Sex, androgens and regulation of pulmonary AR, TMPRSS2 and ACE2.

BioRxiv : the Preprint Server for Biology
M. BaratchianNima Sharifi

Abstract

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.

Citations

Sep 20, 2020·Biology of Sex Differences·Ajay Pradhan, Per-Erik Olsson
Jun 13, 2020·Nature Reviews. Immunology·Eileen P ScullySabra L Klein
Jul 10, 2020·Communications Biology·Dimple ChakravartyAshutosh K Tewari
Oct 30, 2020·European Endocrinology·Gagan PriyaChitra Selvan
Feb 27, 2021·Frontiers in Physiology·Susan Wray, Sarah Arrowsmith
Apr 8, 2021·Experimental & Molecular Medicine·Samantha Y Q OngSimon C Biddie
Apr 12, 2021·JAMA Pediatrics·Benjamin GastonJoe Zein
May 1, 2021·International Journal of Molecular Sciences·Alexandra M HuffmanDamian G Romero
May 26, 2021·Dermatologic Therapy·Hamideh MoravvejFahimeh Abdollahimajd

Datasets Mentioned

BETA
GSE103174
GSE123352
GSE16008
GSE18385
GSE37147
GSE43696
GSE61327
GSE994
GSE4115
GSE7895

Methods Mentioned

BETA
ChIP-seq
PCR
ChIP

Clinical Trials Mentioned

NCT04374279
NCT04475601
NCT04509999
NCT04397718

Related Concepts

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