Gonadotropins as well as intraovarian peptides regulate normal ovarian follicle development which involves dominant follicle selection and cohort atresia. Abnormal development can result in anovulation and infertility, as in polycystic ovarian syndrome (PCOS), where follicle recruitment and growth are limited and dominant follicle selection docs not occur. We and others have recently described the intraovarian insulin-like growth factor (IGF) system, comprised of IGF-I and IGF-II, their binding proteins (IGFBPs, which modulate (mostly inhibit) IGF action), IGFBP proteases (which cleave the BPs and lower their affinity for the IGFs), and IGF receptors in human ovary. Precise mechanisms, however, whereby this system participates in ovarian follicle development, atresia, and arrest of development (as in PCOS) have not been well defined. It is the goal of the current proposal to define the roles of this system in these processes. To this end, we propose to determine what factors regulate IGF-II mRNA expression and protein synthesis in human granulosa and theca, what are the molecular forms of IGF-II in human ovary, what effects IGF-II has on granulosa and thecal steroidogenesis, and through which IGF receptor(s) IGF-II exerts its effects. We have found that follicular fluid IGFBPs correlate with follicular functional status (atretic versus estrogenic), suggesting that intrafollicular levels of IGFBPs (and IGFBP proteases) regulate the biologic availability of intraovarian IGFs, thereby regulating atresia and arrest of development. We propose to elucidate regulation of IGFBP mRNA and protein synthesis in human granulosa and theca by peptides and steroids known to influence follicular development, evaluate the presence of IGFBP proteases in human ovary and determine what effect they have on intraovarian IGF action, and characterize and purify specific BP proteases that we have identified in human preovulatory follicular fluid. Finally, we propose to determine what regulates IGF receptor gene expression in human granulosa and what role IGFs and IGFBPs play in the process of follicular atresia. To achieve these specific aims, experiments have been designed using human granulosa and thecal cells from estrogenic and atretic follicles from normally cycling women, gonadotropin-stimulated, and PCOS follicles, and also cultured human preantral follicles. We have chosen human ovary since several aspects of the IGF system are unique to this tissue compared to extensively used rat and porcine models which are not applicable to clinical investigation. We believe that the proposed studies will provide insight into normal and abnormal ovarian follicle development and may provide the basis for new treatments for ovulation induction and contraception.
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