Abstract: Endocrinology, 2021, Vol. 162, No. 8, 1–4 doi:10.1210/endocr/bqab114 Perspective Perspective Franck Mauvais-Jarvis1,2,3 1 Department of Medicine, Section of Endocrinology, Tulane University School of Medicine, New Orleans, LA, USA; 2Tulane Center of Excellence in Sex-Based Biology & Medicine, New Orleans, LA, USA; and 3 Southeast Louisiana VA Medical Center, New Orleans, LA, USA ORCiD number: 0000-0002-0874-0754 (F. Mauvais-Jarvis). Received: 29 April 2021; Editorial Decision: 1 June 2021; First Published Online: 5 June 2021; Corrected and Typeset: 7 July 2021. Abstract Coronavirus disease 2019 (COVID-19) is characterized by a gender disparity in severity, with men exhibiting higher hospitalization and mortality rates than women. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, infects cells following recognition and attachment of the viral spike glycoprotein to the angiotensin-converting enzyme 2 transmembrane protein, followed by spike protein cleavage and activation by cell surface transmembrane protease serine 2 (TMPRSS2). In prostate cancer cells, androgen acting on the androgen receptor increases TMPRSS2 expression, which has led to the hypothesis that androgen-dependent expression of TMPRSS2 in the lung may increase men’s susceptibility to severe COVID-19 and that, accordingly, suppressing androgen production or action may mitigate COVID-19 severity by reducing SARS-CoV-2 amplification. Several ongoing clinical trials are testing the ability of androgen deprivation therapies or anti-androgens to mitigate COVID-19. This perspective discusses clinical and molecular advances on the rapidly evolving field of androgen receptor (AR) action on cell surface transmembrane protease serine 2 (TMPRSS2) expression and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and the potential effect of anti-androgens on coronavirus disease 2019 (COVID-19) severity in male patients. It discusses limitations of current studies and offers insight for future directions. Key Words: androgens, testosterone, TMPRSS2, ACE2, SARS-CoV-2, COVID-19, sex differences As of June 2021, with over 170 000 000 confirmed cases of COVID-19 worldwide, the percentage of confirmed cases is equal among men and women. However, among more than 3 500 000 deaths globally, for every 10 female confirmed cases that have died from COVID-19, there are 15 males (https:// globalhealth5050.org/the-sex-gender-and-covid-19-project/ the-data-tracker/). Several mechanisms have been proposed to explain this relative female protection from severe COVID-19 outcomes, with the most likely being related to women’s more robust immune response to viruses (1). SARS-CoV-2 entry and infection of cells is mediated by recognition and attachment of the viral spike glycoprotein ISSN Online 1945-7170 © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com https://academic.oup.com/endo   1 Do Anti-androgens Have Potential as Therapeutics for COVID-19? 2 evidence indicates that ADT prevents COVID-19 infection or mitigates COVID-19 severity. Thus, several randomized clinical trials (RCTs) have begun to test the efficacy of ADT in the general population of male COVID-19 patients. The most interesting to..