Caveolin-1 scaffolding domain-derived peptide enhances erectile function by regulating oxidative stress, mitochondrial dysfunction, and apoptosis of corpus cavernosum smooth muscle cells in rats with cavernous nerve injury.

AIM: Increased corpus cavernosum smooth muscle cells (CCSMCs) apoptosis in the penis due to cavernous nerve injury (CNI) is a crucial contributor to erectile dysfunction (ED). Caveolin-1 scaffolding domain (CSD)-derived peptide has been found to exert potential antiapoptotic properties. However, whether CSD peptide can alleviate CCSMCs apoptosis and ED in CNI rats remains unknown. The study aimed to determine whether CSD peptide can improve bilateral CNI-induced ED (BCNI-ED) by enhancing the antiapoptotic processes of CCSMCs. MAIN METHODS: Fifteen 10-week-old male Sprague-Dawley (SD) rats were randomly classified into three groups: sham surgery (Sham) group and BCNI groups that underwent saline or CSD peptide treatment respectively. At 3 weeks postoperatively, erectile function was assessed and the penis tissue was histologically examined. Furthermore, an in vitro model of CCSMCs apoptosis was established using transforming growth factor-beta 1 (TGF-ß1) to investigate the mechanism of CSD peptide in treating BCNI-ED. KEY FINDINGS: In BCNI rats, CSD peptide significantly prevented ED and decreased oxidative stress, the Bax/Bcl-2 ratio, and the levels of caspase3. TGF-ß1-treated CCSMCs exhibited severe oxidative stress, mitochondrial dysfunction, and apoptosis. However, CSD peptide partially reversed these alterations. SIGNIFICANCE: Exogenous CSD peptide could improve BCNI-ED by inhibiting oxidative stress, the Bax/Bcl-2 ratio, and caspase3 expression in penile tissue. The underlying mechanism might involve the regulatory effects of CSD peptide on oxidative stress, mitochondrial dysfunction, and apoptosis of CCSMCs following CNI. This study highlights CSD peptide as an effective therapy for post-radical prostatectomy ED (pRP-ED).

A novel reuptake inhibitor, IP2015, induces erection by increasing central dopamine and peripheral nitric oxide release.

BACKGROUND AND PURPOSE: An estimated 40% of patients with erectile dysfunction have a poor prognosis for improvement with currently available treatments. The present study investigated whether a newly developed monoamine transport inhibitor, IP2015, improves erectile function. EXPERIMENTAL APPROACH: We investigated the effects of IP2015 on monoamine uptake and binding, erectile function in rats and diabetic mice and the effect on corpus cavernosum contractility. KEY RESULTS: IP2015 inhibited the uptake of 5-HT, noradrenaline and dopamine by human monoamine transporters expressed in cells and in rat brain synaptosomes. Intracavernosal pressure measurement in anaesthetized rats revealed that IP2015 dose-dependently increased the number and the duration of spontaneous erections. Whereas pretreatment with the dopamine D2-like receptor antagonists, clozapine and (-)-sulpiride, or cutting the cavernosal nerve inhibited IP2015-induced erectile responses, the phosphodiesterase type 5 inhibitor sildenafil further enhanced the IP2015-mediated increase in intracavernosal pressure. IP2015 also increased the number of erections in type 2 diabetic db/db mice. Direct intracavernosal injection of IP2015 increased penile pressure, and in corpus cavernosum strips, IP2015 induced concentration-dependent relaxations. These relaxations were enhanced by sildenafil and blunted by endothelial cell removal, a nitric oxide synthase inhibitor, NG-nitro-l-arginine and a D1-like receptor antagonist, SCH23390. Quantitative polymerase chain reaction (qPCR) showed the expression of the dopamine transporter in the rat corpus cavernosum. CONCLUSION AND IMPLICATIONS: Our findings suggest that IP2015 stimulates erectile function by a central mechanism involving dopamine reuptake inhibition and direct NO-mediated relaxation of the erectile tissue. This novel multi-modal mechanism of action could offer a new treatment approach to erectile dysfunction.

Safety and efficacy of botulinum neurotoxin in the treatment of erectile dysfunction refractory to phosphodiesterase inhibitors: Results of a randomized controlled trial.

BACKGROUND: There has been recent interest in the use of botulinum neurotoxin (BoNT) in the field of Andrology, whereby it has been investigated in the treatment of penile retraction and premature ejaculation. OBJECTIVES: To evaluate the safety and efficacy of intracavernosal BoNT-A injection in the treatment of patients with erectile dysfunction (ED) refractory to oral phosphodiesterase inhibitors (PDE5Is). PATIENTS AND METHODS: A double-blind randomized placebo-controlled prospective comparative study conducted at one center and involved 70 patients with ED refractory to PDE5Is. At baseline, the following data were collected: erection hardness score (EHS), peak systolic velocity (PSV), end diastolic velocity (EDV), sexual health inventory for men (SHIM), and the sexual encounter profile 2&3 (SEP-2&3) questionnaires. Treatment group (n = 35) received a single ICI of 100 units of BoNT-A in 2 ml of saline and control group (n = 35) received a single ICI of 2 ml of saline. EHS, PSV, and EDV were assessed at 2 weeks post treatment. SHIM, SEP-2, SEP-3, and global assessment questionnaire (GAQ-Q1&Q2) were completed at 2-, 6-, and 12-weeks post treatment. RESULTS: Two weeks post treatment, the treatment group showed a statistically significant improvement in the mean EHS, PSV, EDV, and GAQ-Q1 positive responders (p < 0.001) compared to the control group. At 6- and 12-weeks post treatment, the treatment group showed a statistically significant improvement in the SHIM scores, SEP-2, and GAQ-Q1&Q2 positive responders compared to the control group. At 6 weeks, where there was a 5-point improvement in the mean SHIM score of the treatment group (10±5.9 from 5.4±1.7 at baseline) versus no improvement in the placebo group, 18 patients in the treatment group (53%) were able to have an erection hard enough for vaginal penetration versus only one patient in the control group. CONCLUSION: BoNT-A is safe and effective as a potential treatment for ED refractory to PDE5I therapy.

Restoration of erectile function by a combination of antiapoptosis by JNK inhibitor and preservation of smooth muscle or endothelium by hepatocyte growth factor in a rat model of cavernous nerve injury.

BACKGROUND: Because of structural alterations in the corpus cavernosum after radical prostatectomy (RP), post-RP erectile dysfunction remains a very difficult condition to treat. We aimed to determine if the combined administration of a Jun-amino terminal kinase (JNK) inhibitor and hepatocyte growth factor (HGF) in the immediate post-injury period would restore erectile function by antiapoptotic and pro-regenerative effects through the rectification of molecular pathways related to the structural integrity of the penis in a rat model of bilateral cavernosal nerve crush injury (CNCI). METHODS: A total of 70 rats were divided into five groups: Sham surgery (S), CNCI (I), and once-daily intraperitoneal administration of 10.0 mg/kg JNK inhibitor + twice-weekly intracavernosal administration of low-dose (2.1 µg), medium-dose (4.2 µg), or high-dose (8.4 µg) HGF (I + J + LH or I + J + MH or I + J + HH, respectively) in the immediate post-injury period. Erectile responses to electrostimulation (1.0, 3.0, and 5.0 V), histological staining, caspase-3 activity, and Western blotting were evaluated 9 days after surgery. RESULTS: Group I showed lower intracavernosal pressure (ICP)/mean arterial pressure (MAP) after stimulation at each voltage, lower area under the curve (AUC)/MAP after stimulation at each voltage, less smooth muscle (SM) content, a lower SM/collagen ratio, higher caspase-3 activity, increased cJun phosphorylation, decreased protein expression of PECAM-1, decreased cMet phosphorylation, and decreased endothelial nitric oxide synthase (eNOS) phosphorylation compared to Group S. The SM content, SM/collagen ratio, protein expression of ICP/MAP, or AUC/MAP after stimulation at each voltage in Group I + J + LH were partially restored, despite the normalization of cJun phosphorylation and caspase-3 activity. The ICP/MAP, AUC/MAP, caspase-3 activity, SM content, protein expression of PECAM-1, cJun phosphorylation, cMet phosphorylation, and eNOS phosphorylation in both Groups I + J + MH and I + J + HH were restored to the levels observed in Group S, while the SM/collagen ratio was significantly improved but not completely normalized. CONCLUSIONS: Our data indicated that the combined administration of a JNK inhibitor and medium or high-dose HGF to nerve-injured rats in the immediate post-injury period after CNCI may restore erectile function to a level comparable to the normal level by suppressing cavernosal apoptosis and preserving the integrity of SM or endothelium via rectification of the cJun and cMet/eNOS pathways.

Mechanism by which Huoxue Tongluo Qiwei Decoction improves the erectile function of rats with diabetic erectile dysfunction.

ETHNOPHARMACOLOGICAL RELEVANCE: Huoxue Tongluo Qiwei Decoction is a classical herbal formula, which can improve the symptoms of erectile dysfunction (ED) patients and has a good therapeutic effect on patients with diabetic erectile dysfunction (DIED). The main function of Huoxue Tongluo Qiwei Decoction is to stimulate the blood circulation and dredge collaterals, remove blood stasis, and calm wind. RATIONALE: To further explore the mechanism of Huoxue Tongluo Qiwei Decoction in the treatment of DIED, related animal experiments were designed. MATERIALS AND METHODS: The chemical constituents of Huoxue Tongluo Qiwei Decoction were identified with the help of high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). A rat model was induced by streptozotocin (STZ) and screened by apomorphine (APO). Serum sE-selectin, lysyl oxidase-1 (LOX-1), malondialdehyde (MDA) and other markers of vascular endothelial injury and related indicators of oxidative stress were studied through enzyme-linked immunosorbent assay (ELISA). The endothelial cells and ultrastructure of the corpus cavernosum were examined by electron microscopy and HE staining. The expression of protein and mRNA was detected by western blotting (WB) and real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: The results of the study revealed that the sE-selectin, LOX-1, intercellular adhesion molecule-1 (sICAM-1), endothelial microparticles (EMPs), P-selectin (CD62P), and MDA levels in the serum of group M rats were considerably higher than rats of group K, while the superoxide dismutase (SOD) level showed a significant decrease. In addition, the PKC pathway was activated, and the expression of related proteins and mRNA was increased. After 8 weeks of intervention with Huoxue Tongluo Qiwei Decoction and LY333531, serum level of sE-selectin, LOX-1, sICAM-1, EMPs, CD62P and MDA in L, D and G groups were remarkably lower than group M while SOD level increased significantly, protein kinase C (PKC) pathway was inhibited with the improved erectile function of rats. CONCLUSION: Huoxue Tongluo Qiwei Decoction can inhibit the expression of protein and mRNA of the PKCß signaling pathway related molecules in DIED rats to cure the injury of vascular endothelial, enhance antioxidant capacity, and prevent the activation of platelet, thus improving erectile function in rats with DIED.

Prolonged isoflurane anesthesia-induced acidosis decreases penile intracavernous pressure in rats.

BACKGROUND: Intracavernous pressure measurement following cavernous nerve electrostimulation has been extensively adopted for the evaluation of erectile function in animals. However, the effect of measurement time and acidosis during anesthesia is still lacking. OBJECTIVE: To explore the effect of measurement time and acidosis during anesthesia. MATERIALS AND METHODS: Fifty-six male Sprague-Dawley rats were used and anesthetized by a spontaneous inhalation of isoflurane. In the first step, rats were randomly divided into four groups: a control group and three time-delayed measurement groups (intracavernous pressure measurement beginning at 15, 30, and 45 min after cavernous nerve exposure). In the second step, rats were randomly divided into three groups: a control group and two time-delayed measurement groups. Two intravenous fluid support strategies were used in time-delayed measurement groups: a normal saline solution and an isotonic Na2 CO3 solution. RESULTS: Isoflurane-anesthetized rats developed systemic acidosis that worsens with time during intracavernous pressure measurement, which results in a significant decrease in the maximum intracavernous pressure value, intracavernous pressure/mean arterial pressure ratio, and total intracavernous pressure measured. The Na2 CO3 infusion could effectively correct acidosis. The decrease in intracavernous pressure was related to the reduced nitric oxide synthase activity, decreased cyclic guanosine monophosphate concentration, and reactive oxygen species activation in rat penis under acidosis conditions. DISCUSSION AND CONCLUSION: Prolonged isoflurane anesthesia-induced acidosis markedly depresses the erectile response to cavernous nerve electrostimulation in rats. In this situation, it is recommended to supplement with a Na2 CO3 infusion to maintain a normal acid-base balance.

Influence of anticancer agents on sexual function: An in vivo study based on the US FDA Adverse Event Reporting System.

BACKGROUND: Patients with cancer are treated with chemotherapeutics that cause adverse effects, including erectile dysfunction (ED). OBJECTIVES: We investigated erectile function in rats after the administration of anticancer agents based on data retrieved through mining of the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) database. MATERIALS AND METHODS: The statistical signal strength for the association between anticancer drugs and ED was calculated using the reporting odds ratio (ROR). A drug-event combination was detected when the lower limit of the 95% confidence interval (CI) of the ROR exceeded 1.00. Rats were administered anticancer agents detected in the FDA AERS analysis. Erectile function was assessed using intracavernous pressure (ICP) and mean arterial pressure (MAP) analysis after electrical stimulation of the cavernous nerve. Statistical significance was determined using Welch's t-test or two-way ANOVA. RESULTS: Melphalan (L-PAM; ROR = 4.72, 95% CI = 2.78-8.00), vincristine (VCR; ROR = 2.47, 95% CI = 1.54-3.97), docetaxel (DTX; ROR = 2.25, 95% CI = 1.28-3.95), methotrexate (MTX; ROR = 1.96, 95% CI = 1.39-2.75), and doxorubicin (DOX; ROR = 1.82, 95% CI = 1.07-3.19) enhanced ED risk. L-PAM and MTX decreased the ICP/MAP ratio 1 week after administration. VCR and DOX decreased erectile function 4 weeks after administration. DTX decreased erectile function at all assessed time points. DISCUSSION AND CONCLUSION: Certain anticancer agents should be considered risk factors for ED. Our results provide possible treatment strategies for maintaining erectile function in cancer survivors, including careful erectile function monitoring after treatment.

Efficacy Evaluation of Plant Products in the Treatment of Erectile Dysfunction Related to Diabetes.

Erectile dysfunction affects more than 50% of diabetic male patients, with a higher prevalence compared with the general population. Age, clinical factors, and lifestyle habits have been suggested to contribute to the pathophysiology and worsening of erectile dysfunction in diabetic patients. First- and second-line standard treatments are represented by phosphodiesterase type 5 (PDE5) inhibitors and alprostadil, respectively. However, natural compounds have been suggested to ameliorate this clinical condition. This study aims to preclinically characterize the potential synergism among plant-derived products for the improvement of erectile dysfunction in the diabetic condition. The effects of a nutritional supplement composed of Panax ginseng, Moringa oleifera and rutin, as single agents or as a mixture, were evaluated in a streptozotocin (STZ)-induced diabetic rat model with erectile dysfunction. The treatment efficacy was evaluated by measuring sexual-related parameters (i.e., mount and intromission latencies, the mount and intromission frequencies and the ejaculation latency). Results showed that only the mixture was able to significantly reduce the diabetes-related delay in mount latency (p < 0.01). Substantial similar effects were observed by measuring the intromission latency and the mean number of mounts was very similar between rats treated with the mixture and controls. Single agent treatments showed very low effects in terms of intromission frequency, whereas the mixture was able to increase this parameter. Additionally, a statistically significant reduced ejaculation latency was observed in rats treated with the mixture compared with the STZ control. These results are in agreement with the available literature and suggest that the study mixture may ameliorate sexual behavior compared with the administration of the study natural compounds as single agents in diabetic rats. Further preclinical and clinical studies are needed to perform a more comprehensive evaluation of the efficacy and safety of the study mixture.

Combination Therapy with a JNK Inhibitor and Hepatocyte Growth Factor for Restoration of Erectile Function in a Rat Model of Cavernosal Nerve Injury: Comparison with a JNK Inhibitor Alone or Hepatocyte Growth Factor Alone.

We determined if combined administration of JNK-inhibitors and HGF (hepatocyte-growth-factor) would restore erectile-function through both antiapoptotic and regenerative effects in a rat model of cavernous-nerve-crush-injury (CNCI), and compared the results with administration of JNK-inhibitor alone or HGF alone. We randomized 70 rats into 5 groups: sham-surgery-group (S), CNCI (I) group, a group treated with once-daily intraperitoneal-administration of 10.0-mg/kg of JNK-inhibitors (J), a twice-weekly intracavernosal-administration of 4.2-µg HGF group (H), and a combined-treatment with 10.0-mg/kg JNK-inhibitors and 4.2-µg HGF group (J+H). We investigated erectile-responses to electrostimulation, histological-staining, caspase-3-activity-assay, and immunoblotting at two-weeks postoperatively. The three treatment groups showed improvements in erectile-responses (ICP/MAP and AUC/MAP ratios) compared to Group-I. The erectile-responses in Group-J+H were greater than those in Group-J or Group-H. The erectile-responses in Group-J+H were generally normalized. Caspase-3-activity and cJun-phosphorylation in Group-J and Group-J+H improved compared to Group-I, whereas caspase-3-activity in Group-H partially improved. Protein-expression of PECAM-1, eNOS-phosphorylation, and smooth-muscle content in Group-J+H were normalized, although those in Group-J or Group-H were partially restored. Combination therapy with JNK-inhibitors and HGF can generally normalize erectile-function through anti-apoptosis and preservation of endothelium or SM in rat CNCI model. The combined treatment appears to be superior to the respective agent alone in terms of therapeutic effects.

Ageing-induced hypercontractility is related to functional enhancement of STIM/Orai and upregulation of Orai 3 in rat and human penile tissue.

The role of STIM/Orai calcium entry system on vascular ageing has not been elucidated. We aimed to evaluate the influence of ageing on STIM/Orai signalling and its role on ageing-induced alterations of contractile function in rat corpus cavernosum (RCC) and human penile resistance arteries (HPRA) and corpus cavernosum (HCC). RCC was obtained from 3 months-old and 20 months-old animals. HPRA and HCC were obtained from organ donors of varied ages without history of erectile dysfunction. Aging was associated with enhanced norepinephrine (NE)- and thromboxane analogue (U46619)-induced contractions in RCC which were significantly inhibited by the STIM/Orai inhibitor, YM-58483 (20 µM). Other STIM/Orai inhibitor, 2-aminoethyldiphenylborate also reduced NE-induced contractions in RCC from aged rats. YM-58483 significantly reduced neurogenic contractions and potentiated neurogenic relaxations in RCC from aged rats. In HCC and HPRA, NE-induced contractions were significantly enhanced in older subjects (>65 years-old) but YM-58483 completely reversed ageing-related hypercontractility. Ageing did not modify STIM-1 and Orai1 protein expressions but Orai3 was significantly overexpressed in cavernosal tissue from old rats and older subjects. Contribution of STIM/Orai to cavernosal contraction increases with ageing together with increased expression of Orai3. Orai inhibition could be a potential therapeutic strategy to reduce ageing-related impact on vascular/erectile function.

Ex vivo Akt inhibition reverses castration induced internal pudendal artery and penile endothelial dysfunction.

AIMS: Androgen deprivation therapy is a common prostate cancer treatment which causes men to have castrate levels of testosterone. Unfortunately, most testosterone deficient patients will suffer severe erectile dysfunction (ED) and have no effective ED treatment options. Testosterone deficiency causes endothelial dysfunction and impairs penile vasodilation necessary to maintain an erection. Recent evidence demonstrates testosterone activates androgen receptors (AR) and generates nitric oxide (NO) through the Akt-endothelial NO synthase (eNOS) pathway; however, it remains unknown how castration impacts this signaling pathway. MATERIALS AND METHODS: In this study, we used a surgically castrated rat model to determine how castration impacts ex vivo internal pudendal artery (IPA) and penile relaxation through the Akt-eNOS pathway. KEY FINDINGS: Unlike systemic vasculature, castration causes significant IPA and penis endothelial dysfunction associated with a 50% AR reduction. Though testosterone and acetylcholine (ACh) both phosphorylate Akt and eNOS, castration did not affect testosterone-mediated IPA and penile Akt or eNOS phosphorylation. Surprisingly, castration increases ACh-mediated Akt and eNOS phosphorylation but reduces the eNOS dimer to monomer ratio. Akt inhibition using 10DEBC preserves IPA eNOS dimers. Functionally, 10DEBC reverses castration induced ex vivo IPA and penile endothelial dysfunction. SIGNIFICANCE: These data demonstrate how castration uncouples eNOS and provide a novel strategy for improving endothelial-dependent relaxation necessary for an erection. Further studies are needed to determine if Akt inhibition may treat or even prevent ED in testosterone deficient prostate cancer survivors.

Cardiovascular Disease, Hypogonadism and Erectile Dysfunction: Early Detection, Prevention and the Positive Effects of Long-Term Testosterone Treatment: Prospective Observational, Real-Life Data.

PURPOSE: Erectile dysfunction (ED) is associated with testosterone deficiency and is a symptom of functional hypogonadism. A correlation between ED and cardiovascular disease (CVD) has been recognized, and ED has been proposed as an early marker of CVD. However, the relationship between ED and CVD risk in hypogonadism requires clarification and whether testosterone therapy (TTh) can be a beneficial treatment strategy, but long-term data are limited. This study investigates long-term TTh in men with hypogonadism and ED with a history of CVD. METHODS: Seventy-seven patients with a history of CVD and diagnosed with functional hypogonadism and erectile dysfunction (erectile function domain score <21 on the International Index of Erectile Function questionnaire (IIEF questions 1-5)) were enrolled and TTh effects on anthropometric and metabolic parameters investigated for a maximum duration of 12 years. All men received long-acting injections of testosterone undecanoate at 3-monthly intervals. Eight-year data were analysed. Data collection registry started in November 2004 till January 2015. RESULTS: In hypogonadal men receiving TTh, IIEF increased by 5.4 (p<0.001). Total weight loss was 23.6 ± 0.6 kg after 8 years. HbA1c had declined by an average of 2.0% (P<0.0001). Total cholesterol levels significantly declined following TTh after only 1 year (P<0.0001), and HDL increased from 1.6±0.5 at baseline to 2±0.5 mmol/L following 8 years of TTh (P<0.0001). SBP decreased from 164±14 at baseline to 133±9 mmHg, signifying a reduction of 33±1 mmHg (P<0.0001). CONCLUSION: In hypogonadal men with a history of CVD, TTh improves and preserves erectile function over prolonged periods with concurrent sustained improvements in cardiometabolic risk factors. Measuring ED and testosterone status may serve as an important male health indicator predicting subsequent CVD-related events and mortality and TTh may be an effective add-on treatment in secondary prevention of cardiovascular events in hypogonadal men with a history of CVD.

GYY4137 attenuates functional impairment of corpus cavernosum and reduces fibrosis in rats with STZ-induced diabetes by inhibiting the TGF-ß1/Smad/CTGF pathway.

Erectile dysfunction (ED) is a common diabetic complication. Recent evidence has illuminated the role of hydrogen sulfide (H2S) as a dynamic mediator of the erection process. H2S is a potent endogenous relaxant gas. It has been shown to relax human and animal penile tissue in vitro and induce erection in animals in vivo. The reported penile expression of H2S-synthesizing enzymes also supports the potential role of the endogenous L-cysteine/H2S pathway in penile homeostasis. Several pathological changes take place in the diabetic penile tissue, including inflammation, oxidative stress, neuropathy and fibrosis of the corpus cavernosum (CC), the major erectile structure of the penis. The present study is experimental and has been performed in the diabetic rat model. The study will investigate the role of H2S as a potential protective mediator against diabetes-induced structural and functional alterations in the CC by examining if it: (1) reduces corporal contraction and/or enhances corporal relaxation following pharmacological stimulation, (2) attenuates fibromuscular changes in diabetic CC, and (3) whether there is a link with H2S plasma/urine level and CC tissue generation, as well as studying the expression of some proteins in the transforming growth factor (TGF)-ß1-associated pathway. The major findings of the study reveal that- compared to the nondiabetic controls - the diabetic animals CC showed: (1) augmented contraction and attenuated relaxation in response to phenylephrine and carbachol, respectively, (2) marked fibromuscular degeneration with a significantly lower smooth muscle/collagen ratio and upregulation of TGF-ß-1/Smad/CTGF fibrosis signaling pathway, (3) reduced H2S plasma and urinary levels and cavernosal tissue generation. Chronic GYY4137 treatment prevented most of these pathological changes in diabetic CC, thus may be considered a potential new strategy for the prevention and/or treatment of diabetes-induced ED.

Characteristics and Long Term Follow up of Men Who Suffer Ischemic Priapism Secondary to Recreational Use of Intracavernosal Injectable Medications.

OBJECTIVE: To better understand patient experience, risk factors, culture, and ED outcomes surrounding recreational ICI use that led to ischemic priapism. METHODS: After IRB approval, men presenting for ischemic priapism secondary to recreational ICI use from January 2010 to December 2018 were contacted by mail and then via telephone. Standardized questions were asked of all study participants on the topics of erectile function (IIEF-5), sexual practices, and at-risk behavior at the time of priapism. Qualitative data analysis was performed using grounded theory methodology. RESULTS: 14 men age 24-59 were successfully recruited. All men described themselves as men having sex with men (MSM) and one (7.1%) as having both male and female sexual partners. Average follow up IIEF-5 among participants was 13 (SD 4.0). Eleven men (78.6 %) described illicit drug use at the time of priapism. Qualitative data analysis yielded several preliminary themes: concomitant drug use, naivety, peer pressure, and delay in seeking treatment. Men frequently reported illicit drug use in group sex scenarios and ICI use under pressure to perform sexually or to counteract effects of illicit substances. CONCLUSIONS: Recreational ICI in this cohort was part of a lifestyle of risky behavior. Methamphetamine use and group sex encounters strongly motivate recreational ICI use. Substance abuse centers may offer an entry point into this population for counseling and primary prevention.

A novel flavonoid derivative of icariside II improves erectile dysfunction in a rat model of cavernous nerve injury.

BACKGROUND: Icariside II (ICA II), an active flavonoid monomer, has been proven to restore post-prostatectomy erectile dysfunction in rats; however, the high cost of extraction from natural plants limits the application of ICA II. OBJECTIVE: To investigate the therapeutic effect and possible mechanism of action of YS-10, a new flavonoid compound, which was designed and synthesized based on the structure of ICA II in a rat model in of cavernous nerve injury. MATERIALS/METHODS: Eight of 32 adult male Sprague-Dawley rats were selected as the normal control (NC) group and received vehicle treatment. The remaining rats were subjected to bilateral cavernous nerve injury (BCNI) and randomized into three groups: BCNI group, BCNI + ICA II group (2.5 mg/kg/day), and BCNI + YS-10 group (2.5 mg/kg/day). The total procedure lasted for 21 days, followed by a washout period of 3 days. All animals were evaluated for erectile function, and tissues were harvested for histopathological analyses. RESULTS: It was observed that in YS-10 group, the ratio of intracavernous pressure (ICP) to mean arterial pressure (MAP) and the area under the ICP/MAP curve were effectively enhanced. The maximum ICP/MAP increased by 30% in the YS-10 group (0.86 ± 0.085) compared with the BCNI group (0.66 ± 0.058), which is close to 82% of the NC group (1.05 ± 0.033). Histopathological changes demonstrated significant reduction of smooth muscle atrophy, collagen deposition, and endothelial and neural dysfunction after YS-10 treatment, which have no statistical differences compared with ICA II group. Additionally, high-protein expression levels of ß-Catenin and cyclin D1 were observed in the treatment groups. CONCLUSION: YS-10, a novel synthesized flavonoid compound, could effectively improve erectile dysfunction in rats after BCNI by alleviating pathological impairments; this effect may associate with the upregulation of ß-Catenin and cyclin D1 in Wnt signaling pathway.

Safety of Phosphodiesterase-5 Inhibitors in Valvular Heart Disease.

ABSTRACT: Erectile dysfunction is a common entity in clinical practice. Primary erectile dysfunction, not related to vasculopathy or psychiatric disorder, can be readily treated with phosphodiesterase inhibitors. These drugs have many physiologic effects that can alter a patient's hemodynamic profile considerably, especially in the presence of concomitant structural heart disease, specifically valvular heart disease. Although some contraindications to the use of PDE5 inhibitors in patients with cardiovascular disease are defined, the effect of these drugs in the presence of valvular heart disease is not well documented. The purpose of this review is to analyze the data regarding the safety of PDE5 inhibitors in patients with valvular heart disease.

Prenatal exposure to di-n-butyl phthalate induces erectile dysfunction in male adult rats.

Di-n-butyl phthalate (DBP) is a widely used plasticizer and an environmental endocrine-disrupting compound. However, whether prenatal exposure to DBP can impair erectile function remains unknown. We conducted this study to investigate the potential effects of prenatal exposure to DBP on erectile function and the underlying mechanisms. A rat model of prenatal DBP exposure (12.5, 100 or 800 mg/kg/day by gavage during gestational days 13-21) was established. Prenatal DBP exposure significantly decreased penis/body weight ratio, myelin sheath thickness of cavernosum nerves and serum testosterone level in male rats at the age of 10 weeks. Furthermore, erectile dysfunction was detected in all DBP exposure groups, which exhibited substantial increases in transforming growth factor-ß1 (TGF-ß1) expression and decreases in the expression of alpha smooth muscle actin (α-SMA), neuronal and endothelial nitric oxide synthase (nNOS and eNOS). Additionally, the phospho-B-cell lymphoma 2 (Bcl-2)-associated death promoter (p-Bad)/Bad and phospho-the protein kinase B (p-AKT)/AKT ratios were remarkably lower, but the Bcl-2-associated X protein (Bax)/Bcl-2 ratio and caspase-3 were higher in DBP exposure groups than in the control group. Notably, prenatal exposure to DBP increase the risk of ED in male adult rats, even taking low dose of DBP (12.5 mg/kg/day). DBP exposure causing penile fibrosis, decreased testosterone level, and endothelial dysfunction may be responsible for ED by activating Akt/Bad/Bax/caspase-3 pathway and suppressing NOS/cGMP pathway in penis.

Factors Associated With Corporoglandular Shunting for Patients With First-time Ischemic Priapism.

OBJECTIVE: To establish predictive factors of patients who failed intra-cavernosal injection therapy and ultimately required corporoglandular shunting during first-time ischemic priapism episodes. METHODS: A retrospective review was performed of all patients over the age of 18 who presented to our institution with first-time episode of ischemic priapism from 2009 to 2019. Variables assessed included: body mass index, diabetes, hypertension, race, insurance-type, hypertension, etiology, age, duration of erection prior to evaluation, total amount of phenylephrine injected, and use of corporal irrigation. A receiver operating characteristic (ROC) curve was performed utilizing duration of erection and amount of phenylephrine. RESULTS: One-hundred and forty-seven patients met inclusion criteria of which 24 patients required surgical intervention. There were differences associated with mean total phenylephrine used, duration of erection between shunted patients and non-shunted patients with regards to age (P = .38) or etiology (P = .81). Multivariable analysis revealed differences between duration of erection and BMI greater than 25 kg/m2. ROC curve analyses revealed total amount of phenylephrine injected and duration of erection were acceptable and excellent predictors of need for shunt procedures with area under the curves of 0.72 and 0.90, respectively. Optimal cut-off values for each were found to be 950 mcg and 15.5 hours. CONCLUSION: Our study suggests that patients who require greater than 950 mcg of total phenylephrine or present with erections lasting greater than 15.5 hours are significantly more likely to require corporoglandular shunting and should be counseled appropriately as such.

Study of the risk factors of erectile dysfunction and phospho diestrase type 5 inhibitors usage among Egyptian population with erectile dysfunction: A cross-sectional survey.

OBJECTIVES: We aimed to study the risk factors of erectile dysfunction (ED) and different patterns of phosphodiestrase type 5 inhibitors (PDE5is) usage among Egyptian patients. PATIENTS AND METHODS: One thousand five hundred consecutive Egyptian patients complaining of ED were included in this cross-sectional study from July (2014) to October (2015). Patients were requested to answer the international index of erectile function questionnaire (IIEF-5). Statistical differences between groups were tested using Chi square test and Spearman's rho correlation coefficient for qualitative variables. RESULTS: Remarkably, significant associations between IIEF scores and aging and diabetes mellitus (DM) and hypertension (HTN) and ischaemic heart disease (IHD) and hyperlipidaemia were shown in the studied patients (p<.0001, p<.0001, p<.0001, p<.0001, p<.0001, respectively). Eventually, our study showed significant correlations between different age groups and morning erection and lower urinary tract symptoms and HTN and IHD and DM where the severity of ED was directly proportional to the absence or decreased strength of morning erection with aging and the increased incidence of LUTS and HTN and IHD and DM with aging (p<.0001; p=.001; p<.0001; p<.0001; p<.0001, respectively). CONCLUSION: Our study demonstrated that aging; DM, HTN and hyperlipidaemia are potential major risk factors of ED in Egypt for further validation. In addition, most of the participants used PDE5is without prior medical consultation together with concomitant administration of illicit drugs.