这项研究报告显示,青春期前Turner综合征患者接受生长激素加超低剂量雌激素治疗可改善其成年身高,还可能在神经认知和行为方面带来额外收益。


此前,虽然认识到Turner综合征患儿雌激素不足始于婴儿期,但鉴于普遍认为雌激素会加速骨垢愈合而降低身高,因此临床实践中通常在十多岁才开始雌激素替代疗法。

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。


该研究纳入149例年龄5~13岁的Turner综合征女性患儿。入组时间为1987~1996年,并随访至2003年。患者被随机分为4组,分别接受注射安慰剂+口服雌激素(40例)、注射生长激素+口服安慰剂(35例)、注射生长激素+口服雌激素(35例)或注射安慰剂+口服安慰剂(39例)治疗。

结果显示,注射生长激素组女孩身高较注射安慰剂组高出约5cm,其中注射生长激素+口服雌激素组身高增加更为明显,又高出2.3cm。此外,79%的注射生长激素+口服雌激素组女孩身高显著增加,单纯生长激素治疗组为65%,单纯雌激素治疗组为32%,而双安慰剂组仅为15%。

研究中报告27例严重不良事件,包括妇科疾病、疼痛、脊柱侧凸和甲状腺疾病。但未见新的或意外的生长激素和雌激素安全性问题。

来源:丁香园


英文:

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


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.)


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.