Research article
● Open access
SARS-CoV-2 Infection and Adrenal Dysfunction: A Comprehensive Review of Cortisol Secretion, Glucocorticoid Receptor Signaling, and Hypothalamic-Pituitary-Adrenal Axis Dysregulation
Abstract
COVID-19, caused by SARS-CoV-2, affects multiple organ systems beyond the lungs, including the endocrine system. Recent studies suggest that the adrenal glands and the hypothalamic–pituitary–adrenal (HPA) axis may be disrupted during infection, leading to altered cortisol regulation. This review examines the mechanisms through which SARS-CoV-2 influences adrenal function and cortisol secretion.
A systematic literature review was conducted using PubMed, Scopus, Web of Science, and Embase databases for studies published between 2020 and 2024. The review focused on research addressing adrenal gland involvement, cortisol regulation, glucocorticoid receptor function, and HPA axis alterations in COVID-19 patients.
Evidence indicates that SARS-CoV-2 may directly affect adrenal tissue through ACE2 and TMPRSS2 receptors. Adrenal dysfunction may occur through several mechanisms, including viral cytopathic effects, inflammation during cytokine storm, molecular mimicry affecting ACTH, and glucocorticoid receptor resistance. These processes can lead to conditions such as adrenal insufficiency and critical illness-related corticosteroid insufficiency (CIRCI). Some recovered patients also show temporary hypocortisolism due to central HPA axis disruption.
Overall, SARS-CoV-2 infection can significantly influence cortisol regulation and adrenal function. Awareness of these endocrine complications is important for clinical management and long-term monitoring of post-COVID-19 patients.
Keywords
COVID-19, SARS-CoV-2, Adrenal Gland, Cortisol, HPA Axis, Glucocorticoid Receptor, Adrenal Insufficiency, CIRCI, Cytokine Storm.
References
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de Wit, E., van Doremalen, N., Falzarano, D., & Munster, V. J. (2016). SARS and MERS: Recent insights into emerging coronaviruses. Nature Reviews Microbiology, 14(8), 523-534.
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Fara, S., Allora, A., Castellino, L., di Filippo, L., Loli, P., & Giustina, A. (2021). COVID-19 and the pituitary. Pituitary, 24(3), 465-481.
Ferrau, F., Ceccato, F., Cannavo, S., & Scaroni, C. (2021). What we have to know about corticosteroids use during SARS-CoV-2 infection. Journal of Endocrinological Investigation, 44(4), 693-701.
Fox, B. (1976). Venous infarction of the adrenal glands. Journal of Pathology, 119(2), 65-89.
Gil-Etayo, F. J., Suárez-Fernández, P., Cabrera-Marante, O., Arroyo, D., Garcinuño, S., Naranjo, L., ... & Serrano, A. (2021). T-helper cell subset response is a determining factor in COVID-19 progression. Frontiers in Cellular and Infection Microbiology, 11, 624483.
Glaser, R., & Kiecolt-Glaser, J. K. (2005). Stress-induced immune dysfunction: Implications for health. Nature Reviews Immunology, 5(3), 243-251.
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Hakan, T., Sarı, R., & Toprak, İ. D. (2021). Critical illness-related corticosteroid insufficiency is common in Covid-19 and treatment provide survival benefit. Research Square. https://doi.org/10.21203/rs.3.rs-391924/v1
Hänsel, A., Hong, S., Cámara, R. J., & von Känel, R. (2010). Inflammation as a psychophysiological biomarker in chronic psychosocial stress. Neuroscience and Biobehavioral Reviews, 35(1), 115-121.
Hashim, M., Athar, S., & Gaba, W. H. (2021). New onset adrenal insufficiency in a patient with COVID-19. BMJ Case Reports, 14(1), e237690.
Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., ... & Pöhlmann, S. (2020). SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell, 181(2), 271-280.
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Ilias, I., Vassiliou, A. G., Keskinidou, C., Vrettou, C. S., Orfanos, S., Kotanidou, A., & Dimopoulou, I. (2023). Changes in cortisol secretion and corticosteroid receptors in COVID-19 and non COVID-19 critically ill patients with sepsis/septic shock and scope for treatment. Biomedicines, 11(7), 1801.
Jensterle, M., Herman, R., Janez, A., Mahmeed, A., Al-Rasadi, K., Al-Alawi, K., ... & Rizzo, M. (2022). The relationship between COVID-19 and hypothalamic-pituitary-adrenal axis: A large spectrum from glucocorticoid insufficiency to excess—The CAPISCO international expert panel. International Journal of Molecular Sciences, 23(13), 7326.
Kanczkowski, W., Gaba, W. H., Krone, N., Varga, Z., Beuschlein, F., Hantel, C., ... & Bornstein, S. R. (2022). Adrenal gland function and dysfunction during COVID-19. Hormone and Metabolic Research, 54(8), 532-539.
Katz, A., Altshuler, D., Papadopoulos, J., Amoroso, N., Goldenberg, R., Tarras, E., ... & Brosnahan, S. B. (2022). The use of high-dose corticosteroids versus low-dose corticosteroids with and without tocilizumab in COVID-19 acute respiratory distress syndrome. The Annals of Pharmacotherapy, 57(1), 5-15.
Kunz-Ebrecht, R., Mohamed-Ali, V., Feldman, J., Kirschbaum, C., & Steptoe, A. (2003). Cortisol responses to mild psychological stress are inversely associated with proinflammatory cytokines. Brain, Behavior, and Immunity, 17(5), 373-383.
Leow, M. K., Kwek, D. S., Ng, A. W., Ong, K. C., Kaw, G. J., & Lee, L. S. (2005). Hypocortisolism in survivors of severe acute respiratory syndrome (SARS). Clinical Endocrinology, 63(2), 197-202.
Leyendecker, P., Ritter, S., Riou, M., Wackenthaler, A., Meziani, F., Roy, C., & Ohana, M. (2020). Acute adrenal infarction as an incidental CT finding and a potential prognosis factor in severe SARS-CoV-2 infection: A retrospective cohort analysis on 219 patients. European Radiology, 31(2), 895-900.
Li, M. Y., Li, L., Zhang, Y., & Wang, X. S. (2020). Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues. Infectious Diseases of Poverty, 9(1), 45.
Mao, Y., Xu, B., Guan, W., Xu, D., Li, F., Ren, R., ... & Jiang, L. (2020). The adrenal cortex, an underestimated site of SARS-CoV-2 infection. Frontiers in Endocrinology, 11, 593179.
Miller, W. L., & Auchus, R. J. (2019). The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocrine Reviews, 40(4), 1023-1062.
Müller, J. A., Groß, R., Conzelmann, C., Krüger, J., Merle, U., Steinhart, J., ... & Heller, S. (2021). SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas. Nature Metabolism, 3(2), 149-165.
Oguz, S. H., & Yildiz, B. O. (2023). Endocrine disorders and COVID-19. Annual Review of Medicine, 74, 75-88.
Pal, R. (2022). COVID-19 and hypothalamic-pituitary-adrenal axis: A narrative review. Hormones, 21(2), 211-219.
Pal, R., & Banerjee, M. (2020). COVID-19 and the endocrine system: Exploring the unexplored. Journal of Endocrinological Investigation, 43(7), 1027-1031.
RECOVERY Collaborative Group. (2021). Dexamethasone in hospitalized patients with Covid-19. New England Journal of Medicine, 384(8), 693-704.
Rotondi, M., Coperchini, F., Ricci, G., Denegri, M., Croce, L., Ngnitejeu, S. T., ... & Chiovato, L. (2021). Detection of SARS-CoV-2 receptor ACE2 in human follicular cells: A key to the thyroid tropism of the virus. Journal of Endocrinological Investigation, 44(9), 1917-1924.
Savla, S. R., Prabhavalkar, K. S., & Bhatt, L. K. (2021). Cytokine storm associated with severe COVID-19: A comprehensive review. Inflammopharmacology, 29(3), 683-698.
Sharrack, N., Baxter, C. T., Paddock, M., & Uchegbu, E. (2020). Adrenal haemorrhage as a complication of COVID-19 infection. BMJ Case Reports, 13(11), e238643.
Sher, E. K., Ćosović, A., Džidić-Krivić, A., & Banjari, I. (2023). COVID-19 and immune dysfunction: A comprehensive review of mechanisms and implications. International Journal of Molecular Sciences, 24(3), 2345.
Smith, S. M., & Vale, W. W. (2022). The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues in Clinical Neuroscience, 8(4), 383-395.
Stefunkova, M., Calkovska, A., & Calkovsky, V. (2021). Expression of ACE2 and TMPRSS2 in the adrenal gland: A potential target for SARS-CoV-2 infection. Endocrine Regulations, 55(3), 156-162.
Sungnak, W., Huang, N., Bécavin, C., Berg, M., Queen, R., Litvinukova, M., ... & HCA Lung Biological Network. (2020). SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nature Medicine, 26(5), 681-687.
Vakhshoori, M., Heidarpour, M., & Shafie, D. (2021). Adrenal insufficiency in coronavirus disease 2019: A case report and review of the literature. Journal of Research in Medical Sciences, 26, 45.
Vassiliadi, D. A., Dimopoulou, I., & Tsagarakis, S. (2021). The role of the hypothalamic-pituitary-adrenal axis in the pathophysiology and management of sepsis. Current Opinion in Critical Care, 27(4), 393-399.
Wang, Z., & Xu, X. (2020). scRNA-seq profiling of human testes reveals the presence of the ACE2 receptor, a target for SARS-CoV-2 infection in spermatogonia, Leydig and Sertoli cells. Cells, 9(4), 920.
Wepler, M., Rehm, M., & Thiel, M. (2020). The role of the hypothalamic-pituitary-adrenal axis in sepsis. Anesthesia & Analgesia, 131(2), 421-433.
WHO REACT Working Group. (2020). Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: A meta-analysis. JAMA, 324(13), 1330-1341.
Wolkow, A., Aisbett, B., Reynolds, J., Ferguson, S. A., & Main, L. C. (2015). Relationships between inflammatory cytokine and cortisol responses in firefighters exposed to simulated wildfire suppression. Applied Ergonomics, 48, 42-49.
Wong, R. S. Y., Chee, K. H., & Chong, E. T. J. (2021). The endocrine system in COVID-19: A review of current evidence. Endocrine Connections, 10(3), R77-R90.
Alzahrani, A. S., Mukhtar, N., Aljomaiah, A., Aljamei, H., Bakhsh, A., Alsudani, N., ... & Sulaiman, O. (2020). The impact of COVID-19 viral infection on the hypothalamic-pituitary-adrenal axis. Endocrine Practice, 27(2), 83-89.
Annane, D., Pastores, S. M., Arlt, W., Balk, R. A., Beishuizen, A., Briegel, J., ... & Van den Berghe, G. (2017). Critical illness-related corticosteroid insufficiency (CIRCI): A narrative review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM). Intensive Care Medicine, 43(12), 1781-1792.
Bamberger, C. M., Schulte, H. M., & Chrousos, G. P. (1996). Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids. Endocrine Reviews, 17(3), 245-261.
de Wit, E., van Doremalen, N., Falzarano, D., & Munster, V. J. (2016). SARS and MERS: Recent insights into emerging coronaviruses. Nature Reviews Microbiology, 14(8), 523-534.
DeSantis, A. S., DiezRoux, A. V., Hajat, A., Aiello, A. E., Golden, S. H., Jenny, N. S., ... & Shea, S. (2012). Associations of salivary cortisol levels with inflammatory markers: The multi-ethnic study of atherosclerosis. Psychoneuroendocrinology, 37(7), 1009-1018.
Fara, S., Allora, A., Castellino, L., di Filippo, L., Loli, P., & Giustina, A. (2021). COVID-19 and the pituitary. Pituitary, 24(3), 465-481.
Ferrau, F., Ceccato, F., Cannavo, S., & Scaroni, C. (2021). What we have to know about corticosteroids use during SARS-CoV-2 infection. Journal of Endocrinological Investigation, 44(4), 693-701.
Fox, B. (1976). Venous infarction of the adrenal glands. Journal of Pathology, 119(2), 65-89.
Gil-Etayo, F. J., Suárez-Fernández, P., Cabrera-Marante, O., Arroyo, D., Garcinuño, S., Naranjo, L., ... & Serrano, A. (2021). T-helper cell subset response is a determining factor in COVID-19 progression. Frontiers in Cellular and Infection Microbiology, 11, 624483.
Glaser, R., & Kiecolt-Glaser, J. K. (2005). Stress-induced immune dysfunction: Implications for health. Nature Reviews Immunology, 5(3), 243-251.
Gu, J., & Korteweg, C. (2007). Pathology and pathogenesis of severe acute respiratory syndrome. American Journal of Pathology, 170(4), 1136-1147.
Gupta, A., Madhavan, M. V., Sehgal, K., Nair, N., Mahajan, S., Sehrawat, T. S., ... & Landry, D. W. (2020). Extrapulmonary manifestations of COVID-19. Nature Medicine, 26(7), 1017-1032.
Hakan, T., Sarı, R., & Toprak, İ. D. (2021). Critical illness-related corticosteroid insufficiency is common in Covid-19 and treatment provide survival benefit. Research Square. https://doi.org/10.21203/rs.3.rs-391924/v1
Hänsel, A., Hong, S., Cámara, R. J., & von Känel, R. (2010). Inflammation as a psychophysiological biomarker in chronic psychosocial stress. Neuroscience and Biobehavioral Reviews, 35(1), 115-121.
Hashim, M., Athar, S., & Gaba, W. H. (2021). New onset adrenal insufficiency in a patient with COVID-19. BMJ Case Reports, 14(1), e237690.
Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., ... & Pöhlmann, S. (2020). SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell, 181(2), 271-280.
Hosseini, P., Fallahi, M. S., Erabi, G., Pakdin, M., Zarezadeh, S. M., Faridzadeh, A., ... & Deravi, N. (2022). Multisystem inflammatory syndrome and autoimmune diseases following COVID-19: Molecular mechanisms and therapeutic opportunities. Frontiers in Molecular Biosciences, 9, 804109.
Ilias, I., Vassiliou, A. G., Keskinidou, C., Vrettou, C. S., Orfanos, S., Kotanidou, A., & Dimopoulou, I. (2023). Changes in cortisol secretion and corticosteroid receptors in COVID-19 and non COVID-19 critically ill patients with sepsis/septic shock and scope for treatment. Biomedicines, 11(7), 1801.
Jensterle, M., Herman, R., Janez, A., Mahmeed, A., Al-Rasadi, K., Al-Alawi, K., ... & Rizzo, M. (2022). The relationship between COVID-19 and hypothalamic-pituitary-adrenal axis: A large spectrum from glucocorticoid insufficiency to excess—The CAPISCO international expert panel. International Journal of Molecular Sciences, 23(13), 7326.
Kanczkowski, W., Gaba, W. H., Krone, N., Varga, Z., Beuschlein, F., Hantel, C., ... & Bornstein, S. R. (2022). Adrenal gland function and dysfunction during COVID-19. Hormone and Metabolic Research, 54(8), 532-539.
Katz, A., Altshuler, D., Papadopoulos, J., Amoroso, N., Goldenberg, R., Tarras, E., ... & Brosnahan, S. B. (2022). The use of high-dose corticosteroids versus low-dose corticosteroids with and without tocilizumab in COVID-19 acute respiratory distress syndrome. The Annals of Pharmacotherapy, 57(1), 5-15.
Kunz-Ebrecht, R., Mohamed-Ali, V., Feldman, J., Kirschbaum, C., & Steptoe, A. (2003). Cortisol responses to mild psychological stress are inversely associated with proinflammatory cytokines. Brain, Behavior, and Immunity, 17(5), 373-383.
Leow, M. K., Kwek, D. S., Ng, A. W., Ong, K. C., Kaw, G. J., & Lee, L. S. (2005). Hypocortisolism in survivors of severe acute respiratory syndrome (SARS). Clinical Endocrinology, 63(2), 197-202.
Leyendecker, P., Ritter, S., Riou, M., Wackenthaler, A., Meziani, F., Roy, C., & Ohana, M. (2020). Acute adrenal infarction as an incidental CT finding and a potential prognosis factor in severe SARS-CoV-2 infection: A retrospective cohort analysis on 219 patients. European Radiology, 31(2), 895-900.
Li, M. Y., Li, L., Zhang, Y., & Wang, X. S. (2020). Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues. Infectious Diseases of Poverty, 9(1), 45.
Mao, Y., Xu, B., Guan, W., Xu, D., Li, F., Ren, R., ... & Jiang, L. (2020). The adrenal cortex, an underestimated site of SARS-CoV-2 infection. Frontiers in Endocrinology, 11, 593179.
Miller, W. L., & Auchus, R. J. (2019). The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocrine Reviews, 40(4), 1023-1062.
Müller, J. A., Groß, R., Conzelmann, C., Krüger, J., Merle, U., Steinhart, J., ... & Heller, S. (2021). SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas. Nature Metabolism, 3(2), 149-165.
Oguz, S. H., & Yildiz, B. O. (2023). Endocrine disorders and COVID-19. Annual Review of Medicine, 74, 75-88.
Pal, R. (2022). COVID-19 and hypothalamic-pituitary-adrenal axis: A narrative review. Hormones, 21(2), 211-219.
Pal, R., & Banerjee, M. (2020). COVID-19 and the endocrine system: Exploring the unexplored. Journal of Endocrinological Investigation, 43(7), 1027-1031.
RECOVERY Collaborative Group. (2021). Dexamethasone in hospitalized patients with Covid-19. New England Journal of Medicine, 384(8), 693-704.
Rotondi, M., Coperchini, F., Ricci, G., Denegri, M., Croce, L., Ngnitejeu, S. T., ... & Chiovato, L. (2021). Detection of SARS-CoV-2 receptor ACE2 in human follicular cells: A key to the thyroid tropism of the virus. Journal of Endocrinological Investigation, 44(9), 1917-1924.
Savla, S. R., Prabhavalkar, K. S., & Bhatt, L. K. (2021). Cytokine storm associated with severe COVID-19: A comprehensive review. Inflammopharmacology, 29(3), 683-698.
Sharrack, N., Baxter, C. T., Paddock, M., & Uchegbu, E. (2020). Adrenal haemorrhage as a complication of COVID-19 infection. BMJ Case Reports, 13(11), e238643.
Sher, E. K., Ćosović, A., Džidić-Krivić, A., & Banjari, I. (2023). COVID-19 and immune dysfunction: A comprehensive review of mechanisms and implications. International Journal of Molecular Sciences, 24(3), 2345.
Smith, S. M., & Vale, W. W. (2022). The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues in Clinical Neuroscience, 8(4), 383-395.
Stefunkova, M., Calkovska, A., & Calkovsky, V. (2021). Expression of ACE2 and TMPRSS2 in the adrenal gland: A potential target for SARS-CoV-2 infection. Endocrine Regulations, 55(3), 156-162.
Sungnak, W., Huang, N., Bécavin, C., Berg, M., Queen, R., Litvinukova, M., ... & HCA Lung Biological Network. (2020). SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nature Medicine, 26(5), 681-687.
Vakhshoori, M., Heidarpour, M., & Shafie, D. (2021). Adrenal insufficiency in coronavirus disease 2019: A case report and review of the literature. Journal of Research in Medical Sciences, 26, 45.
Vassiliadi, D. A., Dimopoulou, I., & Tsagarakis, S. (2021). The role of the hypothalamic-pituitary-adrenal axis in the pathophysiology and management of sepsis. Current Opinion in Critical Care, 27(4), 393-399.
Wang, Z., & Xu, X. (2020). scRNA-seq profiling of human testes reveals the presence of the ACE2 receptor, a target for SARS-CoV-2 infection in spermatogonia, Leydig and Sertoli cells. Cells, 9(4), 920.
Wepler, M., Rehm, M., & Thiel, M. (2020). The role of the hypothalamic-pituitary-adrenal axis in sepsis. Anesthesia & Analgesia, 131(2), 421-433.
WHO REACT Working Group. (2020). Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: A meta-analysis. JAMA, 324(13), 1330-1341.
Wolkow, A., Aisbett, B., Reynolds, J., Ferguson, S. A., & Main, L. C. (2015). Relationships between inflammatory cytokine and cortisol responses in firefighters exposed to simulated wildfire suppression. Applied Ergonomics, 48, 42-49.
Wong, R. S. Y., Chee, K. H., & Chong, E. T. J. (2021). The endocrine system in COVID-19: A review of current evidence. Endocrine Connections, 10(3), R77-R90.