“There are profound sex differences in immune systems and this pandemic is revealing them.”
Marcia Stefanick, Stanford University School of Medicine.

More men than women have died of the COVID-19 virus. In China, Italy, South Korea, Germany, France, Iran, the U.S – everywhere around the world, the death rate of men to women is disproportionate. In New York City, men have died at nearly twice the rate.

Death rates from COVID-19 are more evidence of the biological differences between men and women. What are the components of these differences related to the pandemic?

Habits and Comorbidity

Questions about the sex discrepancy in death rates have focused (heretofore) mostly on male behavior: higher rates of tobacco assumption, reluctance to seek medical care, and even lower rates of handwashing.

Smoking is associated with negative progression and adverse outcomes of COVID-19. Smokers are more likely to have lung disease, which is a risk factor for severe infection. Also, smokers are more likely to touch their mouths and face.

But, Sabra Klein, Professor of Molecular Microbiology and Immunology at John Hopkins* suggests that smoking is not the leading factor. “There is a growing observation of increased mortality in men across very diverse countries and cultures. When I see that, it makes me think that there must be something universal that is contributing to this.” Klein’s prior research revealed that men have lower innate antiviral immune responses to a range of infections including hepatitis C and HIV. “Their immune system may not initiate an appropriate response when it initially sees the virus.”

Men also have other “comorbidities”: higher rates of pre-existing conditions such as heart disease, high blood pressure, and diabetes. These conditions increase the risk of death from the virus.

Kathryn Sandberg, Director of the Center for the Study of Sex Differences in Health, Aging and Disease at Georgetown University, says one explanation for the disparity in COVID-19 deaths may have to do with angiotensin-converting enzyme 2 (ACE2), a protein on the surface of the cells in the lungs and other organs. ACE2 is key in regulating blood pressure and it works differently and more favorably for women. COVID-19 binds to ACE2. A study of COVID-19 patients in China found hypertension as the most common risk factor.

Overall Differences in Male and Female Lifespan and Risk of Death

We did not need a pandemic to know men live (on average) 4 years less than women; male suicide rates are much higher; significantly more men die at work and in war. We know men aged 15-25 have a vastly greater risk of injury and death. Evolutionary psychology speaks volumes about the reasons for the risky behavior of men vs. women. (It is related to androgens and mating behavior.)

In the context of a pandemic, it makes sense to remember those markers of health and longevity, but also to look deeper for underlying biological causes.

When it Comes to Survival, Men are the Weaker Sex.

Men are the weaker sex independent of a pandemic; the innate biological advantage of women is apparent at every age and stage of human life. Baby girls are more likely to make it to their first birthday. Eighty percent of all centenarians today are women; ninety-five percent of those who reach the age of 110 are women.

Female survival advantage holds regardless of education, economic factors, and alcohol, drug, or tobacco consumption.

Sandberg underscores the bottom-line: “It doesn’t matter what the infectious agent is, women tend to be better at knocking it down because they have a more robust immune system.”

Genetic Disadvantage for Males and Female Immunity

Female genetic superiority starts at the chromosomal level. The cells of genetic females have two X chromosomes. Having the use of a spare X chromosome gives females an advantage against a virus.

There are more than 2,000 genes on the two X chromosomes that interact and cooperate within a women’s body. Each cell predominantly uses one X chromosome over the other. According to physician and scientist, Sharon Moaelm*, if one X chromosome has genes that better recognize an invading virus like COVID-19, the other X chromosome that can do a different task – like killing cells infected with COVID -19. This makes the fight against the virus more efficient for women. An extra X brings extra immune functioning.

Males have to get by with just one X chromosome. If a male’s genes are not capable of recognizing or killing cells infected with the coronavirus, his ability to fight the infection will be limited. Historically, coronaviruses such as SARS and MERS tended to affect men disproportionately, according to Luis Ostrosky-Zeichner, infectious disease specialist at McGovern Medical School at UTHealth in Texas.

Since women have a greater immune response to the virus, they are quicker to reduce its viral load – the quantity of the virus. Women may also be able to launch an earlier attack on infections in general, saving the body from needing to use all of its virus-fighting capacity later.

It should be noted that women pay a cost for having a more aggressive immune system. Women are more prone to autoimmune diseases. The immune system of genetic females is more likely to attack themselves, which occurs in conditions like rheumatoid arthritis, multiple sclerosis, autoimmune thyroiditis, Sjogren’s syndrome, and lupus.

Hormonal Disadvantage for Males and Advantage for Females

Higher levels of testosterone appear to suppress the immune system. Estrogens have been found to stimulate a more vigorous immune response.

From an evolutionary perspective, some research suggests women have a stronger immune system against viral infections than men because they spend part of their lives with a “foreign body” inside of them; their baby grants them a survival advantage. Ostrosky-Zeichner believes that advantage may be related to hormonal changes.

Going Forward with Tests and Vaccine

A better understanding of men’s and women’s immune system response to the virus could be critical in developing a good vaccine. There are well-documented differences in vaccine effectiveness among men and women, with women tending to be better protected after vaccination. Therefore, it may be especially important to ensure that sex is taken into account when designing and analyzing vaccine trials.

And, as we develop antibody testing, what are the differences in the antibodies produced in men vs. women? Should the test be gender-specific? Sex differences in the immune response to COVID-19 are likely to show up in antibody surveys currently underway across the world.

Conclusion

Knowing more about how the virus differently impacts men and women could help determine the most effective treatment for individual patients. Nearly 20 years ago, the Institute of Medicine of the National Academy of Sciences published a report that claimed: “Being male or female is an important variable that should be considered.”

Moalem claims there has been little tangible progress on this insight in the practice of medicine. “We must now apprehend the real biological strength that each genetic female possesses and how men differ in this regard. The future of medicine depends upon it.”

*Sabra Klein is also President of the Organization for the Study of Sex Differences (OSSD).

**Sharon Moalem is a scientist, physician, and author. His most recent book is The Better Half: On the Genetic Superiority of Women. Moalem is an expert in the fields of rare diseases, sex differentiation, neurogenetics, and biotechnology.

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