The impact of androgens with their regulatory proteins on heart failure
C Evers, N Friedrich, S Gross, T Ittermann, K Lehnert, M Bahls, C Templin, A LebedevaAbstract
Background
Sex differences are well established in heart failure (HF) epidemiology and pathophysiology, with a significant male prevalence, especially in cases with reduced ejection fraction. Yet the role of sex hormone imbalance in early myocardial stress remains incompletely understood.
Purpose
This study investigated sex-specific associations of androgen metabolites and regulators, including sex hormone–binding globulin (SHBG), androstenedione, and testosterone, with N-terminal pro-B-type natriuretic peptide (NT-proBNP) as a biomarker of myocardial stress and incident heart failure.
Methods
Data were derived from the population-based Study of Health in Pomerania (SHIP), with the SHIP-START-0 cohort (n=2,630) used for the initial cross-sectional assessment and the SHIP-START-1 (n=1,862) and SHIP-START-2 (n=1,405) cohorts used for the longitudinal follow-up. Baseline concentrations of SHBG, androstenedione, and total testosterone were analyzed in relation to NT-proBNP levels and the presence of clinically defined incident heart failure with preserved and reduced ejection fraction. Multivariable linear and logistic regression models were used and adjusted for demographic, smoking status, physical activity, metabolic syndrome, diabetes mellitus, arterial hypertension, kidney function, and lipid status.
Results
The correlation with incident heart failure was non-significant for all the hormonal markers, except for a mild association with higher androstenedione levels at a baseline assessment (adjusted hazard ratio [HR] = 0.71; 95% confidence interval [CI]: 0.53-0.94; p = 0.02). However, the NT-proBNP concentration as a marker of myocardial stress was independently positively associated with SHBG and androstenedione levels at a baseline assessment, and these associations remained significant after adjustment for traditional cardiovascular risk factors (adjusted HR and 95% CI = 0.46; 0.22-0.71; p = 0.00 for SHBG; 29.22; 10.93-47.51; p = 0.00 for androstenedione). Moreover, initial SHBG and androstenedione levels were also positively associated with the NT-proBNP concentrations during the follow-up (adjusted HR and 95% CI = 0.32; 0.14-0.49; p = 0.00 for SHBG; 10.32; 3.75-16.89; p = 0.00 for androstenedione).
Conclusion
In this population-based cohort, circulating SHBG and androstenedione, but not total testosterone, were independently positively associated with baseline and longitudinal NT-proBNP concentrations after comprehensive adjustment. These findings suggest that sex hormone regulation and metabolism are linked to myocardial stress in cases without overt heart failure. The lack of a consistent association with clinically manifesting HF indicates that these markers may primarily reflect subclinical cardiac remodeling. Our results highlight the relevance of androgen bioavailability over absolute testosterone levels and support further studies combining hormonal profiling with imaging-based cardiac phenotyping.