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

Epidemiological data in COVID-19 mortality indicate that men are more prone to die of SARS-CoV2 infection than women, but biologic causes for this sexual dimorphism are unknown. We discuss the prospective behavioral and biological differences between the sexes that could be attributed to this gender-based differentiation. The female sex hormones and the immune stimulatory genes including toll-like receptors, interleukins, 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 modulate 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 post-translationally, thereby increasing viral load and delaying viral clearance in men as compared to women. We propose that modulating sex hormones, either by increasing estrogen or anti-androgen, may be a therapeutic option to reduce mortality from SARS-CoV-2.