Tom F. Lue

Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group.

BACKGROUND Sildenafil is a potent inhibitor of cyclic guanosine monophosphate hydrolysis [corrected] in the corpus cavernosum and therefore increases the penile response to sexual stimulation. We evaluated the efficacy and safety of sildenafil, administered as needed in two sequential double-blind studies of men with erectile dysfunction of organic, psychogenic, and mixed causes. METHODS In a 24-week dose-response study, 532 men were treated with oral sildenafil (25, 50, or 100 mg) or placebo. In a 12-week, flexible dose-escalation study, 329 different men were treated with sildenafil or placebo, with dose escalation to 100 mg based on efficacy and tolerance. After this dose-escalation study, 225 of the 329 men entered a 32-week, open-label extension study. We assessed efficacy according to the International Index of Erectile Function, a patient log, and a global-efficacy question. RESULTS In the dose-response study, increasing doses of sildenafil were associated with improved erectile function (P values for increases in scores for questions about achieving and maintaining erections were <0.001). For the men receiving 100 mg of sildenafil, the mean score for the question about achieving erections was 100 percent higher after treatment than at base line (4.0 vs. 2.0 of a possible score of 5). In the last four weeks of treatment in the dose-escalation study, 69 percent of all attempts at sexual intercourse were successful for the men receiving sildenafil, as compared with 22 percent for those receiving placebo (P<0.001). The mean numbers of successful attempts per month were 5.9 for the men receiving sildenafil and 1.5 for those receiving placebo (P<0.001). Headache, flushing, and dyspepsia were the most common adverse effects in the dose-escalation study, occurring in 6 percent to 18 percent of the men. Ninety-two percent of the men completed the 32-week extension study. CONCLUSIONS Oral sildenafil is an effective, well-tolerated treatment for men with erectile dysfunction.

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.

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.

Oral Sildenafil in the Treatment of Erectile Dysfunction

BACKGROUND Sildenafil is a potent inhibitor of cyclic guanosine monophosphate hydrolysis [corrected] in the corpus cavernosum and therefore increases the penile response to sexual stimulation. We evaluated the efficacy and safety of sildenafil, administered as needed in two sequential double-blind studies of men with erectile dysfunction of organic, psychogenic, and mixed causes. METHODS In a 24-week dose-response study, 532 men were treated with oral sildenafil (25, 50, or 100 mg) or placebo. In a 12-week, flexible dose-escalation study, 329 different men were treated with sildenafil or placebo, with dose escalation to 100 mg based on efficacy and tolerance. After this dose-escalation study, 225 of the 329 men entered a 32-week, open-label extension study. We assessed efficacy according to the International Index of Erectile Function, a patient log, and a global-efficacy question. RESULTS In the dose-response study, increasing doses of sildenafil were associated with improved erectile function (P values for increases in scores for questions about achieving and maintaining erections were <0.001). For the men receiving 100 mg of sildenafil, the mean score for the question about achieving erections was 100 percent higher after treatment than at base line (4.0 vs. 2.0 of a possible score of 5). In the last four weeks of treatment in the dose-escalation study, 69 percent of all attempts at sexual intercourse were successful for the men receiving sildenafil, as compared with 22 percent for those receiving placebo (P<0.001). The mean numbers of successful attempts per month were 5.9 for the men receiving sildenafil and 1.5 for those receiving placebo (P<0.001). Headache, flushing, and dyspepsia were the most common adverse effects in the dose-escalation study, occurring in 6 percent to 18 percent of the men. Ninety-two percent of the men completed the 32-week extension study. CONCLUSIONS Oral sildenafil is an effective, well-tolerated treatment for men with erectile dysfunction.

Defining stem and progenitor cells within adipose tissue.

Adipose tissue-derived stem cells (ADSC) are routinely isolated from the stromal vascular fraction (SVF) of homogenized adipose tissue. Freshly isolated ADSC display surface markers that differ from those of cultured ADSC, but both cell preparations are capable of multipotential differentiation. Recent studies have inferred that these progenitors may reside in a perivascular location where they appeared to coexpress CD34 and smooth muscle actin (alpha-SMA) but not CD31. However, these studies provided only limited histological evidence to support such assertions. In the present study, we employed immunohistochemistry and immunofluorescence to define more precisely the location of ADSC within human adipose tissue. Our results show that alpha-SMA and CD31 localized within smooth muscle and endothelial cells, respectively, in all blood vessels examined. CD34 localized to both the intima (endothelium) and adventitia neither of which expressed alpha-SMA. The niche marker Wnt5a was confined exclusively to the vascular wall within mural smooth muscle cells. Surprisingly, the widely accepted mesenchymal stem cell marker STRO-1 was expressed exclusively in the endothelium of capillaries and arterioles but not in the endothelium of arteries. The embryonic stem cell marker SSEA1 localized to a pericytic location in capillaries and in certain smooth muscle cells of arterioles. Cells expressing the embryonic stem cell markers telomerase and OCT4 were rare and observed only in capillaries. Based on these findings and evidence gathered from the existing literature, we propose that ADSC are vascular precursor (stem) cells at various stages of differentiation. In their native tissue, ADSC at early stages of differentiation can differentiate into tissue-specific cells such as adipocytes. Isolated, ADSC can be induced to differentiate into additional cell types such as osteoblasts and chondrocytes.

Penile length in the flaccid and erect states: guidelines for penile augmentation.

PURPOSE We provide guidelines of penile length and circumference to assist in counseling patients considering penile augmentation. MATERIALS AND METHODS We prospectively measured flaccid and erect penile dimensions in 80 physically normal men before and after pharmacological erection. RESULTS Mean flaccid length was 8.8 cm., stretched length 12.4 cm. and erect length 12.9 cm. Neither patient age nor size of the flaccid penis accurately predicted erectile length. Stretched length most closely correlated with erect length. CONCLUSIONS Only men with a flaccid length of less than 4 cm., or a stretched or erect length of less than 7.5 cm. should be considered candidates for penile lengthening.

Clinical Significance of Sacral and Pudendal Nerve Anatomy

The neuroanatomy and neurophysiology of the external urethral closure mechanisms still are under debate because the motor fibers that emanate from the sacral plexus and pudendal nerve to supply this segment have not been traced, nor has their functional interrelationship been established. Therefore, we dissected 3 male human cadavers (aged 31 to 69 years) by tracing the entire sacral plexus, particularly the pudendal nerve, from the cauda equina throughout the branching of the nerves to their final destination. The dissection demonstrated that the extrinsic urethral sphincter, formed by the rhabdosphincter around the membranous urethra as well as the levator ani muscle and pelvic floor (especially the transversus perinei muscle), is innervated by somatic nerve fibers that emanate primarily from sacral roots S2 and S3. In 5 patients with neurogenic lower urinary tract dysfunction electrostimulation of the sacral root and pudendal nerve markedly increased intraurethral closure pressures. Stimulation of the pudendal nerve or its transversus perinei branch alone resulted in an increase in intraurethral closure pressure to 60 to 70 cm. water--an increase similar to that produced by stimulation of the sacral root without neurotomy. By means of neurotomy and/or neural blockade with lidocaine we were able to differentiate between the contributions of each muscular element to the external sphincteric mechanism. Almost 70 per cent of the closure pressure of the external urethral sphincter is induced by stimulation of the S3 ventral root, while the other 30 per cent derives from S2 and S4 neuronal impulses.

Detailed anatomy of penile neurovascular structures: surgical significance.

In 10 formalin-preserved adult male cadavers, dissection of the penile veins, arteries and nerves revealed information of clinical importance. The main venous drainage of the corpora cavernosa is via the cavernous veins, with additional drainage through the circumflex, deep dorsal, and crural veins. The arterial supply of the cavernous bodies varied remarkably, and the incidence of an accessory internal pudendal artery was high. The cavernous nerves, previously believed to be microscopic structures, were in fact identifiable grossly, and we were able to follow them from the region of the hilum of the penis to the prostate. The nature of these nerves was then confirmed by serial histologic sectioning. This detailed knowledge of the venous drainage and arterial and nervous supply of the penis, as well as of the relationships among the cavernous structures in the hilum of the penis, can elucidate the cause of erectile dysfunction and provide a valuable guide for surgical correction of vasculogenic and neurogenic impotence.

Mechanisms of venous occlusion during canine penile erection: an anatomic demonstration

Hemodynamic studies have clearly demonstrated that intracorporeal injection of papaverine causes an increase of venous outflow resistance, and we therefore undertook a study of the venous drainage of the canine penis to delineate the anatomic changes in the venular structure during papaverine-induced erection. In 11 dogs, the corpora cavernosa were examined by corrosion casting in six and serial trichrome staining and histologic sectioning in five. Low-power scanning electron microscopy of the corrosion casts demonstrated the existence of a venular plexus interposed between the tunica albuginea and the sinusoidal spaces. After papaverine injection, this subalbugineal venular plexus is compressed between the dilated sinusoids from below and the tunica albuginea from above, such that venous drainage is effectively impeded. Examination of two cadaveric human penile corrosion casts by low-power scanning electron microscopy revealed evidence of a similar subalbugineal venular plexus draining into the emissary veins along the shaft of the penis. Based on the above, a model for the anatomic basis of venous occlusion during penile erection is outlined. Along with arteriolar and sinusoidal smooth-muscle relaxation, this can account for the three basic hemodynamic changes necessary for erection: increased arterial inflow, increased intracorporeal pressure, and increased venous outflow resistance.

PEYRONIE'S DISEASE IS ASSOCIATED WITH AN INCREASE IN TRANSFORMING GROWTH FACTOR-beta PROTEIN EXPRESSION

PURPOSE Transforming growth factor-beta (TGF-beta) has been implicated in many chronic fibrotic conditions such as pulmonary and hepatic fibrosis. We postulated that TGF-beta may play a role in the pathogenesis of Peyronies disease. MATERIALS AND METHODS Tissues from the tunica albuginea of 30 Peyronies disease patients (study group) and from 6 patients without Peyronies disease, who had undergone penile prosthesis surgery for organic impotence (control group), were subjected to histological examination using Hart and trichrome stains and Western blotting for the detection of TGF-beta protein expression. RESULTS The results of these experiments demonstrate that all tissue from Peyronies disease patients showed a variety of histological changes of the tunica, ranging from chronic inflammatory cellular infiltration to complete calcification and ossification of the tissues. The most prominent changes observed in the majority of patients were focal or diffused elastosis, fenestration and disorganization of the collagen bundles. TGF-beta1 protein expression was detected in 26 patients (86%), while only 7 (23%) and 5 (17%) patients showed TGF-beta2 and TGF-beta3 protein expression, respectively. One patient in the control group showed fibrosis of the tunica albuginea and protein expression of TGF-beta1 and TGF-beta2. This patient had undergone surgery for the revision of his prosthesis twice. Five patients from the control group showed normal histological patterns of the tunica albuginea and no protein expression for TGF-beta1, TGF-beta2 and TGF-beta3. CONCLUSIONS TGF-beta1 protein expression is significantly associated with Peyronies disease, which may provide a new insight and the potential for the prevention and treatment of this disease.