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Androstenedione Up-Regulation of Endometrial Aromatase Expression via Local Conversion to Estrogen: Potential Relevance to the Pathogenesis of Endometriosis

Department of Obstetrics and Gynecology (O.B., T.T.), Division of Reproductive Endocrinology and Infertility, University of Florida College of Medicine, Gainesville, Florida 32610-0294; Departments of Obstetrics and Gynecology (B.R.C., R.A.W., C.R.M.), Endocrinology and Metabolism (R.J.A.), and Biochemistry (D.B.H., C.R.M.), The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9032

Address all correspondence and requests for reprints to: Orhan Bukulmez, M.D., Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Florida College of Medicine, 1600 SW Archer Road, Gainesville, Florida 32610-0294. E-mail: obukulmez{at}obgyn.ufl.edu.

Context: Up-regulation of aromatase expression in endometrial cells disseminated into the peritoneal cavity may enhance their survival via local estrogen synthesis, which may lead to endometriosis. The factors that mediate induction of aromatase in the endometrium are not well defined, but increased expression of steroidogenic factor (SF)-1 may play a role.

Objective: The objective of the study was to determine whether androstenedione (A4), the predominant sex steroid in peritoneal fluid, regulates endometrial aromatase expression.

Design: This was a cell/tissue culture study.

Setting: The study was conducted at an academic center.

Methods: Quantitative real-time PCR, HPLC, and chromatin immunoprecipitation were used in this study.

Results: Treatment of cultured human endometrial explants and stromal cells with A4 (10 nM) significantly up-regulated expression of aromatase mRNA transcripts containing exon IIa at their 5'-ends. In endometrial stromal cells and the human endometrial surface epithelial (HES) cell line, induction of aromatase mRNA by A4 was associated with increased expression of SF-1. In HES cells, tritiated A4 was metabolized to estradiol, testosterone (T), dihydrotestosterone, and androstanediol. Both estradiol and T, but not nonaromatizable androgens, up-regulated aromatase and SF-1 mRNA in HES cells. Chromatin immunoprecipitation revealed that A4 enhanced recruitment of SF-1 to its response element (–136 bp) upstream of CYP19 exon IIa. This, together with the findings that both estrogen receptor antagonist, ICI 182,780, and aromatase inhibitor, fadrozole, suppressed A4 and T induction of aromatase and SF-1 mRNA, indicates that the inductive effects of A4 and T are mediated by their conversion to estrogens.

Conclusions: Exposure of endometrial cells to A4 may enhance CYP19 gene expression through its aromatization to estrogens.