Sex hormones in SARS-CoV-2 susceptibility: key players or confounders?

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has a clear sex disparity in clinical outcomes. Hence, the interaction between sex hormones, virus entry receptors and immune responses has attracted major interest as a target for the prevention and treatment of SARS-CoV-2 infections. This Review summarizes the current understanding of the roles of androgens, oestrogens and progesterone in the regulation of virus entry receptors and disease progression of coronavirus disease 2019 (COVID-19) as well as their therapeutic value. Although many experimental and clinical studies have analysed potential mechanisms by which female sex hormones might provide protection against SARS-CoV-2 infectivity, there is currently no clear evidence for a sex-specific expression of virus entry receptors. In addition, reports describing an influence of oestrogen, progesterone and androgens on the course of COVID-19 vary widely. Current data also do not support the administration of oestradiol in COVID-19. The conflicting evidence and lack of consensus results from a paucity of mechanistic studies and clinical trials reporting sex-disaggregated data. Further, the influence of variables beyond biological factors (sex), such as sociocultural factors (gender), on COVID-19 manifestations has not been investigated. Future research will have to fill this knowledge gap as the influence of sex and gender on COVID-19 will be essential to understanding and managing the long-term consequences of this pandemic.

Sex chromosome complement and sex steroid signaling underlie sex differences in immunity to respiratory virus infection

“…In the COVID-19 pandemic, observations of a male bias in mortality led to clinical trials involving estrogen or selective ER modulator administration or androgen blockade. To date, these clinical trials for COVID-19 have been inconclusive, and the field currently lacks consensus as to whether disparate sex steroid levels drive susceptibility or infection outcomes in the human population [reviewed in ( Lott et al, 2022 )]. Human studies that ascertain hormonal and chromosomal sex will benefit the field, as valuable data may be lost when sex steroid levels and sex chromosome complement are not considered and/or assumed to match overt gender identity.…”

“…Estrus-diestrus levels of E2 promote inflammatory DC differentiation by upregulating IRF4 in myeloid progenitors ( Carreras et al, 2010 ). However, despite these advances in our understanding, differing levels of sex steroids in the human population have not been conclusively linked with infection outcome in the COVID-19 pandemic [reviewed in ( Lott et al, 2022 )].…”

“…Sex differences in lung architecture secondary to sex steroid levels may contribute to differential immunity to respiratory virus infection ( Carey et al, 2007 ). Sex-specific expression levels of viral entry receptors, such as ACE2 or TMPRSS2 for SARS-CoV-2, may impact the initiation or magnitude of infection ( Lott et al, 2022 ).…”

Renin-Angiotensin System and Sex Differences in COVID-19: A Critical Assessment

“… 13 However, clinical studies indicate no significant differences in pulmonary ACE2 expression among females and males, and infection rates are comparable that further suggest similar expression of ACE2. 12 , 23 , 34 , 39 , 40 , 45 ACE2 is subject to posttranscriptional regulation through proteolytic release or shedding from the cell membrane by other proteases such as ADAM17. 13 , 66 The shedding of ACE2 typically results in a soluble protein that retains full catalytic activity and binding to the spike domain of SARS-CoV-2.…”

“…22 A potential consequence of SARS-CoV-2 infection is the disappearance of cell surface ACE2 by internalization of the viral-ACE2 complex and the subsequent activation of the RAS (higher ratio of Ang II:Ang- [1][2][3][4][5][6][7]) to exacerbate the acute inflammatory events in COVID-19 patients and contribute to the cardiovascular effects of long COVID (Figure 2). 13,15,18,[23][24][25] A second striking aspect of SARS-CoV-2 infection is the prevalence of greater disease severity in male COVID-19 patients as compared with females. Indeed, among the major risk factors for COVID-19 severity that include age, obesity, cardiovascular disease, smoking, and diabetes is the male sex.…”