A new interpretation of antiestrogen action.

Despite differences in their pharmacological behavior, type I and type II antiestrogens have certain important properties in common. Both differ from estradiol in that they enhance the immunoreactivity of estrogen receptors, apparently by inducing conformational change that exposes an additional epitope for a particular monoclonal antibody. Moreover, both types of antihormones not only compete with estradiol for its binding to the receptor but they also react with another domain not recognized by the hormone. The binding capacity for either type of antiestrogen is nearly twice that for estradiol, providing definitive evidence for the existence of specific antiestrogen-binding sites that are postulated to be important in antagonist action. These findings suggest a unified two-site model which helps explain how the same substance can be both an agonist and an antagonist; why there may be species variations in the agonist/antagonist relationship of type I compounds; and why type II agents show only antagonistic properties. It is suggested that interaction with secondary, antagonist-specific binding sites may provide a useful screen in the search for new and improved antihormonal agents.