Estrogen-Dependent and -Independent Estrogen Receptor-α Signaling Separately Regulate Male Fertility

Abstract

Estrogen receptor-alpha (ERalpha) plays a critical role in male reproductive tract development and fertility. To determine whether estrogen-dependent and -independent ERalpha mechanisms are involved in male fertility, we examined male estrogen nonresponsive ERalpha knock-in mice. These animals have a point mutation (G525L) in the ligand-binding domain of ERalpha that significantly reduces interaction with, and response to, endogenous estrogens but does not affect growth factor activation of ligand-independent ERalpha pathways. Surprisingly, we found that ligand-independent ERalpha signaling is essential for concentrating epididymal sperm via regulation of efferent ductule fluid reabsorption. In contrast, estrogen-dependent ERalpha signaling is required for germ cell viability, most likely through support of Sertoli cell function. By treating estrogen nonresponsive ERalpha knock-in (ENERKI) mice with the ERalpha selective synthetic agonist propyl pyrazole triol, which is able to bind and activate G525L ERalpha in vivo, we discovered male fertility required neonatal estrogen-mediated ERalpha signaling. Thus, our work indicates both estrogen-dependent and -independent pathways play separable roles in male murine reproductive tract development and that the role of ERalpha in human infertility should be examined more closely.

17β-estradiol signaling and regulation of Sertoli cell function

“…49 Study using estrogen non-responsive ESR1 knock-in (ENERK1) mice, which have a point mutation in the ligand-binding domain of ESR1 that significantly reduces interaction with endogenous estrogens, without affecting ligand-independent ESR1 pathways mediated by growth factors, confirmed that estrogen-dependent ESR1 signaling is required for germ cell viability, most likely through support of Sertoli cell function. 60 The GPER (mRNA and protein) is present in rat Sertoli cells as reported by our laboratory. 49 GPER immunostaining was Figure 1.…”

Influence of the XbaI polymorphism in the estrogen receptor-α gene on human spermatogenic defects

“…The effects of estrogen are mediated by at least 2 ER subtypes (ERα and ERβ), and these subtypes are expressed in various stages of human germ cells (Couse and Korach, 1999;Carreau et al, 2006). An important role for estrogen in male reproduction has been suggested by both animal models and the phenotypes of men with ERα and ERβ gene mutations (Krege et al, 1998;O'Donnell et al, 2001;Gould et al, 2007;Sinkevicius et al, 2009). Consequently, ERα and ERβ have become candidate spermatogenesis genes in humans.…”

A multi-faceted approach to understanding male infertility: gene mutations, molecular defects and assisted reproductive techniques (ART)

“…The ES signaling is known to be mediated by at least two functional isoforms of estrogen receptors (ER) known as ERα and ERβ that are encoded by two different genes on the long arm of chromosomes six (6q25) and 14 (14q23-24), respectively [22]. In human testis, ERα and ERβ were also found in ejaculated spermatozoa, early meiotic spermatocytes and elongated spermatids-independent ERα signaling is important for concentrating epididymal sperm, whereas estrogen-mediated ERβ signaling is essential for germ cell progression or viability [96]. The ER genes thereby represent a logical target for mutational analysis in the infertile male.…”