Title: Estrogen-dependent and -independent estrogen receptor-alpha signaling separately regulate male fertility.
Authors: Sinkevicius, Kerstin W; Laine, Muriel; Lotan, Tamara L; Woloszyn, Karolina; Richburg, John H; Greene, Geoffrey L
Published In Endocrinology, (2009 Jun)
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.
PubMed ID:
19264877
MeSH Terms: Animals; Disease Models, Animal; Estrogen Receptor alpha/drug effects; Estrogen Receptor alpha/genetics*; Estrogen Receptor alpha/physiology*; Estrogens/physiology*; Gene Knock-In Techniques*; Infertility, Male/physiopathology*; Male; Mice; Mice, Mutant Strains; Oligospermia; Phenols; Point Mutation/genetics; Pyrazoles/pharmacology; Seminiferous Epithelium/physiopathology; Sertoli Cells/pathology; Sertoli Cells/physiology; Signal Transduction/physiology*; Testosterone/blood