Higher Estrogen Levels May Protect Against COVID-19 Death

Women with increased estrogen levels had a lower risk of death from COVID-19, suggesting that female sex hormones may have protective effects against severe illness, according to a cohort study from Sweden.

Postmenopausal women who were taking hormone replacement therapy were more than 50% less likely to die from COVID-19 compared with those with natural estrogen levels, and the association remained significant after adjustment for confounders (adjusted OR 0.47, 95% CI 0.34-0.63), reported Anne-Marie Fors Connolly, MD, PhD, of Umeå University in Sweden, and colleagues.

On the other hand, postmenopausal women who had pharmaceutically decreased levels of estrogen due to adjuvant endocrine therapy for breast cancer were more than twice as likely to die of COVID-19 (OR 2.35, 95% CI 1.51-3.65), though this association was no longer significant after adjustment for confounders, they noted in BMJ Open.

“This study shows an association between estrogen levels and COVID-19 death,” Fors Connolly and colleagues wrote. “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 authors also found that older age and comorbidity index were associated with increased risk of death from COVID-19. For every year increase in age, the adjusted odds ratio of COVID-19 death was 1.15 (95% CI 1.14-1.17). For every increase in the weighted comorbidity index, the risk of COVID-19 death was 13% higher (adjusted OR 1.13, 95% CI 1.10-1.16). Low income and education level were also associated with increased risk of death from COVID-19 among this population.

One possible mechanism for the decreased risk of COVID-19 death among women with high estrogen levels is the hormone’s effect on the ACE2 receptor, a key entry point for SARS-CoV-2, Fors Connolly and colleagues said. A previous study found that cells exposed to testosterone and estrogen behaved differently — while testosterone upregulates ACE2 expression in cells, estrogen downregulates it.

This nationwide registry study included 14,685 women ages 50 to 80 who tested positive for COVID-19, grouped into three categories based on their estrogen levels: 2,535 with increased estrogen due to hormone replacement therapy, 227 with decreased estrogen due to anti-estrogen treatment for breast cancer, and 11,923 with native estrogen (control group).

Fors Connolly and team compared COVID-19 deaths in each cohort, adjusting for confounders including age, annual income, education, and medical comorbidities.

Women who had lower levels of estrogen were older and had more comorbidities, and those with higher levels were more likely to have a high income and to have completed post-secondary education.

The absolute risk of death from COVID-19 was 2.1% among women with increased estrogen levels, 10.1% among those with decreased estrogen levels, and 4.6% among those in the control group.

Fors Connolly’s group recognized that this research could not identify actual estrogen modulation levels, which may have limited the findings. Additionally, while there was a trend between decreased estrogen levels and a higher risk of death from COVID-19, the group of women who had decreased estrogen levels was too small to show significance. They also noted that they did not have data for potential confounding factors, such as BMI, nutrition, and smoking habits.