A randomized, open-label, crossover study comparing the effects of oral versus transdermal estrogen therapy on serum androgens, thyroid hormones, and adrenal hormones in naturally menopausal women

In Brief Objective: To compare the changes induced by oral versus transdermal estrogen therapy on the total and free serum concentrations of testosterone (T), thyroxine (T4), and cortisol (C) and the concentrations of their serum binding globulins sex hormone-binding globulin, thyroxine-binding globulin, and cortisol-binding globulin in naturally menopausal women. Design: Randomized, open-label, crossover. Interventions included a 6-week withdrawal from previous hormone therapy (baseline), followed in randomized order by 12 weeks of oral conjugated equine estrogens (CEE) (0.625 mg/d) and 12 weeks of transdermal estradiol (TD E2) (0.05 mg/d), with oral micronized progesterone (100 mg/d) given continuously during both transdermal estrogen therapy regimens. Results: Twenty-seven women were enrolled in the study, and 25 completed both treatment periods. The mean(SD) percentage changes from baseline of sex hormone-binding globulin, total T, and free T with oral CEE were +132.1% (74.5%), +16.4% (43.8%), and −32.7% (25.9%), respectively, versus +12.0% (25.1%), +1.2% (43.7%), and +1.0% (45.0%) with TD E2. The mean (SD) percentage changes of thyroxine-binding globulin, total T4, and free T4 with oral CEE were +39.9% (20.1%), +28.4% (29.2%), and −10.4% (22.3%), respectively, versus +0.4% (11.1%), −0.7% (16.5%), and +0.2% (26.6%) with TD E2. The mean (SD) percentage changes of cortisol-binding globulin, total C, and free C with oral CEE were +18.0% (19.5%), +29.2% (46.3%), and +50.4% (126.5%), respectively, versus −2.2% (11.3%), −6.7% (30.8%), and +1.8% (77.1%) with TD E2. Concentrations of all hormones and binding globulins were significantly different (P ≤ 0.003) during administration of oral versus transdermal estrogen therapy, except for free T4 and free C. Conclusions: Compared with oral CEE, TD E2 exerts minimal effects on the total and free concentrations of T, T4, and C and their binding proteins. This study compared the effects of oral conjugated equine estrogens (0.625 mg/day) versus transdermal estradiol (0.05 mg/day) on the total and free concentrations of testosterone, thyroxine, and cortisol and their serum binding proteins sex hormone-binding globulin, thyroxine-binding globulin, and cortisol-binding globulin in naturally menopausal women. By avoiding the hepatic first-pass effect, transdermal estradiol may be preferable to oral conjugated equine estrogens in maintaining free testosterone levels, minimizing potential interaction with thyroid replacement therapy and having little effect on total or free cortisol levels.