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Purpose: Our aim was to determine if the AUA-recommended prophylaxis (vancomycin + gentamicin alone) for primary inflatable penile prosthesis surgery is associated with a higher infection risk than nonstandard regimens., Materials and Methods: We performed a multicenter, retrospective study of patients undergoing primary inflatable penile prosthesis surgery. Patients were divided into those receiving vancomycin + gentamicin alone and those receiving any other regimen. A Cox proportional-hazards model was constructed adjusted for major predictors. A subgroup analysis to identify the appropriate dosage of gentamicin was also performed., Results: A total of 4,161 patients underwent primary inflatable penile prosthesis placement (2,411 received vancomycin + gentamicin alone and 1,750 received other regimens). The infection rate was similar between groups, 1% vs 1.2% for standard vs nonstandard prophylaxis. In the multivariable analysis, vancomycin + gentamicin (HR: 2.7, 95% CI: 1.4 to 5.4, P = .004) and diabetes (HR: 1.9, 95% CI: 1.03 to 3.4, P = .04) were significantly associated with a higher risk of infection. Antifungals (HR: 0.08, 95% CI: 0.03 to 0.19, P < .001) were associated with lower risk of infection. There was no statistically significant difference in infection rate between weight-based gentamicin compared to 80 mg gentamicin (HR: 2.9, 95% CI: 0.83 to 10, P = .1)., Conclusions: Vancomycin + gentamicin alone for antibiotic prophylaxis for primary inflatable penile prosthesis surgery is associated with a higher infection risk than nonstandard antibiotic regimens while antifungal use is associated with lower infection risk. A critical review of the recommended antimicrobial prophylactic regimens is needed. Prospective research is needed to further elucidate best practices in inflatable penile prosthesis antimicrobial prophylaxis.

Purpose: In order to accurately characterize how a history of radiation therapy affects the lifespan of replacement artificial urinary sphincters (AUSs), all possible sources of device failure must be considered. We assessed the competing risks of device failure based on radiation history in men with replacement AUSs., Materials and Methods: We identified men who had a replacement AUS in a single institutional, retrospective database. To assess survival from all-cause device failure based on radiation history and other factors, we conducted Kaplan-Meier, Cox proportional-hazards and competing risks analyses., Results: Among 247 men who had a first replacement AUS, men with a history of radiation had shorter time to all-cause device failure (median 1.4 vs 3.5 years for men with radiation vs without radiation history, p=0.02). On multivariable Cox-proportional hazards analysis, previous radiation was associated with increased risk of all-cause device failure (HR: 2.12, 95% CI: 1.30-3.43, p=0.002) . On multivariable cause-specific hazards analysis, prior radiation was associated with a higher risk of erosion/infection (HR: 7.57, 95% CI: 2.27-25.2, p <0.001), but was not associated with risk of urethral atrophy (p=0.5) or mechanical failure (p=0.15)., Conclusions: Among men with a replacement AUS, a history of pelvic radiation was associated with shorter time to device failure of any cause. Radiation was also specifically associated with a sevenfold increase in the risk of erosion or infection of replacement AUS, but not with urethral atrophy or mechanical failure. Patients with a replacement AUS should be appropriately counseled on how radiation history may impact outcomes of future revisions.

Purpose: Penile vascularized composite allotransplantation is a powerful tool for penile reconstruction. Traditional methods of reconstruction utilizing free tissue and prostheses have well-known complications, can require reoperation and cannot truly emulate the natural form or function of the penis. While vascularized composite allotransplantation may alleviate these difficulties, penile transplantation carries its own ethical, surgical and medical complications. To date, the procedure has only been attempted 5 times. Broader use of this procedure requires unique surgical considerations. We present the first comprehensive, detailed review of this procedure in order to present lessons learned from both our own and the global experience., Materials and Methods: A review of published reports of penile transplant methods and outcomes was conducted to compile lessons learned from these cases., Results: Five penile transplant cases have been reported in literature, 4 with published methodology and outcomes data. All 4 detailed unique surgical approaches and postoperative immunosuppressive regimens. Three of these cases resulted in successful sensory and functional outcomes., Conclusions: Though all 4 analyzed cases employed unique anastomotic and immunosuppressive approaches, 3 resulted in successful recovery of penile urinary and sexual function. Still, specific approaches used by different teams circumvented otherwise common complications, and these differences should guide future research and penile transplant cases.

Purpose: Erectile dysfunction significantly impacts quality of life for men undergoing radical prostatectomy for prostate cancer. Erythropoietin is a promising neurotrophic factor for neurogenic erectile dysfunction based on preclinical and retrospective data., Materials and Methods: ERECT (NCT00737893) is a phase 2, double-blinded, randomized, placebo-controlled trial (July 2017-December 2019) evaluating the impact of perioperative erythropoietin on recovery of erectile function and other patient-reported, health-related quality of life outcomes after bilateral nerve-sparing radical prostatectomy (3, 6, 9, and 12 months). Erythropoietin (20,000 units) or saline placebo was injected subcutaneously the day before, day of, and day after surgery for 3 total doses., Results: Of 63 patients assessed for eligibility, 56 patients were randomized. Arms (29 erythropoietin, 27 placebo) were well balanced (89.3% robotic, median age 55.5 years). International Index of Erectile Function-Erectile Function Domain (IIEF-EF) scores increased from median 12.5 at 3 months to 24.5 at 12 months. Median 2-week serum hemoglobin was higher for the erythropoietin arm compared to placebo (14.7 vs 13.6, p=0.02). There was no statistically significant difference in IIEF-EF scores at 6 months comparing erythropoietin to placebo (p=0.50) or at other time points (mixed model regression coefficient: -1.7, 95% CI -6.1-2.7, p=0.45). Excellent nerve-sparing rating (10/10) was associated with improved IIEF-EF recovery (+5.2, p=0.022). Other patient-reported, health-related quality of life domains as well as oncologic outcome and complications were similar between arms during followup., Conclusions: In the context of brief perioperative dosing, erythropoietin did not improve recovery of erectile function for men undergoing radical prostatectomy for prostate cancer compared to placebo. Further research to identify effective adjuncts to improve health-related quality of life for these men is needed.

Purpose: Male patients with exstrophy-epispadias complex have a congenitally short penis. Adolescent and adult patients often desire penile reconstruction to enable penetrative intercourse. When penile lengthening using local tissue and/or skin graft is unsuitable, phalloplasty is performed. We provide updated experiences using radial forearm free flap and pedicled anterolateral thigh flap phalloplasty techniques over a 6-year period in exstrophy-epispadias complex patients., Materials and Methods: Consecutive patients who underwent radial forearm free flap or pedicled anterolateral thigh flap phalloplasty between 2013 and 2019 were reviewed. A total of 11 patients were identified, including 8 with classic bladder exstrophy and 3 with cloacal exstrophy. In each case, flap dimensions, donor and recipient vessels and nerves, complications, outcomes and subsequent surgical procedures are reported., Results: A radial forearm free flap was performed in 6 patients and a pedicled anterolateral thigh flap in 5. Flap survival was observed in all cases and 5 patients subsequently received an inflatable penile prosthesis. Among patients undergoing a pedicled anterolateral thigh flap, there was 1 mortality from acute pulmonary embolism, and the other 4 required at least 1 debulking procedure., Conclusions: Phalloplasty is an important procedure in patients with exstrophy-epispadias complex with severe penile inadequacy. Both techniques have favorable long-term outcomes, although the pedicled anterolateral thigh flap frequently requires a later debulking procedure. The radial forearm free flap is preferred but if the radial forearm is overly thin and the risk of inflatable penile prosthesis extrusion is high, the pedicled anterolateral thigh flap is an acceptable alternative.

Purpose: We evaluated the real-world effectiveness of regimented phosphodiesterase type 5 inhibitor dosing on recurrent ischemic priapism outcomes using emergency department visits as a proxy for therapeutic control of the disorder., Materials and Methods: We performed a retrospective chart review of patients with recurrent ischemic priapism who were started on regimented phosphodiesterase type 5 inhibitor therapy from May 2006 to January 2020. We compared the number of emergency department visits per month during a 6-month period before treatment, during treatment and after treatment discontinuation. We extracted and categorized priapism outcomes such as priapism frequency and duration., Results: Of 216 patients identified with all cause priapism 114 were diagnosed with recurrent ischemic priapism and 42 were initiated on regimented phosphodiesterase type 5 inhibitor therapy. Treatment effectiveness was analyzed for 24 evaluable patients. Priapism etiology was idiopathic in 12 patients (50%), sickle cell disease in 11 (46%) and drug-induced in 1 (4%). The median length of regimented phosphodiesterase type 5 inhibitor use was 3 months (IQR 2-7). Treatment decreased emergency department visits per month by 4.4-fold (p <0.001), priapism duration tiers (p <0.001) and priapism frequency tiers (p <0.001). Of 24 patients 22 (92%) reported improvement in priapism outcomes, 9 of whom reported resolution of recurrent ischemic priapism episodes. A subgroup analysis of 17 patients with recurrent ischemic priapism relapse after treatment discontinuation showed a significant increase in priapism duration (p <0.001) and frequency (p <0.001) but no significant change in emergency department visits per month (p=0.91)., Conclusions: Regimented phosphodiesterase type 5 inhibitor therapy was an impactful treatment in managing recurrent ischemic priapism according to objective and subjective parameters. This study provides further support for the use of regimented phosphodiesterase type 5 inhibitor dosing as a preventive strategy for recurrent ischemic priapism.

Purpose: American Urological Association (AUA) antibiotic prophylaxis recommendations may be insufficient for covering organisms commonly found in penile prosthesis infections. In this study we assess the difference between AUA recommended antibiotic prophylaxis and nonstandard prophylaxis in preventing device infections in penile prosthesis surgery performed in diabetic patients., Materials and Methods: A multicenter, retrospective cohort study of diabetic patients undergoing primary penile prosthesis surgery was performed between April 2003 and August 2018. Eighteen institutions from the United States, Europe and Korea contributed. The association between antibiotic prophylaxis type and postoperative penile prosthesis infections, device explantations and revision surgeries was assessed., Results: Standard AUA antibiotic prophylaxis was followed in 48.6% (391) of cases while nonstandard prophylaxis was used in 51.4% (413). Common nonstandard antibiotic prophylaxis included vancomycin-gentamycin-fluoroquinolone, clindamycin-fluoroquinolone, and vancomycin-fluoroquinolone among other combinations. Patients who received AUA prophylaxis had significantly more postoperative device infections (5.6% vs 1.9%, p <0.01) and explantations (8.3% vs 2.0%, p <0.001) compared to those who received nonstandard prophylaxis. Patients who received AUA prophylaxis had significantly higher odds of a postoperative device infection (OR 2.8, 95% CI 1.1-7.3) and explantation (OR 3.6, 95% CI 1.4-9.1) compared to those who received nonstandard prophylaxis., Conclusions: Diabetic men with erectile dysfunction who received standard AUA prophylaxis for penile prosthesis surgery had significantly greater odds of experiencing a postoperative device infection and device explantation compared to patients who received nonstandard prophylaxis. Our study provides a strong rationale for a prospective investigation to establish the most appropriate prophylaxis strategy in penile prosthesis surgery.

Purpose: The purpose of this guideline is to provide a clinical strategy for the diagnosis and treatment of erectile dysfunction., Materials and Methods: A systematic review of the literature using the Pubmed, Embase, and Cochrane databases (search dates 1/1/1965 to 7/29/17) was conducted to identify peer-reviewed publications relevant to the diagnosis and treatment of erectile dysfunction. Evidence-based statements were based on body of evidence strength Grade A, B, or C and were designated as Strong, Moderate, and Conditional Recommendations with additional statements presented in the form of Clinical Principles or Expert Opinions., Results: The American Urological Association has developed an evidence-based guideline on the management of erectile dysfunction. This document is designed to be used in conjunction with the associated treatment algorithm., Conclusions: Using the shared decision-making process as a cornerstone for care, all patients should be informed of all treatment modalities that are not contraindicated, regardless of invasiveness or irreversibility, as potential first-line treatments. For each treatment, the clinician should ensure that the man and his partner have a full understanding of the benefits and risk/burdens associated with that choice., (Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Reconstruction of complex functional structures is increasingly being performed with vascularized composite allotransplantation. Penile transplantation is a novel vascularized composite allotransplantation treatment option for severe penile tissue loss and disfigurement. Three allogeneic human penile transplantations have been reported. We review these cases as well as penile transplant indications, preclinical models and immunosuppression therapy., Materials and Methods: We performed a comprehensive literature review for the years 1970 to 2016 via MEDLINE®, PubMed® and Google with the key words "penis transplantation," "penile rejection," "penile replantation," "penile tissue loss" and "penis vascularized composite allotransplantation." Relevant articles, including original research, reviews and nonscientific press reports, were selected based on contents, and a review of this literature was generated., Results: Three human allogeneic penile transplantations have been performed to date, of which 1 was removed 14 days after transplantation. The second recipient reports natural spontaneous erections and impregnating his partner. All 3 patients were able to void spontaneously through the graft's urethra. The complexity of the transplant is determined by how proximally the penile shaft anastomosis is performed and additional pelvic tissue may be transplanted en bloc if needed., Conclusions: Penile transplantation is a technically demanding procedure with significant ethical and psychosocial implications that can provide tissue and functional replacement, including urinary diversion and natural erections. It is unclear how rejection and immunosuppression may affect graft function. Better models and more preclinical research are needed to better understand and optimize penile transplantation., (Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this guideline is to provide a clinical framework for the diagnosis and treatment of Peyronie's disease., Materials and Methods: A systematic review of the literature using the PubMed®, EMBASE® and Cochrane databases (search dates 1/1/1965 to 1/26/15) was conducted to identify peer-reviewed publications relevant to the diagnosis and treatment of PD. The review yielded an evidence base of 303 articles after application of inclusion/exclusion criteria., Results: The systematic review was used to create guideline statements regarding treatment of PD. When sufficient evidence existed, the body of evidence for a particular treatment was assigned a strength rating of A (high quality evidence; high certainty), B (moderate quality evidence; moderate certainty), or C (low quality evidence; low certainty). Evidence-based statements of Strong, Moderate, or Conditional Recommendation were developed based on benefits and risks/burdens to patients. Additional consensus statements related to the diagnosis of PD are provided as Clinical Principles and Expert Opinions due to insufficient published evidence., Conclusions: There is a continually expanding literature on PD; the Panel notes that this document constitutes a clinical strategy and is not intended to be interpreted rigidly. The most effective approach for a particular patient is best determined by the individual clinician and patient in the context of that patient's history, values, and goals for treatment. As the science relevant to PD evolves and improves, the strategies presented here will be amended to remain consistent with the highest standards of clinical care., Competing Interests: DISCLOSURES All panel members completed COI disclosures. Relationships that have expired (more than one year old) since the panel’s initial meeting, are listed. Those marked with (C) indicate that compensation was received; relationships designated by (U) indicate no compensation was received. Consultant/Advisor: Ralph Alterowitz, MEA, The Center for Intimacy After Cancer Therapy Inc. (U); Mohit Khera, MD, Coloplast (C); American Medical Systems (C); Endo Pharmaceuticals (C); Kevin T. McVary, MD, Watson Pharmaceuticals (C), Lilly/ICOS (C), Health Publishing: Arthur L. Burnett II, MD, Urology Times Editorial Council (C); VIVUS (C); Alan W. Shindel, M.D., Endotext.com (C), International Society for Sexual Medicine (C) Leadership Position: Ralph Alterowitz, MEA, The Center for Intimacy After Cancer Therapy Inc. (U); Alan W. Shindel, M.D., Sexual Medicine Society of North America (C) Meeting Participant or Lecturer: Ralph Alterowitz, MEA, The Center for Intimacy After Cancer Therapy Inc. (U); Kevin T. McVary, MD, Watson Pharmaceuticals (C), Lilly/ICOS (C), Lawrence S. Hakim, MD, ENDO Urology (C), Slate/Auxilium (C) Scientific Study or Trial: Arthur L. Burnett II, MD, Acorda Therapeutics (C); Endo Pharmaceuticals (C); Pfizer (C); Auxilium Inc. (C); American Medical Systems (C); Coloplast (C); Astellas (C); Reflexonic LLC (C); VIVUS (C); Kevin T. McVary, MD, Astellas (C), Lilly/ICOS (C), NxThera (U), American Medical Systems (C), Sophris (C); Hossein Sadeghi-Nejad, MD, Endo Pharmaceuticals/Auxilium (C) Other: Kevin T. McVary, MD, Lilly/ICOS, Principal Investigator (C), NIDDK, Principal Investigator (C), Christian J. Nelson, PhD, American Medical Systems (U)., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Little data exist on the outcome of combined inflatable penile prosthesis and artificial urinary sphincter insertion for erectile dysfunction and stress urinary incontinence. We assessed patient outcomes for combined vs single device implantation at a single institution., Materials and Methods: We retrospectively reviewed the records of all patients who underwent inflatable penile prosthesis and artificial urinary sphincter insertion at our hospital from January 2000 to December 2011. A total of 55 combined procedures were performed compared to the single insertion of 336 inflatable penile prostheses and 279 artificial urinary sphincters., Results: The surgical approach consisted of penoscrotal incisions for inflatable penile prostheses and transperineal incisions for artificial urinary sphincter cuff placement with a secondary lower abdominal incision for reservoir placement. Men treated with combined implantation had greater mean age and were at greater risk for prostate cancer diagnosis and treatment, and at lesser risk for Peyronie disease than men who received an inflatable penile prosthesis alone (each p<0.05). Although operative time was significantly longer for the combined procedure than for the inflatable penile prosthesis alone and the AUS alone (mean 218.1 vs 145.9 and 114.7 minutes, respectively, p<0.0001), the rate of device infection, erosion or malfunction was not increased irrespective of combined or staged procedures (p>0.05)., Conclusions: Combined inflatable penile prosthesis-artificial urinary sphincter implantation and staged prosthesis implantation are feasible without an increased risk of adverse outcomes compared to implantation of a single prosthesis. Patients with concomitant erectile dysfunction and stress urinary incontinence should be counseled about the possible advantages of this surgical option, which include a single anesthesia event and faster resumption of sexual activity and urinary control., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Male patients with bladder and cloacal exstrophy are born with demure genitalia and often desire phalloplasty during late adolescence or early adulthood. Radial forearm free flap phalloplasty was used successfully for congenital aphallia in a few small series. We present a series of patients treated with phalloplasty using a radial forearm free flap after the repair of bladder and cloacal exstrophy., Materials and Methods: We reviewed the records of 10 patients who underwent radial forearm free flap phalloplasty between 2007 and 2012. Indications for phalloplasty were classic bladder exstrophy in 8 cases and cloacal exstrophy in 2. Nine patients underwent prior urinary diversion and 1 underwent urethroplasty at phalloplasty. In each case we reviewed the details of prior exstrophy repair, flap size, donor and recipient vessels, complications, need for subsequent surgeries and self-reported sensation., Results: The graft survived in all 10 patients. Short-term complications requiring surgical intervention developed in 2 patients. Five patients subsequently underwent placement of a penile prosthesis and 2 devices were removed secondary to erosion. All 10 patients reported protective sensation and erogenous sensation with ability to achieve orgasm at last followup., Conclusions: Radial forearm free flap phalloplasty results in a sensate, cosmetic neophallus. No patient had long-term complications related to phalloplasty but complications related to penile prostheses continue to be a challenging aspect of phalloplasty. The long-term results of the forearm free flap are encouraging in this series of patients with bladder and cloacal exstrophy who desired phalloplasty., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We evaluated the safety and efficacy of 100 and 200 mg avanafil for the treatment of adult males with erectile dysfunction after bilateral nerve sparing radical prostatectomy., Materials and Methods: This was a double-blind, placebo controlled, parallel group, phase 3 study in males age 18 to 70 years with a history of erectile dysfunction of 6 months or more after bilateral nerve sparing radical prostatectomy. Patients were randomized to 100 or 200 mg avanafil or placebo (taken 30 minutes before sexual activity) for 12 weeks. Primary end points included successful vaginal insertion (Sexual Encounter Profile [SEP] question 2), successful intercourse (SEP3) and change in score on the erectile function domain of the International Index of Erectile Function (IIEF-EF) questionnaire., Results: A total of 298 patients were randomized and 84.6% completed the study. At baseline 16.1% were age 65 years or older and 71.5% had severe erectile dysfunction (mean overall IIEF-EF domain score 9.2). After 12 weeks there were significantly greater increases in SEP2 and SEP3 and change in mean IIEF-EF domain score with 100 and 200 mg avanafil vs placebo (p <0.01). Following dosing with avanafil 36.4% (28 of 77) of sexual attempts (SEP3) at 15 minutes or less were successful vs 4.5% (2 of 44) for placebo (p <0.01). Avanafil was generally well tolerated. No serious adverse events were reported and fewer than 2% of patients discontinued the study due to an adverse event., Conclusions: Avanafil in 100 and 200 mg doses was effective and well tolerated in improving erectile function after prostatectomy. Results suggest a rapid onset of action and sustained duration of effect, with all 3 primary end points being achieved at both dose levels., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We established erectile dysfunction as an often neglected but valuable marker of cardiovascular risk, particularly in younger men and men with diabetes. We also reviewed evidence that lifestyle change, combined with informed prescribing of pharmacotherapies used to mitigate cardiovascular risk, can improve overall vascular health and sexual functioning in men with erectile dysfunction., Materials and Methods: We performed a PubMed® search for articles and guidelines pertinent to relationships between erectile dysfunction and cardiovascular disease, cardiovascular and all cause mortality, and pharmacotherapies for dyslipidemia and hypertension. The clinical guidance presented incorporates the current literature and the expertise of the multispecialty investigator group., Results: Numerous cardiovascular risk assessment tools exist but risk stratification remains challenging, particularly in patients at low or intermediate short-term risk. Erectile dysfunction has a predictive value for cardiovascular events that is comparable to or better than that of traditional risk factors. Interventional studies support lifestyle changes as a means of improving overall vascular health as well as sexual functioning. Statins, diuretics, β-blockers and renin-angiotensin system modifiers may positively or negatively affect erectile function. Furthermore, the phosphodiesterase type 5 inhibitors used to treat erectile dysfunction may have systemic vascular benefits., Conclusions: Erectile dysfunction treatment should be considered secondary to decreasing cardiovascular risk. However, informed prescribing may prevent worsening sexual function in men receiving pharmacotherapy for dyslipidemia and hypertension. As the first point of medical contact for men with erectile dysfunction symptoms, the primary care physician or urologist has a unique opportunity to identify those who require early intervention to prevent cardiovascular disease., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Bilateral cavernous nerve injury results in up-regulation of ROCK signaling in the penis. This is linked to erectile dysfunction in an animal model of post-prostatectomy erectile dysfunction. We evaluated whether daily treatment with the ROCK inhibitor Y-27632 (Tocris Bioscience, Ellisville, Missouri) would prevent erectile dysfunction in a rat model of bilateral cavernous nerve injury., Materials and Methods: Sprague-Dawley® rats underwent surgery to create sham (14) or bilateral (27) cavernous nerve injury. In the injury group 13 rats received treatment with Y-27632 (5 mg/kg twice daily) and 14 received vehicle. At 14 days after injury, rats underwent cavernous nerve stimulation to determine erectile function. Penes were assessed for neuronal and nitric oxide synthase membrane-endothelial nitric oxide synthase. ROCK2 was assessed by Western blot. Cyclic guanosine monophosphate was determined by enzyme-linked immunosorbent assay. Cavernous homogenates were tested for ROCK and protein kinase G enzymatic activity. Penile apoptosis was evaluated using the Apostain technique (Alexis, San Diego, California). Data were analyzed on ROCK using ANOVA and the t test., Results: While erectile function was decreased in rats with bilateral cavernous nerve injury, daily administration of Y-27632 improved erectile responses. Injury decreased neuronal and nitric oxide synthase membrane-endothelial nitric oxide synthase but ROCK2 was significantly increased. Y-27632 treatment restored neuronal nitric oxide synthase, nitric oxide synthase membrane-endothelial nitric oxide synthase and cyclic guanosine monophosphate levels, and protein kinase G activity. Treatment significantly decreased ROCK2 protein and ROCK activity. There were significantly fewer apoptotic cells after treatment than in injured controls., Conclusions: These results provide evidence for up-regulation of the RhoA/ROCK signaling pathway with detrimental effects on erectile function after bilateral cavernous nerve injury. ROCK inhibition improved erectile dysfunction associated with bilateral cavernous nerve injury by preserving penile nitric oxide bioavailability and decreasing penile apoptosis., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We provide long-term followup on a modification of the Al-Ghorab distal penile corporoglanular shunt surgery for the treatment of ischemic priapism., Materials and Methods: We conducted a retrospective review of patients surgically treated for ischemic priapism at The Johns Hopkins Hospital from January 2008 to April 2012 with the Burnett "Snake" maneuver of the Al-Ghorab shunt. Electronic medical records were reviewed to collect demographic information and telephone followup was performed to verify treatment outcomes. Patients completed the SHIM (Sexual Health Inventory for Men) to assess current erectile function., Results: A total of 10 patients were analyzed (age range 31 to 59 years). Mean followup was 6.7 months (range 0.5 to 17). Priapism etiologies were idiopathic (3), trazodone (2), trazodone and cocaine (3), intracavernous injection of trimix (1) and spinal cord injury (1). There were 6 patients who had previously undergone unsuccessful surgical attempts at priapism decompression and mean priapism duration was 75 hours (range 24 to 288). Of the 10 men 8 achieved successful resolution of priapism with no recurrence. There were 2 men with recurrent priapism refractory to all management who were definitively treated with insertion of an inflatable penile prosthesis. Of 9 men 6 had normal erectile function preoperatively, of whom 2 achieved at least partial erectile function postoperatively. Complications were sustained by 2 men, including wound infection with skin necrosis in 1, and an intraoperative urethral injury in the other with subsequent urethrocutaneous fistula formation and wound infection with skin necrosis., Conclusions: The modified Al-Ghorab corporoglanular shunt using the Burnett snake maneuver is successful in resolving ischemic priapism, particularly in cases refractory to first line management, and in preventing further episodes of priapism., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Priapism is a vasculopathy that occurs in approximately 40% of patients with sickle cell disease. Mouse models suggest that dysregulated nitric oxide synthase and RhoA/ROCK signaling as well as increased oxidative stress may contribute to the mechanisms of sickle cell disease associated priapism. We examined changes in the protein expression of nitric oxide synthase and ROCK signaling pathways, and a source of oxidative stress, NADPH oxidase, in penile erectile tissue from patients with a priapism history etiologically related and unrelated to sickle cell disease., Materials and Methods: Human penile erectile tissue was obtained from 5 patients with sickle cell disease associated priapism and from 6 with priapism of other etiologies during nonemergent penile prosthesis surgery for erectile dysfunction or priapism management and urethroplasty. Tissue was also obtained from 5 control patients without a priapism history during penectomy for penile cancer. Samples were collected, immediately placed in cold buffer and then frozen in liquid nitrogen. The expression of phosphodiesterase 5, endothelial nitric oxide synthase, neuronal nitric oxide synthase, inducible nitric oxide synthase, RhoA, ROCK1, ROCK2, p47(phox), p67(phox), gp91(phox) and β-actin were determined by Western blot analysis. Nitric oxide was measured using the Griess reaction., Results: In the sickle cell disease group phosphodiesterase 5 (p <0.05), endothelial nitric oxide synthase (p <0.01) and RhoA (p <0.01) expression was significantly decreased, while gp91(phox) expression (p <0.05) was significantly increased compared to control values. In the nonsickle cell disease group endothelial nitric oxide synthase, ROCK1 and p47(phox) expression (each p <0.05) was significantly decreased compared to control values. Total nitric oxide levels were not significantly different between the study groups., Conclusions: Mechanisms of sickle cell disease associated priapism in the human penis may involve dysfunctional nitric oxide synthase and ROCK signaling, and increased oxidative stress associated with NADPH oxidase mediated signaling., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Nitric oxide is the major neuronal mediator of penile erection but its role in erectile function status after cavernous nerve injury is uncertain. We determined the function of neuronal nitric oxide signaling in the pathobiology of erectile function recovery after partial cavernous nerve injury using genetic and pharmacological mouse experimental paradigms., Materials and Methods: Erectile function was evaluated in 5 to 7 wild-type and neuronal nitric oxide synthase-α knockout mice per group 1, 3 and 7 days after unilateral crush or sham injury, at day 7 in wild-type mice treated with the nitric oxide synthase inhibitor L-NAME (l-nitro arginine methyl ester) (Sigma-Aldrich®) at baseline and for 6 days after unilateral crush injury. Apoptosis in the penis was evaluated by Western blot analysis of p-Akt-S473, 3-nitrotyrosine and caspase-3 after bilateral crush injury., Results: Intracavernous pressure was significantly decreased at 1, 3 and 7 days in wild-type mice but only at day 1 in knockout mice after unilateral crush injury compared with sham treatment values (p <0.05). L-NAME treated wild-type mice had improved erectile function compared with the vehicle treated group at day 7 after unilateral crush injury (p <0.05). In penes p-Akt-S473 was significantly decreased in vehicle treated (p <0.05) but not in L-NAME treated wild-type mice. In penes 3-nitrotyrosine was significantly decreased in L-NAME treated wild-type and vehicle treated knockout mice (p <0.05). Caspase-3 in penes was significantly increased in vehicle treated (p <0.05) but not in L-NAME treated wild-type mice and vehicle treated knockout mice., Conclusions: Neuronal nitric oxide signaling regulates erectile function recovery early after partial cavernous nerve injury, exerting an inhibitory role via the induction of apoptotic change in penile tissue. Therapeutic strategies to improve erectile function recovery after radical prostatectomy may consider targeting pathogenic sites of nitric oxide neurobiology., (Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: RhoA and rho kinase serve as key regulators of penile vascular homeostasis. The role of RhoA/rho kinase signaling in the penis after cavernous nerve injury has not been fully investigated. We characterized the molecular expression profiles of RhoA/rho kinase signaling that occur in the penis after cavernous nerve injury. We hypothesized that erectile dysfunction after bilateral cavernous nerve injury is accompanied by up-regulation of RhoA/rho kinase activity in the rat penis., Material and Methods: We used 2 groups, including sham operation and bilateral cavernous nerve injury. At 14 days after nerve injury each group underwent cavernous nerve stimulation to determine erectile function at baseline and after intracavernous injection of the rho kinase inhibitor Y-27632 (Tocris Bioscience, Ellisville, Missouri). Penes were assessed at baseline for protein expression of neuronal nitric oxide synthase, RhoA, and rho kinase 1 and 2 by Western blot, immunoreactivity of neuronal nitric oxide synthase, rho kinase 1 and 2, RhoA-guanosine triphosphatase and rho kinase activity., Results: Erectile function was decreased in nerve injured rats. Neuronal nitric oxide synthase protein was significantly decreased while RhoA and rho kinase 2 protein levels were significantly increased in rat penes with nerve injury. Rho kinase 1 protein expression was equivalent. Rho kinase immunoreactivity was qualitatively increased in the corporeal smooth muscle of nerve injured rats. RhoA-guanosine triphosphatase and rho kinase activity was significantly increased in injured rat penes compared to that in sham operated penes. Intracavernous injection of Y-27632 caused a significantly greater increase in intracavernous pressure in nerve injured rats compared to that in sham operated rats, suggesting increased rho kinase activity., Conclusions: Data suggest that RhoA/rho kinase up-regulation in response to cavernous nerve injury contributes to penile vasculature dysfunction after cavernous nerve injury. Thus, the RhoA/rho kinase pathway may be a suitable target for treating post-radical prostatectomy erectile dysfunction., (Copyright © 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Angiotensin II is a known mediator of smooth muscle vasoconstriction and fibrosis. It up-regulates thrombospondin-1, a major activator of latent transforming growth factor-beta. Transforming growth factor-beta induces vascular fibrosis via intracellular SMAD signaling pathways. We evaluated the effect of treatment with the angiotensin II type 1 receptor antagonist losartan on erectile function in the rat following bilateral cavernous nerve injury., Materials and Methods: A total of 36 adult male rats were divided equally into 6 groups, including group 1-sham surgery with cavernous nerve exposure only plus vehicle, group 2-sham surgery plus oral low dose losartan (10 mg/kg per day), group 3-sham surgery plus high dose losartan (40 mg/kg per day), group 4-bilateral cavernous nerve injury (3-minute crush using a hemostat clamp) plus vehicle, group 5-bilateral cavernous nerve injury plus low dose losartan and group 6-bilateral cavernous nerve injury plus high dose losartan. Seven days following surgery erectile function was measured by electrically stimulating the cavernous nerves and monitoring intracavernous pressure. Penile tissue was collected for Western blot analysis of fibronectin, transforming growth factor-beta, thrombospondin-1, alpha-actin, and phosphorylated and total SMAD2 and SMAD3 expression., Results: Erectile function was significantly decreased after bilateral cavernous nerve injury compared with that after sham surgery (p <0.01). Low and high dose losartan preserved erectile function after bilateral cavernous nerve injury compared to that in vehicle controls (p <0.01 and <0.05, respectively). Fibronectin, pSMAD2, pSMAD3, transforming growth factor-beta-1, thrombospondin-1 and alpha-actin expression was up-regulated, and total SMAD2 and SMAD3 expression was down-regulated in the penis after bilateral cavernous nerve injury. Each dose of losartan after bilateral cavernous nerve injury significantly attenuated the up-regulated expression of fibronectin (p <0.01), pSMAD2 (p <0.05) and thrombospondin-1 (p <0.05), and up-regulated total SMAD2 (p <0.05)., Conclusions: These data suggest that fibrotic activators in the penis may cause decreased erectile function after bilateral cavernous nerve injury. Angiotensin II type 1 receptor antagonism may counteract this effect and promote erectile function preservation for conditions associated with penile fibrosis.

Purpose: We determined the effect of passive secondhand cigarette smoke on 1) erectile function in vivo, 2) molecular mechanisms involved in penile vascular function, and 3) erectile function and penile molecular signaling in the presence of phosphodiesterase type 5 inhibitor therapy., Materials and Methods: Four groups of mice were used, including group 1--controls, group 2--mice exposed to 3 weeks of secondhand smoke (5 hours per day for 5 days per week), group 3--control plus sildenafil (100 mg/kg per day) and group 4--smoke exposed plus sildenafil (100 mg/kg per day). Cavernous nerve electrical stimulation and intracavernous injection of acetylcholine were done to assess erectile function. Constitutive and inducible nitric oxide synthase activity, reactive oxygen species generation, nitrotyrosine formation and superoxide anion levels were assessed., Results: Decreased erectile responses to cavernous nerve electrical stimulation and impaired endothelium dependent erectile responses to ACh in mice exposed to secondhand smoke were observed. Superoxide anion was increased in endothelial and corporeal smooth muscle cells of smoking mouse penises. In mice exposed to secondhand smoke constitutive nitric oxide synthase activity was decreased, and inducible nitric oxide synthase activity, reactive oxygen species generation and nitrotyrosine formation increased. Sildenafil therapy restored constitutive nitric oxide synthase activity in the penis of smoking mice, decreased inducible nitric oxide synthase activity, reactive oxygen species generation and nitrotyrosine formation, and improved erectile responses to cavernous nerve electrical stimulation and acetylcholine., Conclusions: Short-term exposure to secondhand smoke impairs erectile function through excessive penile reactive oxygen species signaling and inducible nitric oxide synthase activity. Decreased penile constitutive nitric oxide synthase activity may be attributable to the decreased endothelial nitric oxide synthase activity resulting from increased oxidative stress. Sildenafil therapy restored nitric oxide synthase activity and decreased reactive oxygen species signaling, resulting in improved erectile function.

Purpose: We investigated changes in serum biomarkers of vascular function after short-term, continuous sildenafil dosing in men with type 2 diabetes with erectile dysfunction., Materials and Methods: Men with erectile dysfunction associated with type 2 diabetes mellitus were randomized to receive continuous, daily sildenafil (50 mg for 1 week run-in and 100 mg for 3 weeks) (148), or placebo (144) for 4 weeks (phase I) and then sildenafil (25, 50 or 100 mg) on demand for 12 weeks (phase II). Blood draws at baseline and after phases I and II were analyzed for cyclic guanosine monophosphate (endothelial function marker), 8-isoprostane (oxidative stress marker), and interleukin-6 and interleukin-8 (inflammatory cytokines). Primary and secondary erectile function outcome variables were affirmative responses on Sexual Encounter Profile question 3 (ability to maintain erection sufficient for sexual intercourse) and Erection Hardness Score, respectively., Results: Serum cyclic guanosine monophosphate levels were increased in the sildenafil group relative to the placebo group at 4 (p <0.01) and 16 (p <0.05) weeks, correlating with affirmative responses to Sexual Encounter Profile question 3 at the 4-week interval only (p <0.05). Serum 8-isoprostane levels were decreased to a nonsignificant degree in the sildenafil group at 4 weeks with no further change at 16 weeks, whereas interleukin-6 and interleukin-8 levels were unchanged at either interval, and these levels were unassociated with erectile function outcomes., Conclusions: These data suggest that short-term, continuous sildenafil treatment causes systemic endothelial function to be enhanced and remain so for a duration after its discontinuation. However, they do not indicate any influence of this treatment on systemic oxidative stress or inflammation, or an effect on long-term erectile function improvement.

Purpose: In conjunction with the assignment to update the Guidelines for Management of Clinically Localized Prostate Cancer, the American Urological Association Prostate Cancer Guideline Update Panel performed a side analysis of the reporting of erectile function outcomes in this clinical context as published in the medical literature., Materials and Methods: Four National Library of Medicine PubMed(R) Services literature searches targeting articles published from 1991 through early 2004 were done to derive outcome reporting (efficacy or side effects) for the treatment of clinical stage T1 or T2 N0M0 prostate cancer. A database was constructed containing descriptions relating to erectile function as well as numerical frequency rates of complete erectile dysfunction, and partial and intact erectile function for various treatments. A literature review was also done, consisting of a PubMed Services search of current measures and protocols used for assessing erectile function outcomes and a survey of consensus opinion sources on the management of male sexual dysfunctions., Results: Based on inclusion criteria 436 articles were selected. Of these articles database extraction from 100 pertaining to radical prostatectomy garnered various characterizations of erectile function, including qualitative descriptions, generic terminology and rating systems. Database extraction from 31 articles, in which results for at least 50 patients were reported, yielded ranges of rates for complete erectile dysfunction, partial erectile function and intact erectile function that were 26% to 100%, 16% to 48% and 9% to 86% for radical prostatectomy, 8% to 85%, 21% to 47% and 36% to 63% for external beam radiation, and 14% to 61%, 21% and 18% for interstitial radiation, respectively. The literature review showed an evolution in standards for studying and reporting erectile function outcomes., Conclusions: Clinical studies reporting erectile function outcomes after localized prostate cancer treatment often demonstrate poorly interpretable and inconsistent manners of assessment as well as widely disparate rates of erectile dysfunction and erectile function. Future studies must apply scientifically rigorous methodology and standard outcomes measures to advance this field of study.

Purpose: The American Urological Association Prostate Guideline Update Panel was charged with updating the Guidelines for Clinically Localized Prostate Cancer. In assessing outcomes with treatment, it became apparent that a highly variable number of definitions exist with respect to biochemical recurrence. Herein, we review the variability in published definitions of biochemical recurrence and make recommendations directed toward improving this terminology by recommending a standard definition in patients treated with radical prostatectomy., Materials and Methods: Four PubMed literature searches were performed between May 2001 and April, 2004 and covered articles published from 1991 through early 2004. The search terms included the MeSH major headings of prostate cancer and prostatic neoplasm. All potentially relevant articles were retrieved and a more detailed screen for relevance was performed. An article was considered relevant if it reported treatment outcomes of patients with clinical T1 or T2N0M0 prostate cancer. Data extractors recorded the definition of biochemical recurrence and definitions were then collapsed into categories representing the same criteria. The results of biochemical failure were subcategorized by initial treatment., Results: Of 13,800 citations, a total of 436 articles were selected. Among these, a total of 145 articles contained 53 different definitions of biochemical recurrence for those treated with radical prostatectomy. Of these, the most common definition (35) was a prostate specific antigen of >0.2 ng/mL or a slight variation thereof. In addition, a total of 208 articles reported 99 different definitions of biochemical failure among those treated with radiation therapy. Of these, the American Society for Therapeutic Radiology and Oncology definition (70) and/or a variation thereof was the most commonly reported. In total, 166 different definitions of biochemical failure were identified. Following radical prostatectomy, the Panel recommends defining biochemical recurrence as an initial serum prostate specific antigen of > or =0.2 ng/mL, with a second confirmatory level of prostate specific antigen of >0.2 ng/mL. The Panel recommends the use of the American Society for Therapeutic Radiology and Oncology criteria for patients treated with radiation therapy and acknowledges that these criteria will soon be updated although not yet published., Conclusions: A high degree of variability in the definition of biochemical recurrence exists following treatment for localized prostate cancer. Strict definitions for biochemical recurrence are necessary to identify men at risk for disease progression and to allow meaningful comparisons among patients treated similarly. The Panel acknowledges the American Society for Therapeutic Radiology and Oncology criteria and future modifications thereof for those receiving radiation therapy and recommends the newly developed American Urological Association criteria for those treated with radical prostatectomy. The purpose for the establishment of this standard is for data reporting purposes and for comparison of similarly treated patients. It is not intended to represent a threshold value for which to initiate treatment. The Panel acknowledges that the clinical decision to initiate treatment will be dependent on multiple factors including patient and physician interaction rather than a specific prostate specific antigen threshold value.

Purpose: Erectile dysfunction is a recognized, common adverse consequence of radical prostatectomy as well as various other pelvic surgeries. While a host of management options have been considered to decrease this complication, neuromodulatory therapy has recently been advanced as an intervention that may be applied for this purpose. We evaluated concepts regarding the neuropathic basis for erectile dysfunction following pelvic surgery, principles for establishing neuromodulatory therapy in this clinical context, evidence from preclinical studies supporting neuromodulatory approaches as a therapeutic strategy and the progress of early clinical developments in this field., Materials and Methods: The exercise principally consisted of a current literature search using the National Library of Medicine PubMed Services, a survey of recent abstract proceedings from national meetings relevant to the topic and an Internet online search for current information on federally and privately supported clinical trials specific to this topic. References were made to such key words as neuroprotection, nerve regeneration, nerve growth factors, neurotrophic factors, cavernous nerves, nerve guides and penile erection., Results: Basic science research and clinical studies support the concept that erectile loss after pelvic surgery is frequently related to neuropathic effects, resulting in penile vascular impairment. An assortment of neurobiological studies using rodent models of cavernous nerve injury have shown nerve reconstitutive actions for a host of neurotrophic substances, including classic neurotrophins, growth hormone, cytokines and atypical neurotrophic mediators. Clinical trials of several proposed neuroprotective and neurotrophic applications have been done or are in progress., Conclusions: Erectile dysfunction is a well recognized and yet ineffectively averted complication of pelvic surgery. Neuromodulatory therapy offers a therapeutic approach for addressing the neuropathic changes of the penis that occurs in this context with the goal of maximally preserving erectile function postoperatively. While several specific neuromodulatory applications have gained interest for their potential benefit with pelvic surgery, determining their actual roles awaits the completion of controlled clinical trials.

Purpose: An overview of the latest concepts advanced with regard to the epidemiology, pathophysiology, and management of male ED is provided., Materials and Methods: Published literature and current paradigms promoted by consensus bodies in the field with regard to the management of ED were reviewed., Results: ED is a neurovascular phenomenon modulated by hormonal, local biochemical, and biomechanical/structural factors of the penis. Once viewed primarily as a psychological issue, ED is now understood to represent predominantly organic etiologies. It has a significant association with cardiovascular disease and could serve as a harbinger of subsequent cardiovascular events. Goal directed assessment and management implies a focus on patient (and partner) preferences regarding various treatment options. These options range from oral pharmacological agents to surgery and may be pursued according to a stepwise management approach. Psychosocial interventions also may serve as useful therapeutic adjuncts., Conclusions: ED is a highly manageable disorder in most patients. The patient and his partner have integral roles in the decision making process, since preferences regarding the importance of sexual activity, and the risks and benefits of treatment will vary greatly among individuals.

Purpose: We reviewed recent literature and treatment guidelines regarding the prevalence, pathophysiology, and management of BPO related to BPH; and management of lower urinary tract symptoms secondary to BPH., Materials and Methods: Published literature and current treatment concepts were reviewed regarding the diagnosis and treatment options for BPO., Results: BPH is a histological diagnosis that can contribute to medical problems, including enlargement of the prostate and BPO. These conditions should be treated only if the symptoms are troublesome, there is considerable risk of progression, and/or cancer is suspected. Very effective medical and surgical options are available to treat BPO and improve patient quality of life., Conclusions: BPO is highly treatable, but should be managed in close collaboration with the patient. Pharmacological agents and minimally invasive procedures, when appropriate, are generally preferred to more invasive surgery. Patients with mild or moderate symptoms usually can be treated by a primary care physician; more complicated cases should be referred to a urologist for evaluation and management.

Purpose: We investigated the effects of recombinant human (rh) erythropoietin (EPO) on erectile function recovery in a rat model of cavernous nerve (CN) injury., Materials and Methods: Male rats underwent unilateral CN transection and excision of a 5 mm segment of the contralateral CN. One group received rhEPO (5,000 U/kg) subcutaneously daily for 14 days, while another received rhEPO 1 day and 1 hour prior to nerve injury. An additional group of animals was pretreated with 1 dose of darbepoetin (25 microg/kg). At 14 days following CN injury rats underwent erection physiology studies. Axonal regeneration was evaluated by electron microscopy. EPO receptor expression in the penis and major pelvic ganglion was evaluated immunohistochemically and by real-time polymerase chain reaction., Results: Daily rhEPO effectively recovered erections after CN injury compared with saline treatment. Maximal intracavernous pressure area under the curve normalized to mean arterial pressure was significantly greater in EPO treated vs saline treated animals (p < 0.05). rhEPO and darbepoetin pretreatment was as effective as continuous 14-day therapy. EPO receptor expression was localized to neuronal cell bodies of the major pelvic ganglion, penile nerves and endothelial cells in the penis. Electron microscopy revealed significant improvement in axonal regeneration in rhEPO treated animals 14 days following injury compared to controls., Conclusions: EPO receptors are expressed in local neuronal and vascular tissues. Exogenous administration of rhEPO or darbepoetin in the setting of CN injury promotes erectile function recovery. This occurs through axonal regeneration of the injured nerve and possible penile protection.

Purpose: Conflicting information exists regarding the long-term efficacy of phosphodiesterase-5 (PDE5) inhibitor therapy for erectile dysfunction, particularly in regard to whether therapeutic resistance occurs. We investigated the erectile response, and cavernous PDE5 expression and activity after continuous long-term administration of sildenafil at verified therapeutic plasma concentrations, applying an in vivo rat model of age related erectile dysfunction., Materials and Methods: Male Fisher 344 young (4 months old) and aged (19 months old) rats (National Institute of Aging, Bethesda, Maryland) were injected with sildenafil mesylate (20 mg/kg) or saline subcutaneously every 8 hours for 3 weeks. After a 10 to 18-hour washout period electrical stimulation of the cavernous nerve was performed to assess penile erection. Penes were excised to measure PDE5 protein expression and activity, and blood was collected for sildenafil measurement. Responses were compared with those determined 30 minutes after a single sildenafil injection., Results: Chronic sildenafil treatment increased the detumescence phase in young and aged rats (p <0.05), although aged rats showed a greater increase than young rats. Baseline cavernous PDE5 expression and activity were greater in aged vs young rats (p <0.05). After chronic sildenafil treatment cavernous PDE5 expression was increased in young (p <0.05) but not in aged rats. Chronic and acute sildenafil treatment similarly inhibited PDE5 activity in the penis of young and aged rats (p <0.05), coincident with its free plasma concentrations equivalent to clinically therapeutic ranges., Conclusions: Pharmacological PDE5 inhibitor therapy with sildenafil chronically does not result in treatment resistance. Rather, therapeutic efficacy is maintained and apparently more pronounced with erectile impairment than with normal erectile ability.

Purpose: We investigated the long-term effect of immunophilin ligands on erection physiology and cavernous tissue histology using rat models of unilateral and bilateral cavernous nerve (CN) injury., Materials and Methods: Adult male Sprague-Dawley rats were administered the immunophilin ligand FK506 (5 mg/kg subcutaneously daily for 5 days), the nonimmunosuppressant FK506 derivative GPI1046 (3 to 3-pyridyl)-1-propyl(2 seconds)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidine carboxylate) (40 mg/kg subcutaneously daily for 5 or 28 days) or saline immediately upon induction of 2 paradigms of cavernous nerve injury, namely focal transection of the CN unilaterally, and a combination of focal transection of the CN unilaterally and excision of a 5 mm segment of contralateral CN (BIL treated). At 28 days following CN injury electrical stimulation of the transected CN and penile erection monitoring were performed. Whole penes were removed and evaluated immunohistochemically for the nitric oxide generator neuronal nitric oxide synthase, the neuronal marker synaptophysin, the endothelial marker CD31 and the smooth muscle marker alpha-actin., Results: In unilaterally treated groups erection recovery was significantly greater in FK506 treated than in saline treated animals ((83.5% +/- 9.2% vs 24.3% +/- 8.1%, p <0.001) and similarly greater in GPI1046 treated animals than in the respective saline treated controls for this group (57.9% +/- 12.6% vs 23.8% +/- 7.0%, p <0.05). In BIL treated groups erection recovery for FK506 and GPI1046 treated rats exceeded saline treated values by approximately 70% (p <0.05) and 40% (p = 0.14), respectively. After 28 days of continuous treatment in BIL treated groups erection recovery for GPI1046 treated rats exceeded saline treated values by 140% (p <0.05). Neuronal and endothelial staining was preserved after immunophilin ligand treatment., Conclusions: Immunophilin ligands exert neurotrophic effects on the penile innervation that preserve cavernous tissue structure and promote erectile function recovery in rats after extensive CN injury.

Purpose: The rationale for protecting the nerve supply of the penis derives mainly from the fact that neurological injury or disease states involving this organ commonly result in erectile dysfunction. Novel directions in the management of neurogenic erectile dysfunction that pertain specifically to sustaining penile neuronal function are described., Materials and Methods: The review constitutes a summary of neuroprotective strategies for penile erection that are under investigation at the basic science level or have been brought to clinical practice. The basic exercise consisted primarily of a literature search using the National Library of Medicine PubMed Services, with references made to such keywords as nerve grafts, nerve growth factors, neuroprotection and nerve regeneration., Results: Primary advances in this field have centered on repairing structural defects and restoring the functional integrity of the cavernous nerves of the penis. In the former autologous nerve conduits, such as sural nerve grafts, have been explored and used prominently in the context of radical prostatectomy. In the latter diverse neurotrophic treatments have been investigated, with progress mostly limited to animal models of cavernous nerve injury. Basic concepts and ongoing developments in the neurobiology of axonal regeneration were identified as being applicable to this area of neurourology., Conclusions: Because neurogenic origins represent a leading categorical cause of erectile dysfunction, the importance of developing and applying treatment approaches to alleviate neuropathic effects on the erectile tissue of the penis is certain. Medical and surgical innovations for preserving and reconstituting the functional nerve supply of the penis offer great promise in the management of erectile dysfunction.

Purpose: We assessed the long-term clinical efficacy of sildenafil citrate (SC) and predictors of satisfactory outcome., Materials and Methods: All patients were evaluated with a self-administered questionnaire or by telephone interview before, and 3 months and 2.5 years following the initiation of SC therapy. Current SC use, other therapies and overall level of sexual satisfaction were assessed. Sexual function was measured using an abbreviated version of the International Index of Erectile Function questionnaire., Results: Of the 197 men 97 (49%) were using SC at 2.5 years. Patients with a history of diabetes mellitus or prostate surgery were least likely to be satisfied with SC therapy. Men with vasculogenic etiologies for erectile dysfunction were more likely to be on SC and had better sexual function scores at 2.5 years than men with a history of prostate surgery. The 3-month International Index of Erectile Function questionnaire score was an excellent predictor of sexual satisfaction in men who continued to use SC at 2.5 years. Of the 100 men who discontinued treatment with SC 56% chose not to pursue any other treatment., Conclusions: SC remains a highly effective and durable oral agent for erectile dysfunction. Improved sexual function and sexual satisfaction were well maintained 2.5 years following the initiation of SC therapy, especially in patients with vasculogenic or psychogenic etiologies of erectile dysfunction. Patients who discontinued SC reported significantly decreased sexual function than their counterparts but under used alternative therapies to improve erectile dysfunction.

Purpose: While a modest amount of medical literature has been written on the topic of priapism, reports heretofore have focused predominantly on diagnostic and management related aspects of the disorder, providing meager information in regard to its pathophysiology. Accordingly the intent of this review was to explore the etiological and pathogenic factors involved in priapism., Materials and Methods: The review entailed an overview of traditional and modern concepts that have been applied to the pathophysiology of priapism and an evaluation of assorted observational and experimental data relating to this field of study. The basic exercise consisted of a literature search using the National Library of Medicine PubMed Services, index referencing provided through the Historical Collection of the Institute of Medicine of The Johns Hopkins University and a survey of abstract proceedings from national meetings relevant to priapism., Results: Insight into the pathophysiology of priapism was derived from a synthesis of evolutionary clinical experiences, mythical beliefs, clinical variants and scientific advances associated with the field of priapism. The results can be summarized. 1) Clinicopathological manifestations of priapism support its basic classification into low flow (ischemic) and high flow (nonischemic) hemodynamic categories, commonly attributed to venous outflow occlusion and unregulated arterial overflow of the penis, respectively. 2) Factual information is insufficient to substantiate etiological roles for urethral infection, bladder distention, failed ejaculation, satyriasis and sleep apnea in priapism. 3) Features of the variant forms of priapism invoke changes in nervous system control of erection and penile vascular homeostasis as having pathogenic roles in the disorder. 4) Clinical therapeutic and basic science investigative studies have revealed various effector mechanisms of the erectile tissue response that may act in dysregulated fashion to subserve priapism., Conclusions: This exercise suggested that, while priapism is commonly defined in terms of adverse mechanical contexts affecting penile circulation, it may also be viewed at least in some situations as an unbalanced erectile response involving derangements in possibly diverse systems of regulatory control. An integrative scientific approach that encompasses tissular, cellular and molecular levels of investigation may allow further understanding of the pathophysiology of the disorder. Ongoing elucidation of this pathophysiology can be expected to promote the development of new priapism therapies.

Purpose: Ischemia-reperfusion injury is a relatively common cause of renal tubular cell death and acute renal failure. While nuclear factor-kappaB has been implicated in the pathophysiology of renal ischemia-reperfusion injury, the effect of nuclear factor-kappaB inhibition on ischemia induced renal tubular cell death remains unknown., Materials and Methods: Renal tubular cells (LLC-PK1) were exposed to simulated ischemia in the presence or absence of 10 microM. pyrrolidine dithiocarbamate (nuclear factor-kappaB inhibitor). Nuclear factor-kappaB activation (electrophoretic mobility shift assay and immunohistochemistry) and the effect of pyrrolidine dithiocarbamate on nuclear factor-kappaB activation (electrophoretic mobility shift assay) and ischemia induced apoptosis (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling) were determined., Results: Simulated ischemia induced nuclear factor-kappaB activation and renal tubular cell apoptosis versus controls (mean plus or minus standard error of mean 62 +/- 5.2 versus 0.4 +/- 0.3 apoptotic nuclei per high power field, p <0.05). In contrast, previous cellular exposure to pyrrolidine dithiocarbamate effectively inhibited nuclear factor-kappaB activation and prevented ischemia induced apoptosis (mean 14 +/- 6 apoptotic nuclei per high power field)., Conclusions: Simulated ischemia induces nuclear factor-kappaB intranuclear translocation and activation in renal tubular cells. Furthermore, nuclear factor-kappaB mediates ischemia induced renal tubular cell apoptosis. Further elucidation of the complex role of nuclear factor-kappaB in inflammatory injury may lead to the development of targeted therapeutic strategies that ameliorate ischemic renal injury.

Purpose: We assess the clinical efficacy of sildenafil citrate and predictors of satisfactory outcome., Materials and Methods: All patients treated with sildenafil citrate within the first 6 weeks of its release were evaluated with a self-administered questionnaire before and at completion of therapy to assess etiology of erectile dysfunction, level of sexual function, libido, response to previous therapies, response to therapy with sildenafil citrate and quality of life. Sexual function was measured before and during therapy using an abbreviated version of the International Index of Erectile Function, with a successful outcome defined as a level of satisfaction of 4 or 5 on a 5-point scale., Results: Followup was obtained in 267 of the 308 patients who entered the study. Mean age plus or minus standard deviation was 61+/-9.6 years and duration of erectile dysfunction was 4.1+/-3 years. Overall satisfaction with sildenafil citrate for the entire patient population was 65% and response to prior therapies did not affect satisfaction. There was a significant positive correlation between baseline sexual function and response to sildenafil citrate but even patients with severe erectile dysfunction had a 41% satisfaction rate. Etiology of erectile dysfunction had a significant impact on satisfaction rate, with neurogenic causes of erectile dysfunction (diabetes, prostate surgery and so forth) having significantly lower rates than psychogenic or vasculogenic erectile dysfunction., Conclusions: Sildenafil citrate is a highly effective oral agent for the treatment of erectile dysfunction in clinical practice. The best predictors for response to sildenafil citrate therapy are baseline sexual function and etiology of erectile dysfunction. However, we could not identify any patient characteristic that would predict absolute failure for sildenafil citrate therapy. Therefore, all patients with erectile dysfunction who do not have specific contraindications should be considered for sildenafil citrate therapy.

Purpose: We describe a correlative gross anatomical and histological study of the human male urethral sphincteric complex using methods that delineate skeletal, muscular and fascial components., Materials and Methods: Pelves of 6 fresh frozen male cadavers were sectioned as 4 mm. tissue blocks in planes sagittal and perpendicular to the axis of the prostatomembranous urethra from the bladder neck to the bulb of the corpus spongiosum. Sections were photographed and prepared in situ for histological staining (hematoxylin and eosin, Masson's trichrome and phosphotungstic acid hematoxylin)., Results: The structure of the male urethral sphincteric complex was demonstrated to include the cylindrical rhabdosphincter surrounding the prostatomembranous urethra and a fascial framework, principally consisting of the ventral subpubic fascia and medial fascia of the levator ani musculature. The histological appearance of the rhabdosphincter at its dorsal aspect suggested a suburethral musculofascial plate. Rhabdosphincteric muscle fibers were oriented in vertical and ventrolateral directions with attachments to the subpubic fascia and the medial fascia of the levator ani., Conclusions: The structural components and their relationships suggest mechanisms whereby the complex is suspended and stabilized within the deep pelvis, and achieves urethral closure. Our study furthers an understanding of the anatomical basis for male urinary continence and micturition, and is expected to have primary importance in the effort to preserve urinary function following major pelvic surgery.

Purpose: Our aim was to identify and localize nitric oxide synthase isoforms in the human clitoris in support of the hypothesis that nitric oxide mediates erectile function in this organ., Materials and Methods: Nitric oxide synthase immunohistochemistry studies specific for neuronal, inducible and endothelial isoforms of the enzyme were performed on human clitoral tissue obtained from 4 patients (3 with female pseudohermaphroditism and 1 with true hermaphroditism) at feminizing genitoplasty and from 1 phenotypically normal woman at autopsy., Results: Neuronal nitric oxide synthase immunoreactivity was detected in nerve bundles and fibers coursing within the glans clitoris and corpora cavernosa of the clitoris, predominating in the latter tissue. Specific inducible nitric oxide synthase immunoreactivity was not identified. Endothelial nitric oxide synthase immunoreactivity was detected in vascular and sinusoidal endothelium of these tissues with a predominance in the glans clitoris., Conclusions: The presence and anatomical localizations of nitric oxide synthase isoforms in the human clitoris indicate that nitric oxide is generated in this organ. These data suggest that nitric oxide may be involved in the erectile physiology of the clitoris as a modulator of clitoral smooth muscle activity. Functional studies are required to support this hypothesis.