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.     

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)     

Erectile dysfunction, testosterone deficiency, metabolic syndrome and prostatic disease in Taiwan

The purpose of this article is to review the current status and associations between erectile dysfunction (ED), testosterone deficiency (hypogonadism), the metabolic syndrome (MS) and prostatic disease in Taiwan. The prevalence of ED among Taiwanese men older than 40 years was 17.7%, and self-reported ED was lower than International Index of Erectile Function (IIEF)-5 defined ED. Phosphodiesterase type 5 (PDE-5) inhibitors are the first line treatment, but intracavernosal injection and penile prosthesis still have their place. The serum total testosterone (TT) level showed a decline with age, and is one of the major factors that reduces quality of life (QoL). Testosterone deficiency and hypogonadism are associated with ED, which can be improved by testosterone replacement. The MS was reported to have a prevalence of 14–16% in Taiwanese men, and was associated with an increase in all-cause and cardiovascular disease (CVD) mortality. It was also reported to be associated with hypogonadism and ED. The incidence of prostate cancer (PCa) has been rapidly increasing, and its management has also been changing in Taiwan. In conclusion, we need to pay more attention to men's health in Taiwan.     

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.     

Centrally acting mechanisms for the treatment of male sexual dysfunction

The development of pharmacologic therapy for erectile dysfunction (ED) has been possible because of incremental growth in our understanding of the physiology of normal erections and the complex pathophysiology of ED. Although the oral phosphodiesterase type 5 (PDE5) inhibitors have provided safe, effective treatment of ED for some men, a large proportion of men who have ED do not respond to PDE5 inhibitors or become less responsive or less satisfied as the duration of therapy increases. Also, men who are receiving organic nitrates and nitrates, such as amyl nitrate, cannot take PDE5 inhibitors because of nitrate interactions. The current options for treatment beyond PDE5 inhibitors are invasive, unappealing to some patients, and sometimes ineffective. The search for other options by which ED can be treated has branched out and now encompasses centrally acting mechanisms that control erectile function. Drugs available in Europe include apomorphine. This article focuses on the mechanism of centrally acting agents and reviews clinical data on potential new centrally acting drugs for men who have ED.     

Testosterone in men's health: a new role for an old hormone

Testosterone is an anabolic hormone with a wide range of beneficial effects on men's health. A considerable body of evidence suggests that testosterone (T) deficiency contributes to the onset and/or progression of type 2 diabetes mellitus (T2D), insulin resistance (IR), metabolic syndrome (MetS), cardiovascular disease (CVD), and erectile dysfunction (ED). Low testosterone precedes elevated fasting insulin, glucose, and hemoglobin A1c (HbA1C) values and may even predict the onset of diabetes. Low testosterone also produces adverse effects on cardiovascular health. Androgen deficiency is associated with increased levels of total cholesterol, low density lipoprotein (LDL), increased production of pro-inflammatory factors, increased thickness of the arterial wall, and contributes to endothelial dysfunction. Testosterone therapy of hypogonadal men improves insulin sensitivity, fasting glucose, and hemoglobin A1c levels. Testosterone supplementation restores arterial vaso-reactivity, reduces pro-inflammatory cytokines, total cholesterol, and triglyceride levels and improves endothelial function and high density lipoprotein (HDL) levels. The therapeutic role of testosterone in men's health, however, remains a hotly debated issue for a number of reasons, including the purported risk of prostate cancer. In view of the emerging evidence suggesting that androgen deficiency is a risk factor for MetS, T2D, IR, CVD, and ED, androgen replacement therapy in hypogonadal men may potentially reduce the risk for these pathologies.     

Significance of hypogonadism in erectile dysfunction

To review the role and significance of hypogonadism, defined as a low testosterone (T) level, in erectile dysfunction (ED). Review of literature. Serum T is below 3 ng/ml in 12% of ED patients, including 4% before and 15% after the age of 50. Replacement studies in men with severe hypogonadism demonstrate that sexual desire and arousal, as well as the frequency of sexual activity and spontaneous erections are clearly T-dependant. Psychic erections are partly T-dependant. The effects of T upon sexual function are dose-dependant up to a threshold level that is consistent within an individual, but markedly variable between individuals, ranging from 2 to 4.5 ng/ml. More evidence is required to confirm a significant impact of T on the intrapenile vascular mechanisms of erections in men as it is the case in animals. No convincing association of T with ED has been found in epidemiological studies. As concerns clinical experience, although a meta-analysis of the randomized controlled trials established that T therapy consistently restores erectile function in young hypogonadal patients with T below 3.46 ng/ml, the effects of this treatment have been mostly disappointing when used alone in older patients consulting for ED who are subsequently diagnosed to have hypogonadism following routine T measurement. These poor results may probably be explained by the high prevalence of co-morbidities, and by the fact that ED itself may induce hypogonadism. Combination therapy with T and PDE5 inhibitor (PDE5I) may be effective in the hypogonadal ED patients when T therapy alone fails. However, more evidence is required to confirm the hypothesis that a minimum level of T is required for a complete effect of PDE5I in certain men, since a PDE5I was able to restore complete erections in severely hypogonadal men. Though a low T level is not always the only cause of ED in hypogonadal ED patients, there are important benefits in screening for hypogonadism in ED. A low T level justifies a 3 month trial of T therapy, before combining a PDE5I if T therapy alone fails     

Synergetic effect of testosterone and phophodiesterase-5 inhibitors in hypogonadal men with erectile dysfunction: A systematic review

Testosterone deficiency seems to impair the clinical response to phophodiesterase-5 (PDE-5) inhibitors in patients with erectile dysfunction (ED). In hypogonadal men, testosterone repletion was associated with enhanced sexual function in patients who failed initial treatment with sildenafil or tadalafil. We conducted a systematic review of studies that evaluated combination therapy of testosterone and PDE-5 inhibitors in patients with ED and low, low-normal testosterone levels who failed monotherapy. The studies we examine are heterogeneous with several methodological drawbacks and that, overall, the addition of testosterone to PDE-5 inhibitors might benefit patients with ED associated with testosterone <300 ng/dL (10.4 nmol/L) who failed monotherapy. Further studies, with a randomized placebo-controlled and double blind design, are needed to describe the appropriate target patient group, testosterone cut-off and to define the optimal dose and duration of combination therapy.     

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.     

Testosterone deficiency and risk factors in the metabolic syndrome: implications for erectile dysfunction

The most common cause of erectile dysfunction (ED) is penile vascular insufficiency. This is usually part of a generalized endothelial dysfunction and is related to several conditions, including type 2 diabetes mellitus, hypertension, hyperlipidemia, and obesity. These conditions underlie the pathophysiology of metabolic syndrome (MetS). Hypogonadism, or testosterone deficiency (TD), is an integral component of the pathology underlying endothelial dysfunction and MetS, with insulin resistance (IR) at its core. Testosterone replacement therapy for TD has been shown to ameliorate some of the components of the MetS, improve IR, and may serve as treatment for decreasing cardiovascular and ED risk.     

Hypogonadism and erectile dysfunction: the role for testosterone therapy

The role of low testosterone levels in erectile dysfunction (ED) remains unclear. Both organic and psychogenic factors contribute to ED, with vasculogenic causes being the most common etiology. Approximately 10-20% of patients with ED are diagnosed with hormonal abnormalities. At the physiologic level, two second messenger systems are involved in mediating erections, one involving cyclic adenosine monophosphate (cAMP) and the other involving cyclic guanosine monophosphate (cGMP). PDE5 inhibitors such as sildenafil promote the cGMP pathway, while alprostadil affects the cAMP pathway. Evidence is strong that, in animal systems, testosterone has direct effects on erectile tissue. However, although testosterone clearly has an impact on libido in humans, its effect on penile function is less clear. Evaluation of ED includes medical, sexual, and psychosocial history assessments, as well as laboratory tests to check for diabetes and hormonal abnormalities. Initial interventions should involve correction of potentially reversible causes of ED, such as hypogonadism. First-line therapy for other patients is typically oral PDE5 inhibitors, such as sildenafil, tadalafil, or vardenafil. For patients who fail treatment with PDE5 inhibitors, local therapies such as intracavernous alprostadil are highly successful. Recent data also support the success of combination therapy with sildenafil and testosterone. This opens the possibility of other combinations of testosterone and other treatments of ED. The ability to exploit multiple pathways in the physiologic processes leading to erection may help improve therapy for ED.     

男性骨质疏松症与睾酮关系的研究进展

随着老龄人口的增加,男性骨质疏松症和睾酮缺乏越来越常见。近年来研究表明,睾酮水平与男性骨质疏松症的发生密切相关,睾酮缺乏的患者发生骨质疏松症及骨折的风险增加。睾酮可通过雄激素受体和雌激素受体调节骨代谢,且睾酮替代治疗可以有效增加男性骨密度,降低发生骨质疏松症的风险。本文回顾最近的文献,就睾酮与骨质疏松症的关系做一综述。     

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.     

Combining testosterone and PDE5 inhibitors in erectile dysfunction: basic rationale and clinical evidences

INTRODUCTION: Erectile dysfunction (ED) and decline of testosterone levels are frequently observed with age and also in illnesses with a common basis of endothelial damage. OBJECTIVES: To review molecular mechanisms underlying androgen action upon its receptor and phosphodiesterase type 5 (PDE5) expression and regulation by testosterone in cavernous tissue and their clinical implication in the treatment of ED refractory to PDE5 inhibitors (PDE5-Is). METHODS: From January 2003 to May 2006 [corrected] we performed an extensive, unsystematic MEDLINE literature search reviewing relevant data on basic and clinical studies regarding the efficacy of combination therapies. RESULTS: Most trials using testosterone alone for treatment of ED in hypogonadal men suffer from methodologic problems and report inconsistent results, but overall the trials suggest that testosterone is superior to placebo. Orally effective PDE5-Is, such as sildenafil, tadalafil, or vardenafil, may be ineffective depending on the demonstration of testosterone regulation of PDE5 expression in human corpus cavernous, and their efficacy may be enhanced by testosterone adjunction whenever necessary. CONCLUSIONS: Screening for hypogonadism in all men with ED is necessary to identify men with severe hypogonadism and some cases of mild to moderate hypogonadism, who may benefit from testosterone treatment. Identification of threshold values for testosterone supplementation to appropriately benefit from PDE5-Is failure may improve clinical management of unresponsive patients with minimization of unwanted effects.     

Erectile dysfunction and hypertension

Recent analyses suggest that about 67-68% of men with hypertension have some degree of erectile dysfunction (ED). With about 25 million men in the US with hypertension, substantial numbers of hypertension-related ED exist that tend to be of a more severe nature than the general population. Men with ED are also more likely to have hypertension. Thiazide diuretic and beta-blocker therapy may contribute to ED. Phosphodiesterase-5 (PDE5) inhibitors are effective therapy in men with ED owing to hypertension who are taking antihypertensive medicines including those on multiple antihypertensive medicines. The addition of PDE5 inhibitors to usual common antihypertensive medicines (diuretics, beta blockers, calcium blockers, angiotensin converting enzyme inhibitors and angiotensin receptor blockers) results in either no or small additive reductions in blood pressure (BP) and no increase in serious clinical adverse events. There are however precautions regarding the use of PDE5 inhibitors in patients taking alpha blockers for either hypertension or benign prostatic hypertrophy, as some patients may develop orthostatic hypotension. Organic nitrates remain an absolute contraindication for PDE5 inhibitors because synergistic and symptomatic reductions in BP may occur in some patients with this drug combination.     

The relationship between hypogonadism and erectile dysfunction

It is well known that testosterone enhances sexual interest leading to an increased frequency of sexual acts and an increase in the frequency of sleep-related erections. However, it has little effect on fantasy- or visually induced erections. Exact contribution to erection from testosterone in men remains unclear. Animal studies have well demonstrated that testosterone plays critical physiological (activity of nitric oxide synthases and phosphodiesterases), biochemical (through an endothelial-independent pathway and adrenergic tonicity) and structural (change of fibroelasticity and hollow cell accumulation) roles in erectile function. The supplementation of testosterone to castrated animals can restore erectile function. Clinically, reports of patients with erectile dysfunction (ED) combined with hypogonadism who receive testosterone therapy have inconsistent results. However, testosterone may ameliorate the expression of the phosphodiesterase-5 (PDE5) inhibitor, and the use of testosterone in conjunction with the PDE5 inhibitor revealed convincing results. Because of potential risks in clinical use, testosterone therapy should be individualized, carefully considered and closely monitored, especially, in patients with possible occult prostate cancer, and large benign prostatic hyperplasia. Lower urinary tract symptoms might be worsened by this treatment, since the prostate is an androgen-dependent tissue.     

A Critical Analysis of the Role of Testosterone in Erectile Function: From Pathophysiology to Treatment—A Systematic Review

Context

Androgen modulation of erectile function (EF) is widely accepted. However, the use of testosterone replacement therapy (TRT) in men with erectile dysfunction (ED) has generated an unprecedented debate.

Objective

To summarize the relevant data on the incidence, diagnosis, and management of ED coexisting with hypogonadism and to develop a pathophysiology-based treatment algorithm.

Evidence acquisition

We reviewed the relevant medical literature, with a particular emphasis on original molecular studies, prospective observational data, and randomized controlled trials performed in the past 20 yr.

Evidence synthesis

Testosterone modulates nearly every component involved in EF, from pelvic ganglions to smooth muscle and the endothelial cells of the corpora cavernosa. It also regulates the timing of the erectile process as a function of sexual desire, coordinating penile erection with sex. Epidemiologic studies confirm the significant overlap of hypogonadism and ED; however, most guidelines do not consider the differential diagnosis of hypogonadism or the relevance of subclinical disease. Various clinical tools can help the physician to assess and restore androgen levels in men with ED. Special attention is given to fertility-sparing treatments, due to the increasing number of older men desiring fatherhood. The simultaneous use of phosphodiesterase type 5 inhibitors (PDE5-Is) and TRT has recently been questioned. Originally proposed as a salvage therapy for nonresponders to PDE5-Is, this approach has been inappropriately transformed into a combination therapy. Clinical data are consistent when reinterpreted in the proper framework, whereas molecular evidence remains controversial.

Conclusions

A body of molecular and clinical evidence supports the use of TRT in hypogonadal patients with ED, although the benefit–risk ratio is uncertain in advanced age. Critical appraisal of this evidence enabled the development of a pathophysiology-oriented algorithm designed to avoid inappropriate treatments and support whether to start with TRT, PDE5-I only, or both. Apparently divergent findings are reconciled when TRT is correctly indicated. An improved diagnosis and individualized management is desirable in light of the many available options.     

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 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.