Early Events in Rhesus Macaque Corpus Luteum Formation: Regulation and Role of Progesterone

Abstract

A mid-cycle ovulatory Luteinizing Hormone (LH) surge initiates a series of events leading to a dramatic increase in progesterone, ovulation and transformation of the follicular remnant into the corpus luteum (CL). Progesterone is known as an important factor for the formation, maintenance and function of CL. Therefore regulation of progesterone production and progesterone's local role on luteinizing granulosa cells (GCs) are studied utilizing rhesus macaques as a model. As cholesterol is the precursor for progesterone biosynthesis, it is hypothesized that regulation of transcription factors that regulate cholesterol homeostasis would be among the earliest changes following an ovulatory stimulus. Transcription factors such as the peroxisome proliferator activated receptor-gamma (PPARG) and the liver X receptors (LXRs) are known as important regulators of genes that participate in cholesterol balance. The expression profile of these genes following an ovulatory stimulus showed a rapid and dramatic down-regulation suggesting these negatively regulate steroidogenesis. Utilizing PPARG and LXR agonists it is shown that the ovulatory stimulus along with loss of PPARG expression leads to loss of LXR expression. This loss of LXR is shown to allow expression of steroidogenic genes STARD1, HSD3B2, CYP11A1 and SCARB1 thus aiding in progesterone synthesis. The second part of the study focuses on progesterone's role in promoting the survival of GCs. Although it is known that progesterone promotes GC survival, the exact mechanism by which it brings this about is not clear. It is hypothesized that progesterone by regulating the expression of key genes such as EGF-like ligands, amphiregulin (AREG) and epiregulin (EREG), which acts to promote luteinizing GCs survival, brings about progesterone's pro-survival role and therefore aids in the formation of CL. Evidence is presented to show that progesterone along with LH activated protein kinase A is required for the induction and maintenance of the expression of both AREG and EREG. In addition it is shown that an increase in GC death associated with addition of a PGR antagonist can be reversed by addition of these ligands. Taken together these data provide evidence that progesterone by participating in the expression of EGF ligands promotes GC survival and thereby the formation of CL.