Endometriosis and nuclear receptors

Abstract

BACKGROUND Endometriosis is recognized as a steroid-dependent disorder; however, the precise roles of nuclear receptors (NRs) in steroid responsiveness and other signaling pathways are not well understood. OBJECTIVE AND RATIONALE Over the past several years, a number of paradigm-shifting breakthroughs have occurred in the area of NRs in endometriosis. We review and clarify new information regarding the mechanisms responsible for: (i) excessive estrogen biosynthesis, (ii) estrogen-dependent inflammation, (iii) defective differentiation due to progesterone resistance and (iv) enhanced survival due to deficient retinoid production and action in endometriosis. We emphasize the roles of the relevant NRs critical for these pathological processes in endometriosis. SEARCH METHODS We conducted a comprehensive search using PubMed for human, animal and cellular studies published until 2018 in the following areas: endometriosis; the steroid and orphan NRs, estrogen receptors alpha (ESR1) and beta (ESR2), progesterone receptor (PGR), steroidogenic factor-1 (NR5A1) and chicken ovalbumin upstream promoter-transcription factor II (NR2F2); and retinoids. OUTCOMES Four distinct abnormalities in the intracavitary endometrium and extra-uterine endometriotic tissue underlie endometriosis progression: dysregulated differentiation of endometrial mesenchymal cells, abnormal epigenetic marks, inflammation activated by excess estrogen and the development of progesterone resistance. Endometriotic stromal cells compose the bulk of the lesions and demonstrate widespread epigenetic abnormalities. Endometriotic stromal cells also display a wide range of abnormal NR expression. The orphan NRs NR5A1 and NR2F2 compete to regulate steroid-synthesizing genes in endometriotic stromal cells; NR5A1 dominance gives rise to excessive estrogen formation. Endometriotic stromal cells show an abnormally low ESR1:ESR2 ratio due to excessive levels of ESR2, which mediates an estrogen-driven inflammatory process and prostaglandin formation. These cells are also deficient in PGR, leading to progesterone resistance and defective retinoid synthesis. The pattern of NR expression, involving low ESR1 and PGR and high ESR2, is reminiscent of uterine leiomyoma stem cells. This led us to speculate that endometriotic stromal cells may display stem cell characteristics found in other uterine tissues. The biologic consequences of these abnormalities in endometriotic tissue include intense inflammation, defective differentiation and enhanced survival. WIDER IMPLICATIONS Steroid- and other NR-related abnormalities exert genome-wide biologic effects via interaction with defective epigenetic programming and enhance inflammation in endometriotic stromal cells. New synthetic ligands, targeting PGR, retinoic acid receptors and ESR2, may offer novel treatment options.

Regulation of Inflammation Pathways and Inflammasome by Sex Steroid Hormones in Endometriosis

“…In the case of estrogen receptors (ER), there is an increase of isotype ER-β (ESR2) expression associated with hypomethylation of its promoter (24), and a significant reduction of ER-α (ESR1) expression by hypermethylation of its promoter and through direct inhibition by ER-β. In contrast, both progesterone receptor isoforms PR-A and PR-B (PRG) show a decreased expression; in particular, PR-B undergoes a drastic downregulation (mRNA and protein levels), which is mainly due to hypermethylation of the PR-B promoter (25), therefore affecting downstream hormone target genes (26).…”

An Analysis of ESR2 and CYP19A1 Gene Expression Levels in Women With Endometriosis

“…While the degree of methylation did not affect the expression changes of ESR2 or PGR genes in endometriosis (15). The latest study of the team of Yilmaz and Bulun demonstrated that endometrial stromal cells, which participate in the inflammatory process, are induced by oestrogen, and play a role in the formation of prostaglandins, revealed an extremely low ratio of ESR1 to ESR2 expression, resulting from an excessive increase in the expression of the latter gene (12). The cells also demonstrated a deficit of PGR protein, which leads to resistance to progesterone and defective retinoid synthesis.…”

“…This study aimed to determine whether there were any correlations between the gene expression of ESR2 and CYP19A1 and the incidence of endometriosis. ESR2 and CYP19A1 genes were selected for the study due to their considerable role in hormonal control, in patients with endometriosis, the development of which is largely determined by steroid hormones (10)(11)(12)(13).…”

Genetic, Epigenetic, and Steroidogenic Modulation Mechanisms in Endometriosis

“…It has been demonstrated that there are several abnormalities in the intracavitary endometrium and ectopic endometriotic tissue underlying endometriosis progression: inflammation activated by excess estrogen biosynthesis, defective differentiation due to progesterone resistance, dysregulated differentiation of endometrial mesenchymal cells, and abnormal epigenetic marks. Among these, hypoxia and inflammation play an important role in the regulation of the steroidogenic pathway in the development of endometriosis [75,76]. In endometriosis, progesterone and estrogen signaling are disrupted, commonly resulting in progesterone resistance and estrogen dominance [74].…”

“…As endometriosis is recognized as a steroid-dependent disorder, numerous researchers have investigated the genes of steroid biosynthesis and signaling [17,47,85]. However, the critical genes that confer this steroidogenic transformation have not been defined to date [74,76]. The physiological and pathologic activities of sex steroids are mediated through the estrogen receptor ESR1/ESR2 genes and the PGR gene.…”