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)     

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.     

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.     

Patient satisfaction with testosterone supplementation for the treatment of erectile dysfunction

The long-term efficacy of testosterone supplementation for erectile dysfunction was evaluated using standardized questionnaires and differences between testosterone delivery systems analyzed. Forty-four patients receiving parenteral depo-testosterone, Testoderm scrotal patches, or Testoderm-TTS nonscrotal patches were evaluated with the Erectile Dysfunction Inventory of Treatment Satisfaction and International Index of Erectile Function questionnaires. Global questions regarding libido, energy, and improved erections demonstrated a significantly better response with depo-testosterone and Testoderm-TTS nonscrotal patches as compared to Testoderm scrotal patches. Testoderm-TTS nonscrotal patches and depo-testosterone resulted in significantly higher overall treatment satisfaction (p <.001), confidence in ability to engage in sexual activity (p <.001), and total Erectile Dysfunction Inventory of Treatment Satisfaction and International Index of Erectile Function scores (p <.001). Testoderm-TTS nonscrotal patches were significantly better than depo-testosterone with regard to satisfaction with sexual intercourse (International Index of Erectile Function question 5, p <.05). Testosterone replacement improved the quality of erections and level of libido in patients with erectile dysfunction. Treatment delivery systems appear to impact the success of therapy.     

Hormonal supplementation and erectile dysfunction

The role of testosterone on sexual desire is well established. However, the effects of low testosterone levels in the pathophysiology of erectile mechanism in humans remains unclear. Recent evidence indicate that approximately 10-20% of men with erectile dysfunction (ED) have hormonal abnormalities, raising up to 35% over the age of sixty. It is now clear that sexual desire and erectile function in humans are both responsive to androgens, probably at different threshold values. In fact, different degrees of testosterone deficiency may determine a sequence of molecular penile events leading to reduced capacity of penile smooth muscle and endothelial cells of relaxation, without greatly affecting sexual desire. Also, androgens may directly control the expression and activity of phosphodiesterase type-5 in human corpus cavernosum. In some selected men with total testosterone below 10-13nmol/l and/or free testosterone below 200-250pmol/l, androgen supplementation may improve therapeutic efficacy of phosphodiesterase type-5 inhibitors. For ageing men with partial androgen deficiency (PADAM) who fail first-line oral treatments in whom androgens are not contraindicated, a combination of testosterone and phosphodiesterase type-5 inhibitors may be considered to improve erectile function and improve the quality of life.     

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.     

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.     

The effects of androgen depletion on human erectile function: a prospective study in male-to-female transsexuals

The objective of the study was to determine the effects of androgen depletion on erectile function in a population of male-to-female transsexuals. The erectile function of 25 consecutive male-to-female transsexuals on androgen depletion treatment and scheduled for surgical gender reassignment was prospectively evaluated using medical and sexual history, physical examination, total serum testosterone, International Index of Erectile Function (IIEF-15) questionnaire, penile colour-coded Doppler ultrasonography (CDU) after pharmacological stimulation and nocturnal penile tumescence (NPT) test. All but one had undetectable or low testosterone. Subjective erectile function, according to IIEF-15 scores, and penile CDU findings did not correlate with testosterone levels, whereas NPT test findings correlated well with testosterone levels. These findings would suggest that nocturnal erections are androgen-dependent whereas sexually induced erections are androgen-independent. It can also be assumed that testosterone is important but not essential for male erectile function and that other androgen-independent pathways can be responsible for sexually induced erections.     

Effects of an environmental anti-androgen on erectile function in an animal penile erection model

PURPOSE: Erectile function is testosterone dependent. For example, interference with either the levels or receptor binding of this steroid hormone may induce erectile dysfunction. Several environmental contaminants can interfere with the actions of endogenous hormones and have been termed 'endocrine disrupters.' p,p-DDE, a prominent and persistent metabolite of the insecticide DDT, has been shown to be an androgen receptor antagonist. The objective was to determine whether endocrine disrupters, as exemplified by p,p-DDE, are factors in the etiology of erectile dysfunction. MATERIALS AND METHODS: Using the established rat model of apomorphine-induced (80 microg./kg, s.c.) erections we assessed the dose-response effects of p,p-DDE in comparison to the known androgen receptor antagonist flutamide in acute (0.5 to 12 hours) and short-term (up to 8 weeks) experiments in both intact (Study 1) and castrated (Study 2) rats. As a follow up (Study 3), castrated rats treated with p,p-DDE were given increasing doses of testosterone (0.48 to 2.4 mg./kg., i.p.), eight weeks after p,p-DDE administration, to assess reversibility of p,p-DDE effect. RESULTS: A single dose of flutamide (50 mg./kg., i.p.) was found to significantly decrease apomorphine-induced erections to less than 50% over 12 hours following flutamide administration with recovery of erectile response within 48 hours. In comparison, a single dose of p,p-DDE (500 mg./kg., i.p.) decreased apomorphine-induced erections for at least two weeks (1.15+/-0.3 versus 2.5+/-1.1). Castration significantly decreased apomorphine-induced erections to approximately 0.5 erections/30 minutes. Flutamide (50 mg./kg.; i.p.) or p,p-DDE (50 mg./kg.; i.p.) did not further suppress the apomorphine erections in castrated rats. Testosterone supplementation (480 microg./kg; s.c.) in vehicle treated castrated rats recovered erectile response to pre-castrated levels, whereas p,p-DDE treated castrated rats required 4 times the dose of testosterone (2 mg./kg.; s.c.) given to vehicle treated rats to recover erections. CONCLUSIONS: The endocrine disrupter p,p-DDE can markedly interfere with erectile function and demonstrates persistence after a single dose. This supports our novel concept that environmental hormones may cause erectile dysfunction.     

Testosterone and erectile dysfunction

Aging is associated with a decline in several important health factors in men, including libido. Serum testosterone concentrations also decrease with age, and many age-related clinical features are closely associated with androgen deficiency, including erectile function (ED). Approximately 70% of ED is of organic origin, with the major risk factors being diabetes mellitus, hypercholesterolemia, smoking and chronic medical illnesses. These are also established risk factors for atherosclerosis, which is the predominant predisposing factor of vasculogenic ED. The introduction of phosphodiasterase-5 (PDE-5) inhibitors for the treatment of ED made a significant impact both in terms of clinical efficacy, and increasing the awareness of the condition. In spite of this, some patients fail to respond to PDE-5 inhibitors alone. Both animal and clinical studies indicate that testosterone therapy improves both erectile function and the response to PDE-5 inhibitors in patients with ED and hypogonadism. Indeed, interventional studies demonstrate that testosterone replacement therapy improves erectile function in hypogonadal men who have previously failed to respond to PDE-5 inhibitors alone. Furthermore, it has been demonstrated that the full therapeutic potential of PDE5 inhibitors will only become manifest in a eugonadal state. Recent studies have demonstrated a close relationship between testosterone and ED and suggest that testosterone therapy may be a valuable option for an increasing number of affected men. European guidelines recommend that all men presenting with ED should have their testosterone concentrations measured.     

Erectile dysfunction. Epidemiology, physiology, etiology, diagnosis and therapy

Erectile dysfunction is a common, age-dependent functional disturbance of men associated to various comorbidities. Interdisciplinary cooperation with neurologists in cases of a suspected neurological aetiology and with psychiatrists in cases with normal organic diagnostic findings is necessary. Hormone replacement and psychotherapy can cure certain patients. Oral pharmacotherapy is the most effective therapy for erectile dysfunction with the highest patient preference. Oral PDE-5-inhibitors (sildenafil, tadalafil, vardenafil) are superior in effectiveness to centrally acting drugs (apomorphin, yohimbine). Local pharmacotherapy (MUSE, ICI) is a second line therapy in cases of failure or contraindications for oral pharmacotherapy. Vacuum therapy and operative procedures (penile implants) complete the therapeutic options of erectile dysfunction.     

Hypogonadism and erectile dysfunction: pathophysiological observations and therapeutic outcomes

Androgens have a profound effect in male sexual function in general and erectile physiology in particular. Despite the common belief that male sexuality is fully dependent on normal androgens, hypogonadal men are capable of sexual erections; almost a third of men receiving effective antiandrogen therapy can develop erections when tested with an erotic challenge. However, successful hormonal supplementation that results in normal testosterone values does not always restore libido and erectile function. Although the primary goal of treatment for hypogonadism may be to restore sexual function, there will be other significant benefits and potential drawbacks. Libido, general well-being, osteoporosis, muscle strength, mental acuity, and growth hormone levels will all be positively affected by appropriate management of low testosterone levels. Testosterone replacement therapy should maintain not only physiological levels of serum testosterone but also its metabolites, including dihydrotestosterone and oestradiol. The assessment of hypogonadism, its treatment and monitoring, are unavoidable responsibilities of the urologist.     

Testosteron und erektile Dysfunktion

Primary hypogonadism represents a classic but rare cause of erectile dysfunction (ED) in men. Therapy with testosterone as monotherapy is therefore unlikely to cure ED in the typical ED patient. However, recent developments indicate a much greater role of testosterone in erectile function than has been supposed in the past. Serum testosterone levels decline in men with increasing age. Aging men might develop late-onset hypogonadism (LOH) associated with characteristic symptoms. Typical symptoms of LOH are represented by decreased libido and sexual function, osteoporosis, altered distribution of body fat, overall reduction in physical strength, and alterations in the general mood. Experimental and clinical studies over the last few years have also pointed out that hypogonadism results in characteristic alterations of the erectile tissue of the penis. These alterations might be reversible in response to hormone therapy with testosterone. Particularly testosterone might be a helpful supportive therapy in cases where PDE-5 antagonists have tended to lose their effectiveness on the erectile tissue in the treatment of ED.     

How to optimise treatment of erectile dysfunction above and beyond the beneficial effects of a phosphodiesterase type 5 inhibitor

The introduction in 1998 of the phosphodiesterase type 5 (PDE-5) inhibitors has changed the landscape of diagnosis and, in particular, the treatment of erectile dysfunction (ED). It has paved the road for a more profound insight into ED. ED and other ailments of elderly men, such as atherosclerosis, hypertension, diabetes mellitus and lower urinary tract symptoms were usually regarded as distinct diagnostic/therapeutic entities, but there is growing evidence that they are interrelated and are factors in ED. To optimise the treatment of ED, an integral approach to the health of the ageing male is required. There is an interdependence between the metabolic syndrome, ED and patterns of testosterone in ageing men. The main features of the metabolic syndrome are abdominal obesity, insulin resistance, hypertension and dyslipidaemia, significant factors in the aetiology of erectile function. The metabolic syndrome is associated with lower-than-normal testosterone levels. Testosterone is a determinant of glucose homeostasis and lipid metabolism. Testosterone is not only a factor in libido but also exerts essential effects on the anatomical and physiological substrate of penile erection. With these recent insights, the health problems of elderly men must be placed in a context that allows an integral approach. While PDE-5 inhibitors are the mainstay of treatment of men with ED, treatment of testosterone deficiency is becoming part and parcel of a new approach to both ED and the metabolic syndrome. The diagnostic work-up of ED should comprise measurement of plasma testosterone. If proven deficient, treatment with testosterone is indicated.     

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 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.     

Testosterone levels in men with erectile dysfunction

OBJECTIVE: To investigate the frequency of hypogonadism in men with erectile dysfunction (ED) and to assess which factors are related with low testosterone levels. PATIENTS AND METHODS: In all, 165 men with ED were assessed; the evaluation included: hormonal profiles, serum total and free testosterone (using Vermeulen's formula) levels, and self-reported questionnaires on erectile function and desire domains of the International Index of Erectile Function. The frequency of hypogonadism was established using total and free testosterone levels as diagnostic criteria. The factors that might influence testosterone levels were evaluated by univariate and multivariate statistical analysis, and a logistic regression was used to determine which factors can predict free testosterone levels below normal limits (biochemical hypogonadism). RESULTS: Using the total testosterone levels, 4.8% of the men were hypogonadal, whereas when using the free testosterone levels, 17.6% were hypogonadal. In the univariate analyses, not smoking and hypertension were associated with lower total and free testosterone levels. Ageing, absence of nocturnal erections and a lower erectile function score were only associated with lower free testosterone serum levels. There was no association between total and free testosterone levels and desire. In the multivariate analysis, only total testosterone levels were related to hypertension, while free testosterone levels were related to age and nocturnal erections. For biochemical hypogonadism, simple logistic regression analysis selected age, erectile function score and aetiological diagnosis of ED as predictors. In the multivariate analysis only the erectile function score had significant independent prognostic value. CONCLUSIONS: The frequency of hypogonadism is higher when free testosterone levels are used for diagnosis. The total and free testosterone levels were not related to the level of sexual desire in men with ED. The free testosterone levels could be related to the quality and frequency of nocturnal erections, and when ED is more severe, it is more probable that free testosterone levels are below the 'normal' limit.     

Is sildenafil citrate associated with an amelioration of the symptomatology of androgen decline in the aging male?

PURPOSE: We examined whether treatment of erectile dysfunction with sildenafil citrate is associated with amelioration of the symptomatology of androgen decline in the aging male, and whether this alters the endocrine pattern. MATERIALS AND METHODS: A double-blind, randomized, placebo controlled, crossover study with sildenafil citrate was conducted in 60 men (age range 47 to 75 years old) who presented with erectile dysfunction and screened positively for androgen decline in the aging male by the questionnaire of the same name. The patients were randomized to receive sildenafil citrate or placebo in a 1:1 ratio and were crossed over after 3 months of treatment for an additional 3 months. The evaluation included International Index Erectile Function and Aging Male Symptoms questionnaires, hormonal profiles, total testosterone, and bioavailable testosterone. RESULTS: A total of 40 patients completed the study. Compared to placebo, sildenafil citrate improved erectile function (52.7 +/- 2 vs 39 +/- 1.9, p <0.001) and Aging Male Symptoms score (33.5 +/- 1.3 vs 28.6 +/- 1.3, p <0.001) in the total group. Breakdown into hypogonadal and normal men showed that the International Index of Erectile Function score improved more in normal (Delta 18.5 +/- 3.6) than in hypogonadal men (Delta 6.7 +/- 2.7). There were no differences in improvement on the Aging Male Symptoms questionnaire between hypogonadal and normal men. No treatment changes were observed in total testosterone and bioavailable testosterone. CONCLUSIONS: In the total group of patients sildenafil citrate was associated with expected improvement in erectile function and in the Aging Male Symptoms questionnaire without any alteration in hormonal pattern. The available questionnaires for androgen decline in the aging male are not specific for the diagnosis of biochemical androgen decline in the aging male, although the suboptimal response to sildenafil citrate suggests the presence of hypogonadism.     

Is the measurement of serum testosterone routinely indicated in men with erectile dysfunction?

OBJECTIVE: To investigate the usefulness of serum testosterone levels as a relevant or useful indicator of sexual potency in men attending an erectile dysfunction clinic. PATIENTS AND METHODS: Ninety consecutive men attending the erectile dysfunction clinic completed a sexual-activity questionnaire, and underwent a focused physical examination and questioning about their medical history. The serum testosterone level was measured in all patients and the results analysed in relation to the patient's age. Patients with low serum testosterone levels commenced replacement therapy comprising three intramuscular injections of testosterone (Sustanontrade mark, Organon, The Netherlands) 250 mg every third week. Potency status and serum testosterone were reassessed after 3 months' treatment. RESULTS: Of the 90 men, 28 (31%) were aged < 50 years whilst 62 (69%) were >/=50 years old. Nineteen (21%) patients overall had low testosterone levels; four of these were < 50 and 15 were >/=50 years old. Five of 90 patients had a decreased libido; two of these also had low testosterone levels and all were < 50 years old. Testosterone levels returned to normal in all patients who received replacement therapy but potency returned in only two (10%); both were in the older group. CONCLUSION: Measuring testosterone was not helpful in assessing potency or libido and low serum levels were not related to age. Correcting low testosterone did not improve either impotence or libido.     

Can testosterone level be a good predictor of late‐onset hypogonadism?

Androgens are essential for the development and growth of the genitalia. They regulate the erectile physiology by multiple mechanisms. Several studies have examined associations among sex hormones' serum levels, erectile function and sex drive. We sought to identify a protocol for using testosterone in men with erectile dysfunction and late‐onset hypogonadism (LOH). During a 16‐month period, men with erectile dysfunction who presented to the andrology clinic were selected. They underwent a complete physical examination and filled out the International Index of Erectile Function‐5 questionnaire. Serum luteinising hormone (LH) and testosterone levels were evaluated. Patients received a single intramuscular injection of 250 mg testosterone. Thereafter, serum levels of LH and testosterone were measured 3 weeks later. The mean age was 53 years old. After treating patients with testosterone, 45 (94%) showed improvement in LOH symptoms including libido, loss of energy, irritability and quality of life. The mean International Index of Erectile Function was 9 and 13.1, prior to and after treatment respectively. Mean serum testosterone levels before and after treatment were 4.2 and 4.1 ng ml^?1 respectively (P = 0.849). Mean serum LH revealed a significant decrease after the study (P = 0.004) (6.12 and 5.1 ng ml^?1, before and after the study respectively). Our findings suggested that testosterone replacement therapy improves libido and LOH symptoms in individuals with almost normal or lower limit normal value of serum testosterone levels.