The protective effect of HRT: How oestrogen supplementation is associated with a decreased risk of dying from COVID-19

A recent paper published in BMJ Open has concluded that “oestrogen supplementation in postmenopausal women is associated with a decreased risk of dying from COVID-19” (Sund et al. 2022: 1). Drawing upon data from a nationwide registry-based study in Sweden, the paper details how the hypothesis that increased oestrogen levels have a protective effect against death from Covid-19 was both tested and confirmed. The study included participants ranging between the ages of 50 – 80 who were all identified as post-menopausal. Researchers found that while decreasing systemic oestrogen levels in participants increased the odds of dying from COVID-19, replacing systemic oestrogen by HRT achieved the opposite – it decreased the odds of dying.

The study also concluded that the protective effect of oestrogen in reducing the risk of death against COVID-19 remained significant, even after adjusting for income and education (both of which are known to influence the outcome of a COVID-19 diagnosis).

Similar conclusions have been drawn by a research team based in Miguel Servet University Hospital who have outlined how HRT has a beneficial impact in treating post-menopausal women suffering with COVID-19 (Baquedano et al. 2022). In their retrospective observational study, Baquedano et al.  highlight how quicker recovery from COVID-19 could be observed in instances where HRT had been administered to patients. The researchers’ conclusions were drawn by the lower rates of hospital admission and shorter follow up length observed among these women taking HRT.

Oestrogen is likely to provide protective benefits to participants in the early stages of infection. The study also highlighted the observation that those who had been prescribed HRT were found to return to their daily lives quicker, with isolation ending sooner. This is theorised by the authors to point toward the conclusion that appropriate administration of HRT may also be associated with an improvement in patient wellbeing.

Supporting these conclusions further, data from a cohort study has shown that women taking HRT were nearly 80% less likely to die from COVID-19 compared with women not taking HRT (with an OR of 0.22) (Dambha-Miller et al. 2021).

A publication of a retrospective analysis of electronic health records of 68,466 COVID-19 positive patients from 17 countries using a TriNetX Real-World database provided by a global health research network has also shown that women taking HRT were more than 50% less likely to die from COVID-19 compared to women not taking HRT (Seeland et al. 2020). This was statistically significant with the OR 0.33 and HR 0.29.

Although prospective, placebo-controlled, randomised, double-blinded multicentre clinical trials may be the gold standard, these trials are often slow and expensive to conduct. Moreover, a significant advantage of using real world data to consider, is the large number of patients involved which results in yielding relatively tighter confidence intervals and allows for cohort balancing and patient matching.

So what might explain the protective effect of HRT observed in both of these studies? One possible factor to consider is the role of oestrogen in decreasing the expression of certain viral proteins (such as ACE2 and TMPRSS2) which are known to be implicated in COVID-19 internalisation and reproduction.

Further, it is well established that there are significant differences between sexes when it comes to immune responses to infection, with females having better innate and adaptive immune response than males.

Oestradiol regulates both the innate and adaptive response. It can modulate the differentiation, genetic programming and lifespan of all immune cells including neutrophils, macrophages, dendritic cells and natural killer cells as there are oestradiol receptors on all these cells (Ghosh & Klein 2017). Oestradiol regulates the production of numerous cytokines including IL-6, IFN and TNF and can block IL-6 production. Oestradiol also attenuates the cytokine storm which underlies much of the cellular and organ / tissue damage by COVID-19 infection (Trenti et al. 2018).

Regardless of the why however, the evidence points strongly toward the conclusion that oestrogen modulation through the administration of HRT may well be a good therapeutic option for treating COVID-19 in perimenopausal and menopausal women. The immune modulating effects of oestradiol should therefore not be underestimated.

References

Baquedano L, Navarro, J. et al. (2022) “SARS-Cov-2 Infection in Postmenopausal Women. New Data on Menopause Hormone Therapy”. Research Square. doi:10.21203/rs.3.rs-1157428/v1.

Dambha-Miller H, Hinton W, Joy M, Feher M, de Lusignan S. (2021) “Mortality in COVID-19 amongst women on Hormone Replacement Therapy or Combined Oral Contraception: A cohort study” medRxiv. doi: https://doi.org/10.1101/2021.02.16.21251853

Ghosh S, Klein RS. (2017) “Sex drives dimorphic immune responses to viral infections”.  Journal of Immunology. 198 (5), pp. 1782–1790. doi:10.4049/jimmunol.1601166

Seeland U, Coluzzi F, Simmaco M, Mura C, Bourne PE, Heiland M, Preissner R, Preissner S. (2020) “Evidence for treatment with estradiol for women with SARS-CoV-2 infection”. BMC Med, 18 (369), pp. 2-9. doi:10.1186/s12916-020-01851-z

Sund M, Fonseca-Rodríguez O, Josefsson A, et al. (2022) “Association between pharmaceutical modulation of oestrogen in postmenopausal women in Sweden and death due to COVID-19: a cohort study”. BMJ Open, 12: e053032. doi:10.1136/bmjopen-2021-053032.

Trenti A, Tedesco S, Boscaro C, Trevisi L, Bolego C, Cignarella A. (2018) “Estrogen, Angiogenesis, Immunity and Cell Metabolism: Solving the Puzzle” International Journal of Molecular Sciences,19 (3) 85. doi:10.3390/ijms19030859.