Revisiting the role of Insulin-Like Growth Factor-1 in childhood growth hormone deficiency: Diagnostic accuracy, biological context, and growth outcomes

Background: The diagnostic value of insulin-like growth factor-1 (IGF-1) in pediatric growth hormone deficiency (GHD) is constrained by biological variability and overlap with normal growth variants, particularly constitutional delay of growth and puberty (CDGP). Objective: The primary aim of our review was to assess whether biologically contextualized interpretation of IGF-1, adjusted for bone age and pubertal status, improves diagnostic accuracy and prediction of growth outcomes in children with short stature. Methods: A systematic review of 66 peer-reviewed studies (1987–2025) was conducted, including diagnostic cohorts, longitudinal registries, randomized trials, and methodological analyses. Studies evaluated IGF-1 interpretation based on chronological age (CA), bone age (BA), pubertal stage, and derived indices, and examined associations with GH stimulation testing, growth velocity, and adult height. Results: Age- and sex-adjusted IGF-1 standard deviation scores (SDS) showed high specificity (70–90%) but low sensitivity (20–45%), resulting in frequent false-negative classification in biologically immature children. Adjustment of IGF-1 to bone age markedly improved specificity (85–95%) and positive predictive value. Pubertal stage–specific interpretation yielded the highest rule-in value in peripubertal children, with specificities exceeding 90%. Longitudinal evidence demonstrated stronger correlations between BA-adjusted IGF-1 and first-year growth velocity (r ≈ 0.65) compared with CA-adjusted measures. Although GH stimulation tests retain high sensitivity (85–95%), their reproducibility and safety limitations remain significant. Emerging indices such as the IGF-1/age ratio demonstrated promising screening performance, with an area under the curve (AUC) of approximately 0.92. Conclusion: Integrating bone age and pubertal status into IGF-1 interpretation improves diagnostic specificity, reduces misclassification, and supports more rational use of GH stimulation testing in pediatric growth evaluation.