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Kevin T McVary,1 Bilal Chughtai,2 Larry E Miller,3 Samir K Bhattacharyya,4 Ryan A Dornbier,1 Dean S Elterman5 1Center for Male Health, Department of Urology, Stritch School of Medicine, Loyola University Medical Center, Maywood, IL, USA; 2Department of Urology, Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA; 3Department of Biostatistics, Miller Scientific, Johnson City, TN, USA; 4Health Economics & Market Access, Boston Scientific, Marlborough, MA, USA; 5Division of Urology, University Health Network, Toronto, ON, CanadaCorrespondence: Kevin T McVaryCenter for Male Health, Department of Urology, Stritch School of Medicine, Loyola University Medical Center, 2160 S, First Ave, Maywood, IL 60153, USAEmail kmcvary@gmail.comAbstract: Lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) are highly prevalent in older men. The long-term clinical utility of lifestyle modification and oral medications for LUTS is limited. There is a great clinical need for safe, effective, and durable BPH therapies for men who unsuccessfully attempt conservative measures. Enthusiasm for transurethral resection of the prostate has declined due to surgical risk, high rates of postoperative sexual dysfunction, and the perceived invasive nature therein. Consequently, interest has grown in developing minimally invasive surgical treatments (MISTs) that are efficacious but with a more favorable risk profile in order to better align with patient preferences. This review evaluates currently available MISTs for BPH. Further, we critically examine a “Leave Nothing Behind” philosophy in MIST for BPH since implantation of permanent metallic devices may be associated with increased long-term failure rates.Keywords: benign prostatic hyperplasia, LUTS, minimally invasive surgical treatment, MIST, Rezum, UroLift

Lulu K Lee,1 Amir Goren,1 Natalie N Boytsov,2 Craig F Donatucci,2 Kevin T McVary3 1Health Outcomes Practice, Kantar Health, New York, NY, 2US Real World Outcomes Research, Eli Lily & Company, Indianapolis, IN, 3Division of Urology, Southern Illinois University School of Medicine, Springfield, IL, USA Objective: Erectile dysfunction (ED) and benign prostatic hyperplasia (BPH) frequently co-occur in men aged ≥40, along with lower urinary tract symptoms (LUTS) secondary to BPH. Given little real-world evidence on treatment use or satisfaction with treatment for concurrent BPH/LUTS and/or ED, this study examined medication regimens and differences in satisfaction and health-related quality of life (HRQoL) across regimens among men with concurrent BPH and ED. Methods: A cross-sectional study was conducted using an Internet survey of participants recruited through an online panel. Respondents (N=736) included men (aged ≥40) who self-reported a diagnosis of both ED and BPH with prescription treatment in the past 3 months for both conditions. Treatment satisfaction (eg, convenience and ease of planning) and HRQoL (eg, International Prostate Symptom Score, sleep quality) were self-reported. Generalized linear models examined the association of regimen with treatment satisfaction and HRQoL, adjusting for covariates (eg, age and comorbidities). Results: Final analyses included participants (N=507) using: tadalafil once-daily monotherapy (22%), tadalafil for ED with an alternate BPH therapy (36%), or another phosphodiesterase type-5 inhibitor (PDE5-I) combination (41%). These groups represented the major categories of treatment regimens found in the sample, excluded participants with ambiguous regimens, and were aligned with current standard of care for BPH and ED. Overall, patients reported moderate levels of BPH and a moderate-to-severe degree of ED. Tadalafil monotherapy patients had higher treatment satisfaction scores and greater reported ease of treatment planning and convenience than PDE5-I combination patients. No significant intergroup differences were found on HRQoL. Conclusion: A majority of patients (59%) took tadalafil alone or in combination for BPH/ED treatment. Tadalafil monotherapy patients reported greater treatment satisfaction than patients taking PDE5-I combination therapy. Higher satisfaction for both effectiveness and convenience of once-daily tadalafil may inform both patient and clinician decisions regarding pharmacotherapy regimens. Keywords: once-daily tadalafil, alpha1-adrenergic blockers, 5-alpha-reductase inhibitors, International Prostate Symptom Score, treatment convenience, treatment satisfaction, Treatment Satisfaction Questionnaire for Medication

Mauro Gacci,1 Matteo Salvi,1 Arcangelo Sebastianelli,1 Linda Vignozzi,2 Giovanni Corona,3 Kevin T McVary,4 Steven A Kaplan,5 Mario Maggi,2 Marco Carini,1 Matthias Oelke6 1Department of Urology, University of Florence, Florence, 2Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, 3Endocrinology Unit, Maggiore-Bellaria Hospital, Bologna, Italy; 4Division of Urology, Department of Surgery, Southern Illinois University School of Medicine, Springfield, IL, 5Department of Urology, Weill Cornell Medical College, Cornell University, New York, NY, USA; 6Department of Urology, Hannover Medical School, Hannover, Germany Abstract: A strong and independent association between lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) and erectile dysfunction (ED) has been widely evidenced in several clinical epidemiologic studies. Preclinical animal models have provided a great deal of information on potential common pathogenic mechanisms underlying these two clinical identities. Although the efficacy of the most commonly used treatments for LUTS/BPH is well defined, the negative impact of these treatments on sexual function – in particular, on ED – has triggered the search for new treatment options. In this regard, a new role for phosphodiesterase type 5 inhibitors in the treatment of LUTS/BPH and ED has been claimed. Tadalafil is one of the most extensively investigated phosphodiesterase type 5 inhibitors for this new indication. All evidence reported to date suggests that tadalafil 5 mg once daily is a safe and effective treatment option for both LUTS/BPH and ED. Keywords: phosphodiesterase type 5 inhibitor, LUTS/BPH, ED, sexual function, Cialis

Context: Saw palmetto fruit extracts are widely used for treating lower urinary tract symptoms attributed to benign prostatic hyperplasia (BPH); however, recent clinical trials have questioned their efficacy, at least at standard doses (320 mg/d).Objective: To determine the effect of saw palmetto extract (Serenoa repens, from saw palmetto berries) at up to 3 times the standard dose on lower urinary tract symptoms attributed to BPH.Design, Setting, and Participants: A double-blind, multicenter, placebo-controlled randomized trial at 11 North American clinical sites conducted between June 5, 2008, and October 10, 2010, of 369 men aged 45 years or older, with a peak urinary flow rate of at least 4 mL/s, an American Urological Association Symptom Index (AUASI) score of between 8 and 24 at 2 screening visits, and no exclusions.Interventions: One, 2, and then 3 doses (320 mg/d) of saw palmetto extract or placebo, with dose increases at 24 and 48 weeks.Main Outcome Measures: Difference in AUASI score between baseline and 72 weeks. Secondary outcomes included measures of urinary bother, nocturia, peak uroflow, postvoid residual volume, prostate-specific antigen level, participants' global assessments, and indices of sexual function, continence, sleep quality, and prostatitis symptoms.Results: Between baseline and 72 weeks, mean AUASI scores decreased from 14.42 to 12.22 points (-2.20 points; 95% CI, -3.04 to -1.36) [corrected]with saw palmetto extract and from 14.69 to 11.70 points (-2.99 points; 95% CI, -3.81 to -2.17) with placebo. The group mean difference in AUASI score change from baseline to 72 weeks between the saw palmetto extract and placebo groups was 0.79 points favoring placebo (upper bound of the 1-sided 95% CI most favorable to saw palmetto extract was 1.77 points, 1-sided P = .91). Saw palmetto extract was no more effective than placebo for any secondary outcome. No clearly attributable adverse effects were identified.Conclusion: Increasing doses of a saw palmetto fruit extract did not reduce lower urinary tract symptoms more than placebo.Trial Registration: clinicaltrials.gov Identifier: NCT00603304. [ABSTRACT FROM AUTHOR]

Objective: Although diabetes is known to result in lower urinary tract symptoms (LUTS) in men, it remains unclear if glycemic control can mitigate urinary symptoms. We studied how diabetic characteristics are related to LUTS in the men who completed the urological assessment component (UroEDIC) of the Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study of the Diabetes Control and Complications Trial (DCCT) participants.Research Design and Methods: Study participants were men who completed the UroEDIC questionnaire at the year 10 DCCT/EDIC follow-up examination, which included data on genitourinary tract function and the American Urological Association Symptom Index (AUASI). Analyses were conducted to assess how treatment arm and diabetes characteristics were associated with LUTS using logistic regression.Results: Of the 591 men who completed the AUASI questions, nearly 20% (n = 115) had AUASI scores in the moderate to severe category for LUTS (AUASI score >or=8). No associations were observed between LUTS and treatment arm, or A1C levels at the DCCT baseline or end-of-study or at the year 10 EDIC (UroEDIC) examination. Of the diabetes complications studied, only erectile dysfunction at the UroEDIC examination was associated with LUTS.Conclusions: These data from the UroEDIC cohort do not support the assumption that intensive glycemic control results in decreased lower urinary tract symptom severity in men with type 1 diabetes. This result may be due to a true lack of effect, or it may be due to other factors, for example, the relatively young age of the cohort. [ABSTRACT FROM AUTHOR]

BACKGROUND: Trials of monotherapy with alpha(1)-adrenergic-receptor antagonists (alpha(1)ARAs) and 5 alpha-reductase inhibitors (5ARIs) have found that the former drug class is effective in managing benign prostatic hyperplasia (BPH)-related lower urinary tract symptoms (LUTS) and improving the maximal urinary flow rate in shortand long-term treatment, regardless of prostate size, whereas the latter drug class is effective in reducing prostate size and preventing disease progression in longer-term treatment. The differing mechanisms of action and areas of efficacy of these 2 drug classes make them promising candidates for combination therapy. OBJECTIVE: This article reviews key trials of monotherapy and combination alpha(1)ARV5ARI therapy in the treatment and prevention of BPH-related voiding dysfunction. METHODS: MEDLINE (1976-2006) and the Cochrane Central Register of Controlled Trials (1976-2006) were searched for relevant clinical trials and reviews using the terms benign prostatic byperplasia, lower urinary tract symptoms, LUTS, alpha-adrenergic-receptor antagonists, alpha-blockers, 5 alpha-reductase inhibitors, combination therapy, MTOPS, SMART, PREDICT, adverse events, alfuzosin, doxazosin, tamsulosin, terazosin, dutasteride, and finasteride. Abstracts from selected professional conferences also were reviewed. RESULTS: Three previous trials of alpha(1)ARA/5ARI therapy found no therapeutic benefit for combination therapy relative to monotherapy, but their conclusions were limited to some extent by their designs, particularly the duration of treatment. Data from the Medical Therapy of Prostatic Symptoms (MTOPS) study, however, indicated a potential role for long-term use of alpha(1)ARA/5ARI therapy, particularly in patients with greater symptom severity (mean score of 17 on the American Urological Association symptom index), larger prostate volume (mean, 32 g), and higher prostate-specific antigen (PSA) levels (>1.5 ng/mL) at baseline. In the MTOPS study, combination therapy with the alpha(1)ARA doxazosin and the SARI finasteride was significantly more effective than either component alone in reducing BPH-related symptoms (P=0.006 vs doxazosin monotherapy; P<0.001 vs finasteride monotherapy) and lowering the rate of overall clinical progression (P<0.001 vs either monotherapy). In addition, there are data from a subgroup analysis of MTOPS suggesting that the presence of prostatic inflammation may indicate a greater likelihood of treatment efficacy with combination alpha(1)ARA/5ARI therapy. CONCLUSIONS: The available data suggest that combination alpha(1)ARA/5ARI therapy is beneficial in the treatment of BPH and the associated symptoms. The greatest efficacy was evident in patients with an enlarged prostate, more severe symptoms, and higher PSA levels. There are limited data suggesting that the presence of prostatic inflammation may indicate a greater likelihood of treatment efficacy with combination therapy. [ABSTRACT FROM AUTHOR]

Although the exact effect of smoking on penile function remains unclear, numerous studies suggest a correlation between smoking and erectile dysfunction. This article examines what is currently known--and what remains to be discovered--about the link. [ABSTRACT FROM AUTHOR]

Background: Cavernous nerve (CN) injury, which occurs in prostatectomy and diabetic cases, initiates penile remodeling, including smooth muscle apoptosis and increased collagen in the corpora cavernosa, which are underlying causes of erectile dysfunction. Sonic hedgehog (SHH) is a critical regulator of penile smooth muscle, and SHH treatment suppresses corpora cavernosa remodeling that occurs with CN injury., Aim: We examine if SHH treatment by peptide amphiphile (PA) in the first week after CN injury is sufficient to prevent long-term penis remodeling and if apoptosis inhibitors also suppress penile remodeling., Methods: Bilateral CN crush was performed on adult Sprague-Dawley rats (P115-120) that underwent 1 of 3 treatments with novel extended-release nanofiber PA hydrogels for delivery: SHH protein (n = 10), mouse serum albumin protein (control, n = 7), or caspase 3 inhibitor (AC-DEVD-CHO, n = 10). Rats were sacrificed after 18 to 24 days. Additional rats underwent CN injury (n = 6) or CN injury and SHH PA treatment for 2 and 4 days (n = 8) and included sham controls (n = 3) and nonsurgery controls (n = 3)., Outcomes: Trichrome stain, hydroxyproline assay, and Western analysis for α-actin (smooth muscle) and GAPDH were performed to examine smooth muscle retention and collagen abundance., Results: Smooth muscle decreased with CN injury. Corpora cavernosa showed increased smooth muscle at 2, 4, and 24 days after CN injury with SHH PA treatment in comparison with mouse serum albumin treatment among CN-injured controls. Caspase 3-inhibited penis demonstrated little smooth muscle preservation. Collagen was decreased 23% with SHH PA treatment (P < .001) at 18 to 24 days after CN injury. Collagen was unchanged with caspase 3 inhibitor treatment (P > .99)., Clinical Translation: It is important to know that treatments given at the time of CN injury have a sustained effect on preserving penile architecture and thus erectile function, making them valuable for clinical translation., Strengths and Limitations: SHH PA treatment preserves penile smooth muscle after CN injury. Time points past 24 days were not examined, although penile remodeling takes place acutely after CN injury. Measurement of erectile function was not examined., Conclusions: SHH treatment by PA in the first week after CN injury is sufficient to suppress penile remodeling and to preserve penile smooth muscle over time, which is critical to prevent development of erectile dysfunction. There is a difference in the corpora cavernosa smooth muscle from proximal to distal in the penis of the Sprague-Dawley rat model. It is critical when examining therapy efficacy to ensure that comparable regions of the penis are analyzed., Statement of Significance: In this study, we examine if suppression of apoptosis in penile smooth muscle in the first week after cavernous nerve injury is sufficient to preserve smooth muscle long-term., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society for Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The Princeton Consensus (Expert Panel) Conference is a multispecialty collaborative symposium dedicated to optimizing sexual function and preserving cardiovascular health. The Fourth Princeton Consensus Conference was convened on March 10-11, 2023, at the Huntington Medical Research Institutes in Pasadena, California. Princeton panels I to III addressed the clinical management of men with erectile dysfunction (ED) who also had cardiovascular disease. Thirteen years since Princeton III, Princeton IV builds on previous foundations in several key areas. Mounting evidence supports the need for providers to treat men with ED as being at risk for cardiac events until proven otherwise. Algorithms for the diagnosis and treatment of ED are updated with new recommendations for coronary artery calcium scoring for advanced cardiovascular risk stratification. Optimization of oral phosphodiesterase type 5 inhibitors in the treatment of men with ED and cardiovascular disease is thoroughly explored, including recent evidence of potential cardioprotective effects of these drugs., (Copyright © 2024 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background: The cavernous nerve (CN) is frequently damaged in prostatectomy and diabetic patients with erectile dysfunction (ED), initiating changes in penile morphology including an acute and intense phase of apoptosis in penile smooth muscle and increased collagen, which alter penile architecture and make corpora cavernosa smooth muscle less able to relax in response to neurotransmitters, resulting in ED., Aim: Sonic hedgehog (SHH) is a critical regulator of penile smooth muscle, and SHH treatment suppresses penile remodeling after CN injury through an unknown mechanism; we examine if part of the mechanism of how SHH preserves smooth muscle after CN injury involves bone morphogenetic protein 4 (BMP4) and gremlin1 (GREM1)., Methods: Primary cultures of smooth muscle cells were established from prostatectomy, diabetic, hypertension and Peyronie's (control) (N = 18) patients. Cultures were characterized by ACTA2, CD31, P4HB, and nNOS immunohistochemical analysis. Patient smooth muscle cell growth was quantified in response to BMP4 and GREM1 treatment. Adult Sprague Dawley rats underwent 1 of 3 surgeries: (1) uninjured or CN-injured rats were treated with BMP4, GREM1, or mouse serum albumin (control) proteins via Affi-Gel beads (N = 16) or peptide amphiphile (PA) (N = 26) for 3 and 14 days, and trichrome stain was performed; (2) rats underwent sham (N = 3), CN injury (N = 9), or CN injury and SHH PA treatment for 1, 2, and 4 days (N = 9)., Outcomes: Western analysis for BMP4 and GREM1 was performed; (3) rats were treated with 5E1 SHH inhibitor (N = 6) or IgG (control; N = 6) for 2 and 4 days, and BMP4 and GREM1 localization was examined. Statistics were performed by analysis of variance with Scheffé's post hoc test., Results: BMP4 increased patient smooth muscle cell growth, and GREM1 decreased growth. In rats, BMP4 treatment via Affi-Gel beads and PA increased smooth muscle at 3 and 14 days of treatment. GREM1 treatment caused increased collagen and smooth muscle at 3 days, which switched to primarily collagen at 14 days. CN injury increased BMP4 and GREM1, while SHH PA altered Western band size, suggesting alternative cleavage and range of BMP4 and GREM1 signaling. SHH inhibition in rats increased BMP4 and GREM1 in fibroblasts., Clinical Implications: Understanding how SHH PA preserves and regenerates penile morphology after CN injury will aid development of ED therapies., Strengths and Limitations: SHH treatment alters BMP4 and GREM1 localization and range of signaling, which can affect penile morphology., Conclusion: Part of the mechanism of how SHH regulates corpora cavernosa smooth muscle involves BMP4 and GREM1., (© 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: Cavernous nerve (CN) injury, caused by prostatectomy and diabetes, initiates a remodeling process (smooth muscle apoptosis and increased collagen) in the corpora cavernosa of the penis of patients and animal models that is an underlying cause of erectile dysfunction (ED), and the Sonic hedgehog (SHH) pathway plays an essential role in the response of the penis to denervation, as collagen increases with SHH inhibition and decreases with SHH treatment., Aim: We examined if part of the mechanism of how SHH prevents penile remodeling and increased collagen with CN injury involves bone morphogenetic protein 4 (BMP4) and gremlin1 (GREM1) and examined the relationship between SHH, BMP4, GREM1, and collagen in penis of ED patients and rat models of CN injury, SHH inhibition, and SHH, BMP4, and GREM1 treatment., Methods: Corpora cavernosa of Peyronie's disease (control), prostatectomy, and diabetic ED patients were obtained (N = 30). Adult Sprague Dawley rats (n = 90) underwent (1) CN crush (1-7 days) or sham surgery; (2) CN injury and BMP4, GREM1, or mouse serum albumin (control) treatment via Affi-Gel beads or peptide amphiphile (PA) for 14 days; (3) 5E1 SHH inhibitor, IgG, or phosphate-buffered saline (control) treatment for 2 to 4 days; or (4) CN crush with mouse serum albumin or SHH for 9 days., Outcomes: Immunohistochemical and Western analysis for BMP4 and GREM1, and collagen analysis by hydroxyproline and trichrome stain were performed., Results: BMP4 and GREM1 proteins were identified in corpora cavernosa smooth muscle of prostatectomy, diabetic, and Peyronie's patients, and in rat smooth muscle, sympathetic nerve fibers, perineurium, blood vessels, and urethra. Collagen decreased 25.4% in rats with CN injury and BMP4 treatment (P = .02) and increased 61.3% with CN injury and GREM1 treatment (P = .005). Trichrome stain showed increased collagen in rats treated with GREM1. Western analysis identified increased BMP4 and GREM1 in corpora cavernosa of prostatectomy and diabetic patients, and after CN injury (1-2 days) in our rat model. Localization of BMP4 and GREM1 changed with SHH inhibition. SHH treatment increased the monomer form of BMP4 and GREM1, altering their range of signaling., Clinical Implications: A better understanding of penile remodeling and how fibrosis occurs with loss of innervation is essential for development of novel ED therapies., Strengths and Limitations: The relationship between SHH, BMP4, GREM1, and collagen is complex in the penis., Conclusion: BMP4 and GREM1 are downstream targets of SHH that impact collagen and may be useful in collaboration with SHH to prevent penile remodeling and ED., (© 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.)

Objective: To determine the safety and effectiveness of water vapor thermal therapy (Rezum) in men with large prostate volumes of at least 80cm 3 ., Methods: We performed systematic searches for studies of Rezum therapy in men with prostate volume of at least 80 cm 3 . Meta-analysis outcomes included the International Prostate Symptom Score (IPSS), IPSS Quality of Life (IPSS-QOL), Qmax, postvoid residual, International Index of Erectile Function-Erectile Function (IIEF-EF), and serious (Clavien-Dindo grade III-V) complications, surgical retreatments. Outcomes were analyzed using a random effects meta-analysis model., Results: The review included 15 studies (11 retrospective) of 471 men with prostate volume at least 80 cm 3 treated with Rezum therapy and followed for a median of 6months (range: 3-17months). Rezum therapy resulted in statistically significant improvements in IPSS (mean change: -11.0; 95% CI: -12.2, -9.7; P < .001), IPSS-QOL (mean change: -2.9; 95% CI: -3.5, -2.4; P < .001), Qmax (mean change: 6.5 mL/s; 95% CI: 4.8, 8.2 mL/s; P < .001), and postvoid residual (mean change: -101 mL; 95% CI: -145, -57; P < .001). No change in IIEF-EF was observed (mean change: 0.3; 95% CI: -1.1, 1.6; P = .71). Serious complications occurred in <0.1% (95% CI: 0.0%, 0.4%) and surgical retreatment in 1.2% (95% CI: 0.0%, 3.5%) of patients., Conclusion: Rezum therapy provides a statistically significant and clinically important short-term improvement in lower urinary tract symptoms with low complication rates in men with prostate volume of at least 80 cm 3 . Long-term outcomes with Rezum therapy in large prostates remain unclear., Competing Interests: Declaration of Competing Interest K. McVary reports consultancy, honoraria, and role as Principal Investigator on grants received from NxThera; consultancy, honoraria, role as Principal Investigator on grants received from ProMedeon; consultancy, stock options, role as Principal Investigator on grants received from Rivermark; consultancy, role as investigator, honoraria from Urotronic; consultancy, role as investigator, honoraria from Francis Medical; consultancy, role as investigator from Zenflow; role as Principal Investigator on grants received from NIDDK; patents received, stock ownership in Uronext; royalties from UpToDate; and grants pending, honoraria from Boston Scientific. L. Miller discloses financial support from Boston Scientific. S. Bhattacharyya, K. DeRouen, E. Turner, and P. Zantek report employment with Boston Scientific. M. Abdel-Rassoul reports consultancy with Boston Scientific. T. Miyauchi reports no conflicts of interest. T. Alzahrani reports no conflicts of interest. T. Kohler reports consultancy and research funding with Coloplast., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: In 1999, 1 year after the approval of the first oral phosphodiesterase type 5 (PDE5) inhibitor for the treatment of erectile dysfunction (ED), the first Princeton Consensus Conference was held to address the clinical management of men with ED who also had cardiovascular disease. These issues were readdressed in the second and third conferences. In the 13 years since the last Princeton Consensus Conference, the experience with PDE5 inhibitors is more robust, and recent new data have emerged regarding not only safety and drug-drug interactions, but also a potential cardioprotective effect of these drugs., Aim: In March 2023, an interdisciplinary group of scientists and practitioners met for the fourth Princeton Consensus Guidelines at the Huntington Medical Research Institutes in Pasadena, California, to readdress the cardiovascular workup of men presenting with ED as well as the approach to treatment of ED in men with known cardiovascular disease., Method: A series of lectures from experts in the field followed by Delphi-type discussions were developed to reach consensus., Outcomes: Consensus was reached regarding a number of issues related to erectile dysfunction and the interaction with cardiovascular health and phosphodiesterase-5 inhibitors., Results: An algorithm based on recent recommendations of the American College of Cardiology and American Heart Association, including the use of computed tomography coronary artery calcium scoring, was integrated into the evaluation of men presenting with ED. Additionally, the issue of nitrate use was further considered in an algorithm regarding the treatment of ED patients with coronary artery disease. Other topics included the psychological effect of ED and the benefits of treating it; the mechanism of action of the PDE5 inhibitors; drug-drug interactions; optimizing use of a PDE5 inhibitors; rare adverse events; potential cardiovascular benefits observed in recent retrospective studies; adulteration of dietary supplements with PDE5 inhibitors; the pros and cons of over-the-counter PDE5 inhibitors; non-PDE5 inhibitor therapy for ED including restorative therapies such as stem cells, platelet-rich plasma, and shock therapy; other non-PDE5 inhibitor therapies, including injection therapy and penile prostheses; the issue of safety and effectiveness of PDE5 inhibitors in women; and recommendations for future studies in the field of sexual dysfunction and PDE5 inhibitor use were discussed., Clinical Implications: Algorithms and tables were developed to help guide the clinician in dealing with the interaction of ED and cardiovascular risk and disease., Strengths and Limitations: Strengths include the expertise of the participants and consensus recommendations. Limitations included that participants were from the United States only for this particular meeting., Conclusion: The issue of the intersection between cardiovascular health and sexual health remains an important topic with new studies suggesting the cardiovascular safety of PDE5 inhibitors., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society of Sexual Medicine.)

Objective: To investigate the incidence and risk factors of persistent lower urinary tract symptoms (LUTS) 1 month and later following convective water vapor thermal therapy (CWVTT) in men with LUTS secondary to benign prostatic hyperplasia (BPH)., Methods: Patients who underwent CWVTT from 11/2018-5/2021 at a single institution were eligible for inclusion and retrospectively identified. Pertinent patient, operative, and outcomes data were extracted. The primary outcome was clinically significant LUTS improvement at 4 weeks following CWVTT. Persistent LUTS was defined as failure to reach a minimally clinical important difference of 25% reduction on International Prostate Symptom Score at 4 weeks., Results: One hundred nine patients qualified. Fifty percent of patients experienced persistent LUTS at 1 month. Eighty-two percent of men ultimately reached the minimally clinical important difference. For each additional month following CWVTT, the odds of achieving clinically significant LUTS improved by 9% (Odds ratio (OR) = 0.91, P = .0033). Bladder outlet obstruction index and prior surgical BPH therapy were associated with persistent LUTS on multivariate logistic regression. Every 10-unit increase in Bladder outlet obstruction index noted at baseline was associated with a 15% increased likelihood of achieving minimally clinical important difference in LUTS at 4 weeks following CWVTT (OR = 0.85, P = .01). Patients receiving prior surgical BPH therapy were 3.5 times more likely to experience persistent LUTS at 1 month (OR = 3.47, P = .01)., Conclusion: Fifty percent of men experienced persistent LUTS 1 month following CWVTT. However, LUTS improved with time and the majority of men ultimately achieved clinically significant LUTS improvement. A lower baseline Bladder outlet obstruction index and prior BPH procedures are risk factors for persistent LUTS following CWVTT., Competing Interests: Declaration of Competing Interest KTM: NIDDK, Uronext, SRS Medical Systems, Prodeon, Urotronic, Francis Medical, Boston Scientific., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: Convective water vapor thermal therapy (CWVTT-Rezum) is a minimally invasive surgical therapy that is being increasingly utilized for bladder outlet obstruction. Most patients leave the site of care with a Foley catheter in place for a mean reported duration of 3-4 days. A minority of men will fail their trial without catheter (TWOC). We aim to identify the frequency of TWOC failure following CWVTT and its associated risk factors., Methods: Patients who underwent CWVTT at a single institution from October 2018 to May 2021 were retrospectively identified and pertinent data extracted. The primary endpoint was TWOC failure. Descriptive statistics were performed, and rate of TWOC failure was determined. Potential risk factors for failed TWOC were assessed through univariate and multivariate logistic regression., Results: A total of 119 patients were analyzed. Seventeen percent (20/119) had a failed TWOC on their first attempt. Of those, 60% (12/20) failed in a delayed fashion. In patients who failed, the median number of total TWOC attempts required for success was two (interquartile range [IQR] = 2-3). All patients eventually had a successful TWOC. The median preoperative postvoid residual for successful and failed TWOC was 56 mL (IQR = 15-125) and 87 mL (IQR = 25-367), respectively. Preoperative elevated postvoid residual (unadjusted odds ratio [OR] 1.02, 95% CI: 1.01-1.04; adjusted OR 1.02, 95% CI: 1.01-1.04) was associated with TWOC failure., Conclusions: Seventeen percent of patients failed their initial TWOC after CWVTT. Elevated postvoid residual was associated with TWOC failure., (© 2023 John Wiley & Sons Australia, Ltd.)

Introduction: Patients with a prostatectomy are at high risk of developing erectile dysfunction (ED) that is refractory to phosphodiesterase type 5 inhibitors. The cavernous nerve (CN) is frequently damaged during prostatectomy, causing loss of innervation to the penis. This initiates corpora cavernosal remodeling (apoptosis and fibrosis) and results in ED., Aim: To aid in the development of novel ED therapies, the current aim was to obtain a global understanding of how signaling mechanisms alter in the corpora cavernosa with loss of CN innervation that results in ED., Methods: Microarray and pathway analysis were performed on the corpora cavernosal tissue of patients with a prostatectomy (n = 3) or Peyronie disease (control, n = 3). Results were compared with an analysis of a Sprague-Dawley rat CN injury model (n = 10). RNA was extracted by TRIzol, DNase treated, and purified by a Qiagen Mini Kit. Microarray was performed with the Human Gene 2.0 ST Array and the RU34 rat array. Differentially expressed genes were identified through several analytic tools (ShinyGO, Ingenuity, WebGestalt) and databases (GO, Reactome). A 2-fold change was used as the threshold for differential expression., Outcomes: Pathways that were altered (up- or downregulated) in response to CN injury in the prostatectomy patients and a rat CN injury model were determined., Results: Microarray identified 197 differentially expressed protein-coding genes in the corpora cavernosa from the prostatectomy cohort, with 100 genes upregulated and 97 genes downregulated. Altered signaling pathways that were identified that affect tissue morphology included the following: neurologic disease, cell death and survival, tissue and cellular development, skeletal and muscle development and disorders, connective tissue development and function, tissue morphology, embryonic development, growth and proliferation, cell-to-cell signaling, and cell function and maintenance. These human pathways have high similarity to those observed in the CN-injured rat ED model., Clinical Implications: Significant penile remodeling continues in patients long after the acute surgical injury to the CN takes place, offering the opportunity for clinical intervention to reverse penile remodeling and improve erectile function., Strengths and Limitations: Understanding how signaling pathways change in response to CN injury and how these changes translate to altered morphology of the corpora cavernosa and ensuing ED is critical to identify strategic targets for therapy development., Conclusion: Altered signaling in pathways that regulate tissue homeostasis, morphogenesis, and development was identified in penes of patients with a prostatectomy, and competitive forces of apoptosis and proliferation/regeneration were found to compete to establish dominance after CN injury. How these pathways interact to regulate penis tissue homeostasis is a complex process that requires further investigation., (© The Author(s) 2023. 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.)

Purpose: To create a prospective, multicenter coordinated registry network (CRN) of robust "real world" data for benign prostatic hyperplasia (BPH) that links surgical practices to objective and subjective outcomes of patients who undergo surgery for the improvement in lower urinary tract symptoms (LUTS) secondary to BPH., Methods: We gathered a group of BPH experts from various institutions to identify the minimum core data elements needed to assess BPH procedures. To achieve consensus on the data elements, we used a Delphi method adaptation, in which a series of surveys were answered by the expert panel individually and anonymously. Survey results were collected and analyzed. Questions for the following round were based on response analysis from the prior survey. This process was repeated until consensus was achieved., Results: Participation rates in the first and second rounds were 100% and 90%, respectively. The expert panel reached consensus on 148 data elements out of the 182 proposed, capturing patient medical and surgical history, procedure, discharge, short- and long-term follow-up, device factors, surgery, and surgeon factors., Conclusion: We have successfully developed a set of core data elements to support the study of BPH surgical therapies by gathering an expert panel on BPH and using the Delphi method. These data elements influence provider decisions about treatment and include important outcomes related to efficacy and safety., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: To investigate voiding time (VT) in asymptomatic and symptomatic men, and compare VT to other parameters such as maximum flow rates (Qmax) as a possible solution to disparity related lack of access to standard urodynamic testing., Methods: We conducted a controlled prospective study on a total of 30 patients. Exclusion criteria included ongoing medical therapy for lower urinary tract symptoms (LUTS) or a history of invasive therapy for LUTS. Patients completed International Prostate Symptom Score (IPSS) questionnaire, uroflowmetry, and post-void residual (PVR) testing. Symptomatic LUTS was defined as an IPSS ≥8., Results: On univariate analysis, men with a symptomatic LUTS had a significantly longer VT than asymptomatic men (30.6 seconds (Interquartile rage [IQR] 24.2-42.4) vs 20.5 seconds (IQR 16.6-40.5), P = .04). VT was not otherwise associated with age, race, or primary complaint. There was trend towards lower Qmax in symptomatic patients (13.4 vs 20.5 seconds, P = .07), although this was not statistically significant. Our study demonstrated that the sensitivity of a VT ≥23.5 seconds, or probability of observing a VT exceeding 23.5 seconds when the patient has a symptomatic IPSS, is 85%. On sensitivity and specificity analysis, there was no difference between the abilities of VT and Qmax to predict that a patient would have symptomatic LUTS (P = .80)., Conclusion: In this controlled prospective study, we found that VT was as accurate as Qmax in predicting symptomatic IPSS scores. This novel finding might improve the ability to diagnose and treat LUTS, especially in primary care offices and underserved areas., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Cavernous nerve (CN) injury causes penile remodeling, including smooth muscle apoptosis and increased collagen, which results in erectile dysfunction (ED), and prevention of this remodeling is critical for novel ED therapy development., Aim: We developed 2 peptide amphiphile (PA) hydrogel delivery vehicles for Sonic hedgehog (SHH) protein to the penis and CN, which effectively suppress penile distrophic remodeling (apoptosis and fibrosis), in vivo in a rat CN injury model, and the aim of this study is to determine if SHH PA can be used to regenerate human corpora cavernosal smooth muscle deriving from multiple ED origins., Methods: Corpora cavernosal tissue was obtained from prostatectomy, diabetic, hypertension, cardiovascular disease and Peyronie's (control) patients (n = 21). Primary cultures (n = 21) were established, and corpora cavernosal cells were treated with SHH protein, MSA (control), 5E1 SHH inhibitor, and PBS (control). Growth was quantified by counting the number of cells at 3-4 days. Statistics were performed by ANOVA with Scheffe's post hoc test. Concentration of SHH protein for maximal growth was optimized, and a more active SHH protein examined., Outcomes: Cultures were characterized by immunohistochemical analysis with ACTA2, CD31, nNOS and P4HB, and smooth muscle was quantified in comparison to DAPI., Results: Cultures established were >97% smooth muscle. SHH protein increased growth of smooth muscle cells from prostatectomy, diabetic, and Peyronie's patients in a similar manner (49%-51%), and SHH inhibition decreased growth (20%-33%). There was no difference in growth using 25 ug and 10 ug SHH protein, suggesting a threshold concentration of SHH protein above which smooth muscle growth is enhanced. A more active lipid modified SHH peptide further enhanced growth (15%), indicating a more robust growth response. SHH increased growth in smooth muscle cells from hypertension (37%) and cardiovascular disease (32%) patients. SHH protein increased growth under normal and high glucose conditions, suggesting that high glucose conditions that may be present in under controlled diabetic patients would not detract from SHH regenerative capacity., Clinical Implications: SHH PA would be beneficial to enhance smooth muscle regeneration in patients with ED of multiple etiologies., Strengths and Limitations: Understanding how human corpora cavernosal tissue responds to SHH treatment is critical for clinical translation of SHH PA to ED patients., Conclusion: Corpora cavernosal smooth muscle from all ED patients responded to SHH treatment with increased growth. Stupp, SI. Sonic Hedgehog Signaling in Primary Culture of Human Corpora Cavernosal Tissue From Prostatectomy, Diabetic, and Peyronie's Patients. J Sex Med 2022;19:1228-1242., (Copyright © 2022 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Treatment options for men with moderate-to-severe lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) have variable efficacy, safety, and retreatment profiles, contributing to variations in patient quality of life and healthcare costs. This study examined the long-term cost-effectiveness of generic combination therapy (CT), prostatic urethral lift (PUL), water vapor thermal therapy (WVTT), photoselective vaporization of the prostate (PVP), and transurethral resection of the prostate (TURP) for the treatment of BPH. A systematic literature review was performed to identify clinical trials of CT, PUL, WVTT, PVP, and TURP that reported change in International Prostate Symptom Score (IPSS) for men with BPH and a prostate volume ≤80 cm3. A random-effects network meta-analysis was used to account for the differences in patient baseline clinical characteristics between trials. An Excel-based Markov model was developed with a cohort of males with a mean age of 63 and an average IPSS of 22 to assess the cost-effectiveness of these treatment options at 1 and 5 years from a US Medicare perspective. Procedural and adverse event (AE)-related costs were based on 2021 Medicare reimbursement rates. Total Medicare costs at 5 years were highest for PUL ($9,580), followed by generic CT ($8,223), TURP ($6,328), PVP ($6,152), and WVTT ($2,655). The total cost of PUL was driven by procedural ($7,258) and retreatment ($1,168) costs. At 5 years, CT and PUL were associated with fewer quality-adjusted life years (QALYs) than WVTT, PVP, and TURP. Compared to WVTT, the incremental cost-effectiveness ratios (ICERs) for both TURP and PVP were above a willingness-to-pay threshold of $50,000/QALY (TURP: $64,409/QALY; PVP: $87,483/QALY). This study provides long-term cost-effectiveness evidence for several common treatment options for men with BPH. WVTT is an effective and economically viable treatment in resource-constrained environments., Competing Interests: B Chughtai is a paid clinical consultant for Boston Scientific, MedeonBio, Olympus, and Allergan as well as an investigator for Teleflex. S Rojanasarot, B Cutone, and S Bhattacharyya are employees of Boston Scientific. K Neeser, D Gultyaev, and S Fu are employees of Certara Evidence & Access. K McVary is a principal investigator for NIDDK and Urovant. He is a paid clinical consultant for Boston Scientific and MedeonBio. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Erectile dysfunction (ED) is a debilitating medical condition in which current treatments are minimally effective in diabetic patients due to neuropathy of the cavernous nerve, a peripheral nerve that innervates the penis. Loss of innervation causes apoptosis of penile smooth muscle, remodeling of corpora cavernosa (penile erectile tissue) morphology, and ED., Aim: In this study, microarray and pathway analysis were used to obtain a global understanding of how signaling mechanisms are altered in diabetic patients and animal models as ED develops, in order to identify novel targets for disease management, and points of intervention for clinical therapy development., Methods and Outcomes: Human corpora cavernosal tissue was obtained from diabetic (n = 4) and Peyronie's (control, n = 3) patients that were undergoing prosthesis implant to treat ED, and BB/WOR diabetic (n = 5) and resistant (n = 5) rats. RNA was extracted using TRIzol, DNase treated, and purified by Qiagen mini kit. Microarray was performed using the Human Gene 2.0 ST Array. (i) Alterations in patient and diabetic rat pathway signaling were examined using several analytical tools (ShinyGO, Metascape, WebGestalt, STRING) and databases, (ii) Strengths/weaknesses of the different pathway analysis tools were compared, and (iii) Comparison of human and rat (BB/WOR and Streptozotocin) pathway analysis was performed. Two technical replicates were performed. P value (FDR) < .15 was used as threshold for differential expression. FDR < 0.05 was considered significant., Results: Microarray identified 182 differentially expressed protein-coding genes. Pathway analysis revealed similar enrichments with different analytical tools. Down regulated pathways include development, tubular structure, sprouting, cell death, ischemia, angiogenesis, transcription, second messengers, and stem cell differentiation. ED patients, who have diabetes, incur significant loss of normal regulatory processes required for repair and replacement of injured corpora cavernosal tissue. Combined with loss of apoptotic regulatory mechanisms, this results in significant architectural remodeling of the corpora cavernosa, and loss of regenerative capacity in the penis., Clinical Translation: This first report of microarray and pathway analysis in human corpora cavernosa, is critical for identification of novel pathways pertinent to ED and for validating animal models., Strengths and Limitations: The analysis of tissue specific gene expression profiles provides a means of understanding drivers of disease and identifying novel pathways for clinical intervention., Conclusion: Penis from diabetic ED patients lacks capacity for maintenance of corpora cavernosal architecture and regeneration, which are critical points for intervention for therapy development. Searl T, Ohlander S, McVary KT, et al., Pathway Enrichment Analysis of Microarray Data Fom Human Penis of Diabetic and Peyronie's Patients, in Comparison With Diabetic Rat Erectile Dysfunction Models. J Sex Med 2022;19:37-53., (Copyright © 2021 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Background: The aim of this study was to assess the impact of tadalafil 5 mg/die plus tamsulosin 0.4 mg/die combination therapy on lower urinary tract symptoms (LUTS) and erectile dysfunction (ED), according to presence vs. absence of metabolic syndrome (MetS)., Methods: Seventy-five consecutive men presenting with ED and LUTS were enrolled. Patients were divided into two groups according to MetS presence. All subjects were treated with combination therapy for 12 weeks. Patients were re-evaluated after treatment with uroflowmetry and post-void residual volume (PVR), International Prostate Symptoms Score (IPSS), IPSS Quality of Life (QoL), overactive bladder questionnaire (OAB-q) and International Index Erectile Function-5 (IIEF-5) Score., Results: After enrollment, 50 patients were included: 31 (62.0%) with MetS and 19 (38.0%) without MetS. At baseline, patients without MetS showed a significantly better IPSS, IIEF and OAB-q, as compared to those with MetS. After 12 weeks of combination therapy LUTS, ED and flowmetry significantly improved in both groups (P<0.001). The improvement after 12 weeks was similar between groups in all parameters (P>0.05), except for ∆OAB-q that was significantly better for patients with MetS (P=0.028). Nevertheless, total IPSS, all IPSS subscores and OAB-q were significantly better at 12 weeks in men without MetS (P<0.05). Despite IIEF-5 was significantly different at baseline, after 12 weeks of combination therapy, erectile function was similar in men with or without METS: 16.3±3.8 vs. 17.7±4.7 (P=0.238). No serious adverse event (AE) was reported, and complications were comparable between groups (P>0.05)., Conclusions: Patients with MetS have worse LUTS and ED profiles. However, tadalafil plus tamsulosin combination treatment provided them a similar ED profile and a greater relief of overactive bladder (OAB) symptoms at the end of the trial. Combination therapy had the same safety profile in men besides MetS. Further randomized controlled trials are needed.

Background: Erectile dysfunction (ED) and ejaculatory dysfunction (EjD) are known outcomes of traditional surgery and some pharmacotherapies for treatment of benign prostatic hyperplasia (BPH). Minimally invasive treatment options, including water vapor thermal therapy (WVTT), are now available to treat lower urinary tract symptoms (LUTS) due to BPH., Aim: The objective of this analysis was to evaluate long-term impact of a single water vapor thermal therapy procedure on erectile and ejaculatory function in subjects enrolled in the Rezum II prospective, multicenter, randomized, blinded controlled trial., Methods: Fifteen centers enrolled 197 subjects with International Prostate Symptom Score (IPSS) ≥ 13, maximum flow rate (Qmax) ≤ 15 mL/s, and prostate volume 30-80 cc. Subjects were randomized (2:1) to (WVTT) or sham procedure (control) and followed for 5 years. Erectile and ejaculatory functions were quantitatively assessed at baseline and yearly thereafter. After 3 months, control subjects could opt to requalify for cross-over to WVTT and were followed for 5 years. Results of the per protocol analysis were reported previously. The current post hoc analysis was performed on all treated subjects who were sexually active at baseline with no other surgical or medical management for BPH during the 5-year study period., Outcomes: LUTS was evaluated using IPSS, Benign Prostatic Hyperplasia Impact Index (BPHII), and Qmax. Sexual function was assessed using the International Index of Erectile Function (IIEF-EF) and Male Sexual Health Questionnaire for Ejaculatory Dysfunction (MSHQ-EjD)., Results: A total of 197 subjects (136 treated, 61 control) were enrolled in the study, and 53 control subjects opted to cross-over and receive WVTT. All subgroups experienced significant, durable improvement in IPSS (P < .0001). Subjects with normal sexual function at baseline had little change in function over 5 years (IIEF-EF: -2.4 ± 8.9, P = .1414; MSHQ-EjD Function: -1.6 ± 3.2, P = .0083; MSHQ-EjD Bother: -0.5 ± 1.6, P = .1107). Subjects with baseline medical history of ED and EjD showed slight decline over time that was not clinically significant (ED, IIEF-EF: -3.0 ± 10.1, P = .1259; MSHQ EjD Function: -2.3 ± 4.7, P = .0158; MSHQ-EjD Bother: -0.1 ± 2.6, P = .7764; EjD, IIEF-EF: -4.1 ± 9.2, P = .0127; MSHQ EjD Function: -1.6 ± 4.8, P = .1970; MSHQ-EjD Bother: -0.4 ± 2.6, P = .440)., Clinical Implications: Treatment for BPH with Rezum durably improved IPSS without clinically significant impact on sexual function. Patients with baseline ED/EjD may expect continued decline from other causes but are unimpacted by the therapy., Strengths & Limitations, Conclusion: The results are limited by the post-hoc nature of the analysis and attrition over the 5-year follow-up but provide long-term evidence of durable outcomes after treatment with Rezum without impact on sexual function scores. McVary KT, El-Arabi A, Roehrborn C. Preservation of Sexual Function 5 Years After Water Vapor Thermal Therapy for Benign Prostatic Hyperplasia. Sex Med 2021;9:100454., (Copyright © 2021 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Importance: Benign prostatic hyperplasia (BPH) in older men can cause lower urinary tract symptoms (LUTS), which are increasingly managed with medications. Frailty may contribute to both symptom progression and serious adverse events (SAEs), shifting the balance of benefits and harms of drug therapy., Objective: To assess the association between a deficit accumulation frailty index and clinical BPH progression or SAE., Design, Setting, and Participants: This cohort study used data from the Medical Therapy of Prostatic Symptoms trial, which compared placebo, doxazosin, finasteride, and combination therapy in men with moderate-to-severe LUTS, reduced urinary flow rate, and no prior BPH interventions, hypotension, or elevated prostate-specific antigen. Enrollment was from 1995 to 1998, and follow-up was through 2001. Data were assessed in February 2021., Exposures: A frailty index (score range, 0-1) using 68 potential deficits collected at baseline was used to categorized men as robust (score ≤0.1), prefrail (score 0.1 to <0.25), or frail (score ≥0.25)., Main Outcomes and Measures: Primary outcomes were time to clinical BPH progression and time to SAE, as defined in the parent trial. Adjusted hazard ratios (AHRs) were estimated using Cox proportional hazards regressions adjusted for demographic variables, treatment group, measures of obstruction, and comorbidities., Results: Among 3047 men (mean [SD] age, 62.6 [7.3] years; range, 50-89 years) in this analysis, 745 (24%) were robust, 1824 (60%) were prefrail, and 478 (16%) were frail at baseline. Compared with robust men, frail men were older (age ≥75 years, 12 men [2%] vs 62 men [13%]), less likely to be White (646 men [87%] vs 344 men [72%]), less likely to be married (599 men [80%] vs 342 men [72%]), and less likely to have 16 years or more of education (471 men [63%] vs 150 men [31%]). During mean (SD) follow-up of 4.0 (1.5) years, the incidence rate of clinical BPH progression was 2.2 events per 100 person-years among robust men, 2.9 events per 100 person-years among prefrail men (AHR, 1.36; 95% CI, 1.02-1.83), and 4.0 events per 100 person-years among frail men (AHR, 1.82; 95% CI, 1.24-2.67; linear P = .005). Larger point estimates were seen among men who received doxazosin or combination therapy, although the test for interaction between frailty index and treatment group did not reach statistical significance (P for interaction = .06). Risk of SAE was higher among prefrail and frail men (prefrail vs robust AHR, 1.81; 95% CI, 1.48-2.23; frail vs robust AHR, 2.86; 95% CI, 2.21-3.69; linear P < .001); this association was similar across treatment groups (P for interaction = .76)., Conclusions and Relevance: These findings suggest that frailty is independently associated with greater risk of both clinical BPH progression and SAEs. Older frail men with BPH considering initiation of drug therapy should be counseled regarding their higher risk of progression despite combination therapy and their likelihood of experiencing SAEs regardless of treatment choice.

Purpose: Benign prostatic hyperplasia (BPH) is a histologic diagnosis describing proliferation of smooth muscle and epithelial cells within the prostatic transition zone. The prevalence and severity of lower urinary tract symptoms (LUTS) in aging men are progressive and impact the health and welfare of society. This revised Guideline provides a useful reference on effective evidence-based management of male LUTS/BPH. See the accompanying algorithm for a summary of the procedures detailed in the Guideline (figures 1 and 2[Figure: see text][Figure: see text])., Materials and Methods: The Minnesota Evidence Review Team searched Ovid MEDLINE, Embase, Cochrane Library, and AHRQ databases to identify eligible English language studies published between January 2008 and April 2019, then updated through December 2020. Search terms included Medical Subject Headings (MeSH) and keywords for pharmacological therapies, drug classes, and terms related to LUTS or BPH. When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, information is provided as Clinical Principles and Expert Opinions (table 1[Table: see text])., Results: Nineteen guideline statements pertinent to evaluation, work-up, and medical management were developed. Appropriate levels of evidence and supporting text were created to direct both primary care and urologic providers towards streamlined and suitable practices., Conclusions: The work up and medical management of BPH requires attention to individual patient characteristics, while also respecting common principles. Clinicians should adhere to recommendations and familiarize themselves with standards of BPH management.

Purpose: Surgical therapies for symptomatic bladder outlet obstruction (BOO) due to benign prostatic hyperplasia (BPH) are many, and vary from minimally invasive office based to high-cost operative approaches. This Guideline presents effective evidence-based surgical management of male lower urinary tract symptoms secondary/attributed to BPH (LUTS/BPH). See accompanying algorithm for a detailed summary of procedures (figure[Figure: see text])., Materials/methods: The Minnesota Evidence Review Team searched Ovid MEDLINE, Embase, Cochrane Library, and AHRQ databases to identify eligible studies published between January 2007 and September 2020, which includes the initial publication (2018) and amendments (2019, 2020). The Team also reviewed articles identified by Guideline Panel Members. When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, information is provided as Clinical Principles and Expert Opinions (table[Table: see text])., Results: Twenty-four guideline statements pertinent to pre-operative and surgical management were developed. Appropriate levels of evidence and supporting text were created to direct urologic providers towards suitable and safe operative interventions for individual patient characteristics. A re-treatment section was created to direct attention to longevity and outcomes with individual approaches to help guide patient counselling and therapeutic decisions., Conclusion: Pre-operative and surgical management of BPH requires attention to individual patient characteristics and procedural risk. Clinicians should adhere to recommendations and familiarize themselves with criteria that yields the highest likelihood of surgical success when choosing a particular approach for a particular patient.

Erectile dysfunction (ED) is a common and debilitating condition with high impact on quality of life. An underlying cause of ED is apoptosis of penile smooth muscle, which occurs with cavernous nerve injury, in prostatectomy, diabetic and aging patients. We are developing peptide amphiphile (PA) nanofiber hydrogels as an in vivo delivery vehicle for Sonic hedgehog protein to the penis and cavernous nerve to prevent the apoptotic response. We examine two important aspects required for clinical application of the biomaterials: if SHH PA suppresses intrinsic (caspase 9) and extrinsic (caspase 8) apoptotic mechanisms, and if suppressing one apoptotic mechanism forces apoptosis to occur via a different mechanism. We show that SHH PA suppresses both caspase 9 and 8 apoptotic mechanisms, and suppressing caspase 9 did not shift signaling to caspase 8. SHH PA has significant clinical potential as a preventative ED therapy, by management of intrinsic and extrinsic apoptotic mechanisms., (Published by Elsevier Inc.)

Purpose: We present final 5-year outcomes of the multicenter randomized sham-controlled trial of a water vapor therapy (Rezūm™) for treatment of moderate to severe lower urinary tract symptoms due to benign prostatic hyperplasia., Materials and Methods: A total of 197 subjects > 50 years of age with International Prostate Symptom Score ≥13, maximum flow rate ≤15 ml/second and prostate volume 30 to 80 cc were randomized and followed for 5 years. From the control arm of 61 subjects, a subset of 53 subjects requalified and after 3 months received treatment as part of the crossover group and were also followed for 5 years. The total number of vapor treatments to each lobe of the prostate was determined by length of prostatic urethra and included middle lobe treatment per physician discretion., Results: Significant improvement of lower urinary tract symptoms was observed at < 3 months post-thermal therapy, remaining durable through 5 years in the treatment group (International Prostate Symptom Score reduced 48%, quality of life increased 45%, maximum flow rate improved 44%, Benign Prostatic Hyperplasia Impact Index decreased 48%). Surgical re-treatment rate was 4.4% with no reports of device or procedure related sexual dysfunction or sustained de novo erectile dysfunction. Results within the crossover group were similar through 5 years., Conclusions: Minimally invasive treatment with water vapor thermal therapy provides significant and durable symptom relief as well as flow rate improvements through 5 years, with low surgical re-treatment rates and without impacting sexual function. It is a versatile therapy, providing successful treatment to obstructive lateral and middle lobes.

Purpose: The 2 most common adverse effects of radical prostatectomy are erectile dysfunction and stress urinary incontinence which often require surgical management with penile prosthesis (PP) and artificial urinary sphincter (AUS) implantation, respectively. There are conflicting reports regarding whether these procedures should be combined into 1 surgical setting or staged. We sought to evaluate the safety of performing these procedures in the same operative setting., Materials and Methods: We performed a retrospective analysis using the Healthcare Cost and Utilization (HCUP) State Inpatient Database (SID) and State Ambulatory Surgery Database (SASD) for the states of California (2007-2011) and Florida (2009-2014). ICD-9-CM diagnosis and CPT codes were used to identify adult males who underwent both PP and AUS implantation and outcomes regarding readmissions, emergency room (ER) presentations, and complications were reviewed., Results: Patients undergoing synchronous PP-AUS implantation had significantly higher 90-day readmission rates (13.9% vs 7.2%, p <0.001), suffered higher rates of device complications (6.1% vs 3.4%, p=0.021), and were more likely to have minor complications (8.89% vs 2.35%, p <0.001) compared to nonsynchronous device placement. No differences in major complications or 90-day ER visits were observed., Conclusions: Synchronous PP and AUS implantation is feasible but may be associated with higher readmission rates, device complications and postoperative complications compared to a staged approach. This further validates findings from prior studies.

Objectives: To describe the trend in the impact of lower urinary tract symptoms attributed to benign prostatic hyperplasia (LUTS/BPH) on a global scale using the Global Burden of Disease (GBD) database., Materials and Methods: Using the GBD database, worldwide data aggregated from registries and health systems from 1990 to 2017 were filtered for LUTS/BPH diagnoses. Calculation of years lived with disability (YLD) were compared with other urological diseases. YLD were calculated by a standardized method using assigned disability weights. The GBD-defined sociodemographic index (SDI) was used to assess impact of LUTS/BPH by global SDI quintile., Results: Global Burden of Disease data over the 1990-2017 study period were summarized and global numbers and trends noted with other urological diseases for comparison. A total of 2 427 334 YLD were attributed to BPH in 2017 alone, almost three times more than those attributed to the next highest urological disease, prostate cancer (843 227 YLD). When stratified by SDI quintile, a much lower impact of BPH was found in the bottom three quintiles, despite this subset representing 66.9% of the 2017 world population., Conclusions: Lower urinary tract symptoms attributed to benign prostatic hyperplasia exert a rapidly rising human burden far exceeding other urological diseases. As the population ages and men in a lower SDI enjoy increased life expectancy and decreased competing mortalities, a continually accelerating wave of LUTS/BPH can be forecast. These epidemiological trends have serious implications for the future allocation of resources and the global urological workforce., (© 2020 The Authors BJU International © 2020 BJU International Published by John Wiley & Sons Ltd.)

Background: Current treatments for erectile dysfunction (ED) are ineffective in prostatectomy and diabetic patients due to cavernous nerve (CN) injury, which causes smooth muscle apoptosis, penile remodeling, and ED. Apoptosis can occur via the intrinsic (caspase 9) or extrinsic (caspase 8) pathway., Aim: We examined the mechanism of how apoptosis occurs in ED patients and CN injury rat models to determine points of intervention for therapy development., Methods and Outcomes: Immunohistochemical and western analyses for caspase 3-cleaved, caspase-8 and caspase-9 (pro and active forms) were performed in corpora cavernosal tissue from Peyronie's, prostatectomy and diabetic ED patients (n = 33), penis from adult Sprague Dawley rats that underwent CN crush (n = 24), BB/WOR diabetic and control rats (n = 8), and aged rats (n = 9)., Results: Caspase 3-cleaved was observed in corpora cavernosa from Peyronie's patients and at higher abundance in prostatectomy and diabetic tissues. Apoptosis takes place primarily through the extrinsic (caspase 8) pathway in penis tissue of ED patients. In the CN crushed rat, caspase 3-cleaved was abundant from 1-9 days after injury, and apoptosis takes place primarily via the intrinsic (caspase 9) pathway. Caspase 9 was first observed and most abundant in a layer under the tunica, and after several days was observed in the lining of and between the sinuses of the corpora cavernosa. Caspase 8 was initially observed at low abundance in the rat corpora cavernosa and was not observed at later time points after CN injury. Aged and diabetic rat penis primarily exhibited intrinsic mechanisms, with diabetic rats also exhibiting mild extrinsic activation., Clinical Translation: Knowing how and when to intervene to prevent the apoptotic response most effectively is critical for the development of drugs to prevent ED, morphological remodeling of the corpora cavernosa, and thus, disease management., Strengths and Limitations: Animal models may diverge from the signaling mechanisms observed in ED patients. While the rat utilizes primarily caspase 9, there is a significant flux through caspase 8 early on, making it a reasonable model, as long as the timing of apoptosis is considered after CN injury., Conclusions: Apoptosis takes place primarily through the extrinsic caspase 8 dependent pathway in ED patients and via the intrinsic caspase 9 dependent pathway in commonly used CN crush ED models. This is an important consideration for study design and interpretation that must be taken into account for therapy development and testing of drugs, and our therapeutic targets should ideally inhibit both apoptotic mechanisms. Martin S, Harrington DA, Ohlander S, et al. Caspase Signaling in ED Patients and Animal Models. J Sex Med 2021;18:711-722., (Published by Elsevier Inc.)

Background: Safety and efficacy of tamsulosin and tadalafil for men with benign prostatic enlargement (BPE) and/or erectile dysfunction (ED) are defined. However, there are only a few pilot studies on combination therapy with these drugs for men with lower urinary tract symptom (LUTS)/BPE and ED. Moreover, preliminary reports are limited to 12 wk, without any information about subsequent therapies., Objective: To evaluate the impact of discontinuation of tamsulosin versus tadalafil 12 wk after combination therapy., Design, Setting, and Participants: Fifty consecutive patients with moderate-to-severe LUTS (International Prostate Symptom Score [IPSS] > 7) and mild-to-severe ED (International Index of Erectile Function-5 [IIEF-5] < 22) were treated with combination therapy (tamsulosin 0.4mg/d plus tadalafil 5mg/d) for 12 wk. After 12 wk, 25 patients discontinued tamsulosin (Group TAD), while 25 patients discontinued tadalafil (Group TAM)., Outcome Measurements and Statistical Analysis: Efficacy variables were IPSS (total, voiding, storage) and IIEF-5. Paired samples t test and analysis of variance were used., Results and Limitations: Groups TAD and TAM presented similar features (age, BMI, metabolic profile) including symptoms scores at baseline. Similar and significant improvements in IPSS (total, voiding, and storage) and IIEF-5 were recorded in both groups after 12 wk of combination therapy (all p< 0.001). Total IPSS was similar between the two groups at the end of the trial. However, we found between-group significant differences from baseline to 24 wk and from 12 to 24 wk in storage-IPSS (Group TAD: -3.32 vs Group TAM: -1.24, p= 0.002; Group TAD: +0.24 vs Group TAM: +1.20, p= 0.040, respectively) and in IIEF-5 (Group TAD: +4.64 vs Group TAM: +0.16, p< 0.001; Group TAD: -1.64 vs Group TAM: -4.40, p= 0.003). No significant treatment-related adverse event was recorded in both groups., Conclusions: After 12 wk of combination therapy, monotherapy with tadalafil for further 12 wk allows to preserve the improvement of storage IPSS and IIEF-5, in addition to total IPSS., Patient Summary: In this report we evaluated the discontinuation of tamsulosin or tadalafil after 12 wk of combination therapy. We found that tadalafil monotherapy, for a further 12 wk, aids in retaining the improvement of storage symptoms and erectile function., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: To analyze the safety of mirabegron add-on therapy in men with overactive bladder symptoms concurrently receiving tamsulosin for lower urinary tract symptoms associated with benign prostatic hyperplasia., Methods: The Phase 4 PLUS study comprised a 4-week run-in period (tamsulosin [0.4 mg]) and a 12-week randomized treatment period (add-on treatment: mirabegron [25 mg] or placebo). Doses were increased to mirabegron 50 mg or matched placebo after 4 weeks. Safety assessments: treatment-emergent adverse events (TEAEs), vital signs, 12-lead electrocardiograms, and changes in postvoid residual volume and maximum urinary flow (Q max )., Results: The safety analysis set included 352 tamsulosin plus mirabegron (TAM + MIRA) and 354 tamsulosin plus placebo (TAM + PL) patients. The frequency of overall TEAEs was higher with TAM + PL, although a higher incidence of drug-related TEAEs was observed with TAM + MIRA. Most TEAEs were mild or moderate in severity. Drug-related serious TEAEs were reported for 3 patients (2 TAM + MIRA patients: acute myocardial infarction with cerebral infarction and angina pectoris, 1 TAM + PL patient: lacunar stroke). Hypertension, headache, and nasopharyngitis were the most common TEAEs. Special interest TEAEs were infrequently reported. The most common was urinary retention and 2 TAM + MIRA patients required catheterization (neither led to discontinuation). No major changes in blood pressure or pulse rate were noted and similar electrocardiogram parameters were observed for both groups. Changes in mean postvoid residual volume and Q max were not clinically meaningful., Conclusion: No unexpected safety concerns were noted in men receiving tamsulosin for lower urinary tract symptoms associated with benign prostatic hyperplasia who subsequently received mirabegron add-on therapy., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The surgical reintervention rate after prostatic urethral lift is not well characterized but has been estimated at 2% to 3% per year. We performed a systematic review and meta-analysis to determine the surgical reintervention rate after prostatic urethral lift., Materials and Methods: We systematically searched MEDLINE®, Embase® and the Cochrane Central Register of Controlled Trials for studies of men treated with prostatic urethral lift reporting at least 1 year of maximum followup data. We performed a random effects meta-analysis to estimate the annual rate of surgical reintervention after prostatic urethral lift, including those performed for lower urinary tract symptoms or involving device explant, additions or replacement. The robustness of the meta-analysis conclusions was evaluated in a one-study removed analysis and heterogeneity was investigated with a subgroup analysis., Results: In 11 studies (2,016 patients) 153 surgical reinterventions were performed, among which transurethral resection of the prostate/laser (51.0%), repeat prostatic urethral lift (32.7%) and device explant (19.6%) were most common. The annual rate of surgical reintervention was 6.0% per year (95% CI 3.0-8.9). These results were not significantly influenced by any single study. The annual rate of surgical intervention was significantly influenced by the mean duration of patient followup. Surgical reintervention rates were 4.3% per year in studies with 1 year or less mean followup, 10.7% per year in studies with more than 1 year to 3 years mean followup and 5.8% per year in a single study with more than 3 years mean followup (p=0.04)., Conclusions: The surgical reintervention rate with prostatic urethral lift is 6.0% per year and is higher in studies with longer followup durations.

Purpose of Review: Aim of our systematic review is to evaluate and summarize the efficacy and safety of tadalafil alone or in combination with tamsulosin for the management of lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH) and erectile dysfunction (ED)., Recent Findings: Daily tadalafil, in particular 5 mg, according to retrieved studies, appears to be both safe and effective in treating LUTS/BPH and ED, compared with placebo or tamsulosin. The combination of daily tadalafil 5 mg and tamsulosin 0.4 mg allows a better improvement of LUTS compared with both the monotherapies, even if with an increased, but acceptable and tolerated, adverse events rate. After discontinuation of tamsulosin or tadalafil in patients previously treated with their combination, the improvement of LUTS retains significance compared with baseline. Tadalafil 5 mg should be considered a primary treatment option for patients with LUTS/BPH and ED. Evidence highlight an excellent tolerability, safety, and effectiveness profile, both alone or in combination with tamsulosin 0.4 mg. A better efficacy on LUTS relief has been observed for combination therapy, preserving also sexual function. The further switch to monotherapy allows to preserve LUTS relief, but tadalafil only is able to retain ED improvement. Our results support the evidence for a more and more tailored and modular LUTS treatment.

Purpose: This retrospective cohort study evaluates the characteristics of patients who presented to the emergency department with acute urinary retention., Materials and Methods: Using the Healthcare Cost and Utilization Project State Emergency Department Databases we conducted a retrospective cohort study of patients who presented to emergency departments in Florida between 2005 and 2015. Male patients age 45 years or older who presented with diagnosis codes for acute urinary retention and lower urinary tract symptoms/benign prostatic hyperplasia were considered. Information was collected on age, race/ethnicity, primary insurance and rural-urban commuting area codes., Results: The mean age for males presenting with acute urinary retention was 72.2 years, which was 10.6 years older than those presenting for nonurological complaints (p <0.001). Multivariable analysis adjusted for measured confounders found all covariates to be significant. The risk of presenting to the emergency department for acute urinary retention from lower urinary tract symptoms/benign prostatic hyperplasia increased with age, with the 75 to less than 85-year-old age group at the highest risk (OR 15.96, p <0.001). Other factors associated acute urinary retention included African American (OR 1.15, p <0.001) or Hispanic (OR 1.75, p <0.001) race, Medicare (OR 1.27, p <0.001) or private (OR 1.33, p <0.001) insurance, and urban rural-urban commuting area codes (OR 1.31, p <0.001)., Conclusions: Male patients who presented to the emergency department for acute urinary retention with benign prostatic hyperplasia were more likely to be older, of nonwhite race, have Medicare or private insurance, and live in more urban areas. These data suggest that African American and Hispanic patients may be untreated or under treated for benign prostatic hyperplasia in the outpatient setting, resulting in an increased risk of presentation to the emergency department with acute urinary retention.