Effect of single and compound knockouts of estrogen receptors α (ERα) and β (ERβ) on mouse reproductive phenotypes

Abstract

ABSTRACT The functions of estrogen receptors (ERs) in mouse ovary and genital tracts were investigated by generating null mutants for ERα (ERαKO), ERβ (ERβKO) and both ERs (ERαβKO). All ERαKO females are sterile, whereas ERβKO females are either infertile or exhibit variable degrees of subfertility. Mast cells present in adult ERαKO and ERαβKO ovaries could participate in the generation of hemorrhagic cysts. Folliculogenesis proceeds normally up to the large antral stage in both ERαKO and ERβKO adults, whereas large antral follicles of ERα+/−/ERβKO and ERαβKO adults are markedly deficient in granulosa cells. Similarly, prematurely developed follicles found in prepubertal ERαKO ovaries appear normal, but their ERαβKO counterparts display only few granulosa cell layers. Upon superovulation treatment, all prepubertal ERαKO females form numerous preovulatory follicles of which the vast majority do not ovulate. The same treatment fails to elicit the formation of preovulatory follicles in half of the ERβKO mice and in all ERα+/−/ERβKO mice. These and other results reveal a functional redundancy between ERα and ERβ for ovarian folliculogenesis, and strongly suggest that (1) ERβ plays an important role in mediating the stimulatory effects of estrogens on granulosa cell proliferation, (2) ERα is not required for follicle growth under wild type conditions, while it is indispensable for ovulation, and (3) ERα is also necessary for interstitial glandular cell development. Our data also indicate that ERβ exerts some function in ERαKO uterus and vagina. ERαβKO granulosa cells localized within degenerating follicles transform into cells displaying junctions that are unique to testicular Sertoli cells. From the distribution pattern of anti-Müllerian hormone (AMH) in ERαβKO ovaries, it is unlikely that an elevated AMH level is the cause of Sertoli cell differentiation. Our results also show that cell proliferation in the prostate and urinary bladder of old ERβKO and ERαβKO males is apparently normal.