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 17␤-estradiol (E 2 ) depending on route of administration have not been well characterized.Objective: Our objective was to assess metabolic effects of oral vs transdermal (TD) 17␤-E 2 replacement using estrogen concentration-based dosing in girls with Turner syndrome (TS).Patients: Forty girls with TS, mean age 16.7 Ϯ 1.7 years, were recruited.Design: Subjects were randomized to 17␤-E 2 orally or TD. Doses were titrated using mean E 2 concentrations of normally menstruating girls as therapeutic target. E 2 , estrone (E 1 ), and E 1 sulfate (E 1 S) 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: E 2 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 17␤-E 2 , but suppression of gonadotropins was comparable with no significant changes in lipids, glucose, osteocalcin, or highly sensitive C-reactive protein between groups. However, E 1 , E 1 S, SHBG, and bioestrogen concentrations were significantly higher in the oral group.Conclusions: When E 2 concentrations are titrated to the normal range, the route of delivery of 17␤-E 2 does not affect differentially body composition, lipid oxidation, and lipid concentrations in hypogonadal girls with TS. However, total estrogen exposure (E 1 , E 1 S, and total bioestrogen) is significantly higher after oral 17␤-E 2 . TD 17␤-E 2 results in a more physiological estrogen milieu than oral 17␤-E 2 administration in girls with TS. (J Clin Endocrinol Metab 98: 2716 -2724, 2013) E strogen is indispensable for normal physiological function in females including breast development and feminization, the growth and differentiation of primary sex organs, skeletal maturation, consolidation, and growth. Although a variety of types of estrogen can achieve full feminization in hypogonadal females, it re-

Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting

“…There were no significant differences in glucose (149), insulin tolerance (177,184), fasting insulin concentration, protein turnover, lipolysis (175), osteocalcin, highly sensitive C-reactive protein, BMI or waist-to-hip ratio (184, 185) between groups with TD vs oral estrogen treatment. Glucagon and insulin levels (during an OGTT) as well as insulin resistance tended to be lower following evening oral E2 administration (0.3-0.5 mg/day) (179).…”

“…Therefore, we present data in support of TD use based on available studies and theoretical considerations. Theoretical reasons include: a more physiologic route of delivery without the first-pass effect through the liver, thereby avoiding the accumulation of non-physiologic estrogens observed after the oral route (149). The latter route is associated with a pro-coagulable state (150) and increased risk of stroke in the postmenopausal setting (151).…”

“…Routine monitoring of serum LH or FSH is not recommended during estrogen treatment as concentrations remain elevated in hypergonadotropic hypogonadal women until higher doses of estrogen are given. Estradiol measurement using an ultrasensitive assay allows titrating dosage, if desired, though E2 concentrations for optimal growth remain to be determined (149). Clinical assessment, patient satisfaction, patient age and often residual growth potential are the primary determinants for a dose increase.…”

“…Five studies reported data on HDL cholesterol concentrations (149,160,172,175,176). TD E2 showed a decrease in HDL plasma concentrations compared to oral estrogen as shown in Appendix 4 (weighted mean difference −8.09; 95% CI −12.7, −3.5).…”

“…In two studies, bone mineral density was studied (149,160). Both studies showed a somewhat better lumbar Z-score after TD use compared with oral administration (weighted mean difference 0.93; 95% CI 0.68, 1.19).…”