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OBJECTIVES: To characterize the forms of transforming growth factor-alpha (TGF-alpha) in normal human endometrium, to evaluate the regional and temporal changes in TGF-alpha expression, and to correlate the pattern of TGF-alpha expression with physiologic events in the endometrium. METHODS: Immunohistochemistry and Western blot analyses were performed using two TGF-alpha antisera, one raised against the active extracellular N-terminus and the other recognizing the intracellular carboxy terminus of the protein. Immunohistochemistry was performed on hysterectomy specimens from premenopausal women with normal menstrual cycles. Soluble and membrane-bound endometrial proteins were isolated from fresh tissue for Western blot analysis. RESULTS: Antibodies recognizing the intracellular and extracellular domains of TGF-alpha exhibited identical immunohistochemical staining patterns. Transforming growth factor-alpha localized primarily to endometrial epithelial cells, and the most intense staining was in the luminal surface epithelium. In the surface epithelium, TGF-alpha staining was intense in the proliferative phase, decreased during the early secretory phase, was at its nadir in the midsecretory phase, and rebounded in the late secretory phase. Western blot analysis demonstrated two transmembrane forms. The 28-kD protein contained both intracellular and extracellular antigens, and the 18-kD protein contained only the intracellular antigen. CONCLUSION: Western blot data were consistent with the hypothesis that the extracellular segment of TGF-alpha is cleaved from the transmembrane precursor in vivo, as has been demonstrated in other tissues. Immunohistochemistry demonstrated that the TGF-alpha antigens are concentrated in the luminal surface epithelium and decline and disappear in the early to midsecretory phase. These findings suggest that the most active period of membrane-bound TGF-alpha cleavage corresponds with the interval during which preimplantation embryos are in the uterine cavity.