Effect of single and compound knockouts of estrogen receptors alpha (ER alpha) and beta (ER beta) on mouse reproductive phenotypes

The functions of estrogen receptors (ERs) in mouse ovary and genital tracts were investigated by generating null mutants for ER alpha (ER alpha KO), E R beta (ER beta KO) and both ERs (ER alpha beta KO). All ER alpha KO female s are sterile, whereas ER beta KO females are either infertile or exhibit v ariable degrees of subfertility. Mast cells present in adult ER alpha KO an d ER alpha beta KO ovaries could participate in the generation of hemorrhag ic cysts. Folliculogenesis proceeds normally up to the large antral stage i n both ER alpha KO and ER beta KO adults, whereas large antral follicles of ER alpha (+/-)/ER beta KO and ER alpha beta KO adults are markedly deficie nt in granulosa cells. Similarly, prematurely developed follicles found in prepubertal ER alpha KO ovaries appear normal, but their ER alpha beta KO c ounterparts display only few granulosa cell layers. Upon superovulation tre atment, all prepubertal ER alpha KO females form numerous preovulatory foll icles of which the vast majority do not ovulate. The same treatment fails t o elicit the formation of preovulatory follicles in half of the ER beta KO mice and in all ER alpha (+/-)/ER beta KO mice. These and other results rev eal a functional redundancy between ER alpha and ER beta for ovarian follic ulogenesis, and strongly suggest that (1) ER beta plays an important role i n mediating the stimulatory effects of estrogens on granulosa cell prolifer ation, (2) ER alpha is not required for follicle growth under wild type con ditions, while it is indispensable for ovulation, and (3) ER alpha is also necessary for interstitial glandular cell development. Our data also indica te that ER beta exerts some function in ER alpha KO uterus and vagina. ER a lpha beta KO granulosa cells localized within degenerating follicles transf orm into cells displaying junctions that are unique to testicular Sertoli c ells. From the distribution pattern of anti-Mullerian hormone (AMH) in ER a lpha beta KO ovaries, it is unlikely that an elevated AMH level is the caus e of Sertoli cell differentiation. Our results also show that cell prolifer ation in the prostate and urinary bladder of old ER beta KO and ER alpha be ta KO males is apparently normal.