Role of androgens for urethral homeostasis

Abstract

BackgroundWe observed that patients with hypogonadism are at higher risk to experience artificial urinary sphincter cuff erosion. Sphincter erosions have been found to be associated with urethral atrophy or compromised urethras subsequent to events limiting its blood supply. We therefore analyzed possible mechanisms how a decrease in testosterone serum levels can result decreased urethral blood flow.MethodsIn a cohort of >1,200 urethroplasties, tissue specimens obtained during surgeries were analyzed for expression of androgen receptor (AR), AR-responsive TIE-2 associated with angiogenesis, and the endothelial cell marker CD31 for determination of vessel counts were analyzed immunohistochemically. A total of 11 patients were included in whom both tissue and serum testosterone levels within 2 years of the urethroplasty was available. Low serum testosterone level defined as <280 ng/dL. Image J software was used to analyze expression profiles.ResultsMean serum testosterone level was significant lower in hypogonadal patients (179.4 ng/dL) compared to eugonadal patients (375.0 ng/dL, P=0.003). Urethral tissue of hypogonadal patients showed decreased AR expression [1.11% high power field (HPF)] compared to eugonadal patients (1.62%, P=0.016), decreased TIE-2 expression (1.84% HPF vs. 3.08%, P=0.006), and also decreased vessel counts (44.47 vessels/HPF vs. 98.33, P=0.004). There was a direct correlation of AR and TIE-2 expression levels with serum testosterone levels (rho 0.685, P=0.029, and rho 0.773, P=0.005, respectively). Of note, we did not detect a difference in age, prior radiation, coronary artery disease or hypertension among hypo- or eugonadal patient. However, higher body mass index was associated with low serum testosterone levels.ConclusionsHypogonadal status is associated with decreased expression of AR and TIE-2 and also reduced vessel count in urethral tissue. We believe that the resulting decreased urethral vascularity subsequent to a hypogonadal state may be an important risk factor for complications of urethral surgery.

Addressing the Relationship Between Testosterone Levels and Urethral Stricture: A Case-Control Study

“…[14][15][16][17][18][19][20] A study in castrated rats that underwent urethroplasty showed that supplementation with both testosterone and estrogen increased periurethral vascularization after surgery in supplemented rats compared with nonsupplemented rats. 21 Our analysis did not find any evidence that estrogen levels were related to US. However, in adult men, estrogen levels are uniformly low, making it difficult to identify differences.…”

Most men with artificial urinary sphincter cuff erosion have low serum testosterone levels

“…This study reinforces our initial observation that patients with low serum testosterone levels have a nearly three‐fold higher risk for AUS cuff erosion compared to eugonadal men. The association between LT and urethral fragility appears to validate the foundational concept that androgens are an important contributor to urethral homeostasis 11 . While we suspect that LT potentiates ischemic changes in the periurethral tissues, LT has also been associated with chronic inflammation within the lower urinary tract 14,15 …”

“…The association between LT and urethral fragility appears to validate the foundational concept that androgens are an important contributor to urethral homeostasis. 11 While we suspect that LT potentiates ischemic changes in the periurethral tissues, LT has also been associated with chronic inflammation within the lower urinary tract. 14,15 The overall AUS cuff erosion rate observed in this tertiary referral center study is 26.1%, higher than the 5%-13% erosion range typically described in the literature.…”

“…10 Further human tissue studies verified that normal serum testosterone (NT) levels appear to be fundamental for urethral homeostasis. 11,12 Given that LT is common among men after prostate cancer treatment, both due to age and androgen deprivation therapy, the potential impact on the management of postprostatectomy incontinence is profound. 13 In this study, we sought to update and confirm our initial observation of the link between low testosterone levels and AUS cuff erosion in a large cohort of patients.…”

“…In 2016, we first identified that low serum testosterone (LT) levels may be associated with AUS cuff erosion events 10 . Further human tissue studies verified that normal serum testosterone (NT) levels appear to be fundamental for urethral homeostasis 11,12 . Given that LT is common among men after prostate cancer treatment, both due to age and androgen deprivation therapy, the potential impact on the management of post‐prostatectomy incontinence is profound 13 .…”