Sex differences in COVID-19: candidate pathways, genetics of ACE2, and sex hormones

Am J Physiol Heart Circ Physiol. 2021 Jan 1;320(1):H296-H304. doi: 10.1152/ajpheart.00755.2020. Epub 2020 Dec 4.


Biological sex is increasingly recognized as a critical determinant of health and disease, particularly relevant to the topical COVID-19 pandemic caused by the SARS-CoV-2 coronavirus. Epidemiological data and observational reports from both the original SARS epidemic and the most recent COVID-19 pandemic have a common feature: males are more likely to exhibit enhanced disease severity and mortality than females. Sex differences in cardiovascular disease and COVID-19 share mechanistic foundations, namely, the involvement of both the innate immune system and the canonical renin-angiotensin system (RAS). Immunological differences suggest that females mount a rapid and aggressive innate immune response, and the attenuated antiviral response in males may confer enhanced susceptibility to severe disease. Furthermore, the angiotensin-converting enzyme 2 (ACE2) is involved in disease pathogenesis in cardiovascular disease and COVID-19, either to serve as a protective mechanism by deactivating the RAS or as the receptor for viral entry, respectively. Loss of membrane ACE2 and a corresponding increase in plasma ACE2 are associated with worsened cardiovascular disease outcomes, a mechanism attributed to a disintegrin and metalloproteinase (ADAM17). SARS-CoV-2 infection also leads to ADAM17 activation, a positive feedback cycle that exacerbates ACE2 loss. Therefore, the relationship between cardiovascular disease and COVID-19 is critically dependent on the loss of membrane ACE2 by ADAM17-mediated proteolytic cleavage. This article explores potential mechanisms involved in COVID-19 that may contribute to sex-specific susceptibility focusing on the innate immune system and the RAS, namely, genetics and sex hormones. Finally, we highlight here the added challenges of gender in the COVID-19 pandemic.

Keywords: ACE2; SARS-CoV-2; cardiovascular disease; gender; sex; sex differences.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • ADAM17 Protein / metabolism
  • Adaptive Immunity / genetics
  • Adaptive Immunity / immunology*
  • Androgens / immunology*
  • Androgens / metabolism
  • Angiotensin-Converting Enzyme 2 / genetics*
  • Angiotensin-Converting Enzyme 2 / metabolism
  • COVID-19 / genetics
  • COVID-19 / immunology*
  • COVID-19 / metabolism
  • COVID-19 / mortality
  • Cardiovascular Diseases / genetics
  • Cardiovascular Diseases / immunology
  • Estrogens / immunology*
  • Estrogens / metabolism
  • Female
  • Genes, X-Linked / genetics
  • Genes, X-Linked / immunology
  • Humans
  • Immunity, Innate / genetics
  • Immunity, Innate / immunology*
  • Male
  • Promoter Regions, Genetic
  • Receptors, Coronavirus / genetics*
  • Receptors, Coronavirus / metabolism
  • Renin-Angiotensin System / genetics
  • Renin-Angiotensin System / immunology
  • Response Elements / genetics
  • SARS-CoV-2 / metabolism
  • Severity of Illness Index
  • Sex Characteristics
  • Sex Factors
  • X Chromosome Inactivation


  • Androgens
  • Estrogens
  • Receptors, Coronavirus
  • Angiotensin-Converting Enzyme 2
  • ADAM17 Protein