Estrogen Replacement May Reduce COVID-19 Death Risk

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Estrogen supplementation is associated with a reduced risk of death from COVID-19 among postmenopausal women, new research suggests.

The findings, from a nationwide study using data from Sweden, were published online February 14 in BMJ Open by Malin Sund, MD, PhD, of Umeå University Faculty of Medicine, Sweden, and colleagues.

Among postmenopausal women aged 50-80 years with verified COVID-19, those receiving estrogen as part of hormone replacement therapy (HRT) for menopausal symptoms were less than half as likely to die from it than those not receiving estrogen, even after adjustment for confounders.

"This study shows an association between estrogen levels and COVID-19 death. 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," the investigators write.

However, speaking with Medscape Medical News, coauthor Anne-Marie Fors Connolly, MD, PhD, a resident in clinical microbiology at Umeå University, cautioned: "This is an observational study. Further clinical studies are needed to verify these results before recommending clinicians to consider estrogen supplementation."

Stephen Evans, professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, agrees.

He told the UK Science and Media Center: "This is an observational study comparing three groups of women based on whether they used hormonal therapy to boost estrogen levels or who had, as a result of treatment for breast cancer...reduced estrogen levels or neither. The findings are apparently dramatic."

"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," he warned.

Do Women Die Less Frequently From COVID-19 Than Men?

Studies conducted early in the pandemic suggest women may be protected from poor outcomes of SARS-CoV-2 infection compared with men, even after adjustment for confounders.

According to more recent data from the Swedish Public Health Agency, of the 16,501 people who have died from COVID-19 since the start of the pandemic, about 45% are women and 55% are men. About 70% who have received intensive care due to COVID-19 are men, although cumulative data suggest that women are nearly as likely to die from COVID-19 as men, Connolly told Medscape Medical News.

For the current study, a total of 14,685 women aged 50-80 years were included, of whom 17.3% (2535) had received estrogen supplementation (HRT), 81.2% (11,923) had native estrogen levels with no breast cancer or HRT (controls), and 1.5% (227) had decreased estrogen levels due to breast cancer and antiestrogen treatment.

The group with decreased estrogen levels had a more than twofold risk of dying from COVID-19 compared with controls (odds ratio, 2.35), but this difference was no longer significant after adjustments for potential confounders including age, income, and educational level, and weighted Charlson Comorbidity Index (wCCI).

However, the group with augmented estrogen levels had a decreased risk of dying from COVID-19 before (odds ratio, 0.45) and after (odds ratio, 0.47) adjustment.

The percentages of patients who died of COVID-19 were 4.6% of controls, 10.1% of those with decreased estrogen, and 2.1% with increased estrogen.

Not surprisingly, the risk of dying from COVID-19 also increased with age (odds ratio of 1.15 for every year increase in age) and comorbidities (odds ratio, 1.13 per increase in wCCI). Low income and having only a primary level education also increased the odds of dying from COVID-19.

Data on obesity, a known risk factor for COVID-19 death, weren't reported.

"Obesity would have been a very relevant variable to include. Unfortunately, this information is not present in the nationwide registry data that we used for our study," Connolly told Medscape Medical News.

While the data are observational and can't be used to inform treatment, Connolly pointed to a US randomized clinical trial currently recruiting patients that will investigate the effect of estradiol and progesterone therapy in 120 adults hospitalized with COVID-19.

In the meantime, she warned doctors and patients: "Please do not consider ending antiestrogen treatment following breast cancer — this is a necessary treatment for the cancer."

Evans noted, "There are short-term benefits of menopausal hormone therapy but women should not, based on this or other observational studies, be advised to take HRT for a supposed benefit on death from COVID-19."

The study had several nonpharmaceutical industry funders, including Umeå University and the Knut and Alice Wallenberg Foundation. The authors and Evans have reported no relevant financial relationships.

BMJ Open. Published online February 14, 2022. Full text

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR's Shots blog, and Diabetes Forecast magazine. She is on Twitter: @MiriamETucker.

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