Hartmut Porst

Summary of the recommendations on sexual dysfunctions in men

INTRODUCTION Sexual health is an integral part of overall health. Sexual dysfunction can have a major impact on quality of life and psychosocial and emotional well-being. AIM To provide evidence-based, expert-opinion consensus guidelines for clinical management of sexual dysfunction in men. METHODS An international consultation collaborating with major urologic and sexual medicine societies convened in Paris, July 2009. More than 190 multidisciplinary experts from 33 countries were assembled into 25 consultation committees. Committee members established scope and objectives for each chapter. Following an exhaustive review of available data and publications, committees developed evidence-based guidelines in each area. Main Outcome Measures.  New algorithms and guidelines for assessment and treatment of sexual dysfunctions were developed based on work of previous consultations and evidence from scientific literature published from 2003 to 2009. The Oxford system of evidence-based review was systematically applied. Expert opinion was based on systematic grading of medical literature, and cultural and ethical considerations. RESULTS Algorithms, recommendations, and guidelines for sexual dysfunction in men are presented. These guidelines were developed in an evidence-based, patient-centered, multidisciplinary manner. It was felt that all sexual dysfunctions should be evaluated and managed following a uniform strategy, thus the International Consultation of Sexual Medicine (ICSM-5) developed a stepwise diagnostic and treatment algorithm for sexual dysfunction. The main goal of ICSM-5 is to unmask the underlying etiology and/or indicate appropriate treatment options according to mens and womens individual needs (patient-centered medicine) using the best available data from population-based research (evidence-based medicine). Specific evaluation, treatment guidelines, and algorithms were developed for every sexual dysfunction in men, including erectile dysfunction; disorders of libido, orgasm, and ejaculation; Peyronies disease; and priapism. CONCLUSIONS Sexual dysfunction in men represents a group of common medical conditions that need to be managed from a multidisciplinary perspective.

The efficacy and tolerability of vardenafil, a new, oral, selective phosphodiesterase type 5 inhibitor, in patients with erectile dysfunction: the first at-home clinical trial.

Vardenafil, a novel selective phosphodiesterase type 5 inhibitor, was evaluated in its first large-scale at-home trial. A total of 601 men with mild to severe erectile dysfunction (ED) were enrolled in this multi-centre, randomized, double-blind, placebo-controlled trial of 12 weeks of treatment with either placebo or 5, 10 and 20 mg of vardenafil. Primary endpoints were Q3 (vaginal penetration) and Q4 (maintenance of erection) of the International Index of Erectile Function (IIEF). In the intent-to-treat population (n=580), the changes from baseline for 5, 10 and 20 mg vardenafil (1.2, 1.3 and 1.5, respectively) were all improved (P<0.001) over placebo (0.2) for Q3 and were similarly improved for Q4 (1.4, 1.5 and 1.7) compared to placebo (0.5) (P<0.001). All vardenafil doses improved all IIEF domains compared to placebo (P<0.001). The percentage of successful intercourses was between 71 and 75% for the three vardenafil doses. For the 20 mg dose, 80% of the patients experienced improved erections (GAQ) compared to 30% for placebo. Most frequent treatment-emergent adverse events were headache (7–15%), flushing (10–11%) and up to 7% for dyspepsia or rhinitis. Vardenafil treatment resulted in a high efficacy and low adverse-event profile in a population with mixed ED etiologies.

Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: a randomized controlled trial

OBJECTIVES To examine the therapeutic effects of tadalafil on erectile dysfunction (ED) at 24 and 36 hours after dosing. METHODS A multicenter, randomized, double-blind, placebo-controlled, parallel-group study of 348 men (mean age 57 years) with ED was conducted in Europe and the United States. Patients were stratified by baseline severity of ED using the Erectile Function domain score of the International Index of Erectile Function and then randomly allocated within the severity group to receive tadalafil 20 mg (n = 175) or placebo (n = 173). Subsequently, participants were randomly assigned to two 4-week treatment intervals, during which they were requested to attempt sexual intercourse approximately 24 or 36 hours after tadalafil or placebo dosing. The primary outcome measure was the proportion of successful sexual intercourse attempts (completed to ejaculation) according to patient self-report using the Sexual Encounter Profile diary. RESULTS Of the 348 patients, 327 (94%) completed the trial (163 of 175 in the tadalafil group and 164 of 173 in the placebo group). Thirty-six hours after tadalafil dosing, 59.2% of intercourse attempts were successful versus 28.3% in the placebo group (P <0.001). The proportion of successful intercourse attempts at approximately 24 hours after treatment was also significantly greater with tadalafil (52.9%) than with placebo (29.1%; P <0.001). Tadalafil was well tolerated. The incidences of four treatment-emergent adverse events were significantly greater in the tadalafil group than in the placebo group (all P <0.05): headache, flushing, dyspepsia, and myalgia. CONCLUSIONS Tadalafil 20 mg is an effective and well-tolerated treatment for ED that has a period of responsiveness of up to 36 hours.

Critical analysis of the relationship between sexual dysfunctions and lower urinary tract symptoms due to benign prostatic hyperplasia

CONTEXT This review focuses on the relationship among sexual dysfunction (SD), lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH), and related therapies. OBJECTIVE We reviewed the current literature to provide an overview of current data regarding epidemiology and pathophysiology of SD and LUTS. Moreover, we analysed the impact of currently available therapies of LUTS/BPH on both erectile dysfunction (ED) and ejaculatory dysfunction and the effect of phosphodiesterase type 5 inhibitors (PDE5-Is) in patients with ED and LUTS. EVIDENCE ACQUISITION We conducted a Medline search to identify original articles, reviews, editorials, and international scientific congress abstracts by combining the following terms: benign prostatic hyperplasia, lower urinary tract symptoms, sexual dysfunction, erectile dysfunction, and ejaculatory dysfunction. EVIDENCE SYNTHESIS We conducted a comprehensive analysis of more relevant general population-based and BPH/LUTS or SD clinic-based trials and evaluated the common pathophysiologic mechanisms related to both conditions. In a further step, the overall impact of current BPH/LUTS therapies on sexual life, including phytotherapies, novel drugs, and surgical procedures, was scrutinized. Finally, the usefulness of PDE5-Is in LUTS/BPH was critically analysed, including preclinical and clinical research data as well as possible mechanisms of action that may contribute to the efficacy of PDE5-Is with LUTS/BPH. CONCLUSIONS Community-based and clinical data demonstrate a strong and consistent association between LUTS and ED, suggesting that elderly men with LUTS should be evaluated for SD and vice versa. Pathophysiologic hypotheses regarding common basics of LUTS and SD as discussed in the literature are (1) alteration of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway, (2) enhancement of RhoA-Rho-kinase (ROCK) contractile signalling, (3) autonomic adrenergic hyperactivity, and (4) pelvic atherosclerosis. The most important sexual adverse effects of medical therapies are ejaculation disorders after the use of some α-blockers and sexual desire impairment, ED, and ejaculatory disorders after the use of α-reductase inhibitors. Minimally invasive, conventional, and innovative surgical treatments for BPH may induce both retrograde ejaculation and ED. PDE5-Is have demonstrated significant improvements in both LUTS and ED in men with BPH; combination therapy with PDE5-Is and α1-adrenergic blockers seems superior to PDE5-I monotherapy.

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.

Hypogonadal Men Nonresponders to the PDE5 Inhibitor Tadalafil Benefit from Normalization of Testosterone Levels with a 1% Hydroalcoholic Testosterone Gel in the Treatment of Erectile Dysfunction (TADTEST Study)

INTRODUCTION Addition of testosterone (T) may improve the action of phosphodiesterase type 5 inhibitors (PDE5-Is) in patients with erectile dysfunction not responding to PDE5-Is with low or low-normal T levels. AIMS To confirm this add-on effect of T in men optimally treated with PDE5-Is and to specify the baseline T levels at which such an effect becomes significant. METHODS A multicenter, multinational, double-blind, placebo-controlled study of 173 men, 45-80 years, nonresponders to treatment with different PDE5-Is, with baseline total T levels ≤ 4 ng/mL or bioavailable T ≤ 1 ng/mL. Men were first treated with tadalafil 10 mg once a day (OAD) for 4 weeks; if not successful, they were randomized in a double-blind, placebo-controlled design to receive placebo or a 1% hydroalcoholic T gel (50 mg/5 g gel), to be increased to 10 mg T if results were clinically unsatisfactory. Main Outcomes Measures.  Mean change from baseline in the Erectile Function Domain Score of the International Index of Erectile Function and rate of successful intercourses (Sexual Encounter Profile 3 question). RESULTS Erectile function progressively improved over a period of at least 12 weeks in both the placebo and T treatment groups. In the overall population with a mean baseline T level of 3.37 ± 1.48 ng/mL, no additional effect of T administration to men optimally treated with PDE5-Is was encountered. The differences between the T and placebo groups were significant for both criteria only in the men with baseline T ≤ 3 ng/mL. CONCLUSIONS The maximal beneficial effects of OAD dosing with 10 mg tadalafil may occur only after as many as 12 weeks. Furthermore, addition of T to this PDE5-I regimen is beneficial, but only in hypogonadal men with baseline T levels ≤ 3 ng/mL.

An evidence-based definition of lifelong premature ejaculation: report of the International Society for Sexual Medicine Ad Hoc Committee for the Definition of Premature Ejaculation

To develop a contemporary, evidence‐based definition of premature ejaculation (PE).

Efficacy and Safety of Dapoxetine for the Treatment of Premature Ejaculation: Integrated Analysis of Results from Five Phase 3 Trials

INTRODUCTION Dapoxetine has been evaluated for the on-demand treatment of premature ejaculation (PE) in five phase 3 studies in various populations worldwide and has recently been approved in several countries. AIM To present integrated efficacy and safety data from phase 3 trials of dapoxetine. METHODS Data were from five randomized, multicenter, double-blind, placebo-controlled studies conducted in over 25 countries. Men (N=6,081)≥18 years who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision criteria for PE; four studies required a baseline intravaginal ejaculatory latency time (IELT) of ≤2 minutes. Dapoxetine 30 and 60 mg on demand (prn; 1-3 hours before intercourse) were evaluated for either 12 or 24 weeks in four studies; one study evaluated dapoxetine 60 mg daily (qd; included in safety assessments only) or prn for 9 weeks. MAIN OUTCOME MEASURES End points included stopwatch-measured IELT, Premature Ejaculation Profile (PEP) items, clinical global impression of change (CGIC) in PE, and adverse events (AEs). RESULTS Average IELT (mean [standard deviation], geometric mean [standard error]) increased from baseline (across groups, 0.9 [0.49] minutes, 0.8 [1.01] minutes) to a significantly greater extent with dapoxetine 30 (3.1 [3.91] minutes, 2.0 [1.03] minutes) and 60 mg (3.6 [3.85] minutes, 2.3 [1.03] minutes) vs. placebo (1.9 [2.43] minutes, 1.3 [1.02] minutes; P<0.001 for all) at week 12 (geometric mean fold increase, 2.5, 3.0, and 1.6, respectively). All PEP items and CGIC improved significantly with both doses of dapoxetine vs. placebo (P<0.001 for all). The most common AEs included nausea, dizziness, and headache, and evaluation of validated instruments demonstrated no anxiety, akathisia, suicidality, or changes in mood with dapoxetine use and no discontinuation syndrome following abrupt withdrawal. CONCLUSIONS In this diverse population, dapoxetine significantly improved all aspects of PE and was generally well tolerated.

SOP Conservative (Medical and Mechanical) Treatment of Erectile Dysfunction

INTRODUCTION Erectile dysfunction (ED) is the most frequently treated male sexual dysfunction worldwide. ED is a chronic condition that exerts a negative impact on male self-esteem and nearly all life domains including interpersonal, family, and business relationships. AIM The aim of this study is to provide an updated overview on currently used and available conservative treatment options for ED with a special focus on their efficacy, tolerability, safety, merits, and limitations including the role of combination therapies for monotherapy failures. METHODS The methods used were PubMed and MEDLINE searches using the following keywords: ED, phosphodiesterase type 5 (PDE5) inhibitors, oral drug therapy, intracavernosal injection therapy, transurethral therapy, topical therapy, and vacuum-erection therapy/constriction devices. Additionally, expert opinions by the authors of this article are included. RESULTS Level 1 evidence exists that changes in sedentary lifestyle with weight loss and optimal treatment of concomitant diseases/risk factors (e.g., diabetes, hypertension, and dyslipidemia) can either improve ED or add to the efficacy of ED-specific therapies, e.g., PDE5 inhibitors. Level 1 evidence also exists that treatment of hypogonadism with total testosterone < 300 ng/dL (10.4 nmol/L) can either improve ED or add to the efficacy of PDE5 inhibitors. There is level 1 evidence regarding the efficacy and safety of the following monotherapies in a spectrum-wide range of ED populations: PDE5 inhibitors, intracavernosal injection therapy with prostaglandin E1 (PGE1, synonymous alprostadil) or vasoactive intestinal peptide (VIP)/phentolamine, and transurethral PGE1 therapy. There is level 2 evidence regarding the efficacy and safety of the following ED treatments: vacuum-erection therapy in a wide range of ED populations, oral L-arginine (3-5 g), topical PGE1 in special ED populations, intracavernosal injection therapy with papaverine/phentolamine (bimix), or papaverine/phentolamine/PGE1 (trimix) combination mixtures. There is level 3 evidence regarding the efficacy and safety of oral yohimbine in nonorganic ED. There is level 3 evidence that combination therapies of PDE5 inhibitors + either transurethral or intracavernosal injection therapy generate better efficacy rates than either monotherapy alone. There is level 4 evidence showing enhanced efficacy with the combination of vacuum-erection therapy + either PDE5 inhibitor or transurethral PGE1 or intracavernosal injection therapy. There is level 5 evidence (expert opinion) that combination therapy of PDE5 inhibitors + L-arginine or daily dosing of tadalafil + short-acting PDE5 inhibitors pro re nata may rescue PDE5 inhibitor monotherapy failures. There is level 5 evidence (expert opinion) that adding either PDE5 inhibitors or transurethral PGE1 may improve outcome of penile prosthetic surgery regarding soft (cold) glans syndrome. There is level 5 evidence (expert opinion) that the combination of PDE5 inhibitors and dapoxetine is effective and safe in patients suffering from both ED and premature ejaculation.

Intracavernous Alprostadil Alfadex -- an effective and well tolerated treatment for erectile dysfunction. Results of a long-term European study

Long-term efficacy and safety of Alprostadil-Alfadex (EDEXR/VIRIDALR) in intracavernous self-injection therapy for chronical erectile failure was investigated in a four year running multicenter European trial. Of the 16 886 protocolled injections 93% (15 713) resulted in rigid erections followed by successful sexual intercourse. Reported side effects by patients were prolonged erections >6 h only occurring during the first year in 1.2% (2 out of 162), painful erections in 29% (47 out of 162) during the first year and decreasing to 12.1% by year 4, hematomas, neither requiring therapeutic measures nor impeding sexual performance in 33.3% (54 out of 162) in year 1 with a decrease to 12.1% by year 4, fibrotic penile alterations such as nodules, plaques or deviations in 11.7% (19 out of 162) with spontaneous healing in 48% (9 out of 19). Of the 162 patients involved in this trial 54 completed the 4 y. Of the 54 completers 91.4% considered the tolerability good or very good and were satisfied or very satisfied with self-injection therapy with Alprostadil-Alfadex. The respective rates of the female partners were 51.7% very satisfied and 39.7% satisfied.These data of the world-wide longest running prospective trial with a vasoactive drug in self-injection therapy provided impressive proof that Alprostadil-Alfadex represents a very effective and safe treatment for erectile dysfunction of both psychogenic and organogenic origin.