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.