Sex Differences in Statural Growth Impairment in Pediatric Crohn's Disease

描述（由申请人提供）：身高是儿科患者整体健康状况的动态标志。小儿克罗恩病常见的并发症是体格发育障碍。改善生长障碍和最终成人身高的治疗策略目前是次优的。克罗恩病对生长的影响可能由许多因素介导，包括炎症，营养和药物。了解克罗恩病生长受损的发病机制的一个潜在途径是它在男性中更常见。由于胰岛素样生长因子-1（IGF-1）是生长激素（GH）影响体格生长的主要介质，并且由于性类固醇对青春期生长突增有直接影响，因此我们假设克罗恩病的炎症特征对内分泌生长调节剂有更大的不利影响研究人员发现，在男性中，IGF-1水平，性激素水平和促性腺激素水平的变化，这些更大的负面炎症作用有助于解释男性对生长障碍的易感性增加。这一假设是基于我们对82例前瞻性收集的横断面数据的分析，这些数据显示男性的标准化IGF-1水平较低，并且炎症标志物与男性的性激素和促性腺激素水平相关，而不是女性。这些数据表明，疾病严重程度（炎症）对生长的影响因性别而异。在这里，我们建议通过对125例克罗恩病儿童患者（女性骨龄9-12岁，男性骨龄10-14岁）进行前瞻性多中心纵向队列研究来扩展这些发现，这些患者将接受2年随访。在目的1中，我们将确定激素在克罗恩病性别特异性生长障碍中的作用。在目标2中，我们将确定炎症对克罗恩病中激素（IGF-1、性激素、促性腺激素）和性别特异性生长障碍的影响，通过炎症细胞因子（TNF-α、IL-1β、IL-6、IL-1 RA）和非特异性炎症标志物（ESR、CRP、白蛋白）进行测量。在目标3中，我们将为每种性别开发一种预测模型，以基于一组血清和尿液生物标志物和临床变量来识别具有发生标准治疗方法难治性生长障碍的高风险克罗恩病患者。这里提出的研究是创新的，因为它提供了一个新的关注领域：炎症对下丘脑-垂体-性腺轴的影响，以及GH-IGF-1轴和这些途径对身高速度的影响。此外，我们还将确定标准治疗方法难以治疗的生长障碍高危患者。了解克罗恩病生长障碍的性别差异的潜在机制可能有助于我们开发新的有针对性的药物治疗策略，以改善身高增长速度和最终成人身高，并优化高危患者的当前治疗。这些高风险患者可能受益于早期引入高水平药物（“自上而下”方法），这是一种治疗范式，将成为小儿克罗恩病治疗的主要转折点。

DESCRIPTION (provided by applicant): Statural growth is a dynamic marker of overall health in pediatric patients. Statural growth impairment is a common complication of pediatric Crohn's disease. Treatment strategies for improving growth impairment and final adult height are currently suboptimal. The impact of Crohn's disease on growth is potentially mediated by many factors, including inflammation, nutrition, and medications. One potential avenue for understanding the pathogenesis of impaired growth in Crohn's disease is that it is more common in males. Since insulin-like growth factor-1 (IGF-1) is the primary mediator of growth hormone's (GH) effects on statural growth, and since sex steroids have a direct effect on the pubertal growth spurt, we hypothesize that the inflammation characteristic of Crohn's disease has greater adverse effects on endocrine growth regulators (IGF-1 levels, sex hormone levels, and gonadotropin levels) in males and that these greater negative inflammatory effects help explain the increased susceptibility to growth impairment in males. This hypothesis is based on our analyses of cross-sectional data collected prospectively in 82 patients showing that standardized IGF-1 levels were lower in males and that inflammatory markers were associated with sex hormone and gonadotropin levels in males, not females. These data suggest that the impact of disease severity (inflammation) on growth differs by sex. Here, we propose to extend these findings by conducting a prospective multicenter longitudinal cohort study of 125 pediatric patients with Crohn's disease (bone age 9-12 years in females and 10-14 years in males) who will be followed for 2 years. In Aim 1, we will determine the role of hormones in sex-specific growth impairment in Crohn's disease. In Aim 2, we will determine the impact of inflammation, measured by inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-1RA) and non-specific inflammatory markers (ESR, CRP, albumin), on hormones (IGF-1, sex hormones, gonadotropins) and sex- specific growth impairment in Crohn's disease. In Aim 3, we will develop a predictive model for each sex to identify patients with Crohn's disease at high risk for developing growth impairment refractory to standard therapeutic approaches based on a panel of serum and urine biomarkers and clinical variables. The research proposed here is innovative because it offers a new area of focus: the impact of inflammation on the hypothalamic-pituitary-gonadal axis in addition to the GH-IGF-1 axis and the impact of these pathways on height velocity. Furthermore, we will identify patients at high risk for developing growth impairment refractory to standard therapeutic approaches. Understanding the underlying mechanisms of sex differences in growth impairment in Crohn's disease may help us to develop new targeted medical treatment strategies to improve height velocity and final adult height and to optimize current treatments in high-risk patients. These high risk patients may benefit from early introduction of high level medications ("top-down" approach), a treatment paradigm that would be a major turning point in pediatric Crohn's disease therapy.