What role does estrogen play in the COVID-19 sex difference?

Previous entries in this blog have shown that men who contract the SARS-CoV-2 virus are more likely to develop severe disease symptoms than women. The closely related coronavirus SARS-CoV-1, which also targets the ACE2 protein for cell adhesion and infiltration, showed a similar sexual disparity during the 2002-2004 SARS epidemic. Research into the mechanisms of SARS-CoV-1 pathology over the past eighteen years has provided information which can help guide investigations of the current pandemic. Notably, a 2017 study used a modified version of the virus in mice and found a lower death rate among females. However, ovariectomized females had a similar death rate to males following infection, suggesting that female sex hormone signaling exerts a protective effect and drives the epidemiological difference (1).

Sex hormones have been previously implicated in altering the expression levels of both SARS-CoV-2 target proteins, ACE2 and TMPRSS2 (2). The serine protease TMPRSS2 has been shown to be upregulated by androgen receptor activation (3), although this effect has primarily been observed in male reproductive tissue. An early study found no relationship between androgen and TMPRSS2 levels in mouse pulmonary tissue, although these findings await further collaboration (4).

ACE2 is more promising as a potential candidate for sex hormone-mediated differences in COVID-19 pathology. ACE2, or angiotensin converting enzyme 2, regulates blood pressure by converting vasoconstrictive angiotensin II into the vasodilator angiotensin 1-7. A 2010 study (5) examined the role of sex hormones in ACE2 activity using four-core genotype mice (FCG), a mutant strain where the gonad-determining Sry gene has been translocated from the Y chromosome. Offspring of this strain can potentially have two X chromosomes but develop male gonads or vice versa. Renal ACE2 activity between these groups was hormonally regulated independently of sex chromosomes as shown in Fig 2.

Together these studies indicate a role for estrogen in female protection against COVID-19 severity, and a strong potential for estrogen-mediated ACE2 expression or activation as the main contributing factor. This would explain the interaction between age and sex in COVID-19 fatalities, as older individuals of both sexes experience increased risk but male risk elevates at an earlier age (6-8). As estrogen levels decrease in post-menopausal women, their exposure to severe clinical outcomes begins to resemble the male population.

Written by: Blaine Caslin
Edited by: Jina Zhou and Esther Melamed
4/27/2020