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 CO VID-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 thromboemb olism. 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.
