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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: The optimal approach to estrogen replacement in girls with Turner syndrome has not been determined.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.This study was a prospective, randomized, double-blind, placebo-controlled clinical trial.The study was conducted at two US pediatric endocrine centers.Girls with Turner syndrome (n = 149), aged 5.0-12.5 years, were enrolled; data from 123 girls were analyzable for pubertal onset.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.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.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.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.

SUBMITTER: Quigley CA

PROVIDER: S-EPMC4154082 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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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.

Quigley Charmian A CA Wan Xiaohai X Garg Sipi S Kowal Karen K Cutler Gordon B GB Ross Judith L JL

The Journal of clinical endocrinology and metabolism 20140424 9

<h4>Context</h4>The optimal approach to estrogen replacement in girls with Turner syndrome has not been determined.<h4>Objective</h4>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.<h4>Design</h4>This study was a prospective, randomized, double-blind, placebo-controlled clinical tria ...[more]

PMID: 24762109

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Project description:BackgroundShort stature and ovarian failure are characteristic features of Turner's syndrome. Although recombinant human growth hormone is commonly used to treat the short stature associated with this syndrome, a randomized, placebo-controlled trial is needed to document whether such treatment increases adult height. Furthermore, it is not known whether childhood estrogen replacement combined with growth hormone therapy provides additional benefit. We examined the independent and combined effects of growth hormone and early, ultra-low-dose estrogen on adult height in girls with Turner's syndrome.MethodsIn this double-blind, placebo-controlled trial, we randomly assigned 149 girls, 5.0 to 12.5 years of age, to four groups: double placebo (placebo injection plus childhood oral placebo, 39 patients), estrogen alone (placebo injection plus childhood oral low-dose estrogen, 40), growth hormone alone (growth hormone injection plus childhood oral placebo, 35), and growth hormone-estrogen (growth hormone injection plus childhood oral low-dose estrogen, 35). The dose of growth hormone was 0.1 mg per kilogram of body weight three times per week. The doses of ethinyl estradiol (or placebo) were adjusted for chronologic age and pubertal status. At the first visit after the age of 12.0 years, patients in all treatment groups received escalating doses of ethinyl estradiol. Growth hormone injections were terminated when adult height was reached.ResultsThe mean standard-deviation scores for adult height, attained at an average age of 17.0±1.0 years, after an average study period of 7.2±2.5 years were -2.81±0.85, -3.39±0.74, -2.29±1.10, and -2.10±1.02 for the double-placebo, estrogen-alone, growth hormone-alone, and growth hormone-estrogen groups, respectively (P<0.001). The overall effect of growth hormone treatment (vs. placebo) on adult height was a 0.78±0.13 increase in the height standard-deviation score (5.0 cm) (P<0.001); adult height was greater in the growth hormone-estrogen group than in the growth hormone-alone group, by 0.32±0.17 standard-deviation score (2.1 cm) (P=0.059), suggesting a modest synergy between childhood low-dose ethinyl estradiol and growth hormone.ConclusionsOur study shows that growth hormone treatment increases adult height in patients with Turner's syndrome. In addition, the data suggest that combining childhood ultra-low-dose estrogen with growth hormone may improve growth and provide other potential benefits associated with early initiation of estrogen replacement. (Funded by the National Institute of Child Health and Human Development and Eli Lilly; ClinicalTrials.gov number, NCT00001221.).

Project description:Abstract Background: Turner syndrome (TS) is a disorder characterized by complete or partial absence of the second sexual chromosome and the most commonly found abnormalities are short stature and gonadal failure. Most TS patients need estrogen replacement but individual outcomes on uterine volume, breast development and vertebral bone density are highly variable. To our knowledge, the impact of polymorphisms in estrogen receptor 1 (ESR1) over the variability in the development of secondary sexual characteristics and in adult height has not yet been evaluated in TS patients. Objective: To investigate the association among five ESR1 polymorphisms (rs543650, rs1038304, rs2046210, rs2234693 and rs9340799) and breast development, uterine volume, vertebral bone density, FSH and LH levels and adult height in TS patients. Methods: We selected 80 TS patients receiving adult estrogen dose for a minimum period of one year. Patients who had spontaneous complete pubertal development or who have Y chromosome material in karyotype were excluded from analysis. They were submitted to clinical and laboratory evaluation, pelvic ultrasound, bone densitometry and genotyping of the five chosen ESR1 polymorphisms through real time PCR. These polymorphisms were selected through active search in Pubmed and in GWAS catalogs, based on the following criteria: recurrence in studies, being Tag-single nucleotide polymorphisms (Tag-SNPs) or having a minor allele frequency (MAF) which allowed the present study with the available sample. Results: 61% of patients had 45,X karyotype and their mean target height was 158.9cm. 82% of them were treated with rhGH for 5 years on average and they reached a mean adult height of 149cm. Their average age of puberty onset was 14.4 years old and 10% of them had spontaneous thelarche. Their mean uterine volume was 30.1cc but ranged from 5.9 to 83cc. 91% attained adult breast development (Tanner 5) and 93% had normal vertebral bone mass after correction for height (by using the online calculator from University of Washington: courses.washington.edu/bonephys). Only 15% had FSH and/or LH lower than 10 IU/L in two or more measurements. Considering the ESR1 polymorphisms, all of them were in Hardy-Weinberg equilibrium. Statistical analysis with multiple linear regression showed that none of the studied polymorphisms was able to predict any of the above estrogen therapy outcomes in an isolated manner. Conclusion: We could not find a relationship among the studied ESR1 polymorphisms and estrogen therapy outcomes in patients with TS. However, the high variability in estrogen replacement results suggests that genetic variants play an important role. Other efforts to identify polymorphisms associated to estrogen outcomes may allow for individualization of treatment in TS.

Dataset Information

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.

Publications

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.

Similar Datasets

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