Low Testosterone Levels Result in Decreased Periurethral Vascularity via an Androgen Receptor-mediated Process: Pilot Study in Urethral Stricture Tissue

Abstract

To compare expression of androgen receptor (AR) and angiopoietin 1 receptor TIE-2 and vessel density of urethral stricture tissue among eugonadal and hypogonadal men to identify a pathophysiological basis for our observations that low testosterone is associated with urethral atrophy. Among 1200 men having urethroplasty at our institution, we retrospectively identified 11 patients with testosterone levels drawn within 2 years of surgery. Low testosterone was defined as <280 ng/dL and detected in 5 of 11 (45.5%) patients. Urethral tissue samples were analyzed using immunohistochemistry for AR, TIE-2 (a downstream target of activated AR linking it to angiogenesis), and CD31 expression. Mean testosterone was 179.4 ng/dL for patients classified as having low testosterone and 375.0 ng/dL for controls (P = .003). We found a significant decrease of AR expression (1.11%high power field [HPF] vs 1.62, P = .016), TIE-2 expression (1.84%HPF vs 3.08, P = .006), and vessel counts (44.47 vessels/HPF vs 98.33, P = .004) in men with low testosterone. Expression levels of AR and TIE-2 were directly correlated to testosterone levels (rho: 0.685, P = .029, and rho: 0.773, P = .005, respectively). We did not find a difference in age, radiation, or comorbidities among patients with normal or low testosterone levels, with the exception of higher body mass index in the latter. Men with low testosterone levels demonstrate decreased AR and TIE-2 expression and lower vessel counts in periurethral tissue samples of urethral strictures. Our results provide a rationale for a mechanistic relationship between low testosterone levels and decreased periurethral vascularity that may contribute to urethral atrophy in patients with urethral strictures.