Progesterone Affects Clinic Oocyte Yields by Coordinating with FSH via the PI3K/AKT and MAPK Pathways

Background : Over recent years, progestin has been incorporated into the novel ovary stimulation regimens as an alternative for GnRH analogs to prevent premature luteinizing hormone surge, and has become widely used in treatment for infertility. However, the influence of progesterone administration in terms of clinical outcomes and the mechanisms involved remains poorly understood. Methods: The clinic outcomes from patients undergoing ovary stimulation for in vitro fertilization were analyzed. The mouse ovary stimulation model and follicle culture system were used to evaluate the effect of progesterone on oocyte yield, follicle development, granulosa cell proliferation, hormone secretion. Phospho-Specific Protein Microarray, western blot and RT-PCR were employed to explored the signal mechanism. Findings: We present the evidence from patients suggesting that progesterone decreased the oocyte yields, that was rescued by the higher dose of human menopausal gonadotropin. Using both in vivo and in vitro mouse models, we demonstrated that the administration of progesterone inhibited the proliferation of granulosa cells and therefore reduced the growth rate of follicles. The action of progesterone was mediated by progesterone receptor membrane component-1 and rescued by FSH. Using a phosphorylation array, we identified the PI3K/AKT and MAPK are pivotal pathways that integrated the action of progesterone into the FSH signaling network via the downregulation of cyclin D2 and c-fos in granulosa cells. Interpretation: Our findings highlight the mechanism by which progesterone coordinates with FSH to regulate follicle growth and subsequently influence oocyte outcomes in clinic. These findings advance our understanding of the alterations of ovary response to gonadotrophins during progestin primed ovarian stimulation and gives rise to the opportunity for manipulating individual oocyte yields by signaling regulation. Funding Statement: This study was financially supported by the Natural Science Foundation of Shanghai (Grant number 19ZR1429300, awarded to HL), research grants from the National Natural Science Foundation of China (Grant number 81871163, awarded to QL; Grant number 81771533, awarded to YK; Grant number 81671520, awarded to QC), and the National Key Project (Grant number 2018YFC1003000). Declaration of Interests: The authors have declared that no conflict of interest exists. Ethics Approval Statement: Approval for human retrospective analysis was obtained from the institutional Ethics Committee of Shanghai Ninth People’s Hospital affiliated to Shanghai JiaoTong University’s School of Medicine. Animal studies were approved by the institutional Ethics Committees of Care and Use of Experimental Animals of Shanghai Jiaotong University.