SEMPLE PD'A, LOWE GDO, PATTERSON J et al. Comparison of cerebral blood flow after venesection of bronchitic seconday polycythaemic and primary polycythaemic patienss. Scott. Med. J. 1983; 28:332-337.

172. ARVER S, DOBS A S, MEIKLE A W, ALLEN R P, SANDERS S W, MAZER N A. Improvement of sexual function in testosterone deficient men treated for 1 year with a permeation enhanced testosterone transdermal system. J. Urol. 1996 ; 155 : 1604-1608.

188. HAJJAR RR, KAISER FE, MORLEY JE. Outcomes of long-term testosterone replacement in older hypogonadal males: a retrospective analysis. J. Clin. Endocrinol. Metab. 1997;82:3793-3796.

173. MORALES A, JOHNSTON B, HEATON JW, CLARK A. Oral androgens in the treatment of hypogonadal impotent men. J. Urol. 1994 ; 152 : 1115-1118.

189. SANDBLOM RE, MATSUMOTO AM, SCHOENE RB, LEE KA, GIBLIN EC, BREMNER WJ, PIERSON DJ. Obstructive sleep apnea syndrome induced by testosterone administration N.E.J.M. 1983; 308:508-510.

174. RAKIC Z, STARCEVIC V, STARCEVIC V P, MARINKOVIC J. Testosterone treatment in men with erectile disorder and low levels of total testosterone in serum. Arch. Sex. Behav. 1997 ; 26 : 495-504.

190. URBAN RJ, BODENBURG YH, GILKISON C, FOX-

239

WORTH J, COGGAN AR, WOLFE RR, FERRANDO A. Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis. Am. J. Physiol. 1995; 269:E820-E826. 191. JACKSON JA, WAXMAN J, SPIEKERMAN AM. Prostatic complications of testosterone replacement therapy. Arch. Intern. Med. 1989; 149:2365-2366. 192. CURRAN MJ, BIHRLE W. Dramatic rise in prostatespecific antigen after androgen replacement in a hypogonadal man with occult adenocarcinoma of the prostate. Urology 1999 ;53:423-424. 193. BAGHERI SA AND BOYER JL. Peliosis hepatis associated with androgenic-anabolic steroid therapy; a severe form of hepatic injury. Ann. Intern. Med. 1974; 81:610-618.

196. VERMEULEN A. Clinical review 24. Androgens in the aging male. J. Clin. Endocrinol. Metab. 1991: 73: 221-224. 197. WEKSLER M. Hormone replacement therapy for men: has the time come? Geriatrics 1995; 50: 52-55. 198. MCALPINE JN, DOBS AS. Testosterone replacement in the elderly man. In AUA News January/February 1997. 199. CARTER HB, PARTIN AW. Diagnosis and staging of prostatic cancer. In: Walsh PC, Retik AB, Stamey TA, Vaughan ED (eds): “Campbell's Urology” Philadelphia: W.B. Saunders Company, 1996:2519-2537. 200. MORGENTALER A, BRUNING CO, DEWOLF WC. Occult prostatic cancer in men with low serum testosterone levels. JAMA 1996; 276: 1904-1906.

194. WU FC, FARLEY TM, PEREGOUDOV A AND WAITES GM. Effects of testosterone enanthate in normal men: experience from a multicenter contraceptive efficacy study. WHO task force on methods for the regulation of male fertility. Fertil. Steril. 1996; 65:626-636.

201. GOOREN LJG. A ten-year safety study of the oral androgen testosterone undecanoate. J. Androl. 1994; 15: 212-215. 202. CARTER HB , PEARSON JD. Prostate-specific antigen velocity and repeated measures of prostate-specific antigen. Urol. Clin. North Am. 1997; 24: 333-338.

195. WILSON JD, GRIFFIN JE. The use and misuse of androgens. Metabolism 1980; 29:1278-1295.

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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 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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1.

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.

2.

LAUMANN EO, PAIK A, ROSEN RC. Sexual dysfunction in the United States. Prevalence and predictors. JAMA 1999;281:537-541.

3.

BEECHAM L. UK issues guidance to doctors on Viagra. BMJ 1999; 318:279-281.

4.

KLEINMAN A. Patients and healers in the context of culture. University of California Press. Berkley, 1980.

5.

FELDMAN HA, GOLDSTEIN I, HARTZICHRISTOU DG, KRANE RB, MCKINLEY JB. Impotence and its medical and psychosocial correlates. J Urol 1996; 151:54-59.

6.

Sexuality in America. P Barthalow-Koch, DL Weis (eds) Continuum, New York. 1998:292.

7.

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.

8.

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.

sexual

problems.

BMJ

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

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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).

605

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-

613

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.

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(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 (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.

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4. Were you satisfied with the hardness of your erection? If yes, place 1 in the box. If no, place 0 in the box.

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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.

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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 …………………………………

1

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My sexual life is ………………………………….

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My partnership relation is ………………………..

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My family life 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

X

ECG

V2

V3

V4

V5

X

X

X

X

X

Clinical laboratory tests 1

X

X

X

IIEF

X

X

X

Dispense medication 1

X

Dispense diaries (SEP)

X

X

Collect medication 1

X

Collect and review diaries

X

Begin washout period

X

X

End washout period

X

Dispense medication 2

X

Collect medication 2

X

Monitor adverse events

X

X

X

X

X

Monitor use of concomitant medications

X

X

X

X

X

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.

REFERENCES 1.

2.

SULATANAS, LEAKER B, WYLLIE MG: A comparison between doxazosin and tamsulosin on mean arterial blood pressure and urethral pressure: attenuation of phenylehrine-induced pressor responses in normotensives. Eur J Urol 1998; 33:128A.

17. FREUND K, SCHER H, CHAN S, BEN-ARON M: Experimental analysis of paedophilia. Behav Res Ther 20:105-112, 1982.

FELDMAN HA, GOLDSTEIN I, HATZICHRISTOU DG, KRANE RJ, MCKINLAY JB: Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994; 151:54-61.

3.

LEVINE LA, LENTING EL: Use of nocturnal penile tumescence and rigidity in the evaluation of male erectile dysfunction. Urol Clin No Amer 22:775-788, 1995.

4.

BURRIS AS, BANKS SM, SHERINS RJ: Quantitative assessment of nocturnal penile tumescence and rigidity in normal men using a home monitor. J Androl 10:492498, 1989.

5.

SLOB AK, BLOM JH, VAN DER BOSCH JJ: Erection problems in medical practice: Differential diagnosis with a relatively simple method. J Urol 143:46-50, 1990.

6.

BRADLEY WE, TIMM GW, GALLAGHER JM et al: New method for continuous measurement of nocturnal penile tumescence and rigidity. Urol 26:4-9, 1985.

7.

LEVINE LA, LENTING EL: Use of nocturnal penile tumescence and rigidity in the evaluation of male erectile dysfunction. Urol Clin No Amer 22:775-788, 1995.

8.

LINET OI, OGRINC FG, for the Alprostadil Study Group: Efficacy and safety of intracavernosal alprostadil in men with erectile dysfunction. N Engl J Med 334:873-877, 1996.

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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Heading

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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

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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

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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

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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

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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 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

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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 (