In vitro growth and ovulation of follicles from ovaries of estrogen receptor (ER)α and ERβ null mice indicate a role for ERβ in follicular maturation

Both estrogen receptor (ER) alpha and beta are expressed within the ovary and lack of either of these receptors affects ovarian function. In this study, the role of ER alpha and ER beta in folliculogenesis and ovulation was further analyzed. Evaluation of ovarian follicle populations in wild-type and ER beta knockout (beta ERKO) ovaries revealed reduced late antral growth and ovulatory capacity of beta ERKO follicles, indicated by reduced numbers of large antral follicles and corpora lutea and increased atresia of large antral follicles. An in vitro culture system was used to study growth, rupture, and luteinization of wild-type, ER alpha knockout (alpha ERKO) and beta ERKO ovarian follicles. alpha ERKO follicles exhibited wild-type-like growth and ovulation rates but an increased capacity to synthesize estradiol. In contrast, beta ERKO follicles showed a significant lack of progression from early antral to large antral stage, decreased estradiol production, and reduced ovulation. Expression patterns of several genes involved in follicle maturation and ovulation were analyzed in follicles grown in vitro. Ar, Pgr, and Has2 mRNA expression levels were the same among the three genotypes. However, beta ERKO follicles showed reduced expression of Cyp19 mRNA during follicle maturation and reduced Lhcgr and Ptgs2 mRNA expression after human chorionic gonadotropin stimulus. Luteinization occurs normally in alpha ERKO and beta ERKO follicles, shown by increased progesterone secretion and increased cdkn1b mRNA expression after human chorionic gonadotropin. Collectively, these data indicate that ER beta, but not ER alpha, plays a direct role in folliculogenesis. ER beta appears to facilitate follicle maturation from the early antral to the preovulatory stage.