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Erectile function is an important part of men's health that can significantly impact quality of life. Naturally occurring nighttime erections experienced by men throughout their lifespan provides insight into penile health as well as overall health. Nocturnal penile tumescence (NPT) and nocturnal penile tumescence and rigidity (NPTR) devices that can non-invasively evaluate the presence and quality of erections can have valuable diagnostic and clinical utility. Early devices have several limitations that limit their current use. New, wearable devices have promising applications for the evaluation of erectile function over time. Continued advancements in this technology have the potential to render future generations of these devices as invaluable tools that are useful for both men and healthcare professionals., Competing Interests: Competing interests The authors declare no competing interests., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Erectile dysfunction (ED) is one of the most prevalent chronic conditions affecting men. ED can arise from disruptions during development, affecting the patterning of erectile tissues in the penis and/or disruptions in adulthood that impact sexual stimuli, neural pathways, molecular changes, and endocrine signalling that are required to drive erection. Sexual stimulation activates the parasympathetic system which causes nerve terminals in the penis to release nitric oxide (NO). As a result, the penile blood vessels dilate, allowing the penis to engorge with blood. This expansion subsequently compresses the veins surrounding the erectile tissue, restricting venous outflow. As a result, the blood pressure localised in the penis increases dramatically to produce a rigid erection, a process known as tumescence. The sympathetic pathway releases noradrenaline (NA) which causes detumescence: the reversion of the penis to the flaccid state. Androgen signalling is critical for erectile function through its role in penis development and in regulating the physiological processes driving erection in the adult. Interestingly, estrogen signalling is also implicated in penis development and potentially in processes which regulate erectile function during adulthood. Given that endocrine signalling has a prominent role in erectile function, it is likely that exposure to endocrine disrupting chemicals (EDCs) is a risk factor for ED, although this is an under-researched field. Thus, our review provides a detailed description of the underlying biology of erectile function with a focus on the role of endocrine signalling, exploring the potential link between EDCs and ED based on animal and human studies., (© 2021 S. Karger AG, Basel.)

Tangeretin is a polymethoxyflavone concentrated in citrus peels and has several biological activities. This study examined whether tangeretin improved reproductive dysfunction in N ω -nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced hypertensive rats. Male Sprague-Dawley rats received L-NAME to induce hypertension and reproductive dysfunction for 5 w and were treated with tangeretin (15 or 30 mg/kg) or sildenafil citrate (10 mg/kg) for the final two weeks. Mean arterial pressure (MAP), intracavernosal pressure (ICP) response to cavernous nerve stimulation, endothelial nitric oxide synthase (eNOS), Angiotensin II receptor type 1 (AT 1 R) and gp91 phox protein expressions and malondialdehyde (MDA) level in penile tissues were measured. Sperm concentrations and motility, seminiferous tubule morphology, serum testosterone, testicular eNOS and steroidogenic acute regulatory protein (StAR) expression were evaluated. Aortic superoxide generation, plasma and testicular MDA and plasma nitrate/nitrite levels were determined. Tangeretin reduced blood pressure and increased the maximum ICP/MAP associated with suppression of AT 1 R/gp91phox and upregulation of eNOS expression in hypertensive rats (P < 0.05). Furthermore, improvement of sperm quality relevant to increased testicular eNOS and StAR expression was found in tangeretin treated rats (P < 0.05). Changes in seminiferous tubule morphology in hypertensive rats were recovered by tangeretin (P < 0.05). It increased testosterone levels and reduced oxidative stress biomarkers and raised plasma nitrate/nitrite levels in L-NAME rats (P < 0.05). In conclusion, tangeretin improved maximum ICP/MAP and testicular dysfunction and morphology in rats treated with L-NAME. The molecular mechanisms are mediated by modulations of penile eNOS and AT 1 R/gp91 phox expressions and testicular eNOS and StAR expression., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To define age-specific normal Color Doppler Duplex Ultrasound (CDDU) parameters based on a large institutional database of men referred for vascular erectile testing, but found to have normal and sustained rigidity following penile injection of alprostadil., Methods: A retrospective review of patients who underwent CDDU from January 1, 2005 to December 31, 2014 was conducted. The indications for CDDU assessments included complaint of erectile dysfunction refractory to PDE-5 inhibitors, new-onset penile curvature, or secondary consultation for erectile dysfunction. Pearson correlation test was used to evaluate the association between ordinal age groups with peak systolic velocity (PSV) and resistive index (RI) measurements to determine the effect of age on erectile response., Results: A total of 2043 patients underwent CDDU from January 1, 2005 to December 31, 2014. 259 patients (12.7%) with a mean age 53.7 and a mean BMI of 27.2 were noted to have normal erectile rigidity and normal Doppler parameters (PSV >35 cm/s, RI >0.90). Prolonged erection, defined by need to inject phenylephrine reversal agent at 1-2 hours, occurred in 93% of patients. When age was categorized by decade, a negative correlation coefficient was obtained for previsual sexual stimulation PSV (-0.09, P = .164) and postvisual sexual stimulation PSV (-0.23, P = .005)., Conclusion: In men with normal vascular erections there appears to be a significant, age-related decline in postvisual sexual stimulation PSV without compromise to cavernous venous occlusion as measured by RI. We have used Doppler parameters in patients without vascular ED to define age-specific normalcy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Erectile dysfunction (ED) is an important kind of postoperative complication of pelvic surgery that affects patients' quality of life. Transplantation of mesenchymal stem cells (MSC) has been found to alleviate ED caused by cavernous nerve injury (CNI) in rats. However, little is known about whether induced pluripotent stem cell-derived mesenchymal stem cells (iMSC) have a therapeutic effect on CNI ED. We established an ED model on rats and evaluated the effect of iMSC on it. Methods : Eight-week-old male Sprague-Dawley rats were assigned to four groups and received following operation: sham operation (sham group); bilateral CNI and phosphate-buffered saline (PBS) injections (PBS group); bilateral CNI and adipose-derived mesenchymal stem cells transplantation (adMSC group); or bilateral CNI and iMSC injection (iMSC group). After therapy, the cavernous nerve was stimulated by electricity and the intracavernous pressure (IAP)/mean arterial blood pressure (MAP) was measured. The endothelial and smooth muscle tissue in the penis was assessed histologically with Masson's trichrome stain. Immunofluorescence/immunohistochemical stains were applied for the detection of nNOS, vWF, eNOS, SMA, Desmin, S100β, and caspase-3. Nude rats CNI ED model was established for the evaluation of iMSC longevity and differentiation capacity. The paracrine factors were assessed by real-time PCR. Results : Transplantation of iMSC significantly restored the IAP/MAP in this CNI ED model and showed long-term effects. It could rescue the expression of vWF, eNOS, SMA, and Desmin, which indicated the alleviation of endothelial and smooth muscle tissues of the penis. iMSC therapy also could increase the expression of nNOS in the cavernosum and S100β in the major pelvic ganglia (MPG) which contributed to the erectile function. Moreover, the level of BAX and caspase-3 were reduced and Bcl-2 was increased, which indicated the anti-apoptosis effects of iMSC. The iMSC showed little transdifferentiation and exerted their function by activating the secretome of the host. Conclusion : Transplantation of iMSC significantly improved ED induced by CNI. The iMSC may exert their effects via paracrine factors and may be a promising therapeutic candidate for treating CNI ED in the future., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Electrophysiological examination of penile nerves involves detection of somatic and autonomic nerves, including dorsal nerve somatosensory evoked potential, cavernous muscle reflex, skin sympathetic response, cavernous electromyography, and others, which plays an important role in the diagnosis of male sexual dysfunction, such as ED and premature ejaculation, as well as in the selection of treatment methods and evaluation of therapeutic effects. Due to the complex mechanisms of the brain, spinal cord and peripheral nerve pathways relating to erectile and ejaculatory centers in men and many unknown areas in penile electrophysiological techniques, penile electrophysiological examination has not been widely accepted by doctors and patients. Further studies are needed to provide more scientific and convincing evidence in this field.

Background: The purpose of this study was to report the outcomes of patients who underwent penile implantation with AMS 700 LGX inflatable penile prosthesis (IPP) in a single center by a single surgeon., Methods: A total of 342 patients with erectile dysfunction who underwent AMS 700 LGX IPP implantation between October 2014 and April 2016 were included in this study. All patients were evaluated using the International Index of Erectile Function questionnaire preoperatively and at 3, 6, and 12 months postoperatively. We also investigated the mean stretched flaccid penile length before and after surgery as well as the complications related to and the mechanical reliability of the IPP., Results: The questionnaire scores at 12 months were statistically significantly higher than the baseline scores. The mean stretched flaccid penile length was 11.1 ± 0.8 cm at baseline and was longer at 3 (11.9 ± 0.9 cm, P < 0.001), 6 (12.0 ± 0.9 cm, P < 0.001), and 12 (12.2 ± 0.7 cm, P < 0.001) postoperatively. There were no intraoperative or perioperative complications. However, one patient had infection and 10 patients developed mechanical failure during the follow-up duration., Conclusions: The results of our study suggest that the AMS 700 LGX IPP could be used to prevent penile shortening in patients undergoing IPP implantation. Furthermore, erectile function and patient satisfaction were improved excellently.

Introduction: Diagnostic tests for vascular erectile dysfunction (ED) depend on cavernous smooth muscles (CSM) relaxation following an intracorporal injection (ICI). Enhanced sympathetic tone, which is not uncommon during performance of these tests, can bias its results. Also, CSM diseases can cause veno-occlusive diseases (VOD) ED. Corpus cavernosum electromyography (CC-EMG) potentials' amplitudes represent the integrated sympathetic activity of healthy CSM. Stem-cells and gene-therapy are potential therapeutic options for impaired CSM., Objective: To utilize CC-EMG, as a new diagnostic technique that can confirm the integrity of CSM, and to identify patients with impaired CSM activity, among those diagnosed as vascular ED per Color Duplex Doppler Ultrasonography (CDDU)., Patient and Methods: Group 1 included 24 patients with ED and negative response to ICI. Group 2 included 10 men without ED. Patients included in group 1 had penile CDDU examination and all participants had spontaneous CC-EMG recordings., Results: According to CDDU parameters, group 1 was sub-grouped as nine arterial, ten VOD and five mixed type. CC-EMG potentials' amplitudes ranged 223-320, 179-237, 103-250 and 83-200μV for group 2 and arterial, mixed and VOD subgroups respectively. The widest ranges of potentials' amplitudes were recorded in the subgroups of patients with an element of VOD. Four patients with ED, within these subgroups, had CC-EMG potentials' amplitudes ranged 200-250μV that exceeded/approached the lowest value recorded from men in group 2., Conclusion: CC-EMG recordings elicited marked differences of CSM activity among patients diagnosed with an element of VOD ED per CDDU. This finding highlighted the need to utilize CC-EMG to assess the integrity of CSM. Identifying patients with impaired CSM activity may modify the chosen methods for therapeutic interventions., (Copyright © 2018 Asociación Española de Andrología, Medicina Sexual y Reproductiva. Publicado por Elsevier España, S.L.U. All rights reserved.)

Purpose: Aging changes the balance of sex hormones and causes endothelial dysfunction in the penis, both of which are important determinants of erectile dysfunction (ED). The purpose of this study was to evaluate whether exercise training could protect against erectile dysfunction by increasing serum testosterone and penile eNOS levels in aging rats., Methods: A total of 14 young (2-month-old) and 14 middle-aged (18-month-old) Sprague Dawley rats were randomly assigned to either untrained control (young control, [YC], middle-aged control, [MC]) or endurance exercise-trained (young exercise, [YE], middle-aged exercise, [ME]) groups with seven rats per group. The exercise groups trained with treadmill running for 6 weeks. Body composition parameters (body weight, heart mass, liver mass, and testicular mass), serum sex hormone levels (testosterone, luteinizing hormone, follicle-stimulating hormone, and prolactin), endothelial function-related parameters in the penis (endothelial nitric oxide synthase [eNOS], CD31, alpha smooth muscle actin [α-SMA]), and maximal intracavernous pressure measure (ICP) and total ICP were analyzed in middle-aged rats., Results: The middle-aged groups showed increased body weight, as compared with the young groups, but exercise training attenuated the aging-induced increase in body weight. The middle-aged groups had lower testicular mass compared with the young groups, but exercise training attenuated aging-induced decreases in testicular mass. Exercise training increased serum testosterone levels in both the young and middle-aged groups. However, there were no changes in the levels of luteinizing hormone, follicle-stimulating hormone, and prolactin among the groups. MC group showed decreased protein levels of p-eNOS, as compared with the YC group. However, exercise training protected against aging-induced decrease in eNOS and p-eNOS protein levels in the penis. Interestingly, exercise training also increased protein levels of α-SMA and maximal ICP in the middle-aged group., Conclusions: Exercise training has beneficial effects on erectile function in aged rats through increased testosterone production from the testis and strengthening of the cavernous endothelium with activation of eNOS. Therefore, exercise training may be a therapeutic modality for improving erectile dysfunction associated with aging., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Penile hypersensitivity plays an important role in premature ejaculation (PE), but differences in penile sensitivity among subtypes of PE are unknown. Therefore, we compared penile sensory thresholds in PE subtypes of lifelong and acquired PE, PE with and without erectile dysfunction (ED), PE with an intravaginal ejaculation latency time ≤1 min and >1 min, and PE with and without orgasmic pleasure perceptual dysfunction. During August 2014 to January 2016, 136 patients with PE were included. Penile warm, cold, and vibratory thresholds were measured. Data of clinical characteristics, sexual life, Premature Ejaculation Diagnostic Tool (PEDT) score, and the 5-item version of the International Index of Erectile Function (IIEF-5) score were collected. Vibratory thresholds of the PE with ED group were higher in the right coronal sulcus (median amplitude: 4.92 vs 3.65 μ m, P = 0.02) and the right penile shaft (median amplitude: 3.87 vs 3.30 μ m, P = 0.03), while differences in penile sensory thresholds between other subtypes were not significant. The median PEDT score was lower in the PE without ED group (12 vs 14, P < 0.001). The IIEF-5 and PEDT scores were negatively correlated (r = -0.29, P < 0.001). Patients with orgasmic pleasure perceptual dysfunction had a lower median IIEF-5 score (20 vs 21, P = 0.02). Patients with PE and ED had lower penile sensitivity, and ED was associated with more severe symptoms and weaker orgasmic pleasure perception. In men with PE, management of comorbid ED is necessary. In case of side effects in erectile function, topical anesthetics should be cautiously used in men with PE and ED., Competing Interests: All authors declared no competing interests

Objectives: To investigate the feasibility of the Zucker fatty (ZF) rat as a model for research in to obesity-associated erectile dysfunction (OAED) and to determine the effect of low-intensity extracorporeal shockwave therapy (Li-ESWT) on penile tissue and function in these rats., Materials and Methods: Eight new-born male Zucker lean (ZL group) rats (ZUC-Lepr fa 186) and 16 new-born male ZF rats (ZUC-Lepr fa 185) were injected with 5-ethynyl-2'-deoxyuridine (EdU) at birth to identify and monitor endogenous stem cells. Insulin tolerance testing was performed at 10 weeks of age. Beginning at 12 weeks of age, eight ZF rats were kept as controls, and the remaining eight ZF rats were treated with Li-ESWT (0.02 mJ/mm 2 , 3 Hz, 500 pulses; ZF + SW group) twice a week for 4 weeks. Following a 1-week washout period, erectile function was evaluated by measuring intracavernosal pressure (ICP) and mean arterial pressure (MAP). Penile tissues were then harvested for histological study to assess smooth muscle/collagen content and endothelium content in the corpora cavernosum. LipidTOX™ staining was used to evaluate lipid accumulation. EdU, as a marker of cell activation, and phosphorylated histone 3 (H3P), as a marker of cell mitosis, were also assessed., Results: The ICP/MAP indicated that erectile function was severely impaired in the ZF group as compared with the ZL group. In the ZF + SW group, erectile function was significantly improved (P < 0.05). Muscle atrophy was seen in the ZF group, while Li-ESWT increased the muscle content in ZF + SW group. Moreover, the penile endothelium was damaged in the ZF group, and Li-ESWT enhanced the regeneration of endothelial cells (P < 0.01) in the ZF + SW group. Lipid accumulation was seen in the penile tissue of ZF rats. Li-ESWT significantly reduced both the amount and the distribution pattern of LipidTOX, suggesting decreased overall lipid infiltration. Furthermore, Li-ESWT increased EdU-positive cells and markedly enhanced the phosphorylation level of H3P at Ser-10 in the ZF + SW group. Most H3P-positive cells were located within smooth muscle cells, with some located in the endothelium suggesting that these tissues are the reservoirs of penile stem/progenitor cells., Conclusion: ZF rats can serve as an animal model in which to study OAED. This study reveals that obesity impairs erectile function by causing smooth muscle atrophy, endothelial dysfunction, and lipid accumulation in the corpus cavernosum. Li-ESWT restored penile haemodynamic parameters in the ZF rats by restoring smooth muscle and endothelium content and reducing lipid accumulation. The underlying mechanism of Li-ESWT appears to be activation of stem/progenitor cells, which prompts cellular proliferation and accelerates penile tissue regeneration. Our findings are of interest, not just as a validation of this emerging treatment for erectile dysfunction, but also as a novel and potentially significant method to modulate endogenous stem/progenitor cells in other disease processes., (© 2018 The Authors BJU International © 2018 BJU International Published by John Wiley & Sons Ltd.)

This study aimed to report penile dimensions in diabetic and nondiabetic men with erectile dysfunction (ED) and correlate their dimensions with other study variables. A case-control study was designed through retrospective data analysis of diabetic and nondiabetic patients consulting for ED and a control group ( n = 105, each group). Study data retrieved included history, clinical evaluation, and penile dimensions (pendulous length [PL], total length [TL], and circumference [CF]) at flaccid and erect states. Results identified that patients had lower values (mean, cm) for almost all penile dimensions. The diabetic patients identified significant differences in most dimensions, whether in flaccid (PL: 7.46 vs. 7.51 and 7.81, p = .11; TL: 11.8 vs. 12.77 and 12.88, p = .000; CF: 8.84 vs. 9.1 and 9.14, p = .016) or erect state (PL: 9.66 vs. 9.61 and 10, p = .092; TL: 13.96 vs. 14.88 and 15.04, p = .000; CF: 11.56 vs. 12.06 and 11.92, p = .018) as compared with the nondiabetic patients and controls, respectively. No significant correlation was detected between the dimensions and age, durations of diabetes and ED, or erectile function scores. In conclusion, diabetic and nondiabetic patients with ED presented, in varying degrees, significant decline in their penile dimensions, and this was more prevalent in diabetic patients. As changes in penile size could be a silent corollary of comorbidities, monitoring the changes in penile dimensions should be an important component of the clinical checkup of any patient with ED, especially a diabetic patient.

Objective: To investigate the safety and efficacy of pancreatic kininogenase combined with sildenafil in the treatment of erectile dysfunction(ED) in type 2 diabetes mellitus (DM) patients in the high-altitude area., Methods: This study included 93 ED patients with type 2 DM, all residents of the Xining area 1500 meters above sea level. We randomly divided them into an experimental group (n = 48) and a control group (n = 45), the former treated with pancreatic kininogenase(120 u, tid) and sildenafil (25 mg, qd at bedtime), while the latter with sildenafil only (25 mg, qd at bedtime).After 4 and 8 weeks of medication, we obtained the penile hemodynamic parameters,IIEF-5 scores, and sexual intercourse satisfaction(SIS) scores and compared them between the two groups of patients., Results: There were no statistically significant differences in age or DM course between the two groups of patients (P >0.05).Compared with the baseline, both the experimental and control groups showed remarkably improvement inthe IIEF-5 score (8.81 ± 2.06 vs 11.54 ± 7.72 and 8.29 ± 1.91 vs 9.37± 1.65, P <0.05), SIS score (3.35 ± 2.43vs6.83± 2.61and 3.41 ± 2.38 vs 4.92± 2.49, P <0.05), and penile hemodynamic parameters obtained by color duplex Doppler ultrasonography(P <0.05), with significant differences between the two groups in the IIEF-5 score (11.54 ± 7.72 vs 9.37± 1.65, P <0.05) and SIS score (6.83± 2.61 vs 4.92± 2.49, P <0.05) but not in the penile hemodynamic parameters (P >0.05). Even more remarkable improvement was observed at 8 weeks in the experimental and control groups in the IIEF-5 score (19.29± 1.85 and 15.43± 1.74)(P <0.05), SIS score (11.73 ± 2.57 and 6.55± 2.71) (P <0.05), and penile hemodynamic parameters(P <0.05), all with significant differences between the two groups (P <0.05)., Conclusions: Pancreatic kininogenase combined with sildenafil has a better clinical effect than sildenafil alone on ED in type 2 DM patientsin the high-altitude area.

Objective: The goal of this study was to measure corpus cavernosum (CC) penis rigidity with shear wave elastography (SWE) in healthy volunteers and to evaluate the change of rigidity with age., Methods: SWE was performed in 60 healthy volunteers (age range 20-71, mean 47±12,83 years). Volunteers were divided into 2 groups by age (Group 1 age <50, group 2 age ≥50). We assessed SWE in 3 parts of penis (proximal, middle and glans penis) on both sides of CC. All values of SWE (in kilo Pascal) were noted along with volunteers' ages. The measurements were done both with transverse (T) and longitudinal (L) sections. We compared all SW values of penis parts and their alterations with age., Results: The shear wave elastography values of CC penis increased with increasing age (p<0,01). There was no significant difference between both sides of CC penis (p<0,05). We calculated no significant difference between T and L sections of all parts of penis (p<0,05)., Conclusions: SWE can provide noninvasive quantitative data of CC penis rigidity and its alteration with age. These data may create a new approach in the evaluation process and treatment options for penile pathologies., (Copyright © 2017 Elsevier B.V. All rights reserved.)

We investigated the role of insulin-like growth factor-1 (IGF-1) in spontaneously hypertensive rats with erectile dysfunction. Firstly, we evaluated intracavernous pressure. The bioavailability of IGF-1 at both mRNA and protein levels were measured by quantitative real-time PCR and Western blot respectively. Then, cavernous cyclic guanosine monophosphate concentrations were detected by enzyme-linked immunosorbent assay. The cavernosal pressure was significantly decreased in the hypertensive and the propranolol treatment groups compared to the normal control group (P < 0.01). Cavernous IGF-1 bioavailability and the concentrations of cavernous cyclic guanosine monophosphate were both significantly decreased in the hypertensive and the propranolol treatment groups compared to the normal control group (P < 0.01). This study suggests that an obvious decrease in cavernous IGF-1 levels might play an important role in spontaneously hypertensive rats with erectile dysfunction., (© 2016 Blackwell Verlag GmbH.)

Objective: To evaluate the effects of Shengjing capsule on erectile function in a castrated rat model, and further to investigate the underlying molecular mechanism., Materials and Methods: Thirty male Sprague-Dawley rats were randomly divided into six groups (n = 5 per group), including sham group, castration group, testosterone replacement group, high-dose Shengjing capsule group, medium-dose Shengjing capsule group, and low-dose Shengjing capsule group. The weight of the body and androgen-sensitive organs, and the serum level of testosterone were assessed. Erectile function was evaluated using cavernous nerve electrical stimulation after treatment. Corpus cavernosum tissue was examined by Masson's trichrome staining, immunohistochemistry, quantitative reverse transcriptase-polymerase chain reaction, and Western blot., Results: Serum testosterone level, mean weights of body, and accessory sexual organs were not significantly different between Shengjing capsule treatment and the castration groups (P > .05 for all). Significant recovery of erectile function and the increased smooth muscle components were observed in the Shengjing capsule treatment group as compared with the castration group (P < .01 and P < .01, respectively). The gene and protein expression of 3 subtypes of nitric oxide synthase (NOS)-neuronal (nNOS), inducible (iNOS), and endothelial (eNOS) -in cavernous tissue in Shengjing capsule-treated rats were significantly higher than in the castration group (P < .05 for all). Phosphodiesterase type 5 messenger ribonucleic acid and protein expression in each group followed a trend similar to that of smooth muscle content., Conclusion: These results show that Shengjing capsule improves the erectile function by protecting the smooth muscle content and enhancing NOS activity in penile tissues of castrated male rats., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction and Aim: The multicenter, randomized, double-blind, double-dummy, placebo-controlled REACTT trial suggested that treatment with tadalafil once daily (OaD) started early after bilateral nerve-sparing radical prostatectomy (nsRP) for prostate cancer may contribute to erectile function (EF)-recovery, which was predefined as achieving an International Index of Erectile Function (IIEF)-EF score ≥22. Here, we report descriptive post-hoc analyses, using the more strict definition for EF-recovery of returning back to the pre-surgery IIEF-EF-level ("back-to-baseline analysis")., Methods: REACTT included 422 men <68 years with adenocarcinoma of the prostate and preoperative IIEF-EF ≥22 who underwent nsRP at 50 centers from 9 European countries and Canada. Patients were randomized post-nsRP 1:1:1 to 9-month double-blind treatment (DBT) with tadalafil 5 mg OaD (n = 139), tadalafil 20 mg on-demand (pro-re-nata, PRN; n = 142), or placebo (n = 141), followed by 6-week drug-free washout (DFW) and 3-month open-label tadalafil OaD treatment (OLT)., Main Outcome Measures: Proportion of patients returning to their preoperative IIEF-EF category (22-25 or ≥26) at the end of DBT, DFW, and OLT., Results: Overall, 92.4% of patients had pre-surgery (baseline) IIEF-EF scores ≥26 (tadalafil OaD 94.2%, PRN 91.6%, placebo 91.5%), 7.4% had IIEF-EF 22-25. At the end of DBT, 22.3% of patients on tadalafil OaD had achieved "back-to-baseline" IIEF-EF, compared with 11.3% on tadalafil PRN and 7.8% on placebo. Of all 58 patients "back-to-baseline" at the end of DBT, only 1 PRN-group patient had started from a baseline IIEF-EF <26. The treatment-group difference at the end of DBT was not maintained after DFW. After 3 months of OLT with tadalafil OaD, the proportion of patients with "back-to-baseline" IIEF-EF had almost doubled in all 3 groups., Conclusion: Changing the definition for EF-recovery from IIEF-EF ≥22 to the more strict definition of "returning back-to-baseline IIEF-EF" had no major impact. Tadalafil OaD started early after nsRP improved drug-assisted EF, but had no effect on unassisted EF following treatment cessation after 9 months., (Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

We examined the relationship between chronic hypoxia and erectile dysfunction in rat and its possible pathogenic mechanism. Forty-eight white male adult Sprague-Dawley rats were randomly divided into a test group and a control group. In accordance with the experimental time (2, 6, and 10 weeks), each group was divided into 3 subgroups, with 8 rats in each subgroup. Rats in the test group were fed in an airtight hypoxia cabin, while rats in the control group were maintained in a normal environment, with other conditions kept the same. At 2, 6, and 10 weeks, the rats in each group were observed for erectile function. Affinity purification was used to detect neural nitric oxide synthase (nNOS)-positive nerve fibers and endothelial nitric oxide synthase (eNOS) expression. After hypoxia, erectile frequency decreased significantly compared to before hypoxia (P < 0.001). Comparison of the test group and control group revealed a significant difference in the quantity of nNOS-positive nerve fiber and eNOS protein expression (P < 0.01). Hypoxia may influence erectile function and nNOS and eNOS expression in rats. The decrease in the quantity of nNOS nerve fibers and expression of eNOS may contribute to erectile dysfunction under hypoxic conditions in rats.

The description of the nerve-sparing technique of radical prostatectomy by Walsh was one of the major breakthroughs in the surgical treatment of prostate cancer in the 20(th) century. However, despite this advance and consequent technological refinements to nerve-sparing surgery, a large proportion of men still suffer from erectile dysfunction (ED) as a complication of prostatectomy. A plethora of therapeutic approaches have been proposed to optimize erectile function recovery in these patients. Several preclinical and translational studies have shown benefits of therapies including PDE5 inhibitor (PDE5I) treatment, immunomodulation, neurotrophic factor administration, and regenerative techniques, such as stem cell therapy, in animal models. However, most of these approaches have either failed to translate to clinical use or have yet to be studied in human subjects. Penile rehabilitation with PDE5Is is currently the most commonly used clinical strategy, in spite of the absence of solid clinical evidence to support its use.

Objective: To examine the effect of pioglitazone on erectile function in a rat model of postprostatectomy erectile dysfunction., Methods: Twenty adult rats were divided into 4 groups: (a) sham, (b) control--bilateral cavernosal nerve crush injury (BCNI), (c) BCNI + low-dose pioglitazone (PioL), and (d) BCNI + high-dose pioglitazone (PioH). Sham and control rats were administered phosphate-buffered saline, whereas PioL and PioH rats received 0.65 and 6.5 mg/kg of pioglitazone, respectively. All treatments were administered by oral gavage for 14 days. After treatment, animals underwent surgery for endpoint cavernosal response to define hemodynamic parameters of erectile function, reported as the ratio of intracavernosal pressure to mean arterial pressure. Corporal tissue was retrieved for histologic and molecular analysis., Results: Animals treated with pioglitazone experienced dose-dependent improvements in the ratio of intracavernosal pressure to mean arterial pressure, with the PioH group achieving results similar to the sham group: sham, 0.774; BCNI, 0.421; PioL, 0.616; PioH, 0.758 (P = .0006). PioH animals demonstrated increased expression of endothelial nitric oxide (eNOS) and neuronal nitric oxide (nNOS), whereas both PioL and PioH animals had increased staining for anti--smooth muscle actin antibody and nonsignificant increases in cyclic guanosine monophosphate (cGMP)., Conclusion: Pioglitazone improves erectile function in rats undergoing BCNI via a nitric oxide--mediated pathway., (Copyright © 2014 Elsevier Inc. All rights reserved.)

A pathogenic link between erectile dysfunction (ED) and metabolic syndrome (MetS) is now well established. Nonalcoholic steatohepatitis (NASH), the hepatic hallmark of MetS, is regarded as an active player in the pathogenesis of MetS-associated cardiovascular disease (CVD). This study was aimed at evaluating the relationship between MetS-induced NASH and penile dysfunction. We used a non-genomic, high fat diet (HFD)-induced, rabbit model of MetS, and treated HFD rabbits with testosterone (T), with the selective farnesoid X receptor (FXR) agonist obeticholic acid (OCA), or with the anti-TNFα mAb infliximab. Rabbits fed a regular diet were used as controls. Liver histomorphological and gene expression analysis demonstrated NASH in HFD rabbits. Several genes related to inflammation (including TNFα), activation of stellate cells, fibrosis, and lipid metabolism parameters were negatively associated to maximal acetylcholine (Ach)-induced relaxation in penis. When all these putative liver determinants of penile Ach responsiveness were tested as covariates in a multivariate model, only the association between hepatic TNFα expression and Ach response was confirmed. Accordingly, circulating levels of TNFα were increased 15-fold in HFD rabbits. T and OCA dosing in HFD rabbits both reduced TNFα liver expression and plasma levels, with a parallel increase of penile eNOS expression and responsiveness to Ach. Also neutralization of TNFα with infliximab treatment fully normalized HFD-induced hypo-responsiveness to Ach, as well as responsiveness to vardenafil, a phosphodiesterase type 5 inhibitor. Thus, MetS-induced NASH in HFD rabbits plays an active role in the pathogenesis of ED, likely through TNFα, as indicated by treatments reducing liver and circulating TNFα levels (T or OCA), or neutralizing TNFα action (infliximab), which significantly improve penile responsiveness to Ach in HFD rabbits., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Erectile dysfunction (ED) is a major health problem. We have shown that adrenomedullin (AM) restores erectile function in diabetic rats., Aim: The 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)., Methods: Male Wistar rats were injected with streptozotocin (STZ) to induce diabetes. Adenoviruses expressing 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 Measures: Intracavernous 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., Results: Infection 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., Conclusions: These 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., (© 2013 International Society for Sexual Medicine.)

Erectile dysfunction (ED) is estimated to affect 150 million people worldwide and may indicate diffuse systemic macrovascular disease. Endothelial dysfunction represents the probable pathophysiological link between vasculogenic ED, coronary artery disease (CAD), and peripheral artery disease (PAD), and the artery size hypothesis along with evidence-based research support ED as the incident clinical event. Given that many common risk factors for atherosclerosis, including smoking, diabetes mellitus, hyperlipidemia, and obesity are prevalent and causative in patients with ED, it is likely that metabolic factors play a crucial role in the link between the two disorders. The interplay of these factors provides a unifying physiological, endocrinological, and behavioral model for the association between ED, CAD, and PAD. Current therapy is unlikely to reverse the natural history of ED. Percutaneous revascularization may improve ED symptoms, and thereby quality of life, in a select group of patients. Large prospective studies are needed to define male pelvic arterial anatomy and thus enhance the utilization of internal pudendal angiography and revascularization. In this review, we provide an overview of normal erectile anatomy and physiology, the pathophysiology of ED, currently accepted diagnostic imaging modalities and treatments for ED, and recently investigated endovascular therapies for ED.

Introduction: We investigated the effect angiotensin II (Ang II), a corpus cavernosal smooth muscle (CCSM) constrictor peptide, has on tissue taken from rabbits following chronic partial bladder outlet obstruction (PBOO), as this model is characterized by an increase in corpus cavernosal collagen deposition and a marked reduction and impaired relaxation of CCSM cells., Aim: To determine the interaction between Ang II and nitric oxide (NO) and the development of oxidative stress (OS) in a rabbit model of chronic PBOO., Methods: Corpus cavernosal tissue was obtained from 12 sham-operated and 20 PBOO rabbits. Organ bath studies determined Ang II/NO interaction on CCSM function using losartan (AT1 receptor antagonist), sodium nitroprusside (SNP, NO donor), electrical field stimulation (EFS), and vardenafil (phosphodiesterase type 5 inhibitor). The role of OS in the Ang II response was also determined using diphenylene iodonium chloride (DPI), the nicotinamide adenine dinucleotide phosphate oxidase inhibitor, which inhibits superoxide production and superoxide dismutase (SOD, the enzyme that accelerates the breakdown of superoxide)., Main Outcome Measure: Action of Ang II and AT1 receptor antagonist, as well as SOD and DPI on CCSM function., Results: Ang II caused a dose-dependent contraction of CCSM strips that was enhanced in PBOO rabbits and inhibited by losartan, DPI, and SOD. CCSM relaxation induced by SNP/EFS was impaired in this model and improved by vardenafil and losartan., Conclusions: These findings imply that the increased Ang II contractile response is a pathological consequence of PBOO and that AT1 receptor inhibition may be a therapeutic approach to treat ED associated with PBOO., (© 2012 International Society for Sexual Medicine.)

In this study the effects of yohimbine and sildenafil on cold stress-induced erectile dysfunction in rats were investigated. Yohimbine hydrochloride (0.2 mg/kg, i.p.) and sildenafil citrate (20 mg/kg, i.p) were administered to rats 1h before the stress session daily for 14 consecutive days and their effect was assessed. Results of this section revealed that, immersion of rats in cold water significantly decreased sexual arousal and motivation as indicated by increased latencies and intervals. Furthermore decreased copulatory performance and potency as indicated by decreased ejaculation frequency was observed. Decreased copulatory activity was confirmed by decreased testosterone, luteinizing hormone (LH) and follicle-stimulating-hormone (FSH) levels as well as decreased cholesterol content in rat testes. Treatment with yohimbine or sildenafil significantly increased the sexual arousal and potency and corrected the effects induced by stress on the mating behavior of male rats. On the contrary they did not significantly alter testosterone, FSH and LH levels which is reflected by failure of both drugs to alter cholesterol content in rat testes. Regarding the effect of yohimbine and sildenafil on isolated rat corpus cavernosum, their cumulative dose response curves (3×10(-7), 3×10(-6) and 3×10(-5) M) were determined in corpus cavernosum strips isolated from normal rats and pre-contracted with phenylephrine (3×10(-6) M) were also assessed. Results of this part showed that both yohimbine and sildenafil have a relaxant effect on rat corpus cavernosum strips in a dose dependant manner, which is confirmed by the increase in nitric oxide content in rats' penis shown by sildenafil., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The effect of Cuscuta chinensis extract on the rabbit penile corpus cavernosum (PCC) was evaluated in the present study. Penises obtained from healthy male New Zealand white rabbits (2.5-3.0 kg) were precontracted with phenylephrine (Phe, 10 µmol l(-1)) and then treated with various concentrations of Cuscuta chinensis extract (1, 2, 3, 4 and 5 mg ml(-1)). The change in penile tension was recorded, and cyclic nucleotides in the PCC were measured by radioimmunoassay (RIA). The interaction between Cuscuta chinensis and sildenafil was also evaluated. The result indicated that the PCC relaxation induced by Cuscuta chinensis extract was concentration-dependent. Pre-treatment with an nitric oxide synthase (NOS) inhibitor (Nω nitro-L-arginine-methyl ester, L-NAME), a guanylyl cyclase inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, ODQ), or a protein kinase A inhibitor (KT 5720) did not completely inhibit the relaxation. Incubation of penile cavernous tissue with the Cuscuta chinensis extract significantly increased cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) in the PCC. Moreover, the Cuscuta chinensis extract significantly enhanced sildenafil-induced PCC relaxation. In conclusion, the Cuscuta chinensis extract exerts a relaxing effect on penile cavernous tissue in part by activating the NO-cGMP pathway, and it may improve erectile dysfunction (ED), which does not completely respond to sildenafil citrate.

Objective: To demonstrate the effect of the size of the resultant tunical defect after plaque excision on postoperative erectile function of patients with Peyronie's disease., Methods: The results of 38 patients with plaque excision and dermal grafting were reviewed from April 2007 to June 2011. History, physical examination, self-shot photograph, color duplex ultrasonography were done preoperatively, and the risk factors for erectile dysfunction were evaluated. The tunical defects were ≥ 3 cm for group 1 and <3 cm for group 2. The postoperative need for phosphodiesterase type 5 inhibitors was noted for both groups. The International Index of Erectile Function-5 questionnaire was completed by all patients., Results: Overall, phosphodiesterase type 5 inhibitors were necessary for 13 (34%) of 38 patients; 7 (58.3%) of 12 in group 1 and 6 (23%) of 26 in group 2. The risk factors for postoperative erectile dysfunction were statistically similar for both groups. If patients with ventral defects were excluded from group 2, the number of patients requiring phosphodiesterase type 5 inhibitors was 4 (17%) of 24. The patients in group 2 answered the fifth question (4.6 ± 0.55) significantly different from those in group 1 (3.7 ± 0.88)., Conclusion: Plaque excision and dermal grafting can be recommended only for highly selected patients with Peyronie's disease with good erectile capacity, with a degree of angle not suitable for only plication or Nesbit techniques, for patients who do not accept any significant shortening of the penis, and if the size of the tunical defect will be <3 cm. Additional techniques on the opposite aspect of the lesion are advocated for the remaining curvatures, not to enlarge the tunical defect >3 cm., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Radiation therapy (RT) for prostate cancer is commonly associated with erectile dysfunction (ED), although high-quality data on incidence of ED after brachytherapy (BT) are limited. We reviewed the literature on BT-related ED and propose a clinical pathway for maximal preservation of erectile function (EF) after treatment., Methods and Materials: Erectile physiology and pathophysiology after RT are reviewed. Evidence and rationale for the concept of penile rehabilitation are presented. BT literature that focuses on ED is identified. A clinical care pathway for maximally preserving EF in patients treated with RT for localized prostate cancer is proposed., Results: The mechanisms contributing to ED after prostate irradiation involve injury to the neurovascular bundles, penile vasculature, and cavernosal structural tissue. Reported rates of ED after BT vary widely. Basic science and clinical studies support the concept of a structured program of erectile tissue preservation for optimizing EF after radical prostatectomy and are adapted for the prostate radiation patient., Conclusions: Although definitive evidence for such erectile tissue preservation strategies is pending, there is a solid scientific rationale for the application of available strategies to the radiation patient., (Copyright © 2012 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Introduction: Adenosine has been implicated in normal and abnormal penile erection. However, a direct role of endogenous adenosine in erectile physiology and pathology has not been established., Aim: To determine the functional role of endogenous adenosine production in erectile function., Methods: CD73-deficient mice (CD73(-/-)) and age-matched wild-type (WT) mice were used. Some WT mice were treated with alpha, beta-methylene adenosine diphosphate (ADP) (APCP), a CD73-specific inhibitor. High-performance liquid chromatography was used to measure adenosine levels in mouse penile tissues. In vivo assessment of intracorporal pressure (ICP) normalized to mean arterial pressure (MAP) in response to electrical stimulation (ES) of the cavernous nerve was used., Main Outcome Measurement: The main outcome measures of this study were the in vivo assessment of initiation and maintenance of penile erection in WT mice and mice with deficiency in CD73 (ecto-5'-nucleotidase), a key cell-surface enzyme to produce extracellular adenosine., Results: Endogenous adenosine levels were elevated in the erected state induced by ES of cavernous nerve compared to the flaccid state in WT mice but not in CD73(-/-) mice. At cellular levels, we identified that CD73 was highly expressed in the neuronal, endothelial cells, and vascular smooth muscle cells in mouse penis. Functionally, we found that the ratio of ES-induced ICP to MAP in CD73(-/-) mice was reduced from 0.48 ± 0.03 to 0.33 ± 0.05 and ES-induced slope was reduced from 0.30 ± 0.13 mm Hg/s to 0.15 ± 0.05 mm Hg/s (both P < 0.05). The ratio of ES-induced ICP to MAP in APCP-treated WT mice was reduced from 0.49 ± 0.03 to 0.38 ± 0.06 and ES-induced slope was reduced from 0.29 ± 0.11 mm Hg/s to 0.19 ± 0.04 mm Hg/s (both P < 0.05)., Conclusion: Overall, our findings demonstrate that CD73-dependent production of endogenous adenosine plays a direct role in initiation and maintenance of penile erection., (© 2011 International Society for Sexual Medicine.)

Small variations of electric impedance (bioimpedance) of human penis were examined in healthy volunteers and in patients with vascular erectile dysfunction (ED). The harmonic analysis revealed rhythmic oscillations of penile bioimpedance at frequencies corresponding to the heart and respiration rates and Mayer wave (0.1 Hz) and to multiple frequencies (harmonics) of the respiratory and cardiac oscillations. In normal penile bioimpedance spectrum, the Mayer and respiratory peaks were several times higher than the first cardiac (pulsatile) harmonic indicating neurogenic origin of rhythmic bioimpedance variations in the whole penis. The most of healthy individuals (78%) demonstrated the cardiac harmonics at the frequency range of 4-7 Hz that violated the monotone decrement of the pulsatile harmonic series suggesting the resonant character of oscillations of the penile arteries at this "near" frequency range. In contrast to stable 1-4 cardiac harmonics, the amplitudes of the near-range resonant harmonics could vary during few minutes suggesting a causal relation of the corresponding bioimpedance oscillations with the varying vascular tone in penile arteries. The most patients (89%) with vascular ED demonstrated not only the first 1-4 monotonically decrementing harmonics and the near-resonant ones, but also the stable cardiac harmonics at the "far" frequency range of 8-14 Hz that also disturbed the monotonic character of the cardiac harmonic series indicating the sclerotic alterations in regional arteries. In ED patients, insignificant decrease of the initial cardiac harmonics C1-C3 in comparison with the norm was accompanied by pronounced and significant decrease of the respiratory R1 and Mayer M1 peaks. The study showed that the far-frequency bioimpedance resonances at the range of 8-14 Hz and dramatic drop of Mayer and respiratory peaks are the diagnostic signs of vascular ED independent on the accompanying hormonal or neurogenic disorders.

It has been reported that sodium nitrite (NaNO2) can act as a storage form of nitric oxide (NO) that can have beneficial pharmacologic actions. The present study was undertaken to investigate the effects of NaNO2 on erectile function in the rat. The intracavernosal (i.c.) injection of NaNO2 produced dose-related increases in i.c. pressure and decreases in systemic arterial pressure. NaNO2 was 1000-fold less potent than sodium nitroprusside in increasing i.c. pressure. Increases in i.c. pressure in response to NaNO2 were attenuated by the nitric oxide synthase (NOS) inhibitor N-nitro-L-arginine methyl ester (L-NAME). The increases in i.c. pressure in response to NaNO2 were not altered by the xanthine oxidoreductase inhibitor allopurinol. The decreases in systemic arterial pressure in response to i.c. injections of NaNO2 were attenuated by allopurinol and were either unchanged or increased by L-NAME. These data suggest that NaNO2 is converted to vasoactive NO in the corpora cavernosum and systemic vascular bed of the rat by different mechanisms. The present data suggest that the conversion of NaNO2 to vasoactive NO is mediated by NOS in the corpora cavernosum and by xanthine oxidoreductase in the systemic vascular bed of the rat. These data show NaNO2 can serve as a NO donor that increases erectile activity in the rat.

Stem cell-based therapy targeted at the penile tissue has been lately considered in preclinical studies. This work aimed to assess the effect of intracavernous administration of mesenchymal stem cells (MSCs) in aged rats (n = 100). They were subjected to single intracavernous injection (ICI) of 1.0 million MSCs, followed up for 3, 4 weeks, 3 and 4 months (each group 25 rats) and compared with both adult and aged controls (n = 50). In dissected cavernous tissues, cGMP and histopathology were assessed in addition to intracavernous pressure (ICP) measurement in some anaesthetised rats. The results showed that cavernous tissue cGMP was significantly increased in MSCs transplanted rats in all investigated groups compared with the controls. The mean cavernous cGMP levels after 3 and 4 months of MSCs transplantation were significantly increased compared with those after 3 or 4 weeks. Cavernous tissue ICP measurement showed significant increase in MSCs transplanted groups compared with the controls, more in the long-term follow up than in the shorter one. Histopathological examination detected markedly dilated sinusoidal vascular spaces in the long-term follow-up study. It is concluded that stem cell-based therapy is feasible for age-associated erectile dysfunction and could improve erectile signaling.

Introduction: Significant scientific advances during the past 3 decades have deepened our understanding of the physiology and pathophysiology of penile erection. A critical evaluation of the current state of knowledge is essential to provide perspective for future research and development of new therapies., Aim: To develop an evidence-based, state-of-the-art consensus report on the anatomy, physiology, and pathophysiology of erectile dysfunction (ED)., Methods: Consensus process over a period of 16 months, representing the opinions of 12 experts from seven countries., Main Outcome Measure: Expert opinion was based on the grading of scientific and evidence-based medical literature, internal committee discussion, public presentation, and debate., Results: ED occurs from multifaceted, complex mechanisms that can involve disruptions in neural, vascular, and hormonal signaling. Research on central neural regulation of penile erection is progressing rapidly with the identification of key neurotransmitters and the association of neural structures with both spinal and supraspinal pathways that regulate sexual function. In parallel to advances in cardiovascular physiology, the most extensive efforts in the physiology of penile erection have focused on elucidating mechanisms that regulate the functions of the endothelium and vascular smooth muscle of the corpus cavernosum. Major health concerns such as atherosclerosis, hyperlipidemia, hypertension, diabetes, and metabolic syndrome (MetS) have become well integrated into the investigation of ED., Conclusions: Despite the efficacy of current therapies, they remain insufficient to address growing patient populations, such as those with diabetes and MetS. In addition, increasing awareness of the adverse side effects of commonly prescribed medications on sexual function provides a rationale for developing new treatment strategies that minimize the likelihood of causing sexual dysfunction. Many basic questions with regard to erectile function remain unanswered and further laboratory and clinical studies are necessary.

Androgens are essential for development, growth, and maintenance of penile structure, and regulate erectile physiology by multiple mechanisms. Here we provide a concise overview of the basic research findings pertaining to androgen modulation of erectile tissue architecture and physiology. A significant body of evidence exists pointing to a critical role of androgens in erectile physiology. Studies in animal models have provided fundamental knowledge on the role of androgens in modulating tissue architecture and cellular, molecular, and physiological mechanisms. Based on data from our laboratory and those reported by others, we believe that androgens play a pivotal role in maintaining the structure and function of the peripheral penile nerve network, the structural integrity of the corpora cavernosa, the tunica albuginea, and the endothelium of the cavernous spaces. Further, androgens play an important role in regulating the differentiation of precursor cells into trabecular smooth muscle. In this review, we will focus our discussion on findings pertaining to the role of androgens in regulating penile tissue architectural elements in modulating penile function. This knowledge has a profound impact on the potential use of androgens in the clinical setting to treat patients with erectile dysfunction.

To evaluate the biomarkers of sexual function, we investigated the relationship between questionnaire responses and biological hormones such as testosterone (T) and cortisol (F) in serum and saliva. The study population included 105 men aged 30-72 years (mean: 49+/-4.5, median: 49). Levels of all serum hormones (Total-T, Free-T, Bioavailable-T, Total-F and Bioavailable-F) and salivary hormones (Saliva-T and Saliva-F) were measured directly by liquid chromatography/tandem mass spectrometry. The International Index of Erectile Function (IIEF) was used as a questionnaire to evaluate sexual dysfunction. Free-T and Bioavailable-T showed significant inverse correlations with age (P<0.01). In the group not taking antidepressants, the levels of Bioavailable-F and Saliva-F showed significant inverse correlations with a portion of the IIEF score (P<0.05). However, reductions in Bioavailable-T and Saliva-T showed no association with the IIEF score. In the group taking antidepressants, these hormone levels showed no correlation with IIEF.

Erectile dysfunction (ED) is common after radical prostatectomy (RP). ED has a negative impact on health-related quality of life. Penile rehabilitation is defined as the use of any drug or device at or after RP to maximize erectile function recovery. The purpose of penile rehabilitation is the prevention of corpus cavernosal smooth muscle structural alterations not only to maximize the chances of a man having recovery of functional erections but also returning him to his preoperative erectile function level. Appreciating the value of penile rehabilitation requires understanding five concepts: the pathophysiology of ED after RP, cavernosal oxygenation, venous leak, and both the animal and human data supporting this strategy. This paper gives an overview of these factors and attempts to give a common-sense, practical guide to a rehabilitation program.

Background: Most men following radical retropubic prostatectomy (RRP) are afflicted by erectile dysfunction (ED). RRP-related ED occurs as a result of surgically elicited neuropraxia, leading to histological changes in the penis, including collagenization of smooth muscle and endothelial damage., Aim: To verify whether hypogonadism could contribute to the pathogenesis of RRP-ED., Methods: Effects of testosterone (T), alone or in association with long-term tadalafil (Tad) treatment in a rat model of bilateral cavernous neurotomy (BCN)., Main Outcome Measures: Penile tissues from rats were harvested for vasoreactivity studies 3 months post-BCN. Penile oxygenation was evaluated by hypoxyprobe immunostaining. Phosphodiesterase type 5 (PDE5), endothelial nitric oxide synthase (eNOS), and neuronal nitric oxide synthase (nNOS) mRNA expression were quantified by Real Time quantitative reverse transcription polymerase chain reaction (qRT-PCR)., Results: In BCN rats, we observed the onset of an overt condition of hypogonadism, characterized by reduced T plasma level, reduced ventral prostate weight, reduced testis function (including testis weight and number of Leydig cells), with an inadequate compensatory increase of luteinizing hormone. BCN induced massive penile hypoxia, decreased muscle/fiber ratio, nNOS, eNOS, PDE5 expression, increased sensitivity to the nitric oxide donor, sodium nitroprusside (SNP), and reduced the relaxant response to acetylcholine (Ach), as well as unresponsiveness to acute Tad dosing. In BCN rats, chronic Tad-administration normalizes penile oxygenation, smooth muscle loss, PDE5 expression, SNP sensitivity, and the responsiveness to the acute Tad administration. Chronic Tad treatment was ineffective in counteracting the reduction of nNOS and eNOS expression, along with Ach responsiveness. T supplementation, in combination with Tad, reverted some of the aforementioned alterations, restoring smooth muscle content, eNOS expression, as well as the relaxant response of penile strips to Ach, but not nNOS expression., Conclusion: BCN was associated with hypogonadism, probably of central origin. T supplementation in hypogonadal BCN rats ameliorates some aspects of BCN-induced ED, including collagenization of penile smooth muscle and endothelial dysfunction, except surgically induced altered nNOS expression.

Objective: To assess the functional and histological effects of a bovine thrombin topical haemostatic agent used clinically to aid in surgical haemostasis (FloSeal(TM), Baxter International Inc., Deerfield, IL, USA) on the cavernous nerves in a canine model of survival, as there are concerns that the fibrotic/inflammatory response to this product could affect neural function., Materials and Methods: In phase I, nine adult male dogs had the bilateral neurovascular bundles (NVBs) dissected. A small intravenous catheter placed directly into the erectile bodies of the penis was used to record the intracorporal pressure (ICP). Erection was induced by electrical stimulation of the NVB on each side. After intraoperative randomization to treatment or control, 5 mL of FloSeal was unilaterally applied along the NVB on the treatment side. In phase II, after 2 weeks of survival, both control and treatment NVB were again dissected and re-stimulated to produce an erectile response. The mean arterial pressure and ICP were recorded. The prostate and the NVBs were then removed for histological analysis., Results: All dogs achieved erections after electrical stimulation on both the control and treatment side. There was no statistically significant difference in absolute ICP, pressure increase from baseline or systemic pressure after stimulating the NVB on the treatment side between phases I and II. Histological analysis showed a giant-cell reaction around the FloSeal granules and mild focal perineural oedema, but the cavernous nerves were otherwise normal in appearance., Conclusion: In this short-term functional study, FloSeal did not adversely affect cavernous nerve function, measured as the erectile response to electrical stimulation. We found no evidence contraindicating its use during radical prostatectomy.

The 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7 H-pyrazolo[4,3-d]pyrimidin-7-one, sildenafil, is a cGMP-specific phosphodiesterase-5 (PDE5) inhibitor used for penile erectile dysfunction. In the search for more potent and selective PDE5 inhibitors, new sildenafil analogues (6a-v), characterized by the presence on the sulfonyl group in the 5' position of novel N-4-substituted piperazines or ethylenediamine moiety, were prepared by traditional and microwave-assisted synthesis and tested in rabbit isolated aorta and corpus cavernosum. Similarly to sildenafil, several analogues showed IC50 values in the nanomolar range. In the in vitro studies, all the tested compounds caused concentration-dependent relaxations in both rabbit isolated aorta and corpus cavernosum. All sildenafil analogues potentiated the nitric oxide-dependent vasodilation in endothelium-intact rabbit aorta. Compound 6f exhibited great pEC50 value in corpus cavernosum, and compounds 6r and 6u in isolated aorta were found as potent as sildenafil for inhibiting PDE5. Because several analogues were significantly more lipophilic than sildenafil, these compounds may offer a new lead for development of new sildenafil analogues.

The authors aimed to study the skin surface bioheat perfusion model described in part I numerically. The influence of each constituent in the determination of surface temperature profile was statistically examined. The theoretically derived data will then be benchmarked with clinically measured data to develop the artificial intelligence system for the diagnosis of erectile dysfunction (ED). The new approach is based on the hypothesis that there exists a constitutive relationship between surface temperature profiles and the etiology of ED. By considering the penis model as a group of reservoirs with irregular cavities, we built a numerical model, simplified to save computational costs while still realistically able to represent the actual for partial differential calculation. Incompressible blood flow was assumed coupled with the classical bioheat transfer equation which was solved using the finite element method. Isotropic homogeneous heat diffusivity was assigned to each tissue layer. The results of simulations were tested for sensitivity analysis and further optimized to obtain the 'best' signal from the simulations using the Taguchi method. Four important parameters were identified and analysis of variance was performed using the 2(n) design (n=number of parameters, in this case, 4). The implications of these parameters were hypothesized based on physiological observations. Our results show that for an optimum signal-to-noise (S/N) ratio, the noise factors (thermal conductivity of skin, A and tunica albuginea, B) must be set high and low, respectively. Hence, at this setting, the signal will be captured based on the perfusion rate of the boundary layer of the sinusoidal space and the blood pressure (perfusion of sinusoidal space, C and blood pressure, D) will be optimal as their S/N ratios (C (low) and D (low)) are larger than the former.

The extent to which skin surface bioheat perfusion predicts penile physiological response such as an erection has not been extensively investigated. A biomechanical engineering study was performed to compare bioheat distribution on penile skin surface resulting from an induced erection at steady state to examine the efficacy of such method as an adjunct tool for the diagnosis and classification of erectile dysfunction (ED) due to different etiology. We based our arguments on the principle that blood vessel activity and perfusion to corpus cavernosa at the erect state are almost always higher than that in the flaccid state. Our results showed that a difference of 0.1-0.3 degrees C can be observed and hence used to develop database of 'smart diagnosis' for ED using the machine artificial intelligence. It is anticipated that such basic research into blood flow is critical, as blood perfusion into corpus cavernosa is the most influential factor determining functional erectile quality contributing to successful coitus. Increased understanding of the hemodynamic response profile contributes toward optimal treatment and thus enables clinicians to adopt an appropriate management scheme for ED.

Previous studies have demonstrated that partial bladder outlet obstruction (PBOO) in the rabbit induces an increase in corpus cavernosum smooth muscle (CCSM) tone, which may make it difficult for the CCSM to relax. Thus, to determine whether the corpus cavernosum restores relaxation after reversal of PBOO, we investigated the physiologic, histologic, and cell biology in penises obtained from rabbits 4 weeks and 8 weeks after reversal of PBOO. CCSM from bladder outlet-obstructed and obstruction-reversed rabbits showed significant decreases in the contractile responses to phenylephrine. The relaxation responses to electrical field stimulation (EFS), ATP, acetylcholine, and sodium nitroprusside (SNP) were decreased in obstructed and reversed for 4 weeks groups. By 8 weeks of reversal, the relaxation of CCSM was increased gradually in response to EFS, SNP, and acetylcholine. However, the response to ATP did not result in the relaxation of CCSM to control levels. The ratio of SM to collagen decreased after obstruction and remained low after reversal. Expression of both isoforms of Rho kinase (ROK) was increased in obstruction groups. At 4 weeks of reversal, the expression of ROK alpha remained at obstruction level, whereas ROK beta expression decreased in comparison with the obstruction group. By 8 weeks of reversal, expression of both ROK alpha and beta significantly decreased when compared with the obstruction group. These results suggested that the poor relaxation response at reversal of 4 weeks was associated with incomplete decreased expression of both isoforms of ROK, whereas the incomplete recovery of the CCSM relaxation response at reversal of 8 weeks may be associated with structural alterations in the CC and irreversible damage from PBOO.

Hypoxia is a normal, physiological condition in penile tissue, which is interrupted by reoxygenation associated to sleep-related erections. We previously described in the rat that a penile fibrosis and overexpression of the pro-fibrotic endothelin-1 type B receptor (ETB) are associated to prolonged (3 months) hypoxia induced by the bilateral surgical resection of the cavernous nerves (bilateral cavernous neurotomy (BCN)). The aim of the present study was to define the time frame in which BCN induces hypoxia and ETB overexpression in the penile tissue. In addition, we studied the time-dependency of the rescuing effect of an acute administration of the phosphodiesterase type 5 inhibitor, sildenafil. We found that BCN induced penile hypo-oxygenation (immunohistochemistry for Hypoxyprobe), penile ETB mRNA overexpression (quantitative real-time reverse transcriptase polymerase chain reaction) and hypersensitivity to the ETB agonist IRL-1620 (in vitro contractility study). Sildenafil treatment was able to counteract all these alterations (penile hypoxygenation, hyper-sensitivity to IRL-1620 and ETB overexpression), with its effect being more evident the earlier it was administered.

Aim: We prospectively investigated health-related quality of life (HR-QOL), including sexual function and sexual bother, in patients who underwent nerve grafting during a radical prostatectomy in comparison with those who underwent a non-nerve-sparing radical prostatectomy., Methods: Between August 2001 and May 2004, radical prostatectomies were performed on 69 patients with clinical T1-T2N0/M0 prostate cancer. Of these, 66 patients (22: nerve-grafting patients, 44: non-nerve-sparing and non-nerve-grafting patients) were enroled into this study. The observation periods ranged from 12-46 months (median: 29 months). The general HR-QOL was measured with the SF-36 General Health Survey and disease-specific HR-QOL was measured with the University of California Los Angeles-Prostate Cancer Index., Results: Penile tumescence was observed in 11 out of 15 (73.3%) prostate-specific antigen failure-free patients who underwent unilateral nerve grafting with contra-lateral nerve-sparing or bilateral nerve grafting. Vaginal penetration was observed in six out of 15 (40.0%) patients. The time for partial erection and for intercourse, respectively, ranged from 3-21 months (median = 6 months) and 6-36 months (median = 13.5 months). There were no significant differences in general HR-QOL changes over time between the nerve-grafting patients and the patients without any nerve-preserving procedures. The sexual function score was significantly better in the nerve-grafting (bilateral nerve graft or unilateral nerve graft with contra-lateral nerve-sparing) patients than in the non-nerve-sparing/non-nerve-grafting patients. The sexual bother score, however, was more serious for the patients who underwent nerve-grafting surgery than for the non-nerve-sparing/non-nerve-grafting patients., Conclusion: Sexual bother is serious for patients who attempt to maintain sexual function after special surgical procedures, such as nerve-grafting surgery. We should be aware that careful counseling is needed to avoid impatient and excessive hope for the recovery of sexual function.

Penises are inflatable intromittent organs that transfer sperm to a female during copulation. Most of the time, males store their penises in a flexible detumesced state, but they can rapidly inflate them with blood when an opportunity for reproductive behavior arises. In mammals, the primary erectile tissue is called the corpus cavernosum; its anatomy is a close match to a model hydroskeleton reinforced by an axial orthogonal fiber array. The wall of the corpus cavernosum contains layers of highly organized collagen fibers arranged at 0 degrees and 90 degrees to the penile long axis. Flaccid wall tissue is folded. Collagen fiber straightening during erection expands the tunica albuginea and increases both its stiffness and its second moment of area. These changes make the entire penis larger and harder to bend. Axial orthogonal fiber reinforcement affects the mechanical behavior of the erect corpus cavernosum, making it resistant to tensile, compressive, and bending forces.

Tissue engineering techniques, with their potential applied value for penile reconstruction, are of special interest for andrologists. The purpose of this review is to appraise the recent development and publications in this field. In the past few years, great efforts have been made to develop corpus cavernosum tissues by combining smooth muscle and endothelial cells seeded on biodegradable polyglycolic acid polymer (PGA) or acellular corporal collagen matrices scaffolds. Animal experiment demonstrated that the engineered corpus cavernosum achieved adequate structural and functional parameters. Engineered cartilage rods as an alternative for the current clinical standard of semirigid or inflatable penile implants could be created by seeding chondrocyte cylindrical PGA. A series of studies showed that, compared to commercially available silicone implants, the engineered rods were flexible, elastic and stable. Besides, a variety of decellularized biological materials have been used as grafts not only for substitution of tunica albuginea but also for penile enhancement, with promising results. For treating erectile dysfunction, a new approach to recovering erectile function by cell-based therapy could be the injection of functional cells into corpus cavernosum, which seemed to be promising when combined with cell manipulation by gene therapy prior to cell transfer.

Purpose of Review: The review discusses the efficacy of reconstructing the neurovascular bundle to regain sexual function if nerve-sparing prostatectomy is unfeasible., Recent Findings: Eleven studies could be found describing the reconstruction of neurovascular bundles. All reconstructive procedures displayed technical inadequacies. The effectiveness of unilateral neurovascular bundle reconstruction remains statistically insignificant when compared with procedures without reconstruction. The efficacy of reconstructing both neurovascular bundles ranges between 0 and 43%. Concerning basic anatomy, the neurovascular bundle contains fibers innervating the cavernous nerves, prostate, rectum, and levator ani muscle. The terms cavernous nerve and neurovascular bundle have often been wrongly considered synonymous. The pelvic splanchnic nerves probably do not join the neurovascular bundle proximal to the bladder/prostate junction but rather at variable distances from 10 to 20 mm distal to it. Therefore, described proximal coaptation sites at the bladder/prostate junction possibly encompass only the hypogastric nerve., Summary: Modest clinical results are partly due to inadequate surgical techniques and are mainly due to the anatomical and topographical complexity of the cavernous nerves. Contemporary nerve grafting techniques probably do not allow for the regeneration of all cavernous nerves.

Hypogonadism may play a significant role in the pathophysiology of erectile dysfunction (ED). A threshold level of testosterone may be necessary for normal erectile function. Testosterone replacement therapy is indicated in hypogonadal patients and is beneficial in patients with ED and hypogonadism. Monotherapy with testosterone for ED is of limited effectiveness and may be most promising in young patients with hypogonadism and without vascular risk factors for ED. A number of laboratory and human studies have shown the combination of testosterone and other ED treatments, such as phosphodiesterase type 5 (PDE5) inhibitors, to be beneficial in patients with ED and hypogonadism, who fail PDE5 inhibitor therapy alone. There is increasing evidence that combination therapy is effective in treating the symptoms of ED in patients for whom treatment failed with testosterone or PDE5 inhibitors alone. Testosterone replacement therapy has potentially evolved from a monotherapy for ED in cases of low testosterone, to a combination therapy with PDE5 inhibitors. Screening for hypogonadism may be useful in men with ED who fail prior PDE5 inhibitors, especially in populations at risk for hypogonadism such as type 2 diabetes and the metabolic syndrome.