Metabolic effects of oral versus transdermal 17β-estradiol (E₂): a randomized clinical trial in girls with Turner syndrome

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00837616.

Figure 1.

Mean ± SE plasma concentrations of E₂ (A), E₁ (B), E₁S (C), LH (D), and FSH (E) after oral or TD estradiol treatment (Rx) over 12 months. E₂ levels achieved were comparable between the groups (P = .15) and similar to healthy age-matched controls averaged from follicular and luteal phase values (bar on the right). E₁ and E₁S concentrations were much higher after oral E₂ than TD (P < .001). Gonadotropins decreased comparably over 12 months between groups (P > .20 for both), although there was an increase in both oral and TD LH at 12 months. Black bars represent controls. Analysis was done by mixed-model repeated-measures ANOVA. To convert to SI units, multiply by 3.67 for E₂, 3.699 for E₁, and 2.73 for E₁S.

Figure 2.

Mean ± SE measures of body composition during 12 months of oral and TD 17β-E₂ treatment in girls with Turner syndrome for weight (A), BMI (B), FFM (C), percent fat mass (D), and percent abdominal fat (E). Overall, there were no significant differences between groups in any parameter at 12 months (P > .22 for all).

Figure 3.

Box plots of median IGF-1 concentrations over 12 months after treatment (Rx) with 17β-E₂. Overall, IGF-1 concentrations decreased in the oral group and increased in the TD group at 6 and 12 months (P = .059 between groups) (normal range: prepubertal girls, 118–664 ng/mL; pubertal, 208–1060 ng/mL, data from subjects in Ref. 35).

Figure 4.

Whole-body (A) and lumbar (B) BMD over time after treatment with 17β-E₂. There was significant (P < .05) but similar improvement in whole-body and lumbar BMD over 12 months between groups.