Estrogen Receptor-α is a Key Mediator and Therapeutic Target for Bladder Complications of Benign Prostatic Hyperplasia

Abstract

Estrogens are important in prostate growth and have a role in benign prostatic hyperplasia. However, to our knowledge no current therapy directly targets estrogen action. Estrogens act primarily via estrogen receptors α and β. In a mouse model we evaluated the relative contribution of these receptors to bladder complications of benign prostatic hyperplasia. We also evaluated the prevention of these bladder complications using the selective estrogen receptor modulators raloxifene and tamoxifen (estrogen receptor-α selective antagonists), and R,R-THC (estrogen receptor-β selective antagonist). Adult male C57bl/6 mice received implants of 25 mg testosterone and 2.5 mg 17β-estradiol slow release pellets. Untreated controls underwent sham surgery. We evaluated the contributions of the estrogen receptor subtypes in ERαKO and ERβKO mice compared to their respective wild-type litter mates. Wild-type mice treated with testosterone plus 17β-estradiol were compared to mice treated with testosterone plus 17β-estradiol and 25 mg selective estrogen receptor modulators to evaluate the prevention of benign prostatic hyperplasia complications by selective estrogen receptor modulators. Large bladders with urinary retention developed in ERαWT and ERβWT litter mates treated with testosterone plus 17β-estradiol but such bladders did not develop in ERαKO mice treated with testosterone plus 17β-estradiol. ERβKO mice treated with testosterone plus 17β-estradiol had large bladders with urinary retention and increased bladder mass. Cotreatment with the estrogen receptor-α antagonist raloxifene resulted in decreased bladder mass compared to that in wild-type mice treated with testosterone plus 17β-estradiol. Bladders in mice treated with the estrogen receptor-β antagonist R,R-THC were similar to those in testosterone plus 17β-estradiol treated mice. Estrogen receptor-α but not β is a key mediator of bladder complications of benign prostatic hyperplasia and a potential target for future therapies.