Growth Hormone Plus Childhood Low-Dose Estrogen in Turner Syndrome

Abstract

Characteristic features of Turner syndrome include short stature and ovarian failure. There is considerable evidence from nonrandomized studies that treatment with recombinant human growth hormone increases adult stature in patients with Turner syndrome. It is commonly used in such patients despite the lack of objective data from randomized, double-blind, placebo-controlled studies. Ovarian failure associated with Turner syndrome is treated with estrogen-replacement therapy. It has been proposed that very low-dose physiologic estrogen replacement during childhood combined with growth hormone therapy could provide an additional benefit on adult height than that achieved with growth hormone therapy alone. The aim of this double-blind, placebo-controlled trial was to investigate the independent effect of growth hormone therapy alone and a regimen of growth hormone combined with early ultra–low-dose estrogen on adult height in girls with Turner syndrome. A total of 149 girls (5.0–12.5 years of age) were randomized to receive 1 of 4 regimens: (1) placebo injection plus childhood oral placebo (n = 39), (2) placebo injection plus childhood oral low-dose estrogen (n = 40), (3) growth hormone injection plus childhood oral placebo (n = 35), and (4) growth hormone injection plus childhood oral low-dose estrogen (n = 35). Doses of growth hormone (0.1 mg per kg of body weight) were injected 3 times per week. Ethinyl estradiol or placebo was administered in oral doses, with adjustment for chronologic age and pubertal status. From the first visit after the 12th birthday, escalating doses of ethinyl estradiol were administered to patients in all groups, according to an escalating dosage regimen. Patients were assessed at 6-month intervals. Growth hormone therapy was continued until patients reached their protocol-specified adult height (defined as the last height measured once the height velocity was less than 1.5 cm per year). For adult height attained at 17.0 ± 1.0 years after a mean study period of 7.2 ± 2.5 years, the mean standard deviation scores for the 4 groups were as follows: −2.81 ± 0.85 for the double-placebo group, −3.39 ± 0.74 for the estrogen-alone group, −2.29 ± 1.10 for the growth hormone-alone group, and −2.10 ± 1.02 for the combined growth hormone-estrogen group (P < 0.001 among the 4 groups). Patients treated with growth hormone attained greater adult height compared with placebo (mean difference in standard deviation score, 0.78 ± 0.13, equivalent to about 5.0 cm; P < 0.001). There was a trend toward a modest synergistic growth benefit in the combined growth hormone-estrogen group compared with the estrogen-alone group; the adult height gain with combined therapy was 0.32 ± 0.17 standard deviation score; P = 0.059. These findings provide objective evidence from a placebo-controlled trial that growth hormone treatment initiated in mid-childhood increases adult height in girls with Turner syndrome. The data also suggest that the combination of ultra–low-dose childhood estrogen replacement and growth hormone therapy may improve the height gain achieved with growth hormone alone.