Morning versus evening administration of estradiol to girls with Turner syndrome receiving growth hormone: impact on growth hormone and metabolism. A randomized placebo‐controlled crossover study

Timing of 17β‐estradiol (E2) administration in relation to that of GH could influence the “first pass effect” of E2 on hepatic IGF‐I secretion. In order to test this hypothesis, a randomized double‐blind placebo‐controlled crossover study was conducted. Nine Turner girls (12.8–20.0 y) were treated for 2 mo periods with GH 0.1 IU/kg/d sc at bedtime, and oral E2 6–11 μg/kg/d in the morning and placebo in the evening in one 2‐mo period and vice versa in the other period. After each period, 24‐h blood sampling was performed. IGF‐I and mean 24‐h integrated GH were comparable. However, the IGF‐I/IGFBP‐3 ratio was higher ( p = 0.05) and insulin levels were lower after evening administration of E2 (24 h: p = 0.03). During an oral glucose tolerance test in the morning, glucagon and insulin were lower following evening E2 administration (ANOVA: glucagon, p = 0.03; insulin, p = 0.04), as well as insulin resistance tended to be lower ( p = 0.09). Conclusion : The timing of oral E2 supplementation modulates the IGF‐I/IGFBP‐3 ratio, insulin and glucagon levels in Turner syndrome during GH treatment. Evening administration of oral estrogen together with evening injections of GH may be preferable.