NOVEL CONTRACEPTIVES: CONTROL OF FOLLICULAR MATURATION AND RUPTURE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The principal function of the ovary in female mammals, the production of sex steroid hormones notwithstanding, is to release the fertilizable gamete, the oocyte or egg, in a timely manner during the animal's reproductive lifespan. This function is achieved through the process of ovulation, wherein a fully-developed follicle ruptures in response to the actions of the ovulatory gonadotropin surge, and releases the cumulus-oocyte complex for passage into the reproductive tract and possible fertilization. However, follicle rupture and detachment of the cumulus-oocyte complex from the inner (granulosa) cell layer of the follicle requires significant cellular reorganization and extracellular matrix remodeling via a complex system of proteases. Detachment must be preceded by loss of cell-cell contacts and formation of a hyaluronan-rich extracellular matrix between cumulus cells, resulting in a large increase or "expansion" of the cumulus-oocyte complex. Furthermore, recent data from nonprimate species indicate that cumulus-oocyte expansion (C-OE) involves complex interactions between oocyte-, granulosa/cumulus-, and serum-derived factors, such that targeted disruption of key components impairs ovulation and fertilization. These findings are consistent with the novel concept that it is possible to selectively inhibit follicle proteolysis, C-OE, oocyte release, and hence fertility, without altering other aspects of female reproduction, including ovarian/menstrual cyclicity. Thus the objective of this project is to test the hypothesis that proteases, oocyte- and granulosa/cumulus-derived proteins control follicle rupture and C-OE in primates. Furthermore, it will be determined whether blockade of their synthesis or action will prevent timely C-OE, oocyte release and pregnancy in Old World (macaque) monkeys.