Peroxisome Proliferator-Activated Receptor Gamma, Coactivator 1α Enhances Local Estrogen Biosynthesis by Stimulating Aromatase Activity in Endometriosis

Context: Endometriosis is an estrogen-dependent disease, and estrogen is overproduced by abnormally elevated aromatase in endometriotic tissues. Peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1 alpha) is a transcriptional coactivator-modulating steroid hormone. Objective: To investigate the effect of PGC-1 alpha on aromatase activity in endometriosis. Design: Specimens from ovarian endometrioma (OE), endometrium with endometriosis (EE), and normal endometrium (NE) were analyzed for PGC-1 alpha and aromatase expression. PGC-1 alpha-dependent changes in aromatase expression in primary cultured stromal cells (SCs) were identified using luciferase and enzymatic assays, exon I-specific RT-PCR, and real-time PCR. Environmental stimulus-induced changes in PGC-1 alpha were also examined. Results: PGC-1 alpha was more highly expressed in OE than in EE and NE (P < .01). In OE, PGC-1 alpha was coexpressed with aromatase, and their mRNA expressions were also correlated (r = 0.56, P = .02). PGC-1 alpha was recruited to the nuclear receptor half-site between PI. 3 and PII in the aromatase promoter. PGC-1 alpha overexpression enhanced aromatase promoter activity (P < .01), mRNA expression (P < .05), and enzymatic activity (P < .01) in SCs from OE, but not in SCs from EE or NE. The levels of PI. 3, PII, and exon II mRNA increased and transcriptional enhancement was abolished by mutation of the PGC-1 alpha -interacting site. PGC-1 alpha expression was enhanced in SCs from OE by tumor necrosis factor (TNF)-alpha (P < .05) but not by hypoxia or 17 beta-estradiol. Conclusions: PGC-1 alpha stimulated by TNF-alpha regulates aromatase expression and activity to promote local estrogen biosynthesis in OE, suggesting that PGC-1 alpha is a promising candidate for novel targeted therapies in endometriosis treatment.