Vol 72, No 3 (2021)
Review paper
Published online: 2021-05-05

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Endocrine and metabolic aspects of COVID-19

Marek Pawlikowski1, Katarzyna Winczyk2
Pubmed: 34010445
Endokrynol Pol 2021;72(3):256-260.


The paper presents the theoretical considerations on the role of endocrine and metabolic alterations accompanying COVID-19 infection. These alterations may be presumed on the basis of the following two observations. Firstly, the virus SARS-CoV-2 responsible for the COVID-19 infection uses an important renin–angiotensin system (RAS) element — angiotensin-converting enzyme 2 (ACE2) — as a receptor protein for entry into target cells and, in consequence, disturbs the function of the main (circulating) renin–angiotensin–aldosterone system (RAAS) and of the local renin–angiotensin system localized in different tissues and organs. The binding of SARS-CoV-2 to ACE2 leads to the downregulation of this enzyme and, in the aftermath, to the excess of angiotensin II and aldosterone. Thus, in the later stage
of COVID-19 infection, the beneficial effects of ACEI and ARB could be presumed. It is hypothesized that the local RAS dysregulation in the adipose tissue is the main cause of the negative role of obesity as a risk factor of severe outcome of the COVID-19 infection. Secondly, the outcome of COVID-19 strongly depends on the age of the patient. Age-related hormonal deficiencies, especially those of melatonin and dehydroepiandrosterone, may contribute to morbidity/mortality in older people. The usefulness of melatonin and angiotensin converting enzyme inhibitors/angiotensin receptor 1 blockers (the latter only in later phases of the infection) as adjuvant drugs is probable but needs thorough clinical trials. 

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  1. Gheblawi M, Wang K, Viveiros A, et al. Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2. Circ Res. 2020; 126(10): 1456–1474.
  2. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020; 181(2): 271–280.e8.
  3. Lazartigues E, Qadir MM, Mauvais-Jarvis F. Endocrine Significance of SARS-CoV-2's Reliance on ACE2. Endocrinology. 2020; 161(9).
  4. Li W, Moore MJ, Vasilieva N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003; 426(6965): 450–454.
  5. Li W, Zhang C, Sui J, et al. Angiotensin-converting enzyme 2: a functional receptor for SARS coronavirus. Cell Mol Life Sci. 2004; 61(21): 2738–2743.
  6. Richardson S, Hirsch JS, Sarasimhan M, et al. Presenting characteristics, comorbidities and outcomes among 5700 patients hospitalized with Covid-19 in the New York City Area. JAMA. 2020; 323(20): 2052–2059.
  7. Hanff TC, Harhay MO, Brown TS, et al. Is There an Association Between COVID-19 Mortality and the Renin-Angiotensin System? A Call for Epidemiologic Investigations. Clin Infect Dis. 2020; 71(15): 870–874.
  8. Cabbab IL, Manalo RV. Anti-inflammatory drugs and the renin-angiotensin-aldosterone system: Current knowledge and potential effects on early SARS-CoV-2 infection. Virus Res. 2021; 291: 198190.
  9. Chappell MC, Marshall AC, Alzayadneh EM, et al. Update on the Angiotensin converting enzyme 2-Angiotensin (1-7)-MAS receptor axis: fetal programing, sex differences, and intracellular pathways. Front Endocrinol (Lausanne). 2014; 4: 201.
  10. Gilbert KC, Brown NJ. Aldosterone and inflammation. Curr Opin Endocrinol Diabetes Obes. 2010; 17(3): 199–204.
  11. Chen D, Li X, Song Q, et al. Assessment of hypokaliemia and clinical characteristics in patients with coronavirus disease 2019 in Wenzhou, China. JAMA Netw Open. 2020; 3(6): e2011122.
  12. Deschepper CF, Crumrine DA, Ganong WF. Evidence that the gonadotrophs are the likely site of production of angiotensin II in the anterior pituitary of the rat. Endocrinology. 1986; 119(1): 36–43.
  13. Deschepper CF, Ganong WF. Distribution of angiotensinogen immunoreactivity in rat anterior pituitary glands. Proc Soc Exp Biol Med. 1991; 197(3): 304–309.
  14. Pawlikowski M, Mucha S, Kunert-Radek J. Is estrogen-induced pituitary hyperplasia and hyperprolactinaemia mediated by angiotensin II? In: Mukhopadyay AK, Raizada MK. ed. Tissue Renin-Angiotensin Systems: Current Concepts of Local Regulators in Reproductive and Endocrine Organs. Plenum Press, New York 1995: 371–378.
  15. Pawlikowski M. Immunohistochemical detection of angiotensin receptors AT1 and AT2 in normal rat pituitary gland, estrogen-induced rat pituitary tumor and human pituitary adenomas. Folia Histochem Cytobiol. 2006; 44(3): 173–177.
  16. Mulrow P. Renin–Angiotensin System in the Adrenal. Horm Metab Res. 2007; 30(06/07): 346–349.
  17. Leung P, Chappell M. A local pancreatic renin-angiotensin system: endocrine and exocrine roles. Int J Biochem Cell Biol. 2003; 35(6): 838–846.
  18. Graus-Nunes F, Souza-Mello V. The renin–angiotensin system as a target to solve the riddle of endocrine pancreas homeostasis. Biomed Pharmacother. 2019; 109: 639–645.
  19. Le Gall S, Féral C, Leymarie P. [Renin–angiotensin system of the uterus and ovary in mammalian females]. Reprod Nutr Dev. 1993; 33(3): 185–198.
  20. Ganong W. Reproduction and the renin-angiotensin system. Neurosci Biobehav Rev. 1995; 19(2): 241–250.
  21. Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res. 2020; 81(5): 537–540.
  22. Ferrario CM, Jessup J, Chappell MC, et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation. 2005; 111(20): 2605–2610.
  23. Sommerstein R, Kochen MM, Messerli FH, et al. Coronavirus Disease 2019 (COVID-19): Do Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers Have a Biphasic Effect? J Am Heart Assoc. 2020; 9(7): e016509.
  24. Stefan N, Birkenfeld AL, Schulze MB, et al. Obesity and impaired metabolic health in patients with COVID-19. Nat Rev Endocrinol. 2020; 16(7): 341–342.
  25. Yvan-Charvet L, Quignard-Boulangé A. Role of adipose tissue renin-angiotensin system in metabolic and inflammatory diseases associated with obesity. Kidney Int. 2011; 79(2): 162–168.
  26. Kalupahana NS, Moustaid-Moussa N. The adipose tissue renin–angiotensin system and metabolic disorders: a review of molecular mechanisms. Crit Rev Biochem Mol Biol. 2012; 47(4): 379–390.
  27. Kalupahana NS, Moustaid-Moussa N. The renin–angiotensin system: a link between obesity, inflammation and insulin resistance. Obes Rev. 2012; 13(2): 136–149.
  28. Pahlavani M, Kalupahana NS, Ramalingam L, et al. Regulation and Functions of the Renin-Angiotensin System in White and Brown Adipose Tissue. Compr Physiol. 2017; 7(4): 1137–1150.
  29. Puig-Domingo M, Marazuela M, Giustina A. COVID-19 and endocrine diseases. A statement from the European Society of Endocrinology. Endocrine. 2020; 68(1): 2–5.
  30. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020; 8(4).
  31. Yan Y, Yang F, Zhu X, et al. Analysis of clinical features and pulmonary CT features of coronavirus disease 2019 (COVID-19) patients with diabetes mellitus. Endokrynol Pol. 2020; 71(5): 367–375.
  32. Casqueiro J, Casqueiro J, Alves C. Infections in patients with diabetes mellitus: A review of pathogenesis. Indian J Endocrinol Metab. 2012; 16 Suppl 1: S27–S36.
  33. Salje H, Kiem C, Lefrancq N, et al. Estimating the burden of SARS-CoV-2 in France. Science. 2020; 369(6500): 20–211.
  34. Majewska M. Mortality of Covid-19 in Poland and in the world (in Polish). https://pulsmedycyny.pl smiertelnodc-covid-19-w-polsce-i-na-swiece-1006754.
  35. Pawlikowski M, Karasek M. Dehydroepiandrosterone (DHEA) in aging. In: Karasek M, Karasek M. ed. Aging and age-related diseases: the basic. Nova Sciences Publishers, New York 2006: 65–81.
  36. Kochan Z, Karbowska J. Dehydroepiandrosterone up-regulates resistin gene expression in white adipose tissue. Mol Cell Endocrinol. 2004; 218(1-2): 57–64.
  37. Loria RM, Inge TH, Cook SS, et al. Protection against acute lethal viral infections with the native steroid dehydroepiandrosterone (DHEA). J Med Virol. 1988; 26(3): 301–314.
  38. Nyce JW. Alert to US physicians: DHEA, widely used as an OTC androgen supplement, may exacerbate COVID-19. Endocr Relat Cancer. 2020 [Epub ahead of print].
  39. Karasek M, Pawlikowski M. [Hormones in aging]. Folia Medica Lodziensia. 2003; 30: 11–38.
  40. Karasek M. Role of melatonin in aging. In: Karasek M. ed. Aging and age-related diseases: the basic. Nova Sciences Publishers, New York 2006: 83–102.
  41. Zhang R, Wang X, Ni L, et al. COVID-19: Melatonin as a potential adjuvant treatment. Life Sci. 2020; 250: 117583.
  42. Bahrampour Juybari K, Pourhanifeh MH, Hosseinzadeh A, et al. Melatonin potentials against viral infections including COVID-19: Current evidence and new findings. Virus Res. 2020; 287: 198108.
  43. Reiter RJ, Abreu-Gonzalez P, Marik PE, et al. Therapeutic Algorithm for Use of Melatonin in Patients With COVID-19. Front Med (Lausanne). 2020; 7: 226.
  44. Shneider A, Kudriavtsev A, Vakhrusheva A. Can melatonin reduce the severity of COVID-19 pandemic? Int Rev Immunol. 2020; 39(4): 153–162.
  45. Öztürk G, Akbulut KG, Güney Ş. Melatonin, aging, and COVID-19: Could melatonin be beneficial for COVID-19 treatment in the elderly? Turk J Med Sci. 2020; 50(6): 1504–1512.
  46. El-Missiry MA, El-Missiry ZMA, Othman AI. Melatonin is a potential adjuvant to improve clinical outcomes in individuals with obesity and diabetes with coexistence of Covid-19. Eur J Pharmacol. 2020; 882: 173329.
  47. Feitosa EL, Júnior FT, Nery Neto JA, et al. COVID-19: Rational discovery of the therapeutic potential of Melatonin as a SARS-CoV-2 main Protease Inhibitor. Int J Med Sci. 2020; 17(14): 2133–2146.
  48. Sehirli AO, Sayiner S, Serakinci N. Role of melatonin in the treatment of COVID-19; as an adjuvant through cluster differentiation 147 (CD147). Mol Biol Rep. 2020; 47(10): 8229–8233.
  49. Ziaei A, Davoodian P, Dadvand H, et al. Evaluation of the efficacy and safety of Melatonin in moderately ill patients with COVID-19: A structured summary of a study protocol for a randomized controlled trial. Trials. 2020; 21(1): 882.
  50. García IG, Rodriguez-Rubio M, Mariblanca AR, et al. A randomized multicenter clinical trial to evaluate the efficacy of melatonin in the prophylaxis of SARS-CoV-2 infection in high-risk contacts (MeCOVID Trial): A structured summary of a study protocol for a randomised controlled trial. Trials. 2020; 21(1): 466.
  51. Acuña-Castroviejo D, Escames G, Figueira JC, et al. Clinical trial to test the efficacy of melatonin in COVID-19. J Pineal Res. 2020; 69(3): e12683.
  52. Pawlikowski M. Direct actions of gonadotropins beyond the reproductive system and their role in human aging and neoplasia [Bezpośrednie działanie gonadotropin poza układem rozrodczym i ich rola w starzeniu się i nowotworzeniu u człowieka]. Endokrynol Pol. 2019; 70(5): 437–444.
  53. Pawlikowski M, Winczyk K. Possible role of gonadotropin excess in age-related diseases - return to the old hypothesis in the light of current data. Neuro Endocrinol Lett. 2020; 41(3): 118–122.
  54. Ershler WB. Interleukin-6: a cytokine for gerontologists. J Am Geriatr Soc. 1993; 41(2): 176–181.
  55. Hirano T. The biology of interleukin-6. In: Kishimoto T. ed. Interleukins. Chemical immunology. Karger, Basel 1992: 153–180.
  56. Komorowski J, Stepień H. FSH and LH induce interleukin-6 (IL-6) release from human peripheral blood monocytes cultures in vitro. A dose-response study. Horm Metab Res. 1994; 26(9): 438–439.
  57. Liu B, Li M, Zhou Z, et al. Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)? J Autoimmun. 2020; 111: 102452.