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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

勃起功能障碍全球视点:从科学进展到伴侣的解决方案——第一届亚太地区研讨会纪要

2006年2月24～26日,第一届“勃起功能障碍(ED)全球视点:从科学进展到伴侣的解决方案”亚太地区研讨会在中国上海举行。会议就男性的性健康问题、尤其是勃起功能障碍(ED)的最新科学数据及其对女性伴侣的影响进行了广泛的探讨。主要内容包括ED患者及其伴侣与医生这3者之间交流的重要性,女性伴侣在患者寻求和坚持药物治疗中的作用,慢性疾病对性健康的影响,睾酮在ED中的作用,特殊人群的性健康,如何进行个体化治疗以及如何获得成功的治疗反应,磷酸二酯酶5(PDE5)抑制剂(尤其是伐地那非)治疗ED的显著疗效和安全性,以及亚洲地区ED的治疗现状等。     

Clomiphene increases free testosterone levels in men with both secondary hypogonadism and erectile dysfunction: who does and does not benefit?

Secondary hypogonadism is more common than primary gonadal failure and is seen in chronic and acute illnesses. Although testosterone has a role in erections, its importance in erectile dysfunction (ED) has been controversial. Hypogonadism produced by functional suppression of pituitary gonadotropins has been shown to correct with clomiphene citrate, but with a modest effect on sexual function. We wondered if longer treatment would produce improved results. A total of 178 men with secondary hypogonadism and ED received clomiphene citrate for 4 months. Sexual function improved in 75%, with no change in 25%, while significant increases in luteinizing hormone (P<0.001) and free testosterone (P<0.001) occurred in all patients. Multivariable analysis showed that responses decreased significantly with aging (P<0.05). Decreased responses also occurred in men with diabetes, hypertension, coronary artery disease, and multiple medication use. Since these conditions are more prevalent with aging, chronic disease may be a more important determinant of sexual dysfunction. Men with anxiety-related disorders responded better to normalization of testosterone. Assessment of androgen status should be accomplished in all men with ED. For those with lower than normal age-matched levels of testosterone treatment directed at normalizing testosterone with clomiphene citrate is a viable alternative to giving androgen supplements.     

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.     

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.     

睾酮替代治疗雄激素缺乏ED患者65个月1例报告及文献复习

目的:通过对1例雄激素缺乏的ED患者行65个月的睾酮替代治疗观察,探讨长期睾酮替代治疗的可行性及雄激素缺乏ED的机制,为其合理治疗提供参考。方法:跟踪1例雄激素缺乏的ED患者应用睾酮替代治疗65个月的治疗效果、IIEF-5评分,雄激素变化,PSA、Hb及RBC变化及长期应用睾酮的不良反应监测,并结合相关文献进行分析。结果:46岁男性,IIEF评分7分,在未治疗前血清总睾酮(TT)2.79 ng/ml,反复多次应用多种PDE5抑制剂均无效,诊断为LOH,予以睾酮替代疗法,补充十一酸睾酮胶囊,开始2周80 mg,2次/日,后改为40 mg,2次/日,2个月后TT正常达3.45 ng/ml,体能、焦虑等症状明显好转,但是性功能无明显改善,予以PDE5抑制剂按需服用,感觉应用有效,IIEF评分21分,坚持联合用药45个月后停用PDE5抑制剂,单用睾酮替代治疗18个月,阴茎勃起坚挺,性功能满意,IIEF评分21分,定期复查性激素水平、PSA和血常规未见明显异常。结论:睾酮替代治疗可以改善PDE5抑制剂治疗雄激素缺乏的ED的效果,长期睾酮治疗雄激素缺乏症是安全、有效的。     

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.     

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.     

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.     

Current approaches to erectile dysfunction and testosterone deficiency

Androgens are essential for the development of the penis and it is well known that testosterone play a critical role in the physiology of erectile function. From animal studies, testosterone insufficiency disrupts cellular-signaling pathways and induces pathologic alterations in penile tissues leading to erectile dysfunction. In human, the testosterone threshold for maintaining erection is low which explains the reason why some contracted men still have an erection due to the androgens produced by the adrenal gland. Testosterone alone can improve erectile function in hypogonadic patients. Associated with PDE5-I, testosterone supplementation is a treatment for the hypogonadic patients non responders to therapy. The article reviews the different aspects of the testosterone role in the pathophysiology of erection.     

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.     

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.