Efficacy of transdermal estradiol

Several side effects and risks associated with estrogen replacement therapy are known to stem from the hormone's impact on the liver. With oral administration, the enhanced action at hepatic, as compared with nonhepatic, sites is presumably related to the so-called first-pass effect. Attempts have been made to avoid this action by administering estrogen nonorally, but heightened hepatic effects (comparable with those of other preparations) have nonetheless been seen with both ethinyl estradiol and conjugated equine estrogens given vaginally. We conducted a series of investigations aimed at evaluating the effects of estradiol delivered via a transdermal patch. In a 50-patient study of transcutaneous estradiol (25, 50, 100, or 200 micrograms/day) versus placebo, a dose-dependent beneficial effect on objectively measured hot flashes was demonstrated. A second study was designed to compare the effects of these doses with those of 0.625 and 1.25 mg conjugated equine estrogen administered orally. Effects on nonhepatic markers were similar for the 50 micrograms patch and 0.625 mg tablet, as well as for the 100 micrograms patch and 1.25 mg tablet. None of the doses of transdermal estradiol exerted any measurable action on hepatic markers of estrogen action, whereas both doses of conjugated equine estrogen demonstrated actions on both hepatic protein and lipid synthesis. Our data clearly show that the transdermal administration of estradiol circumvents the enhanced hepatic actions of the hormone. Possible explanations for these results are presented.