Recovery of Serum Testosterone Levels is an Accurate Predictor of Survival From COVID-19 in Male Patients

Background: Infection with SARS-CoV-2 portends a broad range of outcomes, from a majority of asymptomatic cases or mild clinical courses to a lethal disease. Robust correlates of severe COVID-19 include old age, male sex, poverty and co-morbidities such as obesity, diabetes and cardiovascular disease. A precise knowledge is still lacking of the molecular and biological mechanisms that may explain the association of severe disease with male sex. Methods: Clinical biochemical and haematological parameters of admission samples in 249 hospitalized male and 247 female COVID-19 patients, analysed for associations with outcome and sex. Longitudinal analyses of a subcohort of 114 male patients for biochemical and haematological parameters, as well as testosterone, luteinizing hormone and androstenedione, analysed for associations with outcome. Longitudinal analysis of circulating immune populations by flow cytometry in 24 male patients, analysed for associations of specific subpopulations with outcome. Findings: There are quantitative differences in biochemical predictors of disease outcome in male vs. female patients. Longitudinal analyses in a subcohort of male COVID-19 patients indicate that testosterone trajectories are the strongest predictors (AUC of ROC = 92.8%, p < 0.0001) of survival in these patients among all biochemical parameters studied, including single-point admission serum testosterone values. Longitudinal determinations of blood levels of luteinizing hormone (LH) and androstenedione suggest an early inhibition of the central LH-androgen biosynthesis axis in a majority of patients, followed by either full recovery in survivors or a peripheral failure in lethal cases. Finally, failure to reinstate physiological testosterone levels was associated with evidence of impaired T helper differentiation and augmented circulating classical monocytes. Interpretation: Recovery or failure to reinstate testosterone levels is strongly associated with survival or death from COVID-19 in male patients. Our observations are suggestive of a significant role of testosterone status in the immune responses to COVID-19. Funding Information: Ministerio de Ciencia e Innovacion (RTI2018-096055-B-I00), Consejo Superior de Investigaciones Cientificas’ COVID-19 Research Fund (CSIC-COV19-006, CSIC-COV19-201), Agencia de Gestio d’Ajuts Universitaris i de Recerca (2020PANDE00048 and 2017SGR 1411 GRC) and Plan Nacional de I+D (PID-107139RB-C21) and Instituto Nacional de la Salud Carlos III (PI18/00346 and COVID-19_00416). Declaration of Interests: Authors declare no conflict of interest. Ethics Approval Statement: protocol reviewed and approved by the Hospital Vall d’Hebron Institutional Review Board (Medical Research Ethics Committee, protocol number PR(AG)329-2020). Immunophenotyping studies of peripheral blood cells underwent a separate review and approval process (protocol number PR(AG)242/2020).