Sex-related susceptibility in coronavirus disease 2019 (COVID-19): Proposed mechanisms

Abstract

The importance of sex differences is increasingly acknowledged in the incidence and treatment of disease. Accumulating clinical evidence demonstrates that sex differences are noticeable in COVID-19, and the prevalence, severity, and mortality rate of COVID-19 are higher among males than females. Sex-related genetic and hormonal factors and immunological responses may underlie the sex bias in COVID-19 patients. Angiotensin-converting enzyme 2 ( ACE2 ) and transmembrane protease/serine subfamily member 2 ( TMPRSS2 ) are essential proteins involved in the cell entry of SARS-CoV-2. Since ACE2 is encoded on the X-chromosome, a double copy of ACE2 in females may compensate for virus-mediated downregulation of ACE2 , and thus ACE2 -mediated cellular protection is greater in females. The X chromosome also contains the largest immune-related genes leading females to develop more robust immune responses than males. Toll-like receptor-7 (TLR-7), one of the key players in innate immunity, is linked to sex differences in autoimmunity and vaccine efficacy, and its expression is greater in females. Sex steroids also affect immune cell function. Estrogen contributes to higher CD4 + and CD8 + T cell activation levels, and females have more B cells than males. Sex differences not only affect the severity and progression of the disease, but also alter the efficacy of pharmacological treatment and adverse events related to the drugs/vaccines used against COVID-19. Administration of different drugs/vaccines in different doses or intervals may be useful to eliminate sex differences in efficacy and side/adverse effects. It should be noted that studies should include sex-specific analyses to develop further sex-specific treatments for COVID-19.

Cellular Immune Response to BNT162b2 mRNA COVID-19 Vaccine in a Large Cohort of Healthcare Workers in a Tertiary Care University Hospital

“…Other authors did not observe a gender effect [ 12 , 23 , 38 , 39 ]; there is scarceness of literature data on this issue, and this finding should be re-evaluated with more relevant evidence from other studies. For SARS-CoV-2 infection and severity, a role has been proposed for encoding on the X-chromosome of the angiotensin-converting enzyme 2 and the largest immune-related genes leading females to develop more robust immune responses, as well as a role for sex hormones [ 46 ].…”

Estimation of Excess All-Cause Mortality Due to COVID-19 in Thailand

“…These studies revealed that the majority of excess deaths were attributable to COVID-19. Moreover, other studies have suggested that the risk of COVID-related death in males may be related to susceptibility to severe SARS-CoV-2 infections and male hormones [ 46 , 47 , 48 ]. Therefore, gender could be a risk factor for COVID-related mortality.…”

Characterization of Clinical Features of Hospitalized Patients Due to the SARS-CoV-2 Infection in the Absence of Comorbidities Regarding the Sex: An Epidemiological Study of the First Year of the Pandemic in Brazil

“…According to Aksoyalp and Nemutlu-Samur (2021), estrogen regulates ACE negatively and, at the same time, regulates ACE2, AT2 Receptor, and MAS enzyme positively. Therefore, higher ACE2 and Ang 1-7 production are observed in the female population than in men [ 72 ]. Estradiol also inhibits the TMPRSS2, which is needed for the virus to bind with ACE2 and increases disintegrin and metalloprotease 17 expression, which is involved in the ACE2 ectodomain cleavage, allowing higher levels of the soluble ACE2 that neutralize SARS-CoV-2 and prevent it from bonding with ACE2 [ 57 ].…”