Estrogen Receptors and Endometriosis

Abstract

Endometriosis is a frequent and chronic inflammatory disease with impacts on reproduction, health and quality of life. This disorder is highly estrogen-dependent and the purpose of hormonal treatments is to decrease the endogenous ovarian production of estrogens. High estrogen production is a consistently observed endocrine feature of endometriosis. mRNA and protein levels of estrogen receptors (ER) are different between a normal healthy endometrium and ectopic/eutopic endometrial lesions: endometriotic stromal cells express extraordinarily higher ERβ and significantly lower ERα levels compared with endometrial stromal cells. Aberrant epigenetic regulation such as DNA methylation in endometriotic cells is associated with the pathogenesis and development of endometriosis. Although there is a large body of data regarding ERs in endometriosis, our understanding of the roles of ERα and ERβ in the pathogenesis of endometriosis remains incomplete. The goal of this review is to provide an overview of the links between endometriosis, ERs and the recent advances of treatment strategies based on ERs modulation. We will also attempt to summarize the current understanding of the molecular and cellular mechanisms of action of ERs and how this could pave the way to new therapeutic strategies.

Keywords: endometriosis; estrogen receptors; modulation; treatment strategy.

Figure 1

Schematic lateral view of the pelvis illustrating the 4 forms of endometriosis: 1: endometrioma (OMA); 2: superficial peritoneal endometriosis (SUP); 3: deep subperitoneal infiltrating endometriosis (DIE); 4: adenomyoma (Ad).

Figure 2

Respective roles of estrogen receptor α (ERα) and estrogen receptor β (ERβ) in the normal endometrium and endometriosis lesions. On the normal endometrium (left), 17β-estradiol (E2) coming from the circulation acts mainly on ERα while ERβ and G protein-coupled receptor 30 (GPR30) are less expressed. In contrast, in the endometrial lesions, ERβ expression is upregulated and the expression of ERα is attenuated. Moreover, there is a local accumulation of E2 mainly because the endometriotic lesions have the ability to synthetize E2 de novo from cholesterol, due to a higher expressions of steroidogenic acute regulatory protein (StAR) and CYP19A (aromatase), the two enzymes involved in the process of steroidogenesis.

Figure 3

Molecular pathways of ER regulation in endometriosis lesions. (A). Overexpression of ERβ in the stromal endometriotic cells inhibits the TNFα-mediated apoptosis, acts as a suppressor of ERα, induces interleukin-1, co-stimulates Ras-related estrogen-regulated growth inhibitor (RERG) and serum and glucocorticoid-regulated kinase (SGK1) as key ERβ targets with co-stimulating prostaglandin E2 (PGE2) under the action of estradiol. (B). De novo increase of 17β-Estradiol (E2) in endometriosis lesions affecting the ratio of ERα and ERβ, impacting the inflammation and expression of some target genes such as Greb-1 and c-Myc that results in endometriosis progression [2,27].