There is so much we don’t understand about the novel coronavirus, down to seemingly basic things like how infectious it is and how long social-distancing lockdowns might need to last. One attribute of the virus that has become clear, however, is that more men than women are dying of Covid-19, the infectious disease that coronavirus can cause in humans. This sex pattern has held across countries hit hard by the pandemic—in China, Italy, and France, men have died of Covid-19 at higher rates.

This pattern has also held in the United States. A recent analysis of Covid-19 deaths in 13 states, conducted by The Washington Post, bears out the trend: “In every one of those states,” Post reporters wrote earlier this month, “men died more frequently, and that was even the case if they made up fewer total cases of the disease to begin with.” In New York City, more than two men have died for every woman.

According to Sabra Klein, Ph.D., a professor of microbiology and immunology at the Johns Hopkins Bloomberg School of Public Health, current data shows that if men get infected, they are at greater risk of a more severe outcome. “The honest truth is we don’t know why men are suffering a worse outcome from Covid-19,” she says. “Regardless of what we know about why that’s happening, we do know that it is happening.”

Now doctors, immunologists, and researchers of infectious diseases are trying to determine why that’s the case. Pinning down the precise cause has proven tricky. But there are several hypotheses—and these are just that, hypotheses—that might explain why Covid-19 is killing more men than women.

The X Factor

Our immune system—made up of microscopic first responders—is the body’s front-line defense against infections. Its response to pathogens is broken up into two parts. There’s the innate portion that you’re born with, which weakens as you grow older. Then there’s the adaptive portion, which is a blank slate at birth but grows stronger as you age and your body is exposed to antigens—foreign bacteria and viruses, but also vaccines—that induce an immune response in order to produce disease-fighting antibodies.

“Generally, women’s immune systems are stronger,” says Roger Seheult, M.D., a practicing pulmonologist in southern California who is treating patients with Covid-19. A growing body of literature suggests that the sex disparity in immune response comes down to a basic genetic difference you remember from middle-school bio: Women are born with two X chromosomes—one from Mom and another from Dad—while men are born with one X chromosome and one Y chromosome.

According to Klein, there are more than 60 genes on the X chromosome associated with immune function. Generally speaking, there shouldn’t be any advantage to having two X chromosomes: The genes on one of the X chromosomes are randomly inactivated. Nonetheless, about 15 percent of the genes on the inactivated copy of the X chromosome remain active.

“Some of the genes have a greater expression in immune response in some women compared with men,” Klein says. One such X-chromosome gene codes for a protein called "toll-like receptor 7," which assists in immune surveillance in order to detect viral RNA—the single-strand genetic codes that make up the novel coronavirus.

The Family Jewels

Hormones like testosterone and estrogen regulate various aspects of the body’s immune response. Testosterone can reduce inflammation, but also suppress the immune response required to clear a virus. Estrogen, meanwhile, binds to cells in the immune system to kick-start the production of antibodies. And what produces testosterone? The testicles, of course.