Why are men more susceptible to COVID-19, SARS and MERS?

The reason why the new coronavirus "favors" men more may be related to behavioral factors such as androgen, ACE2 concentration, X chromosome, smoking and hand washing.

Written by Ye Yichu

The first clinical data on COVID-19 in Wuhan published in January 2020 showed that three-quarters of hospitalized patients were men[1]. Subsequently, data from countries around the world also confirmed this finding—men are more susceptible to infection with the new coronavirus (SARS-CoV-2) than women.

Preliminary observations in Spain found that many of the patients hospitalized with COVID-19 were bald men (androgen-related alopecia). An Italian study showed that between February 20 and March 18, 82% of the 1,591 patients admitted to the intensive care unit (ICU) were men. Another American study also confirmed that among the 5,700 COVID-19 hospitalized patients in New York City, the mortality rate of men was much higher than that of women. [1] In fact, in previous SARS and MERS cases, there were more men than women. In 2003, the mortality rate of male patients infected with SARS in Hong Kong was 50% higher than that of female patients. In 2015, the mortality rate of male patients infected with MERS was also significantly higher than that of female patients (32% vs 25.8%). [2]

Why are men more susceptible? Scientists have recently discovered some clues.

What are the “culprits”? Androgens

The results of a cell experiment suggest that an enzyme called TMPRSS2 (transmembrane serine protease type 2) plays an important role in the infection process of SARS-CoV-2. [1] TMPRSS2 can cleave the spike protein (also known as S protein) on the surface of SARS-CoV-2, allowing it to better fuse with the human cell membrane and enter the human body. TMPRSS2 is produced when androgens bind to androgen receptors. This means that androgens can enhance the ability of SARS-CoV-2 to invade cells. In fact, TMPRSS2 also plays a role in activating the spike protein in SARS and MERS, inducing the fusion of the virus with the cell membrane [3].

However, androgens are not exclusive to men. Women also have androgens in their bodies. Why are they spared? Indeed, all hormones that can bind to androgen receptors are called androgens, the most important of which is testosterone. In men, androgens are mainly produced by the testicles, while in women, the adrenal glands and ovaries secrete testosterone. This means that there are androgens in women, and when androgens bind to androgen receptors, TMPRSS2 will also be produced. Of course, the amount of androgens in men and women is different. Taking testosterone as an example, the normal range for men is 270~1070 ng/dl (9~38 nmol/l), while for women it is 15~70 ng/dl (0.52~2.4 nmol/l). It is not difficult to see that the level of androgens in women is significantly lower than that in men, and the TMPRSS2 produced may be less, and the impact is correspondingly smaller.

In fact, similar studies have been done on the SARS virus. In an experiment on mice infected with SARS in 2017, when the ovaries of female mice were removed, their mortality rate increased dramatically, indicating that estrogen played a protective role in some way, but blocking androgens in male mice did not cause any significant changes [4].

Scientists believe that androgens may not be the only reason affecting the difference in COVID-19 infection rates between men and women.

The attachment protein "spike" of the new coronavirus uses the same attachment factor ACE2 as SARS-CoV, and both use the cellular protease TMPRSS2 to activate it. Image credit: Markus Hoffmann

ACE2

Studies have found that the difference in the concentration of angiotensin-converting enzyme 2 (ACE2) in men and women also makes men more susceptible to COVID-19. ACE2 is a key molecule in the renin-angiotensin-aldosterone system (RAS) and is also the "key" for SARS-CoV and SARS-CoV-2 to enter the human body. The spike protein (S protein) mentioned above invades by binding to ACE2. The concentration of ACE2 in men's blood is much higher than that in women. This difference in concentration is likely related to men's greater susceptibility [5].

In addition, the proportion of men suffering from hypertension is also higher than that of women. If patients with hypertension are infected with the new coronavirus, the virus binds to the ACE2 receptor, which will trigger a series of changes in the renin-angiotensin system, leading to overactivation of the immune system and making it more likely to develop into a severe case.

chromosome

Previous studies have suggested that women’s X chromosomes may also play a certain protective role [6]. The X chromosome contains most genes related to the immune system. Women have two X chromosomes, which means that women have better immune response diversity. In the above-mentioned SARS-infected mouse experiment, males were more susceptible than females, had lower immune responses, and cleared the virus more slowly. An important reason for this is that the genes that regulate immune responses on the female X chromosome highly express IFN proteins.

Women have stronger immune responses than men in almost all infectious diseases. For example, women with acute HIV infection have 40% less viral genetic material in their blood than men, which also means that there are fewer infectious viruses in their bodies than men. Even the common cold caused by viruses may have more severe symptoms in men than in women. In the case of COVID-19 infection, the X chromosome is likely to protect women, making them less susceptible. But on the other hand, studies have found that 80% of patients with autoimmune diseases are women, who are more likely to suffer from diseases such as rheumatoid arthritis.

Behavioral factors

The impact of smoking should not be underestimated. According to a 2017 survey, 54% of adult men in China smoked, while only 2.6% of adult women did so[7]. Smoking affects the body's immunity, making smokers more susceptible to lung infections. At the same time, smokers are more likely to touch their mouths with their hands. These factors increase susceptibility to COVID-19 and may also increase the risk of disease progression.

In addition to smoking, hand washing is also a possible influencing factor. Previous surveys have shown that men are less likely to wash their hands than women. Whether it is the frequency of hand washing or the seriousness of hand washing, men are worse than women. Contact transmission is one of the ways of infection of new coronary pneumonia, so the difference in hand washing habits between men and women may also lead to differences in incidence.

Men tend to experience more severe symptoms of coronavirus than womenCredit: Getty Images

Can blocking androgens prevent or treat COVID-19? As mentioned above, androgens can produce TMPRSS2, which increases the risk of infection in men. In fact, TMPRSS2 is very common in prostate cancer. Blocking androgens and reducing the production of TMPRSS2 is an effective treatment for prostate cancer. So, can androgen deprivation therapy (ADT), a treatment that blocks androgens, prevent or treat COVID-19?

There is not enough evidence to prove its effectiveness, but some observational evidence suggests that ADT treatment seems to be effective.

An Italian study analyzed data from 42,000 prostate cancer patients and found that the incidence of COVID-19 in patients treated with ADT was significantly lower than that in patients not receiving treatment, and the risk of hospitalization and death was also lower [1].

Another retrospective study also obtained similar results. Among 58 patients with both prostate cancer and COVID-19, those who used ADT had lower rates of hospitalization and need for oxygen. The researchers analyzed that this finding suggests that ADT treatment may help curb the progression of COVID-19 and reduce the incidence of severe cases [1].

Although the level of evidence in these studies is low, the similarity of the results has encouraged researchers to conduct further clinical trials. Currently, many studies are stepping up attempts to conduct clinical trials with approved androgen blocking drugs (such as finasteride, dutasteride, bicalutamide, etc.) to determine whether such drugs can effectively prevent or alleviate COVID-19.

In addition to biomedical trials, behavioral interventions may better help prevent the disease. As mentioned above, quitting smoking and washing hands are two important behavioral factors that may affect men's susceptibility to COVID-19. Since they are behavioral factors, they can be changed. Actively quitting smoking and washing hands frequently can undoubtedly provide effective protection. Of course, this is also a commonplace topic.

In general, the reason why the new coronavirus "favors" men more may be related to behavioral factors such as androgen, ACE2 concentration, X chromosome, smoking and hand washing. In the future, more related reasons may be discovered. It is hoped that in the next clinical trials, treatments targeting these reasons, such as androgen blocking therapy, can be proven to be effective and save male compatriots from the clutches of the new coronavirus.

References

[1] https://www.sciencemag.org/news/2020/06/why-coronavirus-hits-men-harder-sex-hormones-offer-clues

[2] https://doi.org/10.7326/0003-4819-141-9-200411020-00006

[3] Iwata-Yoshikawa N, Okamura T, Shimizu Y, Hasegawa H, Takeda M, Nagata N. TMPRSS2 Contributes to Virus Spread and Immunopathology in the Airways of Murine Models after Coronavirus Infection. J Virol. 2019;93(6):e01815-18.

[4] 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. doi:10.4049/jimmunol.1601896

[5] Gavin Y Oudit, Marc A Pfeffer, Plasma angiotensin-converting enzyme 2: novel biomarker in heart failure with implications for COVID-19, European Heart Journal, Volume 41, Issue 19, 14 May 2020, Pages 1818–1820,

[6] Fischer, J., Jung, N., Robinson, N. et al. Sex differences in immune responses to infectious diseases. Infection 43, 399–403 (2015).

[7] https://www.vox.com/2020/4/9/21215063/coronavirus-covid-19-deaths-men-women-sex-dying-why