It’s one of the long-standing mysteries of the pandemic: why are men more likely to die from Covid than women?

According to a 2020 study, the death rate from Covid among men in 38 countries was on average 1.7 times higher than the rate among women. Recent research by Harvard University scientists found that although men accounted for 49 percent of Covid cases in the United States, from April 2020 to May 2021 men were responsible for 55 percent of Covid deaths.

This week, a study further supported a leading theory about the discrepancy: estrogen may offer some protection against severe Covid.

For the study, published in the journal Family Practice, UK, researchers compared women in England who had received hormone replacement therapy – which helps restore estrogen levels during menopause – within six months of a Covid diagnosis with women who who didn’t. The results showed that the first group had a 78 percent lower all-cause mortality rate than the second group.

In all, the study involved more than 5,400 women, most of whom were white and going through the menopause (about 59 on average). The researchers controlled for socioeconomic status and pre-existing health problems.

“This adds to the evidence as to why we saw really different clinical outcomes for women compared to men, especially early in the pandemic,” said Anita Raj, professor of infectious diseases and global public health at the University of California, San Diego, who did not was involved in the investigation.

Although the relative homogeneity of the study is a limitation, she added, her conclusion still “seems consistent with the notion that it is estrogen specifically that produces the protective effect.”

Estrogen can help balance the immune response

Various other hypotheses have been put forward to explain the difference in Covid mortality between males and females over the past two years. In the Harvard study, researchers suggested that the types of jobs women are more likely to hold and their behavioral tendencies may have an impact on Covid outcomes. In the US, for example, women are more likely to report wearing masks and social distancing, while men are more likely to participate in jobs that expose them to the virus.

However, experts think it makes sense that estrogen could play a protective role against Covid, as the hormone is known to stimulate an immune response by producing antibodies. At the same time, higher estrogen levels can keep the immune system from responding overly aggressively to a viral infection, which can lead to life-threatening inflammation.

“We’re seeing in women that they have a faster and stronger antibody response … to Covid infection, which probably means they can clear the infection faster than the men,” said Dr. Christopher Wilcox, a co-author of the new study and an academic clinical fellow at the University of Southampton.

Wilcox added that “a number of studies have shown that higher estrogen levels appear to be generally associated with lower levels of infectious disease severity.”

For example, a 2016 lab study suggested that estrogen prevented the influenza virus from replicating in cells. And other research has shown that estrogen can also prevent HIV, Ebola, and hepatitis from replicating.

The new research also aligns with a 2020 study that found hormone replacement therapy halved the risk of Covid death in women over 50. However, this research found no difference in premenopausal women.

For this and many other reasons, experts said, it is unknown whether estrogen could be useful as part of a treatment regimen or preventive therapy for Covid. Hormone replacement therapy comes with its own risks, as long-term use can increase the chances of stroke, blood clots, or heart attacks.

“There are some risks with estrogen being prescribed, but is it something that warrants further study? Yes, definitely,” Raj said.

At the very least, Wilcox said, his study suggests women who get Covid don’t need to stop their hormone replacement therapy.

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