Outdated Model of Estrogen Action

This now outdated model of estrogen action produced a number of ideas that are incorrect. For example, there are a number of estrogen compounds, and each compound's biological activity was thought to be directly proportional to its binding affinity. This would mean that all estrogens are functionally the same. In fact, further research has proved these tenets to be wrong.(26,27)

It has been discovered that the old model of estrogen action does not take into account the variation in action that can result from newly discovered postreceptor binding events.

For example, a closer look at conjugated equine estrogen (CEE) in Table 4 shows that binding affinity is not the primary predictor of biological activity.(6) CEE, which is a common agent used for HRT, is a complex blend of several active estrogenic compounds. Ten of its commonly characterized components are listed in Table 4, and comparing their affinity and biological activity produced some surprising results. delta-8, 9-dehydroestrone, which has only 1% the binding affinity of estradiol, exhibited very high biological activity in this assay.

Table 4

What also complicates the picture of how estrogen works is that researchers have learned that estrogens can function as either antagonists (blockers) or agonists (stimulators) at the estrogen receptor. Furthermore, they do not act uniformly in all tissues.

There is some clinical evidence of this variable activity as well. Tamoxifen, which is an antiestrogen or pure antagonist in breast tissue and is used to treat breast cancer, acts as an estrogen agonist in the bone.(28,29) Thus, tamoxifen has been termed the first selective estrogen receptor modulator (SERM). It shows tissue selectivity. Another SERM, raloxifene, functions similarly to tamoxifen in the bone, breast, and cardiovascular system, but exhibits minimal agonist activity in the uterus.(30,31) The implication is that the classification of estrogen agonists or antagonists is complex and tissue-dependent.