greatly extend the biological half-life of oral estradiol. As such, the biological half-life of oral estradiol is a composite parameter that is dependent on interconversion between estradiol and estrogen conjugates, as well as on enterohepatic recirculation. Whereas the biological half-life of estradiol given by intravenous injection is about 0.5 to 2 hours, the biological half-life of oral estradiol has a range of 13 to 20 hours due to the large and long-lasting pool of estrogen conjugates that is formed during first-pass metabolism and that serves to continuously replenish circulating estradiol levels. First-pass effect and differences from other routes The first-pass effect that occurs with oral estradiol results in unusually high levels of estrone and estrogen conjugates in the circulation as well as of estradiol in the liver. These unique properties of oral estradiol result in a number of pharmacological differences relative to the other routes of administration of estradiol. The high levels of estrone and estrogen conjugates that occur with oral estradiol raise the question of the pharmacodynamic significance of these metabolites. In contrast to estradiol however, estrone has very low activity as an estrogen. The affinities of estrone for the human ERs and its estrogenic activity have been reported to be approximately 3 to 4% of those of estradiol. In addition, unlike estradiol and estriol, estrone is not accumulated in target tissues. Because estrone can be transformed into estradiol, most of its activity in vivo is actually due to conversion into estradiol. In accordance, doses of oral and transdermal estradiol that achieve similar levels of estradiol have been found, in spite of markedly elevated levels of estrone with oral estradiol but not with transdermal estradiol, to possess equivalent and non-significantly different potency in terms of clinical measures including suppression of LH and FSH levels, inhibition of bone resorption, and relief of menopausal symptoms such as hot flashes. In addition, estradiol levels were found to correlate with these effects, while estrone levels did not. These findings suggest that estrone contributes very little or not at all to the estrogenic potency of estradiol, while also not antagonizing the estrogenic activity of estradiol. This contradicts some cell-free in-vitro research suggesting that high concentrations of estrone might be able to partially antagonize the actions of estradiol. On the other hand, it has been suggested by some authors that the high levels of estrone and/or estrone conjugates with oral estradiol may result in excessive