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

Abstract

The recent emergence of SARS-CoV-2 and the subsequent COVID-19 pandemic have posed a public health crisis. Higher morbidity and mortality of men with COVID-19 may be explained by androgen-driven mechanisms. One such proposed mechanism is androgen regulation of pulmonary TMPRSS2, the host co-receptor for SARS-CoV-2. We find no evidence for increased TMPRSS2 mRNA expression in the lungs of males compared to females in humans or mice. Furthermore, in male mice, treatment with the androgen receptor antagonist enzalutamide does not decrease pulmonary TMPRSS2 expression. Nevertheless, regardless of sex, smoking significantly increases the expression of TMPRSS2, which reverts back to never-smoker levels in former smokers. Finally, we show that in mouse models, despite equivalent AR transcript levels, males express markedly higher amounts of AR protein. If a similar sex-specific regulation of AR protein occurs in human lung, androgens could play important roles in clinical outcome of COVID-19 through mechanisms other than TMPRSS2 regulation.

Enzalutamide, a prostate cancer therapeutic, downregulates TMPRSS2 in lung and reduces cellular entry of SARS-CoV-2

“…TMPRSS2 expression was also found to be similar between males and females ( Figure 3), but expression in the male lung was found to be slightly and signi cantly higher, in agreement with a previous study 45 . This is however, in contrast to other studies that have found no signi cant difference in TMPRSS2 expression in male and female lungs 37,46,47 . Further, Baratchian et al found higher levels of ACE2 in the male lung and proposed that alterations in the levels of this receptor could, at least in part, explain the gender disparity in COVID-19 severity 46 .…”

“…This is however, in contrast to other studies that have found no signi cant difference in TMPRSS2 expression in male and female lungs 37,46,47 . Further, Baratchian et al found higher levels of ACE2 in the male lung and proposed that alterations in the levels of this receptor could, at least in part, explain the gender disparity in COVID-19 severity 46 . It therefore remains unclear if gender differences in TMPRSS2 expression could explain why men suffer more severe symptoms following infection with SARS-CoV-2.…”

COVID-19 and Cancer: Current Challenges and Perspectives

“…However, it is still unclear whether the regulation of TMPRSS2 expression in normal human lung cells is androgen dependent (as it has been shown to be in prostate tissue). TMPRSS2 gene expression has been found to be similar between males and females in normal lung tissue (Baratchian et al, 2020;Stopsack et al, 2020), arguing against androgen-dependent regulation of TMPRSS2 in lung tissue. Moreover, in mouse models, TMPRSS2 gene and protein expression in lung tissue did not decrease upon exposure to a potent AR antagonist, enzalutamide (Baratchian et al, 2020).…”

“…TMPRSS2 gene expression has been found to be similar between males and females in normal lung tissue (Baratchian et al, 2020;Stopsack et al, 2020), arguing against androgen-dependent regulation of TMPRSS2 in lung tissue. Moreover, in mouse models, TMPRSS2 gene and protein expression in lung tissue did not decrease upon exposure to a potent AR antagonist, enzalutamide (Baratchian et al, 2020). These findings contrasted with those of other studies that found TMPRSS2 to be upregulated by testosterone treatment in a lung adenocarcinoma cell line (A549) and that AR is a regulator of TMPRSS2 in these cell lines based on chromatin immunoprecipitation assays (Mikkonen et al, 2010).…”

“…However, the relationship between age and ACE2 expression in lung tissue is disputed by some other studies that have found either no relationship (Smith et al, 2020a) or an inverse relationship (Booeshaghi and Pachter, 2020) between age and ACE2 expression in lung tissue. In addition, multiple studies have recently found that ACE2 expression in lung tissue is increased in patients who smoke or who suffer from smoking-related lung diseases such as chronic obstructive pulmonary disease (Baratchian et al, 2020;Pinto et al, 2020;Smith et al, 2020a). Moreover, there appears to be a doseresponse relationship between number of pack-years of smok-ing and ACE2 expression (Smith et al, 2020a).…”