Women seem to have a survival advantage over men when it comes to the recent coronavirus pandemic. A recent retrospective study showed that the risk of infection is high for premenopausal women but the risk of death is much higher for men in the same age group. This throws some light on the protective nature of estradiol therapy in women. The infection occurs across all ages.
However, the rate is higher among men, at about 60%, vs. 40% in women. Men are more likely to be critically ill with COVID-19, and two-thirds of all COVID-19-related deaths are in men. In the study, the effects of estradiol and infection rates were studied in two groups of women, one aged over 50 years and once aged 15-49 years. SARS-CoV-2 uses the ACE2 enzyme to enter the host cell which is present in many tissues. It is involved in the renin-angiotensin system that regulates vascular and organ-protective functions and is encoded on the X chromosome, which also houses the AT2 gene.
Due to this location, it has a different expression in the two sexes. Estradiol counter-regulates angiotensin-converting 12 enzymes (ACE)/ angiotensin II (AngII)/ angiotensin II receptor type 1 (AT1R) signalling pathway. Estradiol could also activate the Mas receptor or AT2R, which in turn could inhibit fibrosis, have a vasodilatory and anti-oxidant effect. Androgens up-regulate IL-6 while estrogen downregulates it. IL-6 is believed to play a central role in cytokine storm seen in COVID-19 infection.
The study concluded that the fatality risk for women >50 years receiving estradiol therapy reduced by more than 50%. Highest infection was found in women aged 15-49 years, but men have about 50% higher mortality rates. This can be explained by higher basal levels of ACE2 in premenopausal women. Advancing age can lead to a loss of active ACE2 receptors. Peri- and postmenopausal women aged over 50 years who were receiving estradiol regularly had a survival rate of almost 97% and non-estradiol users had a survival rate of 85%.