Estrogens influence many physiological processes in mammals, including but

not limited to reproduction, cardiovascular health, bone integrity, cognition, and behavior. Given this widespread role for estrogen in human physiology, it is not surprising that estrogen is also implicated in the development or progression of numerous diseases, which include but are not limited to various types of cancer (breast, ovarian, colorectal, prostate, and endometrial), osteoporosis, neuro-degenerative diseases, cardiovascular disease, insulin resistance, lupus erythematosus, endometriosis, and obesity (1). 

    The analysis of knockout mice has provided a framework in which to study the potential functions of ERalpha in human target tissues (2). The 66 kDa ER protein is encoded by 8 exons of a gene which encompasses ,140 kb in length. The ERa gene has been localized to human chromosome 6q24-27.

The estrogen receptor and its ligand estradiol had been thought to be essential for survival, fertility, sexual differentiation and development. The disruption of the mouse ERa gene has generated new and unexpected insights. The lack of ERa does not lead to embryonic lethality nor does its absence affect the processes leading to sex determination. Mice lacking

ERa survive until adulthood but reproductive functions are severely compromised. Both males and

females are infertile.

A mechanistic issue in the field pertains to the “promiscuity” of the estrogen receptor (ER) or why the ER is receptive to a large number of seemingly diverse chemicals (3).  An explanation of this phenomenon requires an understanding of how estradiol binds to its’ receptor and of the chemical similarities that exist between this steroid and nonsteroidal ER ligands (ligand refers to a substance that binds).  The “binding domain” of the ER is oriented in space as a pocket and the estradiol molecule fits into this pocket in a precise fashion. In addition to this fit, attractive forces due to chemical interactions between hormone and receptor contribute to the strength (or affinity) of this binding. Estradiol is comprised of a steroid nucleus with an -OH (or hydroxyl) group at either end, one attached to the A-ring (3-OH) and the other attached to the D-ring (17-OH), the numbers referring to positions on the steroid nucleus. The two hydroxyl groups, as well as the steroid nucleus itself, are important for the binding of estadiol within the binding pocket of the ER. Although not a steroid, DES binds tightly to ER (and is highly estrogenic) because it shares key chemical features with estradiol. DES also contains 2 hydroxyl groups positioned at either end of the molecule.  Most environmental estrogens bind to ER because they exhibit some chemical similarities to estradiol. However, they bind with much less affinity (and, hence, exhibit much less biological activity) because they fit only partially into the receptor due to their chemical differences. Most xenoestrogens posses an unencumbered phenol which interacts with the first point of contact within the binding pocket of ER. Those substances that bind to ER but are not phenolic can either be chemically transformed into phenolic substances within the body (e.g., methoxychlor, tamoxifen, or o.p-DDT) or contain a chemical structure that behave like a phenol (e.g., =O of kepone) (Fig. 1). The relative affinity of binding of xenoestrogens for ER is a function of how well the remaining portion of the molecule can be accommodated by the binding pocket of the ER. A reduced affinity of a ligand for receptor implies that higher concentrations of the substance are required to

activate the receptor, which is consistent with reduced potency of the compound. 

1. Ascenzi P, Bocedi A, Marino M. Structure-function relationship of estrogen receptor alpha and beta: impact on human health. Mol Aspects Med. 2006 Aug;27(4):299-402.

2. B Hanstein, S Djahansouzi, P Dall, M W Beckmann and H G Bender Insights into the molecular biology of the estrogen receptor define novel therapeutic targets for breast cancer. European Journal of Endocrinology (2004) 150 243–255.

3. Witorsch, RJ. Endocrine Disruptors: Can Biological Effects and Environmental

Risks Be Predicted?Regulatory Toxicology and Pharmacology 36, 118–130 (2002)