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Evidence for treatment with estradiol for women with SARS-CoV-2 infection

By Ute Seeland, Flaminia Coluzzi, Maurizio Simmaco, Cameron Mura, Philip E. Bourne, Max Heiland, Robert Preissner, Saskia Preissner

Posted 24 Aug 2020
medRxiv DOI: 10.1101/2020.08.21.20179671

BACKGROUND Given that an individual's age and gender are strongly predictive of COVID-19 outcomes, do such factors imply anything about preferable therapeutic options? METHODS An analysis of electronic health records for a large (68,466-case), international COVID-19 cohort, in five-year age strata, revealed age-dependent sex differences. In particular, we surveyed the effects of systemic hormone administration in women. The primary outcome for estradiol therapy was death. Odds Ratios (ORs) and Kaplan-Meier survival curves were analyzed for 37,086 COVID-19 women in two age groups: pre- (15-49 years) and post-menopausal (>50 years). RESULTS The incidence of SARS-CoV-2 infection is higher in women than men (about +15%) and, in contrast, the fatality rate is higher in men (about +50%). Interestingly, the relationships between these quantities are also linked to age. Pre-adolescent girls had the same risk of infection and fatality rate as boys. Adult premenopausal women had a significantly higher risk of infection than men in the same five-year age stratum (about 16,000 vs. 12,000 cases). This ratio changed again in postmenopausal women, with infection susceptibility converging with men. While fatality rates increased continuously with age for both sexes, at 50 years there was a steeper increase for men. Thus far, these types of intricacies have been largely neglected. Because the hormone 17{beta}-estradiol has a positive effect on expression of the human ACE2 protein--which plays an essential role for SARS-CoV-2 cellular entry--propensity score matching was performed for the women's sub-cohort, comparing users versus non-users of estradiol. This retrospective study of hormone therapy in female COVID-19 patients shows that the fatality risk for women >50 yrs receiving estradiol therapy (user group) is reduced by more than 50%; the OR was 0.33, 95 % CI [0.18, 0.62] and the Hazard Ratio was 0.29, 95% CI [0.11,0.76]. For younger, pre-menopausal women (15-49 yrs), the risk of COVID-19 fatality is the same irrespective of estradiol treatment, probably because of higher endogenous estradiol levels. CONCLUSIONS As of this writing, still no effective drug treatment is available for COVID-19; since estradiol shows such a strong improvement regarding fatality in COVID-19, we suggest prospective studies on the potentially more broadly protective roles of this naturally occurring hormone.

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