The formation, function, and demise of the primate corpus luteum are critical aspects of menstrual cyclicity, infertility, and contraceptive intervention. Recent work by the applicant's laboratory has demonstrated the presence of an intra-ovarian mineralocorticoid system in the non-human primate. In rhesus monkeys undergoing controlled ovarian stimulation, an ovulatory stimulus increases the expression of 21-hydroxylase (CYP21A2) mRNA in a time-dependent manner. CYP21A2 converts progesterone to the potent mineralocorticoid receptor (MR) agonist 11-deoxycorticosterone (DOC), and thus correlates with the observation that the ovulatory hCG bolus increases intra-follicular levels of DOC. In order to verify an ovarian origin for DOC, granulosa cells were isolated prior to an ovulatory stimulus and cultured in the presence of hCG, resulting in a dramatic increase in media concentrations of DOC. MR is expressed in the cytoplasm of both luteinizing granulosa cells as well as the corpus luteum until the mid to mid-late luteal phase, at which time MR is translocated to the nucleus. Importantly, antagonism of MR during luteinization attenuates hCG-induced progesterone, indicating that cytoplasmic MR has a key role in luteinization of granulosa cells in vitro. This R21 application proposes to test the overall hypothesis that MR is critical during the lifespan of the corpus luteum with two specific aims using the non-human primate model.
Specific aim 1 will determine if MR has a critical role in the development of the corpus luteum using an MR antagonist. It is expected that antagonism of MR in vivo will prevent the critical rise in progesterone, leading to anovulation and incomplete luteal formation.
Specific aim 2 will test the hypothesis that MR promotes luteal function through progesterone synthesis, and that intra-luteal levels of DOC increase in parallel with progesterone. In both aims, specific gene targets of MR will be elucidated. These studies will be the first to demonstrate a key role for MR in the ovarian physiology of any species, and are expected to further our understanding of corpus luteum development, maintenance, and demise in a biomedically relevant primate model.
Pathologies associated with the ovary carry a high morbidity and mortality, largely through difficulty in detection, but also from a lack of treatment stemming from a rather incomplete understanding of basic ovarian processes. These include, for example, PCOS, ovarian cancer, and ovarian hyperstimulation syndrome (OHSS). In addition, infertility plagues a growing number of couples in the United States (>6 million;Center for Disease Control);a proportion of this infertility can be linked to insufficiency of P production during the luteal phase, although the underlying causes of this are completely unknown. Novel contraception remains a problem, with a large preponderance of North American women continuing to rely on derivations of combined oral contraception and no new methods in sight. Aging and reproduction is clearly a growing topic in the United States, and a better knowledge of basic ovarian processes will facilitate understanding the menopausal transition in women. These issues all support the idea that ovarian physiology is a relevant topic with profound health outcomes. Overall, these exploratory studies should reveal a novel signaling steroid pathway in the primate ovary that could have clinical significance for contraceptive development, infertility, and potentially ovarian cancer.
