The seX element in COVID-19: Differential mechanisms in SARS-CoV-2 disease susceptibility, severity and mortality
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Gonadal Steroid Hormones
Angiotensin-Converting Enzyme 2
X Chromosome

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García Gutiérrez, A. ., Gil-Osuna, J. D. ., Pimiento-Diaz, M. ., Viveros-Enriquez, J. A. ., & González Clavijo, A. M. . (2022). The seX element in COVID-19: Differential mechanisms in SARS-CoV-2 disease susceptibility, severity and mortality. Revista Colombiana De Endocrinología, Diabetes &Amp; Metabolismo, 9(4).


Background: Coronavirus disease (COVID-19) has a broad symptom spectrum that varies from person to person. However, evidence has been proposed for a sex dependence in symptom severity.

Purpose: To describe the criteria and approaches that suggest the sex differences as factors responsible for the susceptibility to infection and heterogeneity of SARS-CoV-2 disease symptom severity.

Methods: A comprehensive literature search was performed in the PubMed database, deeming articles published from December 2019 to May 2021; languages of publication: English and Spanish; encompassing current and retrospective studies on sexual, hormonal, molecular and genetic factors in SARS-CoV-2 infection and disease.

Results: A total of 58 articles were selected, which mainly addressed the following research lines and topics: epidemiology and public health, biomedical sciences (evolution, reproduction, genetics, immunology, endocrinology, biochemistry, molecular biology) and clinical medicine.

Conclusions: Statistically there is less severity and mortality due to infection in the female population globally. This trend responds to mechanisms that include: a greater reserve of Angiotensin-Converting Enzyme 2 (ACE2) in some tissues, a more effective immune response due to the presence of certain sex hormones that act as protective factors to the disease, as well as mechanisms inherent to sex genes, either the inactivation of X or the expression of miRNA and genes associated to the immune system.
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Llanes A, Restrepo CM, Caballero Z, Rajeev S, Kennedy MA, Lleonart R. Betacoronavirus Genomes?: How Genomic Information Has Been Used to Deal with Past Outbreaks and the COVID-19 Pandemic. 2020;2:1–30.

Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet [Internet]. 2020;395(10224):565–74. Available from:

Statista. COVID-19: número de muertes por país en 2021| Publicado por Abigail Orús, 04 feb. 2022. La estadística muestra el número de muertes a nivel mundial causadas por el SARS-CoV-2, conocido popularmente como el coronavirus de Wuhan, a fecha del 04 de febrero de 2022 [Internet]. [cited 2022 Feb 05]. Available from:

INS. COVID-19 en Colombia [Internet]. [cited 2021 Jan 13]. Available from:

Basso N. Capítulo 24 SISTEMA RENINA-ANGIOTENSINA-ALDOSTERONA. Saha [Internet]. 2014;(24):114–6. Available from:

Oliva Marín JE. SARS-CoV-2: origen, estructura, replicación y patogénesis. Alerta, Rev científica del Inst Nac Salud. 2020;3(2):79–86.

Foresta C, Rocca MS, Di Nisio A. Gender susceptibility to COVID-19: a review of the putative role of sex hormones and X chromosome. J Endocrinol Invest [Internet]. 2020;44(5):951–6. Available from: Figure 1, Proposed mechanisms of sex-related susceptibility to COVID-19

Aksoy H, Karadag AS, Wollina U. Angiotensin II receptors: Impact for COVID-19 severity. Dermatol Ther. 2020;33(6).

Giagulli VA, Guastamacchia E, Magrone T, Jirillo E, Lisco G, De Pergola G, et al. Worse progression of COVID-19 in men: Is testosterone a key factor? Andrology. 2020;9(1):53–64.

Gemmati D, Bramanti B, Serino ML, Secchiero P, Zauli G, Tisato V. COVID-19 and individual genetic susceptibility/receptivity: Role of ACE1/ACE2 genes, immunity, inflammation and coagulation. might the double x-chromosome in females be protective against SARS-COV-2 compared to the single x-chromosome in males? Int J Mol Sci. 2020;21(10):1–23.

Viveiros A, Rasmuson J, Vu J, Mulvagh SL, Yip CYY, Norris CM, et al. Sex differences in COVID-19: Candidate pathways, genetics of ACE2, and sex hormones. Am J Physiol - Hear Circ Physiol. 2020;320(1):H296–304.

Darbani B. The expression and polymorphism of entry machinery for covid-19 in human: Juxtaposing population groups, gender, and different tissues. Int J Environ Res Public Health. 2020;17(10).

Moradi F, Enjezab B, Ghadiri-Anari A. The role of androgens in COVID-19. Diabetes Metab Syndr Clin Res Rev. 2020;14(6):2003–6.

Ferretti L, Gagnat A. Déficit androgénico ligado a la edad. EMC - Urol [Internet]. 2020;52(2):1–5. Available from:

López-Reyes A, Martinez-Armenta C, Espinosa-Velázquez R, Vázquez-Cárdenas P, Cruz-Ramos M, Palacios-Gonzalez B, et al. NLRP3 Inflammasome: The Stormy Link Between Obesity and COVID-19. Front Immunol. 2020;11(October):1–9.

Lee S, Channappanavar R, Kanneganti T. Coronaviruses?: Innate Immunity, Inflammasome Activation, Inflammatory Cell Death, and Cytokines. 2020;(January).

van den Berg DF, te Velde AA. Severe COVID-19: NLRP3 Inflammasome Dysregulated. Front Immunol. 2020;11(June):1–6.

Vardhana SA, Wolchok JD. The many faces of the anti-COVID immune response. J Exp Med. 2020;217(6):1–10.

Li G, Fan Y, Lai Y, Han T, Li Z, Zhou P, et al. Coronavirus infections and immune responses. J Med Virol [Internet]. 2020;92(4):424–32. Available from:

Pinheiro I, Dejager L, Libert C. X-chromosome-located microRNAs in immunity: Might they explain male/female differences?: The X chromosome-genomic context may affect X-located miRNAs and downstream signaling, thereby contributing to the enhanced immune response of females. BioEssays. 2011;33(11):791–802.

Van Der Made CI, Simons A, Schuurs-Hoeijmakers J, Van Den Heuvel G, Mantere T, Kersten S, et al. Presence of Genetic Variants among Young Men with Severe COVID-19. JAMA - J Am Med Assoc. 2020;324(7):663–73.

Fallerini C, Daga S, Mantovani S, Benetti E, Picchiotti N, Francisci D, et al. Association of toll-like receptor 7 variants with life-threatening COVID-19 disease in males: Findings from a nested case-control study. Elife. 2021;10:1–15.

Smit JJ, Lindell DM, Boon L, Kool M, Lambrecht BN, Lukacs NW. The balance between plasmacytoid DC versus conventional DC determines pulmonary immunity to virus infections. PLoS One. 2008;3(3).

Campana P, Parisi V, Leosco D, Bencivenga D, Della Ragione F, Borriello A. Dendritic Cells and SARS-CoV-2 Infection: Still an Unclarified Connection. Cells. 2020;9(9).

Han J, Sun J, Zhang G, Chen H. Dcs-based therapies: Potential strategies in severe sars-cov-2 infection. Int J Med Sci. 2021;18(2):406–18.

Diebold SS, Kaisho T, Hemmi H, Akira S, Reis E Sousa C. Innate Antiviral Responses by Means of TLR7-Mediated Recognition of Single-Stranded RNA. Science (80- ). 2004;303(5663):1529–31.

Zhou R, Kai-Wang To K, Wong Y-C, Liu L, Zhou B, Li X, et al. Acute SARS-CoV-2 Infection Impairs Dendritic Cell and T Cell Responses. 2020;

McNab F, Mayer-Barber K, Sher A, Wack A, O’Garra A. Type I interferons in infectious disease. Nat Rev Immunol. 2015;15(2):87–103.

Laffont S, Rouquié N, Azar P, Seillet C, Plumas J, Aspord C, et al. X-Chromosome Complement and Estrogen Receptor Signaling Independently Contribute to the Enhanced TLR7-Mediated IFN-? Production of Plasmacytoid Dendritic Cells from Women. J Immunol. 2014;193(11):5444–52.

Hadjadj J, Yatim N, Barnabei L, Corneau A, Boussier J. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. 2020;724(August):718–24.

Feng E, Balint E, Poznanski SM, Ashkar AA, Loeb M. Aging and Interferons: Impacts on Inflammation and Viral Disease Outcomes. 2021;

Lopez L, Sang PC, Tian Y, Sang Y. Dysregulated interferon response underlying severe covid-19. Viruses. 2020;12(12).

Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann HH, Zhang Y, et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science (80- ). 2020;370(6515).

Masselli E, Vaccarezza M, Carubbi C, Pozzi G. NK cells: A double edge sword against SARS-CoV-2. 2020;(January).

Zheng M, Gao Y, Wang G, Song G, Liu S, Sun D, et al. Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell Mol Immunol [Internet]. 2020;17(5):533–5. Available from:

Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-?: an overview of signals, mechanisms and functions. J Leukoc Biol. 2004;75(2):163–89.

van Eeden C, Khan L, Osman MS, Tervaert JWC. Natural killer cell dysfunction and its role in covid-19. Int J Mol Sci. 2020;21(17):1–17.

Takahashi T, Ellingson MK, Wong P, Israelow B, Lucas C, Klein J, et al. Sex differences in immune responses that underlie COVID-19 disease outcomes. Nature. 2020;588(7837):315–20.

Kosyreva A, Dzhalilova D, Lokhonina A, Vishnyakova P, Fatkhudinov T. The Role of Macrophages in the Pathogenesis of SARS-CoV-2-Associated Acute Respiratory Distress Syndrome. Front Immunol. 2021;12(May):1–16.

Andrológica. Estrógenos en el hombre [Internet]. 2021 [cited 2022 Jan 13]. Available from:

Salem ML. Estrogen, a double-edged sword: Modulation of TH1- and TH2-mediated inflammations by differential regulation of TH1/TH2 cytokine production. Curr Drug Targets Inflamm Allergy. 2004;3(1):97–104.

Gargaglioni LH, Marques DA. Reply to Jakovac: Sex differences in COVID-19 course and outcome: progesterone should not be neglected. J Appl Physiol. 2020;129(5):107–8.

RECOVERY Collaborative Group. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021;384(8):693–704.

Pradhan A, Olsson PE. Sex differences in severity and mortality from COVID-19: are males more vulnerable? Biol Sex Differ. 2020;11(1):1–11.

Moulton VR. Sex hormones in acquired immunity and autoimmune disease. Front Immunol. 2018;9(OCT):1–21.

Kovats S. Estrogen receptors regulate innate immune cells and signaling pathways. Cell Immunol. 2015;294(2):36–69.

Breithaupt-Faloppa AC, Correia C de J, Prado CM, Stilhano RS, Ureshino RP, Moreira LFP. 17b-estradiol, a potential ally to alleviate SARS-CoV2 infection. Clinics. 2020;75(24):1–8.

Faas M, Bouman A, Moesa H, Heineman MJ, De Leij L, Schuiling G. The immune response during the luteal phase of the ovarian cycle: A Th2-type response? Fertil Steril. 2000;74(5):1008–13.

Barañao RI. Hormonas sexuales y respuesta inmunológica. Saegre. 2009;16(2):20–30.

Mauvais-Jarvis F, Klein SL, Levin ER. Estradiol, Progesterone, Immunomodulation, and COVID-19 Outcomes. Endocrinol (United States). 2020;161(9):1–8.

Chanana N, Palmo T, Sharma K, Kumar R, Graham BB, Pasha Q. Sex-derived attributes contributing to SARS-CoV-2 mortality. Am J Physiol - Endocrinol Metab. 2020;319(3):E562–7.

Liu J, Ji H, Zheng W, Wu X, Zhu JJ, Arnold AP, et al. Sex differences in renal angiotensin converting enzyme 2 (ACE2) activity are 17?-oestradiol-dependent and sex chromosome-independent. Biol Sex Differ [Internet]. 2010;1(1):6. Available from:

Seeland U, Coluzzi F, Simmaco M, Mura C, Bourne PE, Heiland M, et al. Evidence for treatment with estradiol for women with SARS-CoV-2 infection. BMC Med. 2020;18(1):1–9.

Pinna G. Sex and COVID-19: A Protective Role for Reproductive Steroids. CellPress. 2020;(January).

Jakovac H. Sex differences in COVID-19 course and outcome: Progesterone should not be neglected. J Appl Physiol. 2020;129(5):107–8.

Hierweger AM, Engler JB, Friese MA, Reichardt HM, Lydon J, DeMayo F, et al. Progesterone modulates the T-cell response via glucocorticoid receptor-dependent pathways. Am J Reprod Immunol. 2019;81(2).

Kloc M, Ghobrial RM, Kubiak JZ. The Role of Genetic Sex and Mitochondria in Response to COVID-19 Infection. Int Arch Allergy Immunol. 2020;181(8):629–34.

Maan AA, Eales J, Akbarov A, Rowland J, Xu X, Jobling MA, et al. The y chromosome: A blueprint for men’s health? Eur J Hum Genet. 2017;25(11):1181–8.

El-Bacha T, Da Poian AT. Virus-induced changes in mitochondrial bioenergetics as potential targets for therapy. Int J Biochem Cell Biol [Internet]. 2013;45(1):41–6. Available from:

Weinberg SE, Sena LA, Chandel NS. Mitochondria in the regulation of innate and adaptive immunity. Immunity [Internet]. 2015;42(3):406–17. Available from:

Angajala A, Lim S, Phillips JB, Kim JH, Yates C, You Z, et al. Diverse roles of mitochondria in immune responses: Novel insights into immuno-metabolism. Front Immunol. 2018;9(JUL).

Hee JS, Cresswell P. Viperin interaction with mitochondrial antiviral signaling protein (MAVS) limits viperin-mediated inhibition of the interferon response in macrophages. PLoS One. 2017;12(2):1–18.

Wang C, Xie J, Zhao L, Fei X, Zhang H, Tan Y, et al. Alveolar macrophage dysfunction and cytokine storm in the pathogenesis of two severe COVID-19 patients. EBioMedicine [Internet]. 2020;57:102833. Available from:

Silkaitis K, Lemos B. Sex-biased chromatin and regulatory cross-talk between sex chromosomes, autosomes, and mitochondria. Biol Sex Differ. 2014;5(1):1–14.

Lieber T, Jeedigunta SP, Palozzi JM, Lehmann R, Hurd TR. Mitochondrial fragmentation drives selective removal of deleterious mtDNA in the germline. Nature [Internet]. 2019;570(7761):380–4. Available from:

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