Role of estrogen in folliculogenesis through estrogen receptor alpha

Abstract

Estrogens are known to play an important role in the growth, differentiation and function of the female reproductive system. In the development of follicle until ovulation, estrogen actions on the follicular development as autocrine or paracrine. In growing follicles, estrogen promotes the action of gonadotropins, the formation of antrum in granulosa cell, gap junction formation between granulosa cells, and inhibits follicular atresia. Estrogens regulate the synthesis of androgens in theca cells. Estrogen action via the nuclear receptors, estrogen receptor alpha (ERα, Esr1) and beta (ERβ, Esr2). In the different cell types of the ovary, two different ER proteins are differentially localized. ERα is localized in theca/interstitial cell and ERβ is localized in granulosa cell. ERα is known as required for ovulation and ERβ is known as required for antrum formation and preovulatory follicle. However, the function formation and differentiation of follicle cells in ERα mediated folliculogenesis is controversy and not well understood. The importance of estrogen-mediated action via estrogen receptors (ERs) is suggested using estrogen receptor gene knockout mice. In this study, we investigated the role of estrogen receptor on folliculogenesis, especially the differentiation of follicle cells and its effect on oocyte growth. In estrogen receptor alpha knockout mice (ERKO), estrogen cannot action through estrogen receptor alpha in theca cell. Therefore, the effect of estrogen in folliculogenesis through theca cell can be blocked. In the 2D culture the diameter of follicles was increased in E2 treated group of wild type (WT), and was significantly reduced at day 8 in PHTPP treated WT. In 3D culture system, ICI 182,780 administered WT shows decreased follicle size entire experimental days. however KO follicle no significantly change between two different system. In both culture systems, expression of Insl3, theca cell-specific gene, tended to decrease in PHTPP treated ERKO, but increased in WT. In both culture systems, the expression of Fshr and Cyp19a1 significantly increased in E2 treated ERαKO but significantly decreased in PHTPP treated ERαKO. Expression of Ptx3, Ptgs2, and Tnfaip6 in both ERαKO and WT, showed different results according to the culture systems. ERαKO also showed differences in the levels of steroid hormone between the two culture systems. The concentrations of E2 and P4 in both culture systems increased in and PHTPP treated WT. On the other hand, ERαKO mice showed decreased levels of E2 and P4 in 2D culture system, but increased in 3D culture system. These results indicate that estrogens might effect on the growth of follicles, differentiation of granulosa and theca cells, cumulus expansion and production of steroid hormones. In addition, this might provide insight into the local actions of estrogen receptors in folliculogenesis.