Selective Estrogen Receptor Modulators for BPH

New Factors on the Ground

M Garg; D Dalela; D Dalela; A Goel; M Kumar; G Gupta; S N Sankhwar


Prostate Cancer Prostatic Dis. 2013;16(3):226-232. 

In This Article

Estrogens and Its Receptors: Role in BPH

Though BPH typically manifests in later stage of life when androgen levels are declining, androgens are thought to be pre-requisites for the development of BPH.[4,5] With advancing age, plasma androgen levels decrease gradually while estrogen levels remain constant or decrease slightly, resulting in increased ratio of estrogen to androgen in plasma.[4–6] In elderly men, the ratio of free estradiol (E2) to free testosterone (T) was observed to increase by up to 40%.[7,8] Although estrogen level remains fairly constant in the epithelium during the entire age range, they get increasingly accumulated in the stroma with advancing age.[9] This could be of patho-physiological importance for BPH development.

Various animal studies have highlighted that BPH occurs with the stimulation of the prostate by estrogens.[10,11] An animal model of BPH demonstrated that in castrated dogs, treatment with estradiol alone without androgens led to development of squamous prostate epithelial metaplasia,[12] whereas estradiol when given along with androgens resulted in glandular prostatic hyperplasia.[10,12] These studies clearly indicated that estrogens might exert a synergistic effect with androgens in inducing prostatic hyperplasia.

Climent et al.[13] investigated the direct effects of estradiol on the proliferation of BPH-derived prostate cells in culture. Estradiol (10−7 and 10−6 M) moderately increased the proliferation of stromal cells in culture without affecting the proliferation of epithelial cells. Symptomatic BPH patients reveal a 33% increase in stromal volume compared with healthy controls.[14] These findings support the fact that estrogens may have an important role in the pathogenesis of BPH predominantly for the stromal component.

Estrogens exert their effect on target gene expression by binding to specific intracellular estrogen receptors (ERs). These receptors, which act as hormone-inducible transcription factors, are of two distinct types ERα and ERβ. By mediating estrogen signaling and transcription, these receptors drive growth, proliferation, differentiation and many other cellular processes.

ERα and ERβ have specific expression patterns and distinct phenotypes, leading to their different biological functions. In the normal prostate and BPH, ERα is localized to stromal cells, and estrogen mediates its effects on the prostate epithelium through paracrine pathways.[13,15,16] ERα acts as a mediator of cell proliferation while ERβ acts in opposite way by inhibiting ERα-mediated proliferation.[17–23]