The physiological mechanisms whereby the human endometrium avoids hemorrhage during trophoblastic vascular invasion, yet paradoxically permits menstrual-related vascular disruption, are unknown. Similarly, there is a paucity of information on the pathogenic mechanisms underlying abnormal uterine bleeding associated with adverse obstetrical outcomes, anovulation and contraceptive therapy. This fundamental conundrum in reproductive biology is addressed through our hypothesis that decidualized stromal cells contribute to endometrial hemostasis by increased expression of the potent procoagulant tissue factor (TF) in response to progestational stimulation during the luteal phase, and to menstruation via decreased TF expression in response to the withdrawal of progesterone at the end of the luteal phase. This hypothesis will be tested using stromal cells from cycling endometrium and decidual cells from first trimester pregnant endometrium to examine: l) the effects of progestins and progestin antagonists on the rates of synthesis and degradation of TF m-RNA and protein in stromal cell monolayers, and whether these effects involve mediation of intracrine or autocrine factors; 2) the influence exerted on progestin-regulated TF expression in the stromal cell monolayers by exogenous and endogenous growth factors already implicated in the decidualization reaction in women; 3) the role of cell- extracellular matrix (ECM) interactions in modulating progestin and growth factor regulated TF expression in stromal cells and decidual cells; and 4) the role of cell-cell interactions in modulating progestin, growth factor, and ECM-regulated TF expression in stromal cells and decidual cells in co- cultures of endometrial glandular cells-stromal cells and trophoblastic cells-decidual cells. The experimental results will aid in the dissection of mechanisms regulating TF expression associated with decidualization in vitro. Extrapolation of these results to the in vivo state should elucidate the importance of decidual cell-associated TF in peri- implantational events, and during menstruation. Once the physiological role of decidual cell TF is established new diagnostic and therapeutic approaches to deal with abnormal bleeding during these processes can be expected to follow.
