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.

Genomics-guided identification of potential modulators of SARS-CoV-2 entry proteases, TMPRSS2 and Cathepsins B/L

“…Our findings are in excellent agreement with recent studies reporting the significant COVID-19 mitigation potential of estradiol and retinoic acid [40][41][42]. Interestingly, a hypothetical bipartite combination (estradiol and retinoic acid) indicated more robust effects on interactome of SARS-CoV-2 target human host genes compared to monotherapies.…”

DrugWAS: Leveraging drug-wide association studies to facilitate drug repurposing for COVID-19

“…52 A retrospective study using EHR data showed a decreased fatality rate for women 50+ years old receiving estradiol therapy (OR, 0.33; 95% CI, 0.18-0.62). 53…”

“…52 A retrospective study using EHR data showed a decreased fatality rate for women 50+ years old receiving estradiol therapy (OR, 0.33; 95% CI, 0.18-0.62). 53 Multiple clinical trials are currently underway to test the efficacy and safety of using methylprednisolone (NCT04263402, NCT04559113, NCT04636671), ibuprofen (NCT04334629, NCT04382768, NCT04383899), and estradiol (NCT04539626) against COVID-19.…”

Synergy Between Vitamin D and Sex Hormones in Respiratory Functionality of Patients Affected by COVID-19

“…In the same vein, 17β-estradiol increases the expression of ACE2 also playing a protective role in COVID-19 (Seeland et al, 2020). Although epidemiological data indicate that COVID-19 produces more severe symptoms and higher mortality in elderly in comparison to young patients and in men in comparison to women (Pagano et al, 2020;Chen et al, 2021), to date, sex, and age differences in vitamin D status in infected patients have not been evaluated yet.…”