This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yang, S. Articles by Bulun, S. E. Search for Related Content PubMed PubMed Citation Articles by Yang, S. Articles by Bulun, S. E.

Stromal PRs Mediate Induction of 17ß-Hydroxysteroid Dehydrogenase Type 2 Expression in Human Endometrial Epithelium: A Paracrine Mechanism for Inactivation Of E2

Division of Reproductive Endocrinology, University of Illinois at Chicago, Chicago, Illinois 60612

Address all correspondence and requests for reprints to: Serdar E. Bulun, M.D., University of Illinois at Chicago Medical Center, 820 South Wood Street, M/C 808, Chicago, Illinois 60612. E-mail: bulun{at}uic.edu

Progesterone stimulates the expression of 17ß-hydroxysteroid dehydrogenase (HSD) type 2, which catalyzes the conversion of the potent estrogen, E2, to an inactive form, estrone, in epithelial cells of human endometrial tissue. Various effects of progesterone on uterine epithelium have recently been shown to be mediated by stromal PRs in mice. We describe herein a critical paracrine mechanism whereby progesterone induction of 17ß-HSD type 2 enzyme activity, transcript levels, and promoter activity in human endometrial epithelial cells are mediated primarily by PR in endometrial stromal cells. Medium conditioned with progestin-pretreated human endometrial stromal cells robustly increased 17ß-HSD type 2 enzyme activity (2-fold) and mRNA levels (13.2-fold) in Ishikawa malignant endometrial epithelial cells. In contrast, direct progestin treatment of Ishikawa epithelial cells gave rise to much smaller increases in enzyme activity (1.2-fold) and mRNA levels (4-fold). These results suggest that progesterone- dependent paracrine factors arising from stromal cells are primarily responsible for the induction of epithelial 17ß-HSD type 2 expression in the endometrium. We transfected serial deletion mutants of the -1,244 bp 5'-flanking region of the 17ß-HSD type 2 gene into Ishikawa cells. No progesterone response elements could be identified upstream of the 17ß-HSD type 2 promoter. Stromal PR-dependent induction of the 17ß-HSD type 2 promoter was mediated by a critical regulatory region mapped to the -200/-100 bp sequence. Direct treatment of Ishikawa cells with progestin gave rise to a maximal increase in the activity of -200 bp/Luciferase construct only by 1.2-fold, whereas medium conditioned by progestin-pretreated endometrial stromal cells increased promoter activity up to 2.4-fold in a time- and concentration-dependent manner. The stimulatory effect of medium conditioned by progestin-pretreated stromal cells was enhanced strikingly by increasing stromal cell PR levels with the addition of estrogen. This epithelial-stromal interaction was specific for endometrial epithelial cells, since 17ß-HSD type 2 could not be induced in malignant breast epithelial cells by media conditioned with progestin-treated breast or endometrial stromal cells. In conclusion, progesterone regulates the conversion of biologically active E2 to estrone by inducing the 17ß-HSD type 2 enzyme in human endometrial epithelium primarily via PR in stromal cells, which secrete factors that induce transcription mediated primarily by the -200/-100 bp 5'-regulatory region of the 17ß-HSD type 2 promoter.

This article has been cited by other articles:

				A. Jansson, L. Delander, C. Gunnarsson, T. Fornander, L. Skoog, B. Nordenskjold, and O. Stal Ratio of 17HSD1 to 17HSD2 Protein Expression Predicts the Outcome of Tamoxifen Treatment in Postmenopausal Breast Cancer Patients Clin. Cancer Res., May 15, 2009; 15(10): 3610 - 3616. [Abstract] [Full Text] [PDF]

				S. E. Bulun Endometriosis N. Engl. J. Med., January 15, 2009; 360(3): 268 - 279. [Full Text] [PDF]

				S. A. Salama, M. W. Kamel, C. R. Diaz-Arrastia, X. Xu, T. D. Veenstra, S. Salih, S. K. Botting, and R. Kumar Effect of Tumor Necrosis Factor-{alpha} on Estrogen Metabolism and Endometrial Cells: Potential Physiological and Pathological Relevance J. Clin. Endocrinol. Metab., January 1, 2009; 94(1): 285 - 293. [Abstract] [Full Text] [PDF]

				Y.-H. Cheng, P. Yin, Q. Xue, B. Yilmaz, M. I. Dawson, and S. E. Bulun Retinoic Acid (RA) Regulates 17{beta}-Hydroxysteroid Dehydrogenase Type 2 Expression in Endometrium: Interaction of RA Receptors with Specificity Protein (SP) 1/SP3 for Estradiol Metabolism J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 1915 - 1923. [Abstract] [Full Text] [PDF]

				H. Dassen, C. Punyadeera, R. Kamps, B. Delvoux, A. Van Langendonckt, J. Donnez, B. Husen, H. Thole, G. Dunselman, and P. Groothuis Estrogen metabolizing enzymes in endometrium and endometriosis Hum. Reprod., December 1, 2007; 22(12): 3148 - 3158. [Abstract] [Full Text] [PDF]

				E. J Su, Y.-H. Cheng, R. T Chatterton, Z.-H. Lin, P. Yin, S. Reierstad, J. Innes, and S. E Bulun Regulation of 17-Beta Hydroxysteroid Dehydrogenase Type 2 in Human Placental Endothelial Cells Biol Reprod, September 1, 2007; 77(3): 517 - 525. [Abstract] [Full Text] [PDF]

				Y.-H. Cheng, A. Imir, T. Suzuki, V. Fenkci, B. Yilmaz, H. Sasano, and S. E. Bulun SP1 and SP3 Mediate Progesterone-Dependent Induction of the 17beta Hydroxysteroid Dehydrogenase Type 2 Gene in Human Endometrium Biol Reprod, October 1, 2006; 75(4): 605 - 614. [Abstract] [Full Text] [PDF]

				S. Talbi, A. E. Hamilton, K. C. Vo, S. Tulac, M. T. Overgaard, C. Dosiou, N. Le Shay, C. N. Nezhat, R. Kempson, B. A. Lessey, et al. Molecular Phenotyping of Human Endometrium Distinguishes Menstrual Cycle Phases and Underlying Biological Processes in Normo-Ovulatory Women Endocrinology, March 1, 2006; 147(3): 1097 - 1121. [Abstract] [Full Text] [PDF]

				J. A. Rivera, S. Christopoulos, D. Small, and M. Trifiro Hormonal Manipulation of Benign Metastasizing Leiomyomas: Report of Two Cases and Review of the Literature J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3183 - 3188. [Abstract] [Full Text] [PDF]