It's one of the pandemic's prolonged mysteries: Why have men died of Covid at higher rates than women?
Covid's fatality rate for men was 1.7 times higher, on average, than the rate for women across 38 countries, a 2020 study found. More recent research from Harvard University scientists found that although men represented 49 percent of Covid cases in the U.S., they accounted for 55 percent of Covid deaths from April 2020 through May 2021.
This week, a study lent further support to a leading theory about the discrepancy: Estrogen may offer some protection against severe Covid.
For the study, published in the journal Family Practice, U.K., 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 to those who did not. The results showed that the first group had a 78 percent lower mortality rate from all causes of death than the second group.
In total, the study involved more than 5,400 women, most of whom were white and of menopausal age (around 59, on average). The researchers controlled for socioeconomic status and pre-existing health problems.
"This is adding to the body of evidence of why, particularly early in the pandemic, we were seeing really different clinical outcomes for women relative to men," said Anita Raj, a professor of infectious diseases and global public health at the University of California, San Diego, who was not involved in the research.
Although the relative homogeneity of the study is a limitation, she added, its conclusion still "seems to be aligned with the notion that it's estrogen specifically that's producing the protective effect."
Estrogen may help balance the immune response
Various other hypotheses have been floated to explain the difference in Covid mortality between men and women over the last two years. In the Harvard study, the researchers suggested that the types of jobs women more often hold and their behavioral tendencies could have an effect on Covid outcomes. In the U.S., for instance, 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.
But experts say it makes sense that estrogen could play a protective role against Covid, since the hormone is known to stimulate an immune response through the production of antibodies. At the same time, higher levels of estrogen can keep the immune system from responding overly aggressively to a viral infection, which can lead to life-threatening inflammation.
"We see in women, they have a faster and higher antibody response ... to Covid infection, which probably means that they can clear the infection quicker 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 seem to be associated with lower severity from infectious diseases in general."
A 2016 laboratory study, for instance, suggested that estrogen prevented the influenza virus from replicating in cells. And other research has shown that estrogen may prevent HIV, Ebola and hepatitis from replicating as well.
The new research also aligns with a 2020 study that found that hormone replacement therapy cut the Covid fatality risk in half among women over 50. That research did not, however, find a difference among pre-menopausal women.
For that and many other reasons, experts said, it's unknown whether estrogen might be useful as part of a treatment regimen or preventative therapy for Covid. Hormone replacement therapy comes with risks of its own, since long-term use may increase the chances of stroke, blood clots or heart attack.
"There are some risks attached to being prescribed estrogen, but is it something that warrants further study? Yeah, definitely," Raj said.
At the least, Wilcox said, his study suggests that there is no need to for women who get Covid to discontinue their hormone replacement therapy.