Estrogen receptor-β is critical to granulosa cell differentiation and the ovulatory response to gonadotropins

The process of granulosa cell differentiation that occurs in preovulatory follicles is dependent on FSH but requires augmentation by estradiol. To determine which estrogen receptor ( ER) form mediates the effects of estradiol during gonadotropin-induced follicle growth, differentiation, and rupture, we characterized the response of ER alpha- and ER beta-null mice to gonadotropin-induced ovulation. Immature mice were treated with an ovulatory regimen of exogenous gonadotropins and tissues were collected at distinct time points for morphological, biochemical, gene expression, and immunohistochemical analyses. Granulosa cells of ER beta knockout (ERKO) preovulatory follicles exhibited an attenuated response to FSH-induced differentiation, as evident by reduced aromatase activity and estradiol synthesis, and insufficient expression of LH receptor. As a result, beta ERKO ovaries were unable to fully respond to an ovulatory bolus of gonadotropin, leading to a reduced rate of follicle rupture; insufficient induction of prostaglandin-synthase 2 and progesterone receptor; an aberrant increase in aromatase activity and plasma estradiol; and incomplete expansion of the cumulus-oocyte complex. Parallel characterization of alpha ERKO females indicated a minimal role for ER alpha in granulosa cell differentiation, ovulation, and the concomitant changes in gene expression, although some abnormalities were revealed. These studies demonstrate that ER beta-mediated estradiol actions are vital to FSH-induced granulosa cell differentiation; and in the absence of ER beta, preovulatory follicles are deficient in the necessary cellular organization (i.e. antrum and cumulus oocyte complex), enzymatic activity (i.e. capacity to convert androgen precursor to estradiol), and receptor signaling pathways (i.e. LH receptor) to respond to a gonadotropin surge and expel a healthy oocyte.