Reciprocally Divergent Levels of Testosterone and Dihydrotestosterone Accompany Patterns of Androgen Receptor Pathway Signaling to Dictate COVID-19 Outcomes in Men

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Abstract
Background: Adequate management of COVID-19 needs data that predict its outcomes in men and explain its sexual dimorphism. This study evaluated immunoendocrine mediators, gene expression profiles and their correlations in a large cohort of controls and COVID-19 patients with different clinical presentations. Methods: Analyses of a public databank confirmed the sex bias for unfavorable clinical outcomes in Brazilian men infected with SARS-CoV-2. A local cohort was then assessed for clinical outcomes and levels of steroids and immune mediators. This data and global gene expression profiles of blood leukocytes were correlated. Statistical analyses considered confounding factors in order to parse the role of androgens in COVID-19. Findings: In men infected with SARS-CoV-2, levels of inflammation mediators presented significant negative correlations with levels of testosterone, which were partially dependent of age and diabetes, comorbidities related to severe COVID-19. The androgen receptor signaling pathway was significantly upregulated in men presenting with severe COVID-19, including expression of TMPRSS2 and SRD5A1 genes, the products whereof provide for virus entrance and dihydrotestosterone production, respectively. Levels of dihydrotestosterone were significantly and positively associated with relative risk of death; in contrast, levels of testosterone were significantly and positively associated with protection against severe COVID-19. This study also identified combined sets of immune-endocrine parameters that predict progression from non-severe to severe COVID-19 in men. Interpretation: The data points to venues of investigation to determine mechanisms dictating outcomes of COVID-19 in men. Sex-specific management of disease, vaccination and sequelae should be considered when establishing measures to control the COVID-19 pandemic. Funding Information: This work was supported by The São Paulo Research Foundation (Fundação de Amparo à Pesquisa do Estado de São Paulo, FAPESP), under grants #2020/05207-6 for L.H.F., #2020/05270-0 for V.D.B and #2021/04590-3 for C.A.S. This study also had the financial support from National Council for Scientific and Technological Development (CNPq), #302514/2015-5-CNPq for L.H.F.; #303259/2020-5-CNPq for M.D.B. and #309583/2019-5-CNPq for C.R.B.C.; and from the Coordination for the Improvement of Higher Educational Personnel (CAPES-Finance Code 001), as well as Pró-Reitoria de Pesquisa da Universidade de São Paulo, grant-USP-VIDA. Declaration of Interests: All the authors declare no competing interests. Ethics Approval Statement: The study protocols were in accordance with the Brazilian national committee of ethics in research (CONEP), under code CAAE: 30525920∙7∙0000∙5403. Informed consent was obtained from the enrolled participants, as approved by CONEP.