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

18 Pages Posted: 22 Mar 2022

See all articles by Murillo Duarte-Silva

Murillo Duarte-Silva

University of São Paulo (USP) - Departamento de Análises Clínicas, Toxicológicas e Bromatológicas

Camilla Najara S. Oliveira

affiliation not provided to SSRN

Carlos Alessandro Fuzo

affiliation not provided to SSRN

Pedro Vieira da Silva-Neto Silva-Neto

University of São Paulo (USP) - Departamento de Análises Clínicas, Toxicológicas e Bromatológicas

Diana Mota Toro

affiliation not provided to SSRN

Vinícius Eduardo Pimentel

University of São Paulo (USP) - Departamento de Análises Clínicas, Toxicológicas e Bromatológicas; University of São Paulo (USP) - Faculdade de Medicina de Ribeirão Preto

Malena Martínez Pérez Pérez

affiliation not provided to SSRN

Thais F. C. Fraga-Silva

affiliation not provided to SSRN

Jonatan C. S. de Carvalho

affiliation not provided to SSRN

Firmino Martins dos Santos Neto

affiliation not provided to SSRN

Fernando C. Vilar

University of São Paulo (USP) - Ribeirão Preto Medical School

Augusto M. Degiovani

affiliation not provided to SSRN

Leticia F. Constant

affiliation not provided to SSRN

Fátima M. Ostini

affiliation not provided to SSRN

Marley R. Feitosa

affiliation not provided to SSRN

Rogerio S. Parra

affiliation not provided to SSRN

Gilberto G. Gaspar

affiliation not provided to SSRN

José J. R. da Rocha

affiliation not provided to SSRN

Omar Feres

affiliation not provided to SSRN

Angelina L. Viana

affiliation not provided to SSRN

Ana P. M. Fernandes

affiliation not provided to SSRN

Sandra R. Maruyama

affiliation not provided to SSRN

Elisa M. S. Russo

affiliation not provided to SSRN

Vânia L. D. Bonato

affiliation not provided to SSRN

Isabel K. F. M. Santos

affiliation not provided to SSRN

Carlos Arterio Sorgi Sorgi

affiliation not provided to SSRN

Marcelo Dias-Baruffi

affiliation not provided to SSRN

Lúcia Helena Faccioli Faccioli

University of São Paulo (USP) - Departamento de Análises Clínicas, Toxicológicas e Bromatológicas

Cristina Ribeiro de Barros Cardoso

affiliation not provided to SSRN

More...

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.

Keywords: COVID-19, testosterone, dihydrotestosterone, androgen receptor, SARS-CoV-2, sexual dimorphism

Suggested Citation

Duarte-Silva, Murillo and Oliveira, Camilla Najara S. and Fuzo, Carlos Alessandro and Silva-Neto, Pedro and Toro, Diana Mota and Pimentel, Vinícius Eduardo and Pérez, Malena and Fraga-Silva, Thais F. C. and Carvalho, Jonatan C. S. de and Neto, Firmino Martins dos Santos and Vilar, Fernando C. and Degiovani, Augusto M. and Constant, Leticia F. and Ostini, Fátima M. and Feitosa, Marley R. and Parra, Rogerio S. and Gaspar, Gilberto G. and Rocha, José J. R. da and Feres, Omar and Viana, Angelina L. and Fernandes, Ana P. M. and Maruyama, Sandra R. and Russo, Elisa M. S. and Bonato, Vânia L. D. and Santos, Isabel K. F. M. and Sorgi, Carlos and Dias-Baruffi, Marcelo and Faccioli, Lúcia Helena and Cardoso, Cristina Ribeiro de Barros, Reciprocally Divergent Levels of Testosterone and Dihydrotestosterone Accompany Patterns of Androgen Receptor Pathway Signaling to Dictate COVID-19 Outcomes in Men. Available at SSRN: https://ssrn.com/abstract=4063798 or http://dx.doi.org/10.2139/ssrn.4063798

Murillo Duarte-Silva

University of São Paulo (USP) - Departamento de Análises Clínicas, Toxicológicas e Bromatológicas ( email )

Av. do Café, s/n, Vila Monte Alegre
Ribeirão Preto, São Paulo 14040-900
Brazil

Camilla Najara S. Oliveira

affiliation not provided to SSRN ( email )

No Address Available

Carlos Alessandro Fuzo

affiliation not provided to SSRN ( email )

No Address Available

Pedro Silva-Neto

University of São Paulo (USP) - Departamento de Análises Clínicas, Toxicológicas e Bromatológicas ( email )

Av. do Café, s/n, Vila Monte Alegre
Ribeirão Preto, 14040-900
Brazil

Diana Mota Toro

affiliation not provided to SSRN ( email )

No Address Available

Vinícius Eduardo Pimentel

University of São Paulo (USP) - Departamento de Análises Clínicas, Toxicológicas e Bromatológicas ( email )

Av. do Café, s/n, Vila Monte Alegre
Ribeirão Preto, São Paulo 14040-900
Brazil

University of São Paulo (USP) - Faculdade de Medicina de Ribeirão Preto ( email )

Av. do Café, s/n - Jd. Monte Alegre
Ribeirão Preto, São Paulo 14040900
Brazil

Malena Pérez

affiliation not provided to SSRN

Thais F. C. Fraga-Silva

affiliation not provided to SSRN ( email )

No Address Available

Jonatan C. S. de Carvalho

affiliation not provided to SSRN ( email )

No Address Available

Firmino Martins dos Santos Neto

affiliation not provided to SSRN ( email )

No Address Available

Fernando C. Vilar

University of São Paulo (USP) - Ribeirão Preto Medical School ( email )

Augusto M. Degiovani

affiliation not provided to SSRN ( email )

No Address Available

Leticia F. Constant

affiliation not provided to SSRN ( email )

No Address Available

Fátima M. Ostini

affiliation not provided to SSRN ( email )

No Address Available

Marley R. Feitosa

affiliation not provided to SSRN ( email )

No Address Available

Rogerio S. Parra

affiliation not provided to SSRN ( email )

No Address Available

Gilberto G. Gaspar

affiliation not provided to SSRN ( email )

No Address Available

José J. R. da Rocha

affiliation not provided to SSRN ( email )

No Address Available

Omar Feres

affiliation not provided to SSRN ( email )

No Address Available

Angelina L. Viana

affiliation not provided to SSRN ( email )

No Address Available

Ana P. M. Fernandes

affiliation not provided to SSRN ( email )

No Address Available

Sandra R. Maruyama

affiliation not provided to SSRN ( email )

No Address Available

Elisa M. S. Russo

affiliation not provided to SSRN ( email )

No Address Available

Vânia L. D. Bonato

affiliation not provided to SSRN ( email )

No Address Available

Isabel K. F. M. Santos

affiliation not provided to SSRN ( email )

No Address Available

Carlos Sorgi

affiliation not provided to SSRN

Marcelo Dias-Baruffi

affiliation not provided to SSRN ( email )

No Address Available

Lúcia Helena Faccioli

University of São Paulo (USP) - Departamento de Análises Clínicas, Toxicológicas e Bromatológicas ( email )

Av. do Café, s/n, Vila Monte Alegre
Ribeirão Preto, São Paulo 14040-900
Brazil

Cristina Ribeiro de Barros Cardoso (Contact Author)

affiliation not provided to SSRN ( email )

No Address Available

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