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Review
. 2020 Oct;177(19):4375-4385.
doi: 10.1111/bph.15207. Epub 2020 Aug 5.

Sex-related differences in COVID-19 lethality

Claudia Penna  1   2 , Valentina Mercurio  3 , Carlo G Tocchetti  3   4 , Pasquale Pagliaro  1   2
Affiliations
Review

Sex-related differences in COVID-19 lethality

Claudia Penna et al. Br J Pharmacol. 2020 Oct.

Abstract

Many countries have been affected by the worldwide outbreak of COVID-19. Among Western countries, Italy has been particularly hit at the beginning of the pandemic, immediately after China. In Italy and elsewhere, women seem to be less affected than men by severe/fatal COVID-19 infection, regardless of their age. Although women and men are affected differently by this infection, very few studies consider different therapeutic approaches for the two sexes. Understanding the mechanisms underlying these differences may help to find appropriate and sex specific therapies. Here, we consider that other mechanisms are involved to explain this difference, in addition to the protection attributable to oestrogens. Several X-linked genes (such as ACE2) and Y-linked genes (SRY and SOX9) may explain sex differences. Cardiovascular comorbidities are among the major enhancers of virus lethality. In addition, the number of sex-independent, non-genetic factors that can change susceptibility and mortality is enormous, and many other factors should be considered, including gender and cultural habits in different countries.

Keywords: ACE; ACE2; androgens; cardiovascular comorbidities; coronavirus; oestrogens.

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Conflict of interest statement

Relationship: Dr. Tocchetti has a Canadian Patent No. 2,613,477, issued on December 3, 2013 Inventors: Nazareno Paolocci, David A Kass, Carlo G Tocchetti. Owner: Johns Hopkins University Entitled: THIOL‐SENSITIVE POSITIVE INOTROPES JHU Ref.: C04755‐P04755‐05 with royalties paid. No other relationships/conditions/circumstances that present a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Possible role of ACE/ACE2 ratio in therapies against COVID‐19 in the two sexes. It has been proposed that pathological conditions presenting with a high ACE/ACE2 ratio predispose towards worse COVID‐19 outcomes (Gemmati et al., 2020; Pagliaro & Penna, 2020). ACE2 is a membrane‐bound enzyme, whose gene lies on the X chromosome and is up‐regulated by oestrogens in males and females. Throughout the body, the ACE/ACE2 ratio may be lower in women than in men, and this is theoretically protective because of the anti‐inflammatory properties of ACE2. However, it must be kept in mind that ACE2 in the lung may act as the entry gate for COVID‐19, and the ACE/ACE2 ratio may be different in tissues and organs, and that this ratio is influenced by many factors including, exercise, ageing, and diseases (Crisafulli & Pagliaro, 2020). Therefore, more studies are necessary to clarify the role of the ACE/ACE2 ratio in the two sexes
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