In preliminary studies we have established the concept that the GC of pre-antral follicles secrete proteins that diffuse into the stromal compartment adjacent to the growing follicles that have the capability of stimulating the differentiation of pre-theca cells into endocrine cells in the theca interna that express LH receptors and have the capacity to secrete androgens. This process occurs without the need for LH. We have further established that the combination of IGF-1 and SCF, both of which are known to be secreted by GC in pre-antral follicles, can stimulate androgen production independent of LH in a manner very similar to the substances secreted by pre-antral follicles. The most common reproductive endocrine disorder, polycystic ovary syndrome, is characterized by excessive androgen production by the ovarian theca cells but the mechanism stimulating thecal androgen production is incompletely understood. The overall goals of this proposal are to define the roles of IGF-I and SCF in the mechanism of theca differentiation and androgen production in normally developing follicles and to determine whether this mechanism could be involved in the pathogenesis of PCOS. To accomplish these goals we will use our unique model of differentiating ovarian thecal cells to characterize the relative importance and the interactions between IGF-I and SCF with respect to stimulating thecal expression of LH receptor, P450/SCC, 3beta-HSD, P450/17alpha mRNAs and androgen biosynthesis. We will examine the molecular mechanisms by which IGF-1 and SCF complement each other to induce the expression of the key steroidogenic and regulatory genes and activate the steroidogenic machinery in theca cells. We will use strains of mice that have various well-characterized mutation in the SCF gene to examine the nature of reproductive defects caused by the mutations in an effort to understand the role of SCF in reproductive function and thecal differentiation. Finally, we will measure the expression patterns of IGF-I and SCF in follicles at different stages of development in both rats and women with normal menstrual cycles and women with polycystic ovary syndrome to determine if there are alterations in SCF+IGF-I expression that could contribute to hyperandrogenism and ovulatory dysfunction. From these studies we will learn important information regarding a novel pathway regulating ovarian androgen production independent of LH. It is hoped that this will provide novel opportunities for developing new treatments for hyperandrogenism.
