Clinical disorders of impaired luteal function in the human constitute a significant cause of infertility, habitual abortion and miscarriage. An important component of the pathophysiological basis for these disorders resides in defective ovarian follicular development prior to ovulation. However, the precise cellular and biochemical mechanisms that subserve defective maturation of the follicle remain unknown. In the proposed work, we will investigate the critical -- but incompletely understood -- role of estrogen in the final stages of follicular maturation. Studies will focus on cellular and biochemical actions of estrogen alone, and on the mechanisms by which estrogen amplifies the responsiveness of ovarian cells to luteinizing hormone. For this purpose, we will employ both in vivo and in vitro studies of granulosa cells isolated from porcine Graafian follicles in later stages of spontaneous and induced follicular maturation. In particular, based on physiological considerations and significant preliminary data, we will investigate estrogen's control of progesterone biosynthesis in relation to: 1) stage of development of the preovulatory follicle; 2) presence or absence of atresia; and 3) availability of cellular cholesterol as substrate for progesterone biosynthesis. The role of estrogen as a biological amplifier of the actions of luteinizing hormone will be excamined in detail specifically in relation to mechanisms that control the availability of cholesterol as substrate for steroidogenesis. Because extensive prior lipid research in the swine has characterized important similarities to the human, we have chosen this species to investigate the endocrine regulation of cellular cholesterol utilization in steroid-hormone biosynthesis in developing follicles. Significantly these studies will help elucidate the mechanisms by which estrogen and luteinizing hormone prepare the pre-ovulatory follicle for the high rates of progesterone biosynthesis ultimately attained in the corpus luteum. We believe that a more precise understanding of the endocrine determinants of the later stages of normal follicular maturation will permit new approaches to fertility regulation in the human, domestic animal, or endangered wild species.
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