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Endometriosis is an estrogen-dependent disease. The biologically active estrogen, estradiol, aggravates the pathological processes (e.g., inflammation and growth) and the symptoms (e.g., pain) associated with endometriosis. Abundant quantities of estradiol are available for endometriotic tissue via several mechanisms including local aromatase expression. The question remains, then, what mediates estradiol action. Because estrogen receptor (ER)β levels in endometriosis are >100 times higher than those in endometrial tissue, this review focuses on this nuclear receptor. Deficient methylation of the ERβ promoter results in pathological overexpression of ERβ in endometriotic stromal cells. High levels of ERβ suppress ERα expression. A severely high ERβ-to-ERα ratio in endometriotic stromal cells is associated with suppressed progesterone receptor and increased cyclo-oxygenase-2 levels contributing to progesterone resistance and inflammation. ERβ-selective estradiol antagonists may serve as novel therapeutics of endometriosis in the future.

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Loss of progesterone signaling in the endometrium may be a causal factor in the development of endometriosis, and progesterone resistance is commonly observed in women with this disease. In endometriotic stromal cells, the levels of progesterone receptor (PR), particularly the PR-B isoform, are significantly decreased, leading to a loss of paracrine signaling. PR deficiency likely underlies the development of progesterone resistance in women with endometriosis who no longer respond to progestin therapy. Here we review the complex epigenetic and transcriptional mechanisms leading to PR deficiency. The initial event may involve deficient methylation of the estrogen receptor (ER)β promoter resulting in pathologic overexpression of ERβ in endometriotic stromal cells. We speculate that alterations in the relative levels of ERβ and ERα in endometrial tissue dictate E2-regulated PR expression, such that a decreased ERα--ERβ ratio may result in suppression of PR. In this review, we propose a molecular model that may be responsible for changes in ERβ and ERα leading to PR loss and progesterone resistance in endometriosis.