Somatotropic axis drives bone turnover heterogeneity independently of gonadotropin synergy in girls with central precocious puberty
TL;DR
Heterogeneity in bone turnover was more strongly and consistently associated with the somatotropic axis (IGF-1) than with gonadotropin activity, and no significant synergy was observed.
Abstract
Background The classic paradigm of somatotropic-gonadal axis synergy in pubertal bone acquisition lacks validation in central precocious puberty (CPP), and the driver of the significant bone turnover marker (BTM) heterogeneity in this population is unknown. Objective To investigate the independent and potential synergistic associations of insulin-like growth factor-1 (IGF-1) and peak luteinizing hormone (LH) with BTMs in girls with CPP. Methods This retrospective cohort included 190 treatment-naïve girls with CPP. Participants were stratified into Low, Medium, and High bone turnover groups based on tertiles of a bone age-standardized composite Z-score of bone gla protein (BGP) and β-C-terminal telopeptide (β-CTX). We used multiple linear regression adjusted for chronological age, supplemented by E-value analysis. Results Marked BTM heterogeneity was confirmed (p for trend < 0.001). IGF-1 and peak LH levels exhibited significant graded increases across groups (p for trend = 0.003 and 0.030). After age-adjustment, IGF-1 independently correlated with both BGP (β = 0.069, p = 0.005) and β-CTX (β = 0.001, p = 0.030), while peak LH associated only with BGP (β = 0.411, p = 0.026). Critically, the IGF-1 × LH peak interaction was non-significant (p = 0.655 and 0.791 for BGP and β-CTX, respectively). In contrast, glucolipid metabolic parameters showed no differences, arguing against their major role and highlighting neuroendocrine specificity. Conclusion In this cross-sectional study of girls with CPP, heterogeneity in bone turnover was more strongly and consistently associated with the somatotropic axis (IGF-1) than with gonadotropin activity, and no significant synergy was observed. These findings suggest a potential shift toward a somatotropic-dominant mechanism in the context of pathological pubertal acceleration, highlight IGF-1 as a pivotal biomarker for skeletal metabolism assessment, and challenge the classical paradigm of somatotropic-gonadal axis collaboration. The proposed mechanism requires validation in longitudinal studies.