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

Abstract

Background: Given that an individual's age and gender are strongly predictive of coronavirus disease 2019 (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 5-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 peri-/post-menopausal (> 50 years).

Results: The incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is higher in women than men (by about + 15%) and, in contrast, the fatality rate is higher in men (about + 50%). Interestingly, the relationships between these quantities are linked to age: pre-adolescent girls and boys had the same risk of infection and fatality rate, while adult premenopausal women had a significantly higher risk of infection than men in the same 5-year age stratum (about 16,000 vs. 12,000 cases). This ratio changed again in peri- and 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 17ß-estradiol influences expression of the human angiotensin-converting enzyme 2 (ACE2) protein, which plays a role in SARS-CoV-2 cellular entry, propensity score matching was performed for the women's sub-cohort, comparing users vs. non-users of estradiol. This retrospective study of hormone therapy in female COVID-19 patients shows that the fatality risk for women > 50 years 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 (HR) was 0.29, 95% CI [0.11,0.76]. For younger, pre-menopausal women (15-49 years), 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.

Keywords: ACE2; COVID-19; Estradiol; Hormone treatment; SARS-CoV-2; Sex; Women.

Fig. 1

Our CONSORT flow diagram; major stages are indicated in the blue boxes

Fig. 2

Absolute cases of COVID-19 in our cohort, disaggregated by women (red) and men (blue)

Fig. 3

A histogram of death rates in percent for women (red) and men (blue) in 5-year age strata: cumulatively, men were more vulnerable to SARS-CoV-2 infection, with a death rate in some strata that is roughly + 50% higher than that in women

Fig. 4

Kaplan-Meier survival curves for women [16,891] (red) and men [15,688] (blue, dashed), aged 50+ with SARS-CoV-2 infection

Fig. 5

Kaplan-Meier survival curves: The survival probability of age 50+ women who were estradiol users (violet line) is shown, alongside non-users (blue dashed line)