Higher premorbid serum testosterone predicts COVID-19-related mortality risk in men

Objective Men are at greater risk from COVID-19 than women. Older, overweight men, and those with type 2 diabetes, have lower testosterone concentrations, and poorer COVID-19-related outcomes. We analysed associations of premorbid serum testosterone concentrations, not confounded by effects of acute SARS-CoV-2 infection, with COVID-19-related mortality risk in men. Design UK Biobank prospective cohort study of community-dwelling men aged 40-69 years. Methods Serum total testosterone and sex hormone-binding globulin (SHBG) were measured at baseline (2006-2010). Free testosterone values were calculated (cFT). Incidence of SARS-CoV-2 infections and deaths related to COVID-19 were ascertained from 16 March 2020-31 January 2021, and modelled using time-stratified Cox regression. Results In 159,964 men there were 5,558 SARS-CoV-2 infections and 438 COVID-19 deaths. Younger age, higher body mass index, non-white ethnicity, lower educational attainment, and socio-economic deprivation were associated with incidence of SARS-CoV-2 infections, but total testosterone, SHBG, and cFT were not. Adjusting for potential confounders, higher total testosterone was associated with COVID-19-related mortality risk (overall trend P=0.008; hazard ratios, HR [95% confidence intervals] quintile 1, Q1 vs Q5 [reference]: 0.84 [0.65-1.12], Q2:Q5 0.82 [0.63-1.10], Q3:Q5 0.80 [0.66-1.00], Q4:Q5 0.82 [0.75-0.93]). Higher SHBG was also associated with COVID-19 mortality risk (P=0.008), but cFT was not (P=0.248). Conclusions Middle-aged to older men with the highest premorbid serum total testosterone and SHBG concentrations are at greater risk of COVID-19-related mortality. Men could be advised that having relatively high serum testosterone concentrations does not protect against future COVID-19-related mortality. Further investigation of causality and potential underlying mechanisms is warranted.