Why Can Women Fight COVID-19 Better Than Men?

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The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) put an unprecedented burden on the global healthcare system, with more than 425 million infections and 5.8 million deaths to date (March 2022). Regarding disease severity, a gender difference has been observed worldwide, with women developing less severe infections than men.

Social distancing due to COVID-19

Social distancing due to COVID-19. Image Credit: Kzenon/Shutterstock.com

What is the COVID-19 pandemic?

An outbreak of COVID-19 was first detected in Wuhan city of China in December 2019. The causative pathogen of COVID-19 is known as SARS-CoV-2, an enveloped, positive-sense, single-stranded RNA virus belonging to the human beta-coronavirus family.

Although about 80% of COVID-19 patients develop only mild symptoms, the risk of severe infection is significantly higher among elderly people, comorbid patients, and immunocompromised patients.

A growing pool of evidence suggests that being male is also a risk factor for severe COVID-19. It has been estimated that the risk of death from COVID-19 is 20% higher in men than women. In addition, men are more prone than women to developing serious complications that require intensive care unit (ICU) admissions and mechanical ventilation.   

Why are men more susceptible to severe COVID-19 than women?

There are many genetic, immunological, and lifestyle or behavioral factors that might increase the risk of disease severity in men.

Genetic susceptibility      

Infection with SARS-CoV-2 is initiated by the binding of the viral spike protein to host cell receptor angiotensin-converting enzyme 2 (ACE2) present on respiratory epithelial cells. This is followed by the fusion of the viral envelope with the host cell membrane and the transportation of viral RNA into the host cell.

There is evidence indicating that the expression of ACE2 in the human lungs is directly proportional to the severity of SARS-CoV-2 infection. Thus, any living organisms that have higher expression of ACE2 in alveolar epithelial cells are expected to accelerate the viral entry to the respiratory tract.

In this context, single-cell RNA-sequencing analyses have shown that Asian men have significantly higher expression of ACE2 in the lungs than Asian women. Thus, genetic expression and cellular distribution pattern of ACE2 make men more susceptible to SARS-CoV-2 infection than women.

Immunological susceptibility

Women in general exhibit a higher immune response to viral or bacterial infection than men. This could be because women have two X chromosomes instead of the one observed in men.

The X chromosome is known to increase the expression of important immune components that help induce robust infection-controlling immune responses. In addition, female sex hormones including estrogen and progesterone play vital roles in triggering immune signaling and reducing inflammation, respectively.

There is evidence indicating that women produce more antibodies than men in response to influenza vaccination. This highlights their potency in inducing strong immune responses against invading pathogens. However, this special ability sometimes makes women more susceptible to developing autoimmune diseases wherein the body’s immune system starts attacking its own body cells/tissues mistakenly.

The innate immune system of the human body acts as the first-line of defense against any invading pathogens. As a part of the early innate immune response, controlled activation of interferon signaling leads to the production of pro-inflammatory cytokines and chemokines at the site of infection. A measured inflammatory response is vital for eliminating pathogens at the early infection stage.

In COVID-19 patients, hyperinflammation is regarded as the major hallmark of disease severity. In severe COVID-19 patients, uncontrolled activation of type 1 interferon response has been found to cause excessive production of cytokines (cytokine storm), leading to severe lung damage and multiorgan failure.

A recent study conducted on male and female patients with moderate COVID-19 has shown that male patients have higher plasma levels of pro-inflammatory cytokines and chemokines and higher activation of non-classical monocytes than female patients. The same study also highlighted that female patients have significantly higher activation of T cell response than male patients.

The poor T cell response in males is associated with a worse disease prognosis. However, the higher innate immune response in male patients is not associated with worse disease outcomes. In contrast, such responses make female patients more susceptible to developing severe COVID-19.

Given the study findings, the scientists suggest that male and female patients may be benefited from therapeutic interventions that are designed to induce T cell response and suppress an innate immune response, respectively.


SARS-CoV-2 viruses activating neutrophil, conceptual 3D illustration. Overactive neutrophils in COVID-19 are associated with hyperinflammation that drives lung and multi-organ damage. Image Credit: Kateryna Kon/Shutterstock.com

Lifestyle factors

A relatively higher rate of smoking and alcohol consumption has been observed among men globally. The disparity in these lifestyle behaviors between men and women could be a potential reason for gender-based susceptibility to COVID-19. In addition, men are more prone to high-risk behaviors than women, which further increases their chances to contract COVID-19.

Several studies have indicated that women exhibit higher adherence to COVID-19 related control measures, including social distancing, face mask-wearing, hand washing, and movement restrictions. These COVID-19 appropriate behaviors help protect people from contracting COVID-19.

Besides lifestyle and behavioral factors, certain occupational risk factors may also put men at higher risk for COVID-19. In low-skilled occupations like transportation, food processing, delivery, construction, and manufacturing, the number of male workers is significantly higher than female workers. Studies have shown that workers in these occupations are at higher risk of severe COVID-19 and mortality.


Further Reading

Last Updated: Mar 21, 2022

Dr. Sanchari Sinha Dutta

Written by

Dr. Sanchari Sinha Dutta

Dr. Sanchari Sinha Dutta is a science communicator who believes in spreading the power of science in every corner of the world. She has a Bachelor of Science (B.Sc.) degree and a Master's of Science (M.Sc.) in biology and human physiology. Following her Master's degree, Sanchari went on to study a Ph.D. in human physiology. She has authored more than 10 original research articles, all of which have been published in world renowned international journals.


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  1. Aziz Rodan Sarohan Aziz Rodan Sarohan Turkey says:

    Aziz Rodan Sarohan M.D.

    Why is COVID-19 more severe in men than women?

    Although most of the mechanisms described above are true, the main molecules underlying this mysterious mechanism are far from explaining the pathogenesis. Likewise, all the features related to the clinical presentation of COVID-19 can be easily explained through retinol depletion and retinoid signaling disorder, which form the molecular basis of the COVID-19 pathogeny. As an example, I leave a short explanation on this subject below, I present it to your attention.

    As it is known, after the SARS-CoV-2 spike protein binds to ACE2, it is processed by TMPRSS2 and taken into the host cell.
    As it is known, after the spike protein binds to the host cell membrane, the spike protein is processed by TMPRSS2 and taken into the cell. TMPRSS2, which performs this function, is higher in men. Because testosterone increases the expression of this enzyme.
    Dihydrotestosterone (DHT) has previously been shown to be a potent activator of TMPRSS2(1). The presence of DHT and increased expression of TMPRSS2 in COVID-19 also increases the processing and activation of the COVID-19 spike protein to bind to ACE2 receptors in the lung, kidney, and other organs.
    The SARS-CoV-2 virus, which adheres to the cell wall in this way, is mostly taken up by the male host cells.

    Expression of TMPRSS2 is further increased due to retinol deficiency in COVID-19. Since retinol and retinoic acids inhibit dihydrotestosterone activity, they can also reduce the expression of TMPRSS2, and this must be one of the mechanisms underlying the effectiveness of retinoic acids in COVID-19.
    We showed that retinol is depleted in COVID-19 in a clinical study we conducted at the beginning of the pandemic. However, it took a year for the article to be published (2). Retinol depletion in COVID-19 leads to a vicious circle on the spike-ACE2 and TMPRSS2 relationship, resulting in increased TMPRSS2 expression and internalization of the virus into more host cells. Another study showed that 13-cis-retinoic acid competitively and reversibly inhibits dihydrotestosterone (3). Also, in the current study, dihydrotestosterone (DHT) was significantly reduced after treatment in the 13 cis retinoic acid group. Decreased DHT can create a hormonal environment, as in women, reducing the adhesion of Spike protein to the host cell and internalization of the virus.
    It has also been found that ACE2 expression is increased in COVID-19 (4,5,6,7). Depletion of retinol appears to be responsible for this as well. Likewise, it has been previously shown that retinoic acids reduce ACE2 expression (8,9). A study last year wrote that retinol inhibits the uptake of the SARS-CoV-2 spike protein, but the researchers explain the mechanism here by placing ATRA in a deep hydrophobic pocket of the receptor-binding domain (RBD) on top of the SARS-CoV-2 spike protein (S) trimer. They attributed this to the direct binding of the spike protein to the ACE2 receptor. They could not see the relationship between retinol depletion in COVID-19 and the pathogenesis of COVID-19, which I explained above (10).
    1. Zhou F, Gao S, Han D, et al. TMPRSS2-ERG activates NO-cGMP signaling in prostate cancer cells. Oncogene (2019) 38:4397–411. doi: 10.1038/s41388- 019-0730-9
    2. Sarohan AR, Akelma H, Araç E, Aslan Ö, Cen O. Retinol Depletion in COVID-19. Clin Nutr Open Sci. 2022 Jun;43:85-94. doi: 10.1016/j.nutos.2022.05.007. Epub 2022 May 28. PMID: 35664529; PMCID: PMC9142171.
    3. Karlsson T, Vahlquist A, Kedishvili N, Törmä H. 13-cis-retinoic acid competitively inhibits 3 alpha-hydroxysteroid oxidation by retinol dehydrogenase RoDH-4: a mechanism for its anti-androgenic effects in sebaceous glands? Biochem Biophys Res Commun (2003) 303(1):273–8. doi: 10.1016/s0006-291x(03)00332-2
    4. Patel SK, Juno JA, Lee WS, Wragg KM, Hogarth PM, Kent SJ, et al. Plasma ACE2 activity is persistently elevated following SARS-CoV-2 infection: implications for COVID-19 pathogenesis and consequences. European Respiratory Journal. 2021:2003730. pmid:33479113
    5- Lundström A, Ziegler L, Havervall S, Rudberg A-S, von Meijenfeldt F, Lisman T, et al. Soluble angiotensin-converting enzyme 2 is transiently elevated in COVID-19 and correlates with specific inflammatory and endothelial markers. medRxiv.
    6. Nagy B Jr., Fejes Z, Szentkereszty Z, Suto R, Varkonyi I, Ajzner E, et al. A dramatic rise in serum ACE2 activity in a critically ill COVID-19 patient. Int J Infect Dis. 2021;103:412–4. pmid:33249290
    7. Xu H, Zhong L, Deng J, et al. High expression of ACE2 receptor of 2019- nCoV on the epithelial cells of oral mucosa. Int J Oral Sci (2020) 12(1):8. doi: 10.1038/s41368-020-0074-x
    8. Zhong JC, Huang DY, Yang YM, Li YF, Liu GF, Song XH, Du K. Upregulation of angiotensin-converting enzyme 2 by all-trans retinoic acid in spontaneously hypertensive rats. Hypertension. 2004 Dec;44(6):907-12. doi: 10.1161/01.HYP.0000146400.57221.74. Epub 2004 Oct 11. PMID: 15477383.
    9. Zhu X, Mou Z, Han W, Chen L. All-trans retinoic acid inhibits oxidative stress via ACE2/Ang (1-7)/MasR pathway in renal tubular epithelial cells stimulated with high glucose. Drug Dev Res. 2023 Apr 28. doi: 10.1002/ddr.22070. Epub ahead of print. PMID: 37114746.
    10. Tong L, Wang L, Liao S, Xiao X, Qu J, Wu C, Zhu Y, Tai W, Huang Y, Wang P, Li L, Zhang R, Xiang Y, Cheng G. A Retinol Derivative Inhibits SARS-CoV-2 Infection by Interrupting Spike-Mediated Cellular Entry. mBio. 2022 Aug 30;13(4):e0148522. doi: 10.1128/mbio.01485-22. Epub 2022 Jul 13. PMID: 35862773; PMCID: PMC9426596.

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