The broad objectives of this project are to define the roles of matrix metalloproteinases (MMPs) in normal menstruation, to establish whether they are also involved in the abnormal uterine bleeding associated with the use of steroid contraceptives and to examine the similarities and differences in regulation of enzyme production and activation associated with progesterone and its synthetic analogues. Although we have already established that expression of MMPs in the endometrium is temporally related to the process of menstruation, and that MMPs and their tissue inhibitors (TIMPs) are produced at sites of normal menstrual bleeding, their role in the uterine bleeding associated with administration of exogenous steroids is at this time completely unknown. The hypothesis to be tested is that the production and activation of MMPs and TIMPs are associated both spatially and temporally with the abnormal uterine bleeding that occurs with administration of steroid hormones, and that these differ from their production and activation during normal menstruation. The following specific aims will be pursued. A. To determine, at sites of abnormal uterine bleeding associated with steroid hormones: 1. whether MMPs/TIMPs are produced and to define their identities. 2. the cellular origin of MMPs/TIMPs. 3. whether the abnormal bleeding is characterized by breakdown of interstitial matrix or only of basement membranes underlying blood vessels and whether this breakdown is associated with MMP production. 4. which migratory cell types are present and activated in the vicinity of the bleeding sites and which potential activators of MMPs are produced by these. B. To compare 1-4 with data on MMPs/TIMPs at normal menstrual bleeding sites. C. To establish the mechanisms by which progesterone and its synthetic analogues can modify activation and transcription of the MMP/TIMP genes and activation of the MMPs. Using immunohistochemistry and in situ hybridization, we will examine tissues from normally menstruating women and from those with abnormal uterine bleeding associated with Norplant, contraceptive mini-pills, depot Provera and peri- or post-menopausal hormone replacement therapy. Cultures of purified endometrial cell types will be used to examine the regulation of MMPs and TIMPs. These studies will define the relative importance of MMPs and TIMPs in dysfunctional uterine bleeding compared with normal menstruation, and will determine the means by which their expression is controlled and their activation regulated. Overall, they will lead to a better understanding of the causes of endometrial bleeding induced by exogenous hormones and with time, lead to effective therapies.
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