Hypothesis: Sex-Related Differences in ACE2 Activity May Contribute to Higher Mortality in Men Versus Women With COVID-19.

Angiotensin-converting enzyme 2 (ACE2) facilitates the cellular entry of the severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2), which causes the coronavirus-2019 (COVID-19) disease. Recent reports have shown worse outcomes in men with COVID-19 infection compared to women. We review the hypothesis that sex-related differences in outcomes in COVID-19 are due to different activity of ACE2 between men and women. We also show that studies in humans have demonstrated no significant difference in serum ACE2 levels between healthy men and women. However, men with hypertension and heart failure typically have higher level of serum ACE2 activity compared to women. We hypothesize that the worse outcomes in men with COVID-19 compared to women is likely due to higher prevalence of hypertension and heart failure among men compared to women. To test this hypothesis, studies to compare the outcomes of COVID-19 infection between men and women with no preexisting heart diseases are needed.