Estrogen receptor-beta, estrogen receptor-alpha, and progesterone resistance in endometriosis

Abstract

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)beta promoter resulting in pathologic overexpression of ERbeta in endometriotic stromal cells. We speculate that alterations in the relative levels of ERbeta and ERalpha in endometrial tissue dictate E2-regulated PR expression, such that a decreased ERalpha-tauomicron-ERbeta ratio may result in suppression of PR. In this review, we propose a molecular model that may be responsible for changes in ERbeta and ERalpha leading to PR loss and progesterone resistance in endometriosis.

Figure 1

Messenger RNA levels of steroids in primary stromal cells isolated from endometrium and endometriosis (n = 8 patients in each category). Comparable in vivo differences were also observed between whole tissues of endometrium and endometriosis (our unpublished data). ER, estrogen receptor; PR, progesterone receptor; PCR, polymerase chain reaction.

Figure 2

In endometrial stromal cells, a dense CpG island at estrogen receptor (ER)β promoter, which is heavily methylated, suppresses its expression. We speculate that this methylated CpG island is occupied by a repressor complex containing methyl-CpG binding protein-2 (MeCP2) and a corepressor (Co-Repr). In contrast, the same CpG island at ERβ promoter in endometriotic stromal cells is hypomethylated permitting recruitment of an enhancer transcriptional complex including a coactivator (Co-Act).

Figure 3

Chromatin immunoprecipitation (ChIP) polymerase chain reaction characterized estrogen receptor (ER)β or ERα binding to specific ERα promoter regions in stromal cells from ovarian endometriomas. ERα gene structure with selected potential cis-regulatory elements within each promoter region were characterized in the ChIP assay. In the presence or absence of estradiol (E2), ERβ binds via specificity protein 1 (Sp1) and activator protein (AP1) sites in ERα promoter C and the AP1 site in promoter A. In an E2-dependent manner, ERα interacts only with the ERα promoter A via an AP1 site. IgG, immunoglobulin G; PR A, promoter A; PR B, promoter B; PR C, promoter C.

Figure 4

The proposed model for regulation of steroid receptor expression in endometriotic stromal cells. ER, estrogen receptor; PR, progesterone receptor.