Review
Estrogen dependent signaling in reproductive tissues – A role for estrogen receptors and estrogen related receptors

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Abstract

Estrogens play a fundamental role in the development and normal physiological function of multiple tissue systems and have been implicated in the ontogeny of cancers. The biological effects of estrogens are classically mediated via interaction with cognate nuclear receptors. The relative expression of ER subtypes/variants varies between cells within different tissues and this alters the response to natural and synthetic ligands. This review focuses on the role of estrogen and estrogen related receptors in reproductive tissues.

Highlights

► Estrogens regulate the reproductive and cardiovascular systems, the skeleton and the brain. ► Estrogen receptor (ERα, β) genes are subject to alternative splicing. ► Ratios of ER subtypes/variants in cells determines the impact of estrogens on tissue function. ► ERα, β, and ERβ variants, have unique patterns of expression in reproductive tissues. ► Estrogen related receptors (α, β, γ) may play a role in regulation of cell metabolism.

Section snippets

Background

Estrogens play a fundamental role in the development and normal physiological function of multiple tissue systems and have been implicated in the ontogeny of cancers. Estrogens are key regulators of fertility in both males and females. The biological effects of estrogens are classically mediated via their interaction with nuclear receptors that are members of a superfamily of ligand-activated transcription factors (http://www.nursa.org/). A recent review (Levin, 2010) has provided a

Structure of estrogen and estrogen-related receptors

ERs and ERRs, like other members of the NR3A family, contain a conserved arrangement of structural and functional domains (A–F) including a conserved DNA-binding domain (DBD, domain C) consisting of two zinc fingers and a C-terminal domain (domain E/F) that contains amino acids involved in ligand binding, receptor dimerisation and nuclear localization (reviewed in Tremblay and Giguere, 2007, Nilsson et al., 2001) (Fig. 1).

The ligand binding domains of ERα and ERβ have both been crystallized and

Estrogen receptor isoforms

Ponglikitmongkol et al. (1988) reported that the human ERα gene is more than 140 kb in length and is split into eight exons. The human ERβ gene also contains 8 exons and there is considerable conservation between the arrangement of the coding exon/intron boundaries between human and mouse (Enmark et al., 1997).

Human ESR1 and ESR2 are both subject to alternative splicing and although they have similar exon and functional domain organization the splice variant isoforms identified appear to be

Molecular signaling pathways/functional interactions

The effects of estrogens can be mediated through several different pathways (reviewed in Nilsson et al., 2001, Hall et al., 2001, Matthews and Gustafsson, 2003). Classically, ligand-activated ERs form homo- or hetero-dimers that interact with response elements (called EREs, estrogen response elements) within the promoter regions of genes (reviewed in Nilsson et al., 2001). Gene transfer and band shift assays were originally used to identify an ERE consensus binding site within the promoter

Estrogen receptor related proteins – functional activation and potential cross-talk with estrogen receptors

Binding site selection experiments have demonstrated that ERR α binds to a response element (ERRE) containing a single consensus half-site, TNAAGGTCA, as either a monomer or a dimer (Sladek et al., 1997). It has been reported that ERs and ERRs have the capacity for transcriptional cross-talk with E-dependent genes such as osteopontin (reviewed in Vanacker et al., 1999). More recently studies using genomic analyses of binding sites have reported that ERRα and ERα display strict binding site

Expression in the normal reproductive tissues and in reproductive cancers

Estrogen receptors are widely expressed in reproductive tissues details are given in the following sections and summarised in Table 2.

Female reproductive system

The estrogen receptor α knockout (ERαKO) mouse has an ovarian phenotype that is characterized by cystic and hemorrhagic follicles as well as anovulation. Couse et al. (1999) showed this phenotype could be reversed by addition of exogenous gonadotropin concluding the ovarian phenotype was due to disruption of the HPA axis. It was noted that ERαKO mice had an inefficient ovulatory capacity that may suggest an intra-ovarian role for ERα (Couse et al., 1999). The ovaries of theca-specific estrogen

Future perspectives

Estrogen receptors play an essential role in the development and normal physiological function of reproductive and other tissues. The relative expression of both full length and variant isoforms of ERs varies between cells within different tissues and this, together with variations in ligand availability adds to the complexity of responses to natural and synthetic ligands. Cancers of reproductive tissues are often hormone responsive and this has prompted the development of therapies based on

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