Androgen Imbalance, Cardiovascular-Kidney-Metabolic Syndrome Stages, and Mortality in Men

BACKGROUND: Androgen measures reflect adiposity, metabolic health, and systemic illness, but their associations with cardiovascular-kidney-metabolic (CKM) syndrome and mortality may differ across measures and combined profiles. OBJECTIVES: The objective of the study was to examine associations of total testosterone (TT), sex hormone-binding globulin (SHBG), calculated free testosterone (cFT), and joint TT-SHBG phenotypes with prevalent advanced CKM syndrome and mortality. METHODS: We analyzed men aged ≥20 years in the National Health and Nutrition Examination Survey 2013 to 2016 using survey-weighted logistic (odds ratio [OR]) and Cox (hazard ratio [HR]) regression models. Advanced CKM syndrome comprised determinate National Health and Nutrition Examination Survey-adapted stages 3 to 4; cFT was calculated using the Vermeulen equation. Analyses assessed adiposity adjustment and mortality robustness. RESULTS: Among 5,505 men, 4,005 had determinate CKM status. Low measured TT was associated with prevalent advanced CKM syndrome (OR: 1.78; 95% CI: 1.31-2.42), but the association was attenuated after adjustment for body mass index (OR: 1.27; 95% CI: 0.90-1.79) or waist circumference (OR: 1.22; 95% CI: 0.85-1.75), suggesting that adiposity may partly account for this association. Low TT and cFT measures showed no consistent association with all-cause mortality. In exploratory analyses, the low-TT/high-SHBG phenotype was associated with higher all-cause mortality (HR: 2.06; 95% CI: 1.18-3.58). CONCLUSIONS: Low measured TT was associated with prevalent advanced CKM syndrome, but this association was strongly adiposity-dependent. The low-TT/high-SHBG profile showed an exploratory mortality association not observed for TT or cFT alone and may represent a distinct systemic-vulnerability phenotype. These findings underscore the noninterchangeability of androgen measures and support prospective evaluation of combined TT-SHBG profiles.