Does gender explain why women die of the novel coronavirus (COVID-19) at a much lower rate than men do?

Your Menopause Question: Does gender explain why women die of the novel coronavirus (COVID-19) at a much lower rate than men do? 

Note: Originally posted in May 2020. 

Our Response: Human coronaviruses such as the severe acute respiratory syndrome coronavirus (SARS-CoV), the Middle East Respiratory Syndrome coronavirus (MERS-CoV), and the novel coronavirus (2019-nCoV), have all created public health emergencies of international concern. However, despite journal article titles such as COVID-19: the gendered impacts of the outbreak (Lancet, 2020) and releases from news outlets and media (noted in references), little attention has been paid to the discrepancies in death rates within the populations of men and women. This discrepancy raises important questions regarding COVID-19 patients. According to the World Health Organization, while men and women appear to be infected equally, in China, deaths were documented in 2.8% of men, yet in only 1.7 % of women (even though the women’s population was older than that of men) (Peretz, 2015, and Wenham, 2020). In Hong Kong, deaths from SARS-CoV were documented in 22% of men compared with only 13% of women. During the MERS-CoV epidemic, 32% of men died, yet only 22% of women died. Preliminary data from the current COVID-19 pandemic appear to trend in this same direction. Since COVID-19 shares about 80% of the genome of SARS CoV, data from one may be relevant for understanding the other.

Efforts to address the role of estrogen and progesterone to explain this gender-related discrepancy draw from studies of cell cultures, animal studies, human biology, and clinical studies. Consistent with these diverse areas of viral investigation is the adverse role of inflammation. COVID-19 appears to incite a massive inflammatory reaction in the lungs. In addition, the worse outcomes seem to be attributed to the defensive overreaction of the body’s immune response, called a cytokine storm, leading to additional tissue damage. Examining estrogen’s protective role in viral infections may focus on its anti-inflammatory effects. In cell cultures, an estradiol dose-related reduction in production of inflammatory prostaglandins has been documented. (Takao, 2005) 

Gender appears to be critical in this discussion. When cells from nasal swabs from men and women were exposed to the influenza virus, cell replication was reduced only in those samples from women (Peretz, 2015). 

Studies of mice infected with SARS-CoV showed that male mice were more susceptible to the infection than female mice, and the difference was greater in older mice populations. The adverse effects were attributed to increased accumulation of inflammatory monocyte macrophages and neutrophils in the lungs. Female mice with ovaries removed, and therefore deprived of estradiol, exhibited increased mortality from virus exposure (Rudragouda, 2017).

The anti-inflammatory properties of progesterone also may play a role in protecting women from tissue damage (Lei, 2014). Following injury to the central nervous system, microglia cells (cells which are resident immune cells in the central nervous system) have been shown to overact, releasing pro-inflammatory mediators TNF-alpha, prostaglandin E2, and nitric oxide. In microglia cell cultures exposed to lipopolysaccharide (LPS) as a classic model to induce inflammation, progesterone pretreatment reduced TNF-alpha, COX-2, and iNOS, all measures of inflammation.

Finally, genome differences themselves may offer some explanations. The genes for our immune system reside on the X chromosome (Libert, 2010). Normally, in the female, only one X chromosome is active. Still, the possibility that aspects of the less active X chromosome may provide some benefit for immunity to the female cannot be ruled out. On the X chromosome, also, are the genes for the angiotensin-converting enzyme 2 (ACE-2), a vasodilator enzyme, which counteracts the vasoconstrictor effects of angiotensin ll to control blood pressure and blood flow (Srivastava 2020). The ACE-2 receptor is present on the surface of human cells. Why is this important? The 2019 coronavirus has trimeric spike glycoprotein spines that can attach to the ACE-2 receptor and enter the cells by what is described as a “lock and key.” Moreover, these same investigators found that the affinity of the COVID-19 spines to ACE-2 is much stronger than that found in the SARS-CoV (Wrapp, 2020). Could this explain some of the gender differences noted in this virus pandemic? Mouse studies have found that ACE-2 activity is higher in the male kidney compared to the female kidney (Jun, 2010). And, in males, the testes contain high levels of ACE-2, while the ovaries contain no ACE-2 (Cell Science, 2020).

Gender discrepancy among those who died from the current COVID-19 pandemic is but one of many unique characteristics of this pandemic but broadens the biologic foundation from which effective treatments and even vaccines may benefit. A current National Institutes of Health (NIH) study is underway to assess the value of a seven-day estradiol patch at 0.025mg/24 hours administered early in the COVID-19 episode (NIH Clinical Trials.gov).

James Woods | 3/25/2021

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