Ever since the onset of this pandemic it has been observed that men fare worse than women when it comes to having a severe case of a Covid infection – more men than women require admission to ICUs and the death rate from Covid is higher in males. This has raised many eyebrows and a number of papers have been written about this. But we still aren’t sure why this is happening.
Initially it was suspected that social variables played a role. More men than women smoke, particularly in other countries, such as China and Italy. So it was proposed that men had more underlying lung conditions making them more vulnerable to severe disease. In addition, there was speculation that men were less likely than women to consult a physician, leading to delays in treatment that may have allowed their infections to become more advanced.
However, as time passed and these factors were more carefully analyzed, it appeared that there was clearly some sort of biological underpinning that accounted for the differences between how men and women responded to Covid. Something seemed to protect women from developing a more severe reaction to the virus.
This discrepancy in response to an infection isn’t actually new news. It has long been known that women tend to fare better fighting a number of infections – such as tuberculosis, hepatitis, and salmonella. Women also tend to mount a stronger immune response after being given vaccinations. And although this means that women may have more short-term side effects after getting a vaccine (such as we have been seeing with Covid vaccines), in the long run it suggests that the vaccine will be more effective.
So while women do mount a stronger immune response against Covid then men, the underlying biologic basis responsible for this isn’t entirely clear. There are two main theories about this, and I introduced these in an earlier blog, along with a description of how our immune system works. See: Does Estrogen Affect the Coronavirus? – Your Estrogen Questions.
In this post I will review these theories and provide some interesting additional information.
Theory One: The role of the X chromosome
Women have two X chromosomes and 
men only have one (they have an XY configuration). Some of the genes on the X chromosome are responsible for making proteins involved in our immune system. These proteins direct the mobilization of the components of our immune system that attack and destroy infections. Since women have a double dose of these genes, their immune systems would be in a position to jump into action more forcefully to stop a Coronavirus invasion in its tracks before it can become deadly.
To test this theory, scientists have taken blood samples from men and women and measured the levels of various virus-killing immune factors. They found that men have lower levels of some of the bodies’ disease-fighting proteins as well as fewer numbers of some of the specialized white cells that combat viruses. However, there are many elements involved in the immune system, and many scientists are not convinced that these differences fully explain why women fare better.
Theory Two: Is Estrogen the magic bullet?
A main difference between men and women is that women produce large levels of estrogen (up until menopause, that is). So there is speculation that there is something about estrogen that helps protect women from getting overly sick from Covid. There is considerable biologic evidence to suspect this is very plausible. Estrogen has very strong anti-inflammatory properties. While there is always a certain amount of inflammation involved in fighting an infection, one feature of Covid is that overly excessive inflammation can occur, particularly in the lungs. This leads to lung damage causing a more severe infection. Estrogen may play a role in balancing this part of the immune response and protect women from experiencing these pulmonary complications.
The quest to determine if it is the presence of estrogen that benefits women in fighting Covid has prompted scientists to explore this in the lab. I came across a particularly fascinating study involving how estrogen administration affects the SARS-CoV virus in mice. This study consisted of a series of experiments, which very elegantly demonstrated some interesting findings.
The first phase of the study was to expose a group of mice to varying doses of the virus. Not surprisingly, the higher the dose, the more likely the mice became ill and died. The researchers then looked at the differences between young and older mice. Again, not surprisingly, at various doses, the older mice had much higher rates of illness and death than the younger ones. These observations go along with what we know about Covid-19 in humans. Older people, whose immune systems are weaker, are more at risk for severe disease and death.
The next phase of the study was to examine the differences between how male and female mice responded to being infected. Male mice, particularly the older ones, were more likely to become ill and more likely to have a severe infection compared to the females. This is the same pattern we are seeing today with Covid.
The next phase of the study I found particularly interesting. The ovaries from a group of female mice were surgically removed. Removing the ovaries essentially eliminates the source of estrogen causing a “mouse menopause.” Exposing this group of female mice to the virus caused them to respond as poorly as the male mice – they experienced the same rates of infection and death. The conclusion of this study strongly suggests that it was the loss of estrogen that caused these females to be unable to combat the infection.
One, of course, cannot translate these findings to the current Coronavirus pandemic and its human toll, but it is suggestive that our female hormones offer some protection. This has actually prompted several studies in various parts of the world where patients with Covid are being treated with various estrogen products to see if it benefits them. These studies are being performed on postmenopausal women, and even men.
From my standpoint, I can’t help but wonder if women taking HRT may be at less risk for a severe case of Covid than women who do not. I continue to look for data that may shed some light on this. Unfortunately, none of the studies that I have reviewed are detailed enough to identify whether the number of women admitted to the ICU or succumbing to Covid are taking estrogen or not. Perhaps in the future this information may be forthcoming as researchers continue to sift through the massive amounts of data that are being generated during this pandemic.
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