Context: Upregulation 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: To determine if androstenedione (A4), the predominant sex steroid in peritoneal fluid, regulates endometrial aromatase expression.

Design: Cell/tissue culture study

Setting: Academic

Methods: Quantitative real-time polymerase chain reaction, High performance liquid chromatography, Chromatin immunoprecipitation (ChIP)

Results: Treatment of cultured human endometrial explants and stromal cells with A4 (10 nM) significantly upregulated 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 (E₂), testosterone (T), dihydrotestosterone and androstanediol. Both E₂ and T, but not non-aromatizable androgens, upregulated aromatase and SF-1 mRNA in HES cells. ChIP 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.