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Molecular biology and physiology of estrogen action

Sylvia Curtis Hewitt, MS
Kenneth S Korach, PhD
Section Editors
Peter J Snyder, MD
William F Crowley, Jr, MD
Deputy Editor
Kathryn A Martin, MD


Estrogens act most importantly on the reproductive organs, but they also act on other organ systems such as cardiovascular, skeletal, immune, gastrointestinal, and neural sites [1-4]. Examples of the sites of responses to estrogen and the clinical consequences for the activity of estrogen in both females and males are summarized in the figure (figure 1). Their major actions are genomic, mediated by nuclear estrogen receptors (ERs), but they also have non-genomic actions.

The molecular mechanisms of estrogen action will be reviewed here; the physiological actions of estrogens and estrogen analogues (selective estrogen receptor modulators [SERMs]) are discussed separately. (See "Physiology of the normal menstrual cycle" and "Mechanisms of action of selective estrogen receptor modulators and down-regulators" and "Estrogen and cognitive function".)


The genomic actions of estrogens are mediated via estrogen receptors (ERs), which are proteins that bind estrogens with high affinity and specificity. These receptors are members of a family of nuclear hormone receptors that include receptors that bind other steroids, thyroid hormone, and retinoids, and receptors such as peroxisome proliferator-activated receptor (PPAR), farnesoid X receptor (FXR), and liver X receptor (LXR) that mediate metabolic processes [5], as well as many “orphan” receptors for which no ligands have been identified. All these receptors function as ligand-modulated nuclear transcription factors [6-9].

Two ER molecules have been identified: the original ER-alpha, and the ER-beta [10,11]. Their structures are similar to those of the other members of this family of receptors [12,13]. The key components are the C or DNA-binding domain, which binds with high affinity and specificity to DNA sequences (estrogen response elements [EREs]) to regulate transcription rates of target genes, and the E or ligand-binding domain, which binds estrogens and estrogen analogues. (See "Mechanisms of action of selective estrogen receptor modulators and down-regulators".)

The consensus ERE is a 13-base-pair inverted-repeat DNA sequence (GGTCAnnnTGACC), to which dimers of ER complexes bind with high affinity and specificity [14,15], with one receptor molecule in contact with each five-base-pair segment of the response element [16]. Dimerization of ER complexes is facilitated by receptor binding to a response element. Additional sequences located in the ligand-binding domain of the receptor also are involved in dimerization [11,14], as demonstrated by the formation of homodimers by truncated receptors containing only a ligand-binding domain [17].


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