The Role of Estrogen Receptor-a and Estrogen Receptor-b in the Hyperluteinized Mouse Ovary

Abstract

The hypothalamic-pituitary-gonadal (HPG) axis was characterized in female mice lacking one or both forms of estrogen receptor (ERa, ERb) with the aim of elucidating the contribution of each receptor form to gonadotropin homeostasis and ovarian function. These studies consisted of a thorough evaluation of gene expression for the gonadotropin subunits in the pituitary and the components necessary for steroidogenesis in the ovary. These data were corroborated with evaluations of the plasma levels for each of the relevant pituitary and gonadal hormones. Females lacking ERb (bERKO) exhibit minimal disruption in HPG axis function but do exhibit deficits in gonadotropin responsiveness in the ovary. Females lacking ERa (aERKO) exhibit dramatic ovarian phenotypes of hemorrhagic and cystic follicles and exaggerated steroid synthesis in the ovaries. The phenotypes in the aERKO ovary are attributable to chronically elevated LH due to the loss of ERa function in the hypothalamus. Pharmacologic reduction of plasma LH levels in aERKO females abates the ovarian phenotypes. These studies indicate that the hypothalamic functions of ERa are most critical to ovarian function. To better understand the contribution of ERb to the manifestations of LH-hyperstimulation in the ovary, females lacking functional ERb but possessing elevated LH via a transgene (bERKOLHCTP) were generated. Characterization of bERKOLHCTP animals indicates the intraovarian functions of ERb are necessary for the induction of LH-associated cystic follicles but not amplified steroidogenesis. An additional novel finding in aERKO ovaries was ectopic expression of the Leydig cell specific enzyme, 17b-HSD III and correlating male-like testosterone synthesis. This phenotype is dependent on LH-hyperstimulation of ovaries lacking ERa function to manifest. In summary, the predominant contribution of ERa to ovarian function occurs in the hypothalamus, whereas ERb is more important within the ovary itself. Presence of Leydig cell specific gene expression in aERKO ovaries indicates a potential role for estradiol and ERa in gonadal differentiation.