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.
Level 2 - randomized trial
Individual randomized crossover trial
PubMed 17507833 · doi:10.1097/gme.0b013e31803867a
What was done
A randomized, open-label, crossover trial evaluated 27 naturally menopausal women (25 completed both arms). Following a 6-week withdrawal from prior hormone therapy, participants received 12 weeks of oral conjugated equine estrogens (CEE, 0.625 mg/day) and 12 weeks of transdermal estradiol (TD E2, 0.05 mg/day) in randomized order, with oral micronized progesterone (100 mg/day) co-administered continuously during both regimens. Total and free concentrations of testosterone, thyroxine (T4), and cortisol, along with their binding globulins (SHBG, TBG, CBG), were measured.
What was found
Oral CEE markedly increased binding globulins and altered free hormone concentrations, whereas transdermal E2 had minimal effects: - SHBG: +132.1% (SD 74.5%) with oral CEE vs +12.0% (SD 25.1%) with TD E2. - Total testosterone: +16.4% (SD 43.8%) with oral CEE vs +1.2% (SD 43.7%) with TD E2. - Free testosterone: -32.7% (SD 25.9%) with oral CEE vs +1.0% (SD 45.0%) with TD E2. - TBG: +39.9% (SD 20.1%) with oral CEE vs +0.4% (SD 11.1%) with TD E2. - Total T4: +28.4% (SD 29.2%) with oral CEE vs -0.7% (SD 16.5%) with TD E2. - Free T4: -10.4% (SD 22.3%) with oral CEE vs +0.2% (SD 26.6%) with TD E2. - CBG: +18.0% (SD 19.5%) with oral CEE vs -2.2% (SD 11.3%) with TD E2. - Total cortisol: +29.2% (SD 46.3%) with oral CEE vs -6.7% (SD 30.8%) with TD E2. - Free cortisol: +50.4% (SD 126.5%) with oral CEE vs +1.8% (SD 77.1%) with TD E2. Concentrations of all binding globulins and total hormones differed significantly between routes (P <= 0.003), whereas free T4 and free cortisol did not differ significantly.
Why it matters
Unlike oral estrogens, which induce hepatic protein synthesis and reduce bioavailable free testosterone, transdermal estradiol bypasses first-pass hepatic metabolism and avoids major perturbations in binding globulins and circulating hormone levels.
Limits
The sample size was small (27 enrolled, 25 completed), and the trial was open-label. Only specific fixed doses of oral CEE and transdermal estradiol were tested, both in combination with oral micronized progesterone, and the abstract did not report clinical symptoms or long-term outcomes.
Cited by
- context Excessively high estradiol levels can disrupt thyroid binding sites, impair cortisol signaling, and stimulate autoimmune disease, while progesterone protects against autoimmune disease.