Stephanie J. Sexton

Bladder fibrosis during outlet obstruction is triggered through the NLRP3 inflammasome and the production of IL-1β.

Bladder outlet obstruction (BOO) triggers inflammation in the bladder through the NLRP3 inflammasome. BOO also activates fibrosis, which is largely responsible for the decompensation of the bladder in the chronic state. Because fibrosis can be driven by inflammation, we have explored a role for NLRP3 (and IL-1β produced by NLRP3) in the activation and progression of BOO-induced fibrosis. Female rats were divided into five groups: 1) control, 2) sham, 3) BOO + vehicle, 4) BOO + the NLRP3 inhibitor glyburide, or 5) BOO + the IL-1β receptor antagonist anakinra. Fibrosis was assessed by Massons trichrome stain, collagen secretion via Sirius Red, and protein localization by immunofluorescence. BOO increased collagen production in the bladder, which was blocked by glyburide and anakinra, clearly implicating the NLRP3/IL-1β pathway in fibrosis. The collagen was primarily found in the lamina propria and the smooth muscle, while IL-1 receptor 1 and prolyl 4-hydroylase (an enzyme involved in the intracellular modification of collagen) both localized to the urothelium and the smooth muscle. Lysyl oxidase, the enzyme involved in the final extracellular assembly of mature collagen fibrils, was found to some extent in the lamina propria where its expression was greatly enhanced during BOO. In vitro studies demonstrated isolated urothelial cells from BOO rats secreted substantially more collagen than controls, and collagen expression in control cultures could be directly stimulated by IL-1β. In summary, NLRP3-derived-IL-1β triggers fibrosis during BOO, most likely through an autocrine loop in which IL-1β acts on urothelia to drive collagen production.

The Emerging Role of Inflammasomes as Central Mediators in Inflammatory Bladder Pathology.

Irritative voiding symptoms (e.g. increased frequency and urgency) occur in many common pathologic conditions such as urinary tract infections and bladder outlet obstruction, and these conditions are well-established to have underlying inflammation that directly triggers these symptoms. However, it remains unclear as to how such diverse stimuli individually generate a common inflammatory process. Jürg Tschopp provided substantial insight into this conundrum when, working with extracts from THP-1 cells, he reported the existence of the inflammasome. He described it as a structure that senses multiple diverse signals from intracellular/extracellular sources and pathogens and triggers inflammation by the maturation and release of the pro-inflammatory cytokines interleukin-1β and interleukin-18. Recently, many of these sensors were found in the bladder and the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3, has been shown to be a central mediator of inflammation in several urological diseases. In this review, we introduce the nucleotide-binding domain, leucine-rich-containing family, pyrin domaincontaining-3 inflammasome, highlight its emerging role in several common urologic conditions, and speculate on the potential involvement of other inflammasomes in bladder pathology.

Contemporary Review of Male and Female Climacturia and Urinary Leakage During Sexual Activities

INTRODUCTION Urinary leakage during sexual activity is a prevalent and often distressing condition that is under-addressed despite having a range of reasonable treatment options. AIM To review the available literature on prevalence, pathophysiology, and treatment of urinary leakage during sexual activities. METHODS A literature review was performed through PubMed from 1996 to 2017 regarding urinary leakage during sexual activities for men and women including foreplay incontinence, coital incontinence, and climacturia. MAIN OUTCOME MEASURES To assess various physiologic and social factors of urinary leakage during sexual activities for men and women, treatment options, and their reported outcomes. RESULTS Urinary leakage during sexual activity is a prevalent condition that is underdiagnosed and undertreated. The pathophysiology of sexual incontinence is very similar between men and women and is influenced by injury to the pelvic and pudendal nerves, pelvic floor and external sphincter incompetence, and detrusor overactivity. There are different treatment options that are effective and should be offered to patients bothered by their symptoms. CONCLUSION Improved awareness is critical for better addressing the issue of sexual incontinence. There is likely a common pathophysiologic pathway between men and women and many treatment options are effective. However, further study is required to better elucidate this disease process and most effective treatment options. Mendez MH, Sexton SJ, Lentz AC. Contemporary Review of Male and Female Climacturia and Urinary Leakage During Sexual Activities. Sex Med Rev 2018;6:16-28.

Survey on the Contemporary Management of Intraoperative Urethral Injuries During Penile Prosthesis Implantation

BACKGROUND Intraoperative urethral injury is an uncommon event during the placement of a penile prosthesis, and alternative management strategies have been proposed with continuation of implantation after urethral injury. AIM To evaluate surgeon practices in the management of intraoperative urethral injury. METHODS An online survey was sent to the society listservs of the Genitourinary Reconstructive Surgeons (GURS) and the Sexual Medicine Society of North America (SMSNA). Physicians were queried on their fellowship training, experience with penile prosthesis implantation, and management of urethral injuries during prosthesis placement. The response data were analyzed using SAS 9.4 (SAS Institute, Cary, NC, USA). The χ2 test and Fisher exact test were used to determine associations between variables. OUTCOMES Survey responses. RESULTS 131 survey responses were analyzed. Of the responders, 41.2% were GURS fellowship trained, 19.1% were SMSNA trained, 30.5% were non-fellowship trained, and 9.2% were trained in other fellowships. 25.4% of participants performed more than 50 implantations per year, 37.7% performed 20 to 50 per year, and 36.9% performed fewer than 20 per year. Urethral injury during prosthesis implantation was uncommon, with 26.2% reporting 0 injury, 58.5% reporting 1 to 3 injuries, and 15.4% reporting more than 3 career injuries. Injuries were most commonly encountered during corporal dilation (71.1%) compared with corporal exposure (12.5%) or penile straightening maneuvers (7.0%). There was no statistically significant difference with aborting or continuing implantation among GURS-trained, SMSNA-trained, other fellowship-trained, and non-fellowship-trained surgeons. Of all responders, 55% would abort the procedure after distal urethral injury, whereas 45% would continue the procedure with unilateral or bilateral insertion of cylinders. Patient factors that increased likelihood of terminating the procedure in the case of urethral injury included immunosuppression, spinal cord injury, and clean intermittent catheterization dependence. CLINICAL IMPLICATIONS A urethral injury during penile prosthesis implantation might not mandate termination of the procedure despite classic teaching. STRENGTHS AND LIMITATIONS The strength of this study is that it provides difficult to obtain epidemiologic data on the frequency and management of this clinically significant injury. Limitations include the inherent biases from a survey-based study including response bias and recall bias. The survey response rate could not be obtained. CONCLUSION Urethral injury during penile prosthesis implantation is a rare but clinically significant risk of the procedure, with many variations in management of the injury. Termination and delayed implantation might not be necessary after injury, although long-term outcome data are difficult to obtain. Sexton SJ, Granieri MA, Lentz AC. Survey on the Contemporary Management of Intraoperative Urethral Injuries During Penile Prosthesis Implantation. J Sex Med 2018;15:576-581.

Urethral Injury and the Penile Prosthesis

INTRODUCTION The relative infrequency of urethral injuries during penile prosthesis implantation has caused the event to be understudied relative to the morbidity and cost associated with their management. AIM To draw attention to both acute intraoperative and delayed urethral injuries via cylinder erosion by compiling and evaluating the available literature on their cause, diagnosis, and management. METHODS A literature review was performed through PubMed from 1985 to 2018 regarding urethral injuries in the setting of penile prosthesis implantation. Comorbidities and anatomic factors that predispose a patient to a urethral injury were also queried. MAIN OUTCOME MEASURES The goal is to identify at-risk populations and assess options for managing distal, mid-pendulous, and proximal acute urethral injuries that occur in the setting of penile prosthesis implantation. We also examine strategies to manage prosthesis erosion into the urethra. RESULTS Although urethral injuries are rare, certain patient populations are at higher risk for the event. Injuries at various locations along the urethra present unique challenging and morbid clinical scenarios. However, there are a variety of management options available that allow a patient to ultimately void normally and have a successfully implanted penile prosthesis. CONCLUSION Overall, penile prostheses offer many patients an improved sexual quality of life. In the setting of prosthesis implantation both acute and delayed urethral injuries are rare, but their associated morbidity can undercut the benefits of the device. Our understanding of these injuries has matured, and we now possess management strategies that can mitigate the morbidity and frustration that accompany this complication. Carlos EC, Sexton SJ, Lentz AC. Urethral injury and the penile prosthesis. Sex Med Rev 2019;7:360-368.

Bladder decompensation and reduction in nerve density in a rat model of chronic bladder outlet obstruction is attenuated with the NLRP3 inhibitor glyburide

Bladder outlet obstruction (BOO) leads to progressive voiding dysfunction. Acutely, obstruction triggers inflammation that drives bladder dysfunction. Over time, inflammation leads to decreased bladder nerve density and increased fibrosis, responsible for eventual decompensation and irreversibility. We have previously shown that BOO triggers inflammation, reduced bladder nerve density and increased fibrosis via activation of the NLRP3 inflammasome in an acutely obstructed (12-day) rat model. However, as BOO progresses, the bladder may become decompensated with an increase in postvoid residual volume and decreased voiding efficiency. Currently, we have examined rat bladder function and nerve densities after chronic BOO to determine whether NLRP3 plays a role in the decompensation at this stage. Four groups were examined: control, sham-operated, BOO, or BOO+gly (glyburide; an NLRP3 inhibitor). After 42 days, bladder weight, inflammation (Evans blue), urodynamics, and nerve density were measured. BOO greatly enhanced bladder weights and inflammation, while inflammation was prevented by glyburide. Voiding pressures were increased, and flow rates decreased in BOO and BOO+gly groups, demonstrating physical obstruction. No difference in frequency or voided volume was detected. However, postvoid residual volumes were greatly increased in BOO rats while BOO+gly rats were not different than controls. Moreover, there was a dramatic decrease in voiding efficiency in the chronic BOO rats, which was prevented with glyburide treatment. Finally, a reduction in nerve density was apparent with BOO and attenuated with glyburide. Together the results suggest a critical role for NLRP3 in mediating bladder decompensation and nerve density during chronic BOO.

MP25-19 SURVEY ON THE CONTEMPORARY MANAGEMENT OF INTRAOPERATIVE URETHRAL INJURIES DURING PENILE PROSTHESIS IMPLANTATION

INTRODUCTION AND OBJECTIVES: Intraoperative urethral injury is an uncommon event during the placement of an inflatable penile prosthesis (IPP) with an estimated incidence of up to 3%. The conventional teaching is to perform primary repair, place a transurethral catheter, and abort the procedure. Recently, alternative management strategies have been proposed with continuation of the implant following urethral injury. The objective of this study is to evaluate surgeon management of urethral injury during IPP and determine if fellowship training influences practice. METHODS: An online survey was sent to the society listservs of the Genitourinary Reconstructive Surgeons (GURS) and The Sexual Medicine Society of North America (SMSNA). Physicians were queried on their fellowship training, experience with IPP and urethroplasty, IPP surgical approach, and management of urethral injuries during IPP implantation. The response data was analyzed using SAS 9.4 (SAS Institute Inc., Cary, NC). Chi-squared test and Fisher’s exact test were used to determine associations between variables. RESULTS: There were a total of 131 survey responses. Of the responders, 41.2% were GURS fellowship trained, 19.1% were SMSNA trained, 30.5% were non-fellowship trained, and 9.2% trained in other fellowships. 25.4% of participants perform >50 IPPs per year, while 37.7% perform 20-50 and 36.9% perform fewer than 20 per year. Urethral injury during IPP implantation was uncommon, with 26.2% reporting 0 injuries, 58.5% reporting 1-3 injuries, and 15.4% reporting >3 career injuries. Injuries were most commonly encountered during corporal dilation (71.1%), compared to corporal exposure (12.5%), or penile straightening maneuvers (7.0%). There was no statistically significant difference with aborting or continuing implantation among GURS, SMSNA, and/or non-fellowship trained surgeons. Of all responders, 55% abort the procedure after distal urethral injury, while 45% continue the procedure with unilateral or bilateral insertion of cylinders. For those who chose to abort the procedure, the next implant was attempted in <6 weeks in 9.3%, 612 weeks in 45.7%, and >12 weeks in 41.1%. Patient factors that increased likelihood of aborting procedure in the case of urethral injury included immunosuppression, spinal cord injury, and clean intermittent catheterization-dependence. CONCLUSIONS: Urethral injury during IPP implantation is a rare but established risk of the procedure. Fellowship training does not appear to have an effect on intraoperative management of this injury.

The Artificial Urinary Sphincter: Evolution and Implementation of New Techniques in the Man with Stress Incontinence After Treatment for Prostate Cancer

Purpose of ReviewUrinary incontinence is a burdensome sequelae of prostate cancer treatment with a significant impact on quality of life. The artificial urinary sphincter has been the gold standard for management of incontinence. A variety of modifications to the implantation technique to improve continence and minimize infections have been implemented. Herein, we review these changes.Recent FindingsPost-prostatectomy incontinence requires a detailed evaluation in order to determine the best method of treatment. Despite alternative devices on the market, the success and side effect profile continues to favor the artificial urinary sphincter (AUS) for management of most men with post-prostatectomy incontinence. While the overall risk of complications from the AUS is low, recent efforts have focused on measures to reduce infection and erosion rates.SummaryThe AUS is a commonly utilized method to treat post-prostate cancer treatment incontinence. This remains the gold standard for management given its low side effect profile.