Sex-derived attributes contributing to SARS-CoV-2 mortality

Abstract

Epidemiological data in COVID-19 mortality indicate that men are more prone to die of SARS-CoV-2 infection than women, but biological causes for this sexual dimorphism are unknown. We discuss the prospective behavioral and biological differences between the sexes that could be attributed to this sex-based differentiation. The female sex hormones and the immune stimulatory genes, including Toll-like receptors, interleukins, and micro-RNAs present on X-chromosome, may impart lesser infectivity and mortality of the SARS-CoV-2 in females over males. The sex hormone estrogen interacts with the renin-angiotensin-aldosterone system, one of the most critical pathways in COVID-19 infectivity, and modulates the vasomotor homeostasis. Testosterone on the contrary enhances the levels of the two most critical molecules, angiotensin-converting enzyme 2 (ACE2) and the transmembrane protease serine-type 2 (TMPRSS2), transcriptionally and posttranslationally, thereby increasing viral load and delaying viral clearance in men as compared with women. We propose that modulating sex hormones, either by increasing estrogen or antiandrogen, may be a therapeutic option to reduce mortality from SARS-CoV-2.

Keywords: SARS-CoV-2; hormones; immunity; morbidity; sex bias.

Fig. 1.

COVID-19 fatality may be influenced by sex-based differentiation. The reported COVID-19 fatality rate is higher in men as compared with women as per the available data for 47 countries. Source: https://globalhealth5050.org/covid19. Black bars represent %COVID-19 fatality rate in males and light gray bars %COVID-19 fatality rate in females for each country. Bars are presented in decreasing order of countrywise %difference between the male and female death rates.

Fig. 2.

Behavioral, hormonal, and X-chromosomal influence on COVID-19 infectivity. Straight vertical black arrows with respective heights represent the relative influence of each of the behavioral and biological factors on the 2 sexes. Behavioral factors in men such as increased smoking and drinking, lower rates of hand washing, delayed admission to a hospital, and noncompliance with social restrictions could attribute to their increased susceptibility to infection and fatality. Biologically, beneficial effects of estrogen over testosterone could be linked to sex-based differentiation between sexes. Furthermore, increased expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine type 2 (TMPRSS2) in men may attribute to their increased viral load and decreased viral clearance capacity. Potential beneficial effects of immune-stimulatory genes encoded from the 2 X-chromosomes in women vs. 1 X-chromosome and 1 Y-chromosome in men may influence sex-based difference between sexes.