The midcycle surge of luteinizing hormone (LH), the low tonic levels of LH circulating during the luteal phase of the menstrual cycle, and the exponentially rising levels of chorionic gonadotropin (CG) in early pregnancy have a common function - to stimulate progesterone (P) production by the primate corpus luteum at specific times during its lifespan. Since we determined that P receptors are present in luteal cells of rhesus monkeys, this ongoing project is testing the hypothesis that other actions attributed to LH/CG are mediated, at least in part, by P produced in response to these gonadotropins. Studies in the current and upcoming year focus on whether P mediates LH actions in the periovulatory interval leading to ovulation (i.e., follicle rupture and release of the egg) and luteinization (i.e., conversion of the follicle wall into the corpus luteum). To date, very little is known about the cascade of events initiated by midcycle LH surge that culminate in ovulation ~ 40 hours later. Therefore, initial experiments were designed to elucidate the dynamics of cellular and molecular events occurring during this so-called "periovulatory interval". Adult, female rhesus monkeys received recombinant human gonadotropins (r-hFSH q r-hLH) to promote development of multiple preovulatory follicles. Peripheral blood samples, aspirates (containing follicular fluid and granulosa cells) of follicles, and the intact ovary were removed before (0 hr) or 12, 24 and 36 hr after administering an ovulatory gonadotropin bolus. Follicular fluid P levels increased 180-fold within 12 hr post-bolus and remain at this level. Experiments indicated that increased P production by granulosa cells collected at 12-36 hr was associated with acquisition of the ability to convert cholesterol to P (i.e., P450 side-chain cleavage enzyme activity and/or cholesterol transport into mitochondria). Expression of PR mRNA by granulosa cells also increased 13-fold within 12 hr, and preliminary data indicate that the nuclei of granulosa cells contain significant PR protein at this time. These data indicate that P may act via PR-mediated pathways early (s12 hr) in the periovulatory interval to promote processes leading to rupture and luteinization of the primate follicle. Ongoing studies indicate significant changes in protease (matrix metalloproteinases MMP-1,2,7,9) and protease inhibitor (TIMP-1 and -2) mRNA and activity in the follicle between 0-36 hr, with patterns of expression differing between MMPs and TIMPs. These changes may be critical for follicle rupture or luteinization. Studies in 1998 will examine changes in other follicular parameters (e.g., cyclooxygenase-1 and -2 expression and prostaglandin production). Moreover, ablation/replacement approaches (using pharmacologic agents) will begin to determine which of these processes is regulated locally by P. This research should provide insight into mechanisms potentially leading to certain types of infertility (e.g., anovulation, luteinized unruptured follicle or LUF syndrome) and suggest novel methods for controlling fertility by preventing ovulation in women.
NIH ExPorter
NIH ExPorter