COVID-19: Is there a weaker sex?

Sex is one of the most relevant factors often associated with health, disease severity, mortality, and life expectancy [1]. From neonatal diseases to non-communicable disorders, men often have higher risks and poorer prognosis; however, the causes of these disparities are still subject to debate [2–7]. In this context, the new coronavirus disease of 2019 (COVID-19) has again called attention to these differences, mainly due to the observations of a higher level of complications and fatality rates among men [8]. According to data from the Global Health 50/50 initiative, which collects sex-disaggregated information from COVID19 cases worldwide, from the 75 countries reporting case and death data by sex, 63 revealed a male:female ratio of mortality over 1, three countries having a value of 1 and only nine a ratio below this mark (Fig. 1). Furthermore, a recent study observed that although the male: female ratio of deaths per 100,000 individuals varied by age, the probability of death remained higher in males across all age categories [9]. In addition, a recently published study from India revealed that themagnitude of the differential risk by sex was higher as age increased, suggesting a role of age in this association [10]. Beyond these population observations, several studies have concluded that male sex is a risk factor for COVID-19 adverse outcomes, even in multivariate analyses after adjusting for potential confounders [11–14]. The association between male gender and adverse outcomes, such asmortality, seems consistent across all geographical areas, as revealed by several meta-analyses [15–18]. The reasons for this trend are likely to be multifactorial, including physiological factors, lifestyle, and socio-cultural behaviors [19] (Fig. 2). The physiological differences between the sexes may initially be directly involved in this differential risk of COVID-19 adverse outcomes [20]. For example, recent evidence has suggested that SARSCoV-2 expression may induce angiotensin-converting enzyme-2 (ACE2) downregulation due to the binding of the viral spike protein to its receptor, then promoting a decrease in the angiotensin[1–7] production [21]. In this context, there is evidence suggesting an important role of sex hormones in the regulation of ACE-2 in a tissue-specific manner [20]. For example, female mice were observed to have a higher expression of ACE-2 in adipose tissue compared with male mice, leading to higher levels of Ang[1–7], which in turn were associated with lower levels of hypertension, another risk factor for COVID-19 negative outcomes [22,23]. Similarly, higher testosterone levels in males may be related to a higher risk of coagulation disorders, resulting in complications such as venous thromboembolism and systemic embolisms, which are frequently observed in severe COVID-19 patients [24,25]. Furthermore, differences in the immune responses against SARSCoV-2 between sexes may also play an important role. Takahashi et al.