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Departments of Obstetrics-Gynecology (K.Z., K.T., N.M., S.A., A.J., L.M., M.P., B.C., S.E.B.) and Biochemistry (N.M., S.A.), University of Texas Southwestern Medical Center, Dallas, Texas 75235; and the Department of Pathology, Tohoku University School of Medicine (T.S.), Sendai, Japan
Address all correspondence and requests for reprints to: Serdar E. Bulun, M.D., Department of Obstetrics-Gynecology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235-9051. E-mail: bulun{at}grnctr.swmed.edu
Aberrant aromatase expression in stromal cells of endometriosis gives rise to conversion of circulating androstenedione to estrone in this tissue, whereas aromatase expression is absent in the eutopic endometrium. In this study, we initially demonstrated by Northern blotting transcripts of the reductive 17ß-hydroxysteroid dehydrogenase (17ßHSD) type 1, which catalyzes the conversion of estrone to 17ß-estradiol, in both eutopic endometrium and endometriosis. Thus, it follows that the product of the aromatase reaction, namely estrone, that is weakly estrogenic can be converted to the potent estrogen, 17ß-estradiol, in endometriotic tissues.
It was previously demonstrated that progesterone stimulates the inactivation of 17ß-estradiol through conversion to estrone in eutopic endometrial epithelial cells. Subsequently, 17ßHSD type 2 was shown to catalyze this reaction, and its transcripts were detected in the epithelial cell component of the eutopic endometrium in secretory phase. Because 17ß-estradiol plays a critical role in the development and growth of endometriosis, we studied 17ßHSD-2 expression in endometriotic tissues and eutopic endometrium. We demonstrated, by Northern blotting, 17ßHSD-2 messenger ribonucleic acid (RNA) in all RNA samples of secretory eutopic endometrium (n = 12) but not in secretory samples of endometriotic lesions (n = 10), including paired samples of endometrium and endometriosis obtained simultaneously from eight patients. This messenger RNA was not detectable in any samples of proliferative eutopic endometrium or endometriosis (n = 4) as expected. Next, we confirmed these findings by demonstration of immunoreactive 17ßHSD-2 in epithelial cells of secretory eutopic endometrium in 11 of 13 samples employing a monoclonal antibody against 17ßHSD-2, whereas 17ßHSD-2 was absent in paired secretory endometriotic tissues (n = 4). Proliferative eutopic endometrial (n = 8) and endometriotic (n = 4) tissues were both negative for immunoreactive 17ßHSD-2, except for barely detectable levels in 1 eutopic endometrial sample. Finally, we sought to determine whether deficient 17ßHSD-2 expression in endometriotic tissues is due to impaired progesterone action in endometriosis. We determined by immunohistochemistry the expression of progesterone and estrogen receptors in these paired samples of secretory (n = 4) and proliferative (n = 4) eutopic endometrium and endometriosis, and no differences could be demonstrated. In conclusion, inactivation of 17ß-estradiol is impaired in endometriotic tissues due to deficient expression of 17ßHSD-2, which is normally expressed in eutopic endometrium in response to progesterone. The lack of 17ßHSD-2 expression in endometriosis is not due to alterations in the levels of immunoreactive progesterone or estrogen receptors in this tissue and may be related to an inhibitory aberration in the signaling pathway that regulates 17ßHSD-2 expression.
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