Recent insights into androgen action on the anatomical and physiological substrate of penile erection

Erectile response is centrally and peripherally regulated by androgens.The original insights into the mechanismsof action of androgens were that androgens particularly exert effects on libido and that erections in response to eroticstimuli were relatively androgen-independent.It was shown that sexual functions in men required androgen levels atthe low end of reference values of testosterone.So it seemed that testosterone was not useful treatment for men witherectile difficulties,particularly following the advent of the phosphodiesterase type 5(PDE5)inhibitors.However,approximately 50% of those treated with PDE5 inhibitors discontinue their treatment.A number of recent develop-ments shed new light on testosterone treatment of erectile dysfunction(ED)in aging men.(1)A recent insight is that,in contrast to younger men,elderly men might require higher levels of testosterone for normal sexual functioning.(2)Several studies have indicated that PDE5 inhibitors are not always sufficient to restore erectile potency in men,andthat testosterone improves the therapeutical response to PDE5 inhibitors considerably.(3)There is growing insightthat testosterone has profound effects on tissues of the penis involved in the mechanism of erection and that testoster-one deficiency impairs the anatomical and physiological substrate of erectile capacity,reversible upon androgenreplacement.The synthesis of PDE5 is upregulated by androgens,and the arterial inflow into the penis is improved bygiving androgen.The above invites a re-examination of the merits of giving testosterone to aging men with ED.Thebeneficial effects of PDE5 inhibitors may only be optimally expressed in a eugonadal environment.(Asian J Androl2006 Jan;8:3-9)     

Androgens are Fundamental in the Maintenance of Male Sexual Health

The presence of a sufficient amount of androgens is essential for adequate sexual function in men. Gonadal hormones profoundly affect cognitive functions and, therefore, are fundamental in maintaining sexual desire. The earliest manifestation of hypogonadism is diminished libido. Furthermore, androgens also act peripherally, maintaining the integrity of penile structures and facilitating the erectile mechanisms. Severe androgen deficiency results in anatomical and hemodynamic changes leading to erectile dysfunction that can be corrected with testosterone supplementation.     

Testosterone and erectile dysfunction

The role of testosterone on sexual desire, interest and motivation is well established, but its effects on erectile function remain controversial. Animal data show that experimental or medical castration results in loss of the intracavernosal pressure, smooth muscle/connective tissue balance, and penile tissue concentration of nitric oxide synthase-containing nerves, which alter the fibroelastic properties of penile tissue compliance, leading to veno-occlusive dysfunction and therefore erectile dysfunction. Castration also induces apoptosis of penile erectile tissue, and new DNA synthesis is induced by treatment with testosterone. In an animal model of venogenic erectile dysfunction, intracavernous vascular endothelial growth factor (VEGF), in addition to testosterone, restores the smooth muscle/connective tissue balance, endothelial cell hypertrophy and hyperplasia and normalizes the diameter of the dorsal nerve fibres, thereby preventing veno-occlusive dysfunction. There is some evidence that treatment with testosterone may be beneficial to men with erectile dysfunction who have low baseline testosterone levels. Androgens may also control the expression and activity of phosphodiesterase type-5 (PDE-5) in the penile corpus cavernosum. Oral drug therapy with PDE-5 inhibitors fails in some patients with erectile dysfunction. However, when testosterone is used together with a PDE-5 inhibitor, sexual function is restored in these patients, creating the potential for pharmacological combination therapy with testosterone for the treatment of erectile dysfunction.     

Hypogonadism and erectile dysfunction： an overview

In humans androgen decline is presented as a clinical picture which includes decreased sexual interest, diminished erectile capasity, delayed or absent orgasms and reduced sexual pleasure. Additionally, changes in mood, diminished well being, fatigue, depression and irritability are also associated with androgen insufficiency. The critical role of androgens on the development, growth, and maintanence of the penis has been widely accepted. Although, the exact effect of androgens on erectile physiology still remains undetermined, recent experimental studies have broaden our understanding about the relationship between androgens and erectile function. Preclinical studies showed that androgen deprivation leads to penile tissue atrophy and alterations in the nerve structures of the penis. Furthermore, androgen deprivation caused to accumulation of fat containing cells and decreased protein expression of endothelial and neuronal nitric oxide synthases （eNOS and nNOS）, and phosphodiesterase type-5 （PDE-5）, which play crucial role in normal erectile physiology. On the light of the recent literature, we aimed to present the direct effect of androgens on the structures, development and maintanence of penile tissue and erectile physiology as well. Furhermore, according to the clinical studies we conclude the aetiology, pathophysiology, prevalance, diagnosis and treatment options of hypogonadism in aging men.     

雄激素缺乏与勃起功能障碍

雄激素可通过增强性欲、性唤起等间接促进阴茎勃起,在维持阴茎正常的勃起组织结构方面起重要作用。睾酮缺乏可导致小梁平滑肌减少、细胞外基质增多、白膜下脂肪细胞沉积等。勃起时,阴茎组织的上述改变可引起静脉闭塞不全而发生静脉漏,从而出现勃起功能障碍;睾酮还可影响一氧化氮合酶(NOS)、RhoA/Rho激酶的表达及活性从而直接影响阴茎勃起。对单用磷酸二酯酶5(PDE5)抑制剂无反应的性腺功能减退的ED患者补充睾酮可收到良好的治疗效果。     

The Role of Andorgens in the Erectile Response: A 1999 Perspective

Evidence from several laboratories strongly supports a critical role for androgens in the maintenance of the mammalian erectile response. In animal studies, androgens appear to act at the end-organ level (i.e., corporal tissue and vasculature), as well as in the portions of the nervous system which mediate erection. Particularly in the rat model, androgens act centrally to support copulatory behavior and peripherally to maintain the production of nitric oxide and support the veno-occlusive mechanisms. Other studies suggest that alternative, non-NO-dependent, pathways may also be androgen sensitive. However, despite this expanding knowledge base about how androgens act in the erectile response in laboratory animals, the recent studies have not greatly clarified the role of androgens in human penile erection. There does not seem to be a strong cause and effect relation between blood androgen concentrations and erectile function; even in severely hypogonadal men, the erectile response is not always lost, and testosterone treatment of hypogonadal men with erectile dysfunction does not necessarily restore lost erectile function. In addition, different types of erection (nocturnal, in response to visual sexual stimulation, in response to sexual partner) may require different degrees of androgenic support.     

Testosterone therapy increases sexual desire in ageing men with low-normal testosterone levels and symptoms of androgen deficiency

Although decline in sexual function is a common reason for ageing men to seek advice regarding testosterone therapy, placebo-controlled trial data have been unable to show a consistent, beneficial role for testosterone. The objective of this study was to determine the effect of testosterone therapy on sexual function in non-obese ageing men with symptoms of androgen deficiency and low-normal serum testosterone levels. A total of 60 men aged 55 years or older in good general health with total testosterone (TT) levels <15 nM, and with symptoms suggestive of androgen deficiency, were randomized in a double-blinded protocol to transdermal testosterone patches or placebo for 12 months. Sexual function was assessed using the International Index of Erectile Function at weeks 0, 26 and 52. In men receiving testosterone TT levels increased by 30% (P=0.01) and luteinizing hormone decreased by 50% (P<0.001). Relative to placebo, testosterone therapy improved sexual desire (P=0.04); however other parameters of sexual function including erectile function were unaffected by the treatment. Ageing men in good general health and with symptoms of androgen deficiency and low-normal serum testosterone levels receiving 12 months of transdermal testosterone therapy experienced, relative to placebo, improved sexual desire but no effect on other parameters of sexual function.     

The role of testosterone in erectile function and dysfunction

Erectile response is centrally and peripherally regulated by androgens. Severe hypogonadism in men usually results in loss of libido and potency which can be restored by androgen administration.It was originally thought that androgens exert their effects on libido and that effects on erections were secondary to effects on libido. It is now clear that androgens are necessary for the maintenance of the anatomical and physiological substrate of erections. Restoring testosterone levels to normal is required in cases of erectile dysfunction.It was long assumed that sexual functions required androgen levels below or at the low end of reference values of testosterone. It is now clear that there are individual differences while the threshold increases with aging.The administration of PDE-5-inhibitors is not always sufficient to restore erectile potency in men, and administration of testosterone improves the therapeutic response to PDE-5-inhibitors considerably.Erectile dysfunction is strongly age-related, and it is evident that its etiology is multi-factorial. It is intriguing that testosterone is interrelated with a number of etiological factors such as obesity, diabetes mellitus and atherosclerosis.     

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

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 1991-2006 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.     

The effects of testosterone on the cavernous tissue and erectile function

Summary A review of the current literature is conducted to explore the developmental aspects, animal and human experiences and the effects of pharmacological manipulation to explain the role androgens play in sexual function with special emphasis on erectile function and the erectile tissue. This review reveals that androgens are necessary for the normal development of the penis and their deficiency results in significant structural abnormalities. Although androgen receptors in the penis decrease after puberty, they usually do not disappear completely. Animal data show that androgens support erectile function through a direct effect on the erectile tissue. Experimental castration results in impaired erectile response to central and peripheral stimulation and decrease in penile tissue concentration of nitric oxide synthase-containing nerves. Testosterone replacement reverses these abnormalities. In the rat penis, apoptosis is induced by castration and new DNA synthesis is induced by testosterone replenishment. Human data are less clear than animal data. Castration results in loss of libido and in erectile dysfunction. However, these effects are not universal. Testosterone enhances libido, frequency of sexual acts and sleep-related erections. Its effects on erotic erections are not clear.     

Should genitourinary medicine clinic attendees with sexual dysfunctions have routine assessment of testosterone levels?

Background Many genitourinary medicine departments see patients with sexual dysfunction. The use of routine testosterone assays in men complaining of erectile dysfunction is commonplace. Some departments also carry out screening of women complaining of loss of libido.
Methods A search of the literature was undertaken to assess the evidence for usefulness of testosterone assay in males complaining of erectile dysfunction and women with low sex drive or arousal problems. The optimal assay was similarly assessed.
Results and discussion There is no place for the routine assay of serum testosterone levels in men with erectile dysfunction unless they complain of low sexual desire, or there are grounds for suspecting that they are clinically hypogonadal. In women who complain of low sexual desire or arousal, serum testosterone levels need to be assayed only if there is a history of oöphorectomy of cytotoxic therapy, or other reasons for suspecting endocrine abnormalities. Where the vulva might be deemed hypoplastic, the level of 5 alpha dihydrotestosterone might be low. Where possible, free or bioavilable testosterone levels rather than total testosterone should be measured as these provide a more sensitive and specific indication of the true androgen level. The ration of total testosterone to sex hormone binding gives the `free testosterone index', which may also be used. The additional costs to these procedures are grounds for limiting their use to situations where they are likely to prove of real benefit in undertaking treatment.     

Molecular pharmacotherapeutic targeting of PDE5 for preservation of penile health

The molecular science of erection physiology has established that phosphodiesterase 5 (PDE5) serves an important biological role in the penis. Current research in the field has revealed this molecular effector to be relevant for penile erection, controlling the erectile response by degrading the second messenger product of the erection mediatory nitric oxide (NO) signaling pathway, 3', 5'-cyclic guanosine monophosphate. Accordingly, PDE5 has been targeted for sexual medicine purposes, and orally administered PDE5 inhibitors such as sildenafil, tadalafil, and vardenafil comprise a foremost intervention for erectile dysfunction (ED). New investigation of PDE5 regulation in the penis has suggested alternative roles for the enzyme and new therapeutic opportunities involving its molecular interactions. In particular, PDE5 function is altered under derangements of androgen deficiency, decreased NO bioactivity, and oxidative stress-associated inflammatory changes, thus contributing to an assortment of erectile disorders including hypogonadism-associated ED, recurrent ischemic priapism, penile vasculopathy, and penile fibrosis. This review provides a critical examination of the multifaceted role of the PDE5 regulatory system in the penis and its relevance for applying existing and emerging therapeutic strategies for erectile disorders.     

Testosterone undecanoate improves erectile dysfunction in hypogonadal men with the metabolic syndrome refractory to treatment with phosphodiesterase type 5 inhibitors alone

At least 30–35% of men with erectile dysfunction (ED) fail to respond to treatment with phosphodiesterase type 5 (PDE‐5) inhibitors. Testosterone (T) has effects not only on sexual desire, but also on the anatomical and physiological substrate of erection. This study analysed the effects of T administration to men unsuccessfully treated for ED with PDE‐5 inhibitors only. Twenty‐nine men aged 36–75 years (mean 59 years) with ED were studied. They suffered from ED for a mean of 2.7 years and had subnormal plasma T levels (total T <3.5 ng ml^?1). They received parenteral testosterone undecanoate for 102 weeks. Changes of the domains of the International Index of Erectile Function (IIEF) were assessed. After 6 weeks of T treatment, the sexual desire domain of IIEF had improved (from 4.1 ± 1.4 to 7.2 ± 1.7) and erectile function as measured by IIEF started to improve, reaching a plateau after 30 weeks (from 9.1 ± 2.1 to 26.5 ± 2.3). Features of the metabolic syndrome also improved. There were no adverse effects of T administration. Addition of T to treatment of hypogonadal men unsuccessfully treated with PDE‐5 inhibitors only, appeared useful and acceptably safe.     

Testosterone and Erection: Practical Management for the Patient with Erectile Dysfunction

Although erectile dysfunction (ED) and testosterone deficiency syndrome are two independently distributed disorders, there is a degree of overlap between them. Testosterone replacement therapy, either alone or combined with other treatments such as a phosphodiesterase type 5 (PDE5) inhibitor, may therefore be useful in some men with ED. Corrective treatment of ED includes sex therapy, risk factor modification, chronic usage of PDE5 inhibitors, and testosterone replacement. Studies have shown that testosterone replacement in men with hypogonadism improves libido and erectile function in a significant proportion of cases. If corrective treatment fails or is not indicated, symptomatic treatments such as oral PDE5 inhibitors or intraurethral/intracavernous therapy are available. PDE5 inhibitors are an excellent first-line choice, although a significant proportion of men still fail to respond to monotherapy. Testosterone deficiency may be overlooked in some men with ED and, because this may be associated with lower expression of PDE5 in the penis, it could result in failure of PDE5 inhibitor therapy. Recent recommendations, therefore, suggest the need for combination therapy in some patients. In conclusion, all men presenting with ED should have their testosterone levels checked, and testosterone replacement should be considered in those with low levels. Testosterone replacement should also be considered in hypogonadal men with ED not responding to PDE5 inhibitors. If erections remain insufficient after 3 mo, a combination of testosterone and a PDE5 inhibitor may be beneficial.     

Central nervous system agents in the treatment of erectile dysfunction

In the last two decades, a better understanding of the mechanisms governing erectile function and the pathophysiologies underlying erectile dysfunction (ED) have led re-searchers to investigate novel treatment concepts. Selective type-5 phosphodiesterase inhibitors are recommended as first-line therapy because of their high efficacy, but 30% to 40% of patients who have ED do not respond adequately to these agents and require alternative methods. The central nervous system plays a fundamental role in sexual behavior. Animal models have advanced our understanding of the neuroanatomic and neuropharmacologic basis of centrally induced penile erections. Clinical research with apomorphine has demonstrated efficacy in men who have a range of ED. Recent interest has focused on other centrally acting agents for ED treatment, including the melanocortin receptor agonists.     

Intramuscular testosterone undecanoate for the treatment of male hypogonadism–review of recent data

Androgen preparations are indicated for the treatment of male hypogonadism. The re-establishment of normal testosterone (T) levels in hypogonadal men has been shown to result in improved libido, erectile quality and mood and to have positive effects on body composition and other parameters. Several treatment options exist for hypogonadal patients; the most commonly used include injectable intramuscular testosterone esters such as testosterone enanthate administered at intervals of 2–3 weeks, which often leads to temporary fluctuations in serum testosterone levels. A novel injectable testosterone ester, testosterone undecanoate (TU), is as effective and safe as the standard injectable formulation and requires only four injections per year in long-term treatment while maintaining serum T levels within the physiological range. Recent data confirm the safety and efficacy of long-term TU therapy in patients treated over a period of up to 7.5 years and show the positive impact of testosterone on the cavernosal tissues that are pathologically altered due to androgen deficiency in an animal model and in humans. Men with erectile dysfunction and low serum testosterone may benefit from testosterone administration and the combination of phosphodiesterase 5-inhibitors and testosterone may be indicated in men who do not respond sufficiently to testosterone alone.     

Endothelial dysfunction and erectile dysfunction in the aging man

Penile erection is a vascular event that requires an intact endothelium to occur. A dysfunctional endothelium is an early marker for the development of atherosclerotic changes and can also contribute to the occurrence of acute cardiovascular events. The pathogenesis of both endothelial and erectile dysfunction (ED) is intimately linked through decreased expression and activation of endothelial nitric oxide (NO) synthase, and the subsequent blunted physiological actions of NO naturally occurring with aging. It is now well-understood that ED is a symptom of underlying disease rather than a disease itself; for this reason in the near future both general practitioners, internal medicine practitioners and many specialists will have to interplay with sexual medicine. Aging in the man is also associated with several changes in arterial structure and function, part of them related to the decline of circulating levels of steroids, that is, testosterone and estradiol. These changes may be responsible, in part, for the lack of efficacy of ED treatments. The recent discovery that chronic administration of phosphodiesterase type 5 inhibitors may improve erectile and endothelial responsiveness of men previously non-responsive to on-demand regimes, and the knowledge that testosterone is one of the main modulators of the expression of penile phosphodiesterase type 5 isoenzyme, opens a new scenario in the treatment of men with ED and co-morbidities. The aim of this review is to discuss the pathophysiology of endothelial dysfunction and its relationship with ED in the aging male, and to suggest possible strategies to improve arterial function with regard to sexual dysfunctions.     

Hormonal erectile dysfunction. Evaluation and management

The clinical diagnosis of hypogonadism in the adult is difficult to establish on the basis of a history and physical examination and universally requires biochemical investigations. A serum testosterone determination is justified in men complaining of erectile dysfunction with or without alterations in sexual desire. Among the causes of erectile dysfunction, hypotestosteronemia rates are low. The prevalence of erectile dysfunction particularly is common at a period in life when alterations occur in male hormonal environment. The treatment of hypogonadal erectile dysfunction, regardless of age, is readily available, safe, and effective. The positive impact of treatment on the overall quality of life can be significant. The presence of erectile dysfunction in an aging man (> 55 years) does not imply the presence of hypogonadism, and, even if the two conditions are present, the indications for treatment require good clinical judgment. Persistent low testosterone levels may have significant detrimental effects in other organ systems; therefore, a timely diagnosis of androgen deficiency and appropriate treatment may have significant effects outside the narrow field of sexual performance.     

Newer phosphodiesterase inhibitors: comparison with established agents

Erectile dysfunction is defined as the consistent or recurrent inability to attain or maintain penile erection sufficient for sexual performance. Self-reported erectile dysfunction has increased significantly as men seek effective therapy, such as oral phosphodiesterase 5 inhibitors (PDE5i). PDE5i are now the drugs of choice in the initial therapy of erectile dysfunction. This review compares the currently available PDE5i with the second-generation PDE5i, which are soon to be available.     

Sildenafil improves nocturnal penile erections in organic impotence.

We studied the effects of sildenafil on nocturnal penile erections. We prospectively evaluated 36 patients with organic or psychogenic impotence and 5 normal, potent men. All patients completed 3 sessions of consecutive nights using the RigiScan Plus device. The first two nights the patients were asked to take placebo before the session and to take 50 mg of sildenafil before the third session. In the organic impotence group the use of sildenafil induced a significant improvement in time of rigidity 60-100%, rigidity and tumescence activity unit values and rigidity and tumescence activity unit values per hour in the tip and base. In the psychogenic impotence group it caused significant improvement only in rigidity activity unit per hour in the tip. In the potent men, changes were statistically insignificant. Sildenafil improves nocturnal penile erectile activity in organic impotence. Our study shows that phosphodiesterase inhibitors can improve penile erections not induced by sexual stimulation.