JACC Advances · Nov 5, 2026

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

By Liu K, Wang Y, Wang Z et al.

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.

doi.org/10.1016/j.jacadv.2026.103431 Open access PubMed 42987715 Populations