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.
Sulfamate substitution (-O-SO2-NH2) at carbon atom 3 of the steroid skeleton leads to orally active prodrugs of estrogens with much higher systemic, but lower hepatic, estrogenic activity than their parent steroids. This dissociation is achieved by first passage through the liver in erythrocytes, followed by systemic hydrolysis which releases the 'parent' estrogen. In the rat, orally administered tritiated estradiol sulfamate, unlike estradiol, appears in the circulation at high concentrations. At Cmax, approximately one third of the administered dose forms a depot in the circulation (98% in erythrocytes, 2% in plasma). Significant estradiol, estrone and estrone sulfate concentrations were recorded in plasma during depletion of the red blood cell pool. Estradiol sulfamate (J995) has no estrogen receptor affinity per se or estrogenic activity in vitro ( i.e. without hydrolysis). Its oral uterotropic activity in rats is approximately 100 times greater than that of estradiol, however, its hepatotropic activity is only marginally elevated. These functions include bile secretion, the secretion of angiotensinogen, lipoproteins (total and high-density lipoprotein cholesterol) and insulin-like growth factor I (IGF-I). Orally administred estradiol sulfamate led to systemic estrogenic effects without significant hepatic responses, whereas estradiol and other 'conventional' estrogens exerted parallel systemic and hepatic estrogenic effects. Sulfamate technology represents an approach to the use of natural estrogens for fertility control and hormone replacement therapy in both genders. In this context, reduced effects on hemostatic factors, angiotensinogen, bile and IGF-I secretion seem the most important aspects. In addition, blood concentrations of estrogens are less variable than with conventional estrogens.
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