Normal reproductive function in women requires the operation of precise endocrine mechanisms that regulate steroid-hormone biosynthesis in the ovary. More exacting knowledge of such detailed hormonal mechanisms is ultimately essential, if we are to maintain or interrupt human ovarian function safely and selectively in health or disease. For the present work, our overall objective is a more refined understanding of the mechanisms subserving gonadotropin action in the ovary. To date, gonadotropin action in the ovary has been understood primarily in relation to the classical cyclic AMP effector system. However, calcium ions are now also recognized to play a pivotal role in the expression of hormone action in target organs, including endocrine glands. Our preliminary studies in the ovary have already delineated highly specific and significant actions of calcium ions on progesterone biosynthesis. Moreover, we have demonstrated that ovarian cells contain high concentrations of the calcium-regulatory protein, calmodulin, and that selective inhibitors of calmodulin significantly influence gonadotropin action. Based upon xtensive background work, we now propose to specifically study how calcium ions control cholesterol's utilization in progesterone biosynthesis, and then investigate the involvement of calmodulin in that step(s). For this purpose, we will use a well established in vitro system of swine ovarian cells, in which major, circumscribed actions of calcium on steroidogenesis are demonstrable. We believe that a more comprehensive knowledge of mechanisms of hormone action in the ovary will have important implications in reproductive medicine and biology. In particular, our studies of calcium as a new and pivotal regulator of gonadotropin action are likely to generate significant and novel insights into the endocrine control of ovarian function. Such insights should ultimately foster more rational approaches to fertility regulation in the human, domestic animal, and endangered wild species.
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