托马斯杰斐逊大学的Judith L. Ross博士及其同事首次进行随机双盲对照临床试验，旨在确认Turner综合征患儿在儿童中期接受生长激素常规治疗改善身体矮小的疗效，以及观察该年龄段患儿接受超低剂量雌激素对成年身高的影响。
Growth Hormone plus Childhood Low-Dose Estrogen in Turner's Syndrome
Judith L. Ross, M.D., Charmian A. Quigley, M.B., B.S., Dachuang Cao, Ph.D., Penelope Feuillan, M.D., Karen Kowal, P.A., John J. Chipman, M.D., and Gordon B. Cutler, Jr., M.D.
N Engl J Med 2011; 364:1230-1242March 31, 2011
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.
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.
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.
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.)
Supported by the National Institute of Child Health and Human Development and Eli Lilly.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
We thank the patients and their families for their participation in this study, Mike Massa and Xiaohai Wan for technical assistance, and Jeff Baron and Werner Blum for helpful discussions.
This article is dedicated to the memory of our colleague Penelope Feuillan, M.D., for her commitment to her patients and clinical research aimed at improving their lives.