Why Women Have Protection Against Severe Covid-19
Since the start of the pandemic, research consistently shows that Covid-19 affects men worse than women. But why?
The novel coronavirus is by definition new to scientists, and they’ve been scrambling to understand who’s most at risk. But one thing has been clear from the very beginning—simply being a man puts you at greater risk of serious illness from Covid-19. “In early March we were attracted to the news reports from China showing a male sex tendency in Covid-19 severity, which was soon confirmed by Italian data showing almost a four-fold greater number of males with Covid-19 admitted to inpatient care facilities than females,” says Leanne Groban, MD, a researcher at Wake Forest School of Medicine.
According to a July 2020 report from the Centers for Disease Control and Prevention (CDC), globally, more men than women have died of Covid-19 in 41 of 47 countries, and the ratio of Covid-19 cases to deaths is 2.4 times higher among men than among women. In China, the Covid-19 death rate among men was 2.8 percent, compared to 1.7 percent among women. About 57 percent of American Covid-19 deaths have been men, although the report notes that the states haven’t been consistent in reporting data regarding gender. In addition, Covid-19 hits people of color harder. Here’s how racism plays a role.
Although the data isn’t perfect, it has clearly shown than men are more greatly affected by Covid-19 than women. But it doesn’t explain why.
The reasons men may be more at risk
Like most things in medicine, the underlying reasons for gender differences can depend on a lot of factors, says Michelle DallaPiazza, MD, an associate professor in the department of medicine at the Rutgers New Jersey Medical School. A large part of the disparity may be related to social factors and risky behaviors. “The differences in social and lifestyle factors include that men are more likely to be smokers and alcohol consumers, which increase the risk for respiratory infections,” says Dr. Groban.
Plus: “Men are less likely to seek medical attention when needed, and this delay in treatment might worsen outcomes. Some reports suggest that men might be less ‘practiced’ at handwashing and mask-wearing, which could further heighten their risk,” Dr. Groban adds. Men are also more likely to have other medical conditions that put them at greater risk for a serious case of Covid-19, such as high blood pressure, diabetes, and heart disease, both doctors point out. (Many of these theories are supported by scientific evidence, including the American College of Cardiology’s JACC: Case Reports journal.)
But in addition, there may be some innate biological reasons men are more likely to be affected by Covid-19. Part of this is literally in women’s genes: Their extra X chromosome, which contains a lot of immune-related genes, might be one explanation for women’s seemingly stronger immune systems. This difference in defense mechanisms against foreign cell invaders such as Covid-19 is called “innate immunity,” Dr. Groban says.
“People with two X chromosomes tend to have a different immunologic response to viral pathogens, which is potentially more robust and less likely to cause a destructive inflammatory storm as in Covid-19,” Dr. DallaPiazza says.
The role of estrogen
Another biological factor that may hold an important key to the mystery of why men are more vulnerable to Covid-19 is the sex hormone estrogen. “We know from other viruses that sex differences in immune responses may be due to hormonal differences—in females, estrogen and progesterone might be protective, while testosterone in males might lower immune responses,” Dr. Groban says. Estrogen also helps protect premenopausal women against the inflammation that can lead to heart disease, compared to men of the same age, she says.
“Given the apparent crossroads between Covid-19, severity, sex, and estrogen, we decided to review the preclinical animal studies, including some from our team, that might shed light on the potential reasons for this relationship,” Dr. Groban says.
An enzyme that’s higher in men
Dr. Groban published a review of studies on gender differences and Covid-19 in August 2020 in the journal Current Hypertension Reports. Her research led her to an enzyme called ACE2, which helps blood vessels stay relaxed and healthy, protecting against heart disease. “We know from some clinical studies involving patients with cardiovascular disease that ACE2 may be higher in men than women,” she says. “Also, in animal studies involving hypertension [high blood pressure] or kidney disease, higher ACE2 levels were reported in the hearts and kidneys of male rats when compared to female rats.”
While ACE2 can be protective when it comes to some chronic conditions, it also happens to be a receptor for the novel coronavirus (called SARS-CoV-2), says Dr. Groban. “ACE2 is found on the cells that line the inside surfaces of the lung, heart, kidney, testis, and the GI tract—once the virus attaches to the ACE2 receptor, it is taken into the cell of that organ, which is the key event in the infection,” she says. Higher levels of ACE2 increases the coronavirus infection; decreased ACE2 helps lower viral spread in the body, she says.
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Could estrogen be protective?
Dr. Groban says women’s extra X chromosome might reduce ACE2, and therefore lessen the effects of Covid-19. “Studies from our group show that chronic estrogen therapy lowered ACE2 in heart tissue from animals that were deficient in estrogen,” she says. Similar results were found in animals treated with estrogen for kidney problems.
This might mean that estrogen therapy holds promise to treat Covid-19 as well. “Two clinical trials are currently underway to examine whether short-term treatment of male Covid-19 patients with an estrogen patch is beneficial” in boosting immune system response, lowering ACE2, and limiting symptoms of Covid-19 infection, Dr. Groban says.
What about post-menopausal women?
If the estrogen theory is correct, it could account for higher rates of Covid-19 among women who’ve gone through menopause. “The question arises, ‘Could the increased susceptibility to Covid-19 among older women be related to their loss of estrogen protection after menopause—making them as prone to Covid-19 disease severity as men?'” Dr. Groban says. “This could be responsible for the relative uptick in Covid-19-related mortality in older women in the seventh to eighth decade of life.”
Dr. Groban’s results are intriguing, but some researchers aren’t convinced. “The role of sex hormones may be limited, as newer studies show that women over 50, when they most likely have lower estrogen levels, still have better outcomes with Covid-19 when compared to men,” Dr. DallaPiazza says. “And among men, outcomes worsen with older age, even though older men tend to have lower androgen [testosterone] levels.”
Treating men and women for Covid-19
Dr. Groban says that much more research and data-gathering is needed, including what hormone medication women may be on. But the most likely reason for the sex differences isn’t just one thing: “Ultimately, more research is needed to determine the underlying cause for the difference, including rigorous studies that are able to account for many of the social, cultural, and behavioral factors that influence Covid risk,” Dr. DallaPiazza says. “And if biological factors are implicated in having a strong influence on the differences in health outcomes, additional studies would be needed to find out the exact mechanisms before recommending any sex- or gender-based treatment differences.” For right now, she says, advice and treatment for Covid-19 is the same for both men and women.
While researchers continue to figure out how Covid-19 works, both men and women should follow all the recommendations for avoiding the virus, including frequent handwashing, mask-wearing, social distancing, and maintaining a healthy lifestyle.
Next, be on the lookout for these troubling new Covid-19 symptoms and complications.
- JAMA: "Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy"
- Leanne Groban, MD, Wake Forest School of Medicine
- Centers for Disease Control and Prevention: "Men and COVID-19: A Biopsychosocial Approach to Understanding Sex Differences in Mortality and Recommendations for Practice and Policy Interventions"
- Global Health 5050: "COVID-19 sex-disaggregated data tracker"
- Michelle DallaPiazza, MD, associate professor, department of medicine at the Rutgers New Jersey Medical School
- JACC: Case Reports: "Sex Differences in Mortality From COVID-19 Pandemic: Are Men Vulnerable and Women Protected?"
- Human Genomics: "The X chromosome and sex-specific effects in infectious disease susceptibility"
- Current Hypertension Reports: "Is Sex a Determinant of COVID-19 Infection? Truth or Myth?"
- Centers for Disease Control and Prevention: "Coronavirus Disease 2019: Older Adults"