Role of estrogen receptor-β in endometriosis

Abstract

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.

Figure 1

Estradiol production in endometriosis. Aromatase is encoded by a single gene and represents the rate-limiting step for estradiol biosynthesis. In a premenopausal woman with endometriosis, estradiol arises from three major tissue sites that express aromatase. (1) Aromatase is expressed under the influence of follicle-stimulating hormone and accounts for fluctuating serum estradiol levels. (2) Aromatase is also present in peripheral tissues such as the adipose tissue and is responsible for relatively small but clinically significant quantities of circulating estradiol levels. (3) Estradiol is produced locally in endometriosis per se via the presence of aromatase and other steroidogenic enzymes in this pathological tissue.

Figure 2

Nuclear receptor expression in endometriosis. A subfamily of nuclear receptors may act as transcription factors in a ligand-independent fashion. Steroidogenic factor (SF)1 belongs to the orphan nuclear receptor subfamily. Members of the steroid receptor subfamily, on the other hand, interact with ligands that activate their transcriptional activity at multiple gene promoters across the human genome. The estrogen receptors (ER)α and ERβ and the progesterone receptor (PR) are activated by their ligands, estradiol and progesterone, respectively. PR-B is the full-length variant of PR. These nuclear receptors are differentially expressed between endometrial and endometriotic tissues. The numbers on columns represent fold expression between the tissues. Endometrial tissues were obtained from five disease-free women; ovarian endometrioma walls were collected from a separate group of five women. Error bars represent standard error of mean. PCR, polymerase chain reaction.

Figure 3

Epigenetic regulation of the estrogen receptor (ER)β gene and its downstream effects in endometriosis. In endometriotic stromal cells, a dense CpG island at ERβ promoter remains in an unmethylated state. This is associated with the presence of a transcriptional enhancer complex, which activates this promoter. In endometrial stromal cells, in contrast, this CpG island is heavily methylated and suppresses ERβ expression. In endometriotic cells, pathologically high ERβ levels suppress ERα and progesterone receptor (PR) (dotted lines) and stimulate cyclo-oxygenase (COX)2 expression (solid line).