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.     

磷酸二酯酶5抑制剂治疗勃起功能障碍的疗效和安全性比较

磷酸二酯酶 5 (PDE 5 )抑制剂西地那非的问世使男性勃起功能障碍 (ED)的治疗手段发生了根本性的改变。1998年以来有 10 0多个国家的 2 0 0 0多万患者使用了西地那非 ,患者的死亡率与总体人群的死亡率差异无显著性。西地那非治疗ED平均有效率达 80 %以上 ,成为治疗ED的首选手段。随着新的PDE 5抑制剂伐地那非和泰地那非在国外先后进入临床使用 ,药物治疗ED有了更多的选择。本文通过比较 3种PDE 5抑制剂的药效学、药动学及不良反应以评价其疗效和安全性。     

Sildenafil: A 4-year update in the treatment of 20 million erectile dysfunction patients

Sildenafil citrate, the first internationally approved and widely used oral agent for the treatment of erectile dysfunction (ED), has revolutionized the treatment of ED throughout the past 5 years. This phosphodiesterase type-5 (PDE-5) inhibitor is selective for corpus cavernosum smooth muscle tissue and produces excellent erectile function. Its efficacy and safety over a wide variety of etiologies of ED and severities of ED demonstrates its usefulness in the clinical treatment of these patients. More than 20 million men have been treated worldwide with sildenafil with excellent results. ED caused by difficult-to-treat etiologies such as radical prostatectomy, severe diabetes, and spinal cord injury have demonstrated efficacy. Although sildenafil citrate, like all PDE-5 inhibitors, is contraindicated in patients taking nitrate medications for cardiac disease, it is effective and safe for those cardiovascular patients who are not taking nitrate medications. The incidence of adverse cardiovascular events in patients taking sildenafil does not differ from those of the general population. Investigations into the pharmacologic effect of sildenafil on coronary myocardial tissue further supports the safety of this medication. Sildenafil has been safe and effective in patients taking various medications including multiple antihypertensive drugs, selective serotonin reuptake inhibitors, cardiac, and diabetic medications.     

Use of combined intracorporal injection and a phosphodiesterase-5 inhibitor therapy for men with a suboptimal response to sildenafil and/or vardenafil monotherapy after radical retropubic prostatectomy

OBJECTIVE: To report experience with combined therapy using intracorporal injection (ICI) of alprostadil and oral phosphodiesterase 5 (PDE-5) inhibitors for the minimally invasive treatment of erectile dysfunction (ED) after radical prostatectomy (RP), as PDE-5 inhibitors are effective but a few patients may have a suboptimal response. PATIENTS AND METHODS: In a retrospective study, 34 men (aged 46-66 years) had a nerve-sparing retropubic RP and subsequent ED. Patients were titrated on sildenafil citrate or vardenafil to maximum doses. All had a suboptimal response after a maximum of eight doses of oral therapy and were then treated with ICI therapy using 15 or 20 microg alprostadil. Erectile function was assessed with the Sexual Health Inventory for Men (SHIM). RESULTS: Of the 32 patients who continued combined therapy, 22 (68%) had an improvement in erectile function after ICI therapy, as assessed by the SHIM score. On follow-up, 36% of these patients used ICI therapy only intermittently, instead of regularly, as they felt that this was adequate enough for good results. CONCLUSIONS: PDE-5 oral pharmacotherapy is the most commonly used effective therapy for ED but may not be as effective in patients who have radical surgery; the addition of testosterone patches may have side-effects or be considered a risk in patients with a history of prostate cancer. The use of ICI therapy as an adjunct or maintenance therapy to their oral medication may be another alternative in these patients.     

Sexual functions of men with obstructive sleep apnoea syndrome and hypogonadism may improve upon testosterone administration: a pilot study

This study examined 72 patients with obstructive sleep apnoea syndrome (OSAS), confirmed by polysomnography. Thirty-two patients were suffering from erectile dysfunction (ED) assessed by IIEF-5 questionnaires and confirmed by nocturnal penile tumescence examination. Their testosterone levels were measured. Eight patients had normal testosterone levels and were treated with a PDE-5 inhibitor (vardenafil) only; after 6 months of treatment, 6 of these patients (75%) showed significant improvement in erectile function. The remaining 24 patients with OSAS, ED and hypogonadism (total testosterone <12 nmol l⁻¹), were divided into two groups based on the indication for continuous positive airway pressure (CPAP) therapy: five patients received CPAP therapy (group 1) and 19 patients did not (group 2). The patients of group 2 received only a PDE-5 inhibitor (vardenafil 20 mg) for ED; and eight patients (42%) showed an improvement after 3 months of treatment. The five patients receiving CPAP therapy were treated with a combination of parenteral testosterone undecanoate and a PDE-5 inhibitor (vardenafil) and all had normal erectile function after 3 months of therapy. The results suggest positive effects of addition of testosterone to treatment with PDE-5 inhibitors in hypogonadal men with OSAS, which should be confirmed in larger controlled studies.     

The effects of chronic phosphodiesterase-5 inhibitor use on different organ systems

Phosphodiesterase-5 (PDE-5) inhibitors selectively inhibit PDE-5 enzymes that are present in various tissues like penile tissue, platelets, vascular, and smooth muscle tissue. The drug's actions on these tissues have lead to the successful therapeutic use in patients suffering from conditions such as erectile dysfunction (ED) and pulmonary hypertension. PDE-5 inhibitors (PDE-5i) act on the erectile tissue causing penile smooth muscle relaxation and vasodilatation leading to penile erection. In addition, in particular when used in conjunction with prostaglandin inhibitors, PDE-5i cause vasodilatation in pulmonary vasculature hence decreasing both the pulmonary arterial pressure and resistance. PDE-5i have also shown to mildly decrease blood pressure, increase cardiac index, and increase coronary blood flow in experimental animals as well as in human studies. The Food and Drug Administration (FDA) has approved three PDE-5i for the treatment of ED: sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) and one for pulmonary hypertension: sildenafil (Revatio). These agents are highly selective for PDE-5 enzymes as compared to other subclasses of PDE enzymes and have the almost identical pharmacological action but slightly different pharmacokinetics. Only little data exist about long-term use of PDE-5i and their effects on different organ system. This paper reviews the current information available on chronic PDE-5 inhibitor use.     

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.     

Sildenafil inhibits the up-regulation of phosphodiesterase type 5 elicited with nicotine and tumour necrosis factor-alpha in cavernosal vascular smooth muscle cells: mediation by superoxide

OBJECTIVES: To determine whether there is an association between vascular phosphodiesterase type 5 (PDE-5) and NADPH oxidase (NOX) in cavernosal vascular smooth muscle cells (CVSMCs), and to study the actions of the PDE-5 inhibitor sildenafil; the pro-erectile actions of nitric oxide (NO) are reduced by PDE-5 which hydrolyses cGMP to inactive GMP, thus an up-regulation of PDE-5 and over-production of O(2)(-) derived from NOX might promote erectile dysfunction (ED). MATERIALS AND METHODS: To study the effects of nicotine and tumour necrosis factor-alpha (TNF-alpha) on superoxide (O(2)(-)) production and PDE-5 expression, CVSMCs from rabbit penis were incubated with nicotine or TNF-alpha, and superoxide dismutase (SOD), catalase, sildenafil citrate, or apocynin (NADPH inhibitor) for 16 h. The expression of PDE-5 and of glyceraldehyde-3-phosphate dehydrogenase (internal standard) was assessed using Western blotting. O(2)(-) was measured spectrophotometrically. RESULTS: After a 16-h incubation, both nicotine (maximal at 10 microm) and TNF-alpha (10 ng/mL) significantly increased O(2)(-) formation in CVSMCs; this effect was blocked by co-incubating with SOD, catalase, and sildenafil (1 microm). Apocynin also inhibited O(2)(-) formation when added after 16-h incubation with nicotine (10 microm) or TNF-alpha. PDE-5 expression was also significantly increased in CVSMCs incubated with nicotine and TNF-alpha. This effect was negated by 16-h co-incubation with SOD, catalase, apocynin, and sildenafil. CONCLUSIONS: Nicotine and TNF-alpha up-regulate PDE-5 expression in CVSMCs through an a priori up-regulation of NOX and formation of O(2)(-). As PDE-5 hydrolyses cGMP, this effect might 'blunt' the pro-erectile actions of NO. Sildenafil inhibits O(2)(-) formation, and 'normalizes' PDE-5 expression. This represents a novel pathogenic mechanism underlying ED, and a novel mechanism of action of sildenafil.     

Combined use of androgen and sildenafil for hypogonadal patients unresponsive to sildenafil alone

To investigate the therapeutic effect of androgen on hypogonadal patients unresponsive to sildenafil alone. In total, 32 hypogonadal patients with erectile dysfunction (ED), initially had an inadequate response to sildenafil (100 mg). Oral testosterone undecanoate (Restandol, 80 mg, bid or tid) alone was supplied for 2 months, and if patients could not achieve a satisfactory erection, combined use of testosterone and sildenafil was continued thereafter. Total testosterone (TT), free testosterone (FT), and the parameters of the International Index of Erectile Function (IIEF), International Prostate Symptom Score (IPSS), and uroflow rate (UFR) were assessed. Eleven patients (34.3%) achieved satisfactory erectile function after testosterone replacement only. Another 12 (37.5%) patients experienced satisfactory intercourse after combined therapy. Serum TT and FT levels significantly increased after the use of testosterone alone (415+/-163 vs 220+/-101 ng/dl, P<0.01; 10.4+/-4.6 vs 5.1+/-1.9 ng/dl; P<0.01, respectively) and the combined use of testosterone and sildenafil (498+/-178 vs 220+/-101 ng/dl, P<0.01; 11.7+/-4.6 vs 5.1+/-1.9 ng/dl, P<0.001, respectively); as did the IIEF score (14.8+/-6.8 vs 12.6+/-7.5, P<0.01, 17.5+/-5.2 vs 12.6+/-7.5, P<0.001, respectively). However, no statistical differences were demonstrated for IPSS or UFR. In conclusions, one-third of hypogonadal patients with ED who failed to respond to sildenafil, responded to testosterone alone, another third responded to sildenafil again after normalization of testosterone. So, in hypogonadal patients with ED, androgen supplementation is first-line therapy. If patients are unresponsive to androgen alone or sildenafil alone, combined use may improve erectile function and enhance the therapeutic effect of PDE-5 inhibitors.     

全面康复:勃起功能障碍治疗的新目标

5型磷酸二酯酶(PDE5)抑制剂有效改善勃起功能障碍(ED)患者的勃起功能。枸橼酸西地那非的应用范围不断扩展,肺动脉高压已成为新的适应证。临床研究发现,西地那非能改善多种血管性疾病患者的内皮功能。在ED领域的研究进展包括:动物实验发现,西地那非可以改善海绵体内皮功能,增强磷酸化内皮型一氧化氮合酶(eNOS)蛋白表达,逆转缺血或缺氧导致的海绵体内压(ICP)降低。临床研究证实,西地那非可以使50%以上ED患者阴茎勃起恢复到最充分的硬度(4级勃起);使50%以上保留神经的根治性前列腺切除术后患者勃起功能康复,自发产生足以性交的勃起;使ED患者的自尊心、自信心和性关系满意度等社会心理功能恢复正常。从勃起功能到社会心理功能的全面恢复可能成为今后ED治疗的新目标。     

Common approach to managing lower urinary tract symptoms and erectile dysfunction

The present paper serves as a review of the associations between lower urinary tract symptoms （LUTS） and erectile dysfunction （ED）, with a focus on common and combined pathways for treatment. LUTS and ED are common conditions seen in general urologic practice. Research has started to establish epidemiologic and pathophysiologic links between the two conditions and a strong association confirmed across multiple studies. Men seeking care for one condition should always be interviewed for complaints of the other condition. Proposed common pathways include α-1 adrenergic receptor imbalance, Rho-kinase overactivity, endothelial cell dysfunction and atherosclerosis-induced ischemia. Medical therapy has replaced surgery as the first-line treatment for LUTS in most patients, with the incorporation of α-adrenergic receptor antagonists （α-ARAs） and 5-α-reductase inhibitors （5-ARIs） into everyday practice. Treatment with α-ARAs contributes to some improvement in ED, whereas use of 5-ARIs results in worsened sexual function in some patients. Phosphodiesterase-5 （PDE-5） inhibitors have revolutionized the treatment of ED with a simple oral regimen, and new insights demonstrate a benefit of combined use of PDE-5 inhibitors and α-ARAs. The mechanisms of action of these medications support these observed benefits, and they are being studied in the basic science and clinical settings. In addition, novel mechanisms for therapy have been proposed based on clinical and research observations. The minimally invasive and surgical treatments for LUTS are known to have adverse effects on ejaculatory function, while their effects on erectile function are still debated. Much remains to be investigated, but it is clear that the associations between LUTS and ED lay the foundation for future therapies and possible preventative strategies.     

Phosphodiesterase type 5 inhibitors for erectile dysfunction

The cyclic nucleotide signalling pathway mediates the smooth-muscle relaxing effects of nitric oxide necessary for normal erectile function. Down-regulation of this pathway is central to the pathophysiology of many forms of erectile dysfunction (ED), which is often associated with other chronic diseases (e.g. hypertension, type 2 diabetes mellitus) and treatments (e.g. certain drugs, radical prostatectomy). Conversely, selective inhibition of the enzyme that catalyses the degradation of cGMP (phosphodiesterase type 5, PDE-5) promotes erectile responses to sexual stimulation. The successful launch and commercialization of the selective PDE5 inhibitor (PDE5I) sildenafil transformed the treatment of ED, not only by providing an effective, well tolerated oral ED therapy, but also by fostering greater candour about the problem among men. Sildenafil is highly effective in promoting erectile responses across a wide spectrum of severity and causes of ED, including patients with ED that is often refractory to treatment. The recent advent of vardenafil, which has the highest in vitro potency of all available PDE5Is, and tadalafil, which has a prolonged half-life that may enable couples to have sexual activity with less planning, represent further advances. Other PDE5Is offering further potential improvements are under active investigation.     

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.     

Prevalence and medical management of erectile dysfunction in Asia

Erectile dysfunction (ED) is an important worldwide health issue that has a significant negative impact on the quality of life and life satisfaction of both the affected individual and his partner. Here we review the prevalence of ED in Asia, associated factors that may influence sexual attitudes and sexual behaviours, and randomized clinical trials (RCTs) of phosphodiesterase-5 (PDE-5) inhibitors to evaluate the clinical efficacy and safety of PDE-5 inhibitors in Asian men. We searched for English-language articles in MEDLINE and PubMed from January 2000 to September 2010. Our results showed that the overall reported prevalence rate of ED in Asia ranged widely, from 2% to 88%. This finding indicates that ED is a common and major health problem in this region. However, sociocultural and economic factors in Asia prevent people from seeking and obtaining appropriate medical care. We found reports on five kinds of PDE-5 inhibitors for the management of ED: sildenafil, vardenafil, tadalafil, udenafil and mirodenafil. The results of RCTs showed that these five PDE-5 inhibitors are more effective than placebo in improving erectile function in Asian men with ED and that these drugs have similar efficacy and safety profiles.     

同期内使用3种PDE5抑制剂治疗ED的经验

目的:观察与比较同期内使用3种PDE5抑制剂治疗ED患者的疗效,满意情况和不良反应。分析影响患者疗效、接受度、倾向性的因素。方法:11个月在门诊应用3种PDE5抑制剂治疗ED患者331例。使用西地那非134例,他达拉非88例,及伐地那非109例。医师详细指导药物的应用,注意事项,观察的内容等,并互留电话,列表登记、随访。结果:复诊或电话随访时间,结果为:①获得良好的疗效及满意率为西地那非72例(79.12%),他达拉非52例(78.78%),伐地那非63例(81.81%)。②PDE5抑制剂单纯或交叉应用的资料分析显示:青年患者或新婚者,偏好伐地那非;③中青年患者倾向于他达拉非;中老年及较长期应用PDE5抑制剂的患者多选用西地那非。3种PDE5抑制剂用于早泄均有一定疗效。④对不能继续用此类药治疗ED的原因进行了分析,分别为:价高,不治本,效果差,耽心不良反应。结论:①同期3种PDE5抑制剂治疗ED的疗效基本相近。亦各有一些优势和特点。②3种PDE5抑制剂的安全性均好,一般、轻度不良反应相近,中度、特殊的不良反应少,严重不良反应均无发生。③PDE5抑制剂的疗效观察,目前众多的问卷、量表实际均仍以主观的感受为主。对同一个人以相同形式、相同问题、繁简一致阐述,获得的有关疗效满意情况、感受等简易回答是有可比性、可信度和实用性的。     

Efficacy of PDE-5-inhibitors for erectile dysfunction. A comparative meta-analysis of fixed-dose regimen randomized controlled trials administering the International Index of Erectile Function in broad-spectrum populations

This meta-analytic study aims to estimate the likely improvements of erectile dysfunction (ED) measured by the International Index of Erectile Function (IIEF) at the highest fixed dosages of the three available PDE-5-inhibitors: sildenafil, tadalafil, and vardenafil. MEDLINE and the Cochrane Library were searched electronically for efficacy trials of PDE-5-inhibitors for treating ED. In addition drug manufacturers were contacted to provide unpublished or unrecorded congress proceedings. Randomized, double-blind, placebo-controlled, parallel-group, maximum fixed-dose, broad-spectrum efficacy trials using IIEF were included in the analysis. Data were independently extracted by two reviewers. The results were pooled using weighted mean differences. A formal indirect comparison (including Bonferroni-correction) was conducted to estimate the differences between agents. A total of 14 trials were included in the meta-analysis (three with 100 mg sildenafil, eight with 20-25 mg tadalafil, and three with 20 mg vardenafil). All trials were of good methodological quality. Overall heterogeneity was moderate: I(2)=33.2%, chi(2)=19.47, P=0.11. The funnel plot suggested moderate likelihood of publication bias. Pooled results of IIEF-improvement were for sildenafil 9.65 (95% CI: 8.50, 10.79) points, tadalafil 8.52 (7.61, 9.42) points, and vardenafil 7.50 (6.50, 8.50) points, respectively. Sildenafil proved to be significantly more effective than vardenafil (d=2.15, P=0.006), other pairwise comparisons showed no difference in efficacy. All PDE-5-inhibitors are highly effective in the treatment of ED. At maximum dosage they improve erectile function 7-10 points on the IIEF compared to placebo-treatment. There is evidence that sildenafil might be more efficacious than vardenafil, although this is to be interpreted with caution. To prove higher efficacy truly independent comparative trials are needed.     

Clinical update on phosphodiesterase type-5 inhibitors for erectile dysfunction

Erectile dysfunction (ED) affects the sexual lives of millions of men. The first-line oral pharmacotherapy for most ED patients is phosphodiesterase type-5 (PDE-5) inhibitors, of which three are available. Sildenafil is the most widely prescribed oral agent for ED and has a very satisfactory efficacy–safety profile in all patient categories. Tadalafil and vardenafil were introduced in the European Union and in the United States in 2003 and 2004, respectively. The three PDE-5 inhibitors share many pharmacological and clinical characteristics, and each has unique features. This review, which is based on the contemporary literature on PDE-5 inhibitors, describes the chemical, pharmacological, and clinical features of sildenafil, vardenafil, and tadalafil. The first section reviews the pathophysiology of penile erection and PDE-5 inhibitor pharmacology. The second section summarizes data regarding efficacy and safety of the three drugs in treating ED in the general population as well as in selected patient categories.     

Erectile dysfunction in the cardiac patient

Erectile dysfunction (ED) often is caused by endothelial dysfunction and may be a sign that a patient has vascular disease elsewhere in the body. Risk factors for coronary artery disease such as lipid abnormalities, smoking, diabetes, and hypertension also are risk factors for ED. Oral therapy for ED, such as sildenafil, inhibits phosphodiesterase-5 (PDE-5) and the breakdown of cyclic guanosine monophosphate. PDE-5 inhibitors have been shown to be safe and effective for the therapy for ED, but remain contraindicated in patients receiving organic nitrates. These agents are mild vasodilators and are being investigated for their treatment potential for patients with pulmonary hypertension, heart failure, and endothelial dysfunction.     

Treating erectile dysfunction by endothelial rehabilitation with phosphodiesterase 5 inhibitors

A large body of evidence has accumulated demonstrating that a common pathway in conditions such as hypertension, atherosclerosis, hypercholesterolemia, diabetes mellitus, and erectile dysfunction (ED) is endothelial dysfunction. Although a complete pharmacological cure for ED is currently unavailable, the phosphodiesterase 5 (PDE5) inhibitors sildenafil, vardenafil, and tadalafil are efficacious oral therapy for ED. Results from recent studies suggest that regular treatment with a PDE5 inhibitor may lead to enhanced erectile function (EF) beyond that observed with on-demand usage, possibly through improvement of endothelial function. Such an effect may be viewed as rehabilitation of damaged erectile tissue. The present review focuses on several recent studies which provide evidence for the beneficial effect of regular PDE5 inhibitor administration on the improvement of EF by rehabilitation of vascular endothelium.