Estrogen receptors

Oestrogen receptors, like androgen receptors, are steroid receptors which belong to the superfamily of nuclear receptors NR3I (nuclear receptor subfamily 3, group I) and are mainly activated by the steroid hormone oestrogen. The estrogen receptors (ER) are DNA-binding transcription factors that regulate the gene expression of the target gene. The estrogen receptors are present in 2 isoforms:

• oestrogen receptor α (ERα, NR3A1)
• and
• Oestrogen receptor β (ERβ, NR3A2)

The molecular structure of both receptor subtypes is comparable. Both have six domains (A-F):

• A/B domain: Contains a ligand-independent transcriptional activation function (AF-1)
• C domain: DNA binding domain (DBD). It contains two zinc finger motifs.
• D-domain: dimerization region.
• E/F domain: Contains the ligand binding domain (LBD) and a so-called transactivation region at the C-terminus (AF-2).

Since both subtypes are expressed in many cells simultaneously, hormone-activated receptor dimerization results in the formation of ERα (αα) or ERβ (ββ) homodimers or ERαβ (αβ) heterodimers.

Different ligands can differ in their affinity for the two receptor isoforms:

• Estradiol and coumestrol bind to both receptors (coumestrol is a coumarin derivative formed by some plant species (e.g. alfalfa). S.u. Phyto-SERMs.
• Estron and raloxifene bind preferably to ERα
• Estriol and genistein bind to ERβ
• Selective estrogen receptor modulators (SERMs) bind preferentially to either the α or β subtype of the receptor.

Action: Both receptor subtypes are estrogen dependent nuclear transcription factors. In the inactive state, estrogen receptors are located in the cytoplasm of cells and bind to so-called heat shock proteins. When estradiol binds to the estrogen receptor, a conformational change of the receptor takes place. This leads to the release of the heat-shock protein with subsequent dimerisation of the hormone-receptor complex. This can now migrate into the cell nucleus and bind to so-called "estrogen-responsive elements" of the DNA in the form of the dimer. By recruiting and binding coregulatory proteins, the expression of certain target genes is promoted or inhibited. Furthermore, estradiol can also bind to estrogen receptors on the cell membrane. Cytoplasmic signalling cascades can be activated by the regulation of membrane-bound ion channels (see figure).

The estrogen receptors are expressed differently by different tissues.

• ERα receptors are found in the endothelium of vessels, in the breast, uterus, vagina, pituitary gland and hypothalamus
• ERβ receptors are found in the prostate, lung, bones, vessels, hippocampus and higher centers of the central nervous system.

Besides interactions with DNA or cytoplasmic transcription factors, non-genomic effects play an important role in estriol (interactions with G-protein coupled receptors or ion channels).

Estron and estriol have a significantly lower affinity to ER than estradiol.

The mode of action of the phyto-SERMs (older name: phytoestrogens) has not yet been exactly determined (Morito K et al. 2002). Chemically they are different chemical compounds like coumetanes, isoflavones e.g. genistein and daidzein in soy and red clover, formononetin, lignans in linseed-sesame seeds and sunflower seeds, stilbenes like resveratrol in red wine, and various organic acids. Well-known plants used in gynaecological diseases are:

• Quercus cortex (oak bark)
• Bursae pastoris herba (shepherd's purse)
• Hyperici herba (St John's wort)
• Matricariae flos (chamomile flowers)
• Agni casti fructus (cudgeudge fruit)
• Cimicifugae racemosae rhizoma (Cimicifuga rootstock)
• Trifolii pratensis flores cum summitatibus (red clover flowers with - shoot tips)
• among others (Schilcher H 2015)

1. Björnström L et alk. (2005) Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol Endocrinol 19:833-842.
2. Eyster KM (2016) The Estrogen Receptors: An Overview from Different Perspectives. Methods Mol Biol 1366:1-10.
3. Jia M et al (2015) Estrogen receptor alpha and beta in health and disease. Best Pract Res Clin Endocrinol Metab 29:557-568.
4. Morito K et al (2002): Interaction of phytoestrogens with estrogen receptors alpha and beta (II). In: Biol Pharm Bull 25: 48-52.
5. Pakdel F (2018) Molecular Pathways of Estrogen Receptor Action. Int J Mol Sci 19:2591.

6. Schilcher H (2015) Gynecological Diseases and Obstetrics. In: Guide to Phytotherapy. Urban and Fischer Publishing House Munich, S. 745-795