contrast to EE as well as to oral estradiol, transdermal estradiol shows few or no effects on liver protein synthesis at typical menopausal dosages. Pharmacokinetics Absorption The oral bioavailability of EE is 45% on average, with a wide range of 20% to 74% (though most commonly between 38 and 48%) that is due to high interindividual variability. Although relatively low, the oral bioavailability of EE is considerably higher than that of micronized estradiol (5%). Following a single 20 μg dose of EE in combination with 2 mg norethisterone acetate in postmenopausal women, EE concentrations have been found to reach a maximum of 50 pg/mL within an average of 1.5 hours. Following the first dose, mean levels of EE in general further increase by about 50% until steady-state concentrations are reached; steady-state is reached after one week of daily administration. For comparison, the mean peak levels of estradiol achieved with 2 mg micronized estradiol or estradiol valerate are 40 pg/mL following the first dose and 80 pg/mL after three weeks of administration. These maximal concentrations of estradiol are in the same range as the concentrations of EE that are produced by an oral dose of EE that is 100 times lower by weight, which is in accordance with the approximately 100-fold increased oral potency of EE relative to estradiol. In accordance with the high interindividual variability in the oral bioavailability of EE, there is a large degree of interindividual variation in EE levels. A dosage of EE of 50 μg/day has been found to achieve a wide range of circulating EE levels of about 100 to 2,000 pg/mL. Taking EE in combination with a high-fat meal has been found to significantly decrease its peak concentrations. EE levels after a single 50 μg dose by intravenous injection are several times higher than levels of EE after a single 50 mg dose given orally. Besides the difference in levels, the course of elimination is similar for the two routes. There may be gender-specific differences in the pharmacokinetics of EE, such that EE may have greater oral potency in women than in men. A study found that a combination of 60 μg/day EE and 0.25 mg/day levonorgestrel in women and men resulted in peak levels of EE of 495 pg/mL and 251 pg/mL, area-under-the-curve levels of EE of 6.216 pg/mL/hour and 2.850 pg/mL/hour, and elimination half-lives of 16.5 hours and 10.2 hours, respectively. It