PG Adaikan, SC Ng, C Chan, S Arulkumaran and SS Ratnam

Department of Obstetrics & Gynaecology, National University Hospital, National University of Singapore, 5 Lower Kent Ridge Road, Singapore 119074

An understanding f the actions of neurotransmitters and receptoral affinities in the corpus cavernosum (CC) muscle of the human penis has contributed immensely to the pharmaceutical manipulation of drug therapy for the treatment of impotence. Currently several routes of administration are being tested; these include oral (and sublingual), topical gel and patches, intraurethral and intracavernous routes of administration of vasoactive and smooth-muscle relaxing agents. Intracavernous (I/C) injections of agents that readily mimics the psychological erection has greatly simplified the multidisciplinary diagnostic investigations and management of impotence. For obvious reasons, other routes of administrations do not give the maximal efficacy as I/C routes as yet. The most widely tested drugs for I/C routes are the alpha-adrenoceptor blocking agents, papaverine and prostaglandin E1. Appropriate selection of cocktails will also enhance the efficacy of I/C injection. However, in recent years, there is a great surge and need for an efficient oral form of treatment for impotence. Currently used compounds such as yohimbine, phentolamine, trazodone, L-arginine and apomorphine have limited efficacy by oral use. Phosphodiesterase inhibitors (eg. Sildenafil) are also undergoing intensive trials by this route.

Many of the drugs used for erectile dysfunction exert their actons either through nitric oxide-cyclic GMP or AMP pathways or by unmasking the antierectile adrenergic tone. However, the existence of several other intermediary pathways under physiological and/or pathological conditions should not be discounted and further elucidations in these areas are necessitated. A greater understanding of the cellular mechanism, not only at the cavernosum level but also at the central and peripheral pathways and the mechanism related to hormones and libido would further contribute to more efficient drug development and therapy in the future.

Patients can be divided into three groups in terms of treatment procedures.

The physiology of erection and the relationship to pharmacotherapy for impotence will be discussed further.

Krane RJ, Boston University Medical Center, The University Hospital, USA

In 1973 intracavernosal penile prostheses were introduced in the United States. They were either non-inflatable or inflatable. Both types of prostheses have undergone many changes over the ensuing 24 years. Non-inflatable penile prostheses have become more mechanical and aesthetically pleasing, especially in the flaccid state. Inflatable penile prostheses have improved in terms of decreasing components, changes in material used, etc. The excellent results of penile prostheses have largely been maintained and it would be expected that greater than 90% of patients who receive them will be satisfied as will their partners.

The role of the penile prosthesis has obviously changed since 1973 when it was the only non-psychological therapeutic strategy available. At present, its role has really become the last therapy to be used after all other non-surgical therapies have been tried. In our clinic patients are offered all other forms of therapy before discussion of penile prostheses is even begun. Only after failing other therapies or refusing other therapies would we consider implantation of a prosthesis. In this paper a discussion will be presented of some of the newer forms of inflatable devices and their positive and negative characteristics.

Tom F Lue, M.D., Department of Urology, University of California, San Francisco, USA

Patient Selection Due to the multiple risk factors and overlapping causes of impotence, the majority of older patients with arteriogenic impotence are not candidates for arterial revascularization. However, young patients with discrete arterial lesions secondary to traumatic pelvic injuries are a good candidate.

Surgical Technique We prefer epigastric to dorsal artery bypass if the angiogram or color duplex ultrasound shows communication between the dorsal and the cavernous arteries. We routinely measure intraluminal pressure of the epigastric and the dorsal arteries via an arterial line setup. An arterio-arterial bypass is performed only if the pressure in the epigastric artery is 10 mmHg higher than the dorsal artery. If the pressure difference is less than 10 mmHg, an epigastric artery-dorsal vein anastomosis is performed.

Patient Selection Older men with venous leakage may have degenerative changes involving tunica albuginea, cavernous smooth muscle, nerve terminals and endothelium and therefore are not good candidates for venous surgery. The best candidates are patients with congenital or trauma-induced venous leakage.

Surgical Technique We prefer deep dorsal vein resection and crural ligation. The procedure is performed through an inguinoscrotal incision. After releasing the suspensory ligaments, the penis is detached from the pubic bone. The deep dorsal vein is identified and both proximal and distal ends are ligated to prevent the exit of agent toward the glans or the systemic circulation. The deep dorsal vein is ligated and resected. Careful microscopic dissection of the cavernous and dorsal arteries and the dorsal and cavernous nerves was then performed at the hilum of the penis. Once the entrance of the cavernous arteries is identified and the dorsal neurovascular bundle lifted from the tunica, a urethral catheter is inserted and a 1/2 cm segment of the crura isolated. Two umbilical tapes are then looped around each crus and ligated. The penis was then reattached to the periosteum of the pubis with nonabsorbable sutures and the tissue closed in layers to prevent penile shortening.

We prefer a Patient's goal-directed approach. At the first visit, the following is obtained: medical and psychosexual history, physical examination, and a blood test (complete blood count, fasting glucose, lipid profile, creatinine and testosterone, others if indicated). Patient is then given a pamphlet containing treatment options including, advantages, disadvantages and cost. We

explain the physiology of erection and various causes of erectile dysfunction to the patient. We then ask the patient (and partner, if present) his expectation and treatment goal. Additional work-up is tailored according to patient's age, general health and treatment goal.

Gorm Wagner, Department of Medical Physiology.
Panum Institute. University of Copenhagen. Denmark.

Traditionally ejaculatory disorders have been treated by sexologists and overwhelmingly by psychosocial modalities. Premature ejaculation is the most common disorder and is most often seen in men who have never masturbated and thus not been through a self-learning period. Most often cultural and/or religious attitudes are reasons for non-masturbatory behavior.

There are no clear or authorized definitions of P.E. and in principle fast ejaculation after vaginal intromission is a physiologically important event, as ejaculation is essential in reproduction.

The stop-start technique may help some but recent pharmacological studies and case reports have shown that serotonin uptake inhibitors are useful.

Retarded ejaculation is rather rare compared to P.E. No consensus as to etiology is existing and the condition is difficult to treat by psychological methods.

Anejaculation, complete and primary is extremely rare and gives rise to infertility.

Ejaculation can be provoked by penile vibratory stimulation and in this way it is possible to collect semen. Vibration and its use will be discussed.

A special group of anejaculators consists of man with spinal cord injury. Using vibration with a different amplitude makes it possible to obtain antegrade ejaculation in the majority of these patients.

Krane RJ, Boston University Medical Center, The University Hospital, USA

Prostaglandin El acts on corporal smooth musculature via its own receptor and works through the CAMP pathway to produce smooth muscle relaxation. It has been used both intracorporally, intraurethrally, and topically.

Initial reports on PGE1 were intracorporal and largely came from the Viennese experience in the latter part of the 1930s. Since then there has been a considerable amount of experience with intracorporal PGE1, either used alone or in combination with phentolamine and/or papaverine. Results of these studies will be presented. In addition, PGE1 was the first medical therapy approved by the FDA in both intracavemosal and intraurethral forms. A review of the multisite studies used in both forms will be presented. PGE1 has also been used in topical form and an early review of topical PGE1 will be presented.

The main side effect associated with this drug has been penile pain. This appears to be dose related as patients who have pain with PGE1 alone used intracavernosally, often are able to use bimix or trimix without significant side effects.

A review of the basic science and clinical studies using PGE1 will be presented in this paper.

Hartmut Porst, Hamburg

Based on numerous in-vitro and in-vivo animal and human studies dealing with the biochemical pathways involved in attaining and maintaining an erection, pharmaceutical facilities for the treatment of erectile dysfunction increased tremendously. Principally different pharmaceutical approaches for cavernous smooth muscle relaxation are presently available.

1 st : c-AMP pathway (CGRP, PGE1, Forskolin), 2nd : c-GMP-pathway mediated by NO-release (VIP, Nodonors), 3rd : Phosphodiesterase-inhibitors (Papaverin, Milrinone, Quazinone, Zaprinast, Sildenafil), 4th : Hyperpolarization by stimulation of maxi-K+ channels (PGE1, Potassium-channel-openers), 5th : influence on adrenergic tone (PGE1, a -adrenergic blockers like Phentolamine, Yohimbine), 6th : Inhibitors of Angiotensin 11 secretion/efficacy (Papaverine, PGE1, Ang II-antagonists Losartan, Valsartan). Due to the aforementioned multiplex approach PGE1, (Alprostadil) convincingly proved its superiority to other vasoactive substances like Papaverine/Phentolamine, Moxisylyte, Linsidomine, CGRP and was proclaimed as "First Choice Drug" by the Erectile Dysfunction Clinical Guidelines Panel of the American Urological Association 1996.

The personal experience with Alprostadil (up to 40 m g) in more than 6500 pts. Showed efficacy rates of 76% with priapisms >6h in only 0.25% and painful sensations in 9.5%.

In prospective long-term studies conducted by Schwarz Pharma Germany and Pharmacia & Upjohn, USA the total efficacy-rates at home use were > 90% in more than 31,000 injections. Penile fibrotic alterations were encountered in 11.7% (19/162) after 4 years of follow-up with Alprostadil-Alfadex (Viridalâ ) with spontaneous healing in 8/19 (42%). After Alprostadil-Sterile-Powder (Caverjectâ ) fibrotic changes were observed in 7.5% (51/683) after 18 months of follow-up and disappeared spontaneously in 33% (17/5 1). That indicates, that in only 5.3% of all patients develop plaques or deviations in longterm use of Alprostadil will persist.

Based on the available literature and considering both efficacy and safety, Alprostadil provided considerable superiority to Papaverine and Phentolamine. Futural promising drugs for self-injection therapy could be PDE III-V-inhibitors, Potassium channel openers, VIP/Phentolamine, PGEI/Forskolin and Ang IIantagonists.

Ross A Cartmill, Department of Urology,
Princess Alexandra Hospital, Brisbane, Australia.

This paper discusses the cost of the investigation, diagnosis and treatment sexual dysfunction in Australian society.

While Australia's health costs have been 8.5% of GDP for many years, other OECD countries spend more. USA spends 50% more per person on health care than Australia but Australia has one of the highest hospital admission rates and doctor visits per person per year. It is in this context that this paper discusses the costs involved in managing sexual dysfunction in Australian society.

The incidence of sexual dysfunction in Australia is not known. However in a population of approximately five million adult males more than 30,000 men began using intracavernosal injection therapy in the financial year 96/97. It is therefore probable the number of men seeking advice during this period would be approximately 100,000,

The majority of patients treated in Australia would be in the private sector. It is estimated that up to 50% of patients originally presenting do not have any investigations or treatment beyond the initial consultation. In the last financial year

1400 patients underwent a duplex cavernosal artery study costing $0.35 million. It is estimated that three million dollars is the cost for psychiatric counselling for patients with psychogenic dysfunction. Many more patients would be treated by psychologists and sex counsellors.

The most popular interventional method of treating erectile dysfunction is by intracavernosal injection of Prostaglandin. Consultation and teaching this technique would cost more than six million dollars while current estimates are that forty five million dollars is a conservative estimate of the cost of Prostaglandin. The Pharmaceutical Benefits Scheme would subsidise this to thirty five in overall cost at three million dollars per year. The PBS scheme is increasing in overall cost at three million dollars per year. It follows that Prostaglandin is a significant contributor to this rising cost of the Pharmaceutical Benefits Scheme.

Penile prostheses are a less significant cost in the overall management. Two hundred and thirty six one of the highest hospital admission rates and year with the total cost estimated at 2.9 million dollars. Another 0.75 million was spent on revisions of penile protheses.

These figures should be compared to a total Medicare outlay of six billion dollars.

There are hidden costs involved with managing sexual dysfunction when consideration is given to the social ramifications of this physiological problem. Given that one of Australia's greatest health problems is the spiralling cost of pharmaceuticals the current popularity of ramifications in future planning of Government health spending. Other surgical procedures relating to penile function consitute a minor segment of Australia's health spending.

METHODS: TOMHS, funded by NHLBI, was a double-blind, randomized control trial of 902 hypertensive individuals, treated with placebo or one of five active drugs including :

All participants also received intensive lifestyle counselling on weight loss, sodium reduction, alcohol reduction, and increased physical activity.

RESULTS : At baseline, 14.3% of men reported problems with sexual function . In men, the most common problem was obtaining and/or maintaining erections. Erection problems increased with age. Incidence of erection problems in men was 7.1 % over two years. Erection problems reported at baseline were somewhat self-limited, disappearing in over 50% of men by 24 months. Men with erection problems differed from those without at baseline in that they were older, more likely to have been on prior antihypertensive drugs, had higher baseline systolic blood pressure, and lower plasma HDL. At 24 months, incidence of erection problems ranged from 6% with doxazosin to 17% with chlorthalidone. 100% (8/8) participants on doxazosin who had erection problems at baseline had the problem disappear after randomization vs. 43% (6/14) on placebo (p=.04).

CONCLUSIONS : Type of antihypertensive therapy was related to incidence of erection problems in men. Disappearence of the problem was greatest on doxazosin. Doxazosin should be considered in patients with impotency, especially when treating BPH and/or hypertensives.

If age-specific prevalence rates are found to be comparable in Asia to those found in the US, almost 1 million men in Malaysia alone and as many as 190 million men throughout Asia may have some degree of ED.

A complete overview of medically prescribed oral medication used for treatment of e.d. will be given.
The problems regarding papers published in the literature will be discussed.
Further for discussion will be presented the difficulty in assessing the endpoints of treatment and clinical trials.

Young Chan Kim, M.D., Seok Hee Chung, M.D. Department of Urology, Pundang CHA Hospital,
Pochon CHA Medical University
Department of Oriental Rehabilitation Medicine,
College of Oriental Medicine, Kyung Hee University, Korea

"Jamu" (Pulverized plant product) is the oldest Traditional Indonesian Medicine (TIM), arguable safest and effective drug used for centuries to care human health. TIM has survived the storm of history and continues to grow from the emperic status to modern phytopharmaca and counterparts the Modern Western Medicine (MWM).

As MWM subscribes to the "single agent" theory, whereby disease is blamed on a very specific pathogen that invades the body, TIM would have taken a different approach. It traces illness to the root that cause critical imbalance and deficiency that govern and dysregulate the proper function of the human body, such as in ED. Although mechanism of erection is now well understood and many MWM are introducted with success to induce erection in man with ED, in fact ED is not a mere single symptom of a disease. ED is a result of a complex manifestation that cause mal function of the whole process of sexual function. Hence it is of paramount importance to focus on TIM with a good scientific research design, to avoid any undesirable effects as it has been skeptically looked by the modern world. Certain animal and plant product is still used for ED treatment. Myths of dried crocodile penis, testis, lamb meat, Susu-Telur-Madu-Jahe (Milk-Egg-Honey-Ginger) or "STMJ" are well-known believes among layman for ED treatment. Pasak bumi (Eurycoma longifolia), Kolesom (Talium paniculatum), diversities of Ginseng (radix Ginseng), Tangkur (radix Angelica sinensis), Purwaceng (Pimpinella pruacen), can be found as a single or mixed constituent in jamu. "ESHA", "SrongPas", "Kuku Bima", "Manergizer", are few samples of it. Regretful most jamu product is arguable for a scientific discussion. Only a few plant product is recently well studied on modem scientific views. Tribulus terrestris L. is one of it that has been experimented on a randomize double blind research design for its most active agent Protodioscin. TTL can achieve pregnancies in women of infertile couples with subfertile husbands, increase frequency of successful intercourses. Details on this matter will be discussed.

M.T.M. Ismail, Acting Director, Specialist Reproductive Research Center, National Population and Development Board, National Population and Family Development Board, Malaysia

Time immemorial, Asian folklores have described various decoctions and cure-alls prepared from plants and animal tissues that can enhance male virility or cure impotence.

In a recent Focus Group Discussion on Male Erectile Dysfunction conducted in the Specialist Reproductive Research Centre, National Population and Family Development Board, two FGD, each consists up of I I males from different walks of life from three main ethnic groups (Malay, Chinese and Indian) whose ages ranges from 40-80 yrs, mentioned that the practices of Asian Medicine are prevalent in their communities. The Chinese believes that taking ginseng and wine soaked in wild boar or tiger penises cure MED. The Indian believes that taking herbs to warrn up the body and eating drumsticks improve male virility. The Malays believe taking roots of herbs 'jamu' and 'majun' and undergoing traditional body massages overcome impotence and maintains virility.

The root of the common Asian Medicinal plant locally known as 'Tongkat Ali' has been mentioned by the FGDs to be effective in the management of MED. This plant is scientifically known as Eurycoma Longifolia, a somewhat tall slander shrub tree from the simaroubaceace family is commonly found along the hilly jungle slopes of Malaysia. This plant has been reputed to increase male prowess as described by J.D. Gimlette and J.W. Thomson in the 'A Dictionary of Malayan Medicine' Oxford University Press (1977) and decoction of the roots in water has been proven to be anticulcer, antipyretic and antimalaria. The aphrodisiac property of this plant has been evaluated by H.N. Ang and co-workers, School of Pharmaceutical Sciences, University Science Malaysia on mate mice.

In his paper entitled 'Enhancement, of Sexual motivation in Sexually Naive Male Mice, Ang found that oral administration of 0.5g/kg daily of different fraction of E.Longifolia in chloroform, methanol, water and butanol resulted in an enhancement of sexual motivation (mating) of the mice after 3 days post treatment, which further enhanced after 8 days, post treatment.

In a separate study by Johari M.Ali and co-workers, Biochemistry Unit, Faculty of Medicine, Department of Zoology, Faculty of Science, University Malaya, he was able to detect a 480% increase in hormone testosterone in mate mice after I week of treatment with Tongkat Ali explaining the mechanism of the aphrodisiac effect.

Obviously these studies have opened avenues towards practice of Asian medicine in the management of E.D. Human trial on the product has been proposed and is to be conducted by Institute of Medical Research, Ministry of Health and University Putra Malaysia with participation of LPPKN, early next year.

Gingell C, Ballard SA, Tang K, Turner LA, Price M Naylor AM
Bristol Urological Institute, Bristol, United Kingdom

Penile erection is a hemodynamic process involvin relaxation of smooth muscle of the corpus cavernosu and its associated arterioles. This relaxation proces results in an increased flow of blood into the trabecula spaces of the corpora cavernosa. Smooth muscl relaxation is mediated by nitric oxide (NO) which, durin sexual stimulation, is synthesized in the nerve terminal of parasympathetic non-adrenergic, non-cholinergi (NANC) neurons in the penis and by the endothelial cells lining blood vessels and the lacunar spaces of the corpora cavernosal. The NO activates guanylate cyclase resulting in an increased conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). CGMP provides the signal which leads to relaxation of smooth muscle of the corpus cavernosum and penile arteriolesi. The level of CGMP is regulated by a balance between the rate of synthesis by guanylate cyclase and the rate of hydrolytic breakdown to guanosine 5' monophosphate (GMP) by cyclic nucleotide phosphodiesterase (PDE) isozymes (see Beavo 1995 for a recent review)2. Therefore, agents that inhibit CGMP hydrolysis may increase the CGMP signal and could be expected to enhance relaxation of smooth muscle in the corpus cavernosum and thereby facilitate penile erectile responses.

Of the PDE isozymes, PDE5 and PDE6 are monospecific for CGMP as a substrate. PDE 3 and PDE4 preferentially hydroiyse cyclic adenosine monophosphate (cAMP), and PDEI and PDE2 accept both CGMP and CAMP as substrates2. We have shown that the major PDE activity in human corpus cavernosal tissue is cGMP-specific PDE5, with lower levels of PDE2 and PDE3 also present3. Sildenafil is a potent inhibitor of the CGMPspecific PDE5 isolated from human corpus cavemosum (HCC). It effectively blocks PDE5-mediated hydrolysis of CGMP and has an IC50 of 3.9 nM3. Sildenafil has low potency against PDE2 and PDE3, the other phosphodiesterases found in HCC, and is also a weak inhibitor of PDE4 (lC50 values>7300 nM). It has moderate activity against PDE1 from human cardiac ventricle (lC50 290 nM) and inhibits PDE6 activity isolated from bovine retina with a mean lC50 of 33 nM, ic. 9-fold higher than that for inhibition of PDE5.

The effects of sildenafil on the relaxation of human corpus cavernosum have been investigated in vitro using samples of fresh tissue obtained from men with erectile dysfunction who underwent surgery for implantation of penile prostheses. Electrical field stimulation (EFS) of the tissue samples caused transient frequency dependent relaxation responses that were shown to be mediated by neuronal NO acting via stimulation of guanylate cyclase. Sildenafil (0.001-1@M) enhanced the NO-dependent relaxation of HCC in a concentration-dependent manner, the response in the presence of I pM sildenafil was increased by up to 3-fold compared with pretreatment levels. Furthermore, sildenafil has been shown to increase CGMP, but not CAMP, in rabbit corpus cavernosal tissue in the presence of an NO-donor4. These results are consistent with the proposal that sildenafif inhibits breakdown of CGMP in corpus cavernosal tissue and thereby enhances the neuronal NO/cGMP pathway involved in relaxation of corpus cavernosum and penile erection.

There is now considerable evidence that NO, acting via CGMP, is the main physiological mediator of penile erection. The results of in vitro and clinical studies with sildenafil summarised here, are consistent with the proposal that PDE5 is the main regulator of CGMP levels during penile erection, and therefore selective inhibitors of PDE5 can enhance the erectile process. As a consequence, inhibitors of PDE5, such as sildenafil, represent an exciting new class of oral agents for the treatment of erectile dysfunction.

1. Burnett, A.L.: Role of nitric oxide in the physiology of erection. Biol. Reprod., 52:485-489, 1995.

2. Beavo, J.A.: Cyclic nucleotide phophodiesterases: Functional implications of multiple isoforms. Physiol. Rev., 75: 725-748, 1995.

3. Boolell, M., Allen, M.J., Ballard, S.A., Gepi-Attee, S., Muihead, G.J., Naylor, A.M., Osterloh, I.H., and Gingell, J.C.: Sildenafil: an orally active type 5 cyclic GMPspecific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int. J. Imp. Res., 8: 47-52, 1996.

Tom F Lue, M.D., Department of Urology, University of California, San Francisco, USA

Phentolamine Gwinup reported that 50mg of oral phentolamine HCI, 1.5 hours before coitus resulted in erection in 11/16 patients. Zorgniotti (1994) reported success in 36/85 (42.3%) patients with oral and 21/69 (31.8%) with buccal form of phentolamine mesylate (20 mg). Clinical trials are currently in progress in the US.

Yohimbine An CC2-adrenergic antagonist, has been reported to be effective in psychogenic impotence, a positive response rate of 62% (vs. 16% in placebo group) was noted. For patients with organic impotence, the response rate is marginal at best.

Trazodone A mild antidepressant with a rare incidence of priapism. Its effect on penile erection is thought to be the result of serotonergic and (a -adrenolytic activity. Clinical trials have shown a positive effect on nocturnal penile erection (Saenz de Tejada et al., 1991) and sexually stimulated erection (Lal et al., 1987). A combination of trazodone and yohimbine has also been reported to improve erectile function in some patients (Montorsi, 1994). The major problem of trazodone is its marked sedative effect, which may render sexual activity more difficult.

Pentoxifylline 400 mg t.i.d. was shown to be effective in improving penile brachial pressure index and erection in a placebo controlled trial.

Sildenafil A type V phosphodiesterase inhibitor that inhibits the breakdown of cyclic guanosine monophosphate (CGMP) has been shown to be effective in several clinical trials. In a study of more than 300 mostly "organic impotent" patients, 100 mg of sildenafil was reported to improve erection in about 80% of patients versus 30% in those who took placebo. The most common side effects include headaches (2-1 1 %), vasodilation (08.5%), dyspepsia (0-8.5%) and diarrhea (0-5%).

Apomorphine is well known to cause yawning and erection in animals and humans. Lal et al. (1987) have shown it to induce erections when injected subcutaneously, and sublingual apomorphine is also reportedly successful with minimal side effects (occasional nausea and vomitting).

Clinical trials are in progress (Heaton et al., 1995).

Raymond C Rosen. Ph.D.

UMDNJ-Robert Wood Johnson Medical School Center for Sexual and Marital Health

With the development of multiple new pharmacologic agents for erectile dysfunction (ED), it is essential that treatment outcome be assessed in a valid and reliable manner. Although laboratory-based diagnostic procedures are available, sexual function is best assessed in a naturalistic setting with patient self-report scales. These scales offer major advantages in terms of patient acceptance, ease of scoring and administration and standardization across test sites. Until recently, few validated scales were available; however two specific instruments are multidimensional, self-report questionnaire measures of male sexual function.

Tihe Brief Male Sexual Function Inventory (BMSFI) is an 11-item questionnaire for measuring male sexual function in a research for clinical setting. The scale includes questions for each of the major areas of sexual function: desire/sexual drive (2 items). Erection (3 items), ejaculation (2 items), perception of sexual problems (3 items), and overall satisfaction (1 item). Each item is scored on a 5-point scale, and domain scores are calculated for each major area. Advantages of this scale include a relatively high degree of internal consistency and test-retest reliability, a high degree of discriminant validity for three of the domains (erectile function, sexual problems, and overall satisfaction), and its brevity and ease of use. Limitations include the restricted assessment of erectile and orgasmic function, and the lack of data concerning its sensitivity and specificity in assessing treatment responsiveness.

The International Index of Erectile Function (IIEF) is a 15-item questionnaire specifically used for assessment of male erectile function. The instrument was developed in several stages, including initial pretesting with selected patient groups and expert panel consultants, followed by an intensive linguistic validation process. Factor analytic methods were used to develop five subscales (erectile function sexual desire, orgasmic function, intercourse satisfaction and overall satisfaction). Extensive psvchometric evaluation has shown the IIEF to be highly reliable in terms of internal consistency and test-retest reliability. Additionally, the scale has adequate construct validity and sensitivity and specificity in assessing treatment responsiveness. In large-scale clinical trials with the new oral agent sildenafil, the IIEF was shown to be highly sensitive to treatment efficacy. The measure is ideally suited for large-scale clinical trials of treatment outcome for ED. This scale is at present, available in more than 20 languages. The IIEF is currently being used in a large number of clinical trials with a variety of oral pharmacologic agents.

Bv means of these instruments, if is now possible to reliably assess erectile dysfunction in both clinical and research settings. Despite their advantages in efficiency and cost, these measures should not substitute for a complete medical and sexual history. Rather they should be used for initial detection or screening purposes, or for assessment of long-term changes following treatment.

References:

O'Leary MP, Fowler FJ, Lenderking WR, et al. A brief male sexual function inventory for urology.

Urology: 1995;46:697-706

Rosen RC, Riley A, Wagner G. Osteloh IH, Kirkpatrick J. Mishra A. The International Index of Erectile Function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology. In press.

Fidela LI. Moreno, M.D., The ASSESS Study Group, sponsored by Pfizer Southeast Asia/China Regional Office, Hong Kong

Sildenafil (SIL) is a novel, orally active, selective inhibitor of type 5 phosphodiesterase, the main isoenzyme involved in the metabolism of cyclic guanosine monophosphate in the corpus cavernosum. SIL has demonstrated efficacy in patients with erectile dysfunction (ED) in previous trials. ASSESS consists of 3 clinical trials whose objective is to determine the efficacy, safety and toleration of SIL taken as required (PRN) one hour prior to anticipated sexual activity. This abstract describes the ASSESS study design and methodology. Methods : Using a protocol whose design is identical to USA/EU studies, each of the 3 ASSESS trials is a doubleblind, randomized, placebo-controlled, parallel-group, multicenter, flexible dose study of SIL in Asian male outpatients with well-documented history (>6months) of ED of broad-spectrum etiology. ASSESS involves 23 sites in 7 countries : Hong Kong, Indonesia, Malaysia, Philippines, Singapore, Taiwan and Thailand. Each site will recruit 20-30 patients, for a total database of 690 patients. Following screening, patients will undergo a 4week no treatment run-in period, after which qualified patients will be randomized equally to PRN doses of 50 mg SIL or a corresponding placebo. Depending on efficacy, safety and toleration, the dose may be increased to 100 mg SIL or decreased to 25 mg SIL (or corresponding placebo). Double-blind treatment will be 12 weeks. The main efficacy endpoints are responses to a 15-item, self-administered questionnaire (International Index of Erectile Function; IIEF), addressing the patient's ability to achieve successful vaginal intercourse. The IIEF was validated and translated into all Asian languages required. ASSESS will begin in July 1997 and end in March 1998. It is anticipated that study results of ASSESS will be completed in August 1998.

John R Delk II, Southwest Impotence Center, Van Buren, AR, USA

Inflatable penile prosthesis implantation as a treatment for erectile dysfunction has been available to urologists for the past 20 years. A recent survey by the AUA (J Urol. 156:1636, 1996) showed nearly all urologists (94%) treat impotence, but only 3.5% of urologists used inflatable prosthesis implantation as a treatment. This bias against a very effective impotence solution has developed because of urologists' early experience with poor mechanical reliability and difficult clinical situations.

In an effort to stimulate more interest in the rapidly changing field of inflatable prosthetics, this presentation summarizes some exciting advances which have occurred in prosthetic urology in the last two years. Subjects covered include :

We conclude that advances in prosthetic urology should encourage the urologic practitioner to consider adding inflatable implants to their treatment regimen.

SS Ratnam. VHH Goh. Department of Obstetrics & Gynaecology, National University of Singapore. National University Hospital, Kent Ridge, Singapore 119074

Transsexualism is known to exist since antiquity. In the 1960s, many controversies revolved around the debate on the existence of transsexualism as a distinct psychosexual syndrome, the criteria for its diagnosis, and the use of sex change surgery is a viable treatment modality. However, it is now accepted as a distinct condition requiring medical attention.

The sex reassignment surgery is one of the mainstay in the management of transsexualism. The primary goal in the total management of transsexuals is to help them attain a sexual identity that no longer interferes with their capacity to live a full and meaningful life. The total rehabilitation of transsexuals into society requires psychologists, psychiatrists, surgeons, gynaecologists and endocrinologists teamed up to work in collaboration with legal and sometimes, religious and other professionals.

Over the last 26 years, a total of 862 transsexuals have been seen in the Gender Identity Clinic in the National University Hospital. Out of these, 548 were male transsexuals and the remainder, 314 were female transsexuals. A total of 341 and 173 male and female transsexuals, respectively, had thus far completed their sex reassignment surgery. The main genital surgery for male transsexuals includes bilateral orchidectomy, penectomy, vaginoplasty, and in most cases, augmentation mammoplasty. For female transsexuals, the main genital surgery includes total hysterectomy, bilateral salpingooophorectomy and the fashioning of the penile pedicle, as well as reduction mammoplasty. In most cases, patients are generally satisfied with the outcome of the surgery.

Tom F. Lue., M.D., Department of Urology, University of California, San Francisco, USA

The high drop-out rate from intracavernous injection therapy has prompted the search for alternate routes of delivering vasoactive drugs into the corpus cavernosum. Intraurethral administration of prostaglandin E2 was found to induce full tumescence in 30% and partial tumescence in 40% of patients (Wolfson et al., 1993). Subsequently, alprostadil (prostaglandin El) was also found to be effective, and was approved by the Food and Drug Administration in the US in 1996. In a double-blind, placebo-controlled study of 1,511 men with organic impotence (Padma-Nathan et al, NEJM, 1997) 996 men (65.9 percent) had erections sufficient for intercourse when tested in the clinic. Of these men, when they tried the drug at home, 64.9% had intercourse successfully at least once. The most common side effect was mild penile pain and hypotension. The mechanism of intraurethral drug delivery seems to involve 1) communications between corpus spongiosum and cavemosum and 2) retrograde transport from the emissary veins to the corpora cavernosa. In an intraoperative study involving injecting methylene blue solution into the corpus spongiosum, we found that the amount of methylene that appears in the corpus cavernosum varied greatly among patients. To improve drug delivery, we prefer to place a rubber band and have the patient stand for 10 minutes followed by self stimulation. This technique has improved response rate in our patients.

Ridwan Shabsigh, M.D.
Dept of Urology, Presbyterian Hospital, Columbia University

Two major factors are simultaneously influencing the field of erectile dysfunction. The first is the aging of the population and the consequent increase in the numbers of patients with erectile dysfunction. The second is the development of several new, less invasive, effective therapies for erectile dysfunction.

It is estimated that erectile dysfunction may affect as many as 30 million men in the United States alone. As the population ages, the proportion of people with vascular disease, diabetes, prostate cancer, or drug prescriptions will rise and the incidence of erectile dysfunction will correspondingly increase. Predictions of the numbers of patients with erectile dysfunction and of patients seeking treatment will be presented according to various medical economic analyses.

As public awareness and education increase and new therapies become available, more patients are seeking out healthcare professionals and the latest treatments. Treatment options commonly used in the U.S. include vacuum therapy, arterial reconstructive surgery, penile implant surgery, intracavernosal injection therapy, and most recently transurethral pharmacotherapy. Investigational treatments include oral sildenafil, buccal apomorphine, oral phentolamine, topical preparations, and combination pharmacotherapy delivered transurethrally or by intracavernosal injection. The efficacy, side effect profile, and patient outcomes for each of these treatments will be discussed.

Fran E. Kaiser, M.D. St. Louis University School of Medicine

Introduction : Large clinical studies were conducted to evaluate the efficacy, safety, and effect on quality of life (QoL) of transurethral alprostadil therapy in men with complete organic erectile dysfunction.

Methods : 1511 couples were enrolled in a prospective, double-blind, placebo-controlled, multicenter study. The 996 patients who responded to transurethral alprostadil (125, 250, 500, and 1000 mg) in the clinic were randomly assigned to home treatment with active drug or placebo. Both patients and partners completed QoL questionnaires before and after the study. Safety data from this study and several other double-blind, controlled trials were compiled over a two-year period.

Results : In the clinic, 65.9% of men achieved an erection sufficient for intercourse. At home, 64.9% of these patients (which is 43% of all patients) had intercourse on active medication compared to 18.6% (or 12% of all patients) on placebo (p<0.001). QoL improved significantly in the emotional well-being (anxiety, selfesteem, mood/depression) domain for responsive patients (p<0.004) and in the relationship with partner domain for responsive patients (p<0.001) and their partners (p<0.001) in the active group when compared to placebo. Overall, hypotension and dizziness occurred in 3% and 4%, respectively, of patients in the clinic. Drug-related side effects included penile pain in 29%, minor urethral bleeding in 5%, and dizziness in 2% of patients in the largest studies. Penile fibrosis and priapism occurred in I % and <O. I % of patients, respectively.

CONCLUSIONS : Transurethral alprostadil is well tolerated and can restore erections and sexual intercourse in men with chronic erectile dysfunction. Successful treatment with this therapy is associated with improvement in quality of life for patients and their partners.

A.Vermeulen

Aging is accompanied by a variety of changes in the endocrine system: growth hormone secretion decreases significantly (somatopause), adrenal androgen secretion is only a fraction of the secretion in young adults, partial insulin resistance develops and in women cyclical ovarian activity and fertility comes to an end.

In men, although fertility persists until very old age, testicular androgen secretion decreases progressively with age and at age 75, the mean level of plasma testosterone is only 60% of mean levels at age 25, the decrease in the bioavailable testosterone being even more pronounced and corresponding at age 75 to only 40% of levels in young adults with, however, important interindividual variations. Moreover, in 25% of men over 65 yrs old, plasma testosterone levels are in the hypogonadal range. As some androgens are still secreted, the androgen deficiency is partial, hence the appropriate term to describe this hypogonadism is PADAM, partial androgen deficiency of the elderly man.

This androgen deficiency has been confirmed both by longitudinal and cross sectional studies. This decrease is reflected clinically by a decrease in energy and strength, decrease of muscle mass, in libido and sexual activity, decrease in cognitive function and a significant increase in osteoporosis, which occurs however about 10 yrs later than in women.

It is evident that these signs and symptoms are not uniquely the consequence of the decrease in androgen levels, and that the decrease in growth hormone, for example, and the aging process itself contribute also to this symptomatology. Nevertheless, clinical studies on the effects of substitutive testosterone therapy of males with PADAM, have shown that the latter treatment induces an improvement in general well-being, an increase in muscle mass and strength, energy and libido and a decrease of the biochemical markers of bone resorption.

Testosterone replacement therapy is generally achieved either by I.M. injection of testosterone-esters (enanthate 250 mg every 3-4 weeks) or oral administration of testosterone-undecanoate 3-6 x 40 mg/day. Recently several new galenic forms of testosterone (transdermal patches; microcristals; gels) were introduced but the experience with these galenic forms is still limited.

When care is taken that testosterone levels achieved by this therapy do not reach supraphysiological levels, no serious side effects are observed, but the presence of a prostatic carcinoma should be carefully excluded before starting substitution therapy.

Young Chan Kim, M.D.
Department of Urology, Pundang CHA Hospital Pochon CHA Medical University, Korea

Take home messages

Dr ET Koh, Dr CCM Lei*, Dr Patrick Mah KK, Dr Khairullah Hj Abdullah
Institute of Urology and Nephrology, Kuala Lumpur Hospital, UNIMAS Sarawak*

No study has yet been done to know the extent of sexual rehabilitation among the spinal cord injured in Malaysia. We have started a study investigating the urological management of these patients with particular emphasis on their sexual dysfunction. This is a prospective clinical study involving spinal cord injured male patients with at least one year post-injury. Our patients included spinal patients registered with the Malaysian Spinal Injuries Association (MASIA), spinal injured patients attending the urology clinics at Kuala Lumpur Hospital and Kuching Hospital, Sarawak and patients from the spinal ward, Kuala Lumpur Hospital. The patients are interviewed using a standard format along with the questionnaire derived from IIEF (International Index of Erectile Functions). The answers were recorded by the investigators. Our preliminary reports are as follows. Industrial accident contributes 38% of spinal injury. Motor vehicle accident still remains as the leading cause. It mainly affects the thoracic spine (59%). Many of them (83%) needed to be hospitalised for more than 3 months during the acute phase. It reflects a significant shortage of highly specialised medical personnel in this field. Many of spinal cord injured patients developed urological complications like bladder stones, repeated urosepsis, urethral fistulas, hydronephrosis etc. Majority of our patients experienced a normal premorbid sexual function. However, after the spinal injury, 90% of them have never enjoyed sexual intercourse. All of them are dissatisfied with their sexual performance. Patients with spinal cord injury are often treated during the acute phase at a tertiary referral centre where acute management and subsequent rehabilitation takes a very protracted course. Sexual counselling and treatment of erectile dysfunction remained a very much neglected aspect in the rehabilitation of the spinal injured patients.

W Wallace Dinsmore, David K Alderdice, M O'Gorman, S McKernan.
Department of Genito Urinary Medicine, Royal Victoria Hospital, Belfast, Northern Ireland.

Vasoactive intestinal polypeptide and phentolamine have respectively potent penile veno-occlusive and arterial inflow stimulators properties.

Seventy consecutive erectile clinic attendees who had failed therapy with intracavernosal prostaglandin El 20mcg and papaverine 30mg combination with I mg phentolan-iine mesylate were given intracavemosal injections of initially 25mcg VEP/Img phentolaniine mesylate (Invicorp I) and if unsuccessful 25mcg VIP/2mg phentolamine mesylate (Invicorp2). Both Invicorp I and Invicorp2 were pre-mixed in an autoinjector with a 30 guage needle. Patient diagnoses were spinal cord I-.sion 8, diabetes 2 1, ischaeniic heart disease 12, hypertension 6, othe diagnoses 9, idiopathic 14.

Fortyseven (67%) of patients achieved erections sufficient for sexual intercourse (33 Invicorpl and 14 Invicorp2), initially under clinical supervision and subsequently for home use.

Minor side-effects were transient facial flushing 37 (53%), torsal flushing 6 (91%), bruising 14 (20%), pain from injection needle 8 (I 1%). No patients reported priapism or other serious adverse events.

Conclusion: Invicorpl and Invicorp2 were safe and effective treatments in patients whom other therapies had failed.

Chris McMahon M.B.B.S. F.A.C.S.H.P, Sydney, Australia.

The management of erectile dysfunction requires the development of a concise practical approach to diagnosis. Diagnosis must reflect a cost effective approach to patient care. Patient goal directed treatment is implicit in the sound and cost-effective management to erectile dysfunction.

A general discussion of the various treatment options available to the patients with erectile dysfunction should be a part of the initial visit. Based upon the patient and his partner's treatment goals, his general medical condition and age, certain diagnostic steps may be omitted, streamlining and simplifying diagnostic process.

Since the observation in 1982 that the intracavernous injection of papaverine induced penile tumescence and in some cases, an erection, many drugs capable of causing the same phenomenon have been described. As a direct result of this observation, both the diagnosis and treatment of erectile dysfunction have been revolutionised. During the same decade penile haemodynamics, functional anatomy, neuroanatomy and the pharmacology of erection have been clarified. Major advances have occured in the understanding of neurotransmitters for intracavernous smooth muscle relaxation and contraction, the function of vascular endothelial cells and their gap junctions.

The use of intracavernous injections gives the clinican a powerful tool to undertake preliminary investigation of the impotent patient in the office setting. The ability of these drugs to produce sinusoldal smooth muscle and vascular smooth muscle relaxation, an increase in cavernosal artery blood flow, tumescence and in some cases an erection has enabled the study of the penile arterial and venous system in greater detail with duplex ultrasound, pharmacoarteriography.

Vasoactive intestinal polypeptide (VIP), which is a very potent vasodilator, was in the early eighties recognized as a possible neurotransmitter in the penile erection. Injections of this compound in nontoxic concentrations into the corpora cavernosum will result in tumescence of the penis but not in a sufficient erection, neither in normal men nor in impotent patients. In combinations with other vasodilators, however, VEP seems interesting. In Copenhagen we have used VEP in a combination with phentolamine (first called vasopotin, now Invicorp) since 1988 for treatment of various types of erectile impotence in an open labelled trial. This drug-combination appeared to be effective in cases where alfa-blocker alone is insufficient and nearly as effective as prostaglandin E1 and papaverine phentolaniine. The side effect profile is more beneficial for Invicorp compared with PGE 1 and Pap Phen. Furthermore constrating PGE 1 and Pap Phen Invicorp produces an erection which follows the normal coital cycle, starting with tumescence or seniirigidity shortly after the injection, full rigidity when sexually stimulated and loss of rigidity or detumescence after the ejaculation.

Krane RJ, Boston University Medical Center, The University Hospital, USA

Patients present for several reasons with Peyronie's disease. These include: A penile mass alone, penile curvature alone, penile curvature not permitting sexual function, and inability to have a rigid erection. Surgical therapy should only be considered for patients who either cannot have a rigid erection or cannot have sexual relations by virtue of the fact that their curvature limits this possibility.

In patients who are impotent with Peyronie's disease, vascular evaluation is mandatory to determine if venoocclusive dysfunction is present. In those situations it becomes realistic to incorporate a straightening procedure in conjunction with a non-surgical approach or penile prosthesis implantation. These procedures will be discussed.

In patients with rigid erections and penile curvature obviating sexual intercourse, one has the options of removing the plaque and grafting with dermis, or more conservative approach is such as the Nesbitt procedure. In between these two procedures one has the option of directly cutting the plaque transversely and putting in small grafts within the plaque to avoid the penile shortening that the Nesbitt procedure may cause. Often these grafts are venous in nature. Conservative approaches as outlined above will be presented in detail.

Institution : Urology Research Centre, Perth, Western Australia

Conclusion :

The clinician, his staff, the hospitals and nurses attending patients with sexual problem