Hideki Tokunaga, Gonca Imir, Erkut Attar, David Redwine, Dale B. Hales, Rukset Attar, Bilgin Gurates, Nobuo Yaegashi, M. Bertan Yilmaz, Serdar E. Bulun, Michael Putman, [Attar, Erkut -- Tokunaga, Hideki -- Imir, Gonca -- Yilmaz, M. Bertan -- Bulun, Serdar E.] Northwestern Univ, Feinberg Sch Med, Dept Obstet & Gynecol, Div Reprod Biol Res, Chicago, IL 60611 USA -- [Attar, Erkut] Istanbul Univ, Capa Sch Med, Dept Obstet & Gynecol, Istanbul, Turkey -- [Tokunaga, Hideki -- Yaegashi, Nobuo] Tohoku Univ, Dept Obstet & Gynecol, Sendai, Miyagi 9808575, Japan -- [Redwine, David] Cumhuriyet Univ, Sch Med, Dept Obstet & Gynecol, Sivas, Turkey -- [Redwine, David] St Charles Hosp, Dept Obstet & Gynecol, Bend, OR 97701 USA -- [Putman, Michael] Baylor Univ Hosp, Dept Obstet & Gynecol, Dallas, TX 75246 USA -- [Gurates, Bilgin] Firat Univ, Dept Obstet & Gynecol, Sch Med, TR-23169 Elazig, Turkey -- [Attar, Rukset] Yeditepe Univ Hosp, Dept Obstet & Gynecol, Istanbul, Turkey -- [Hales, Dale B.] Univ Illinois, Dept Mol Physiol & Biophys, Chicago, IL 60612 USA, and yilmaz, bertan -- 0000-0001-5558-3299
WOS: 000263072700045, PubMed ID: 19001523, Context: Products of at least five specific steroidogenic genes, including steroidogenic acute regulatory protein (StAR), which facilitates the entry of cytosolic cholesterol into the mitochondrion, side chain cleavage P450 enzyme, 3 beta-hydroxysteroid-dehydrogenase-2, 17-hydroxylase/17-20-lyase, and aromatase, which catalyzes the final step, are necessary for the conversion of cholesterol to estrogen. Expression and biological activity of StAR and aromatase were previously demonstrated in endometriosis but not in normal endometrium. Prostaglandin E-2 (PGE(2)) induces aromatase expression via the transcriptional factor steroidogenic factor-1 (SF1) in endometriosis, which is opposed by chicken-ovalbumin upstream- transcription factor (COUP-TF) and Wilms' tumor-1 (WT1) in endometrium. Objective: The aim of the study was to demonstrate a complete steroidogenic pathway leading to estrogen biosynthesis in endometriotic cells and the transcriptional mechanisms that regulate basal and PGE(2)-stimulated estrogen production in endometriotic cells and endometrium. Results: Compared with normal endometrial tissues, mRNA levels of StAR, side chain cleavage P450, 3 beta-hydroxysteroid- dehydrogenase-2, 17-hydroxylase/17-20-lyase, aromatase, and SF1 were significantly higher in endometriotic tissues. PGE(2) induced the expression of all steroidogenic genes; production of progesterone, estrone, and estradiol; and StAR promoter activity in endometriotic cells. Overexpression of SF1 induced, whereas COUP-TFII or WT1 suppressed, StAR promoter activity. PGE(2) induced coordinate binding of SF1 to StAR and aromatase promoters but decreased COUP-TFII binding in endometriotic cells. COUP-TFII or WT1 binding to both promoters was significantly higher in endometrial compared with endometriotic cells. Conclusion: Endometriotic cells contain the full complement of steroidogenic genes for de novo synthesis of estradiol from cholesterol, which is stimulated by PGE(2) via enhanced binding of SF1 to promoters of StAR and aromatase genes in a synchronous fashion. (J Clin Endocrinol Metab 94: 623-631, 2009), National Institutes of Health [HD38691, HD40093]; Friends of Prentice, This work was supported by grants from the National Institutes of Health (HD38691 and HD40093) and Friends of Prentice.