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Prostaglandin E₂ Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis

Division of Reproductive Biology Research (E.A., H.T., G.I., M.B.Y., S.E.B.), Department of Obstetrics and Gynecology, Feinberg School of Medicine at Northwestern University, Chicago, Illinois 60611; Department of Obstetrics and Gynecology (E.A.), Istanbul University Capa School of Medicine, Istanbul, Turkey; Department of Obstetrics and Gynecology (H.T., N.Y.), Tohoku University, Sendai, Japan 980-8575; Department of Obstetrics and Gynecology (G.I.), Cumhuriyet University School of Medicine, Sivas, Turkey; Department of Obstetrics and Gynecology (D.R.), St. Charles Medical Center, Bend, Oregon 97701; Department of Obstetrics and Gynecology (M.P.), Baylor University Hospital, Dallas, Texas 75246; Department of Obstetrics and Gynecology (B.G.), Firat University School of Medicine, Elazig, Turkey; Department of Obstetrics and Gynecology (R.A.), Yeditepe University Hospital, Kozyatagi, Istanbul, Turkey; and Department of Molecular Physiology and Biophysics (D.B.H.), University of Illinois at Chicago, Chicago, Illinois 60612

Address all correspondence and requests for reprints to: Serdar E. Bulun, M.D., Professor and Chief, Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, 303 East Superior Street, 4-123, Chicago, Illinois 60611. E-mail: s-bulun{at}northwestern.edu.

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, 3β-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 E₂ (PGE₂) 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 PGE₂-stimulated estrogen production in endometriotic cells and endometrium.

Results: Compared with normal endometrial tissues, mRNA levels of StAR, side chain cleavage P450, 3β-hydroxysteroid-dehydrogenase-2, 17-hydroxylase/17-20-lyase, aromatase, and SF1 were significantly higher in endometriotic tissues. PGE₂ 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. PGE₂ 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 PGE₂ via enhanced binding of SF1 to promoters of StAR and aromatase genes in a synchronous fashion.

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