Why are more men dying from COVID-19?

The novel coronavirus tends to affect men more severely than it does women. Though nobody can yet explain the oddity, researchers are hot on the case.

It's possible that the sex hormones estrogen and testosterone play a role, according to previous research on respiratory illnesses. Or perhaps it's because the X chromosome (which women have two of, but men have only one) has a larger number of immune-related genes, giving women a more robust immune system to fight off the coronavirus, SARS-CoV-2. Or, maybe the virus is hiding in the testes, which has abundant expression of ACE2 receptors, the portal that allows SARS-CoV-2 into cells.

Uncovering the real reason is, of course, imperative because it could help improve patient "outcomes during an active public health crisis," according to an editorial published April 10 in the Western Journal of Emergency Medicine (WJEM).

What are the numbers?

Since the first known COVID-19 case was reported in China late last year, countless studies have shown that the disease tends to be more severe and deadly in men than in women.

For instance, in an analysis of 5,700 COVID-19 patients hospitalized in New York City, just over 60% were men, according to an April 22 study published in the journal JAMA. What's more, "mortality rates were higher for male compared with female patients at every 10-year age interval older than 20 years," the researchers wrote in the study.

Furthermore, of the 373 patients who ended up in intensive care units, 66.5% were men, the JAMA study reported.

Results are similar in other studies. When the WJEM editorial was published in early April, the authors noted that between 51% and 66.7% of hospitalized patients in Wuhan, China, were male; 58% in Italy were male; and 70% of all COVID-related deaths worldwide were male. In one large study of more than 44,600 people with COVID-19 in China, 2.8% of men died versus just 1.7% of women.

Are men more susceptible?

These COVID-19 sex differences are not unexpected. Other coronavirus outbreaks, including outbreaks of SARS in 2003 and the Middle East respiratory syndrome (MERS) in 2012, had higher fatality rates in men than in women, according to the WJEM editorial. For example, a 2016 study found that men had a 40 percent higher odds of dying of MERS than women did.

Even the comically labeled "man flu" is so named because men tend to have a weaker immune response to respiratory viruses that cause flu and the common cold. As a result, men tend to get more severe symptoms from these viruses than women do, a 2017 review in BMJ found. That review pinned these results on the differences in "sex dependent hormones" in men and women.

A mouse experiment offers clues about this hormonal mystery; when scientists infected both male and female mice of different ages with SARS, the male mice were more susceptible to the infection than females of the same age, according to a 2017 study, which was published in The Journal of Immunology. However, when the female mice had their estrogen-producing ovaries removed or were treated with an estrogen-receptor blocker, they died at higher rates than those with working ovaries and normal estrogen.

"These data indicate that sex hormones produced in female [mice] may help to defend against coronaviruses like SARS and SARS-CoV-2," Akiko Iwasaki, a professor of immunobiology at Yale University School of Medicine, who was not involved in the study, told Live Science.

To learn more, scientists at Cedars-Sinai Medical Center in Los Angeles and the Renaissance School of Medicine at Stony Brook University in New York are testing estrogen or another sex hormone called progesterone on small groups of people who have COVID-19, Live Science previously reported.

There's another way to look at the COVID-19 sex difference; perhaps the X chromosome is protective because it has more immune-related genes than the Y chromosome does. This may also explain why women are more likely than men to have autoimmune diseases, the authors of the WJEM editorial noted.

The second X chromosome is usually silenced in women, but almost 10% of those genes can be activated, Veena Taneja, who studies differences in male and female immune systems at the Mayo Clinic, told NPR. "Many of those genes are actually immune-response genes," she said. This could give women a "double-dose" of protection, Taneja said, although research is needed to see whether these genes factor into protection against COVID-19.

Hiding in the testes?

New research offers yet another idea; men seem to clear SARS-CoV-2 from their bodies more slowly than women do. To explain that possibility, researchers have suggested the virus may have found a hiding place in men: the testes.

In the research, published on the preprint medRxiv database, 68 people confirmed to have COVID-19 in Mumbai, India, were tested with nasal swabs until they tested negative for the virus. At the end of the experiment, scientists found that women cleared the virus from their bodies in an average of 4 days, compared with men's average of 6 days. The same test in three different Mumbai households found similar results.

"Our collaborative study found that men have more difficulty clearing coronavirus following infection, which could explain their more serious problems with COVID-19 disease," study lead researcher Dr. Aditi Shastri, assistant professor of medicine at the Albert Einstein College of Medicine in New York City and a clinical oncologist at the Montefiore Einstein Center for Cancer Care, said in a statement.

Previous research has shown that SARS-CoV-2 invades certain human cells by plugging into these cells' ACE2 receptors. So, the researchers consulted a database, and found that the testes have high levels of ACE2 expression. In contrast, ACE2 could not be detected in the ovaries, the female equivalent of the testes.

However, the research did not actually look in the testes to see if SARS-CoV-2 is hanging out there, so "it does not tell us whether the virus infects testes or whether it is a reservoir of virus," said Iwasaki, who was not involved in the research.

What about smoking?

Other research has suggested that smoking may play a role, as smoking is related to higher expression of ACE2 receptors. But while more men than women smoke in China, that's not true in other countries, which likely puts a kibosh on smoking to explain the sex difference.

"What we saw in Wuhan [with the sex difference] has been replicated in every country around the world where we have accurate reporting," Sabra Klein, a researcher at the Johns Hopkins Center for Women's Health, Sex, and Gender Differences, told NPR. "In countries like Spain, where the percentages of males and females who report smoking is not significantly different, we still are seeing this profound male bias in severity of COVID-19."

Other explanations: Women are simply less likely to engage in health-related risks and are better at washing their hands, studies find, and perhaps that's behind the gender disparity

Sex differences aren't the only factor at play, however. Other groups more vulnerable to COVID-19 include the elderly and people with diabetes, high blood pressure and obesity, Live Science previously reported.

Originally published on Live Science.