We are developing a model where we utilize subcutaneous endometrial autografts in rhesus monkeys as a model system for the study of factors regulating breakthrough endometrial bleeding and menstruation. Two experiments were conducted. In experiment 1, we compared the effect of estradiol (E2) treatment alone versus E2 plus progesterone (P) at the time of transplantation on the establishment and histology of endometrial autografts. We found that endometrial graft acceptance was greater when transplantation was done under E2 plus P (88%) than after E only for 5 days (47%). However, when grafts did establish, the well-established grafts menstruated after P withdrawal and the endometrium from the grafts was histologically similar regardless of the hormonal state for transplantation. In experiment 2, we examined the expression of 3 metalloproteinases; MMP-7 (matrilysin), MMP-2 (gelatinase A), MMP3 (stromelysin 1) in endometrial autografts during the luteal-follicular transition period. In this experiment, endometrial autografts were transplanted in monkeys treated with Silastic implants of E2 and P. After three artificial cycles, grafts were collected on days 0,1,2,3,4,5,6 after P withdrawal. As anticipated, the grafts showed evidence of menstruation on days 3, 4 and 5 after P withdrawal. Immunocytochemistry for MMPs revealed specific staining for MMP-2, MMP-3 and MMP-7 in the menstruating grafts. MMP-2 and MMP-3 staining was localized to the menstruating surface of the grafts. MMP-7 staining was localized to glands of the grafts. These patterns of MMP expression are similar to the pattern seen in the endometrium in situ. In summary, we have shown that transplantation of the endometrium under E2 plus P treatment for 7-8 days provides the best conditions for endometrial graft establishment. These grafts respond similarly to the native endometrium in situ when P is withdrawn, and express multiple MMPs. This model provided an excellent situation for further investigating the role of MMPs during menstruation.
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