The role of glucocorticoid receptor in the ovary

Abstract Ovarian disorders in women, including defects in ovulation and subsequent corpus luteum development, account for up to 30% of all infertility cases. Understanding the mechanism underlying these processes is critically important because this knowledge serves as a foundation for our ability to aid or manage female fertility. Glucocorticoids (GCs) are potent hormones involved in various cellular functions, including inflammatory responses and cellular metabolism, which are also hallmarks of the ovulatory process and luteal development. In the ovary, the level of cortisol, an active glucocorticoid, dramatically increases in the follicular fluid after an ovulatory human chorionic gonadotropin (hCG) stimulation in women and monkeys, whereas the level of cortisone, an inactive form, rapidly decreases. Our recent studies and preliminary data demonstrated that the administration of an ovulatory bolus of hCG increased the expression of crucial components required for cortisol production and action in granulosa cells of periovulatory follicles in normally cycling women, monkeys, and mice. Moreover, our experimental data indicate that GCs/glucocorticoid receptor (GR) plays critical roles in cumulus expansion, ovulation, and luteal development. However, little is known about the mechanisms by which GCs/GR regulate these processes and their physiological significance in the ovary. The present proposal will address these critical questions by utilizing experimental models from three key species to gain a comprehensive understanding of the role of GCs/GR in the pivotal process in the ovary. In Aim 1, using transgenic mouse models in which GR expression is ablated in ovarian follicular cells, we will determine the physiological significance of GR and identify GR-mediated transcriptomic, genomic, and functional changes necessary for successful ovulation and luteal development. In Aim 2, we will utilize adult female rhesus monkeys to demonstrate that the inhibition of GR in preovulatory follicles negatively affects ovulation and luteal development and determine the specific function(s) and transcriptomic regulation affected by GR inhibition. In Aim 3, using dominant preovulatory follicles obtained from normally cycling women across the ovulatory period and primary human granulosa/lutein cells, we will delineate the mechanisms by which GCs/GR signaling regulates ovulatory changes and luteinization by first identifying direct downstream target genes of GR in primary human granulosa cells, then characterizing their expression in dominant follicles during the ovulatory period, and lastly assessing functional impacts of GR inhibition. By demonstrating the physiological significance and identifying specific actions of GCs/GR in the periovulatory ovary across multiple species, the proposed study will provide novel insights into the species-specific and -conserved mechanism controlling ovulation and luteinization. This fundamental knowledge will be valuable for developing strategies to assist women experiencing infertility due to anovulatory disorders and luteal insufficiency.