Abstract

Peak stimulated growth hormone (GH) levels are known to decrease with increasing body mass index (BMI), possibly leading to overdiagnosis of GH deficiency (GHD) in children with overweight and obesity. However, current guidelines do not guide how to interpret the peak GH values of these children. This systematic review and meta-analysis aimed to study the effect of the BMI standard deviation score (SDS) on stimulated peak GH values in children, to identify potential moderators of this association, and to quantify the extent to which peak GH values in children with obesity are decreased. This systematic review was performed by the PRISMA guidelines. Medline, Embase, Cochrane, Web of Science, and Google Scholar databases were searched for studies reporting the impact of weight status on peak GH in children. Where possible, individual participant data was extracted and/or obtained from authors. Quality and risk of bias were evaluated using the Scottish Intercollegiate Guidelines Network (SIGN) checklists. The primary outcome was the association between peak GH values and BMI SDS. The pooled correlation coefficient r, 95% confidence interval (CI), and heterogeneity statistic I² were calculated under a multilevel, random-effects model. In addition, exploratory moderator analyses and meta-regressions were performed to investigate the effects of sex, pubertal status, presence of syndromic obesity, mean age and mean BMI SDS on the study level. For the individual participant dataset, linear mixed-models regression analysis was performed with BMI SDS as the predictor and ln(peak GH) as the outcome, accounting for the different studies and GH stimulation agents used. In total, 58 studies were included, providing data on n = 5135 children (576 with individual participant data). Thirty-six (62%) studies had high, 19 (33%) medium, and 3 (5%) low risks of bias. Across all studies, a pooled r of −0.32 (95% CI −0.41 to −0.23, n = 2434 patients from k = 29 subcohorts, I² = 75.2%) was found. In meta-regressions, larger proportions of males included were associated with weaker negative correlations (p = 0.04). Pubertal status, presence of syndromic obesity, mean age, and mean BMI SDS did not moderate the pooled r (all p > 0.05). Individual participant data analysis revealed a beta of −0.123 (95% CI −0.160 to −0.086, p < 0.0001), i.e. per one-point increase in BMI SDS, peak GH decreases by 11.6% (95% CI 8.3–14.8%). To our knowledge, this is the first systematic review and meta-analysis to investigate the impact of BMI SDS on peak GH values in children. It showed a significant negative relationship. Importantly, this relationship was already present in the normal range of BMI SDS and could lead to overdiagnosis of GHD in children with overweight and obesity. With the ever-rising prevalence of pediatric obesity, there is a need for BMI (SDS)-specific cutoff values for GH stimulation tests in children. Based on the evidence from this meta-analysis, we suggest the following weight status-adjusted cutoffs for GH stimulation tests that have cutoffs for children with normal weight of 5, 7, 10, and 20 µg/L: for overweight children: 4.6, 6.5, 9.3, and 18.6 µg/L; and for children with obesity: 4.3, 6.0, 8.6, and 17.3 µg/L.

摘要

已知峰值刺激生长激素 (GH) 水平随着体重指数 (BMI) 的增加而降低，这可能导致超重和肥胖儿童对 GH 缺乏症 (GHD) 的过度诊断。然而，目前的指南并未指导如何解释这些儿童的峰值 GH 值。本系统评价和荟萃分析旨在研究 BMI 标准偏差评分 (SDS) 对儿童刺激峰值 GH 值的影响，以确定该关联的潜在调节因子，并量化患有以下疾病的儿童的峰值 GH 值的程度肥胖减少。本系统评价由 PRISMA 指南执行。在 Medline、Embase、Cochrane、Web of Science 和 Google Scholar 数据库中搜索了报告体重状态对儿童 GH 峰值影响的研究。在可能的情况，个人参与者数据是从作者那里提取和/或获得的。使用苏格兰校际指南网络 (SIGN) 检查表评估了偏倚的质量和风险。主要结果是 GH 峰值与 BMI SDS 之间的关联。合并相关系数r、95% 置信区间 (CI) 和异质性统计量I ²在多水平随机效应模型下计算。此外，还进行了探索性调节分析和元回归，以研究性别、青春期状态、是否存在综合征性肥胖、平均年龄和平均 BMI SDS 对研究水平的影响。对于个体参与者数据集，使用 BMI SDS 作为预测因子和 ln（GH 峰值）作为结果进行线性混合模型回归分析，考虑到不同的研究和使用的 GH 刺激剂。总共纳入了 58 项研究，提供了关于n = 5135 名儿童（576 名有个人参与者数据）。36 项 (62%) 研究具有高偏倚风险、19 项 (33%) 中偏倚风险和 3 (5%) 低偏倚风险。在所有研究中，发现汇总r为 -0.32（95% CI -0.41 至 -0.23，n  = 2434 名患者来自k  = 29 个亚组，I ² = 75.2%）。在元回归中，包括的男性比例越大，负相关越弱（p  = 0.04）。青春期状态、综合征性肥胖的存在、平均年龄和平均 BMI SDS 并没有缓和汇总r（所有p  > 0.05）。个体参与者数据分析显示 beta 为 -0.123（95% CI -0.160 至 -0.086，p < 0.0001)，即 BMI SDS 每增加 1 个点，GH 峰值降低 11.6%（95% CI 8.3–14.8%）。据我们所知，这是第一次调查 BMI SDS 对儿童 GH 峰值影响的系统评价和荟萃分析。它显示出显着的负相关。重要的是，这种关系已经存在于 BMI SDS 的正常范围内，并可能导致超重和肥胖儿童对 GHD 的过度诊断。随着儿童肥胖率的不断上升，需要针对儿童 GH 刺激测试的 BMI (SDS) 特定临界值。根据这项荟萃分析的证据，我们建议采用以下体重状态调整的 GH 刺激试验临界值，这些临界值适用于体重正常的儿童 5、7、10 和 20 µg/L：对于超重儿童：4.6， 6.5、9.3 和 18.6 µg/L；