A large observational study has detected a link between increased levels of the hormone estrogen in older women and a reduced risk of dying from COVID-19. The research cannot establish evidence of causality but does call for clinical trials to explore whether estrogen supplementation can prevent severe COVID-19 in some people.

One of the first epidemiological observations to come out of China early on in the pandemic was that men were struck with more severe illness than women. A large meta-analysis late in 2020 verified those early suspicions, finding men were nearly three times more likely to need intensive care treatment and were at greater risk of death.

A number of studies have tried to understand why men seem to suffer from more severe COVID-19 than women. Many researchers hypothesize testosterone plays a role in these epidemiological observations. But on the other side of the fence, researchers are now beginning to find evidence indicating estrogen may play a protective role in reducing disease severity in women.

This new study, published in the journal BMJ Open, looked at retrospective data from public health records in Sweden. Focusing on women over the age of 50 with confirmed COVID-19, the researchers generated three groups: women on estrogen blocker drugs, women on hormone replacement therapy (HRT), and a control group of women not receiving any treatment enhancing or reducing systemic estrogen levels.

The results found those women in the decreased estrogen group were twice as likely to die from COVID-19 compared to those women receiving HRT. Absolute risk of death from COVID-19 for the estrogen-boosted women was 2.1 percent, compared to the estrogen blocker group at 10.1 percent. The control group sat in middle showing absolute risk of death from COVID-19 at 4.6 percent.

“This study shows an association between estrogen levels and COVID-19 death,” the researchers concluded in the study. “Consequently, drugs increasing estrogen levels may have a role in therapeutic efforts to alleviate COVID-19 severity in postmenopausal women and could be studied in randomized control trials.”

Stephen Evans, from the London School of Hygiene and Tropical Medicine, says it is unlikely these new findings mean older women will benefit from estrogen supplementation as a way to reduce their risk of severe COVID-19. He points out these kinds of observational studies are often riddled with biases and confounding factors.

“… it must be remembered that there is a long history of observational studies, especially in relation to hormone therapy, making dramatic claims of benefits that have not been confirmed in randomized trials,” said Evans, who did not work on this new study. “It is quite likely that this study follows in such a line, and at the very least, great caution should be exercised in thinking that menopausal hormone therapy will have substantial, or even any, benefits in dealing with COVID-19.”

There are already ongoing trials exploring the effects of estrogen on COVID-19 in hospitalized patients. So there should be some answers soon as to whether estrogen supplementation offers any protection from severe COVID-19.

However, prior observational studies have consistently indicated a relationship between low estrogen levels and severe COVID-19. One big UK study, still in preprint, echoes these Swedish findings, showing lower rates of death from COVID-19 in women undergoing HRT. Another interesting study from 2020 found women taking the combination contraceptive pill (containing estrogen and progestin) were less likely to experience severe COVID-19 symptoms compared to those not taking the pill.

The new research was published in the journal BMJ Open.

Source: BMJ Open