Effects of low-dose estrogen replacement during childhood on pubertal development and gonadotropin concentrations in patients with Turner syndrome: results of a randomized, double-blind, placebo-controlled clinical trial

Abstract

Context: The optimal approach to estrogen replacement in girls with Turner syndrome has not been determined.

Objective: The aim of the study was to assess the effects of an individualized regimen of low-dose ethinyl estradiol (EE2) during childhood from as early as age 5, followed by a pubertal induction regimen starting after age 12 and escalating to full replacement over 4 years.

Design: This study was a prospective, randomized, double-blind, placebo-controlled clinical trial.

Setting: The study was conducted at two US pediatric endocrine centers.

Subjects: Girls with Turner syndrome (n = 149), aged 5.0-12.5 years, were enrolled; data from 123 girls were analyzable for pubertal onset.

Intervention(s): Interventions comprised placebo or recombinant GH injections three times a week, with daily oral placebo or oral EE2 during childhood (25 ng/kg/d, ages 5-8 y; 50 ng/kg/d, ages >8-12 y); after age 12, all patients received escalating EE2 starting at a nominal dosage of 100 ng/kg/d. Placebo/EE2 dosages were reduced by 50% for breast development before age 12 years, vaginal bleeding before age 14 years, or undue advance in bone age.

Main outcome measures: The main outcome measures for this report were median ages at Tanner breast stage ≥2, median age at menarche, and tempo of puberty (Tanner 2 to menarche). Patterns of gonadotropin secretion and impact of childhood EE2 on gonadotropins also were assessed.

Results: Compared with recipients of oral placebo (n = 62), girls who received childhood low-dose EE2 (n = 61) had significantly earlier thelarche (median, 11.6 vs 12.6 y, P < 0.001) and slower tempo of puberty (median, 3.3 vs 2.2 y, P = 0.003); both groups had delayed menarche (median, 15.0 y). Among childhood placebo recipients, girls who had spontaneous breast development before estrogen exposure had significantly lower median FSH values than girls who did not.

Conclusions: In addition to previously reported effects on cognitive measures and GH-mediated height gain, childhood estrogen replacement significantly normalized the onset and tempo of puberty. Childhood low-dose estrogen replacement should be considered for girls with Turner syndrome.

Trial registration: ClinicalTrials.gov NCT00001221.

Figure 1.

Kaplan-Meier analysis of ages at Tanner stage ≥2 breast development and menarche. A, Kaplan-Meier plot of age at attainment of Tanner stage ≥2 breast development. Starting at approximately 8.5 years of age, the curve for girls who received childhood low-dose estrogen is shifted to the left, indicating significantly earlier thelarche (P < .001), compared with that for girls who received oral placebo during childhood with initiation of pubertal estrogen replacement at the first study visit after age 12. All girls received escalating dosages of EE2 for pubertal induction from the first visit after the 12th birthday (arrow). The dotted line represents the curve for general population standards for attainment of Tanner breast stage 2, based on data from the US National Health and Nutrition Examination Survey III (29). B, Kaplan-Meier analysis of age at attainment of menarche; the curves for the two groups are not significantly different (P = .986). All girls received escalating dosages of EE2 for pubertal induction from the first visit after the 12th birthday (arrow). Median age at menarche for girls in the US general population (12.6 years [Ref. 51]) is shown by the cross.

Figure 2.

Oral study drug dosages in micrograms per day (mean ± SD) by integer age for patients receiving oral placebo during childhood or low-dose EE2 during childhood, and escalating dosages of EE2 during pubertal induction. During the childhood phase of the study (left), patients in the oral placebo group (open symbols) received no active oral medication, whereas those in the low-dose estrogen group (closed symbols) received EE2 at the mean daily dosages indicated on the vertical axis. The protocol-specified dosages in ng/kg/d were 5–8 years, 25 ng/kg/d; >8–12 years, 50 ng/kg/d. During the pubertal induction phase (right) all girls received escalating dosages of EE2 based on age and weight: protocol-specified dosages in ng/kg/d were >12–14 years, 100 ng/kg/d; >14–15 years, 200 ng/kg/d; >15–16 years, 400 ng/kg/d; >16 years, 800 ng/kg/d. Note that the scale on the vertical axis differs for the childhood and pubertal phases of the study.

Figure 3.

Effect of low-dose estrogen on gonadotropins. A, Scatter plots of LH values (left, circles) and FSH values (right, diamonds) by age during the childhood phase of the study (multiple study visits and values per patient). Upper panels (open symbols) display values for girls who received oral placebo during childhood; lower panels (closed symbols) display values for girls who received childhood low-dose estrogen. All girls received escalating dosages of EE2 for pubertal induction from the first visit after the 12th birthday. Solid lines represent lines of best fit for the data. To avoid compressing the vertical axis, FSH values above 200 IU/L are not shown. Dashed lines represent the designated upper limit of normal (2 SD values above the mean for the relevant assays). B, Proportions of values by treatment group above upper limit of normal at each integer age for LH (15 IU/L, upper graph) and FSH (20 IU/L, lower graph); P values <.1 for differences between pooled treatment groups are provided. At ages 8–11 years (childhood phase), a significantly greater proportion of FSH values were supranormal for girls who received oral placebo (open bars) vs those who received low-dose estrogen during childhood (filled bars). During the latter stages of the pubertal induction phase there was a nonsignificant trend toward greater proportions of supranormal LH and FSH values in the original childhood low-dose estrogen recipients, likely as a result of lower EE2 dosages in this group during the pubertal phase of the study, due to prior estrogen dose reductions during childhood. Because 80% of patients had 45,X karyotype, no separate analysis was performed for patients with chromosomal mosaicism.