Summary
The severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection disease (COVID-19) was first described in December 2019 in Wuhan, Hubei province, China and officially declared a Public Health Emergency by the WHO on January 30, 2020, having infected more than 100,000 people in over 100 countries [1]. Although age and gender have been implicated as strong predictors of COVID-19 outcomes few studies have explored this gender difference. Seeland et al [2] have performed an 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 [2].
In particular, they surveyed the effects of systemic hormone administration in women. The primary outcome for oestradiol therapy was death. Odds ratios (ORs) and Kaplan-Meier survival curves were analysed for 37,086 COVID-19 women in two age groups: pre- (15–49 years) and peri-/post-menopausal (> 50 years). There results found that the incidence of severe COVID-19 was higher in women than men by around 15%; however, the fatality rate was higher in men by around 50%.
While fatality rates increased continuously with age for both sexes, at 50 years, there was a steeper increase for men. This study showed that the fatality risk for women > 50 years receiving oestradiol therapy (user group) was reduced by more than 50% compared to those women not taking oestradiol; the odds ratio (OR) was 0.33, 95% CI (0.18, 0.62) and the hazard ratio (HR) was 0.29, 95% CI (0.11,0.76).
Commentary
There are marked gender differences in morbidity and mortality due to COVD-19, with men at a higher risk of presenting severe COVID-19 disease and death when compared to women. Although prospective, placebo-controlled, randomised, double-blinded multicentre clinical trials are the gold standard, these are expensive and take time to be carried out. However, a significant advantage of using the real world data is the large number of patients involved yielding relatively tighter confidence intervals and allowing for cohort balancing and patient matching.
Previous coronavirus studies (SARS-coronavirus infection) in mice have shown that the female sex hormone estrogen protected against fatality and lung inflammation and mice who underwent oophorectomies had more severe disease with more lung inflammation and increased mortality [3].
A study from Wuhan has shown that women with low oestradiol levels had more severe infection with COVID-19 [4]. There are numerous mechanisms by which oestradiol can influence the response to COVID-19 infection. Its effect on immune function is likely to be key here. Oestradiol regulates both the innate and adaptive response; modulating 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 cell types [5]. In addition, oestradiol can inhibit cytotoxic NK cells and regulate the production of numerous cytokines (i.e IL-6, IFN and TNF), blocking IL-6 production and attenuating the cytokine storm which underlies much of the cellular and organ / tissue damage caused by COVID-19 infection [6,7].
On the other hand, oestradiol downregulates the angiotensin II receptor type I signalling pathway, inhibiting ACE activity and exerting a positive effect on the expression of the ACE 2 protein [8]. This leads to protective effects on the heart, lung, kidneys, central nervous system and gut.
The regulation of the immune system seems to protect women from very severe courses of the disease. If the positive effect of sex hormone therapy on mortality in postmenopausal women is confirmed in further studies, this is an indication of the positive influence of female sex hormones on the course of the disease and a serious option for treatment of symptomatic women with COVID-19.
Louise Newson
Menopause Specialist
Newson Health Menopause and Wellbeing Centre
References
- Wu F, Zhao S, Yu B, et al. A new coronavirus associated with human respiratory disease in China. Nature. 2020;579(7798):265-269.
https://pubmed.ncbi.nlm.nih.gov/32015508/ - Seeland U, Coluzzi F, Simmaco M, Mura C, Bourne PE, Heiland M, Preissner R, Preissner S. Evidence for treatment with estradiol for women with SARS-CoV-2 infection. BMC Med. 2020;18(1):369.
https://pubmed.ncbi.nlm.nih.gov/33234138/ - Channappanavar R, Fett C, Mack M, Ten Eyck PP, Meyerholz DK, Perlman S. Sex-Based Differences in Susceptibility to Severe Acute Respiratory Syndrome Coronavirus Infection. J Immunol. 2017;198(10):4046-4053.
https://pubmed.ncbi.nlm.nih.gov/28373583/ - Ding T, Zhang J, Wang T, Cui P, Chen Z, Jiang J, et al. A Multi-hospital Study in Wuhan, China: Protective Effects of Non-menopause and Female Hormones on SARS-CoV-2 infection. medRxiv 2020;
https://www.medrxiv.org/content/10.1101/2020.03.26.20043943v1 - Fukuma N, Takimoto E, Ueda K, et al. Estrogen Receptor-alpha Non-Nuclear Signaling Confers Cardioprotection and Is Essential to cGMP-PDE5 Inhibition Efficacy. JACC Basic Transl Sci. 2020;5(3):282-295.
https://pubmed.ncbi.nlm.nih.gov/32215350/ - Ghosh S, Klein RS. Sex drives dimorphic immune responses to viral infections. J Immunol. 2017;198(5):1782–1790.
https://pubmed.ncbi.nlm.nih.gov/28223406/ - Trenti A, Tedesco S, Boscaro C, Trevisi L, Bolego C, Cignarella A. Estrogen, Angiogenesis, Immunity and Cell Metabolism: Solving the Puzzle. Int J Mol Sci. 2018; 19(3):859.
https://pubmed.ncbi.nlm.nih.gov/29543707/ - La Vignera S, Cannarella R, Condorelli RA, Torre F, Aversa A, Calogero AE. Sex-Specific SARS-CoV-2 Mortality: Among Hormone-Modulated ACE2 Expression, Risk of Venous Thromboembolism and Hypovitaminosis D. Int J Mol Sci. 2020;21(8):2948.
https://pubmed.ncbi.nlm.nih.gov/32331343/
