OVARIAN IGFS: ENDOCRINE VS PARACRINE EFFECTS

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This proposal seeks to determine the relative significance of endocrine, autocrine, and paracrine components of the IGF system for the function of the porcine ovary in vivo. It builds on several years of work emphasizing in vivo techniques which have defined the secretion and action of the ovarian IGFs and their binding proteins (IGFBPs). These data lead to the presumption of a critical role for this growth factor system in ovarian function-a hypothesis which will be tested in the current proposal. To address these issues, we will first determine the ovarian sites of biosynthesis, localization, and binding of IGFs and their BPs during the reproductive cycle. These histochemical studies are expected to reveal an extracellular targeting network in which the IGFBPs govern the distribution of locally produced and circulating IGFs within the ovary. Next we will determine the access of circulating IGFs to the several functional components of the ovary through a series of in vivo perfusion studies. We expect to find that circulating IGFs have access to she ovary in a selective and targeted fashion, governed in large measure by the IGFBPs. Finally, we will assess the physiological effects of perfused IGFs and their BPs on steroidogenesis and follicular development; in addition, we will block ovarian IGF effects by perifusing the ovary in vivo with antibodies to IGF-I. In the aggregate, these studies will provide essential missing information about the importance and function of the IGFs and their BPs in ovarian physiology; at present these functions can only be presumed from studies in culture or in vivo correlations. These results should have significant implications for disease processes in humans. Attempts to manipulate the IGF system in patients have already been introduced -to infertility clinics. Data from in vitro and histochemical studies in humans have implicated distortions of this system in disease processes such as the polycystic ovary syndrome.