has been suggested that this phenomenon could represent a "protection mechanism" of males against environmental estrogen exposure. Distribution The plasma protein binding of EE is 97 to 98%, and it is bound almost exclusively to albumin. Unlike estradiol, which binds with high affinity to SHBG, EE has very low affinity for this protein, about 2% of that of estradiol, and hence does not bind to it importantly. Metabolism Due to high first-pass metabolism in the intestines and liver, only 1% of an oral dose of an EE appears in the circulation as EE itself. During first-pass metabolism, EE is extensively conjugated via glucuronidation and sulfation into the hormonally inert ethinylestradiol glucuronides and ethinylestradiol sulfate (EE sulfate), and levels of EE sulfate in circulation are between 6- and 22-fold higher than those of EE. For comparison, with oral administration of 2 mg micronized estradiol, levels of estrone and estrone sulfate are 4- to 6-fold and 200-fold higher than those of estradiol, respectively. In contrast to estradiol, EE, due to steric hindrance by its C17α ethynyl group, is not metabolized or inactivated by 17β-HSD, and this is the primary factor responsible for the dramatically increased potency of oral EE relative to oral estradiol. EE is also not metabolized into estradiol. Aside from sulfate conjugation, EE is mainly metabolized by hydroxylation into catechol estrogens. This is mainly by 2-hydroxylation into 2-hydroxy-EE, which is catalyzed primarily by CYP3A4. Hydroxylation of EE at the C4, C6α, and C16β positions into 4-, 6α-, and 16β-hydroxy-EE has also been reported, but appears to contribute to its metabolism to only a small extent. 2- and 4-methoxy-EE are also formed via transformation by catechol O-methyltransferase of 2- and 4-hydroxy-EE. Unlike the case of estradiol, 16α-hydroxylation does not occur with EE, owing to steric hindrance by its ethynyl group at C17α. The ethynylation of EE is largely irreversible, and so EE is not metabolized into estradiol, unlike estradiol esters. A review found that the range of the reported elimination half-life of EE in the literature was 13.1 to 27.0 hours. Another review reported an elimination half-life of EE of 10 to 20 hours. However, the elimination half-life of EE has also been reported by other sources to be as short as 7 hours and as long as 36 hours. Unlike the case of estradiol, in which there is a rapid rise in its levels and which remain elevated in a