Association between vitamin D and central precocious puberty in children: Threshold effects and mediation mechanisms based on LC-MS/MS quantitation.

PURPOSE: To investigate the association between serum 25-hydroxyvitamin D [25(OH)D] levels and central precocious puberty (CPP) in children, with emphasis on sex-specific threshold effects and mediation pathways.

METHODS

This cross-sectional study enrolled 494 CPP patients (female: 413; male: 81) and 2,259 age-matched healthy controls who underwent ​liquid chromatography-tandem mass spectrometry (LC-MS/MS) based 25(OH)D quantification, Tanner-Whitehouse 3 bone age assessment, and hormonal profiling. Dose-response relationships were analyzed via restricted cubic splines (RCS), and causal mediation analysis with 1,000 bootstrap resamples were quantified using structural equation models.

RESULTS

CPP patients exhibited significantly lower 25(OH)D levels than controls (median (IQR): females, 20.00 (14.00-24.20) vs. 23.40 (18.10-29.22) ng/mL, P < 0.001; males, 21.60 (16.00-27.10) vs. 23.30 (18.30-28.83) ng/mL, P = 0.033), with higher deficiency rates (females: 49.6% vs. 33.0%; males: 43.2% vs. 32.8%). RCS analysis revealed inverse 25(OH)D-CPP associations, with threshold concentrations at 35.4 ng/mL (females) and 19.5 ng/mL (males).​ Each 1 ng/mL increment in serum 25(OH)D was associated with 3.6% reduced risk of advanced pubic hair maturation (adjusted OR = 0.964, P = 0.009). Sex-stratified logistic regression showed elevated CPP risks in vitamin D-insufficient/deficient groups versus sufficient counterparts: females (OR = 2.13, P = 0.037; OR = 2.26, P = 0.030) and males (OR = 3.89, P = 0.059; OR = 4.71, P = 0.034). Mediation analysis identified bone age acceleration (64.6% mediation) and gonadotropin activation (14.6%) dominated pathways in females.

CONCLUSION

Vitamin D demonstrated sex-dimorphic associations with CPP risk, requiring higher protective thresholds in females. Bone age acceleration and gonadotropin activation emerged as primary mediators in females. These findings advocated sex-specific vitamin D supplementation strategies for CPP prevention.