Differences in the composition and quantity of endogenous estrogens produced in pregnant and non-pregnant women 3. Differences in the biological activity of pregnancy and non-pregnancy estrogens 4. Biological activity of estrogens contained in Premarin

Endogenous estrogens exert an array of biological actions on women, many of which are mediated by the estrogen receptors (ERs) α and ß. Results from our recent studies suggest that the human ERα and ERß systems are differentially activated under different physiological conditions. In non-pregnant young women, the ERα system is preferentially activated over the ERß system, mainly by estrone (E1) and its major oxidative metabolite, 2-hydroxy-E1. These two estrogens are among the quantitatively major estrogens present in young women, and have approximately 4-fold preferential activity for ERα over ERß. During pregnancy, however, there is a preponderance of activation of ERß over ERα conferred by various pregnancy estrogens such as estriol and other D-ring derivatives of 17ß-estradiol (E2). These estrogens have an up to 18-fold preference for binding to ERß than for ERα, and some of them are produced in unusually large quantities. Given this new information, it is hypothesized that the estrogens ideal for female hormone replacement therapy (HRT) would be those which produce a hormonal condition mirroring that found in non-pregnant young women rather than in pregnant women. Endogenous estrogen derivatives, such as the sulfated conjugates of E1, may be among the ideal candidates for achieving this clinical purpose. In comparison, Premarin, the most commonly-used HRT containing a mixture of conjugated estrogens isolated from pregnant mare's urine, is less suitable because several of its estrogenic components can produce a strong preferential overstimulation of the human ERß signaling system.