Mediating role of peripheral thyroid hormone conversion efficiency in the association between BMI and IGF-1 in children with growth retardation: a cross-sectional study

Objective To examine the association between body mass index (BMI) standard deviation score (SDS) and insulin-like growth factor-1 (IGF-1) SDS and whether thyroid hormones mediate it, focusing on the peripheral conversion marker free triiodothyronine/free thyroxine (FT3/FT4) ratio, in prepubertal children (2.0–9.0 years) with height SDS < –1.0. Methods This retrospective cross-sectional study included 1,242 such children. Restricted cubic splines assessed the BMI-IGF-1 relationship, and Bootstrap mediation (5,000 resamples) tested indirect effects of FT3/FT4, FT3, FT4, and thyroid-stimulating hormone (TSH), adjusted for sex, age and height SDS. Reverse mediation, subgroup, interaction, Monte Carlo power, and E-value sensitivity analyses were also performed. Results A significant linear positive association was found (P-overall < 0.001; P-nonlinear = 0.0719). FT3/FT4 and FT3 showed significant partial mediation, accounting for 9.12% (P < 0.001) and 11.60% (P = 0.0108) of the total effect, respectively; TSH and FT4 did not. Sensitivity analyses confirmed robustness after stricter prepubertal cutoffs and exclusion of overweight/obese children. Notably, only FT3/FT4 remained significant after excluding suspected Growth Hormone Deficiency (GHD) (IGF-1 SDS < –2.0). The FT3/FT4 ratio remained a significant mediator across all subgroup analyses. Reverse mediation analysis yielded a substantially smaller indirect effect in the reverse direction. E-values for FT3/FT4 and FT3 were 1.0764 and 1.0609, respectively. Conclusion In this growth-retarded prepubertal cohort, BMI and IGF-1 are linearly associated. The FT3/FT4 ratio is statistically supported as a partial mediator with moderate effect size but strong statistical robustness, while the central TSH pathway is uninvolved, supporting a peripheral “thrifty” regulatory strategy and offering a potential target for nutritional intervention. These mediation findings reflect statistical associations and require prospective validation.