Abstract
OBJECTIVE: Age-related decline in circulating testosterone (T) levels in men varies significantly and is often linked to comorbidities such as Type 2 diabetes and cardiovascular disease (CVD). While the genetic basis of T levels is well studied, the role of genetics in age-related T decline remains unclear. This study aims to investigate the genetic contribution to age-related T decline in men and its association with comorbidities.
DESIGN: A longitudinal, population-based study in 6354 men including consecutive T, bioavailable testosterone (BAT), and sex hormone-binding globulin (SHBG) measurements.
METHODS: We assessed the association of longitudinal serum biomarker changes with changes in disease prevalences and a polygenic score (PGS) for BAT developed in 183 909 UK Biobank participants.
RESULTS: In the follow-up cohort (mean age: 58.2 years; mean follow-up: 4.3 years), baseline levels of BAT, T, and SHBG were each negatively associated with their respective relative changes at follow-up (all P < .001). A PGS for BAT, strongly associated with baseline levels (P = 2.2 × 10-16, R²=0.16), was not associated with BAT decline over time. Genome-wide analysis of BAT change identified no significant genetic loci. Instead, the BAT decline was associated with prevalence of several comorbidities including cancers and CVD (P = .007 and .012, respectively).
CONCLUSIONS: Non-genetic factors are strongly associated with age-related BAT decline, whereas genetic predisposition may have a limited role. However, this does not rule out a potential genetic contribution. Our findings offer insight into the relationship between comorbidities and hormonal changes, supporting further research into their roles in T decline and related health risks in aging men.