DIRECT GONADOTROPIN REGULATION OF HUMAN FALLOPIAN TUBES

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Human fallopian tubes, which have never previously been considered a direct target of hCG/LH regulation, express hCG and its receptor genes. The expression of these genes is dependent on the anatomical region of the tube and reproductive state of the women. Tubal mucosa, which undergoes cell division and is active in macromolecular synthesis and secretion, expresses more than any other tubal cell layer. Incubation of tubal tissue with highly purified hCG resulted in a dose and time dependent increase of catalytically active 5-lipoxygenase, cyclooxygenase (COX)-1 and COX-2 enzymes in tubal mucosa. These findings suggest that hCG and LH can regulate tubal mucosal functions independent of ovarian steroid hormones. However, there may be interactions between these hormones and growth factors in overall regulation of tubes. The present grant application proposes to investigate: 1) the role of exogenous and endogenous hCG and its receptor in mucosal cell division and macromolecular synthesis and secretion; 2) whether tubal hCG and its receptors are regulated by ovarian steroid hormones, growth factors and hCG/LH; 3) what signaling mechanisms and mediators are involved in hCG action and 4) finally whether ovarian steroid hormones and growth factors can mimic and/or modify hCG action. Functional equivalency of hCG and hLH will be tested because these two hormones are structural and functional homologs that bind to the same receptors. Only tubal mucosa from secretory phase will be used because it abundantly co-expresses hCG and its receptors and this expression is higher in secretory phase as compared to other reproductive states. These investigations will be aided by antisense cDNA expression technology, other molecular biology, cell biology and biochemical techniques. The overall goal of this proposal is to advance our current understanding of the role and regulation of hCG and its receptors in fallopian tubes and to place all the potential regulators of fallopian tube functions in a proper perspective. Such knowledge can further stimulate research on hCG/LH regulation of tubal functions as it may relate to numerous events of early pregnancy, in vitro fertilization, ectopic pregnancy and pelvic inflammatory disease. In addition, it could lead to the development of newer methods of tubal contraception or treatment of infertility due to tubal dysfunction. Adequate amounts of tubal tissue from premenopausal women, including minority subjects, undergoing tubal ligation or hysterectomy will be available. The proposed studies have never previously been performed on fallopian tubes or uteri of humans or other species.