Reversing Urethral Hypovascularity Through Testosterone and Estrogen Supplementation

• DOI: 10.1016/j.urology.2020.06.103
• Publication Date: 2020-09-03T00:56:05Z
• Authors: Emily M. Yura; Matthew I. Bury; Yvonne Chan; Allen F. Morey; Arun K. Sharma; Matthias D. Hofer
• Keywords: Vascularity; Estrogen receptor beta

To determine the ability of testosterone and estrogen to reverse urethral hypovascularity secondary to hypogonadism, we analyzed the effects of testosterone and estrogen supplementation on castrated Sprague Dawley rats.Twenty four Sprague-Dawley rats were divided into 4 groups: (1) non-castrate (NC) controls; (2) castrate (C) unsupplemented rats; (3) castrate rats that received testosterone (T), or (4) castrate rats that received estradiol (E). With immunohistochemistry, we measured vessel density (endothelial cell marker CD31), expression levels of androgen receptor (AR), TIE-2, and estrogen receptors ER-alpha and GPER1.Urethral vascularity was significantly increased after both testosterone and estrogen supplementation (T: 8.92%, E: 7.66%, vs C: 3.62%; P <0.001 for both), surpassing that of NC (5.86%, P <0.001 for both). Testosterone restored AR expression to physiologic levels (T: 5.21%, NC: 4.54%, P =0.135), and upregulated expression of TIE-2 (T: 0.20%, NC: 0.43%, P <0.001), neither of which was expressed in the absence of testosterone. Expression levels of nuclear ER-alpha was nearly undetectable (0.06%-0.38%), while membrane-bound GPER1 expression was upregulated by estrogen (3.30%) compared to other groups (T: 2.01%, NC: 1.02%, C: 0.37%, P <0.01 for all). Increased vessel density was significantly associated with increased AR (r = 0.22, P = 0.019) and GPER1 expression (r = 0.25, P = 0.018) suggesting a mechanistic relationship.Testosterone and estrogen exposure both restore periurethral vascularity in castrate (hypogonadal) rats via upregulation of AR/TIE-2 and GPER1 expression. Our results provide a foundation for testosterone or estrogen replacement in hypogonadal men to reverse atrophic effects of hypogonadism on the urethra.