RT Journal Article SR Electronic T1 Sex, androgens and regulation of pulmonary AR, TMPRSS2 and ACE2 JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.04.21.051201 DO 10.1101/2020.04.21.051201 A1 Mehdi Baratchian A1 Jeffrey M. McManus A1 Mike Berk A1 Fumihiko Nakamura A1 Sanjay Mukhopadhyay A1 Weiling Xu A1 Serpil Erzurum A1 Judy Drazba A1 John Peterson A1 Eric A. Klein A1 Ben Gaston A1 Nima Sharifi YR 2020 UL http://biorxiv.org/content/early/2020/10/14/2020.04.21.051201.abstract AB The sex discordance in COVID-19 outcomes has been widely recognized, with males generally faring worse than females and a potential link to sex steroids. A plausible mechanism is androgen-induced expression of TMPRSS2 and/or ACE2 in pulmonary tissues that may increase susceptibility or severity in males. This hypothesis is the subject of several clinical trials of anti-androgen therapies around the world. Here, we investigated the sex-associated TMPRSS2 and ACE2 expression in human and mouse lungs and interrogated the possibility of pharmacologic modification of their expression with anti-androgens. We found no evidence for increased TMPRSS2 expression in the lungs of males compared to females in humans or mice. Furthermore, in male mice, treatment with the androgen receptor antagonist enzalutamide did not decrease pulmonary TMPRSS2. On the other hand, ACE2 and AR expression was sexually dimorphic and higher in males than females. ACE2 was moderately suppressible with enzalutamide therapy. Our work suggests that sex differences in COVID-19 outcomes attributable to viral entry are independent of TMPRSS2. Modest changes in ACE2 could account for some of the sex discordance.Competing Interest StatementThe authors have declared no competing interest.