Activated glucocorticoid and eicosanoid pathways in endometriosis
2012
Monsivais, Diana | Bray, Jeffrey D. | Su, Emily | Pavone, Mary Ellen | Dyson, Matthew T. | Navarro, Antonia | Kakinuma, Toshiyuki | Bulun, Serdar E.
OBJECTIVE: To define altered gene expression networks in endometriosis. DESIGN: Experiments using endometriotic tissues and primary cells. SETTING: Division of Reproductive Biology Research, Northwestern University. PATIENT(S): Premenopausal women. INTERVENTION(S): Matched samples of eutopic endometrium and ovarian endometriosis (n = 8 patients) were analyzed by microarray and verified in a separate set of tissues (n = 6 patients). Experiments to define signaling pathways were performed in primary endometriotic stromal cells (n = 12 patients). MAIN OUTCOMES MEASURE(S): Using a genome-wide in vivo approach, we identified 1,366 differentially expressed genes and a new gene network favoring increased glucocorticoid levels and action in endometriosis. RESULT(S): Transcript and protein levels of 11β-hydroxysteroid dehydrogenase (HSD11B1), which produces cortisol, the biologically active glucocorticoid, were strikingly higher, whereas messenger RNA (mRNA) levels of the cortisol-degrading HSD11B2 enzyme were significantly lower in endometriotic tissue. Glucocorticoid receptor mRNA and protein levels were significantly higher in endometriosis. The inflammatory cytokine tumor necrosis factor robustly induced mRNA and protein levels of HSD11B1 and glucocorticoid receptor but suppressed HSD11B2 mRNA in primary endometriotic stromal cells, suggesting that tumor necrosis factor stimulates cortisol production and action. We also uncovered a subset of genes critical for prostaglandin synthesis and degradation, which favor high eicosanoid levels and activity in endometriosis. CONCLUSION(S): The proinflammatory milieu of the endometriotic lesion stimulates cortisol synthesis and action in endometriotic lesions.
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