The role of sexual dimorphism in susceptibility to SARS-CoV-2 infection, disease severity, and mortality: facts, controversies and future perspectives

Abstract

Former studies have revealed intersex variability in immune response to infectious diseases, including Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological surveillance of the ongoing pandemic has demonstrated a male vulnerability to morbidity and mortality, despite similar infection rates between the two sexes. Divergence in the frequency of comorbidities between males and females, differences in hormonal profile, chromosomal composition and gender behavior have all been proposed as potential causative factors. Data deriving from the immunization process indirectly support the existence of a sex-specific response to SARS-CoV-2, since females apparently produce higher numbers of antibodies while simultaneously exhibiting higher rates of side effects, indicating a stronger immune reactivity to the vaccine’s elements. Interpreting intersex differences in immune response to SARS-CoV-2 could lead to a deeper understanding of the COVID-19 pathophysiology and enable healthcare professionals to conduct a more accurate patient risk assessment and better predict the clinical outcome of the disease. This narrative review aims to discuss the pathophysiological and behavioral basis of the disproportionate male morbidity and mortality observed in COVID-19, in the context of most research findings in the field.

The Reserve/Maximum Capacity of Melatonin’s Synthetic Function for the Potential Dimorphism of Melatonin Production and Its Biological Significance in Mammals

“…A current example is the obvious gender difference in SARS-CoV-2 infection. Female COVID-19 patients experience, on average, less serious symptoms and lower death rates than males, findings that have been attributed to a variety of factors [ 107 , 108 ]. The disadvantages identified in male COVID19 patients have also been linked to the deficiencies of mitochondrial function and melatonin production [ 109 , 110 , 111 ].…”

Sex and gender influence on immunity and autoimmunity

“…Genetic and epigenetic factors are responsible for the sexual dimorphism of the immune system (10). These factors influence the development of autoimmune disease (11)(12)(13).…”

Autoimmune hepatitis after COVID-19 vaccination

“…Despite similar COVID-19 infection rates in the two sexes, males are more vulnerable to morbidity and mortality (70). This has been explained by differences in hormonal profiles, chromosomal compositions, and gender behaviors.…”

“…This has been explained by differences in hormonal profiles, chromosomal compositions, and gender behaviors. Females apparently produce higher numbers of antibodies while simultaneously exhibiting higher rates of side effects, indicating a stronger immune reactivity to a vaccine's elements (70). The X chromosome carries several genes involved in the immune response, including Toll-like receptor 7 (TLR7), TLR8, and intereukin-1 receptor-associated kinase 1 (IRAK1) (71).…”