Stanniocalcin-2 Regulates Linear Growth via Growth Hormone/Insulin-like Growth Factor-1 Axis in Idiopathic Short Stature

Background: Idiopathic short stature (ISS) is characterized by a height below the mean for age, sex, and population, without identifiable systemic, endocrine, nutritional, or chromosomal abnormalities. Dysregulation of the growth hormone/insulin-like growth factor-1 (IGF-1) axis, particularly IGF-1 bioavailability, is a suspected contributor. Stanniocalcin-2 (STC2) inhibits pregnancy-associated plasma protein-A2, a protease that releases IGF-1 from its binding proteins. To investigate the association between circulating STC2 level, free IGF-1 bioavailability, and linear growth in children with ISS. Methods: This case–control study included 88 participants (45 children with ISS, 43 controls) aged 4–18 years. Serum STC2, total IGF-1, free IGF-1, and insulin-like growth factor-binding proteins (IGFBP)-3 levels were measured by the ELISA. Results: Children with ISS exhibited significantly lower free IGF-1 (213 vs. 291 pg/mL, P = 0.001) and IGFBP-3 (5.17 vs. 6.18 ng/mL, P = 0.003) levels than controls, while total IGF-1 remained comparable ( P = 0.415). The IGF-1/IGFBP-3 ratio was reduced (27.4% vs. 32%, P = 0.039), as was the free/total IGF-1 ratio (0.14% vs. 0.18%, P = 0.021). STC2 was elevated in ISS patients aged ≥11 years (50.2 vs. 33.7 pg/mL, P = 0.034). Correlation analysis revealed negative associations between STC2 and both height ( r s = −0.351, P = 0.004) and free IGF-1 ( r s = −0.463, P < 0.05). Mediation analysis confirmed that free IGF-1 mediates STC2 effect on height (indirect effect β = −0.073). Multivariate logistic regression identified free IGF-1 as an independent predictor of ISS (Odds ratio = 0.99, P = 0.0016). Conclusion: Impaired growth in ISS was more closely associated with reduced IGF-1 bioavailability than with deficient production. Elevated STC2 levels, particularly in older children, contribute to a decrease in free IGF-1 levels.