What role does estrogen play in the COVID-19 sex difference?
Written by: Blaine Caslin
Edited by: Jina Zhou and Esther Melamed
4/27/2020
Previous entries in this blog have shown that men who contract the SARS-CoV-2 virus are more likely to develop severe disease symptoms than women. The closely related coronavirus SARS-CoV-1, which also targets the ACE2 protein for cell adhesion and infiltration, showed a similar sexual disparity during the 2002-2004 SARS epidemic. Research into the mechanisms of SARS-CoV-1 pathology over the past eighteen years has provided information which can help guide investigations of the current pandemic. Notably, a 2017 study used a modified version of the virus in mice and found a lower death rate among females. However, ovariectomized females had a similar death rate to males following infection, suggesting that female sex hormone signaling exerts a protective effect and drives the epidemiological difference (1).
Sex hormones have been previously implicated in altering the expression levels of both SARS-CoV-2 target proteins, ACE2 and TMPRSS2 (2). The serine protease TMPRSS2 has been shown to be upregulated by androgen receptor activation (3), although this effect has primarily been observed in male reproductive tissue. An early study found no relationship between androgen and TMPRSS2 levels in mouse pulmonary tissue, although these findings await further collaboration (4).
ACE2 is more promising as a potential candidate for sex hormone-mediated differences in COVID-19 pathology. ACE2, or angiotensin converting enzyme 2, regulates blood pressure by converting vasoconstrictive angiotensin II into the vasodilator angiotensin 1-7. A 2010 study (5) examined the role of sex hormones in ACE2 activity using four-core genotype mice (FCG), a mutant strain where the gonad-determining Sry gene has been translocated from the Y chromosome. Offspring of this strain can potentially have two X chromosomes but develop male gonads or vice versa. Renal ACE2 activity between these groups was hormonally regulated independently of sex chromosomes as shown in Fig 2.
Together these studies indicate a role for estrogen in female protection against COVID-19 severity, and a strong potential for estrogen-mediated ACE2 expression or activation as the main contributing factor. This would explain the interaction between age and sex in COVID-19 fatalities, as older individuals of both sexes experience increased risk but male risk elevates at an earlier age (6-8). As estrogen levels decrease in post-menopausal women, their exposure to severe clinical outcomes begins to resemble the male population.
References
- Channappanavar et al. Sex-Based Differences in Susceptibility to Severe Acute Respiratory Syndrome Coronavirus Infection. J Immunol May 15, 2017, 198 (10) 4046-4053; DOI: https://doi.org/10.4049/jimmunol.1601896
- Hoffmann, M et al. (2020). SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically-proven protease inhibitor. Cell, DOI: 10.1016/j.cell.2020.02.052
- Lin B, Ferguson C, White JT, Wang S, Vessella R, True LD, Hood L, Nelson PS (1999). Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2 Cancer Res 59, 4180–4184
- Baratchian et al. (2020). No evidence that androgen regulation of pulmonary TMPRSS2 explains sex-discordant COVID-19 outcomes. bioRxiv 2020.04.21.051201; doi: https://doi.org/10.1101/2020.04.21.051201. Preprint.
- Liu J, Ji H, Zheng W, et al. Sex differences in renal angiotensin converting enzyme 2 (ACE2) activity are 17β-oestradiol-dependent and sex chromosome-independent. Biol Sex Differ. 2010;1(1):6. Published 2010 Nov 5. doi:10.1186/2042-6410-1-6
- Informe nº 19. Situación de COVID-19 en España a 1 de abril de 2020. Equipo COVID-19. RENAVE. CNE. CNM (ISCIII)
- “Epidemia COVID-19” (PDF). epicentro.iss.it (in Italian). Istituto Superiore di Sanità. 30 March 2020. Retrieved 2 April 2020.
- Borghesi et al. Radiographic severity index in COVID-19 pneumonia: relationship to age and sex in 783 Italian patients. Nuclear Medicine & Medical Imaging 2020. Published online 27 March 2020.
What is driving the sex difference in COVID-19?
Written by: Blaine Caslin
Edited by: Jina Zhou and Esther Melamed
4/20/2020
The current evidence for a male predisposition toward increased risk of severe disease from SARS-CoV-2 infection is consistent across age groups and cultural demographics. Smoking was examined as a possible risk factor based on early studies on COVID-19 epidemiology out of China, where the noticable sex difference in disease severity was paired with a national difference in smoking rates between males and females. Approximately 50% of Chinese men smoke compared to ~2% of women according to the WHO, and this was posited as a potential explanation for the male predisposition to COVID-19 (1). However, data from Italy and Spain have indicated that this sexual disparity persists in countries with less egregious differences in smoking rates between sexes (2,3). Additionally, examination of pediatric COVID-19 cases from the United States and China have found that males are disproportionately represented among children who present COVID-19 symptoms (4,5), suggesting that the origin of this disparity is biological rather than behavioral.
Although it is still too early to tell exactly what is causing this sex difference in susecptibility to SARS-Cov-2, the related virus SARS-CoV-1 has been under investigation for a longer period of time and may shed some light on the potential mechanisms of the current pandemic. The 2002-2004 SARS outbreak in Southeast Asia showed similar sex patterns to the current COVID-19 pandemic, and researchers have been able to develop animal models to examine the infection profile. In a 2017 study, researchers found that male mice infected with a modified version of SARS-CoV-1 had a higher mortality rate than their female counterparts (6).
This pattern was seen in transgenic mice with a Rag1 knockout mutation, which do not produce mature T or B cells, indicating that the sexual disparity exists independently of underlying sex differences in the adapative immune system. However, gonadectomy of female wild-type mice removed this protective survival effect while gonadectomy of male mice did not affect survival rates. This suggests that the relative protection afforded to female SARS-CoV-1 patients is mediated through estrogen receptor signalling, although further research will be needed to validate these findings in SARS-CoV-2 infections and to fully elucidate the responsible mechanism (6).
References
- Sex difference and smoking predisposition in patients with COVID-19. Lancet 2020. Published Online March 11, 2020 https://doi.org/10.1016/ S2213-2600(20)30117-X
- Informe nº 19. Situación de COVID-19 en España a 1 de abril de 2020. Equipo COVID-19. RENAVE. CNE. CNM (ISCIII)
- “Epidemia COVID-19” (PDF). epicentro.iss.it (in Italian). Istituto Superiore di Sanità. 30 March 2020. Retrieved 2 April 2020.
- Liu, et al. Detection of Covid-19 in Children in Early January 2020 in Wuhan, China. New England Journal of Medicine 2020.
- Coronavirus Disease 2019 in Children — United States, February 12–April 2, 2020. MMWR Morb Mortal Wkly Rep 2020;69:422–426. DOI: http://dx.doi.org/10.15585/mmwr.mm6914e4
- Channappanavar et al. Sex-Based Differences in Susceptibility to Severe Acute Respiratory Syndrome Coronavirus Infection. J Immunol May 15, 2017, 198 (10) 4046-4053; DOI: https://doi.org/10.4049/jimmunol.1601896
Are there sex differences in COVID-19 epidemiology?
Written by: Blaine Caslin
Edited by: Jina Zhou and Esther Melamed
4/13/2020
As the novel coronavirus continues to spread across the world, global health organizations have begun to identify patterns of uniquely susceptible populations.
When discussing the epidemiology of this virus, it is important to distinguish between SARS-CoV-2 infection and the development of the COVID-19 disease. Approximately 50% of people who become infected with the virus do not develop any disease symptoms and may not know they have been infected, although they are still contagious and able to infect others for a period of approximately two weeks following their exposure. The distinction between asymptomatic and symptomatic patients is particularly important because, in situations where entire populations are tested en masse, there appears to be no sex difference in infection rates (4,5). For example, when the cruise ship Diamond Princess was quarantined off of Yokohama, Japan in February of 2020, all 3,711 passengers were tested. In this population, 634 tested positive for SARS-CoV-2 and of these, there was a roughly equal ratio between the sexes (50.6% male vs. 49.4% female) (Fig 1) (4). This finding has been confirmed by large-scale population testing in Iceland, where all citizens are subject to screening regardless of their symptomatic state (5).
While it appears that men and women are equally susceptible to becoming infected by the virus, it is evident that men are more likely to develop symptoms and become severely ill from their infection. The earliest studies of COVID-19 epidemiology in China indicated a male predisposition to developing severe complications from SARS-CoV-2 infection (1-3). This disposition has been maintained in later studies conducted across multiple countries, although the exact mechanism responsible remains unknown. As of April 1, 2020, statistics kept by the Spanish National Epidemiological Surveillance Network showed that 64% of COVID-19 deaths were male (6). Furthermore, the Spanish data shows a notable sexual disparity in symptom severity, wherein women who contract the virus are less likely to require hospitalization and men are more likely to require intensive care (Fig. 2).
These epidemiological patterns have been repeated across the world in infected regions. In Italy, the virus has a 13.3% mortality rate among men compared to a 7.4% rate among women. Overall, 69.1% of fatalities in Italy have been male (7). Clinical studies have identified more severe disease indicators among male patients regardless of survival rate, including an Italian study of chest X-rays from COVID-19 patients demonstrating more severe lung damage among male patients compared to age-matched female patients (Fig. 3). Such studies combined with epidemiological patterns indicate an interaction between age and sex in susceptibility to severe illness from SARS-CoV-2 infection. While older individuals are at higher risk for developing respiratory problems requiring hospitalization and intensive care, this risk is exacerbated in males, who experience a higher risk at an earlier age compared to females.
Finally, it is important to note that the bias toward more severe disease in males seems to be consistent across age groups, as pediatric COVID-19 studies from both China (9) and the United States (10) have found that approximately 57% of SARS-CoV-2 positive symptomatic children are male. This strongly indicates that there is a genetic component to the male predisposition toward severe illness. Socio-behavioral factors such as diet or smoking rates have been proposed for the sex difference in COVID-19 severity, but these are insufficient to explain the discrepancy seen across cultures and age groups. Further study and expanded testing of asymptomatic populations will be necessary to fully elucidate the risk profile of SARS-CoV-2 infection and the development of COVID-19 disease symptoms.
References
- Zhang JJ, Dong X, Cao Y, et al. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy 2020; published online Feb 19.
- Yang X, Yu Y, Xu J, 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; published online Feb 24.
- Guan W, Ni Z, Liang W, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; published online Feb 28.
- Mizumoto Kenji , Kagaya Katsushi , Zarebski Alexander , Chowell Gerardo . Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19)cases on board the Diamond Princess cruise ship, Yokohama, Japan, 2020. Euro Surveill. 2020;25(10):pii=2000180.
- Berghildur skrifar – Um Helmingur Greindra Í Skimun Einkennalaus Eða Einkennalítill -Vísirhttps ://www.visir.is/g/2020140116d/um-helmingur-greindra-i-skimun-einkennalaus-eda-einkennalitill
- Informe nº 19. Situación de COVID-19 en España a 1 de abril de 2020. Equipo COVID-19. RENAVE. CNE. CNM (ISCIII)
- “Epidemia COVID-19” (PDF). epicentro.iss.it (in Italian). Istituto Superiore di Sanità. 30 March 2020. Retrieved 2 April 2020.
- Borghesi et al. Radiographic severity index in COVID-19 pneumonia: relationship to age and sex in 783 Italian patients. Nuclear Medicine & Medical Imaging 2020. Published online 27 March 2020.
- Dong Y, Mo X, Hu Y, et al. Epidemiology of COVID-19 Among Children in China. Pediatrics. 2020;145(6):e20200702
- Coronavirus Disease 2019 in Children — United States, February 12–April 2, 2020. MMWR Morb Mortal Wkly Rep. ePub: 6 April 2020. DOI: http://dx.doi.org/10.15585/mmwr.mm6914e4