Pharmacotherapy for Erectile Dysfunction: Recommendations From the Fourth International Consultation for Sexual Medicine (ICSM 2015).

INTRODUCTION: Treatment of erectile dysfunction is based on pharmacotherapy for most patients. AIM: To review the current data on pharmacotherapy for erectile dysfunction based on efficacy, psychosocial outcomes, and safety outcomes. METHODS: A review of the literature was undertaken by the committee members. All related articles were critically analyzed and discussed. MAIN OUTCOME MEASURES: Levels of evidence (LEs) and grades of recommendations (GRs) are provided based on a thorough analysis of the literature and committee consensus. RESULTS: Ten recommendations are provided. (i) Phosphodiesterase type 5 (PDE5) inhibitors are effective, safe, and well-tolerated therapies for the treatment of men with erectile dysfunction (LE = 1, GR = A). (ii) There are no significant differences in efficacy, safety, and tolerability among PDE5 inhibitors (LE = 1, GR = A). (iii) PDE5 inhibitors are first-line therapy for most men with erectile dysfunction who do not have a specific contraindication to their use (LE = 3, GR = C). (iv) Intracavernosal injection therapy with alprostadil is an effective and well-tolerated treatment for men with erectile dysfunction (LE = 1, GR = A). (v) Intracavernosal injection therapy with alprostadil should be offered to patients as second-line therapy for erectile dysfunction (LE = 3, GR = C). (vi) Intraurethral and topical alprostadil are effective and well-tolerated treatments for men with erectile dysfunction (LE = 1, GR = A). (vii) Intraurethral and topical alprostadil should be considered second-line therapy for erectile dysfunction if available (LE = 3, GR = C). (viii) Dose titration of PDE5 inhibitors to the maximum tolerated dose is strongly recommended because it increases efficacy and satisfaction from treatment (LE = 2, GR = A). (ix) Treatment selection and follow-up should address the psychosocial profile and the needs and expectations of a patient for his sexual life. Shared decision making with the patient (and his partner) is strongly recommended (LE = 2, GR = A). (x) Counterfeit medicines are potentially dangerous. It is strongly recommended that physicians educate their patients to avoid taking any medication from unauthorized sources (LE = 2, GR = A). The first seven recommendations are the same as those from the Third International Consultation for Sexual Medicine and the last three are new recommendations. CONCLUSION: PDE5 inhibitors remain a first-line treatment option because of their excellent efficacy and safety profile. This class of drugs is continually developed with new molecules and new formulations. Intracavernosal injections continue to be an established treatment modality, and intraurethral and topical alprostadil provide an alternative, less invasive treatment option.

Sexual Inhibition and Sexual Excitation Profiles in Men with and Without Erectile Disorder.

OBJECTIVE: To investigate sexual excitation (SE) and sexual inhibition (SI) profiles in men with erectile dysfunction (ED) and to examine how these dimensions discriminate between men with and without ED. METHODS: A clinical sample of 37 men with situational (psychogenic) ED and a control group of 40 sexually healthy men (matching the clinical group in age, marital status, and educational level) were constituted. Participants completed self-reported questionnaires assessing sexual function and the propensity for SI and SE. RESULTS: Higher propensities for SI due to the threat of performance failure (SIS1, P < .001) and SI due to the threat of performance consequences (SIS2, P < .01) were found in the group of men with ED. No significant differences were found between the 2 groups in the propensity for SE. CONCLUSION: Findings offer additional support for the Dual Control Model of Sexual Response and underscore the relevance of inhibitory mechanisms as potential psychobiological risk factors for the development and maintenance of ED. Findings also highlight the importance of a multidisciplinary approach in the clinical management of ED.

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 men's and women's 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; Peyronie's disease; and priapism. CONCLUSIONS: Sexual dysfunction in men represents a group of common medical conditions that need to be managed from a multidisciplinary perspective.

Initial characterization of hydrogen sulfide effects in female sexual function.

INTRODUCTION: In our male animal models, hydrogen sulfide (H(2)S) displayed significant vasodilatory and smooth muscle relaxant effects suggestive of an endogenous physiological role in erectile process. AIM: In this first exploratory study, we aimed to identify the existence and mechanism of H(2)S pathway in female sexual physiology. METHODS: Vaginal and clitoral cavernosal smooth muscle strips from New Zealand white rabbits (N = 12) were exposed to stable H(2)S donor, sodium hydrosulfide hydrate (NaHS.xH(2)O, 100 microM-1.6 mM), in isometric tension studies. The NaHS responses were repeated after incubations with (i) N(omega)-nitro-L-arginine (50 microM), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10 microM) or cis-N-[2-phenylcyclopentyl]-azacyclotridec-1-en-2-amine (MDL 12,330A) (10 microM); and (ii) potassium chloride medium (high K(+) 60 mM/low K(+) 10 mM), tetraethylammonium (10 mM) or glibenclamide (100 microM). Relaxant effect of NaHS was also compared with those of nitroglycerine (0.18-78.2 microM) and sildenafil (0.084-25.3 microM). Additionally, samples (N = 16) were collected for estimations of plasma and tissue H(2)S and expression levels of cystathionine gamma-lyase (CSE) and cystathionine beta-synthase (CBS) proteins. MAIN OUTCOME MEASURES: In vitro evidences for H(2)S formation and its physiopharmacological effects. RESULTS: NaHS produced significant concentration-dependent relaxation of vaginal and cavernosal smooth muscles with inhibitions by combination of ODQ and MDL 12,330A (26.4%), N(omega)-nitro-L-arginine (22.2%), high K(+) (15.1%) or glibenclamide (10.1%). Based on molar potency, NaHS was 18.3 and 6.3 times weaker than nitroglycerine and sildenafil, respectively. Quantitative assays indicated that plasma H(2)S level was 16.5 +/- 2.58 microM, and H(2)S was synthesized in the clitoral and vaginal smooth muscles (1.8 and 3.9 nmol/mg soluble protein compared with 26.5 nmol/mg in the liver: positive control). Similarly, western blotting identified the protein expression bands of CSE (44.5 kDa) and CBS (63 kDa) in these genital tissue samples. CONCLUSION: These pilot studies clearly indicate the smooth muscle relaxant effect of H(2)S in female genital tract, mediating through cyclic adenosine 3':5'-monophosphate, nitric oxide-cyclic guanosine monophosphate and K(+)(ATP) channels. Taken together with biochemical and molecular evidences for endogenous formation, H(2)S pathway could be a contributing factor in female sexual responses.

Oxytocic activity of thrombin: modulation of thrombin-induced gravid rat myometrial contractions by 5-hydroxytryptamine receptor antagonists.

BACKGROUND: Thrombin possesses potent oxytocic activity in vitro and in vivo. This activity has been proposed to play a role in post-parturitional uterine contractions and possibly, preterm birth related to intrauterine hemorrhage. Previous workers have demonstrated that cyclo-oxygenase pathway may not play a significant role in oxytocic activity of thrombin. However, the role of 5-hydroxytryptamine (a mediator of some of the biological activities of thrombin) in the oxytocic activity of thrombin is unknown. The present study therefore aimed to examine the possible involvement of 5-hydroxytryptamine in thrombin-induced myometrial contractions. METHODS: Effect of 5-hydroxytryptamine receptor antagonists on thrombin-induced contractions of isolated gravid rat myometrium was studied using isolated tissue bath system. RESULTS: Thrombin-induced myometrial contractions were significantly and concentration-dependently inhibited by ketanserin and methysergide. Furthermore, 12 +/- 2% increase in the force of contractions of gravid rat myometrium pre-contracted with 5-hydroxytryptamine (1 microM) was provoked by 1 U/ml of thrombin. Thrombin-induced augmentation of the uterine stimulating effect of 5-hydroxytryptamine was characterized by pronounced increase in the contractile tone. CONCLUSIONS: 5-hydroxytryptamine may possibly play a role in oxytocic activity of thrombin. Uterine hyperactivity associated with intrauterine hemorrhage could hence involve thrombin-induced 5-hydroxytryptamine production in the uterus.

Pharmacotherapy for erectile dysfunction.

INTRODUCTION: Advances in understanding of the biochemistry and physiology of penile erection have led to breakthroughs in pharmacotherapy of erectile dysfunction. AIM: To provide recommendations/guidelines concerning state-of-the-art knowledge for the putative molecular and cellular mechanisms of action of centrally and peripherally acting drugs currently utilized in pharmacotherapy of erectile dysfunction. METHODS: An international consultation in collaboration with the major urology and sexual medicine associations assembled over 200 multidisciplinary experts from 60 countries into 17 committees. Committee members established specific objectives and scopes for various male and female sexual medicine topics. The recommendations concerning state-of-the-art knowledge in the respective sexual medicine topic represent the opinion of experts from five continents developed in a process over a two-year period. Concerning the Pharmacotherapy for Erectile Dysfunction Committee there were 25 experts from 10 countries. MAIN OUTCOME MEASURE: Expert opinion was based on grading of evidence-based medical literature, widespread internal committee discussion, public presentation and debate. RESULTS: Selective and potent oral PDE5 inhibitors have significantly more affinity than cGMP and form broader molecular interactions with multiple amino acids, thereby blocking access to cGMP in the catalytic sites of the PDE5 enzyme. PDE5 inhibitors, which vary as to biochemical potency, selectivity and pharmacokinetics, lead to cGMP elevation and relaxation facilitation of penile corpus cavernosum smooth muscle cells following sexual stimulation. Various centrally acting drugs influence sexual behaviour. In particular, the dopaminergic substance apomorphine is a central enhancer that acts in the paraventricular nucleus of the hypothalamus as a dopamine (D2) receptor agonist, induces and increases penile erection responses via disinhibition, following sexual stimulation. CONCLUSIONS: There is a need for more research in the pharmacotherapeutic development of central and peripheral agents for safe and effective erectile dysfunction treatment.