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

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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.