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Background: Transformation of resident fibroblasts to profibrotic myofibroblasts in the tunica albuginea is a critical step in the pathophysiology of Peyronie's disease (PD). We have previously shown that myofibroblasts do not revert to the fibroblast phenotype and we suggested that there is a point of no return at 36 hours after induction of the transformation. However, the molecular mechanisms that drive this proposed irreversibility are not known., Aim: Identify molecular pathways that drive the irreversibility of myofibroblast transformation by analyzing the expression of the genes involved in the process in a temporal fashion., Methods: Human primary fibroblasts obtained from tunica albuginea of patients with Peyronie's disease were transformed to myofibroblasts using transforming growth factor beta 1 (TGF-β1). The mRNA of the cells was collected at 0, 24, 36, 48, and 72 hours after stimulation with TGF-β1 and then analyzed using a Nanostring nCounter Fibrosis panel. The gene expression results were analyzed using Reactome pathway analysis database and ANNi, a deep learning-based inference algorithm based on a swarm approach., Outcomes: The study outcome was the time course of changes in gene expression during transformation of PD-derived fibroblasts to myofibroblasts., Results: The temporal analysis of the gene expression revealed that the majority of the changes at the gene expression level happened within the first 24 hours and remained so throughout the 72-hour period. At 36 hours, significant changes were observed in genes involved in MAPK-Hedgehog signaling pathways., Clinical Translation: This study highlights the importance of early intervention in clinical management of PD and the future potential of new drugs targeting the point of no return., Strengths and Limitations: The use of human primary cells and confirmation of results with further RNA analysis are the strengths of this study. The study was limited to 760 genes rather than the whole transcriptome., Conclusion: This study is to our knowledge the first analysis of temporal gene expression associated with the regulation of the transformation of resident fibroblasts to profibrotic myofibroblasts in PD. Further research is warranted to investigate the role of the MAPK-Hedgehog signaling pathways in reversibility of PD., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society of Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Peyronie's disease (PD) is a fibrotic disorder characterized by plaque formation in the tunica albuginea (TA) of the penis, and we have previously shown that inhibition of transformation of TA-derived fibroblasts to myofibroblasts using a combination phosphodiesterase type 5 (PDE5) inhibitors and selective estrogen receptor modulators (SERMs) is effective in slowing the progression of early PD., Aim: The study sought to investigate whether combinations of statins with PDE5 inhibitors or SERMs would affect myofibroblast transformation in vitro., Methods: Primary fibroblasts were isolated from TA of patients with PD and stimulated with transforming growth factor β1 in the absence and presence of a range of concentrations of statins, PDE5 inhibitors, SERMs, and their combinations for 72 hours before quantifying α-smooth muscle actin using in-cell enzyme-linked immunosorbent assay., Outcomes: The prevention of transforming growth factor β1-induced transformation of TA-derived fibroblasts to myofibroblasts was measured in vitro., Results: Statins (simvastatin, lovastatin) inhibited myofibroblast transformation in a concentration-dependent manner with half maximal inhibitory concentration values of 0.77 ± 0.07 μM and 0.8 ± 0.13 μM, respectively. Simvastatin inhibited myofibroblast transformation in a synergistic fashion when combined with vardenafil (a PDE5 inhibitor; log alpha >0). Combination of tamoxifen (a SERM) and simvastatin did not show synergy (log alpha <0). When 3 drugs (simvastatin, vardenafil, and tamoxifen) were combined, the effect was not synergistic, but rather was additive., Clinical Implications: A combination of a statin with a PDE5 inhibitor might be useful in the clinic to slow the progression of the disease in patients with early PD; however, caution should be taken with such a combination because of the reported myopathy as a side effect., Strengths and Limitations: The use of primary human cells from patients with PD is a strength of this study. The mechanisms by which these drug classes exert synergy when used in combination was not investigated., Conclusion: This is the first demonstration of an antifibrotic synergy between statins and PDE5 inhibitors., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society of Sexual Medicine.)

Rationale: Penile Prosthesis Implantation (PPI) is the definitive treatment for Erectile Dysfunction not responsive to conservative management strategies. Furthermore, it is a staple of surgical treatment of severe Peyronie's Disease (PD) and phallic reconstruction. Expert implantologists occasionally face disastrous complications of penile implant surgery which can prove to be very challenging. In this article we present a selected number of case reports which exemplify this kind of situations and discuss management strategies while also commenting on plausible aetiologies., Patients' Concerns: The first case describes a PPI performed in end-stage fibrotic corpora after multiple instances of implantation/explant. The second and third cases show two diametrically opposed approaches to the management of glans necrosis after PPI in post-radical cystectomy patients. The fourth case describes the history of a diabetic patient suffering from glandular, corporal and urethral necrosis after a complicated PPI procedure. The fifth case reports the surgical treatment of a case of recurring PD due to severe scarring and shrinking of a vascular Dacron patch applied in a previous operation., Diagnosis: Complication diagnosis in all patient was mainly clinical, intra- and postoperative, with Penile Color Doppler Ultrasonography performed when needed in order to demonstrate penile blood flow., Interventions: The patients underwent complex surgical procedures that addressed each specific complication. Complex penile implants with fibrosis-related complications, penile prosthesis explant with and without surgical debridement of necrotic areas, penile prosthesis explant with necrotic penile shaft and urethral amputation with perineostomy, and complex corporoplasty with scar tissue excision and patch application with PPI were performed in the five patients., Outcomes: Penile anatomy and erectile function with PPI was achieved in 4 out of 5 patients. 1 of 5 patient is scheduled to undergo a total phallic reconstruction procedure at the time of this writing., Lessons: Management of disastrous complications of penile implant surgery can be very challenging even in expert hands. In-and-out knowledge of possible PPI and PD complications is required to achieve an acceptable outcome. Bettocchi C, Osmonov D, van Renterghem K, et al. Management of Disastrous Complications of Penile Implant Surgery. J Sex Med 2021;18:1145-1157., (Copyright © 2021 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Background: A chief complaint of men with stuttering priapism (SP) and sleep-related painful erections (SRPE) is bothersome nocturnal erections that wake them up and result in poor sleep and daytime tiredness. SP and SRPE are rare entities that have similarities in their clinical features, but that require different treatment approaches., Aim: The aim of this study was to describe the clinical features, investigations, and effective management options for men with SP and SRPE., Methods: Retrospective cohort study of 133 men with bothersome nocturnal painful erections that attended a tertiary andrology unit between 2004 and 2018. These men were divided into 3 groups. Group 1 (n = 62) contains men with sickle cell SP; group 2 (n = 40) has men with non-sickle cell SP and group 3 (n = 31) contains men with SRPE., Outcome: To determine the effectiveness of medical and surgical treatments for men with SP and SRPE., Results: Hydroxyurea and automated exchange transfusion were the most effective treatment options in the sickle cell SP group. Hormonal manipulation and α-agonist therapies were effective in both SP cohorts (groups 1 and 2). Baclofen was the most effective therapy in men with SRPE. For men who failed medical management, implantation of a penile prosthesis resulted in complete resolution of the symptoms in men with SP (groups 1 and 2). Surgical management (penile prosthesis implantation and embolization) did not improve the patients' symptoms in the SRPE group., Clinical Implications: This study differentiates between sickle cell SP, non-sickle cell SP, and SRPE and describes effective treatment options for each group., Strengths & Limitations: This is the largest cohort study for both SP and SRPE, respectively. Limitations include its retrospective nature and single-center experience., Conclusion: Managing men in these 3 groups differently and in accordance with the proposed treatment pathway provides a more structured approach to the management of these rare conditions. Johnson M, McNeillis S, Chiriaco G, et al. Rare Disorders of Painful Erection: A Cohort Study of the Investigation and Management of Stuttering Priapism and Sleep-Related Painful Erection. J Sex Med 2021;18:376-384., (Copyright © 2020. Published by Elsevier Inc.)

Background: Myofibroblast transformation is a key step in the pathogenesis of Peyronie's disease (PD). Phosphodiesterase type 5 inhibitors (PDE5is) and selective estrogen receptor modulators (SERMs) can prevent the formation of fibrosis in in vitro and in vivo models of PD. However, it is unknown whether these drugs can also reverse established fibrosis., Aim: To investigate whether PDE5is and SERMs can reverse transforming growth factor beta 1 (TGF-β1)-induced myofibroblast transformation and determine the point of no return., Methods: In-Cell enzyme-linked immunosorbent assay was used to quantify TGF-β1-induced myofibroblast transformation of human primary fibroblasts isolated from tunica albuginea (TA) of patients undergoing surgery for treatment of PD. Extracellular matrix production and collagen contraction assays were used as secondary assays. Reverse transcription-quantitative polymerase chain reaction and In-Cell enzyme-linked immunosorbent assay were used to measure drug target expression. PDE5i (vardenafil) and SERM (tamoxifen) were applied at various time points after TGF-β1., Outcomes: Reversibility of myofibroblast transformation and drug target expression were investigated in a time-dependent manner in TA-derived fibroblasts., Results: Vardenafil or tamoxifen could not reverse the myofibroblast traits of alpha-smooth muscle actin expression and extracellular matrix production, whereas only tamoxifen affected collagen contraction after 72 hours of TGF-β1 treatment. Phosphodiesterase 5A and estrogen receptor (ER)-β were downregulated after 72 hours, and estrogen receptor -α protein could not be quantified. Tamoxifen could prevent myofibroblast transformation until 36 hours after TGF-β1 treatment, whereas vardenafil could prevent only 24 hours after TGF-β1 treatment. This was mirrored by downregulation of drug targets on mRNA and protein level. Furthermore, antifibrotic signaling pathways, peroxisome proliferator-activated receptor gamma and betaglycan (TGFB receptor III), were significantly downregulated after 36 hours of TGF-β1 exposure, as opposed to upregulation of profibrotic thrombospondin-1 at the same time point., Clinical Translation: This study suggests that using PDE5is and SERMs might only help for early-phase PD and further highlights the need to test drugs at the appropriate stage of the disease based on their mechanism of action., Strengths & Limitations: The study uses primary human TA-derived fibroblasts that enhances translatability of the results. Limitations include that only 1 example of PDE5i- and SERM-type drug was tested. Time course experiments were only performed for marker expression experiments and not for functional assays., Conclusion: This is the first study to demonstrate that timing for administration of drugs affecting myofibroblast transformation appears to be vital in in vitro models of PD, where 36 hours of TGF-β1 treatment can be suggested as a "point of no return" for myofibroblast transformation. Ilg MM, Stafford SJ, Mateus M, et al. Phosphodiesterase Type 5 Inhibitors and Selective Estrogen Receptor Modulators Can Prevent But Not Reverse Myofibroblast Transformation in Peyronie's Disease. J Sex Med 2020;17:1848-1864., (Copyright © 2020 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Ischemic priapism (IP) is the most common form of priapism. In cases of priapism persisting for >36 hours, conservative management usually fails, and the patients' erectile tissue will be inevitably compromised, resulting in corporal fibrosis, shortening of the penis, and refractory erectile dysfunction. In this subset of patients, early implantation of a penile prosthesis (PP) could be a solution for both the priapic episode and the erectile dysfunction., Aim: To analyze the current literature with regard to the correlation between refractory ischemic priapism and immediate implantation of PP., Methods: An extensive literature research was conducted to retrieve studies focusing on immediate PP implantation in patients suffering from refractory ischemic priapism (RIP)., Main Outcome Measures: We evaluated the functional outcomes of patients who have undergone the immediate insertion of a PP as treatment for an acute episode of IP refractory to medical therapy or shunt surgery., Results: Nine studies were included in this systematic review, including 3 case reports and 6 retrospective analyses. All studies agreed that in patients with RIP, early insertion of a PP is a safe and effective procedure, and all studies but 1 preferred malleable implants to inflatable implants., Conclusion: The systematic review does not demonstrate superiority of immediatePP implantation over delayed PP implantation, because none of the studies was designed with this purpose. However, considering the reduced complication rate and the ease of the procedure, all studies are in favor of early implantation over delayed implantation. Capece M, La Rocca R, Mirone V, et al. A Systematic Review on Ischemic Priapism and Immediate Implantation: Do We Need More Data? Sex Med Rev 2018;7:530-534., (Copyright © 2019 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Peyronie's disease (PD) is a chronic fibrotic disease of the penis affecting a significant number of men worldwide without effective medical treatments. Myofibroblasts are pivotal in the pathogenesis of PD. Adenosine and adenosine receptors have been suggested to be involved in the pathophysiology of fibrosis., Aim: To understand the role of adenosine receptors in myofibroblast transformation in PD., Methods: Fibroblasts were isolated from the non-PD tunica albuginea (TA) tissue and PD plaque tissue and were transformed into myofibroblasts using transforming growth factor (TGF)-β1. Quantification of α-smooth muscle actin and adenosine receptors (adenosine receptor A1 [ADORA1], adenosine receptor A2A, adenosine receptor A2B [ADORA2B], and adenosine receptor A3) was performed using immuno-cytochemistry, in-cell enzyme-linked immuno-sorbent assay (ICE), and real-time reverse transcription quantitative polymerase chain reaction. The effect of various adenosine receptor agonists or antagonists on TGF-β1-induced myofibroblast transformation was measured using ICE., Outcomes: Expression of adenosine receptors in myofibroblasts obtained from human TA and the effect of adenosine receptor ligands on myofibroblast transformation were investigated., Results: The experiments showed that the protein and messenger RNA levels of α-smooth muscle actin in non-PD TA cells and PD plaque-derived cells were significantly higher in cells exposed to TGF-β1 than those not treated with TGF-β1. 2 of 4 adenosine receptors (ADORA1 and ADORA2B) were found to be expressed in both cell populations. Among various adenosine receptor agonists/antagonist investigated, only ADORA2B agonist, BAY 60-6583, significantly inhibited myofibroblast transformation in a concentration-dependent manner when applied simultaneously with TGF-β1 (IC 50  = 30 μmol/L)., Clinical Translation: ADORA2B agonists may be clinically efficacious in early-stage PD. STRENGTHS & LIMITATIONS: The strength of this study is the use of primary fibroblasts from human TA. Limitation of the study is the high concentrations of the ligands used., Conclusion: The effect of an ADORA2B agonist on TGF-β1-induced myofibroblast transformation shows a novel potential therapeutic target for PD if applied during early, non-stable phase of PD. Mateus M, Ilg MM, Stebbeds WJ, et al. Understanding the Role of Adenosine Receptors in the Myofibroblast Transformation in Peyronie's Disease. J Sex Med 2018;15:947-957., (Copyright © 2018 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Because of the low incidence of penile fracture, many aspects of the diagnostic process and of the surgical and functional outcomes are rarely reported., Aim: To systematically review the current literature on the surgical management of penile fracture, focusing on etiology, diagnosis, functional outcomes, and postoperative complications., Methods: The present review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) declaration standards for systematic reviews. A systematic search for the terms penile fracture, fracture of penis, trauma of penis, rupture of corpora cavernosa, and immediate management of penile fracture was been carried out in the PubMed, EMBASE, Cochrane, SCOPUS, and Science Citation Index databases., Main Outcome Measures: Etiology of penile fracture, clinical presentation, types of radiologic investigations and their accuracy, surgical approach, suture material used for tunica repair, timing of surgical exploration, intraoperative findings, surgical complications, and functional outcomes., Results: The total number of patients analyzed was 438, and the patients' an average age was 36 years. The most frequent reported cause of penile fracture was sexual intercourse (80% of cases). The most common finding at examination was a penile hematoma (97.5%). Although operator dependent, in experienced hands, ultrasonography was found to be a useful tool in confirming the location of the albuginea tear and identifying the presence of any concomitant urethral injury, helping the surgeon to choose the best surgical approach. Early surgical repair of a penile fracture was found to be a safe procedure, although long-term complications are not uncommon. Tertiary referral centers that managed a larger number of cases seemed to obtain more satisfactory long-term results with a significantly smaller number of complications., Conclusion: A low incidence of postoperative complications and full satisfactory functional outcomes are reported when early repair is performed in high-volume centers. Falcone M, Garaffa G, Castiglione F, Ralph DJ. Current Management of Penile Fracture: An Up-to-Date Systematic Review. Sex Med Rev 2018;6:253-260., (Copyright © 2017 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Current treatments for erectile dysfunction (ED) have some limitations., Aim: This study evaluated the efficacy and tolerability of MED2005, a 0.2% glyceryl trinitrate topical gel, formulated into an enhanced absorption topical delivery system (DermaSys), administered on demand, in the treatment of ED., Methods: This randomized, double-blinded, placebo-controlled, phase II crossover trial involved 232 men with ED (231 treated, 230 assessed for efficacy) and their partners. After a 4-week run-in period, patients were randomized to 1 of 2 treatment sequences, MED2005-placebo or placebo-MED2005. Each treatment was given for 4 weeks, separated by a 1-week washout interval. Efficacy was assessed by the International Index of Erectile Function (IIEF), the Sexual Encounter Profile, a Global Assessment Questionnaire (GAQ), and specific questions about the onset and offset of action and treatment preferences (patients and partners)., Outcomes: The primary outcome measure was the IIEF erectile function domain (IIEF-EF) score. Other efficacy assessments were secondary outcomes., Results: The mean baseline IIEF-EF score was 17.1 (SD = 5.7), and this increased to 19.6 (SD = 7.5) after MED2005 treatment and 18.5 (SD = 6.7) after placebo (P = .0132). Overall, 23.1% of patients showed a clinically relevant (≥4-point) increase in IIEF-EF scores after treatment with MED2005 only compared with 14.5% who responded after MED2005 and placebo, 14.0% who responded after placebo only, and 48.4% who did not respond after either treatment (P = .0272). MED2005 also was associated with significant improvements compared with placebo in the other IIEF domains, and this was consistent with patients' and partners' responses to the GAQ. For all assessments, significant effects of MED2005 were seen primarily in patients with mild ED. The start of erection was noticed within 5 and 10 minutes in 44.2% and 69.5%, respectively, of all intercourse attempts with MED2005. Patients and partners showed significant preferences for MED2005 over placebo. The most commonly reported adverse events during MED2005 treatment were headache (patients, n = 18 [7.9%]; partners, n = 3 [1.3%]) and nasopharyngitis (patients, n = 13 [5.7%]; partners, n = 2 [0.9%])., Clinical Implications: These findings suggest that topical glyceryl trinitrate could be a useful treatment option in ED., Strengths and Limitations: Strengths of this study include the use of a validated outcome measure. Limitations include the use of only 1 dosage., Conclusion: Further studies are warranted to investigate the efficacy of topical glyceryl trinitrate to include higher doses, thereby improving clinical significance, especially in cases of moderate and severe ED. Ralph DJ, Eardley I, Taubel J, et al. Efficacy and Safety of MED2005, a Topical Glyceryl Trinitrate Formulation, in the Treatment of Erectile Dysfunction: A Randomized Crossover Study. J Sex Med 2018;15:167-175., (Copyright © 2017 Futura Medical. Published by Elsevier Inc. All rights reserved.)

Background: Collagenase Clostridium histolyticum (CCH) is indicated for the treatment of penile curvature in adult men with Peyronie's disease (PD) with palpable plaque and curvature deformity of at least 30° at the start of therapy., Aim: To evaluate the efficacy and safety of CCH plus vacuum-pump therapy with and without penile modeling for the management of PD., Methods: Adult men with PD and penile curvature of at least 30° were randomly assigned to receive CCH 0.58 mg plus vacuum therapy alone (n = 15) or with penile plaque modeling (n = 15). Patients received no more than four treatment cycles (cycle = ∼6-week duration), each consisting of two intralesional injections of CCH administered 24 to 72 hours apart. Vacuum therapy was applied twice daily from 14 days after the second injection of each cycle until the following cycle. Modeling was performed 24 to 72 hours after the second injection of each cycle., Outcomes: The primary end point was change in penile curvature from baseline to week 36; additional end points included changes in Peyronie's Disease Questionnaire (PDQ) domain scores, composite response (≥20% decrease in penile curvature and decrease in PDQ bother score ≥ 1 point), and global response (small but important, moderate, or much improvement in the Global Assessment of PD)., Results: At week 36, improvement in penile curvature from baseline was similar in the two groups (mean change from baseline = -23.7° [SD = 10.9] for CCH + vacuum + modeling and -23.3° [SD = 7.2] for CCH + vacuum; between-group difference = -0.3°, 95% CI = -7.3 to 6.6). Improvements in most PDQ domains, including bother, were observed from baseline to week 36 in the two groups. Most patients were composite (66.7% and 84.6% with CCH + vacuum + modeling and CCH + vacuum, respectively) and global (86.7% and 92.3%, respectively) responders. The most common adverse events were penile contusion, penile swelling, and penile pain., Clinical Implications: Vacuum-pump therapy administered alone or in combination with modeling after CCH treatment could improve PD symptoms., Strengths and Limitations: This was a pilot study with a small sample and limited follow-up duration., Conclusion: CCH and vacuum-pump therapy (alone or combined with modeling) could be an appropriate consideration for men with PD and warrants further investigation. Ralph DJ, Abdel Raheem A, Liu G. Treatment of Peyronie's Disease With Collagenase Clostridium histolyticum and Vacuum Therapy: A Randomized, Open-Label Pilot Study. J Sex Med 2017;14:1430-1437., (Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.)

Introduction: Penile prosthesis infections remain challenging despite advancements in surgical technique, device improvements, and adoption of antibiotic prophylaxis guidelines., Aim: To investigate penile prosthesis infection microbiology to consider which changes in practice could decrease infection rates, to evaluate current antibiotic prophylaxis guidelines, and to develop a proposed algorithm for penile prosthesis infections., Methods: This retrospective institutional review board-exempt multi-institutional study from 25 centers reviewed intraoperative cultures obtained at explantation or Mulcahy salvage of infected three-piece inflatable penile prostheses (IPPs). Antibiotic usage was recorded at implantation, admission for infection, and explantation or salvage surgery. Cultures were obtained from purulent material in the implant space and from the biofilm on the device., Main Outcome Measures: Intraoperative culture data from infected IPPs., Results: Two hundred twenty-seven intraoperative cultures (2002-2016) were obtained at salvage or explantation. No culture growth occurred in 33% of cases and gram-positive and gram-negative organisms were found in 73% and 39% of positive cultures, respectively. Candida species (11.1%), anaerobes (10.5%) and methicillin-resistant Staphylococcus aureus (9.2%) constituted nearly one third of 153 positive cultures. Multi-organism infections occurred in 25% of positive cultures. Antibiotic regimens at initial implantation were generally consistent with American Urological Association (AUA) and European Association of Urology (EAU) guidelines. However, the micro-organisms identified in this study were covered by these guidelines in only 62% to 86% of cases. Antibiotic selection at admissions for infection and salvage or explantation varied widely compared with those at IPP implantation., Conclusion: This study documents a high incidence of anaerobic, Candida, and methicillin-resistant S aureus infections. In addition, approximately one third of infected penile prosthesis cases had negative cultures. Micro-organisms identified in this study were not covered by the AUA and EAU antibiotic guidelines in at least 14% to 38% of cases. These findings suggest broadening antibiotic prophylaxis guidelines and creating a management algorithm for IPP infections might lower infection rates and improve salvage success. Gross MS, Phillips EA, Carrasquillo RJ, et al. Multicenter Investigation of the Micro-Organisms Involved in Penile Prosthesis Infection: An Analysis of the Efficacy of the AUA and EAU Guidelines for Penile Prosthesis Prophylaxis. J Sex Med 2017;14:455-463., (Copyright © 2017 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Obesity is an independent risk factor for erectile dysfunction (ED) and lower urinary tract symptoms (LUTS). Bariatric surgery has been shown to improve erectile function and urinary symptoms in medium- to long-term studies (3- to 12-month postoperative follow-up)., Aim: To investigate the early effect (1 month postoperatively) of bariatric surgery on ED and LUTS, which has not previously been investigated., Methods: Morbidly obese men (body mass index > 35 kg/m 2 ) undergoing bariatric surgery were asked to complete the International Index of Erectile Function (IIEF) and International Prostate Symptom Score (IPSS) questionnaires before surgery and 1, 3, and 6 months after surgery., Main Outcome Measure: The influence of bariatric surgery on urogenital function, body mass index, fasting blood glucose, and glycated hemoglobin were analyzed using parametric and non-parametric tests for paired samples., Results: Of 30 patients who completed the study, 18 reported ED (IIEF score < 25) and 14 reported moderate or severe LUTS (IPSS ≥ 8) before the operation. Twelve patients had ED and moderate or severe LUTS. IIEF score, IPSS, body mass index, percentage of weight loss, fasting blood glucose, and glycated hemoglobin showed significant and rapid improvement after bariatric surgery starting at the 1-month postoperative time point and improvement continued throughout the study in all patients with ED or moderate to severe LUTS., Conclusion: This is the first study showing improvement in erectile and urinary function within 1 month after bariatric surgery, an effect that was parallel to glycemic improvement and weight loss., (Copyright © 2016 International Society for Sexual Medicine. All rights reserved.)

The Surgical Techniques Section is sponsored in part by Coloplast., (Copyright © 2016. Published by Elsevier Inc.)

Introduction: Although genital injuries in civilian centers are rare, the scenario is completely different in the battlefield. If the penile distal stump is not adequate for primary reimplantation or it cannot be found, then delayed penile reconstruction needs to be considered., Aim: To report a single-center experience with total phallic reconstruction using radial artery based forearm free flap (RAFFF) after penile traumatic loss., Methods: We retrospectively reviewed the clinical records of 10 patients who underwent total phallic reconstruction with the use of the RAFFF from September 2001 through August 2015 after traumatic amputation of the penis., Main Outcome Measures: Patients' baseline features, surgical outcomes, complications, and satisfaction are reported., Results: The average age at the time of penile reconstruction was 36 years (range = 27-52 years). The causes of penile loss were self-amputation owing to an acute schizophrenic episode (n = 2), road traffic accident (n = 3), blast injury (n = 3), donkey bite (n = 1), and Fournier gangrene (n = 1). The average time from the trauma to reconstruction with the RAFFF was 7 years (range = 2-15 years). The urethral stump was adequate for primary anastomosis, with phallic neourethra construction in six patients. The remaining patients had complete avulsion of the penis and were voiding though a perineal urethrostomy. In consequence, they required a two-stage urethroplasty. An acute arterial thrombosis of the microsurgical anastomosis occurred in two patients and was managed successfully with immediate exploration. A neourethra stricture and fistula occurred in one patient, which needed revision. All patients who underwent complete urethral reconstruction could void and ejaculate from the tip of the phallus. After a median follow-up of 51 months (range = 1-114 months), all patients were satisfied with the size, cosmetic appearance, and sensation of the phallus. Six patients underwent inflatable penile prosthesis implantation and could engage in penetrative sex. However, revision surgery was needed in three patients (infection, n = 2; mechanical failure, n = 1)., Conclusion: Despite the high incidence of postoperative complications and the possible need for multiple operations, in expert hands and in large-volume centers, penile reconstruction with the RAFFF after traumatic loss of the penis yields excellent results and allows patients to regain sexual and urinary functions., (Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Peyronie's disease (PD) is an acquired benign connective tissue disorder that involves the tunica albuginea of the penis and can cause penile deformity and shortening. Because this condition is frequently associated with cardiovascular risk factors, a degree of erectile dysfunction is frequently present. The surgical management of PD should be offered once the acute phase of the disease has settled and the deformity is stable., Aim: To critically review the most recent literature published on the surgical management of PD., Methods: A nonstructured PubMed-based review of the literature published in the last 10 years, searching for the words "Peyronie's disease," "erectile dysfunction," "plication," "grafting," "plaque," and "penile prosthesis," has been carried out., Main Outcome Measure: The outcome of the various surgical procedures is reported., Results: Surgery represents at present the gold standard treatment for PD. The type of procedure should be decided according to the degree of deformity, the quality of the erection, and penile length., Conclusions: Surgery still represents the gold standard treatment in patients with PD and aims at obtaining a penis straight, rigid, and long enough for penetrative sexual intercourse. Adequate preoperative patient's selection, counselling and the choice of the right type of procedure according to the degree of penile shortening, the type of deformity and the quality of the erection are paramount to achieving satisfactory results. Garaffa G, Kuehhas FE, De Luca F, and Ralph DJ. Long-term results of reconstructive surgery for Peyronie's disease. Sex Med Rev 2015;3:113-121., (Copyright © 2015 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Collagenase clostridium histolyticum (CCH; Xiaflex, Auxilium Pharmaceuticals, Inc., Chesterbrook, PA, USA) is a Food and Drug Administration-approved, intralesional treatment for Peyronie's disease (PD)., Aim: The aim of this study was to assess the safety and effectiveness of CCH in the treatment of PD., Methods: This phase 3, open-label study enrolled subjects who were CCH-naïve, were enrolled in a previous pharmacokinetic study, or had received placebo in an earlier phase 2 CCH study. Each treatment cycle included two intralesional injections of CCH 0.58 mg, approximately 24-72 hours apart, and plaque modeling 24-72 hours after the second injection of each cycle. The treatment cycle was repeated after 6 weeks for ≤4 treatment cycles., Main Outcome Measures: The co-primary end points were the mean percent change in penile curvature deformity and the mean improvement in PD bother score (range 0-16) from baseline to week 36., Results: Of the 347 subjects treated with ≥1 injection, 238 had both a penile curvature measurement and a Peyronie's Disease Questionnaire response at baseline and ≥1 subsequent time point. Mean baseline penile curvature deformity was 53.0° and mean PD symptom bother was 7.3. Statistically significant mean improvements from baseline to week 36 were observed in both penile curvature deformity (34.4% [95% confidence interval {CI}, 31.2%, 37.6%]) and PD symptom bother score (3.3 [95% CI, 2.8, 3.7]). Most adverse events (AEs) were mild or moderate in severity and local to the penis. There were three serious treatment-related AEs, two penile hematomas and one corporal rupture; all resolved with treatment., Conclusions: Potentially clinically meaningful and statistically significant improvements in penile curvature deformity and PD symptom bother scores were observed with intralesional injection of CCH compared with baseline in men with PD. CCH was generally well tolerated, with AEs primarily transient and local to injection site. In conjunction with previous studies, the results of this open-label study support the use of CCH in the treatment of PD., (© 2014 International Society for Sexual Medicine.)

Aim: To review the current literature regarding penile prosthesis implantation in acute and chronic priapism., Methods: A nonstructured Pubmed base search using the terms ischemic priapism, penile prosthesis, and refractory erectile dysfunction has been carried out., Main Outcome Measures: Surgical outcome and patient satisfaction following penile prosthesis implantation are reported., Results: Implantation of a penile prosthesis in acute and chronic ischemic priapism is associated with increased complication rates, when compared with virgin implants. Implantation in acute priapism allows the painful priapic episode to settle and to preserve penile length, while implantation in chronic priapism is technically much more challenging and often requires the use of downsized shorter cylinders., Conclusion: Implantation of a penile prosthesis in acute refractory ischemic priapism should be the solution of choice, as the dilatation is easier and allows the preservation of penile length, which is one of the main factors influencing postoperative patient's satisfaction in prosthetic surgery. Garaffa G and Ralph D. Penile prosthesis implantation in acute and chronic priapism. Sex Med Rev 2013;1:76-82., (Copyright © 2013 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Implantation of a penile prosthesis in severely scarred corporal bodies represents a great challenge as fibrosis can compromise dilatation and subsequent closure of the corpora cavernosa and limit size, type, and function of the device., Aim: The aim of this study is to report our experience of simultaneous corporeal reconstruction and penile prosthesis implantation in patients with severe penile contracture consequence of diffuse fibrosis., Methods: Between March 2006 and February 2010, 18 patients with severe penile contracture and coporeal fibrosis underwent simultaneous corporeal reconstruction and placement of a penile prosthesis., Main Outcome Measures: Surgical outcome and complications have been recorded during postoperative follow-up. Patients' satisfaction has been assessed 6 months postoperatively with the administration of the modified erectile dysfunction index of treatment satisfaction questionnaire., Results: Although the dilatation of the corpora was extremely difficult due to the severe fibrosis, a penile prosthesis has been implanted in all patients. A malleable penile prosthesis has been inserted in four patients and a three-piece inflatable device in the remainder. After an average follow-up of 26 months (range 6-36), revision surgery was required in four patients (elective exchange to three-piece inflatable device in three patients and upsizing of the implant in one patient). Although all patients were able to achieve penetrative sexual intercourse, four patients were partially dissatisfied because of significant penile shortening., Conclusion: In expert hands, simultaneous penile prosthesis implantation and corporal reconstruction of severely scarred corpora yield satisfactory results. Patients must be warned that complication rate in presence of severe fibrosis is significantly higher than in virgin cases and that downsized cylinders might be required due to the contracture of the tunica albuginea., (© 2012 International Society for Sexual Medicine.)

Introduction: Due to loss of length, patients who had penile prosthesis implantation for Peyronie's disease (PD) show a statistically significant reduction in their levels of satisfaction when compared with the general implant population., Aim: The aim of this study is to report our experience of penile lengthening with circumferential graft during penile prosthesis implantation in patients with PD and severe penile shortening., Methods: Between March 2006 and February 2008, 23 patients with PD, refractory erectile dysfunction, and severe penile shortening underwent penile lengthening with circumferential graft and concomitant implantation of an inflatable penile prosthesis., Main Outcome Measures: Surgical outcome and complications have been recorded during postoperative follow-up. Patients' satisfaction has been assessed 6 months postoperatively with the administration of the modified Erectile Dysfunction Index of Treatment Satisfaction (EDITS) questionnaire., Results: After an average follow-up of 22 months (range 6-36), 20 patients attended all the postoperative follow-up visits and returned the EDITS questionnaire. An average length gain of 2.8 cm (range 2.2-4.5) was recorded, and all patients were able to cycle the device and engage in penetrative sexual intercourse. Patient recorded complications included diminished glans sensitivity in four (20%) and persistent dorsal curvature of less than 15° in three (15%). Overall, 18 patients (90%) were satisfied with the cosmetic and functional result of surgery., Conclusion: Penile lengthening with circumferential graft during penile prosthesis implantation in patients with PD represents a safe and reproducible technique that yields higher satisfaction rates than penile prosthesis implantation alone in patients with severe penile shortening., (© 2011 International Society for Sexual Medicine.)

Introduction: Lichen sclerosus (LS) of the glans penis is a chronic, progressive, scleroatrophic inflammatory process of unknown etiology affecting the glans penis, prepuce, and urethra and may lead to severe impairment of sexual and urinary function., Aims: To report our experience of surgical management of LS of the glans penis., Main Outcome Measures: Complications, patients' satisfaction, cosmesis, resolution of pain and puritus, and postoperative sexual function and were recorded retrospectively., Methods: The surgical outcome of the 31 patients who have undergone resurfacing of the glans penis with the use of skin grafting for the management of genital LS in our institute is reported., Results: After a median follow-up of 12.8 months, 26 patients (84%) were fully satisfied with cosmetic and functional results, and 71% of them have resumed sexual activity., Conclusions: Resurfacing of the glans penis represents a simple and reproducible technique for the management of LS and yields excellent functional and cosmetic results., (© 2011 International Society for Sexual Medicine.)

Introduction: Many patients with Peyronie's disease (PD) have one or more risk factors (RFs) for atherosclerosis and endothelial dysfunction. It is well recognized that such RFs commonly lead to the development of systemic vascular abnormalities. While not necessarily so, this may implicate vascular dysfunction in its pathogenesis. The cause of PD remains obscure despite intense research over the years and investigating the role of vascular dysfunction in the pathogenesis of PD is a novel approach worth undertaking., Aim: To test our hypothesis that PD is associated with systemic vascular changes even in the absence of RFs for atherosclerosis and endothelial dysfunction., Methods: Vascular function was assessed using high-resolution brachial artery ultrasound in 23 PD patients (aged 30-65 years) without RFs for endothelial dysfunction and atherosclerosis, and 23 age-matched healthy controls. Endothelium-dependent, flow-mediated brachial artery dilation was measured in response to increased shear stress (reactive hyperemia induced by 5 minutes of forearm ischemia). This response was contrasted with that of 400 microg sublingual glyceryl trinitrate, an endothelium-independent vasodilator. Anthropometric characteristics, blood pressure, fasting lipids, and glucose were also measured., Main Outcome Measure: Endothelium-dependent, flow-mediated brachial artery dilation and glyceryl trinitrate-induced endothelium-independent vasodilation., Results: Endothelium-dependent flow-mediated dilation (FMD) was impaired in PD patients compared to controls (5.62 +/- 0.58% vs. 7.46 +/- 0.56%, P = 0.03). In contrast, responses to glyceryl trinitrate were similar in PD patients and controls as were blood pressure, lipid, and glucose values. FMD remained impaired after multivariable adjustment for potential confounders., Conclusion: Patients with Peyronie's disease have evidence of systemic vascular changes in the way of systemic conduit artery endothelial impairment even in the absence of RFs for atherosclerosis and endothelial dysfunction. These wider vascular abnormalities in PD are likely to be of clinical relevance and require further study.

Introduction: Acute priapism can be managed by corporal blood aspirations and the instillation of alpha adrenergic agonists such as phenylephrine if patients present early. Following prolonged ischaemic priapism, this regimen is often unsuccessful, and the use of phenylephrine is limited due to systemic cardiovascular side effects., Aim: To investigate the effects of high-dose phenylephrine on human corpus cavernosal smooth muscle obtained from patients presenting with refractory ischaemic priapism., Methods: Strips of corpus cavernosum were obtained from six patients presenting with prolonged ischaemic priapism (duration 60-240 hours), where detumescence was refractory to conventional doses of phenylephrine. The smooth muscle contractile response to high doses of phenylephrine were then compared with that of normal control corpus cavernosum obtained from four patients undergoing a penectomy for penile cancer. The tissue was then analyzed using TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) to assess its viability., Main Outcome Measures: The in vitro response to high-dose phenylephrine of corpus cavernosum smooth muscle obtained from patients with refractory priapism compared with normal human corpus cavernosum., Results: Corporal blood gas analysis confirmed hypoxia (pO(2) 1.5-2.3 kPa), acidosis (pH 6.9-7.1), and glucopenia (0-0.3 mmol/L) in all six patients confirming the ischaemic nature of the priapism. Application of high doses of phenylephrine produced a marked muscle contraction in the control tissue, but there was no contractile response at all in any of the priapism patients. Analysis with TUNEL indicated widespread smooth muscle cell apoptosis in all the priapism tissue., Conclusions: This study has shown that patients with ischaemic priapism that fails to respond to conventional doses of an alpha-agonist are unlikely to benefit from continual or high-dose phenylephrine administration, as there is usually widespread apoptosis of the cavernosal smooth muscle preventing further contraction.

Background: The aim of this study was to analyse the semen quality of patients before and after gonadotoxic therapy., Patients and Methods: We evaluated semen quality in 314 patients over a 26 year period. The diagnostic categories were leukaemia (n = 13); lymphoma (n = 128); testicular cancer (n = 102); benign conditions (n = 13); and other malignant neoplasms (n = 58). The degree of azoospermia or oligozoospermia for each disease category was recorded. We then analysed the recovery in semen quality over time for each disease category., Results: The mean patient age was 27.9 years (range 13-65 years). A total of 1115 post-treatment semen samples were analysed from 314 patients. There was a significant reduction in the post-treatment sperm concentration, sperm motility and semen volume compared with pre-treatment levels (P < 0.05) in the entire cohort. However, the sperm movement and motility grade remained unaffected. Patients with testicular carcinoma had the lowest pre-treatment sperm concentrations but also the lowest incidence of azoospermia after cancer treatment. Patients with lymphoma and leukaemia had the highest incidence of post-treatment azoospermia and oligospermia. Patients having the largest reductions in their sperm concentration after treatment required the longest recovery period for spermatogenesis. The diagnostic category was the only significant predictor of post-treatment azoospermia., Conclusion: Gonadotoxic treatment results in a significant reduction in sperm quality. The type of cancer or disease, and the pre-treatment sperm concentrations were found to be the most significant factors governing post-treatment semen quality and recovery of spermatogenesis. All categories of patients displayed varying degrees of azoospermia and oligozoospermia, and recovery of gonadal function from these states was not significant. This highlights the importance of ensuring sperm banking before treatment, including for patients with benign conditions. Several factors and associations are discussed further in order to give an insight into the pre- and post-gonadotoxic treatment effects.

Introduction: In conditions with severe deficiency of endogenous nitric oxide (NO), such as long-term diabetes and cavernosal nerve injury, phosphodiesterase type 5 (PDE5) inhibitors have reduced efficacy in the treatment of erectile dysfunction. NO-releasing PDE5 inhibitors could be an alternative therapeutic approach in such cases., Aim: We therefore aimed to compare sildenafil and NO-releasing sildenafil (NCX-911) in relaxing human corpus cavernosum in the absence or presence of endogenous NO., Methods: The two compounds were compared in reducing the phenylephrine-induced tone of human corpus cavernosum in the presence or absence of an inhibitor of NO synthase (L-NAME; 500 microM) or an inhibitor of soluble guanylate cyclase (ODQ, 10 microM)., Results: NCX-911 was as potent as sildenafil in control conditions (EC(50) = 733.1 +/- 94.4 nM and 800.7 +/- 155.8 nM, respectively). The potency of NCX-911 was not altered but that of sildenafil decreased significantly in the presence of L-NAME (EC(50) = 980.4 +/- 106.7 nM and 2446.7 +/- 256.8 nM, respectively; P < 0.001 for sildenafil vs. control). Both compounds below 1 microM failed to induce relaxation in the presence of ODQ (EC(50) = 6,578 +/- 1150 nM and 6,488 +/- 938 nM for NCX-911 and sildenafil, respectively)., Conclusion: These results show that the potency of NCX-911 was maintained unlike sildenafil in the absence of endogenous NO confirming the potential use of NO-releasing PDE5 inhibitors in NO-deficient conditions.

During spermatogenesis in human adults, testicular germ cells proliferate, differentiate, and die by apoptosis. However, little is known about the temporal or spatial nature of this programmed cell death. Such information may be useful for understanding prenatal developmental biology as well as spermatogenesis during adulthood, particularly in the context of germ cell disorders. We undertook this study to determine 1) whether apoptosis occurred in a cell-specific fashion in the germ cell population and the supporting somatic cells; and 2) whether apoptosis varied with gestational age. We examined human fetal testicular tissues obtained from 17 karyotypically and structurally normal fetuses of mothers who underwent spontaneous or induced abortions. Three gestational ages were defined as follows: group A, 12-13 wk gestation (n = 5); group B, 20-22 wk gestation (n = 7); and group C, 37-40 wk gestation (n = 5). Morphology in conjunction with in situ end labeling was used to identify and quantify apoptotic nuclei in fetal gonadal tissues. The results of this study suggest that gonadal apoptosis occurred in germ cells, Sertoli cells, and Leydig cells at all gestational ages. Apoptotic death was highest in the Leydig cells, followed by germ cells and Sertoli cells. There was a significant positive correlation between the apoptosis of germ cells and Sertoli cells (P < 0.01) and a negative correlation between healthy germ cells and Sertoli cells (P < 0.001). There was also a negative correlation between the intratubular cell number and the gestational age. Specifically, the proportion of Sertoli cells decreased with gestational age, although there was no significant change in the germ cell in relation to gestational age. No such relationship was found in the Leydig cell population, all of which reside outside the seminiferous tubules. These results are the first to suggest that fetal testicular apoptosis begins in the first trimester, occurs in the three major cell types, and continues throughout pregnancy. Our data also suggest that in the fetal gonad, germ and Sertoli cell proliferation and death may be controlled by a genetic program distinct from that of the Leydig cells. This information is relevant to the understanding of abnormal spermatogenesis associated with infertility and to germ cell tumors in adult life.