NOVEL CONTRACEPTIVES: CONTROL OF FOLLICULAR MATURATION AND RUPTURE

Oregon Health & Science University, Portland OR

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The principal function of the ovary in female mammals is to release a fertilizable oocyte during the animal's reproductive lifespan. This is achieved through the process of ovulation, wherein a fully-developed follicle ruptures following the mid-cycle gonadotropin surge, releasing the cumulus-oocyte complex (COC) for passage into the reproductive tract and possible fertilization. However, follicle rupture and detachment of the COC from the inner (granulosa) cell layer of the follicle requires significant 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 "expansion" of the COC. 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 suggest 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 determine if proteases, oocyte- and granulosa/cumulus-derived proteins involved in C-OE are suitable targets for the control of fertility in primates. Progress to date has revealed that the metallo- superfamily of proteases are the predominant proteolytic enzymes expressed prior to ovulation and that inhibition of their activity prevents follicle rupture and the release of an oocyte. Furthermore, recent studies have revealed that prostaglandin E2 serves to initiate molecular processes in rhesus macaque COCs (e.g., hyaluronan synthesis) required for C-OE.