In the course of studies to elucidate the endocrine mechanisms of corpus luteum regression, a novel observation was made: adenine-derived purines produce an enormous amplification of gonadotropin action in both rat and human ovarian cells, but not in testicular Leydig cells. Moreover, adenosine competitively inhibits the antigonadotropic action of PGF2 Alpha directly in the rat luteal cell. The endocrine-like action of purines is an emerging field of investigation, and virtually no information was available until the above studies, which indicated that purines modulate endocrine-dependent responses in the ovary. Purines are natually ubiquitous, and tissue levels in situ are known to rapidly increase in response to hypoxia, nerve stimulation and to other stimuli. In addition, the specificity, rapidity and magnitude of purine and prostaglanding endocrine-modulatory actions in ovarian cells lends credence to the hypothesis that they serve important functional roles in vivo. Consequently, the major thrust of this application is to elucidate the physiological, biochemical and endocrinological mechanisms of purine-prostaglandin interactions in the ovary, and to assess the scope of the endocrine-like actions of purines in other tissues of the lower reproductive tract. We, therefore, propose: 1. To identify the nature, levels and physiological regulation of purines delivered to, and present within, tissues and fluids of the female reproductive tract. 2. To elucidate the biochemical mechanism of amplification of gonadotropin action by purines in ovarian cells. 3. To elucidate the mechanisms of the inhibitory action of PGF2Alpha on purine interactions in the luteal cell. 4. To explore whether purines modulate ovarian androgen synthesis in response to LH and Sertoli cell responses to FSH. Information derived from this novel area of research may provide a greater understanding of endocrine control and regulation of theovary. Moreover, advances in purine and prostaglandin pharmacology and the information from this research may result in avenues for therapeutic control of reproductive processes in health and disease heretofore unrecognized.
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