Poly(ADP‐Ribose) Polymerase Inhibition Improves Erectile Function in Diabetic Rats

IntroductionErectile dysfunction (ED) is a common and hard‐to‐treat complication of diabetes mellitus (DM). Multiple lines of evidence have shown that poly(ADP‐ribose) polymerase (PARP) activation plays an important role in neurovascular dysfunction in diabetes, which is the crucial mechanism for diabetic ED.AimTo investigate the preventive benefit of a PARP inhibitor in a rat model of ED induced by diabetes.MethodsEstablished streptozotocin‐diabetic male Sprague‐Dawley rats were given PJ‐34, a selective PARP inhibitor, by oral gavage at a dose of 10 mg/kg twice daily for 8 weeks. Erectile responses under electrical stimulation of the cavernous nerve, PARP activity and reactive oxygen species (ROS) production were measured. Nitric oxide synthase (NOS) isoforms were evaluated by Western blot and real‐time quantitative PCR. Nuclear factor‐kappa B activition and apoptosis in corpus cavernosa (CC) were also investigated.Main Outcome MeasuresThe effects of PARP inhibition on the development of diabetic ED were determined.ResultsDiabetes markedly attenuated the erectile responses (intracavernosal pressure/mean systemic arterial blood pressure) and these were partially prevented by PJ‐34 treatment. Promoted oxidative stress associated PARP activation was found in CC from vehicle‐treated diabetic rats. PJ‐34 blocked PARP activity and the diabetes‐associated ROS generation. Decreased expression and activity of constitutive NOS (cNOS), including endothelial NOS (eNOS) and neuronal NOS (nNOS), associated with enhanced inducible NOS (iNOS) expression and activity were observed in vehicle‐treated diabetic rats. Although PJ‐34 had no effect on eNOS expression, it significantly prevented the decrease in nNOS expression and cNOS activity, and inhibited iNOS expression and activity in diabetic rats. PARP blockade by PJ‐34 to some extent prevented diabetes‐associated apoptosis and NF‐κB activation.ConclusionsOur results indicate that PARP activation plays an important role in the pathogenesis of diabetic ED and PARP inhibition may be a promising strategy to prevent development of diabetic ED. Wan ZH, Li WZ, Li YZ, Chen L, Li GH, Hu WF, Peng S, Yu JJ, and Guo F. Poly(ADP‐Ribose) polymerase inhibition improves erectile function in diabetic rats.     

Chronic Treatment with an Oral Rho‐Kinase Inhibitor Restores Erectile Function by Suppressing Corporal Apoptosis in Diabetic Rats

IntroductionIt has been suggested that the up‐regulation of the contractile RhoA/Rho‐kinase (ROCK) signaling pathway is one of the important mechanisms for diabetes‐associated erectile dysfunction (ED). However, the exact role of RhoA/ROCK signaling in the pathogenesis of diabetes‐related ED has not been fully delineated.AimTo determine whether the RhoA/ROCK pathway is involved in the regulation of corporal apoptosis and whether administration of insulin or fasudil, a specific ROCK inhibitor, could ameliorate ED in streptozotocin‐induced diabetic rats.Main Outcome MeasuresAt 16 weeks after diabetes induction, erectile function was assessed by cavernous nerve stimulation. Penile tissue was assessed for apoptosis with terminal deoxynucleotidyl transferase‐mediated 2′‐deoxyuridine 5′‐triphosphate (dUTP) nick end labeling assay. Expression of myosin phosphatase target subunit 1 (MYPT1), protein kinase B (Akt), and phospho‐endothelial nitric oxide synthase (eNOS) were evaluated by Western blot. Immunohistochemical study was carried out for smooth muscle alpha‐actin, B‐cell leukemia/lymphoma 2 (Bcl‐2), and Bcl‐2‐associated X Protein (Bax). Activity of caspase‐3 and phosphatase and tensin homolog deleted on chromosome ten (PTEN) was also determined.MethodsMale Sprague‐Dawley rats (8 weeks old) were randomly divided into four groups: age‐matched controls, diabetic controls, and diabetic rats treated with insulin (10 U/day, subcutaneous injection) or fasudil (30 mg/kg/day, oral) for the last 4 weeks of the 16 weeks after diabetes induction.ResultsDiabetic rats showed impairment of erectile function, increased MYPT1 phosphorylation, and corporal apoptosis. Expression of phospho‐Akt, phospho‐eNOS, and Bcl‐2 were decreased, whereas activity of PTEN and caspase‐3 and expression of Bax were increased. Treatment with fasudil normalized these molecular and histologic alterations, and restored erectile function. Insulin treatment showed similar effects to those of fasudil, however, the effects were smaller than fasudil.ConclusionsThis study indicates that up‐regulation of the penile RhoA/ROCK pathway in diabetic rats enhances corporal apoptosis via the PTEN/Akt pathway resulting in ED, which could be prevented by chronic treatment with fasudil. Li WJ, Park K, Paick J‐S, and Kim SW. Chronic treatment with an oral rho‐kinase inhibitor restores erectile function by suppressing corporal apoptosis in diabetic rats.     

Valproic Acid Prevents Penile Fibrosis and Erectile Dysfunction in Cavernous Nerve‐Injured Rats

IntroductionBilateral cavernous nerve injury (BCNI) causes profound penile changes such as apoptosis and fibrosis leading to erectile dysfunction (ED). Histone deacetylase (HDAC) has been implicated in chronic fibrotic diseases.AimsThis study will characterize the molecular changes in penile HDAC after BCNI and determine if HDAC inhibition can prevent BCNI‐induced ED and penile fibrosis.MethodsFive groups of rats (8–10 weeks, n = 10/group) were utilized: (i) sham; (ii and iii) BCNI 14 and 30 days following injury; and (iv and v) BCNI treated with HDAC inhibitor valproic acid (VPA 250 mg/kg; 14 and 30 days). All groups underwent cavernous nerve stimulation (CNS) to determine intracavernosal pressure (ICP). Penile HDAC3, HDAC4, fibronectin, and transforming growth factor‐β1 (TGF‐β1) protein expression (Western blot) were assessed. Trichrome staining and the fractional area of fibrosis were determined in penes from each group. Cavernous smooth muscle content was assessed by immunofluorescence to alpha smooth muscle actin (α‐SMA) antibodies.Main Outcome MeasuresWe measured ICP; HDAC3, HDAC4, fibronectin, and TGF‐β1 protein expression; penile fibrosis; penile α‐SMA content.ResultsThere was a voltage‐dependent decline (P < 0.05) in ICP to CNS 14 and 30 days after BCNI. Penile HDAC3, HDAC4, and fibronectin were significantly increased (P < 0.05) 14 days after BCNI. There was a slight increase in TGF‐β1 protein expression after BCNI. Histological analysis showed increased (P < 0.05) corporal fibrosis after BCNI at both time points. VPA treatment decreased (P < 0.05) penile HDAC3, HDAC4, and fibronectin protein expression as well as corporal fibrosis. There was no change in penile α‐SMA between all groups. Furthermore, VPA‐treated BCNI rats had improved erectile responses to CNS (P < 0.05).ConclusionHDAC‐induced pathological signaling in response to BCNI contributes to penile vascular dysfunction. Pharmacological inhibition of HDAC prevents penile fibrosis, normalizes fibronectin expression, and preserves erectile function. The HDAC pathway may represent a suitable target in preventing the progression of ED occurring post‐radical prostatectomy. Hannan JL, Kutlu O, Stopak BL, Liu X, Castiglione F, Hedlund P, Burnett AL, and Bivalacqua TJ. Valproic acid prevents penile fibrosis and erectile dysfunction in cavernous nerve‐injured rats. J Sex Med 2014;11:1442–1451.     

Reversible Erectile Dysfunction in a Patient with Brain Tumor‐Related Epilepsy in Therapy with Zonisamide in Add‐On

IntroductionLiterature data do not report any cases of erectile dysfunction (ED) during treatment with new antiepileptic drugs in patients with brain tumors.AimConcerning zonisamide (ZNS) therapy, data on sexual dysfunction are not available either in patients with epilepsy or in patients with brain tumor‐related epilepsy.MethodsOur case study concerns one patient with partial epilepsy associated with oligoastrocytoma in whom reversible ED developed while taking ZNS. He came to our center already having undergone therapy with phenobarbital, oxcarbazepine, phenitoin, and clobazam. Due to the presence of psychomotor slowness and uncontrolled seizures, we substituted phenobarbital with ZNS 200 mg/day.Main Outcome MeasuresThe main outcome measures were seizure frequency and side effects.ResultsDuring ZNS therapy, we observed beneficial effects on seizure frequency with a notable reduction from 2–3 seizures per day to 2–3 per week. One month after starting therapy with ZNS, the patient complained about ED that disappeared when we suspended the drug.ConclusionsIn the literature on patients with brain tumor‐related epilepsy, sexuality is a subject that is often neglected by health‐care providers who focus primarily on controlling systemic diseases and maintaining physical comfort. For this reason, the possible impact of antiepileptic therapies on sexuality should be taken into consideration. Maschio M, Saveriano F, Dinapoli L, and Jandolo B. Reversible erectile dysfunction in a patient with brain tumor‐related epilepsy in therapy with zonisamide in add‐on. J Sex Med **;**:**–**.     

Erectile Dysfunction Precedes Coronary Artery Endothelial Dysfunction in Rats Fed a High‐Fat,High‐Sucrose,Western Pattern Diet

IntroductionIt is suggested that erectile dysfunction (ED) may be an early risk factor for cardiovascular disease.AimThe goal of this study was to determine whether development of ED precedes the onset of coronary artery endothelial dysfunction in response to a Western diet (WD), thereby establishing whether the WD differentially impacts the endothelium in a time‐dependent manner. Additionally, a goal was to determine if diet‐induced ED is reversible with intracavernosal sepiapterin treatment.MethodsMale Sprague‐Dawley rats were fed a WD for 4, 8, or 12 weeks, or a control diet for 8 weeks. Erectile function was evaluated by measuring the mean arterial pressure (MAP) and intracavernosal pressure (ICP) in response to electrical field stimulation of the cavernosal nerve near the major pelvic ganglion, in the absence and presence of sepiapterin. Coronary artery endothelial function was evaluated ex vivo with cumulative doses of acetylcholine (ACh) applied to segments of the left anterior descending coronary artery preconstricted with serotonin.Main Outcome MeasuresErectile function was assessed as the ICP response to electrical field stimulation (EFS), normalized to MAP. Coronary artery endothelial function was assessed as the effective concentration producing 50% of a maximal response (EC₅₀) of the ACh response.ResultsThe ICP/MAP response to EFS was significantly attenuated following both 8 and 12 weeks of the WD compared with the control diet (P < 0.05). Sepiapterin treatment augmented the ICP/MAP response in all WD groups (P < 0.05). The coronary artery EC₅₀ of the ACh response was not different from control following 4 or 8 weeks but was significantly elevated following 12 weeks of the WD (P < 0.01).ConclusionsThese data suggest that erectile function is reduced prior to coronary artery endothelial function in response to the WD. Improvement of erectile function with sepiapterin in WD rats indicates that nitric oxide synthase uncoupling is a key mechanism in diet‐induced ED. La Favor JD, Anderson EJ, Hickner RC, and Wingard CJ. Erectile dysfunction precedes coronary artery endothelial dysfunction in rats fed a high‐fat, high‐sucrose, Western pattern diet. J Sex Med 2013;10:694–703.     

Change to Either a Nonandrogenic or Androgenic Progestin‐Containing Oral Contraceptive Preparation is Associated with Improved Sexual Function in Women with Oral Contraceptive‐Associated Sexual Dysfunction

IntroductionIt is a commonly held belief that combined oral contraceptive (COC) pills containing an androgenic progestin may be less likely to impair sexual function than COCs containing an anti‐androgenic progestin.AimThe study aims to compare the effects of a COC containing a progestin with an anti‐androgenic profile (estradiol valerate [E₂V]/dienogest [DNG]) to that of one with an androgenic progestin (ethinyl estradiol [EE]/levonorgestrel [LNG]) on sexual function in women with COC‐associated sexual dysfunction.MethodsIn this multicenter, randomized, double‐blind, noninferiority study, women with COC‐associated female sexual dysfunction (FSD) were randomized to E₂V/DNG or EE/LNG for six cycles. The primary outcome was the change in the sum of Female Sexual Function Index (FSFI) desire and arousal component scores between baseline and cycle 6. Secondary outcome measures included changes to the FSFI domains, the Female Sexual Distress Scale (FSDS‐R), Vaginal Health Assessment, the Atrophy Symptom Questionnaire, and the Psychological General Well Being Index over six treatment cycles.Main Outcome MeasureThe main outcome is the change in the sum of FSFI desire and arousal component scores between baseline and cycle 6.ResultsOf 276 women screened, 213 received treatment and 191 completed the study. The mean increase in the sum of FSFI desire and arousal component scores was 5.90 (standard deviation [SD] 5.45) for E₂V/DNG and 5.79 (SD 6.17) for EE/LNG (change from baseline P < 0.0001, both groups). Both treatments showed equal efficacy and were associated with improvements in all domains of the FSFI, with no between‐group differences. Both COCs reduced the distress associated with FSD, as indicated by reduced FSDS‐R scores.ConclusionIn women with COC‐associated FSD, switching to either E₂V/DNG or EE/LNG was associated with equivalent improvements in symptoms, challenging the perception that COCs containing anti‐androgenic progestins have a detrimental effect on sexual function relative to those containing androgenic progestins. Davis SR, Bitzer J, Giraldi A, Palacios S, Parke S, Serrani M, Mellinger U, and Nappi RE. Change to either a nonandrogenic or androgenic progestin‐containing oral contraceptive preparation is associated with improved sexual function in women with oral contraceptive‐associated sexual dysfunction. J Sex Med 2013;10:3069–3079.     

Poly(ADP‐Ribose) Polymerase Inhibition Improves Erectile Function by Activation of Nitric Oxide/Cyclic Guanosine Monophosphate Pathway in Diabetic Rats

IntroductionEndothelial dysfunction‐induced abnormalities of the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling pathway in the corpus cavernosum are thought to be the main factors involved in the pathogenesis of diabetes‐induced erectile dysfunction (ED). Recent studies have shown that the poly(adenosine diphosphate ribose) polymerase (PARP) pathway plays a critical role in diabetic endothelial dysfunction.AimThe aim of this study is to determine whether activation of the PARP pathway is involved in diabetic cavernosal endothelial dysfunction and abnormalities of the NO/cGMP pathway.MethodsMale Sprague‐Dawley rats were randomly divided into three groups: age‐matched controls, diabetic controls (DM), and the 3‐aminobenzamide (3‐AB, a PARP inhibitor)‐treated diabetic group (DM+3‐AB). Diabetes was induced by intraperitoneal injection of streptozotocin. Eight weeks after inducing diabetes, the DM+3‐AB group was treated with 3‐AB for 4 weeks.Main Outcome MeasuresErectile function was assessed at 12 weeks after inducing diabetes by stimulating the cavernous nerve. Expression of poly(ADP‐ribose), protein kinase B (Akt), phospho‐Akt, endothelial nitric oxide synthase (eNOS), phospho‐eNOS, and neuronal nitric oxide synthase (nNOS) were evaluated by Western blot. Cavernous NO generation and cGMP levels were also determined.ResultsThe DM group showed impaired erectile function and significantly increased PARP activity. Expression of total eNOS and nNOS, phospho‐Akt, and eNOS decreased significantly in the DM group compared with those in the control group. In addition, cavernous NO generation and cGMP levels decreased significantly in the DM group compared with those in the control group. Treatment with 3‐AB restored erectile function and significantly reversed all molecular alterations except decreased nNOS expression.ConclusionOveractivation of the PARP pathway in the corpus cavernosum of diabetic rats was involved in cavernosal endothelial dysfunction and abnormalities of the NO/cGMP pathway resulting in ED. These findings may be applied to develop novel therapies for patients with diabetic ED. Li WJ, Peng Y, Zhou J, Li B, Wang H, Zhang J, and Wang Z. Poly(ADP‐ribose) polymerase inhibition improves erectile function by activation of nitric oxide/cyclic guanosine monophosphate pathway in diabetic rats. J Sex Med 2012;9:1319–1327.     

Varicocele Is Associated with Erectile Dysfunction: A Population‐Based Case‐Control Study

IntroductionWhile many studies have been conducted investigating the efficacy of varicocele treatment on fertility, the literature is comparatively sparse concerning the association between varicocele, varicocelectomy, and erectile dysfunction (ED).AimThis study aimed to estimate the associations between varicocele, varicocelectomy, and ED using a population‐based dataset.MethodsThis study used data from the Longitudinal Health Insurance Database 2000 in Taiwan. A total of 32,856 cases and 98,568 randomly selected controls were included in this study. Conditional logistic regression analyses were used to examine associations between ED and having been previously diagnosed with varicocele or having underwent a varicocelectomy.Main Outcome MeasureThe odds of prior varicocele or having underwent a varicocelectomy between cases and controls.ResultsOf the sampled patients, the prevalence of prior varicocele was 3.3% and 1.2% for cases and controls, respectively (P < 0.001). Conditional logistic regression analysis suggested that the odds ratio (OR) of being previously diagnosed with varicocele for cases was 3.09 (95% confidence interval [CI] = 2.67–3.49) when compared with controls after adjusting for monthly income, geographic location, hypertension, diabetes, coronary heart disease, hyperlipidemia, hypogonadism, obesity, and alcohol abuse/alcohol dependence syndrome. Furthermore, cases were 1.92 (95% CI = 1.52–2.43) times more likely to have undergone a varicocelectomy than controls. Furthermore, subjects aged between 18 and 29 had the highest ORs for prior varicocele among cases when compared with controls (OR = 5.20; 95% CI = 3.27–8.28).ConclusionThis investigation succeeded in identifying an association between both varicocele and ED. We also realized that varicocele patients who underwent a varicocelectomy had lower magnitudes of association with ED than those who did not. Keller JJ, Chen Y‐K, and Lin H‐C. Varicocele is associated with erectile dysfunction: A population‐based case‐control study. J Sex Med 2012;9:1762–1769.     

Long‐Term Testosterone Treatment in Elderly Men with Hypogonadism and Erectile Dysfunction Reduces Obesity Parameters and Improves Metabolic Syndrome and Health‐Related Quality of Life

IntroductionLate‐onset hypogonadism (LOH) is diagnosed when declining testosterone concentrations in the aging male cause unwanted symptoms such as erectile dysfunction (ED), reduced bone density and muscle strength, and increased visceral obesity. Testosterone deficiency is also associated with insulin resistance and the metabolic syndrome (MetS). Restoring testosterone to physiological concentrations has beneficial effects on many of these symptoms; however, it is not known whether these effects can be sustained in the long term.AimsTo investigate whether treatment with testosterone undecanoate (TU) has a long‐term and sustained effect on parameters affected by the MetS in men with LOH and ED, to determine whether long‐term testosterone treatment can improve the overall health‐related quality of life in these men, and to establish the safety of long‐term testosterone treatment.MethodsTwo hundred sixty‐one patients (mean age 59.5 ± 8.4 years) diagnosed with LOH and ED were treated with long‐acting TU in a prospective, observational, and longitudinal registry study. Men received intramuscular injections of 1,000 mg TU at day 1, at week 6, and every 3 months thereafter.Main Outcome MeasuresParameters affected by the MetS, including obesity parameters (body weight, waist circumference, and body mass index [BMI]), total cholesterol, low‐density lipoprotein (LDL), high‐density lipoprotein (HDL), triglycerides, glucose, HbA_1c (glycated hemoglobin), and blood pressure, as well as total testosterone levels and health‐related quality of life, were assessed.ResultsWe found TU significantly improved obesity parameters (body weight, waist circumference, and BMI) and lowered total cholesterol, LDL cholesterol, triglycerides, fasting blood glucose, HbA_1c, and blood pressure over the 5‐year study. HDL cholesterol was increased. TU treatment resulted in a sustained improvement in erectile function and muscle and joint pain, which contributed to an improvement in long‐term health‐related quality of life. Furthermore, we found a relationship between health‐related quality of life and waist circumference. Finally, we found no evidence that long‐term treatment with TU increases the risk of prostate carcinoma.ConclusionLong‐term TU in men with LOH and ED reduces obesity parameters and improves metabolic syndrome and health‐related quality of life. Yassin DJ, Doros G, Hammerer PG, and Yassin AA. Long‐term testosterone treatment in elderly men with hypogonadism and erectile dysfunction reduces obesity parameters and improves metabolic syndrome and health‐related quality of life. J Sex Med 2014;11:1567–1576.     

Rapamycin Supplementation May Ameliorate Erectile Function in Rats With Streptozotocin–Induced Type 1 Diabetes by Inducing Autophagy and Inhibiting Apoptosis,Endothelial Dysfunction,and Corporal Fibrosis

Introduction

Erectile dysfunction (ED), which is common in patients with diabetes mellitus (DM), seriously affects quality of life. Previous studies on the treatment of DM–induced ED (DMED) involve autophagy, but the specific effect and mechanism of treatment are not yet clear.

TNF‐α, Erectile Dysfunction,and NADPH Oxidase‐Mediated ROS Generation in Corpus Cavernosum in High‐Fat Diet/Streptozotocin‐Induced Diabetic Rats

IntroductionPatients with diabetes‐associated erectile dysfunction (ED) are characterized by an increase in circulating tumor necrosis factor‐alpha (TNF‐α). However, no study has indicated whether and how TNF‐α plays a role in the pathogenesis of ED associated with diabetes.AimWe examined the effects and potential mechanism of infliximab (INF), a chimeric monoclonal antibody to TNF‐α, on reactive oxygen species (ROS) generation in corpus cavernosum and ED in diabetic rats.MethodsFour groups of male rats were used: age‐matched normal controls; diabetic rats induced by a high‐fat diet (HFD) combined with a single streptozotocin (STZ) injection (35 mg/kg body weight, intraperitoneal [i.p.]); nondiabetic rats receiving INF (5 mg/kg body weight/week, i.p.), and diabetic rats receiving INF. Erectile function was assessed with electrical stimulation of the cavernous nerve after 8 weeks. The blood and penile tissues were harvested for plasma biochemical determinations, serum TNF‐α measurement, penile ROS detection, and molecular assays of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, endothelial nitric oxide synthase (eNOS), phospho‐eNOS, and neural nitric oxide synthase (nNOS) in the penis.Main Outcome MeasuresThe effect of INF on HFD/STZ‐induced diabetic ED and NADPH oxidase‐mediated ROS generation was studied in diabetic corpus cavernosum.ResultsUntreated diabetic rats displayed significantly decreased erectile parameters, and increased plasma TNF‐α levels, penile ROS production, p47^phox and gp91^phox expression compared with nondiabetic controls. INF neutralized TNF‐α and significantly reduced ED in diabetic rats, in which marked decreases in p47^phox and gp91^phox expression and ROS generation in corpus cavernosum were noted. The ratio of phospho‐eNOS to eNOS and expression of nNOS in the penis were significantly increased in INF‐treated vs. untreated diabetic rats.ConclusionsIncreased TNF‐α expression associated with diabetes contributes to ED by promoting NAPDH oxidase‐mediated ROS generation in corpus cavernosum. INF protects against diabetic ED by neutralizing TNF‐α. Long T, Liu G, Wang Y, Chen Y, Zhang Y, and Qin D. TNF‐α, erectile dysfunction, and NADPH oxidase‐mediated ROS generation in corpus cavernosum in high‐fat diet/streptozotocin‐induced diabetic rats. J Sex Med 2012;9:1818–1831.     

The Self‐Estimation Index of Erectile Function‐No Sexual Intercourse (SIEF‐NS): A Multidimensional Scale to Assess Erectile Dysfunction in the Absence of Sexual Intercourse

IntroductionA new concept of Erectile Dysfunction with No Sexual Intercourse (ED‐NS) is proposed to acknowledge the subpopulation of patients who are unable to achieve or sustain an erection in the absence of sexual intercourse. Since the commonly used ED diagnostic tool, International Index of Erectile Function Questionnaire is not able to adequately assess the erectile function (EF) in the absence of intercourse, the researchers developed a new 10‐item questionnaire to better evaluate the EF in this special patient subpopulation: Self‐Estimation Index of Erectile Function‐No Sexual Intercourse (SIEF‐NS).AimTo validate the reliability, sensitivity and specificity of SIEF‐NS.MethodsThe study was carried out in three phases. Phase one applied component analysis to 126 ED‐NS patients to search for the primary factors and Cronbach's alpha standardized statistic values for SIEF‐NS. Phase two applied discriminant analysis to participants' (212 ED‐NS patients and 193 normal controls) scores on each question item, each factor and the overall 10‐item questionnaire. Phase three investigated SIEF‐NS's capability of evaluating treatment effect on 41 ED‐NS patients.Main Outcome MeasuresReliability, sensitivity and specificity were defined and used to evaluate the performance of SIEF‐NS.ResultsEF by autonomic response (factor 1) and EF with potential sexual partners (factor 2) are the two primary factors with eigenvalues greater than 1.0. High degree of internal consistency was observed for the two factors and the 10‐item questionnaire (Cronbach's alpha values: 0.871 for 10 items, 0.84 for factor 1, and 0.823 for factor 2). SIEF‐NS demonstrated adequate construct validity, high sensitivity (0.925) and specificity (0.829) to diagnose ED‐NS. The EF scores of ED‐NS patients post treatment showed significant improvement (P < 0.05).ConclusionSIEF‐NS can be used to identify ED‐NS patients and detect treatment‐related EF changes in ED‐NS patients. Yuan Y, Zhang Z, Gao B, Peng J, Cui W, Song W, Xin Z, and Guo Y. The Self‐Estimation Index of Erectile Function‐No Sexual Intercourse (SIEF‐NS): A multidimensional scale to assess erectile dysfunction in the absence of sexual intercourse. J Sex Med 2014;11:1201–1207.     

Adrenomedullin and Angiopoietin‐1 Additively Restore Erectile Function in Diabetic Rats: Comparison with the Combination Therapy of Vascular Endothelial Growth Factor and Angiopoietin‐1

IntroductionErectile dysfunction (ED) is a major health problem. We have shown that adrenomedullin (AM) restores erectile function in diabetic rats.AimThe aim of this study is to explore a better treatment for ED, we examined whether combination of AM and angiopoietin‐1 (Ang‐1) was more effective to treat ED than treatment with AM alone or Ang‐1 alone. We also compared the effect of the combination therapy with that of treatment with vascular endothelial growth factor‐A (VEGF‐A).MethodsMale Wistar rats were injected with streptozotocin (STZ) to induce diabetes. Adenoviruses expessing AM (AdAM), Ang‐1 (AdAng‐1), and VEGF‐A (AdVEGF‐A) were injected into the penis 6 weeks after STZ administration. Erectile function, penile histology, and protein expression were analyzed 4 weeks after the injection of the adenoviruses.Main Outcome MeasuresIntracavernous pressure and mean arterial pressure were measured to evaluate erectile function. The morphology of the penis was analyzed by Elastica van Gieson stain and immunohistochemistry. The expression of α‐smooth muscle actin (SMA), VE‐cadherin and type I collagen was assessed by Western blot analysis.ResultsInfection with AdAM plus AdAng‐1 more effectively restored erectile function than infection with AdAM alone or AdAng‐1 alone. This combination therapy restored erectile function to a level similar to that observed in the age‐matched Wistar rats. Expression of SMA and VE‐cadherin increased more significantly in the AdAM plus AdAng‐1‐treated group than in the AdAM‐ or AdAng‐1‐treated group. Although AdVEGF‐A infection restored erectile function significantly, it also caused enlargement of the trabeculae of the cavernous body, aberrant angiogenesis, and overproduction of type I collagen.ConclusionsThese results suggested that combination therapy with AM and Ang‐1 potently restored erectile function and normal morphology of the cavernous body compared with VEGF‐A administration. This combination therapy will be useful to treat ED patients with a severely damaged cavernous body. Nishimatsu H, Suzuki E, Nomiya A, Niimi A, Suzuki M, Fujimura T, Fukuhara H, and Homma Y. Adrenomedullin and angiopoietin‐1 additively restore erectile function in diabetic rats: Comparison with the combination therapy of vascular endothelial growth factor and angiopoietin‐1. J Sex Med **;**:**–**.     

The Identification of Prediabetes Condition with ARIC Algorithm Predicts Long‐Term CV Events in Patients with Erectile Dysfunction

IntroductionThe Atherosclerosis Risk in Communities (ARIC) algorithm is one of the most efficient instruments for the prediction of incident type 2 diabetes. Recently, it has been shown to predict another relevant cardiovascular (CV) risk factor, such as chronic kidney disease.AimTo verify whether, in patients with erectile dysfunction (ED), the use of ARIC diabetes risk score might improve the efficacy in predicting major CV events of other CV risk algorithms specifically developed for the assessment of CV risk.MethodsA consecutive series of 2,437 men (mean age 52.5 ± 12.9 years) attending our outpatient clinic for sexual dysfunction was retrospectively studied. A subset of this sample (N = 1,687) was enrolled in a longitudinal study (mean follow‐up of 4.3 ± 2.6 years).Main Outcome MeasuresThe assessment of metabolic risk was evaluated with the ARIC algorithm. The assessment of CV risk was evaluated using the Progetto Cuore risk engine.ResultsIn the cross‐sectional study, ARIC score was inversely related with testosterone levels, sexual functioning, and penile blood flow. When longitudinal sample was analyzed, higher baseline ARIC score significantly predicted major adverse cardiovascular event (MACE) even when subjects with diabetes mellitus at baseline were excluded from the analysis (hazard ratio = 1.522 [1.086–2.135]; P = 0.015 for trend). In addition, among subjects classified as “low risk” (CV risk <20% at 10 years corresponding to <9% at 4.3 years) by Progetto Cuore, a receiving operating curve (ROC) analysis for ARIC (vs. MACE) allowed the identification of a threshold of 0.22, which had a positive predictive value for 4.3‐year MACE of 9%. Applying the ARIC score (with a threshold of 0.22) to Progetto Cuore “low‐risk” subjects, we could classify as “at high risk” 89.8% of subjects with incident MACE vs. 79.6% with Progetto Cuore only.ConclusionsIn patients with ED, identifying prediabetes, even with algorithms, predicts long‐term CV events.     

Nitric Oxide‐Releasing Polymeric Microspheres Improve Diabetes‐Related Erectile Dysfunction

IntroductionWe have used a long‐acting nitric oxide (NO)‐releasing polymer to develop injectable biodegradable microspheres capable of localized NO release over prolonged periods of time.AimThe aim of this study was to evaluate the therapeutic potential of these microspheres for diabetes‐related erectile dysfunction (ED) in the rat model.MethodsNO‐releasing microspheres were incubated in physiologic buffer, and in vitro NO release was measured using a Griess assay. To ensure no migration, microspheres were fluorescently tagged and injected into the corpus cavernosum of adult rats, and fluorescent imaging was performed weekly for 4 weeks, at which point rats were sacrificed. To assess physiologic efficacy, diabetes was induced in 40 rats using streptozotocin (STZ), whereas 10 rats were kept as age‐matched controls. Diabetic rats were divided into four groups: no treatment, sildenafil, NO‐releasing microspheres, and combination therapy. For each rat, the cavernosal nerve (CN) was stimulated at various voltages, and intracavernosal pressure (ICP) and mean arterial pressure (MAP) were measured via corpus cavernosum and carotid artery catheterization, respectively. Long‐term efficacy was determined by injecting diabetic rats with microspheres and measuring erectile response at predetermined intervals for up to 5 weeks.Main Outcome MeasuresErectile response was determined via calculation of mean peak ICP/MAP and area under curve (AUC) for each experimental group.ResultsUnder physiologic conditions in vitro, microspheres continued NO release for up to 4 weeks. Fluorescent imaging revealed no detectable signal in tissues besides cavernosal tissue at 4 weeks postinjection. Upon CN stimulation, peak ICP/MAP ratio and AUC of diabetic rats improved significantly (P < 0.05) in microsphere and combination therapy groups compared with no treatment and sildenafil groups. In long‐term efficacy studies, microspheres augmented the effect of sildenafil for 3 weeks following injection (P < 0.05).ConclusionsNO‐releasing microspheres significantly improved erectile response in diabetic rats for 3 weeks and hence offer a promising approach to ED therapy, either as monotherapy or combination therapy. Soni SD, Song W, West JL, and Khera M. Nitric oxide‐releasing polymeric microspheres improve diabetes‐related erectile dysfunction. J Sex Med 2013;10:1915‐1925.     

PDEI‐5 for Erectile Dysfunction: A Potential Role in Seizure Susceptibility

IntroductionThere is a high prevalence of erectile dysfunction (ED) in men with epilepsy; however, few studies have been conducted concerning the treatment of ED in this neurological group.AimThe main purpose of this review is to highlight the influence of phosphodiesterase type 5 inhibitor (PDEI‐5) for ED on seizure susceptibility.MethodsAll available online articles with information pertaining to PDEI‐5 and seizure susceptibility were included in this review.Main Outcome MeasuresThe main outcome assessed demonstrated the intriguing role of PDEI‐5 and its metabolites on seizure susceptibility.ResultsCase reports in men without epilepsy described seizure occurrence and electrophysiological changes following sildenafil, tadalafil, or vardenafil treatment. Consistent with these findings, preclinical studies suggested a proconvulsant effect of PDEI‐5 on models of seizure induction.ConclusionsEvidence suggests an influence of PDEI‐5 on seizure susceptibility in humans. In addition, preclinical studies have demonstrated the role of nitric oxide metabolites in the facilitation of paroxysmal phenomenon. Although there are many causes of seizures, medical professionals should be aware of the possible influence of PDEI‐5 on seizure susceptibility. Further investigation by physicians and scientists is required to improve our understanding of this important topic. Matos G, Scorza FA, Cavalheiro EA, Tufik S, and Andersen ML. PDEI‐5 for erectile dysfunction: A potential role in seizure susceptibility. J Sex Med 2012;9:2111–2121.     

Assessment of Androgen Replacement Therapy for Erectile Function in Rats with Type 2 Diabetes Mellitus by Examining Nitric Oxide‐Related and Inflammatory Factors

IntroductionType 2 diabetes mellitus (T2DM) has become a major public health issue and is considered a risk factor for erectile dysfunction (ED). T2DM is also associated with androgen deficiency. However, there have been few basic studies on androgen replacement therapy (ART) for ED treatment in T2DM animal models, and the mechanism underlying the effect of ART on T2DM‐induced ED is unclear.AimTo investigate the effect of ART on ED in T2DM rats by examining inflammatory and nitric oxide (NO)‐related factors.MethodsOtsuka Long‐Evans Tokushima Fatty (OLETF) rats and their controls, Long‐Evans Tokushima Otsuka (LETO) rats, were distributed into three groups: LETO, OLETF, and ART. In the ART group, OLETF rats were treated daily with testosterone (3 mg/kg/day, subcutaneously) from 20 to 25 weeks of age; LETO and OLETF rats received vehicle only.Main Outcome MeasuresWe measured erectile function by using measurements of the ratio between intracavernosal pressure (ICP) and mean arterial pressure (MAP) following electrical stimulation of the cavernous nerve and by evaluating the endothelial function of the corpus cavernosum in an isometric tension study. Expression of endothelial NO synthase (eNOS), inducible NO synthase (iNOS), sirtuin‐1 (Sirt1), interleukin‐6 (IL‐6), and tumor necrosis factor alpha (TNF‐α) mRNA was detected using polymerase chain reaction.ResultsThe ICP/MAP ratio in the OLETF group was significantly decreased and that in the ART group was significantly improved (P < 0.01). The response to acetylcholine was significantly decreased in the OLETF group and improved in the ART group (P < 0.01). Although expression of eNOS and Sirt1 mRNA was decreased and that of iNOS, IL‐6, and TNF‐α mRNA was increased in the OLETF group, ART improved mRNA expression.ConclusionsART suppressed inflammation in rats with T2DM and metabolic disorders and improved their endothelial and erectile functions. ART could be effective for T2DM‐induced ED and may be considered a potential ED treatment method. Kataoka T, Hotta Y, Maeda Y, and Kimura K. Assessment of androgen replacement therapy for erectile function in rats with type 2 diabetes mellitus by examining nitric oxide‐related and inflammatory factors. J Sex Med 2014;11:920–929.     

Erectile Function Is Improved in Aged Rats by PnTx2‐6, a Toxin from Phoneutria nigriventer Spider Venom

IntroductionAge‐associated erectile dysfunction (ED) involves a decrease in nitric oxide (NO) availability and impaired relaxation. PnTx2‐6, a toxin from the Phoneutria nigriventer spider, has been demonstrated to improve erectile function via NO/cyclic guanosine monophosphate (cGMP) pathway. This spider's venom is characterized by several symptoms, including erection. PnTx2‐6 has been implicated in this phenomenon. Animal venoms have been postulated as potential drugs to treat ED.AimPnTx2‐6 toxin improves erectile function in aged rats via NO/cGMP. We investigated the effect of PnTx2‐6 in the erectile function of aged rats.Main Outcome MeasuresED was evaluated through changes in intracavernosal pressure/mean arterial pressure ratio during electrical field stimulation (EFS) of the pelvic ganglion of aged and adult rats (70 vs. 14 weeks). In functional studies, EFS‐induced relaxation of corpus cavernosum (CC) strips were performed with or without PnTx2‐6 (10‐8M).ResultsThe decrease in erectile function associated with age was partially restored 15–20 minutes after injection of PnTx2‐6 and further improved by sildenafil. PnTx2‐6 enhanced EFS‐induced relaxation, as well as cGMP levels in CC, from young and aged rats. Relaxation due to PnTx2‐6 was further increased after 30 minutes incubation with Y‐27632, a Rho‐kinase inhibitor (10‐6 M), in aging CC. Nitric oxide synthase (NOS) activity in aged and young cavernosal tissue was increased by incubation with PnTx2‐6 (10 minutes). However, this toxin did not modify NOS expression.ConclusionPnTx2‐6 improves penile relaxation in aged rats, via increased NOS activity and NO release, resulting in enhanced cGMP levels. Nunes KP, Toque HA, Borges MH, Richardson M, Webb RC, and de Lima ME. Erectile function is improved in aged rats by PnTx2‐6, a toxin from Phoneutria nigriventer spider venom. J Sex Med **;**:**–**.