Wayne J.G. Hellstrom

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.

Investigation, Treatment, and Monitoring of Late-Onset Hypogonadism in Males: ISA, ISSAM, EAU, EAA, and ASA Recommendations

The new ISA, ISSAM, EAU, EAA and ASA recommendations on the investigation, treatment and monitoring of late-onset hypogonadism in males provide updated evidence-based information for clinicians who diagnose and treat patients with adult onset, age related testosterone deficiency.

Treatment of Men with Erectile Dysfunction with Transurethral Alprostadil

BACKGROUND Erectile dysfunction in men is common. We evaluated a system by which alprostadil (prostaglandin E1) is delivered transurethrally to treat this disorder. METHODS Alprostadil was delivered transurethrally in a double-blind, placebo-controlled study of 1511 men, 27 to 88 years of age, who had chronic erectile dysfunction from various organic causes. The men were first tested in the clinic with up to four doses of the drug (125, 250, 500, and 1000 microg); those who had sufficient responses were randomly assigned to treatment with either the effective dose of alprostadil or placebo for three months at home. RESULTS During in-clinic testing, 996 men (65.9 percent) had erections sufficient for intercourse. Of these men, 961 reported the results of at least one home treatment; 299 of the 461 treated with alprostadil (64.9 percent) had intercourse successfully at least once, as compared with 93 of the 500 who received placebo (18.6 percent, P<0.001). On average, 7 of 10 alprostadil administrations were followed by intercourse in men responsive to treatment. The efficacy of alprostadil was similar regardless of age or the cause of erectile dysfunction, including vascular disease, diabetes, surgery, and trauma (P<0.001 for all comparisons with placebo). The most common side effect was mild penile pain, which occurred after 10.8 percent of alprostadil treatments, but the pain rarely resulted in refusal to continue in the study. Hypotension occurred in the clinic in 3.3 percent of men receiving alprostadil. Hypotension-related symptoms were uncommon at home. No men had priapism or penile fibrosis. CONCLUSIONS In men with erectile dysfunction, transurethral alprostadil therapy resulted in erections in the clinic and in intercourse at home.

Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA and ASA recommendations

Demographic data clearly demonstrate that the percentage of the population in the older age group is increasing. Androgen deficiency in the aging male has become a topic of increasing interest and debate throughout the world. Cross-sectional and longitudinal data indicate that the testosterone falls progressively with age and that a significant percentage of men over the age of 60 years have serum testosterone levels that are below the lower limits of young adult (age 20–30 years) men (1–4). The principal questions raised by these observations are whether older hypogonadal men will benefit from testosterone treatment and what will be the risks associated with such intervention. The past decade has brought evidence of benefit of androgen treatment of hypogonadal men on multiple target organs and the recent studies show short-term beneficial effects of testosterone in older men that are similar to those in younger men. This has been comprehensively reviewed and summarized by the Institute of Medicine in ‘Testosterone and Aging: Clinical Research Directions’ (5). Long-term data on the effects of testosterone treatment in the older population are limited mainly to effects on body composition and bone mass (6–11). Key questions of the effects of testosterone on patient reported outcomes and functional benefits that may retard physical or mental frailty of the elderly or improve the quality of life are not yet available. Specific risk data on the prostate and cardiovascular systems are needed.

Characterization of reactive oxygen species induced effects on human spermatozoa movement and energy metabolism.

Reactive oxygen species (ROS) inhibit sperm movement and have been implicated in male infertility. In this study, we determined the effects of specific ROS produced by activated leukocytes on human spermatozoa and investigated their metabolic site of action. We used chemiluminescence and electron paramagnetic resonance (EPR) to characterize the ROS generated by both blood and seminal leukocytes. We also determined the effects of these ROS on sperm energy metabolism using biochemical analyses and flow cytometry. Both blood and seminal leukocytes produced the same characteristic ROS which were determined to be hydrogen peroxide (H2O2) and superoxide radicals (O2*-). EPR using the spin trapping technique indicated that superoxide radical-dependent hydroxyl radicals (HO.) were also generated. ROS generated by PMA-stimulated blood leukocytes (2-5 x 10(6)/ml) caused inhibition of sperm movement in 2 h (p < .01). Using the hypoxanthine/ xanthine oxidase (0.5 U/ml) system to generate ROS, we determined that spermatozoa ATP levels, after ROS treatment, were reduced approximately eight-fold in 30 min (0.10 x 10(10) moles/10(6) sperm cells) compared to control (0.84 X 10(-10) moles/10(6) sperm cells) (p < .01). Sperm ATP reduction paralleled the inhibition of sperm forward progression. Neither superoxide dismutase (100 U/ml) nor dimethyl sulfoxide (100 mM) reversed these effects; however, protection was observed with catalase (4 X 10(3) U/ml). Flow cytometric analyses of sperm treated with various doses of H2O2 (0.3 mM-20.0 mM) showed a dose-dependent decrease in sperm mitochondrial membrane potential (MMP); however, at low concentrations of H2O2, sperm MMP was not significantly inhibited. Also, sperm MMP uncoupling with CCClP had no effect on either sperm ATP levels or forward progression. These results indicate that H2O2 is the toxic ROS produced by activated leukocytes causing the inhibition of both sperm movement and ATP production. O2*- and HO. do not play a significant role in these processes. Low concentrations of H2O2 causing complete inhibition of sperm movement and ATP levels inhibit sperm energy metabolism at a site independent of mitochondrial oxidative phosphorylation.

Efficacy and tolerability of dapoxetine in treatment of premature ejaculation: an integrated analysis of two double-blind, randomised controlled trials

BACKGROUND No drugs are approved for treatment of premature ejaculation. Our aim was to determine the efficacy and tolerability of on-demand dapoxetine in patients with severe premature ejaculation. METHODS We determined the efficacy of dapoxetine in a prospectively predefined integrated analysis of two 12-week randomised, double-blind, placebo-controlled, phase III trials of identical design done independently, in parallel, at 121 sites in the USA. Men with moderate-to-severe premature ejaculation in stable, heterosexual relationships took placebo (n=870), 30 mg dapoxetine (874), or 60 mg dapoxetine (870) on-demand (as needed, 1-3 h before anticipated sexual activity). The primary endpoint was intravaginal ejaculatory latency time (IELT) measured by stopwatch. Safety and tolerability were assessed. All analyses were done on an intention-to-treat basis. The trials are registered at ClinicalTrials.gov, numbers NCT00211107 and NCT00211094. FINDINGS 672, 676, and 610 patients completed in the placebo, 30 mg dapoxetine, and 60 mg dapoxetine groups, respectively. Dapoxetine significantly prolonged IELT (p<0.0001, all doses vs placebo). Mean IELT at baseline was 0.90 (SD 0.47) minute, 0.92 (0.50) minute, and 0.91 (0.48) minute, and at study endpoint (week 12 or final visit) was 1.75 (2.21) minutes for placebo, 2.78 (3.48) minutes for 30 mg dapoxetine, and 3.32 (3.68) minutes for 60 mg dapoxetine. Both dapoxetine doses were effective on the first dose. Common adverse events (30 mg and 60 mg dapoxetine, respectively) were nausea (8.7%, 20.1%), diarrhoea (3.9%, 6.8%), headache (5.9%, 6.8%), and dizziness (3.0%, 6.2%). INTERPRETATION On-demand dapoxetine is an effective and generally well tolerated treatment for men with moderate-to-severe premature ejaculation.

International Society for Sexual Medicine's guidelines for the diagnosis and treatment of premature ejaculation.

INTRODUCTION Over the past 20 years our knowledge of premature ejaculation (PE) has significantly advanced. Specifically, we have witnessed substantial progress in understanding the physiology of ejaculation, clarifying the real prevalence of PE in population-based studies, reconceptualizing the definition and diagnostic criterion of the disorder, assessing the psychosocial impact on patients and partners, designing validated diagnostic and outcome measures, proposing new pharmacologic strategies and examining the efficacy, safety and satisfaction of these new and established therapies. Given the abundance of high level research it seemed like an opportune time for the International Society for Sexual Medicine (ISSM) to promulgate an evidenced-based, comprehensive and practical set of clinical guidelines for the diagnosis and treatment of PE. AIM Develop clearly worded, practical, evidenced-based recommendations for the diagnosis and treatment of PE for family practice clinicians as well as sexual medicine experts. Method.  Review of the literature. RESULTS This article contains the report of the ISSM PE Guidelines Committee. It affirms the ISSM definition of PE and suggests that the prevalence is considerably lower than previously thought. Evidence-based data regarding biological and psychological etiology of PE are presented, as is population-based statistics on normal ejaculatory latency. Brief assessment procedures are delineated and validated diagnostic and treatment questionnaires are reviewed. Finally, the best practices treatment recommendations are presented to guide clinicians, both familiar and unfamiliar with PE, in facilitating treatment of their patients. CONCLUSION Development of guidelines is an evolutionary process that continually reviews data and incorporates the best new research. We expect that ongoing research will lead to a more complete understanding of the pathophysiology as well as new efficacious and safe treatments for this sexual dysfunction. Therefore, it is strongly recommended that these guidelines be re-evaluated and updated by the ISSM every 4 years.

Effects of Smoking on Testicular Function, Semen Quality and Sperm Fertilizing Capacity

PURPOSE The effects of smoking on testicular function and sperm physiology were studied. MATERIALS AND METHODS Left testicular biopsy was performed in 49 smokers and 28 nonsmokers. Seminal specimens from these men were analyzed. RESULTS Testosterone levels in the left testicular vein, left testicular androgen-binding protein secretion rate (in vitro), sperm motility, percentage of morphologically normal spermatozoa, sperm morphometric parameters and outcome of sperm function tests were significantly lower (p < 0.05) in smokers than in nonsmokers. CONCLUSIONS Morphological sperm abnormalities due to secretory dysfunction of the Leydig and Sertoli cells may be the cause of impaired sperm fertilizing capacity in smokers.

Priapism: a refined approach to diagnosis and treatment.

The recent introduction of intracorporeal injections of papaverine and phentolamine for the diagnosis and treatment of impotence has resulted in an increased incidence of iatrogenic priapism. Based on our research into penile hemodynamics we propose a refined approach to all types of priapism. Intracorporeal blood gas and pressure monitoring should be used to differentiate ischemic (low flow) from nonischemic (high flow) types. Most cases of papaverine-induced or phentolamine-induced priapism will respond to aspiration alone or in combination with intracorporeal instillation of a diluted alpha-adrenergic agent. In spontaneous priapism alpha-adrenergic agents can be tried first if patients have only mild or no ischemia. In patients with severe ischemia stagnant blood should be evacuated and a shunt procedure should be performed to allow metabolic replenishment of tissue. Intracorporeal pressure monitoring will help to determine the size and number of shunts needed to re-establish corporeal circulation.

Clinical Efficacy, Safety and Tolerability of Collagenase Clostridium Histolyticum for the Treatment of Peyronie Disease in 2 Large Double-Blind, Randomized, Placebo Controlled Phase 3 Studies

PURPOSE IMPRESS (Investigation for Maximal Peyronies Reduction Efficacy and Safety Studies) I and II examined the clinical efficacy and safety of collagenase Clostridium histolyticum intralesional injections in subjects with Peyronie disease. Co-primary outcomes in these identical phase 3 randomized, double-blind, placebo controlled studies included the percent change in the penile curvature abnormality and the change in the Peyronie disease questionnaire symptom bother score from baseline to 52 weeks. MATERIALS AND METHODS IMPRESS I and II examined collagenase C. histolyticum intralesional injections in 417 and 415 subjects, respectively, through a maximum of 4 treatment cycles, each separated by 6 weeks. Men received up to 8 injections of 0.58 mg collagenase C. histolyticum, that is 2 injections per cycle separated by approximately 24 to 72 hours with the second injection of each followed 24 to 72 hours later by penile plaque modeling. Men were stratified by baseline penile curvature (30 to 60 vs 61 to 90 degrees) and randomized to collagenase C. histolyticum or placebo 2:1 in favor of the former. RESULTS Post hoc meta-analysis of IMPRESS I and II data revealed that men treated with collagenase C. histolyticum showed a mean 34% improvement in penile curvature, representing a mean ± SD -17.0 ± 14.8 degree change per subject, compared with a mean 18.2% improvement in placebo treated men, representing a mean -9.3 ± 13.6 degree change per subject (p <0.0001). The mean change in Peyronie disease symptom bother score was significantly improved in treated men vs men on placebo (-2.8 ± 3.8 vs -1.8 ± 3.5, p = 0.0037). Three serious adverse events (corporeal rupture) were surgically repaired. CONCLUSIONS IMPRESS I and II support the clinical efficacy and safety of collagenase C. histolyticum for the physical and psychological aspects of Peyronie disease.