Estrogen Receptor Function: Impact on the Human Endometrium

Abstract

The physiological role of estrogen in the female endometrium is well established. On the basis of responses to steroid hormones (progesterone, androgen, and estrogen), the endometrium is considered to have proliferative and secretory phases. Estrogen can act in the endometrium by interacting with estrogen receptors (ERs) to induce mucosal proliferation during the proliferative phase and progesterone receptor (PR) synthesis, which prepare the endometrium for the secretory phase. Mouse knockout studies have shown that ER expression, including ERα, ERβ, and G-protein-coupled estrogen receptor (GPER) in the endometrium is critical for normal menstrual cycles and subsequent pregnancy. Incorrect expression of ERs can produce many diseases that can cause endometriosis, endometrial hyperplasia (EH), and endometrial cancer (EC), which affect numerous women of reproductive age. ERα promotes uterine cell proliferation and is strongly associated with an increased risk of EC, while ERβ has the opposite effects on ERα function. GPER is highly expressed in abnormal EH, but its expression in EC patients is paradoxical. Effective treatments for endometrium-related diseases depend on understanding the physiological function of ERs; however, much less is known about the signaling pathways through which ERs functions in the normal endometrium or in endometrial diseases. Given the important roles of ERs in the endometrium, we reviewed the published literature to elaborate the regulatory role of estrogen and its nuclear and membrane-associated receptors in maintaining the function of endometrium and to provide references for protecting female reproduction. Additionally, the role of drugs such as tamoxifen, raloxifene, fulvestrant and G-15 in the endometrium are also described. Future studies should focus on evaluating new therapeutic strategies that precisely target specific ERs and their related growth factor signaling pathways.

Keywords: G-protein-coupled estrogen receptor; endometrium; estrogen receptor α; estrogen receptor β; human.

Graphical Abstract

Figure 1

Estrogen receptor-mediated signaling pathways in the endometrial. E2 promotes endometrial growth, while progesterone and other progesterone hormones block endometrial growth and promote differentiation. E2 mediates its biological response by binding to ERs via genomic and non-genomic pathways. There are 3 main mechanisms of genomic regulation. Firstly, in genomic regulation, E2 ligands passively enter the cells by diffusion. ERα and ERβ are located in the cytosol. The binding of E2 to the ER promotes the formation of dimers, enters the nucleus and is directly binding to EREs, or to transcription factors which regulate transcription of its target genes. Secondly, the nonclassical pathway involves binding the E2-bound ER to TFs that are already bound to the DNA. The third mechanism is hormone-independent. The ER can regulate E2 responses by activating the signaling of growth factors via the phosphorylation of different serine (118/167) residues on the receptor. In non-genomic regulation, binding of E2 to ERs and GPR30 at the plasma membrane leads to various nongenomic responses, such as calcium signaling, PKC, and cAMP/PKA pathways. E2, 17β-estradiol; ER, estrogen receptor; GPER, G-protein-coupled estrogen receptor; EGFR, epidermal growth factor receptor; PKA, protein kinase A; SF-1, steroidogenic factor 1; TNFα, tumor necrosis factor α; PR, progesterone receptor; MAPK, mitogen-activated protein kinases; PI3K, phosphoinositide-3-kinase. ERE, estrogen response element.

Figure 2

Molecular pathways regulated by ER in endometrial diseases. E2, estradiol; ER, estrogen receptor; GPER, G-protein-coupled estrogen receptor; SF-1, steroidogenic factor 1; TNFα, tumor necrosis factor α; PR, progesterone receptor; MAPK, mitogen-activated protein kinases; PI3K, phosphoinositide-3-kinase.

Figure 3

Treatments for endometrial diseases. ER, estrogen receptor; GPER, G-protein-coupled estrogen receptor; EGFR, epidermal growth factor receptor; ERE, estrogen response element; MMP, matrix metallopeptidase; LBD, ligand-binding domain; P, phosphorylation.