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Differential Expression of Members of the bcl-2 Gene Family in Proliferative and Secretory Human Endometrium: Glandular Epithelial Cell Apoptosis Is Associated with Increased Expression of bax¹

Vincent Center for Reproductive Biology (X.-J.T., K.I.T., D.V.M., J.L.S., J.L.T., K.B.I.) and Division of Reproductive Endocrinology and Infertility (J.L.S., K.B.I.), Department of Obstetrics and Gynecology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02114; and,The Burnham Institute (S.K., J.C.R.), La Jolla, California 92037

Address all correspondence and requests for reprints to: Keith B. Isaacson, M.D., Vincent Memorial Obstetrics and Gynecology Service, WACC II, Massachusetts General Hospital, Boston, Massachusetts 02114.

Glandular epithelial cells of the human endometrium initiate apoptosis in the secretory phase of the cycle. To better understand the regulation of apoptosis in this paradigm of endocrine-regulated cell turnover, we studied the expression of the cell death regulatory genes, bax, bcl-2, and bcl-x, in human proliferative and secretory endometria relative to the absence or presence of apoptosis. As assessed by immunohistochemistry, levels of BAX protein were modest in proliferative endometrium and increased dramatically in the secretory phase when apoptosis was most prevalent. Expression of BAX was predominantly localized to epithelial cells of the functionalis layer of the secretory endometrium. In contrast, BCL-2 immunoreactivity was maximal during the proliferative phase and decreased in the secretory phase. Moreover, BCL-2 was topographically concentrated in the basalis layer. Immunoreactive BCL-X protein was observed mostly in glandular epithelial cells of the human endometrium. Compared with proliferative endometrium, secretory endometrium showed stronger BCL-X staining, especially in the functionalis layer. By Western blotting we confirmed that both proliferative and secretory endometrium expressed the long or antiapoptosis form as well as the short or proapoptosis form of the BCL-X protein. Taken together, our results demonstrate a coordinated pattern of expression of bcl-2 gene family members in human endometrium during the menstrual cycle, with a shift toward greater levels of the proapoptosis protein, BAX, occurring in glandular epithelial cells during the secretory phase of the cycle. Therefore, we conclude that cyclic changes in endometrial growth and regression may be precisely regulated by shifts in the ratio or balance of BCL-2 and related proteins in glandular epithelial cells.

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