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 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.     

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.     

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.     

Erectile dysfunction and treatment of carcinoma of the prostate

Prostate cancer is the leading malignancy in men in the United States and causes more than 60,000 deaths annually. Treatment of prostate cancer, whether it be with surgery, radiation therapy, cryotherapy, or medical treatment, is associated with significant life-altering morbidity. Incontinence and erectile dysfunction (ED) too often are sequelae of these treatment alternatives. ED can be a significant complication and can alter the life of the patient with prostate cancer and his partner. Newer modifications of the radical prostatectomy with nerve-sparing techniques are the cornerstone of erection preservation. Time following radical prostatectomy has been shown to increase erectile function such that more patients have functional erections at 3 years than 1 year after surgery. With the advent of phosphodiesterase-5 (PDE-5) inhibitors, many men can have improved functional erections and return to active coitus. Prevention of ED also is an important management technique. Evidence is gathering that prophylaxis with regular vasoactive injection or daily PDE-5 agents may be an integral part of preservation of corpus cavernosum smooth muscle function. Combination medical therapy and surgical penile prosthesis implantation also are options for patients who do not respond to oral PDE-5 inhibitors.     

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.     

PDE-5 inhibitors: current status and future trends

Phosphodiesterase-5 (PDE-5) inhibitors are a well-established, first-line therapy for erectile dysfunction (ED). Extensive clinical trials and clinical experience established the highly significant efficacy and the safety of this class of drugs in the treatment of ED.Furthermore, the efficacy of PDE-5 inhibitors has been established in men with ED with a broad range of etiologies and comorbidities. The future of PDE-5 inhibitors includes the expansion of indications such as the treatment of pulmonary hypertension and the potential of treatment of symptomatic BPH.     

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.     

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.     

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.     

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.     

Androgen deficiency in the etiology and treatment of erectile dysfunction

The evaluation and management of erectile dysfunction (ED) has evolved dramatically following the introduction of oral phosphodiesterase-5 inhibitors. Despite the limited role of directed diagnostic testing in the evaluation of the impotent patient, routine de-termination of a serum testosterone likely is indicated based on evidence that testosterone modulates erectile function, that hypogonadism is prevalent among elderly men and men with ED, and that symptomatology alone rarely detects hypogonadism. Forms of testosterone commonly used include oral, parenteral, transdermal, and implantable preparations, each with significant advantages and disadvantages. The risks and benefits of testosterone supplementation have been characterized incompletely and will require further validation before widespread use of testosterone as hormone replacement therapy in aging men.     

Alpha-adrenoceptors are a common denominator in the pathophysiology of erectile function and BPH/LUTS--implications for clinical practice

A literature search of PubMed documented publications and abstracts from proceedings of scientific meetings was made to review the available data on benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS) and erectile dysfunction (ED) with a special focus on the role of alpha-adrenoceptors as critical mediators of pathophysiology. The reader is introduced to clinical results on the therapeutic potential of alpha-blockers alone and in combination with phosphodiesterase type 5 (PDE-5) inhibitors in the treatment of ED associated with LUTS/BPH. Epidemiological studies clearly show that an association exists between ED and LUTS/BPH. The severity of LUTS is correlated with the risk for ED. A significant number of LUTS/BPH patients are nonresponsive to the common ED treatment with PDE-5 inhibitors. As smooth muscle contractility is regulated by adrenoceptors in the corpus cavernosum, prostate and detrusor, the alpha-adrenoceptor system may be considered a common pathophysiological mediator in the development of ED and LUTS/BPH. Blockade of alpha-adrenoceptors for the treatment of BPH/LUTS may have the potential of improving sexual function. Conversely, PDE-5 inhibitors may exhibit positive effects in LUTS patients. Pilot studies on combination regimens of alpha-adrenoceptor antagonists and PDE-5 inhibitors have yielded encouraging results in LUTS patients with persistent ED. On the basis of pharmacological and clinical evidence, it is established that the alpha-adrenoceptor system plays an important role in the pathophysiology of ED and LUTS secondary to BPH. Larger trials on the combination of alpha-adrenoceptor antagonists with PDE-5 inhibitors are necessary to develop an integrated treatment approach for BPH/LUTS patients with comorbid ED.     

Erectile dysfunction secondary to nerve-sparing radical retropubic prostatectomy: Comparative phosphodiesterase-5 inhibitor efficacy for therapy and novel prevention strategies

Postprostatectomy erectile dysfunction appears to be initiated by neuropraxia and perpetuated by cavernosal smooth muscle apoptosis. Phosphodiesterase-5 (PDE-5) inhibitor therapy is the current cornerstone of erectile dysfunction (ED) therapy in this population. Although no head-to-head trials have been performed with sildenafil, vardenafil, and tadalafil in this population, there are numerous studies in the general ED population. The results of these studies demonstrate that neither of the new PDE-5 inhibitors met statistical noninferiority to sildenafil. Sildenafil has been studied in a novel primary prevention modality using nightly administration after a bilateral nerve-sparing prostatectomy. In this novel approach, it effected a sevenfold improvement in return of spontaneous, normal erectile function 2 months after drug discontinuation. This effect appears to be mediated by properties unique to sildenafil that include improved endothelial function and neuronal regeneration and neuroprotection. In primary prevention, unlike ED therapy, one has only “one shot” by definition. Therefore, it is even more critical to apply evidence-based medicine.     

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)     

Testosterone improves erectile function in hypogonadal patients with venous leakage

The goal of this study was to assess the therapeutic benefits of long-acting testosterone therapy in hypogonadal patients with erectile dysfunction (ED). We recruited 29 patients with ED, ranging in age from 32 to 65 years (mean +/- SD, 47 +/- 9.7 years), with low plasma testosterone, who did not respond to phosphodiesterase type 5 inhibitor therapy. To evaluate penile arterial and venous blood flow, we employed duplex Doppler ultrasonography. For confirmation of diagnosis of venous leakage, pharmacocavernosography was carried out in 9 patients and magnetic resonance imaging with intracavernous contrast enhancement was carried out in 8 patients. All patients were treated with 1000 mg injectable testosterone undecanoate on day 1, followed by another injection after 6 weeks and every 3 months thereafter, in accordance with Nebido therapy protocol. Plasma testosterone levels were determined in all patients at baseline and after 18 and 30 weeks of testosterone treatment. The International Index of Erectile Function (IIEF-5) was administered at baseline and after 18 and 30 weeks of testosterone treatment. At baseline total testosterone ranged from 7 to 11.8 nmol/L (200 to 345 ng/dL) in 25 patients. Eighteen and 30 weeks after testosterone treatment, the mean testosterone plasma levels were 18 and 21.5 nmol/L (520 and 625 ng/dL), respectively. After 18 and 30 weeks of testosterone treatment, 20 out of the 29 patients demonstrated marked improvement in erectile function domain, as assessed by the IIEF-5. This was also associated with diminution of venous leakage. We suggest that, in hypogonadal men with ED, testosterone therapy improves erectile function in patients with ED and venous leakage.     

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.     

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.     

Can Phosphodiesterase Type 5 Inhibitors Cure Erectile Dysfunction?

INTRODUCTION AND OBJECTIVES: To systematically analyze and review the available evidence about the potential role of chronic administration of phosphodiesterase type 5 (PDE-5) inhibitors for the cure of erectile dysfunction (ED) based on clinical and basic science data. METHODS: Analysis of published full-length papers that were identified with Medline and Cancerlit from January 1993 to September 2005. Abstracts published in the journals European Urology, the Journal of Urology, the International Journal of Impotence Research, and the Journal of Sexual Medicine as official proceedings of internationally known scientific societies held in the same time period were also assessed. RESULTS: Chronic administration of PDE-5 inhibitors have reportedly been associated with increased persistent vascular and endothelial function--which represents a key factor in maintaining vascular tone and inducing vasodilation--by increasing the level of endothelial cGMP generated by activation of endothelial nitric oxide. Clinical studies have revealed a potential protective role of these compounds on endothelial function in short- and long-term assessments. Several studies based on animal models have provided direct experimental support for the role of PDE-5 inhibitors in improving the structure and function of the cavernosal tissue and have suggested potential molecular mechanisms involved. CONCLUSIONS: Although evidence increasingly supports the potential role of chronic administration of PDE-5 inhibitors for improving erectile function in patients affected by ED, long-term data are lacking. However, data available from animal models support the evidence of potential benefits induced on endothelial function by chronic exposure to PDE-5 inhibitors.