Published in The British Medical Journal - 13th February 2022

Principal findings

The major finding of this nationwide registry-based study is that pharmaceutical augmentation of oestrogen levels is associated with decreased odds of death due to COVID-19 in postmenopausal women.

Comparison with related studies

There are several possible biological explanations for the lower risk experienced by women. These include mechanisms directly involved in viral internalisation and reproduction, where oestrogen has been shown to decrease expression of vital proteins such as ACE2 and TMPRSS2,9–11 inherent sex-linked differences in the immune system, and direct oestrogen effects.12 As an example, Kalidhindi et al have studied the effect of testosterone and oestrogen on ACE2, a key cell entry for SARS-CoV-2 virus, using in vitro experiments on isolated human airway smooth muscle cells of male and female origin.13 Most interestingly, they show that cells exposed to oestrogen and testosterone behave differently, as testosterone significantly upregulates ACE2 expression in cells from both sexes, whereas oestrogen downregulates ACE2.13 ACE2 expression and differences in its expression in relation to sex could also be linked to the higher mortality in relation to hypertension, venous thromboembolism and SARS-CoV-2 infection between men and women.14 Our findings are also supported by in vitro studies where 17β-oestradiol treatment reduced SARS-CoV-2 viral load.9 Previous experimental studies in mice on SARS-CoV have, moreover, shown that female mice are less susceptible to infection and that this protection was lost on oophorectomy, thus indicating a direct protective role of oestrogen signalling.15 Furthermore, Barh et al, using a multiomics approach on SARS-CoV-2-infected host interactome, proteome, transcriptome and bibliome datasets, demonstrated that oestrogen modulation could be a potential therapeutic option in COVID-19.16 Our results are in line with those by Seeland et al using real-world evidence from multiple institutions and the TriNetX platform. They found by using propensity score matched analysis of data for women aged 50 years and above with COVID-19 (n=439) that there was a survival benefit for oestradiol hormone users versus non-users (OR 0.33 (95% CI 0.18 to 0.62)). Although based on a large real-world dataset, the risk of selection bias was more difficult to discern since the cohort was neither population based nor adjusted for central confounders although likely mitigated by the propensity score matched analysis.17 In our study, the effect of increased systemic oestrogen levels on reducing the risk of COVID-19 death remained significant after adjusting for education level and income, both factors known to influence COVID-19 outcome,18 further supporting the protective role of oestrogen in women. Adjusting for income and education is important as we have previously shown how these affect the risk of dying due to COVID-19 in Sweden.19

The hypothetical inverse, a worsening effect of reduced systemic oestrogen levels in women with a previous BC receiving adjuvant endocrine therapy, was initially significant but not after adjusting for confounders. This population differs from the control group in that they all have been diagnosed with BC and it has been shown that patients, both men and women, with any cancer are harder hit by COVID-19.20 However, in a previous study, patients with BC were shown to be healthier compared with the background population in terms of ischaemic cardiac disease and CCI,21 and the wCCI adjustments may therefore overcompensate for this cancer-related vulnerability. Although not significant, a trend towards worse outcome remained and thus a larger population of patients with BC on endocrine therapy is likely needed to verify the finding. Thus, this study cannot exclude an increased risk of death from COVID-19 if systemic oestrogen levels are pharmaceutically decreased.

Strengths and limitations

The strengths of this study are that this is a nationwide cohort in a country with high COVID-19 incidence using well-validated registry data. A weakness is that the level of oestrogen modulation cannot be exactly measured in each individual, and that the number of women with BC on anti-oestrogen medication ended up being too small to show significance although there was a clear trend. Furthermore, we do not have data on the exact duration of postmenopausal HT for the individuals. The postmenopausal HT group, however, proved large enough to show the clear protective effect. A further limitation is that confounding factors such as body mass index, nutrition and smoking habits are not available in the nationwide registry data.

Implications and conclusion

This study shows an association between oestrogen levels and COVID-19 death. Consequently, drugs increasing oestrogen levels may have a role in therapeutic efforts to alleviate COVID-19 severity in postmenopausal women and could be studied in randomised control trials.

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