Metabolic Effects of Oral Versus Transdermal 17β-Estradiol (E2): A Randomized Clinical Trial in Girls With Turner Syndrome

CONTEXT: The long-term effects of pure 17β-estradiol (E₂) depending on route of administration have not been well characterized. OBJECTIVE: Our objective was to assess metabolic effects of oral vs transdermal (TD) 17β-E₂ replacement using estrogen concentration-based dosing in girls with Turner syndrome (TS). PATIENTS: Forty girls with TS, mean age 16.7 ± 1.7 years, were recruited. DESIGN: Subjects were randomized to 17β-E₂ orally or TD. Doses were titrated using mean E₂ concentrations of normally menstruating girls as therapeutic target. E₂, estrone (E₁), and E₁ sulfate (E₁S) were measured by liquid chromatography tandem mass spectrometry and a recombinant cell bioassay; metabolites were measured, and dual-energy x-ray absorptiometry scan and indirect calorimetry were performed. MAIN OUTCOME: Changes in body composition and lipid oxidation were evaluated. RESULTS: E₂ concentrations were titrated to normal range in both groups; mean oral dose was 2 mg, and TD dose was 0.1 mg. After 6 and 12 months, fat-free mass and percent fat mass, bone mineral density accrual, lipid oxidation, and resting energy expenditure rates were similar between groups. IGF-1 concentrations were lower on oral 17β-E₂, but suppression of gonadotropins was comparable with no significant changes in lipids, glucose, osteocalcin, or highly sensitive C-reactive protein between groups. However, E₁, E₁S, SHBG, and bioestrogen concentrations were significantly higher in the oral group. CONCLUSIONS: When E₂ concentrations are titrated to the normal range, the route of delivery of 17β-E₂ does not affect differentially body composition, lipid oxidation, and lipid concentrations in hypogonadal girls with TS. However, total estrogen exposure (E₁, E₁S, and total bioestrogen) is significantly higher after oral 17β-E₂. TD 17β-E₂ results in a more physiological estrogen milieu than oral 17β-E₂ administration in girls with TS.