Effects of testosterone on erectile function: implications for the therapy of erectile dysfunction

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1 Mini Reviews SAAD et al. Effects of testosterone on erectile function: implications for the therapy of erectile dysfunction Farid Saad, Anca S. Grahl 1, Antonio Aversa 2, Aksam A. Yassin 3,4, Atez Kadioglu 5, Ignacio Moncada 6 and Ian Eardley 7 GBU Gynecology Andrology, Bayer Schering Pharma, Berlin, Germany, and 1 Freelance (Medical Writer), Ulm, Germany, 2 School of Medicine and Surgery, La Sapienza, University of Rome, Italy, 3 Segeberger Kliniken, Norderstedt Hamburg, Germany, 4 School of Medicine, Gulf Medical College, Ajman, United Arab Emirates, 5 Faculty of Medicine, Section of Andrology, University of Istanbul, Istanbul, Turkey, 6 Urology/Andrology, Hospital Gregorio Marañón, Madrid, Spain, and 7 Pyrah Department of Urology, St James s University Hospital, Leeds, UK Accepted for publication 17 November 2006 Sexual potency declines with age, as does the efficiency of erection. Many studies show that different patterns of erectile dysfunction (ED), varying from occasional inability to obtain a full erection, impairment throughout intercourse and total absence of erectile response, might not be triggered by psychological factors only. Recent research indicates that ED relies on organic causes, and has challenged the development of new therapies. One therapeutic approach in patients who have testosterone deficiency is based on androgen therapy. Thus, we reviewed data on testosterone-induced effects relative to erectile function, summarizing the results from studies reported in on testosterone therapy in patients with ED and hypogonadism, with a special focus on men not responding to phosphodiesterase-5 (PDE-5) inhibitors. We searched several computerized databases parallel with printed bibliographic references. Many studies have established animal models, which confirm that testosterone is important in modulating the central and peripheral regulation of ED. Testosterone deprivation has a strong negative impact on the structure of penile tissues and erectile nerves, which can be prevented by androgen administration. Combined therapy regimens with PDE-5 inhibitors and testosterone might improve ED in patients with hypogonadism of different causes. Thus, androgen treatment in hypogonadic patients, including those unresponsive to PDE-5 inhibitors, often results in an improvement of ED. Testosterone therapy is safe and convenient, while rapidly correcting low testosterone levels. KEYWORDS hypogonadism, testosterone, replacement therapy, erectile function INTRODUCTION Reproduction is the most distinguishing characteristic of life, driving evolution throughout the diversity of plant and animal species. Human beings follow a primordial reproductive impulse towards the perpetuation of life, and experience emotions within the sphere of sexual behaviour. Therefore, human sexuality cannot be reduced simply to an the function of insemination only. However, the human reproductive system is very similar to that of many other mammals [1]. The anatomy of the male genitalia is very complex. The penis consists of a pair of erectile chambers, the corpora cavernosa, filled with spongy material composed predominantly of smooth muscles and connective tissue [2]. An erection, which can be triggered by direct stimulation of the genitalia or through integrated sensorial stimuli, is therefore a complex, partly involuntary, neuropsychological, and hormone-mediated vascular event. It occurs when blood rapidly flows into the penis and becomes trapped in the cavernosa. Accordingly, penile erection is not a random phenomenon but a discrete, timely and adjusted event, consequent to sexual desire and arousal. Physiologically, the vascular response is achieved by two parallel mechanisms, increased inflow of blood and decreased outflow [3]. This event is controlled by parasympathetic mechanisms and modulated through the action of androgens [4 10]. The major mediator of smooth muscle relaxation in cavernosal arteries and trabecular muscle is nitric oxide (NO), which activates guanylate cyclase and increases cgmp levels [6,11,12]. The cellular cgmp level reflects a dynamic balance between its production and degradation by cyclic nucleotide phosphodiesterases (PDEs). Testosterone plays a role in balancing the cgmp levels [13], and both cgmp formation and degradation are affected by testosterone. Because testosterone positively controls both the initiation (NO synthase, NOS) and the end (PDE-5) of the erectile process, its overall effect on erection is modest. Hence, erections are still possible in hypogonadal conditions, where decreased cgmp formation, due to impaired NO production, is most probably counterbalanced by reduced PDE-5 activity and cgmp hydrolysis. The main physiological action of testosterone is therefore to synchronize the erectile process as a function of sexual desire, thereby finalizing erections to sex. ERECTILE DYSFUNCTION (ED): DEFINITION AND AETIOLOGY What exactly constitutes ED of sufficient severity to require therapy? Since 1974, the WHO has described ED as a persistent inability (for 3 months) to attain and/or maintain a sufficient erection, resulting in unsatisfactory sexual intercourse [14]. In randomized trials, ED is diagnosed based on the score obtained using the International Index of Erectile Function (IIEF), a questionnaire using the best 988 JOURNAL COMPILATION 2007 BJU INTERNATIONAL 99, doi: /j x x

2 discriminative criteria of a man s ability to initiate, maintain and complete sexual intercourse. Using the IIEF-5 score (for which only the five most significant questions are assessed), the maximum score was established as 25 and the minimum as 5. Men with no ED have a mean score of 23 and men with ED a mean score of 11. Pathological conditions (e.g. diabetes, hypertension, neurological disorders, multiple sclerosis, TURP, coronary artery disease or spinal cord injuries) or risk factors like smoking, alcohol consumption and drug use, increase the prevalence of ED. Hormonal dysregulation such as elevated prolactin, hypo- and hyperthyroidism and Cushing syndrome might also cause ED [15]. ED: THE ROLE OF TESTOSTERONE Androgens are regulators of the male reproductive system. In the testes, Leydig cells synthesise and secrete testosterone in response to LH, which is counter-regulated by feedback influences of testosterone and its metabolites [16]. Testosterone and its potent 5α metabolite dihydrotestosterone (DHT) exert androgenic influences during embryogenesis, puberty and adulthood. During fetal development, they cause normal differentiation of male internal and external genitalia. At puberty, testosterone and DHT are required for the development and maintenance of male secondary sexual characteristics. DHT affects prostate growth and masculinization of the skin, while the remaining androgenic effects on muscle, bone, larynx, testes, phallus, libido, and sexual function are produced by testosterone itself. In adults, testosterone and DHT are needed to maintain intact libido and potency, muscle mass and strength, fat distribution, bone mass, erythropoiesis, prostate growth, male hair growth, and spermatogenesis. Testosterone seems to have a major role in modulating erectile function [17,18]. It determines the frequency of nocturnal penile tumescence and has a regulatory action within the CNS through apomorphine-like effects [19]. There is a normal decline of testosterone levels with age; the age-dependent down-regulation of testosterone level is paralleled by increase in its serum-binding counterpart, sex hormonebinding globulin (SHBG). This condition is commonly referred to as late-onset hypogonadism [14,17]. In this review, we introduce the link between testosterone and erectile function, and present clinical studies on testosterone therapy in patients with ED, and in particular those not responding to PDE-5 inhibitors. ANIMAL STUDIES ON THE LINK BETWEEN TESTOSTERONE AND ERECTILE FUNCTION Many studies have established animal models for investigating the role of androgens in the control of erectile function. The rat and the rabbit are optimal, as their erectile function is androgen-dependent. Interestingly, when New Zealand White male rabbits were either kept intact (control), surgically castrated or treated for 2, 4 or 8 weeks with 107 µg/kg per month of the LHRH agonist leuprolide acetate for medical castration, plasma testosterone levels after 2 weeks decreased to 12.8% in castrated rabbits and to 57.4% in leuprolidetreated rabbits, compared with control rabbits [20]. Medical castration in the rabbit was proposed to serve as a study model for testosterone deprivation in ageing men, as the reduction in testosterone levels to about half mimics the subphysiologal testosterone level in ageing men. Further effects of surgical or medical castration in this study were assessed by recording the intracavernosal arterial pressure relative to systemic measurements, after electrical stimulation of the pelvic nerve. Androgen deprivation reduced the intracavernosal pressure at all frequencies tested but did not alter the systemic arterial pressure. The analysis of PDE-5 and NOS activity was not changed by either of the castration methods, by contrast with similar studies in rats, where there was reduced nnos mrna. The authors of the study concluded that androgen deprivation by surgical or medical castration affected penile haemodynamics and erectile function, and induced structural alterations in the corpus cavernosum, with veno-occlusive phenomenon [20]. This observation led to further histopathological investigations. The penile sections were stained with Masson s trichrome and haematoxylin-eosin for smooth muscles and connective tissue, and toluidine blue for fat-containing cells. Orchidectomy resulted in penile atrophy, based on reduced trabecular smooth muscle, increased connective tissue content and accumulation of adipocytes in the subtunical region of the corpus cavernosum. Most strikingly, androgen deprivation seemed to promote the differentiation of progenitor stromal cells into adipogenic lineages, producing fat-containing cells and altering erectile function [21]. Parallel studies in rats showed that castration induces apoptosis of cells from cavernosal and spongiosal tissues, which could be blocked by testosterone [22]. Other structural and biochemical components of erection were also shown to be modulated by testosterone [9]. For instance, Giuliano et al. [23] suggested that the site of androgen action within the penile tissues might be on the pro-erectile postganglionic parasympathetic neurones. Furthermore, recent castration studies in rats showed that testosterone deprivation might alter the dorsal nerve ultrastructure, as the diameter of both myelinated and unmyelinated axons appeared smaller by transmission electron microscopy [24]. TESTOSTERONE THERAPY IN MEN WITH ED In Europe, men with low sexual desire have been treated with testosterone since 1940; this therapy recently re-emerged in the field of ED. In a meta-analysis conducted in 2000, based on a Medline search for , the mean confidence level of response to testosterone treatment was 16.7% in the placebo and 65.4% in the testosteronetreated groups (P < 0.001), indicating the usefulness of testosterone therapy for ED [25]. Recent studies corroborate that some results of testosterone therapy in animals might also apply to humans. Aversa et al. [6] showed that low free testosterone levels correlate with impaired relaxation of cavernous endothelial and corporeal smooth muscle cells to vasoactive challenge [26]. It was reported that nocturnal penile tumescence, arterial cavernosal inflow and visually stimulated erection became normal on testosterone therapy [19]. A recent limited series of case reports suggested that therapy with a novel, long-acting injection of testosterone undecanoate improves erectile function in hypogonadal men by restoring veno-occlusive function [27,28]. Since 1998, there have been three oral medications to treat ED, sildenafil, tadalafil and vardenafil; all belong to the chemical class of PDE-5 inhibitors and have transformed the treatment of ED by providing an effective, well tolerated oral medication. However, especially in patients with comorbidities, ED is often refractory to treatment with PDE-5 inhibitors. Testosterone therapy has been suggested for hypogonadal men not responding to PDE-5 inhibitors; a range of studies corroborate that ED can be JOURNAL COMPILATION 2007 BJU INTERNATIONAL 989

3 SAAD ET AL. effectively treated with currently available preparations of testosterone when combined with PDE-5 inhibitors [29 31]. The erectile response to sildenafil and the arterial inflow into the penis increases in men not responding to sildenafil when they are also given testosterone [27]. In a prospective study including 40 sildenafil nonresponders, testosterone had beneficial effects on erectile response and patient satisfaction [32]. In a randomized, placebo-controlled, doubleblind, parallel-group, multicentre study, 75 hypogonadal men with ED in whom sildenafil monotherapy had failed were selected if they had a morning serum total testosterone level of 400 ng/dl and were aged years. After treatment with a supplementary daily dose of 1% testosterone gel during a 12-week period, there was an improvement in IIEF erectile function score that was statistically significant at 4 weeks (4.4 vs 2.1, P = 0.029, 95% CI ). There were similar trends for improvements in orgasmic function, overall satisfaction and total IIEF score. The gel significantly (P 0.004) increased total and free testosterone levels, although there were no significant correlations between testosterone levels and the IIEF at the endpoint [33]. In a further independent study, 49 hypogonadal patients with ED and a mean age of 60.7 years were treated with testosterone gel as monotherapy for 6 months. After 3 months of treatment, those not responding were given 100 mg of sildenafil as adjuvant medication, after which all responded positively. Moreover, 31 patients receiving testosterone therapy alone reported, after 6 months, an improvement in sexual desire score from a mean (SD) of 4.2 (0.8) to 8.6 (0.4), and of erectile function from 13.6 (1.9) to 27 (0.8) [34]. In a study in the USA, 24 men with a testosterone level of <400 ng/dl (range , mean 231.4) were treated with 1% testosterone gel alone for 4 weeks, and subsequently for an additional 12 weeks with 1% testosterone gel and sildenafil 100 mg. Although testosterone levels had become normal after 4 weeks of testosterone monotherapy, erectile function was not restored; however, with combined testosterone and sildenafil, 92% of the men reported improved potency [35]. Hwang et al. [30] evaluated combined therapy with testosterone and sildenafil in 32 hypogonadal men not responding to sildenafil, based on the variables of the IIEF, the IPSS, and urinary flow rate. While the IIEF score significantly increased, there were no statistical differences for the IPSS or urinary flow rate. In a small prospective pilot study in a few patients with renal-replacement therapy who had ED due to hypogonadism and cavernosal insufficiency, the combined use of testosterone injections and oral sildenafil led to a marked improvement in the overall sexual performance, as assessed by the IIEF score [36]. Yassin et al. [37] conducted an openlabel, retrospective trial with 69 hypogonadal patients with ED, in whom tadalafil monotherapy had failed, using the IIEF score and a partner questionnaire for evaluation; after combined therapy with tadalafil and testosterone, there was an increase in erectile function score. Although the magnitude of the clinical response in patients with ED remains difficult to evaluate, lower testosterone levels at the beginning of therapy correlate with good efficacy and a positive clinical outcome [38]. Overall, if patients are unresponsive to either testosterone or PDE-5 inhibitors alone, it has clearly become clinical practice that the short-term combination can produce an improvement in erectile function and enhance the therapeutic effect of PDE-5 inhibitors. Further randomized, placebocontrolled, multicentre studies with consistent follow-up periods are encouraged to provide final confirmation for this very controversial issue. DISCUSSION The biological mechanisms by which supplementary testosterone acts remains little understood. The normal endogenous concentration of testosterone is nmol/ L. In serum, endogenous testosterone binds to SHBG and, with low affinity, to albumin. The albumin-bound fraction is bioactive, as it dissociates easily [16,17]. However, the systemic availability of testosterone in healthy men declines gradually after the third decade of life by 1% every year, reaching subphysiological values of 35 50% in the sixth decade. Recent studies indicate that low testosterone levels also have a negative correlation with body mass index [18,39]. The consecutive androgen deprivation reflects multisite failure in the GnRH-LH-testosterone axis; this might often result in ED [40]. The ageing male symptoms with subsequent hormonal changes might result from concerted endocrine dysregulation, including modifications of dehydroepiandrosterone and oestradiol levels [41]. During androgen therapy, endogenous testosterone release is inhibited through feedback mechanisms on pituitary LH secretion. Parallel with the classical activation of the androgen receptors, one independent pathway might lead to nongenomic effects like rapid vasodilatation. This might be the result of calcium-channel activation, the vascular endothelial growth factor pathway and/or NO mechanism with cgmp release. Classical and other testosterone binding sites might coexist in the same cells. Furthermore, epigenetic and tissue-specific transcription factors might have a combinatorial role in mediating the effects of testosterone at the molecular level and influence its bivalent action towards the production or destruction of cgmp molecules. There is still controversy on the benefit of testosterone in ageing men [42,43]. In a study of 32 patients with documented hypogonadism and ED, the normalization of testosterone levels was associated with only a short-term improvement in erectile function and sexual satisfaction. However, as the impact of concomitant diseases and of important risk factors of ED was not addressed, and additive therapy with PDE-5 inhibitors was not investigated, the data of this study might not be representative [44]. Androgens are contraindicated in men with known or suspected carcinoma of the prostate; the International Society for the Study of the Aging Male, European Association of Urology, and the Endocrine Society guidelines for testosterone therapy, list the precautions to be followed when administering testosterone [45,46]. The therapeutic regimens with testosterone alone or combined with other drugs must be adjusted for each patient with ED. Important considerations must include age, documented comorbidities, severity of testosterone deficiency, potential side-effects, ease of use and cost of the therapy. CONCLUSIONS A sufficient testosterone level is crucial for the development, growth and function of penile tissue and the regulation of erectile function. Satisfactory options are currently available for testosterone therapy in patients with ED due to low testosterone levels. When not contraindicated, the safe principle is to mimic the normal endogenous concentration of testosterone and its active metabolites. This is achieved by the currently available testosterone patches, gels, and the long- 990 JOURNAL COMPILATION 2007 BJU INTERNATIONAL

4 acting injection of testosterone undecanoate. Combined therapy with PDE-5 inhibitors and testosterone often result in a significant improvement in potency, sexual activity and feelings of well-being, and lead to improved erectile function. In patients with ED in who PDE-5 inhibitor monotherapy has failed, testosterone salvage might temporarily restore the positive clinical response. Further research into the mechanism of testosterone regulation, and controlled data on its longterm safety, must be conducted to provide evidence for more comprehensive therapeutic links. CONFLICT OF INTEREST None declared. Funding for medical writing: Bayer Schering Pharma. REFERENCES 1 Kinsey AC, Pomeroy WB, Martin CE. Sexual behavior in the human male Am J Public Health 2003; 93: Conti G, Virag R. Human penile erection and organic impotence: normal histology and histopathology. Urol Int 1989; 44: Tudoriu T, Bourmer H. The hemodynamics of erection at the level of the penis and its local deterioration. 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