Evidence for treatment with estradiol for women with SARS-CoV-2 infection
Ute Seeland, Flaminia Coluzzi, Maurizio Simmaco, Cameron Mura, Philip E Bourne, Max Heiland, Robert Preissner, Saskia Preissner, Ute Seeland, Flaminia Coluzzi, Maurizio Simmaco, Cameron Mura, Philip E Bourne, Max Heiland, Robert Preissner, Saskia Preissner
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.
Conflict of interest statement
The authors declare that they have no competing interests.
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References
- Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708–1720. doi: 10.1056/NEJMoa2002032.
- Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020;8(5):475–481. doi: 10.1016/S2213-2600(20)30079-5.
- Verity R, Okell LC, Dorigatti I, Winskill P, Whittaker C, Imai N, et al. Estimates of the severity of coronavirus disease 2019: a model-based analysis. Lancet Infect Dis. 2020;20(6):669–677. doi: 10.1016/S1473-3099(20)30243-7.
- Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054–1062. doi: 10.1016/S0140-6736(20)30566-3.
- Cai H. Sex difference and smoking predisposition in patients with COVID-19. Lancet Respir Med. 2020;8(4):e20. doi: 10.1016/S2213-2600(20)30117-X.
- Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271–280. doi: 10.1016/j.cell.2020.02.052.
- Crackower MA, Sarao R, Oudit GY, Yagil C, Kozieradzki I, Scanga SE, et al. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature. 2002;417(6891):822–828. doi: 10.1038/nature00786.
- Gheblawi M, Wang K, Viveiros A, Nguyen Q, Zhong JC, Turner AJ, et al. Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2. Circ Res. 2020;126(10):1456–1474. doi: 10.1161/CIRCRESAHA.120.317015.
- Fischer M, Baessler A, Schunkert H. Renin angiotensin system and gender differences in the cardiovascular system. Cardiovasc Res. 2002;53(3):672–677. doi: 10.1016/S0008-6363(01)00479-5.
- Harrison-Bernard LM, Schulman IH, Raij L. Postovariectomy hypertension is linked to increased renal AT1 receptor and salt sensitivity. Hypertension. 2003;42(6):1157–1163. doi: 10.1161/01.HYP.0000102180.13341.50.
- Turner AJ, Hiscox JA, Hooper NM. ACE2: from vasopeptidase to SARS virus receptor. Trends Pharmacol Sci. 2004;25(6):291–294. doi: 10.1016/j.tips.2004.04.001.
- Foresta C, Rocca MS, Di Nisio A. Gender susceptibility to COVID-19: a review of the putative role of sex hormones and X chromosome. J Endocrinol Invest. 2020. PubMed PMID: 32936429. PMCID: PMC7492232. Epub 2020/09/17.
- 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). PubMed PMID: 32331343. PMCID: PMC7215653. Epub 2020/04/26.
- Xie X, Chen J, Wang X, Zhang F, Liu Y. Age- and gender-related difference of ACE2 expression in rat lung. Life Sci. 2006;78(19):2166–2171. doi: 10.1016/j.lfs.2005.09.038.
- Straub RH. The complex role of estrogens in inflammation. Endocr Rev. 2007;28(5):521–574. doi: 10.1210/er.2007-0001.
- Dubey RK, Jackson EK. Cardiovascular protective effects of 17beta-estradiol metabolites. J Appl Physiol (1985) 2001;91(4):1868–1883. doi: 10.1152/jappl.2001.91.4.1868.
- Gebhard C, Regitz-Zagrosek V, Neuhauser HK, Morgan R, Klein SL. Impact of sex and gender on COVID-19 outcomes in Europe. Biology of sex differences. 2020;11(1):29 PubMed PMID: 32450906. PMCID: PMC7247289. Epub 2020/05/27.
- Klein SL, Dhakal S, Ursin RL, Deshpande S, Sandberg K, Mauvais-Jarvis F. Biological sex impacts COVID-19 outcomes. PLoS Pathog. 2020;16(6):e1008570. doi: 10.1371/journal.ppat.1008570.
- Robert-Koch-Institut. COVID-19 disease in Germany presented by the Robert-Koch Institute (RKI) 2020 [Available from: .
- Dorak MT, Karpuzoglu E. Gender differences in cancer susceptibility: an inadequately addressed issue. Front Genet. 2012;3:268. doi: 10.3389/fgene.2012.00268.
- Erfinanda L, Ravindran K, Kohse F, Gallo K, Preissner R, Walther T, et al. Estrogen-mediated upregulation of the Mas receptor contributes to sex differences in acute lung injury and lung vascular barrier regulation. Eur Respir J. 2020; PubMed PMID: 32764118. Epub 2020/08/09.
- Carey MA, Card JW, Voltz JW, Germolec DR, Korach KS, Zeldin DC. The impact of sex and sex hormones on lung physiology and disease: lessons from animal studies. Am J Physiol Lung Cell Mol Physiol. 2007;293(2):L272–L278. doi: 10.1152/ajplung.00174.2007.
- Speyer CL, Rancilio NJ, McClintock SD, Crawford JD, Gao H, Sarma JV, et al. Regulatory effects of estrogen on acute lung inflammation in mice. Am J Physiol Cell Physiol. 2005;288(4):C881–C890. doi: 10.1152/ajpcell.00467.2004.
- Breithaupt-Faloppa AC, Correia CJ, Prado CM, Stilhano RS, Ureshino RP, Moreira LFP. 17beta-Estradiol, a potential ally to alleviate SARS-CoV-2 infection. Clinics (Sao Paulo) 2020;75:e1980. doi: 10.6061/clinics/2020/e1980.
- Gemmati D, Bramanti B, Serino ML, Secchiero P, Zauli G, Tisato V. COVID-19 and individual genetic susceptibility/receptivity: role of ACE1/ACE2 genes, immunity, inflammation and coagulation. Might the double X-chromosome in females be protective against SARS-CoV-2 compared to the single X-chromosome in males? Int J Mol Sci. 2020;21(10). PubMed PMID: 32423094. PMCID: PMC7278991. Epub 2020/05/20.
- Balaton BP, Cotton AM, Brown CJ. Derivation of consensus inactivation status for X-linked genes from genome-wide studies. Biol Sex Differences. 2015;6:35. doi: 10.1186/s13293-015-0053-7.
- Li G, Fan Y, Lai Y, Han T, Li Z, Zhou P, et al. Coronavirus infections and immune responses. J Med Virol. 2020;92(4):424–432. doi: 10.1002/jmv.25685.
- McGonagle D, Sharif K, O'Regan A, Bridgewood C. The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease. Autoimmun Rev. 2020;19(6):102537. doi: 10.1016/j.autrev.2020.102537.
Source: PubMed