{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T02:23:05Z","timestamp":1785896585883,"version":"3.56.0"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,1,8]],"date-time":"2021-01-08T00:00:00Z","timestamp":1610064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>The majority of the critically ill patients may have critical illness-related corticosteroid insufficiency (CIRCI). The therapeutic effect of dexamethasone may be related to its ability to improve cortical function. Recent study showed that dexamethasone can reduce COVID-19 deaths by up to one third in critically ill patients. The aim of this article is to investigate whether SARS-CoV-2 can attack the adrenal cortex to aggravate the relative adrenal insufficiency.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We summarized the clinical features of COVID-19 reported in currently available observational studies. ACE2 and TMPRSS2 expression was examined in human adrenal glands by immunohistochemical staining. We retrospectively analyzed serum cortisol levels in critically ill patients with or without COVID-19.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>High percentage of critically ill patients with SARS-COV-2 infection in the study were treated with vasopressors. ACE2 receptor and TMPRSS2 serine protease were colocalized in adrenocortical cells in zona fasciculata and zona reticularis. We collected plasma cortisol concentrations in nine critically ill patients with COVID-19. The cortisol levels of critically ill patients with COVID-19 were lower than those in non-COVID-19 critically ill group. Six of the nine COVID-19 critically ill patients had random plasma cortisol concentrations below 10 \u00b5g\/dl, which met the criteria for the diagnosis of CIRCI.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We demonstrate that ACE2 and TMPRSS2 are colocalized in adrenocortical cells, and that the cortisol levels are lower in critically ill patients with COVID-19 as compared to those of non-COVID-19 critically ill patients. Based on our findings, we recommend measuring plasma cortisol level to guide hormonal therapy.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2020.593179","type":"journal-article","created":{"date-parts":[[2021,1,8]],"date-time":"2021-01-08T14:42:02Z","timestamp":1610116922000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":74,"title":["The Adrenal Cortex, an Underestimated Site of SARS-CoV-2 Infection"],"prefix":"10.3389","volume":"11","author":[{"given":"Yanfei","family":"Mao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbin","family":"Guan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dunfeng","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongrong","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lai","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,1,8]]},"reference":[{"key":"B1","unstructured":"Coronavirus disease 2019 (COVID-19): situation report, 1112020"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.1097","article-title":"The Novel Coronavirus Originating in Wuhan, China: Challenges for Global Health Governance","volume":"323","author":"Phelan","year":"2020","journal-title":"JAMA"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1101\/2020.02.07.937862","article-title":"Severe acute respiratory syndrome-related coronavirus: The species and its viruses \u2013 a statement of the Coronavirus Study Group","author":"Gorbalenya","year":"2020","journal-title":"bioRxiv"},{"key":"B4","unstructured":"Coronavirus Disease (COVID-19) Situation Reports"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.1585","article-title":"Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China","volume":"323","author":"Wang","year":"2020","journal-title":"JAMA"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30566-3","article-title":"Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study","volume":"395","author":"Zhou","year":"2020","journal-title":"Lancet"},{"key":"B7","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"B8","doi-asserted-by":"publisher","first-page":"e00127\u201320","DOI":"10.1128\/JVI.00127-20","article-title":"Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus","volume":"94","author":"Wan","year":"2020","journal-title":"J Virol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1007\/s11684-020-0754-0","article-title":"Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection","volume":"14","author":"Zou","year":"2020","journal-title":"Front Med"},{"key":"B10","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/s40249-020-00646-x","article-title":"Epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (COVID-19) during the early outbreak period: a scoping review","volume":"9","author":"Adhikari","year":"2020","journal-title":"Infect Dis Poverty"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-020-06022-5","article-title":"Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19)","volume":"46","author":"Alhazzani","year":"2020","journal-title":"Intensive Care Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30920-X","article-title":"SARS-CoV-2 and viral sepsis: observations and hypotheses","volume":"395","author":"Li","year":"2020","journal-title":"Lancet"},{"key":"B13","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/S0140-6736(20)30183-5","article-title":"Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China","volume":"395","author":"Huang","year":"2020","journal-title":"Lancet"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-018-5366-7","article-title":"Adrenocortical function during prolonged critical illness and beyond: a prospective observational study","volume":"44","author":"Peeters","year":"2018","journal-title":"Intensive Care Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-017-4914-x","article-title":"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)","volume":"43","author":"Annane","year":"2017","journal-title":"Intensive Care Med"},{"key":"B16","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1186\/s13054-017-1768-0","article-title":"Dehydroepiandrosterone sulfate and dehydroepiandrosterone sulfate\/cortisol ratio in cirrhotic patients with septic shock: another sign of hepatoadrenal syndrome","volume":"21","author":"Tsai","year":"2017","journal-title":"Crit Care"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2001282","article-title":"A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19","volume":"382","author":"Cao","year":"2020","journal-title":"N Engl J Med"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.4326","article-title":"Characteristics and Outcomes of 21 Critically Ill Patients With COVID-19 in Washington State","volume":"323","author":"Arentz","year":"2020","journal-title":"JAMA"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(20)30079-5","article-title":"Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study","volume":"8","author":"Yang","year":"2020","journal-title":"Lancet Respir Med"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2009-2010","article-title":"Adrenocortical zonation in humans under normal and pathological conditions","volume":"95","author":"Nishimoto","year":"2010","journal-title":"J Clin Endocrinol Metab"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-017-4919-5","article-title":"Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017","volume":"43","author":"Annane","year":"2017","journal-title":"Intensive Care Med"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-019-0185-7","article-title":"Adrenal function and dysfunction in critically ill patients","volume":"15","author":"T\u00e9blick","year":"2019","journal-title":"Nat Rev Endocrinol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/j.cell.2020.02.058","article-title":"Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein","volume":"181","author":"Walls","year":"2020","journal-title":"Cell"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-020-05976-w","article-title":"Imaging changes in severe COVID-19 pneumonia","volume":"46","author":"Zhang","year":"2020","journal-title":"Intensive Care Med"},{"key":"B25","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.yjmcc.2020.04.031","article-title":"SARS-CoV-2 receptor ACE2-dependent implications on the cardiovascular system: From basic science to clinical implications","volume":"144","author":"Gro\u00df","year":"2020","journal-title":"J Mol Cell Cardiol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2020.04.001","article-title":"Diarrhea During COVID-19 Infection: Pathogenesis, Epidemiology, Prevention, and Management","volume":"18","author":"D\u2019Amico","year":"2020","journal-title":"Clin Gastroenterol Hepatol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00217.2020","article-title":"COVID-19, ACE2, and the cardiovascular consequences","volume":"318","author":"South","year":"2020","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1186\/s40249-020-00662-x","article-title":"Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues","volume":"9","author":"Li","year":"2020","journal-title":"Infect Dis Poverty"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/nm0502-473","article-title":"Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase","volume":"8","author":"Hafezi-Moghadam","year":"2002","journal-title":"Nat Med"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200309-1311OC","article-title":"Dexamethasone blocks hypoxia-induced endothelial dysfunction in organ-cultured pulmonary arteries","volume":"170","author":"Murata","year":"2004","journal-title":"Am J Respir Crit Care Med"},{"key":"B31","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1016\/j.jsbmb.2019.04.006","article-title":"The adrenal gland in stress - Adaptation on a cellular level","volume":"190","author":"Berger","year":"2019","journal-title":"J Steroid Biochem Mol Biol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/jez.1402320332","article-title":"Stress and adrenal function","volume":"232","author":"Harvey","year":"1984","journal-title":"J Exp Zool"},{"key":"B33","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1210\/edrv.21.1.0389","article-title":"How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions","volume":"21","author":"Sapolsky","year":"2000","journal-title":"Endocr Rev"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2014.11.012","article-title":"The HPA axis response to critical illness: New study results with diagnostic and therapeutic implications","volume":"408","author":"Peeters","year":"2015","journal-title":"Mol Cell Endocrinol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1097\/MCC.0b013e32818a6d74","article-title":"Mechanisms and clinical consequences of critical illness associated adrenal insufficiency","volume":"13","author":"Marik","year":"2007","journal-title":"Curr Opin Crit Care"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1210\/me.2015-1087","article-title":"Suppression of the HPA Axis During Cholestasis Can Be Attributed to Hypothalamic Bile Acid Signaling","volume":"29","author":"McMillin","year":"2015","journal-title":"Mol Endocrinol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijid.2005.08.001","article-title":"Adrenal infections","volume":"10","author":"Paolo","year":"2006","journal-title":"Int J Infect Dis"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.062170099","article-title":"Adenoviral vectors can impair adrenocortical steroidogenesis: clinical implications for natural infections and gene therapy","volume":"99","author":"Alesci","year":"2002","journal-title":"Proc Natl Acad Sci USA"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2015.02.005","article-title":"Dynamics of adrenal glucocorticoid steroidogenesis in health and disease","volume":"408","author":"Spiga","year":"2015","journal-title":"Mol Cell Endocrinol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0b013e318206b980","article-title":"Endotoxin tolerance of adrenal gland: attenuation of corticosterone production in response to lipopolysaccharide and adrenocorticotropic hormone","volume":"39","author":"Liu","year":"2011","journal-title":"Crit Care Med"},{"key":"B41","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1038\/d41586-020-01824-5","article-title":"Coronavirus breakthrough: dexamethasone is first drug shown to save lives","volume":"582","author":"Ledford","year":"2020","journal-title":"Nature"},{"key":"B42","doi-asserted-by":"publisher","first-page":"920","DOI":"10.3390\/cells9040920","article-title":"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","volume":"9","author":"Wang","year":"2020","journal-title":"Cells"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1101\/2020.02.12.20022418","article-title":"ACE2 Expression in Kidney and Testis May Cause Kidney and Testis Damage After 2019-nCoV Infection","author":"Fan","year":"2020","journal-title":"medRxiv"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.rbmo.2020.04.009","article-title":"SARS-CoV-2 and the testis: similarity with other viruses and routes of infection","volume":"40","author":"Cardona Maya","year":"2020","journal-title":"Reprod BioMed Online"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1101\/2020.03.21.20037267","article-title":"Effect of SARS-CoV-2 infection upon male gonadal function: A single center-based study","author":"Ma","year":"2020","journal-title":"medRxiv"},{"key":"B46","unstructured":"MolinaP\n          Endocrine Physiology"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30317-2","article-title":"Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury","volume":"395","author":"Russell","year":"2020","journal-title":"Lancet"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-014-3468-4","article-title":"Prognostic significance of hypothalamic-pituitary-adrenal axis hormones in early sepsis: a study performed in the emergency department","volume":"40","author":"Zhang","year":"2014","journal-title":"Intensive Care Med"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(20)30149-2","article-title":"Use of glucocorticoids in patients with adrenal insufficiency and COVID-19 infection","volume":"8","author":"Isidori","year":"2020","journal-title":"Lancet Diabetes Endocrinol"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2020.593179\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,14]],"date-time":"2021-01-14T03:50:59Z","timestamp":1610596259000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2020.593179\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,8]]},"references-count":49,"alternative-id":["10.3389\/fendo.2020.593179"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2020.593179","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,8]]},"article-number":"593179"}}