When Rob Master spent a week debilitatingly ill with COVID-19, lying “barely lucid” on a pull-out couch in his family’s home in Larchmont, N.Y., his wife, Lori, cared for him every day. But somehow, despite exposure to Rob’s serious illness, Lori never tested positive for the virus.
Master, an athletic 49-year-old with no underlying health problems, says he wants his story to be “a public service announcement” to other healthy men who may think they’re at low risk of contracting a serious case of coronavirus. As Master knows too well, the reality is just the opposite: data from multiple countries suggest men are considerably more likely than women to suffer a serious case of COVID-19, and to die from it.
The question is why—and whether a quirk of female biology, genetics or behavior could hold clues about how to treat COVID-19.
“A gender lens is critical for understanding the patterns that we are currently seeing,” says Patricia Rieker, a medical sociologist and visiting professor at Boston University. “It gives us a window into how we might understand who gets this disease and who recovers from it and who dies from it.”
To really answer questions about who gets COVID-19 and why, Rieker says researchers need more robust data about disease outcomes by age, sex, race and socioeconomic background, and various combinations of those categories. But early numbers aren’t encouraging for men.
What we know so far
February data from the Chinese Center for Disease Control and Prevention placed COVID-19’s case fatality rate for men more than a percentage point higher than for women: 2.8% versus 1.7%.
In the U.S., an April 22 paper published in JAMA found that, out of 5,700 patients hospitalized for COVID-19 in the New York City area, 60% were men.
And a not-yet-peer-reviewed paper posted on the medical research site MedRxiv on April 29 found that, among 14,000 COVID-19 patients from multiple countries, men were at higher risk of coronavirus-related hospitalization, mechanical ventilation, and death, even after adjusting for common risk factors like underlying health conditions. The disparity was particularly apparent among adults 50 and older.
Understanding that discrepancy, and how it could relate to treatment, is vital.
Studying female sex hormones
Two sets of researchers—one at New York’s Stony Brook University, and one at California’s Cedars-Sinai Medical Center—are studying whether male COVID-19 patients do better when they’re treated with doses of female sex hormones. Their hunch is that female hormones such as estrogen and progesterone could be providing women some protection against COVID-19, making them a possibly effective therapy.
But some experts say hormones can’t fully explain the disparity. Older women who have gone through menopause, causing their sex-hormone levels drop substantially, are still surviving at higher rates than men their age, as the MedRxiv study pointed out. (The Stony Brook trial is also open to female patients 55 and older.)
“A 70-year-old woman will have the same estrogen, pretty much, as a 70-year-old man,” says Dr. Frances Hayes, an endocrinologist at Massachusetts General Hospital and associate professor at Harvard Medical School. “Rarely in life is something as simple as we would like.”
Possible gender differences in immunity
The immune system may hold other clues. Hayes notes that some genes on the X chromosome (women have two, while men have one X and one Y) contribute to immunity. Studies have also long shown that women generally have stronger immune responses than men.
At the Yale School of Medicine, a team led by immunobiologist Akiko Iwasaki is analyzing blood samples from male and female COVID-19 patients, as well as a healthy control group of health-care workers. That control group is crucial, Iwasaki says, because if any of these individuals do end up getting COVID-19, researchers will be able to analyze their immune responses starting from the earliest days of their illnesses. If, for example, the researchers find that women are mounting a stronger immune response shortly after contracting the virus, ultimately leading to shorter and milder cases, researchers could look for drugs, antibodies or other therapies that help men react to the pathogen similarly, Iwasaki explains.
Carolyn Mazure, who founded the Yale’s Women’s Health Research center that is funding Iwasaki’s study, says there’s almost never one tidy answer when it comes to sex-related health disparities.
“You have to start by identifying where there’s [a difference in outcomes] and then systematically investigate what’s really behind that difference,” she says. Often, social determinants of health are as important as biological factors.
Smoking is one example. Men worldwide smoke in far higher numbers than women. Since smoking is terrible for respiratory health and leads to many of the underlying conditions common among COVID-19 patients, it’s logical to think the habit could help explain, at a population level, why more men are getting seriously ill.
But Tom Glynn, a tobacco-control expert and adjunct lecturer at Stanford Medicine, says the data paint a complicated picture. “Smokers appear, at least in initial studies, to be underrepresented among COVID patients, exactly the opposite of what would be expected,” Glynn says.
Glynn says it’s possible studies aren’t differentiating between ex-smokers—who still have some amount of lung damage—and never-smokers. But at this point, he says, it’s difficult to draw any clear line between smoking status and COVID-19.
Rieker says it can be more useful to think about a lifetime’s worth of subtle differences, rather than one single behavioral explanation. Research shows, for example, that men are more reluctant than women to see a doctor. That has obvious ramifications for COVID-19 outcomes—if men are waiting until they’re very sick to get treatment, they’ll likely fare worse—but also for overall health, Rieker says.
“If men have a lifetime of thinking about their health last and not being willing to go to doctors,” they may have more small issues that could predispose them to a severe disease course, she says. Social expectations around masculinity could also make men less likely to follow safety guidance like wearing masks or regularly washing their hands, she adds.
Accounting for decades and decades of these differences is difficult to do, Rieker acknowledges, but it’s crucial to understanding who the virus affects and why.
“I would like to see a better portrait of the men who died compared to the women who died,” she says, but gathering years’ worth of health and behavior information isn’t easy. “It’s a far more complex story for which we don’t really have data.”