Isoflavone Research Initiative

Skip to content

Information

Subscribe to Isoflavone News

Physiological functions of estrogen receptors

Friday, 25 September 2009 07:59

The female sexual hormone estrogen primarily triggers its hormonal effects through the binding to and the transactivation of the estrogen receptor. Estrogen is responsible for the proliferation of breast and uterus tissue during the female cycle and pregnancy. Up to the year 1996, only one, the “classical” estrogen receptor was known: the receptor subtype which today is called estrogen receptor alpha (ER-α). The working group of Gustafsson from the Swedish Karolinska institute was the first to describe a second class of estrogen receptors with distinctly different functions: the estrogen receptor beta (ER-β) (Kuiper et al. 1996). The hormone estradiol activates both ER-α and ER-β with approximately the same selectivity. Whereas the activation of ER-α is related to proliferation-enhancing effects, binding of estrogens to ER-β activates a protective system which in a complex manner is the counter-player of ER-α (Matthews and Gustafsson 2003). ER-β triggers protective effects against excessive hormonal reactions. Among other effects, the activation of ER-β leads to

- The normalisation of cell proliferation at the breast, the uterus and (in men) the prostate;
- A reduction of hot flushes;
- Health benefits for the cardiovascular system, and
- An improvement of bone mineral turnover (Handa et al. 2008; Harris 2007; Heldring et al. 2007).

ER-β is found (among other organs) in breast, uterus, ovaries, bone tissue and the brain. Its discovery was said to have caused a change of paradigms in biology (Koehler et al. 2005). The newly found receptor was immediately a matter of vivid interest, as with this receptor various discrepancies in observations of estrogen effects could finally be explained (Kuiper and Gustafsson 1997; McCarty 2006). Research interest in ER-β is reflected in a still rapidly increasing number of publications on functions of the receptor and its relationship with ER-α. Special attention was given to the promising implications for the development of potential anti-cancer drugs with an ER-β activating efficacy.

Isoflavones serve as model-substances, as they represent one of the first known classes of natural compounds displaying ER-β selectivity (Barkhem et al. 1998; Choi et al. 2008; Harris et al. 2005; Harris 2007; Heldring et al. 2007; Kuiper et al. 1998). Again, this selectivity of isoflavones at the ER-β allowed to explain why isoflavones to a certain degree share the advantages of estrogen effects (e.g., in alleviating menopausal complaints), but do obviously not share the disadvantages. The former are caused by an activation of ER-β through estrogens and isoflavones, the latter essentially by the binding of estrogens to ER-α.

Adiol as an alternative natural binding partner to ER-β

Estradiol is not the only physiological binding partner of ER-β. Newly emerging and not yet fully understood science points to a complex pattern of activation and modulation of estrogenic effects not only by the estrogens themselves (e.g., estradiol or estrone), but also by metabolites of androgens (male sexual hormones) such as 5α-androstane-3β,17β-diol (also called 3β-adiol), which no longer have androgenic effects (Pettersson et al. 2008).

3β-Adiol is produced by the female organism even before the first appearance of noteworthy quantities of estrogens in puberty. In the fertile years the blood levels of 3β-adiol parallel those of estrogen (Mishra et al. 2006; Remer et al. 2005). This parallel development may contribute to the understanding why despite of proliferation-enhancing effects of estrogens the regular occurrence of very high levels of estrogen during puberty, the menstrual cycle and pregnancy does not lead to an increased incidence of cancer.

In menopause the levels of both hormones, estrogen and 3β-adiol, are reduced (Labrie et al. 1997; Wright et al. 1978). Consequently the occurrence of menopausal complaints does not only correlate with reduced estrogen levels, but also with reduced levels of 3β-adiol (Barbaccia et al. 2000) – and therefore with a diminished activation of ER-α.

ER-β and menopausal hot flushes

The interaction between estrogen and 3β-adiol, respectively the receptors ER-α and ER-β, allows explaining certain discrepancies regarding menopausal hot flushes. Hot flushes can be treated with estrogen, but obese women – who have higher estrogen levels than normal-weight women due to the endogenous estrogen production in the fat tissue – still suffer more from menopausal complaints than lean women (Thurston et al. 2007). Typical menopausal symptoms such as hot flushes and depressed mood are related to the HPA-system („Hypophyseal-Pituitary-Adrenocortical axis”), and thus to the system of stress hormones (Butareva et al. 1989; Thomson and Craighead 2007). As demonstrated in a recent publication, the HPA system is regulated through ER-β (Handa et al. 2008). Although the physiological binding partner is not estrogen, but 3β-adiol, the authors could demonstrate that sufficiently high doses of estradiol – as present upon supplementation in postmenopause – accumulate in the HPA tissue, and lead to the same type of activation of ER-β as would be expected from 3β-adiol (Handa et al. 2008). This effect on the HPA system leads to a reduction of hot flushes, but requires blood levels of estradiol which can only be reached after supplementation in postmenopausal women, but not with the naturally increased blood levels of obese women.

Isoflavones, which most likely act through the same mechanism of action – activation of ER-β in the HPA-system – are therefore not phyto-„estrogens“, but rather phyto-„adiols". This differentiation is important, as it has immediate consequences for debates related to safety of application. Under physiological conditions ER-β-mediated effects of isoflavones do not involve induction of proliferation of estrogen-sensitive tissues via activation of ER-α. Such effects (e.g., the direct stimulation of proliferation of MCF-7 breast cancer cells) are exclusively observed with isoflavones under non-physiological and highly artificial conditions, and with doses by far exceeding the levels which can be found in the human organism (Klein and King 2007).