Serap Gur

Effects of 5-alpha reductase inhibitors on erectile function, sexual desire and ejaculation

Introduction: Treatment with 5-alpha reductase inhibitors (5ARI) is commonly utilized for the treatment of benign prostatic hyperplasia (BPH). The true prevalence of sexual side effects with 5ARI treatment is currently unknown. Areas covered: The current article reviews the reported adverse effects of 5ARI in regard to erectile function, sexual desire and ejaculation. A PubMed search was performed of all articles from 1990 to present, which reported any sexual side effects with finasteride or dutasteride. Preference was given to more recent and human studies where available. Expert opinion: Clinical trials with 5ARI report prevalence rates of de novo erectile dysfunction of 5 – 9%. Decreased circulating dihydrotestosterone (DHT) resulting from 5ARI use is associated with diminished sexual desire and/or orgasm. The presence of adverse sexual effects is associated with decreased self-esteem, quality of life and ability to maintain an intimate relationship. Inhibition of 5ARI additionally influences progesterone and deoxycorticosterone levels and may alter psychological functions, including increased depression, melancholy and loss of general well being. Ejaculatory dysfunction has not been well studied in patients using 5ARI. Patients receiving therapy with 5ARI should be counseled as to potential sexual and psychological adverse effects. Future clinical studies are needed to further investigate the sexual side effects associated with this class of drugs.

Current status and new developments in Peyronie's disease: medical, minimally invasive and surgical treatment options

Introduction: Peyronies disease (PD) is a wound-healing disorder of the tunica albuginea of the penis which affects 3 – 9% of adult males. Clinically, any combination of plaque formation, penile pain, angulation and erectile dysfunction may appear. This condition may progress, stabilize or, uncommonly, regress during the initial acute phase (6 – 18 months). Areas covered: Information regarding this review was searched in PubMed until August 2010. Vitamin E, paraaminobenzoate and colchicine are sparingly employed oral medical therapies. Intralesional injections as a minimally invasive therapy for PD includes injection with verapamil, interferon-α-2b, and collagenase. Men suffering with PD who have significant penile deformity precluding successful coitus can be appraised for surgical correction. Surgery is considered the gold standard and includes plication, incision and grafting- or penile-prosthesis-related procedures. Expert opinion: This paper provides a broad overview of the subject of PD, available nonsurgical options and surgical approaches that will aid in the routine clinical diagnosis and management of PD. Increased public and medical awareness of PD prevalance, presentation, diagnosis and treatment options will serve well the large population of men who suffer in silence with this common condition.

The Effects of Chronic 5‐Alpha‐Reductase Inhibitor (Dutasteride) Treatment on Rat Erectile Function

INTRODUCTIONnNumerous clinical series have reported an association between 5-alpha-reductase inhibitors (5ARIs) and sexual dysfunction, but there are limited preclinical data available.nnnAIMnTo further investigate the mechanisms of erectile dysfunction (ED) related to 5ARI therapy using a rat model.nnnMAIN OUTCOME MEASURESnOutcome measures include serum dihydrotestosterone (DHT), relaxant and contractile properties of cavernosal muscle, and nitric oxide synthase expression.nnnMETHODSnTwenty adult male Sprague-Dawley rats were randomized into control (N = 10) and dutasteride (0.5 mg/rat/day, in drinking water, N = 10) groups. Serum samples were obtained at baseline, from which DHT was measured after 30 days of treatment via radioimmunoassay (Beckman Coulter, Fullerton, CA, USA). Before the terminal blood draw, erectile response was measured using cavernosal nerve stimulation. The relaxant and contractile properties of cavernosal muscle strips were evaluated in tissue baths, and immunohistochemical (IHC) staining for nitric oxide synthase (NOS) and collagen deposition was performed.nnnRESULTSnMean serum DHT was suppressed by 86.5% (range 64.2-94.8%) after 30 days of 5ARI treatment and was statistically significant (P = 0.0024). In vivo erectile response in the dutasteride treated group decreased significantly compared with control (P < 0.001). While electrical field stimulation (EFS)-induced and acetylcholine-induced relaxation was decreased, EFS-induced and phenlyephrine-induced adrenergic contraction was significantly enhanced in the dutasteride group (P < 0.01). IHC studies demonstrated increased collagen deposition in the treatment arm as well as altered expression of neuronal NOS (nNOS) and inducible NOS (iNOS).nnnCONCLUSIONSnThe 5ARIs, as demonstrated in these rat cavernosal smooth muscle studies, have a detrimental effect on erectile function. Enhanced iNOS expression may protect penile smooth muscle from fibrosis. The effect of 5ARIs on human sexual function warrants further investigation.

A Comprehensive Review of Metabolic Syndrome Affecting Erectile Dysfunction

INTRODUCTIONnMetabolic syndrome (MetS) is the most important public health issue threatening the health of men and women all over the world. Its current prevalence (i.e., approximately 30%) is continuously increasing. MetS by itself is considered a risk factor for erectile dysfunction (ED).nnnAIMnTo focus on the definition epidemiology, pathogenesis, and possible mechanistic links between MetS and ED in order to provide guidelines for treating such individuals.nnnMETHODSnThe search strategies yielded total records screened from PubMed.nnnMAIN OUTCOME MEASURESnRegardless of the definition, MetS consists of insulin resistance, hypertension, dyslipidemia, and obesity. MetS is not an end disease but is a disorder of energy utilization and storage.nnnRESULTSnThe prevalence of ED in patients with MetS is almost twice than in those without MetS, and about 40% of patients with ED have MetS. An important mechanism linking MetS and ED is hypogonadism.nnnCONCLUSIONSnRecognizing through ED, underlying conditions such as hypogonadism, diabetes and MetS might be a useful motivation for men to improve their health-related choices. The clinical management of MetS can be done by therapeutic interventions that include lifestyle modifications, hormone replacement alone or in combination with phosphodiesterase 5 inhibitors, and other pharmacological treatments.

Altered Relaxant Responses to Adenosine and Adenosine 5′-Triphosphate in the Corpus cavernosum from Men and Rats with Diabetes

The present study was aimed at investigating the effects of diabetes on the cavernosal smooth muscle relaxations mediated by adenosine and adenosine triphosphate (ATP) in tissues obtained from men and rats. Adenosine- and ATP-induced relaxant responses showed an enhanced sensitivity with an unaltered effectiveness in diabetic men. Adenosine-elicited relaxation in diabetic rat corporeal tissues exhibited enhanced effectiveness with unaltered sensitivity, whereas ATP-induced relaxations were decreased in diabetic animals when compared to control animals. Tetraethylammonium pretreatment, but not glibenclamide, L-NAME and 8-phenyltheophylline, normalized enhanced apparent affinity to adenosine in tissue from diabetic men and effectiveness (Emax) to adenosine in diabetic rats. These results suggest that adenosine-elicited relaxation in diabetes is controlled at the receptor level events including K+ channels in men whereas in rats postreceptor-related events including K+ channels control the adenosine-induced relaxation. These relaxations to adenosine and ATP in men and rats with and without diabetes may be nitric oxide-independent mechanisms. Our results also suggest that ATP-induced relaxation did not involve KATP channels and Ca-activated K+ channels.The present study was aimed at investigating the effects of diabetes on the cavernosal smooth muscle relaxations mediated by adenosine and adenosine triphosphate (ATP) in tissues obtained from men and

Pharmacological Management of Peyronie's Disease.

Peyronie’s disease is a localised, fibrosing condition of the penis that occurs in up to 9% of men. Although its aetiology has not been elucidated, Peyronie’s disease probably results from the presence of a predisposing genetic susceptibility combined with an inciting event, most probably trauma. Following appropriate clinical evaluation, initial treatment consists of a trial of oral and/or intralesional pharmacotherapy. Oral therapies most commonly employed include para-aminobenzoate (Potaba®) and tocopherol (vitamin E), with colchicine, tamoxifen, propoleum and acetyl-L-carnitine being used less frequently. Placebo-controlled studies examining these agents have failed to show a consistent beneficial effect on Peyronie’s disease, with the exception of para-aminobenzoate, which may decrease plaque size and curvature, and acetyl-L-carnitine, which may reduce erectile pain and inhibit disease progression. Intralesional injection therapy for Peyronie’s disease is commonly used as a first-line therapy along with oral medications. The current standard of care involves injection with interferon-α-2a or -2b, verapamil or collagenase over 2-week intervals for a period of 5–6 months. Interferon-α-2b, in particular, has been documented in a large, multicentre, placebo-controlled study to be significantly more effective than placebo in decreasing penile curvature, plaque size, penile pain and plaque density. However, interferon treatment is also associated with significant adverse effects, including fever and other flu-like symptoms. Other available therapies that have not consistently shown efficacy in placebo-controlled studies include corticosteroids and orgotein. Surgery is considered in patients with Peyronie’s disease who have not responded to a trial of conservative medical therapy for 1 year and who are precluded from sexual intercourse. Procedures commonly performed include the Nesbit procedure (or variations of the Nesbit), penile plaque incision/excision with or without grafting, and implantation of a penile prosthesis. Further basic scientific research in Peyronie’s disease is likely to identify additional targets for future pharmacotherapy.

Impaired endothelium-dependent and neurogenic relaxation of corpus cavernosum from diabetic rats: improvement with L-arginine

Abstract This study describes the relaxant response to acetylcholine, electrical field stimulation and sodium nitroprusside after contraction by phenylephrine (10−5u2009M) in corpus cavernosum from control and diabetic rats. The response to acetylcholine (10−9–10−3u2009M) and electrical field stimulation (0.5–64u2009Hz) is decreased and can be restored by the addition of nitric oxide synthatase substrate, l-arginine(10−5u2009M). The response to sodium nitroprusside is not changed in diabetic rats compared to control rats. NADPH-diaphorase staining was enhanced in a diabetic preparation compared to control preparations. The findings suggest a role for the depletion of l-arginine in diabetes mellitus. The enhanced NADPH-diaphorase staining may be due to a deficiency of NOS substrate l-arginine in the endothelium and nerves of diabetic tissues.

A critical appraisal of erectile function in animal models of diabetes mellitus.

The study of erectile function in diabetic animal models has revealed physiological alterations in neural, vascular, hormonal and endothelial function. The aims of this review are to further elucidate pathophysiological changes induced by diabetes mellitus and to introduce new concepts in the study of erectile dysfunction (ED) in animal models. The recognized pathophysiological mechanisms causing diabetic ED include oxidative stress and hormonal imbalance. The evolving treatments for ED include advanced glycosylated endproduct (AGE) inhibitors, phosphodiesterase type 5 inhibitors, protein kinase C (PKC) inhibitors, hormone replacement, and gene transfer techniques. Our current understanding of how these multiple pathophysiological mechanisms contribute to ED is discussed. In this review, diabetic animal model studies have documented that oxidative stress is a pre-eminent pathophysiological mechanism and several anti-oxidants, such as alpha-lipoic acid, vitamin E, sodium selenate, melatonin, and ascorbic acid, reverse both neurogenic and endothelial dysfunction in diabetic models. Further, the peroxynitrite decomposition catalyst - FeTMPyP, PKC beta selective inhibitor - LY333531, I kappaB kinase 2 inhibitor - AS602868, AGE inhibitors - aminoguanidine and ALT-711 show promise by exploring different cellular mechanisms in treating diabetic problems. A number of vectors have been used to insert genes to increase the expression of nitric oxide synthase, superoxide dismutase, maxi-K channel (hSlo), neurotrophin-3, and vasoactive intestinal polypeptide for the treatment of erectile function. Further investigation of the hormonal treatment of diabetes associated with hypogonadism may improve sildenafil responsiveness in diabetic patients. We are optimistic that novel prevention and treatment strategies for diabetic ED are on the horizon.

Incomplete Recovery of Erectile Function in Rat after Discontinuation of Dual 5‐Alpha Reductase Inhibitor Therapy

AIMnThe association of 5-alpha reductase inhibitor (5ARI) therapy and sexual dysfunction has been reported. Some patients claim persistent erectile dysfunction despite long-term discontinuation of 5ARI treatment. The aim of this study was to assess erectile function after cessation of 5ARI therapy using a rat model.nnnMETHODSnTwenty-six adult male Sprague-Dawley rats were randomized into three groups: (i) control (Nu2003=u200310); (ii) 8-week dutasteride treatment (0.5u2003mg/rat/day, in drinking water, Nu2003=u20038); and (iii) 6-week dutasteride treatment followed by a 2-week washout period (Nu2003=u20038). The experiments were performed after 8 weeks from the initiation of treatment in all groups. In vivo erectile activity and in vitro contractile and relaxant responses of cavernosal smooth muscle were investigated.nnnRESULTSnIn vivo erectile activity (intracavernosal pressure [ICP]/mean arterial pressure [MAP] and total ICP) in treatment groups were significantly decreased compared with controls (ICP/MAP: Pu2003<u20030.001 for 2.5u2003v, 5u2003v, and 7.5u2003v; total ICP: Pu2003<u20030.001 for 5u2003v and Pu2003<u20030.01 for 7.5u2003v). Acetylcholine-induced relaxations were diminished in treatment groups (Pu2003<u20030.05). Relaxant responses to electrical field stimulation (EFS) were decreased in the 8-week treatment group (Pu2003<u20030.05) but were similar to controls in the washout group. Sodium nitroprusside (SNP)-induced endothelium-independent relaxations were reduced in the 8-week dutasteride treatment group (Pu2003<u20030.01), while these responses were restored in the washout group. The contractile responses to the alpha1-adrenergic agonist phenylephrine were decreased in treatment groups compared with controls (Pu2003<u20030.01). Direct neurogenic contractile responses in the dutasteride groups were significantly lower than controls between 1 and 15u2003Hz frequencies (but not at 20u2003Hz) and washout partially restored the responses at 10 and 15u2003Hz.nnnCONCLUSIONnDiscontinuation of dutasteride improved the relaxant responses to EFS and SNP, while cholinergic and adrenergic responses remained depressed. Our findings suggest a time-dependent detriment of dutasteride on erectile function. The withdrawal/washout effect of 5ARIs on parameters of human sexual function warrants further investigation.

Exploring the Potential of NO-Independent Stimulators and Activators of Soluble Guanylate Cyclase for the Medical Treatment of Erectile Dysfunction

Nitric oxide (NO)-sensitive soluble guanylyl cyclase (sGC) is the receptor that catalyzes the formation of the intracellular messenger cyclic guanosine monophosphate (cGMP). Binding of the physiological activator, NO, to the reduced heme moiety of sGC increases the conversion of guanosine triphosphate (GTP) to cyclic GMP (cGMP) and engages crucial effector systems such as protein kinases, phosphodiesterases, and ion channels. The development of compounds that activate sGC independent of NO release has therapeutic implications. Recent studies have demonstrated the potential use of heme-dependent sGC stimulators (e.g. YC-1, BAY 41-2272, BAY 41-8543, BAY 63-2521, CFM-1571 and A-350619) and heme-independent sGC activators (e.g. BAY 58-2667, HMR-1766, S-3448, A-778935) in the treatment of cardiovascular diseases. Erectile dysfunction (ED) affects millions of men. Phosphodiesterase (PDE)-5 inhibitors, produce an NO-dependent increase in intracellular cGMP concentration, have been a successful approach in the treatment of ED. However, >30% of men with ED do not respond to PDE-5 inhibitor therapy, implying that endogenous NO production may be impaired to such an extent that inhibition of cGMP degradation produces no significant therapeutic advantage. Endogenous NO released from nitrergic nerves in the corpora cavernosa is significantly decreased in various conditions (e.g. diabetes, aging, and hypertension) and have reduced activation of the NO-sGC-cGMP pathway. It is conceivable that sGC stimulators and/or activators may be more effective than PDE5 inhibitors in the treatment of ED in such circumstances by improving NO-sGC-cGMP signaling and erectile function. This novel drug therapy approach for the treatment of ED shows promise.