It has recently been demonstrated that the biologic activity of an estrogen is not proportional to its ER binding affinity. Furthermore, some estrogens function as antagonists in some tissues and as agonists in others. For example, tamoxifen, which is an antiestrogen or pure antagonist in breast tissue used to treat breast cancer, acts as an estrogen agonist in bone. The newest SERM, raloxifene, functions similarly to tamoxifen in the bone, breast, and cardiovascular system, but exhibits minimal agonist activity in the uterus. Several mechanisms have been proposed to explain these findings, but the two key events that control the tissue selectivity of an estrogen are the receptor shape and the interaction with adaptor proteins.
Different ligands can induce variable receptor conformations that determine biologic activity.
For example, a pure agonist such as estrogen binds to a receptor creating an active configuration, whereas a pure antagonist renders the receptor inactive. Figure 1 illustrates this concept by showing that different ligands bind to receptors and force them into different shapes and therefore distinct biologic activities. A number of compounds have been identified that induce conformational changes intermediate between those induced by agonists or antagonists. At least 3 distinct classes of antiestrogens have been identified. Different compounds induce different structural alterations within the estrogen receptor.