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

Abstract

Purpose While estrogens are important in prostate growth and play a role in benign prostatic hyperplasia (BPH), no current therapies directly target estrogen action. Estrogens act primarily via estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). Using a mouse model, we evaluated the relative contribution of these receptors to bladder complications of BPH. We also evaluated prevention of these bladder complications by selective estrogen receptor modulators (SERMs), raloxifene and tamoxifen (ERα selective antagonists) and (R,R)-5,11-Diethyl-5,6,11,12-tetrahydro-2,8-chrysenediol (R,R-THC, ERβ selective antagonist). Materials and Methods Adult male C57bl/6 mice received implants of 25 mg testosterone (T) and 2.5 mg 17β-estradiol (E2) slow release pellets and untreated controls underwent sham surgery. We used ERα and ERβ knockout (KO) mice compared to their respective wild type (WT) littermates to probe contributions of ER subtypes. WT mice treated with T+E2 were compared to mice treated with T+E2 and 25 mg SERM to evaluate prevention of BPH complications with SERMs. Results While ERαWT and ERβWT littermates treated with T+E2 developed large bladders with urinary retention, ERαKO mice treated with T+E2 did not. ERβKO mice treated with T+E2 developed large bladders with urinary retention and increased bladder mass. Co-treatment with the ERα antagonist raloxifene resulted in decreased bladder mass compared to WT mice treated with T+E2, while bladders from mice treated with the ERβ antagonist R,R-THC were similar to T+E2-treated mice. Conclusions ERα, but not ERβ, is a key mediator of bladder complications of BPH, and is a potential target for future therapies.

Vitamin D Deficiency as a Potential Marker of Benign Prostatic Hyperplasia

“…Fifty percent of men over the age of 50 will have BPH, while 90% of men at age of 80 will have an enlarged prostate [3]. While aging and androgens are considered to have a role in BPH development [4], the role of other risk factors, namely, inflammation [5], inflammatory mediators, oxidative stress, hormones [6], physical activity, dietary factors, cardiovascular disease, obesity and diabetes [7] had been under investigation.…”

Estrogens and Male Lower Urinary Tract Dysfunction

“…We recently tested the SERMs raloxifene and tamoxifen for prevention of bladder complications in male mice treated with T+E 2 . While raloxifene prevented both bladder enlargement and prostate growth, an ERβ antagonist did not [32]. These results support that ERα is both a key mediator and therapeutic target in BPH.…”

“…In a small cohort of elderly men, raloxifene was well tolerated but did not affect markers of bone turnover or lipid levels [43]. While we did not compare efficacy of raloxifene and tamoxifen in BPH prevention directly, we demonstrated that raloxifene decreased both bladder and prostate mass in the male mouse treated with T+E 2 [32]. It is unknown whether treatment with raloxifene will reverse BPH-LUTS, once established, in animal models.…”

“…ERs are expressed in the male lower urinary tract and reproductive tissues such as the bladder [31], prostate [31], urethra, and testis [32]. Human and rabbit bladders and prostates express ERα and ERβ [33, 31].…”

“…This work is important in establishing the relevance of investigating markers of interest in the human disease process prior to embarking on mechanistic studies with BPH-LUTD models. Using the male mouse treated with T+E 2 , we demonstrated that ERα, but not ERβ, is necessary for the development of urinary retention and bladder hypertrophy, common bladder complications of BPH [32]. In addition, ERα, but not ERβ, was necessary for hormonal induction of prostate growth in male mice treated with T+E 2 .…”