Growth hormone plus childhood low-dose estrogen in Turner's syndrome

Abstract

Background: Short 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.

Methods: In 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.

Results: The 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.

Conclusions: Our 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.).

Figure 1. Study Design, Randomization, and Analysis Populations

The factorial study design is shown in Panel A. As shown in Panel B, a total of 149 patients were randomly assigned to four treatment groups: placebo injection plus oral placebo, placebo injection plus childhood oral low-dose estrogen, growth hormone injection plus childhood oral placebo, and growth hormone injection plus childhood oral low-dose estrogen. Patients were stratified according to their baseline height into upper, middle, and lower thirds of the Turner’s syndrome height standards for age and were randomly assigned to treatment in a 1:1:1:1 ratio with the use of a computer-generated randomization table. The intention-to-treat population consisted of 137 girls whose height measurement was available 120 days or more after randomization; the adult-height population consisted of 91 girls whose height measurement was available after their height velocity was less than 1.5 cm per year.

Figure 2. Oral Doses of Ethinyl Estradiol (or Oral Placebo Equivalent) during the Childhood Phase, as Compared with Protocol-Specified Doses, and Average Daily Doses in the Intention-to-Treat Population, According to Age Group

Panel A shows the mean (±SD) dose of estrogen or placebo for each age group, as compared with the protocol-specified dose. During the childhood phase of the study (until the age of 12.0 years), patients were randomly assigned to receive either oral low-dose ethinyl estradiol or oral placebo. Starting at the first visit after 12.0 years of age, all the study groups received pubertal estrogen-replacement therapy in escalating doses. The protocol-specified doses of estradiol (or placebo during the childhood phase of the study) were 25 ng per kilogram of body weight per day from study entry until the age of 8.0 years and 50 ng per kilogram per day after the age of 8.0 years until 12.0 years of age. Pubertal-phase doses were 100 ng per kilogram per day after the age of 12.0 to 14.0 years of age, 200 ng per kilogram per day after the age of 14.0 to 15.0 years of age, 400 ng per kilogram per day after the age of 15.0 to 16.0 years of age, and 800 ng per kilogram per day after the age of 16.0 years. To individualize the oral dosage regimen, a protocol-specified dose-reduction schedule was used, whereby the dose could be reduced by 50% at the discretion of the investigator for any of the following reasons: breast development reached Tanner stage 2 or higher before the age of 12.0 years (premature breast development), vaginal bleeding occurred before the age of 14.0 years (premature vaginal bleeding), bone age advanced by 2 years within 1 year, or bone age exceeded chronologic age up to the age of 14.0 years. If the dose was reduced, it was doubled at the next protocol-specified dose increase, but thereafter, the dose remained below the protocol-specified dose according to age. Panel B shows the mean ±SD total daily dose in micrograms according to age group.

Figure 3. Effects of Treatment on Adult Height

In Panel A, the graph on the left shows the growth hormone treatment effect on adult height. The observed treatment effect (least-squares mean [±SE] difference in the change in standard-deviation score [SDS] from baseline to adult height, 0.78±0.13 [equivalent to 5.0 cm], on the basis of analysis of covariance [ANCOVA]) results from the combined effects of the gain in the height SDS observed in the groups treated with growth hormone and prevention of the height SDS loss observed in the placebo injection groups. The graph on the right shows the effects of the interaction of growth hormone and childhood estrogen therapy. The mean between-group difference (growth hormone plus estrogen vs. growth hormone plus placebo) of 0.32±0.17 in the SDS change (equivalent to 2.1 cm) represents the incremental effect of childhood low-dose estrogen in combination with growth hormone. The graph in Panel B shows the change in the height SDS from baseline for the adult-height population according to number of years in the study. Annual data points represent the ANCOVA least-squares mean (±SE) values, with baseline age and baseline height SDS as covariates. Changes above the horizontal line represent gains in the SDS for height; changes below the horizontal line represent decreases in the SDS for height. In the adult-height population, the groups treated with growth hormone had consistent increases in height for the first 5 years of the study, whereas the groups that received placebo injections had progressive declines in height SDS. Panel C shows the changes in the SDS for height from baseline to the last available height measurement for individual patients in the intention-to-treat population. Solid lines represent patients with adult-height measurements, and dashed lines patients without adult-height measurements. One patient in the estrogen-alone group who received surreptitious growth hormone during the study is not included. Large symbols represent the group means (±SD) at baseline and at the time of the last height measurement. Mean baseline SDS and end-point SDS in the four groups were as follows: double-placebo group, −2.59±0.96 and −3.08±0.95; estrogen-alone group, −3.01±0.74 and −3.40±0.74; growth hormone–alone group, −2.65±0.91 and −2.45±1.13; and growth hormone–estrogen group, −2.71±0.81 and −2.18±1.00 (P<0.001 for the comparison among the four groups). Individual gains in the height SDS for patients with adult-height measurements (i.e., change in height SDS from baseline to adult height >0) were observed for 15% of patients in the double-placebo group, 32% in the estrogen-alone group, 65% in the growth hormone–alone group, and 79% in the growth hormone– estrogen group (P<0.001 for the comparison among the four groups).