Sex-dimorphic phenotypic divergence in metabolically driven thyroid nodules: the interplay of systemic inflammation and adiposity

Abstract

Metabolic dysfunction has been increasingly implicated in thyroid nodule development; however, the sex-specific interplay between systemic glucolipotoxicity, adiposity, inflammation, and thyroid nodule risk remains poorly understood. This study aimed to evaluate the association between the composite cholesterol, high-density lipoprotein, and glucose (CHG) index and thyroid nodules (TNs) and to explore the potential factors underlying sex-specific differences across Thyroid Imaging Reporting and Data System (TI-RADS) risk categories. This large-scale health check-up cohort included 24,878 participants who underwent routine health examinations in a unique sub-plateau cohort (altitude, ~ 2,000 m). The TNs were identified using high-resolution ultrasonography and classified using the TI-RADS grading system. The CHG index was used to quantify systemic metabolic burden. Guided by directed acyclic graphs (DAGs) for covariate selection, multivariable logistic regression was used to evaluate independent associations, and restricted cubic splines were used to assess nonlinear dose–response relationships. Statistical mediation analysis using red blood cell distribution width (RDW) as the mediator quantified the proportion attributable to systemic inflammation. Multivariable analyses revealed significant sex-dimorphic associations between the CHG index and TN risk. In men, elevated CHG levels were consistently associated with increased risk across nodular grades. Notably, the association with high-risk nodules (TI-RADS 4) was markedly attenuated and no longer statistically significant after adjusting for BMI, suggesting that adiposity may partly account for this association. Mediation analysis indicated that low-grade systemic inflammation (RDW) statistically explained a significant proportion of the metabolic-nodule association in men. In women, higher CHG was inversely associated with early-stage (TI-RADS 2) nodules. This pattern was more apparent among women aged ≥ 50 years, suggesting potential age-related heterogeneity; however, this finding should be interpreted with caution because direct hormonal data were unavailable. Furthermore, the CHG index demonstrated superior risk reclassification utility compared to isolated lipid parameters. The CHG index is associated with thyroid risk stratification in a sex-specific manner. These findings indicate that sex-dependent physiological characteristics may modify the association between metabolic factors and high-risk thyroid morphological patterns. In men, these patterns were more strongly associated with adiposity and inflammation, whereas in older women, these patterns may be related to adaptive morphological changes. These findings may inform sex-specific metabolic management strategies for thyroid care.