Sex Disparities in COVID-19 Severity and Outcome: Are Men Weaker or Women Stronger?

Abstract

The COVID-19 outbreak is a global public health issue, having profound effects on most aspects of societal well-being, including physical and mental health. A plethora of studies, globally, have suggested the existence of a sex disparity in the outcome of COVID-19 patients, that is mainly due to mechanisms of viral infection, immune response to the virus, development of a hyperinflammation, and development of systemic complications, particularly thromboembolism. These differences appear to be more pronounced in elderly COVID-19 patients. Epidemiological data report a sex difference in the severity and outcome of COVID-19 disease with a more favourable course of the disease in women compared to men, regardless of age range although the rate of SARS-CoV-2 infection seems to be similar in both sexes. Sex hormones, including androgens and estrogens, may not only impact viral entry and load, but also shape the clinical manifestations, complications and, ultimately, the outcome of COVID-19 disease. The current review comprehensively summarizes current literature on sex disparities in susceptibility and outcomes of COVID-19 disease as well as the literature underpinning the pathophysiological and molecular mechanisms, which may provide a rationale to a sex disparity. These include sex hormone influences on molecules that facilitate virus entry and priming, as well as the immune and inflammatory response, as well as coagulation and thrombosis diathesis. Based on present evidence, women appear to be relatively protected from COVID-19 because of a more effective immune response and a less pronounced systemic inflammation, with consequent moderate clinical manifestations of the disease, together with a lesser predisposition to thromboembolism. Conversely, men appear to be particularly susceptible to COVID-19 disease because of a less effective immune response with consequent increased susceptibility to infections, together with a greater predisposition to thromboembolism. In elderlies, sex disparities in overall mortality following SARS-CoV-2 infection is even more palpable, as elderly men appear more prone to severe COVID-19 because of a greater predisposition to infections, a weaker immune defence and an enhanced thrombotic state compared to women. The review highlights potential novel therapeutic approaches employing the administration of hormonal or anti-hormonal therapy in combination with antiviral drugs in COVID-19 patients.

Are Geographic Factors Associated With Poorer Outcomes in Patients Diagnosed With Covid-19?

“…Other variables in our study, age and sex, were significant factors in explaining the prognosis of the patients diagnosed in PHC, which agrees with most previous studies that have stated that male and older patients (≥50 years) are at higher risk of greater severity and death 23–25 . Older adults had greater initial comorbidities, more severe symptoms and are more likely to experience multiorgan involvement 24 , whereas the sex disparity in the outcomes of patients with COVID-19 could be explained by the fact that men are more likely than women to experience severe forms of infection, and have higher mortality rates and a higher prevalence of the main risk factors of COVID-19 26 .…”

“…Other explanations include the mechanisms of viral infection, the immune response, and the development of hyperinflammation and systemic complications, particularly thromboembolism. Women therefore have a more favourable disease course than men, regardless of age range, although the rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection appears to be similar for both sexes 25 . Our results reinforce these findings, showing a major difference in ICU admissions by sex, probably due to the lower severity of the disease in women, making ICU admission unnecessary.…”

ACE2 in the second act of COVID‐19 syndrome: Peptide dysregulation and possible correction with oestrogen

“…In animal models, it has been demonstrated that oestrogen reduces platelet aggregation and thrombus formation, whereas androgens enhance them. Under conditions of normal levels of oestrogen exposure, this also appears to apply in humans because the risk of thromboembolism is higher in men throughout the life cycle whereas women's risk is lowest in their fertile years, gradually increasing during menopause 79 . However, it is worth noting that conditions of supraphysiological oestrogen levels such as pregnancy and the use of oral oestrogen‐containing contraceptives increase the production of procoagulant factors (eg, factor X, factor XII) at the same time as decreasing the production of anticoagulant factors (eg, protein S and antithrombin III).…”

“…Under conditions of normal levels of oestrogen exposure, this also appears to apply in humans because the risk of thromboembolism is higher in men throughout the life cycle whereas women's risk is lowest in their fertile years, gradually increasing during menopause. 79 However, it is worth noting that conditions of supraphysiological oestrogen levels such as pregnancy and the use of oral oestrogen-containing contraceptives increase the production of procoagulant factors (eg, factor X, factor XII) at the same time as decreasing the production of anticoagulant factors (eg, protein S and antithrombin III). Although this may warrant caution with respect to the use of oestrogen in COVID-19, in hormone replacement therapy, the risk of thromboembolism appears to increase significantly only beyond the fourth month of treatment.…”

Environmental Determinants of Coronavirus Disease 2019 (COVID-19)

“…Other demographic risk factors include male sex, race, and socioeconomic status ( Fig. 1) [19,20]. Indeed, racial minorities and people of low socioeconomic status in general represent an outsized portion of COVID-19 deaths [21][22][23][24].…”