The hypothesis underlying the present proposal is that reactive oxygen species, particularly H202, are generated in the ovary and serve an important role in the regulation of normal function. But, unbridled production of H202 may cause ovarian dysfunction. These propositions arose directly from recent findings of this laboratory that describe for the first time endocrine regulation of H202 production in the ovary whose appearance results in inhibition of gonadotropin action and steroidogenesis, lipid peroxidation, depletion of antioxidants, damage of RNA and DNA, inhibition of protein synthesis, and depletion of ATP. Such effects reflect cells in stress and may be the basis of the novel finding that heat shock protein induction blocks luteal cell function.
The specific aims of this proposal are to unveil the cellular origins and mechanisms of regulation of H202 production in the ovary, determine the mechanisms of protection against and detoxification of H202 in the corpus luteum, and to evaluate the role of heat shock proteins as possible mediators of stress responses in the corpus luteum. While PGF2alpha was found to induce H202 production in the corpus luteum, a major hypothesis to be tested is that LH also induces this response, but via a different mechanism. Leukocytes will be examined as a potential ovarian source of H202, possibly induced by PGF2alpha whereas LH is postulated to stimulate H202 production by luteal cells. Peroxidase-ascorbate coupled reactions are posited as a vital detoxification mechanism of H202, which is the basis for the high levels of ascorbate in the corpus luteum and the intense depletion of this antioxidant during intervals of H202 generation. The nature of ovarian peroxidases and the regulation of ascorbate turnover are therefore important targets of investigation. Stress protein induction is proposed as a mediator of ovarian cell responses to reactive oxygen and other mediators of functional ablation of luteal function. Methods to be employed in these investigations include both in vitro and in vivo models of ovarian function, and analysis of ovarian hormones, H202, peroxidases, antioxidants, and heat shock proteins. Information from these studies may reveal novel insights into the etiology and therapeutic treatment of ovarian cancer as oxygen radicals are known mutagens. Ovarian pathologies associated with elevated levels of LH that may be related to increased production of H202 in the ovary include the life-threatening inflammatory response associated with ovulation of hyperstimulated ovaries and ovarian stromal responses to excess LH that occurs in the perimenopause, and in polycystic ovarian disease.
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