Craig F. Donatucci

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.

alpha1-ADRENERGIC RECEPTOR SUBTYPES IN HUMAN DETRUSOR

PURPOSE To identify and quantitate alpha1-adrenergic receptor (alpha1AR) subtype expression in human detrusor. MATERIALS AND METHODS Initial studies to determine alpha1AR expression in human detrusor were performed using saturation binding with [125I]HEAT. Once the presence of alpha1ARs was documented, subtype (alpha1a, alpha1b, alpha1d) expression at the mRNA level (and comparison with rat) was determined with RNase protection assays (human detrusor) and RT-PCR (human detrusor, rat whole bladder). Competition binding analysis with the alpha1dAR-selective ligand BMY7378 was used to measure alpha1AR subtype expression at a protein level in human detrusor. RESULTS Alpha1AR expression in human detrusor was low but reproducible (6.3 +/- 1.0 fmol./mg. total protein). RNase protection assays performed on total RNA extracted from human detrusor revealed the following alpha1AR subtype expression: alpha1d (66%) > alpha1a (34%), and no alpha1b. RT-PCR confirmed alpha1AR subtype mRNA distribution in human detrusor with alpha1d (approximately 60-70%) > alpha1a (approximately 30-40%), and a lack of alpha1b mRNA. Rat whole bladder expressed different alpha1AR subtype mRNA than human detrusor, with alpha1a approximately alpha1b approximately alpha1d. The presence of alpha1d > alpha1a expression in human detrusor was confirmed at a protein level by competition analysis utilizing BMY7378 which revealed a two-site fit, with Ki and high affinity binding (66%) consistent with the alpha1dAR subtype. CONCLUSIONS Human detrusor contained two alpha1AR subtypes (alpha1d > alpha1a), a finding that is different from rat, another commonly used animal model. Since non-subtype selective alpha1AR antagonists ameliorate irritative bladder symptoms (in men and women with/without outlet obstruction), and Rec 15/2739 (alpha1a selective antagonist) does not improve symptom scores in BPH, our findings suggest bladder alpha1dARs may provide a potentially novel mechanism underlying these therapeutic benefits.

Pharmacotherapy for erectile dysfunction.

INTRODUCTION Pharmacotherapy is the usual initial therapy for most men with erectile dysfunction. AIM To review the current data relating to the efficacy, tolerability and safety of drugs used in the treatment of men with erectile dysfunction. METHODS A critical review of the literature relating to the use of pharmacotherapeutic agents was undertaken by a committee of eight experts from five countries, building on prior reviews. MAIN OUTCOME MEASURES Expert opinion and recommendations were based on grading of evidence-based literature, internal committee dialogue, open presentation, and debate. RESULTS Almost all currently available evidence relates to sildenafil, tadalafil, and vardenafil. Phosphodiesterase type 5 (PDE5) inhibitors are first-line therapy for most men with erectile dysfunction who do not have a specific contraindication to their use. There is no evidence of significant differences in efficacy, safety, and tolerability between the PDE5 inhibitors and apomorphine. Intracavernosal injection therapy with alprostadil should be offered to patients as second line therapy for erectile dysfunction. Intraurethral alprostadil is a less effective treatment than intracavernosal alprostadil for the treatment of men with erectile dysfunction. CONCLUSIONS PDE5 inhibitors are effective, safe, and well-tolerated therapies for the treatment of men with erectile dysfunction. Apomorphine, intracavernosal injection therapy with alprostadil, and intraurethral alprostadil are all effective and well-tolerated treatments for men with erectile dysfunction. We recommend some standardization of the assessment of psychosocial outcomes within clinical trials in the field of erectile dysfunction.

The Role of Cyclic Adenosine Monophosphate, Cyclic Guanosine Monophosphate, Endothelium and Nonadrenergic, Noncholinergic Neurotransmission in Canine Penile Erection

To elucidate the neuropharmacology of erection, we undertook an in vivo canine study to examine the role of cholinergic and nonadrenergic, noncholinergic (NANC) neuroeffectors and the sinusoidal endothelium in erection induced by electrostimulation. We also examined the effect of adenylate cyclase and guanylate cyclase blockers by intravenous injection of N-ethylmaleimide and methylene blue, respectively. In addition, the effects of intracavernous injection of the nitric oxide-releasing substance, nitroprusside, and bromocyclic adenosine monophosphate (AMP) and bromocyclic guanosine monophosphate (GMP) were also studied. In contrast to in vitro results, atropine reduced the increase of intracavernous pressure after neurostimulation (p = 0.029). Intracavernous injection of CHAPS to destroy the sinusoidal endothelium abolished the response to acetylcholine (p = 0.001), but only partially inhibited the response to electrostimulation (mean = 75% pressure increase, p = 0.022), indicating that neuronal nitric oxide plays a major role in penile erection. Methylene blue, a guanylate cyclase inhibitor, significantly inhibited the erectile response to both neurostimulation and sodium nitroprusside (p = 0.000 and 0.017, respectively). However, N-ethylmaleimide, an adenylate cyclase inhibitor, could not reduce the response to neurostimulation (p = 0.078). The erectile response to intracavernous injection of cGMP was significantly better than that induced by cAMP (p = 0.025). Our results suggest that both the cholinergic and NANC neuroeffectors and the sinusoidal endothelium are involved in erection. In addition, our data imply that the neuronal nitric oxide/cyclic GMP system is the most likely pathway for penile smooth muscle relaxation and erection.

Facilitating research participation and improving quality of life for African American prostate cancer survivors and their intimate partners. A pilot study of telephone-based coping skills training.

African American men experience worse prostate cancer outcomes compared with those of Caucasian men, not only in incidence and mortality rates, but also in coping with the side effects of treatment. Unfortunately, African American men have been significantly under‐represented in research evaluating the efficacy of psychosocial interventions for improving coping in prostate cancer survivors. This pilot study explored the feasibility and efficacy of coping skills training (CST), an intervention developed to enhance coping with treatment side effects in a sample of African American prostate cancer survivors and their intimate partners. The intervention was delivered in a telephone‐based format designed to facilitate research participation. A total of 40 couples were randomized to either 6 sessions of CST or usual care. Survivors completed measures of disease‐specific quality of life (QOL) related to urinary, sexual, bowel, and hormonal symptom domains, as well as measures of global QOL (i.e., physical functioning and mental health). Partners completed measures of caregiver strain, mood, and vigor. Analysis of data from 30 couples (12 couples in CST, 18 couples in usual care) indicated that CST produced moderate to large treatment effects for QOL related to bowel, urinary, sexual, and hormonal symptoms. Partners who underwent CST reported less caregiver strain, depression, and fatigue, and more vigor, with moderate effect sizes observed that approached conventional levels of statistical significance. These preliminary findings suggest that telephone‐based CST is a feasible approach that can successfully enhance coping inAfrican American prostate cancer survivors and their intimate partners. Cancer 2007.

Pharmacology of tamsulosin: Saturation-binding isotherms and competition analysis using cloned α1-adrenergic receptor subtypes

α1‐adrenergic receptors (α1 ARs) are important in the dynamic component of benign prostatic hyperplasia (BPH). Currently, several α1AR antagonists are being used in the treatment of BPH.

The Combined Intracavernous Injection and Stimulation Test: Diagnostic Accuracy

A retrospective review was done of the results of the combined intracavernous injection and stimulation test, an office based functional test for impotence. In this procedure the quality of erection is assessed 15 minutes after injection of a vasoactive drug. In our series 90 patients did not achieve full rigidity and were instructed to perform genital self-stimulation for 5 minutes before reevaluation. Of the 90 patients 67 (74%) improved with stimulation and 23 (26%) showed no improvement. At 5 minutes after stimulation a decrease in the quality of the erection was found in 25 patients--a finding suggestive of venogenic impotence. When cavernosometry and cavernosography were performed 21 patients (84%) had moderate to severe venous leakage and 4 (16%) showed none. Self-stimulation after diagnostic injection of intracavernous agents can improve patient response, and may better predict the potential success of a therapeutic self-injection program and the diagnosis of suspected venogenic impotence.

Anatomy of cavernous nerves distal to prostate: microdissection study in adult male cadavers

Retrograde and antegrade dissections from the penile hilum to the prostatic area and the glans penis were performed in 4 formalin-preserved adult male cadavers. In addition to the medial branches accompanying the urethra, the lateral branches of the cavernous nerves pierced the urogenital diaphragm 4 to 7 mm from the striated muscles of the external sphincter. At the penile region, multiple communications between the cavernous and dorsal nerves were noted that suggest that either the cavernous nerves use the dorsal nerve as a carrier to the distal portion of the penis or the dorsal nerve may itself contain autonomic fibers. These findings will improve our ability to preserve erectile function during pelvic, urethral, and penile surgery.

Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a 1-year, open-label extension study.

Study Type – Therapy (cohort)
Level of Evidence 2b

Antiandrogens in the treatment of priapism

Recurrent priapism in young men is a potentially devastating condition that may result in irreversible penile fibrosis. Hormonal manipulation using estrogens and gonadotropin-releasing hormone analogues has been successful in treating episodes of priapism refractory to other treatment forms, but it is associated with significant adverse effects, in particular the loss of libido and erectile function. We present 2 patients with sickle-cell disease and 1 patient with a spinal cord injury who had recurrent and refractory priapism. All 3 patients were successfully treated with low-dose antiandrogens without major side effects. Our observations suggest a role for antiandrogens in the treatment of men with refractory priapism that should be evaluated in the setting of a controlled study.