Follicle rupture and release of the of the oocyte and associated cumulus granulosa cells, the cumulus-oocyte complex (COC), from the mural granulosa cell layer requires significant cellular reorganization and extracellular matrix (ECM) remodeling via the action of proteases. Moreover, loss of cell-cell contacts and formation of a hyaluronan-rich matrix between cumulus cells leads to an "expanded" COC (cumulus-oocyte expansion;C-OE) that can detach from the follicle wall. While follicle rupture and C-OE are known to be critical for fertility, the individual cellular events required for these processes have not been fully elucidated. A genomic study conducted by the Co-P.l.s (Drs. Stouffer and Hennebold) identified mRNAs whose levels increase through the periovulatory interval and are likely involved in ECM remodeling (e.g., proteases) and C-OE (e.g., prostaglandin synthesis and signaling components). Proof-of-principle studies revealed that COC release and expansion could be prevented by intrafollicular delivery of compounds that block metalloproteinase activity and prostaglandin E2 receptor (PTGER) subtype 2 signaling, respectively. Further analysis of the genomic database also revealed the presence of a gene target that is expressed selectively in the ovary and only during the periovulatory interval, suggesting a potential critical role for the encoded protein in ovulation. As part (Project ll) of the U54 CDRC application entitied "Contraception by Blockade of Periovulatory Events In Primates", proposed experiments will evaluate the potential for PTGER antagonists to prevent C-OE and serve as reversible contraceptives in fertile, female macaques, as well as to establish their pharmacokinetic and pharmacodynamic profiles in women (AIM 1);determine whether inhibiting the action of select proteases expressed preferentially in the primate follicle prevents its rupture (AIM 2), and evaluate the ability of specific inhibitors of ovary- and ovulation-selective gene products to block ovulation in rhesus macaques (AIM 3). Specific inhibitors/approaches that block individual metalloproteinases, PTGER signaling, and a select ovary-specific gene product (ACPP) will be tested for their ability to prevent follicle rupture and C-OE. Contraceptive potential and reversibility of C-OE inhibitors, e.g., PTGER antagonists, will be performed in the Nonhuman Primate Contraceptive Core, while preclinical trials involving women volunteers will be conducted to further define their safety and efficacy profiles. Collectively, these studies will establish the potential for inhibitors of ovulation/C-OE to serve as novel, non-hormonal methods of contraception in women.
Current contraceptive methods feature failure rates, side effects, or other characteristics that limit their acceptance by some women, thus contributing to high rates of unintended pregnancy. The objective of this research, therefore, is to identify and develop non-hormonal contraceptives that directly block the release of the egg from the ovary, without affecting the systemic hormonal milieu or menstrual cyclicity.
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