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-

Transdermal E(2) results in E(2), E(1), and bioestrogen concentrations closer to normal and achieves greater suppression of LH/FSH in lower doses compared with normal. Whether the long-term metabolic effects of estrogen differ using the same form of E(2), depending on route, awaits further study in TS.

Atorvastatin lowered LDL-C, apoB, and atherogenic lipoprotein subparticles in children with T1D and elevated LDL-C without worsening insulin resistance. The drug was well tolerated and safe. Long-term studies would provide better insight on the impact of these interventions in the development of cardiovascular disease in children with diabetes.