October 07, 2021 11 min read
During the coronavirus disease 2019 (COVID-19) pandemic, much emphasis was initially placed on the elderly or those who have pre-existing health conditions for presenting a higher risk of contracting and/or dying of COVID-19.
Since the outbreak there has been a vast amount of evidence on certain populations, age, and gender characteristics.
A huge cross-sectional study in China found that 80% of patients who contracted SARS-CoV-2 exhibited mild or moderate symptoms shared with other viral respiratory infections.1
On the other hand, SARS-CoV-2 has also demonstrated an ability to cause severe disease among certain groups, including older populations and individuals with underlying health conditions such as obesity, cardiovascular disease, and diabetes.2
Nevertheless, a clear picture of the epidemiology of COVID-19 is not yet well understood, but it is now becoming evident that being male is also a factor.3
In support of this, a recent study stated that men and women were equally likely to contract the novel coronavirus.
However, it was reported that men are significantly more likely to suffer severe effects of the disease. In one large subset of COVID-19 patients in this study, more than 70 percent of those who died were men. Interestingly, this study also found similar results when they examined research from the 2003 outbreak of severe acute respiratory syndrome (SARS).4
New findings from this research are:
The World Health Organization (WHO) has also reported that 63 percent of deaths related to COVID-19 in Europe have been among men.
Higher rates of death among men in pandemics is not new. Research on the worldwide flu of 1918, for example, found that non-elderly adult males died at a much higher rate than women, possibly because more men had a history of lung-damaging tuberculosis.5
There are some very recent discoveries and there is much more research that needs to be done in this area. There is a lot of science in understanding the mechanisms behind this.
I will break down some of the “hot” areas of research within this area below.
Why are men more at risk?
While it is still too early to determine why the gender gap is emerging, we will take a look at some of the potential aspects such as genetics, immunology, and behavioral as the associated factors.
Research is showing that genetics can play a part in how susceptible someone is to COVID-19.6 It seems that the expression and distribution of a receptor influences the route of virus infection which has a main effect for understanding the pathogenesis and dictate therapeutic strategies.7
Angiotensin-converting enzyme (ACE 2) which is encoded by ACE 2 gene has been demonstrated to be the receptor for both the SARS-coronavirus (SARS-CoV) and human respiratory coronavirus NL63.8
Angiotensin-converting enzyme is an enzyme that helps regulate blood pressure. It plays a central role in generating angiotensin II from angiotensin I. Capillary blood vessels in the lung are one of the major sites of ACE expression and angiotensin II production in the human body.
Current evidence on the receptors for SARS-CoV-2 suggest that ACE2 are the receptors responsible for SARS-CoV-2. Research shows similar receptor binding properties between SARS-CoV-2 and SARS-CoV. 9
Essentially, this means an organism which elevated expression of ACE2 protein has a simplified environment for pathogenesis of coronavirus. Research demonstrates that circulating ACE2 levels are higher in men than in women and in patients with diabetes or cardiovascular diseases.10
In addition, evidence shows that ACE2 is expressed more in the lungs of males compared to females.7
Limited human data suggest that SARS-CoV-2 binding to ACE2 may attenuate residual ACE2 activity, thus slanting ACE/ACE2 balance toward a state of heightened angiotensin II production. This leads to pulmonary vasoconstriction, inflammation, and oxidative-related organ damage resulting in an increased risk for acute lung injury.
It’s possible that greater ACE2 produced more cardioprotective angiotensisn 1-7, essentially providing greater protection for women. It’s also possible that higher ACE2 activity provides a more efficient “sink” in eliminating the virus or preventing its attachment for target cell entry.
Essentially, there are immunological checkpoints that play an important role in balancing the immune system during microbial infection by stimulating and controlling hyperimmune mediated responses.11
Research shows that a certain receptor (CD200R) and sex are host factors that together determine the outcome of viral infection. It was shown that a lack of this receptor signaling strongly enhanced type I interferon production and viral clearance and improved the outcome of mouse hepatitis coronavirus infection, particularly in female mice.12
In essence, this means that organisms with high amounts of this receptor signaling have an enhance clearance of viral infection.
A review which looked on association between sex difference in immune responses concluded that sex-based immunological differences contribute to variations in the susceptibility to infectious diseases and responses to vaccines in males and females.13
Antiandrogens, Testosterone and Estrogens
A likely explanation of a worse prognosis in men could be the androgenic-enhanced expression of type II transmembrane serine protease (TMPRSS2). TMPRSS2 is an endothelial cell surface protein that is involved in the viral entry and spread of coronaviruses including SARS-CoV-2. Blocking TMPRSS2 could potentially be an effective clinical therapy for COVID-19.
However, young men have superior outcomes than older men despite having greater levels of testosterone.
Among young men, those with androgenic alopecia (i.e. male pattern baldness) display a higher risk of severe COVID-19 forms and worse outcomes14 apparently due to increased intracellular conversion from testosterone to 5-alpha dihydrotestosterone (DHT), thus facilitating SARS-CoV-2 to increase infectivity.
Antiandrogenic treatment, particularly androgen receptor inhibitors as cyproterone, spironolactone, eplerenone or flutamide and 5-alpha-reductase inhibitors, as well as finasteride and dutasteride, seem to be protective from COVID-19 in men. However, this question remains very contentious at the moment.15
Dutasteride and finasteride are 5-alpha-reductase inhibitors that block the conversion of testosterone to 5-alpha DHT and mitigate TMPRSS2 expression in prostate cancer.16
For these effects, they have been proposed as an adjuvant treatment for SARS-CoV-2 infection, particularly in men with androgenic alopecia.17
Clinical trials are underway at the moment, therefore it is still too early to know if these treatments are effective.
Low Testosterone and disease severity
A recent study found that men with severe COVID-19 had approximately 65% to 85% lower testosterone concentrations compared with men with a milder disease course. This difference was independent of other known risk factors associated with severity of COVID-19, such as age, BMI, comorbidities, smoking, and race.
Testosterone concentrations were similarly low in men who developed severe COVID-19 illness during their hospital stay as in those who presented with severe illness compared with men with milder courses of COVID-19. In that regard, testosterone was a marker associated with severe and impending severe COVID-19 illness.
Epidemiologic data imply that while men are not more predisposed to contracting COVID-19, they are more likely to develop severe illness following the infection compared with women. Unlike the common presumption, researching indicates that testosterone may not be a propagator of COVID-19 severity in either gender. On the contrary, it may be protective in men.18
Alternatively, it is also likely that the men who developed severe COVID-19 had testosterone values that were chronically less than the reference range, even prior to their illness. Men with chronically low testosterone have decreased muscle mass and strength. This may contribute to decreased lung capacity and ventilator dependence.19
This is a plausible explanation for the association between lower testosterone concentrations and worse hospital outcomes in patients.
Future research should ascertain whether men with testosterone concentrations below the reference range prior to contracting COVID-19 are more likely to develop severe disease. If true, this would support a mediator role for testosterone and suggest that long-term testosterone treatment has potential to prevent respiratory compromise in illnesses and acute infections that target the respiratory tract.
Estrogen acts as an immune-stimulating factor
A very recent review documented that women; especially during their reproductive years, are at increased risk of developing autoimmune diseases but are more resistant to infections than men. This is possibly mediated by several sex hormones and X chromosome has been well described where blocking estrogen receptors increased the mortality due to SARS-CoV infection among female mice. This suggests that estrogen receptor signaling might offer some protective effect for female mice.20
The observed resistance to SARS-CoV-2 in women can be attributed to sex hormones, specifically estrogen, which is known to enhance the immune activity of both B as well as T-helper cells.21
Therefore, estrogen, the primary female sex hormone, is a prominent biological factor making women’s immune system more active against the virus.22
Estrogen level is inversely related with the regulation of cardiac troponin secreted during ischemic or anoxic conditions, which leads to irreversible injury to cardiac cells.23
It was seen that over 50% of patients with COVID-19 die due to cardiac injury.24
Death rates were reported to be progressively higher in patients with cardiovascular disease and elevated cardiac troponin levels compared to normal troponin levels. It seems that estrogen is a key factor because a higher proportion of men (~65%) had increased cardiac troponin as compared to women (~42%) with COVID-19.24
In addition, estrogen has been reported to decrease low-density lipoprotein cholesterol and increase the high-density lipoprotein.25 17β-estradiol is known to mediate the activation of early and late endothelial nitric oxide synthase via estrogen receptor interaction.26
Cells in our hearts carry the functional estrogen receptor that regulate nitric oxide synthase to prevent cardiovascular system from damage.27
COVID-19 affects men and women differently likely due to the difference in genetic nature and influence of sex hormones. COVID-19 enters the host body via the upper respiratory system, through contacting droplets. Estrogen has a valuable impact on the entire respiratory tract system.21
Estrogen activates the response of mucosa of the nose by regulating turbinate hypertrophy (thus prevents obstruction) and boosting secretion of nasal mucus containing anti-viral, antibacterial, and immune factors such as: IgA, lysozyme, mucins, lactoferrin, electrolytes, and oligosaccharides, which are important for restricting upper airway infections.28 (See figure for reference below:)
Fig: Schematic representation showing the protective effects of estrogen on the upper and lower respiratory tract cells and its benefits on the immune response27
In conclusion, estrogens, particularly estradiol, could be eventually protective against COVID-19 and may prevent severe complications. There are ongoing clinical trials using estrogens, progesterone and anti-androgens compounds, but no final data are currently available.
In the two hardest hit European nations, majority of the COVID-19 deaths in Italy 3 were male, while in Spain, almost twice as many men as women have died. There is no arguing that part of this is biology (genetics and immunology), but a large of the discrepancy is driven by gender behavior (life style), such as far higher levels of smoking and drinking among men compared to women.29
In addition, a recent study conducted in Spain (one of the hardest hit countries in Europe) reported that women had more responsible attitude toward the COVID-19 pandemic than men.30
This may reversibly affect their responsibility of preventive measures such as frequent hand washing, face masking, and stay at home orders.
The decreased incidence rate of COVID-19 symptoms in women can be also related to physical activity. Women perform more moderate exercise whereas men prefer prolonged and intensive exercises.31
Prolonged and vigorous exercise may lead to immunosuppression; however, mild and moderate exercise enhances immune response and significantly minimizes the risk and severity of respiratory viral infection. There is a vast amount of research supporting the notion and explain that a moderate level of exercise lowers inflammation and boosts immune function.
Consistent mild physical activity influences the level of hormones related to stress, which downregulates intense inflammation of the respiratory tract and aids in activating the anti-viral innate immunity polarizing the immune function towards a Th2 profile.27
Th2 cells mediate the activation and maintenance of the humoral, or antibody-mediated, immune response against extracellular parasites, bacteria, allergens, and toxins. More research is needed to understand the cellular and molecular cascades through which exercise regulates immune responses.
Immunity, X-chromosome associated genes, and sex hormones are the main characteristic factors that are likely to offer greater resistance against SARS-CoV-2 in women. The evidence suggesting important decisive factors of gender-related disparity in immunity may impact on the onset of COVID-19 and vaccination outcomes.
There has been a tremendous amount of research done to date on COVID-19, but there is a need for further research to understand and delineate potential therapeutic strategies.
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