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The human stress response

Abstract

The human stress response has evolved to maintain homeostasis under conditions of real or perceived stress. This objective is achieved through autoregulatory neural and hormonal systems in close association with central and peripheral clocks. The hypothalamic–pituitary–adrenal axis is a key regulatory pathway in the maintenance of these homeostatic processes. The end product of this pathway — cortisol — is secreted in a pulsatile pattern, with changes in pulse amplitude creating a circadian pattern. During acute stress, cortisol levels rise and pulsatility is maintained. Although the initial rise in cortisol follows a large surge in adrenocorticotropic hormone levels, if long-term inflammatory stress occurs, adrenocorticotropic hormone levels return to near basal levels while cortisol levels remain raised as a result of increased adrenal sensitivity. In chronic stress, hypothalamic activation of the pituitary changes from corticotropin-releasing hormone-dominant to arginine vasopressin-dominant, and cortisol levels remain raised due at least in part to decreased cortisol metabolism. Acute elevations in cortisol levels are beneficial to promoting survival of the fittest as part of the fight-or-flight response. However, chronic exposure to stress results in reversal of the beneficial effects, with long-term cortisol exposure becoming maladaptive, which can lead to a broad range of problems including the metabolic syndrome, obesity, cancer, mental health disorders, cardiovascular disease and increased susceptibility to infections. Neuroimmunoendocrine modulation in disease states and glucocorticoid-based therapeutics are also discussed.

Key points

  • The hypothalamic–pituitary–adrenal (HPA) axis is a key system that synchronizes the stress response with circadian regulatory processes.

  • Regulation of the HPA axis is very dynamic with both ultradian and circadian oscillations.

  • Short-term and longer-term stress result in different regulatory mechanisms involving hypothalamic, pituitary and adrenal activity, as well as cortisol metabolism.

  • Chronic elevation and nonphysiological patterns of cortisol result in poor cognitive, metabolic and immune function.

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Fig. 1: Coordination of central and peripheral clocks by glucocorticoids.
Fig. 2: Human cortisol ultradian rhythmicity under basal and stressful conditions.
Fig. 3: Schematic representation of the hypothalamic–pituitary–adrenal axis showing natural inbuilt adrenal delays.
Fig. 4: The importance of gene pulsing.

References

  1. 1.

    Szabo, S., Tache, Y. & Somogyi, A. The legacy of Hans Selye and the origins of stress research: a retrospective 75 years after his landmark brief “letter” to the editor of Nature. Stress 15, 472–478 (2012).

    CAS  PubMed  Google Scholar 

  2. 2.

    Levine, S. Influence of psychological variables on the activity of the hypothalamic-pituitary-adrenal axis. Eur. J. Pharmacol. 405, 149–160 (2000).

    CAS  PubMed  Google Scholar 

  3. 3.

    Brown, S. A. & Azzi, A. Peripheral circadian oscillators in mammals. Handb. Exp. Pharmacol. 2013, 45–66 (2013).

    Google Scholar 

  4. 4.

    Roenneberg, T. & Merrow, M. The circadian clock and human health. Curr. Biol. 26, R432–R443 (2016).

    CAS  PubMed  Google Scholar 

  5. 5.

    Bass, J. & Lazar, M. A. Circadian time signatures of fitness and disease. Science 354, 994–999 (2016).

    CAS  PubMed  Google Scholar 

  6. 6.

    Turek, F. W. Circadian neural rhythms in mammals. Annu. Rev. Physiol. 47, 49–64 (1985).

    CAS  PubMed  Google Scholar 

  7. 7.

    Skene, D. J. et al. Separation of circadian- and behavior-driven metabolite rhythms in humans provides a window on peripheral oscillators and metabolism. Proc. Natl Acad. Sci. USA 115, 7825–7830 (2018).

    CAS  PubMed  Google Scholar 

  8. 8.

    Buhr, E. D. & Takahashi, J. S. Molecular components of the mammalian circadian clock. Handb. Exp. Pharmacol. 217, 3–27 (2013).

    CAS  Google Scholar 

  9. 9.

    Takahashi, J. S. Transcriptional architecture of the mammalian circadian clock. Nat. Rev. Genet. 18, 164–179 (2017).

    CAS  PubMed  Google Scholar 

  10. 10.

    Baron, K. G. & Reid, K. J. Circadian misalignment and health. Int. Rev. Psychiatry 26, 139–154 (2014).

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Potter, G. D. et al. Circadian rhythm and sleep disruption: causes, metabolic consequences, and countermeasures. Endocr. Rev. 37, 584–608 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Zhang, R., Lahens, N. F., Ballance, H. I., Hughes, M. E. & Hogenesch, J. B. A circadian gene expression atlas in mammals: implications for biology and medicine. Proc. Natl Acad. Sci. USA 111, 16219–16224 (2014).

    CAS  PubMed  Google Scholar 

  13. 13.

    Smarr, B. L. & Schirmer, A. E. 3.4 million real-world learning management system logins reveal the majority of students experience social jet lag correlated with decreased performance. Sci. Rep. 8, 4793 (2018).

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Gardner, M. et al. Dysregulation of the hypothalamic pituitary adrenal (HPA) axis and cognitive capability at older ages: individual participant meta-analysis of five cohorts. Sci. Rep. 9, 4555 (2019).

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    Selye, H. Stress and the general adaptation syndrome. BMJ 1, 1383–1392 (1950).

    CAS  PubMed  Google Scholar 

  16. 16.

    Russell, G. M. & Lightman, S. L. Can side effects of steroid treatments be minimized by the temporal aspects of delivery method? Expert Opin. Drug Saf. 13, 1501–1513 (2014).

    CAS  PubMed  Google Scholar 

  17. 17.

    Sorrells, S. F. & Sapolsky, R. M. An inflammatory review of glucocorticoid actions in the CNS. Brain Behav. Immun. 21, 259–272 (2007).

    CAS  PubMed  Google Scholar 

  18. 18.

    Busillo, J. M. & Cidlowski, J. A. The five Rs of glucocorticoid action during inflammation: ready, reinforce, repress, resolve, and restore. Trends Endocrinol. Metab. 24, 109–119 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    McEwen, B. S. et al. The role of adrenocorticoids as modulators of immune function in health and disease: neural, endocrine and immune interactions. Brain Res. Rev. 23, 79–133 (1997).

    CAS  PubMed  Google Scholar 

  20. 20.

    Elenkov, I. J. & Chrousos, G. P. Stress system — organization, physiology and immunoregulation. Neuroimmunomodulation 13, 257–267 (2006).

    CAS  PubMed  Google Scholar 

  21. 21.

    Brinkmann, V. & Kristofic, C. Regulation by corticosteroids of Th1 and Th2 cytokine production in human CD4+ effector T cells generated from CD45RO- and CD45RO+ subsets. J. Immunol. 155, 3322–3328 (1995).

    CAS  PubMed  Google Scholar 

  22. 22.

    Wiegers, G. J. & Reul, J. M. Induction of cytokine receptors by glucocorticoids: functional and pathological significance. Trends Pharmacol. Sci. 19, 317–321 (1998).

    CAS  PubMed  Google Scholar 

  23. 23.

    Abraham, I. M., Meerlo, P. & Luiten, P. G. Concentration dependent actions of glucocorticoids on neuronal viability and survival. Dose Response 4, 38–54 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Plaschke, K., Muller, D. & Hoyer, S. Effect of adrenalectomy and corticosterone substitution on glucose and glycogen metabolism in rat brain. J. Neural Transm. 103, 89–100 (1996).

    CAS  PubMed  Google Scholar 

  25. 25.

    Belanoff, J. K., Gross, K., Yager, A. & Schatzberg, A. F. Corticosteroids and cognition. J. Psychiatr. Res. 35, 127–145 (2001).

    CAS  PubMed  Google Scholar 

  26. 26.

    Roozendaal, B. Stress and memory: opposing effects of glucocorticoids on memory consolidation and memory retrieval. Neurobiol. Learn. Mem. 78, 578–595 (2002).

    CAS  PubMed  Google Scholar 

  27. 27.

    Brown, E. S. Effects of glucocorticoids on mood, memory, and the hippocampus. Treatment and preventive therapy. Ann. NY Acad. Sci. 1179, 41–55 (2009).

    CAS  PubMed  Google Scholar 

  28. 28.

    de Kloet, E. R., Oitzl, M. S. & Joels, M. Stress and cognition: are corticosteroids good or bad guys? Trends Neurosci. 22, 422–426 (1999).

    PubMed  Google Scholar 

  29. 29.

    Decani, S., Federighi, V., Baruzzi, E., Sardella, A. & Lodi, G. Iatrogenic Cushing’s syndrome and topical steroid therapy: case series and review of the literature. J. Dermatolog. Treat. 25, 495–500 (2014).

    PubMed  Google Scholar 

  30. 30.

    Kenna, H. A., Poon, A. W., de los Angeles, C. P. & Koran, L. M. Psychiatric complications of treatment with corticosteroids: review with case report. Psychiatry Clin. Neurosci. 65, 549–560 (2011).

    CAS  PubMed  Google Scholar 

  31. 31.

    Buijs, R. M., Markman, M., Nunes-Cardoso, B., Hou, Y. X. & Shinn, S. Projections of the suprachiasmatic nucleus to stress-related areas in the rat hypothalamus: a light and electron microscopic study. J. Comp. Neurol. 335, 42–54 (1993).

    CAS  PubMed  Google Scholar 

  32. 32.

    Watts, A. G. & Swanson, L. W. Efferent projections of the suprachiasmatic nucleus: II. Studies using retrograde transport of fluorescent dyes and simultaneous peptide immunohistochemistry in the rat. J. Comp. Neurol. 258, 230–252 (1987).

    CAS  PubMed  Google Scholar 

  33. 33.

    Jacobson, L. Hypothalamic-pituitary-adrenocortical axis regulation. Endocrinol. Metab. Clin. North Am. 34, 271–292 (2005).

    CAS  PubMed  Google Scholar 

  34. 34.

    Herman, J. P., Ostrander, M. M., Mueller, N. K. & Figueiredo, H. Limbic system mechanisms of stress regulation: hypothalamo-pituitary-adrenocortical axis. Prog. Neuropsychopharmacol. Biol. Psychiatry 29, 1201–1213 (2005).

    CAS  PubMed  Google Scholar 

  35. 35.

    Dallman, M. F. et al. Corticosteroids and the control of function in the hypothalamo-pituitary-adrenal (HPA) axis. Ann. NY Acad. Sci. 746, 22–31 (1994).

    CAS  PubMed  Google Scholar 

  36. 36.

    Jasper, M. S. & Engeland, W. C. Splanchnic neural activity modulates ultradian and circadian rhythms in adrenocortical secretion in awake rats. Neuroendocrinology 59, 97–109 (1994).

    CAS  PubMed  Google Scholar 

  37. 37.

    Buijs, R. M. et al. Anatomical and functional demonstration of a multisynaptic suprachiasmatic nucleus adrenal (cortex) pathway. Eur. J. Neurosci. 11, 1535–1544 (1999).

    CAS  PubMed  Google Scholar 

  38. 38.

    Kiessling, S., Sollars, P. J. & Pickard, G. E. Light stimulates the mouse adrenal through a retinohypothalamic pathway independent of an effect on the clock in the suprachiasmatic nucleus. PLOS ONE 9, e92959 (2014).

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Husse, J., Leliavski, A., Tsang, A. H., Oster, H. & Eichele, G. The light-dark cycle controls peripheral rhythmicity in mice with a genetically ablated suprachiasmatic nucleus clock. FASEB J. 28, 4950–4960 (2014).

    CAS  PubMed  Google Scholar 

  40. 40.

    Ishida, A. et al. Light activates the adrenal gland: timing of gene expression and glucocorticoid release. Cell Metab. 2, 297–307 (2005).

    CAS  PubMed  Google Scholar 

  41. 41.

    Oster, H. et al. The circadian rhythm of glucocorticoids is regulated by a gating mechanism residing in the adrenal cortical clock. Cell Metab. 4, 163–173 (2006).

    CAS  PubMed  Google Scholar 

  42. 42.

    Charmandari, E. et al. Peripheral CLOCK regulates target-tissue glucocorticoid receptor transcriptional activity in a circadian fashion in man. PLOS ONE 6, e25612 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Bailey, S. L. & Heitkemper, M. M. Circadian rhythmicity of cortisol and body temperature: morningness-eveningness effects. Chronobiol. Int. 18, 249–261 (2001).

    CAS  PubMed  Google Scholar 

  44. 44.

    Donner, N. C., Montoya, C. D., Lukkes, J. L. & Lowry, C. A. Chronic non-invasive corticosterone administration abolishes the diurnal pattern of tph2 expression. Psychoneuroendocrinology 37, 645–661 (2012).

    CAS  PubMed  Google Scholar 

  45. 45.

    Lightman, S. L. The neuroendocrinology of stress: a never ending story. J. Neuroendocrinol. 20, 880–884 (2008).

    CAS  PubMed  Google Scholar 

  46. 46.

    Nicolaides, N. C., Kyratzi, E., Lamprokostopoulou, A., Chrousos, G. P. & Charmandari, E. Stress, the stress system and the role of glucocorticoids. Neuroimmunomodulation 22, 6–19 (2015).

    CAS  PubMed  Google Scholar 

  47. 47.

    Gibbison, B. et al. Dynamic pituitary-adrenal interactions in response to cardiac surgery. Crit. Care Med. 43, 791–800 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Spiga, F. et al. Dynamic responses of the adrenal steroidogenic regulatory network. Proc. Natl Acad. Sci. USA 114, E6466–E6474 (2017).

    CAS  PubMed  Google Scholar 

  49. 49.

    Ma, X. M., Levy, A. & Lightman, S. L. Emergence of an isolated arginine vasopressin (AVP) response to stress after repeated restraint: a study of both AVP and corticotropin-releasing hormone messenger ribonucleic acid (RNA) and heteronuclear RNA. Endocrinology 138, 4351–4357 (1997).

    CAS  PubMed  Google Scholar 

  50. 50.

    Dallman, M. F. Stress update: adaptation of the hypothalamic-pituitary-adrenal axis to chronic stress. Trends. Endocrinol. Metab. 4, 62–69 (1993).

    CAS  PubMed  Google Scholar 

  51. 51.

    Henley, D. E. et al. Hypothalamic-pituitary-adrenal axis activation in obstructive sleep apnea: the effect of continuous positive airway pressure therapy. J. Clin. Endocrinol. Metab. 94, 4234–4242 (2009).

    CAS  PubMed  Google Scholar 

  52. 52.

    Boonen, E. et al. Reduced cortisol metabolism during critical illness. N. Engl. J. Med. 368, 1477–1488 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Peeters, B. et al. Adrenocortical function during prolonged critical illness and beyond: a prospective observational study. Intensive Care Med. 44, 1720–1729 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    De Kloet, E. R., Vreugdenhil, E., Oitzl, M. S. & Joels, M. Brain corticosteroid receptor balance in health and disease. Endocr. Rev. 19, 269–301 (1998).

    PubMed  Google Scholar 

  55. 55.

    Reul, J. M. & de Kloet, E. R. Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation. Endocrinology 117, 2505–2511 (1985).

    CAS  PubMed  Google Scholar 

  56. 56.

    Dallman, M. F. Fast glucocorticoid actions on brain: back to the future. Front. Neuroendocrinol. 26, 103–108 (2005).

    CAS  PubMed  Google Scholar 

  57. 57.

    Russell, G. M. et al. Rapid glucocorticoid receptor-mediated inhibition of hypothalamic-pituitary-adrenal ultradian activity in healthy males. J. Neurosci. 30, 6106–6115 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Lowenberg, M., Verhaar, A. P., van den Brink, G. R. & Hommes, D. W. Glucocorticoid signaling: a nongenomic mechanism for T cell immunosuppression. Trends Mol. Med. 13, 158–163 (2007).

    PubMed  Google Scholar 

  59. 59.

    Orchinik, M., Murray, T. F., Franklin, P. H. & Moore, F. L. Guanyl nucleotides modulate binding to steroid receptors in neuronal membranes. Proc. Natl Acad. Sci. USA 89, 3830–3834 (1992).

    CAS  PubMed  Google Scholar 

  60. 60.

    Orchinik, M., Murray, T. F. & Moore, F. L. A corticosteroid receptor in neuronal membranes. Science 252, 1848–1851 (1991).

    CAS  PubMed  Google Scholar 

  61. 61.

    Joels, M., Pasricha, N. & Karst, H. The interplay between rapid and slow corticosteroid actions in brain. Eur. J. Pharmacol. 719, 44–52 (2013).

    CAS  PubMed  Google Scholar 

  62. 62.

    Walker, J. J. et al. The origin of glucocorticoid hormone oscillations. PLOS Biol. 10, e1001341 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Patel, P. D. et al. Glucocorticoid and mineralocorticoid receptor mRNA expression in squirrel monkey brain. J. Psychiatr. Res. 34, 383–392 (2000).

    CAS  PubMed  Google Scholar 

  64. 64.

    Groeneweg, F. L., Karst, H., de Kloet, E. R. & Joels, M. Rapid non-genomic effects of corticosteroids and their role in the central stress response. J. Endocrinol. 209, 153–167 (2011).

    CAS  PubMed  Google Scholar 

  65. 65.

    de Kloet, E. R., Fitzsimons, C. P., Datson, N. A., Meijer, O. C. & Vreugdenhil, E. Glucocorticoid signaling and stress-related limbic susceptibility pathway: about receptors, transcription machinery and microRNA. Brain Res. 1293, 129–141 (2009).

    PubMed  Google Scholar 

  66. 66.

    Russell, G. M., Kalafatakis, K. & Lightman, S. L. The importance of biological oscillators for HPA activity and tissue glucocorticoid response: coordinating stress and neurobehavioural adaptation. J. Neuroendocrinol. 27, 378–388 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Lewis, J. G. et al. Plasma variation of corticosteroid-binding globulin and sex hormone-binding globulin. Horm. Metab. Res. 38, 241–245 (2006).

    CAS  PubMed  Google Scholar 

  68. 68.

    Lewis, J. G., Bagley, C. J., Elder, P. A., Bachmann, A. W. & Torpy, D. J. Plasma free cortisol fraction reflects levels of functioning corticosteroid-binding globulin. Clin. Chim. Acta 359, 189–194 (2005).

    CAS  PubMed  Google Scholar 

  69. 69.

    Hammond, G. L., Smith, C. L. & Underhill, D. A. Molecular studies of corticosteroid binding globulin structure, biosynthesis and function. J. Steroid Biochem. Mol. Biol. 40, 755–762 (1991).

    CAS  PubMed  Google Scholar 

  70. 70.

    Frairia, R. et al. Influence of naturally occurring and synthetic glucocorticoids on corticosteroid-binding globulin-steroid interaction in human peripheral plasma. Ann. NY Acad. Sci. 538, 287–303 (1988).

    CAS  PubMed  Google Scholar 

  71. 71.

    Cameron, A. et al. Temperature-responsive release of cortisol from its binding globulin: a protein thermocouple. J. Clin. Endocrinol. Metab. 95, 4689–4695 (2010).

    CAS  PubMed  Google Scholar 

  72. 72.

    Kyrou, I., Chrousos, G. P. & Tsigos, C. Stress, visceral obesity, and metabolic complications. Ann. NY Acad. Sci. 1083, 77–110 (2006).

    CAS  PubMed  Google Scholar 

  73. 73.

    Chapman, K., Holmes, M. & Seckl, J. 11beta-hydroxysteroid dehydrogenases: intracellular gate-keepers of tissue glucocorticoid action. Physiol. Rev. 93, 1139–1206 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Seckl, J. R. 11beta-hydroxysteroid dehydrogenases: changing glucocorticoid action. Curr. Opin. Pharmacol. 4, 597–602 (2004).

    CAS  PubMed  Google Scholar 

  75. 75.

    Verma, M. et al. 11beta-hydroxysteroid dehydrogenase-1 deficiency alters brain energy metabolism in acute systemic inflammation. Brain Behav. Immun. 69, 223–234 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Follenius, M., Simon, C., Brandenberger, G. & Lenzi, P. Ultradian plasma corticotropin and cortisol rhythms: time-series analyses. J. Endocrinol. Invest. 10, 261–266 (1987).

    CAS  PubMed  Google Scholar 

  77. 77.

    Hartmann, A., Veldhuis, J. D., Deuschle, M., Standhardt, H. & Heuser, I. Twenty-four hour cortisol release profiles in patients with Alzheimer’s and Parkinson’s disease compared to normal controls: ultradian secretory pulsatility and diurnal variation. Neurobiol. Aging 18, 285–289 (1997).

    CAS  PubMed  Google Scholar 

  78. 78.

    Rivest, R. W., Schulz, P., Lustenberger, S. & Sizonenko, P. C. Differences between circadian and ultradian organization of cortisol and melatonin rhythms during activity and rest. J. Clin. Endocrinol. Metab. 68, 721–729 (1989).

    CAS  PubMed  Google Scholar 

  79. 79.

    Waite, E. J. et al. Ultradian corticosterone secretion is maintained in the absence of circadian cues. Eur. J. Neurosci. 36, 3142–3150 (2012).

    PubMed  Google Scholar 

  80. 80.

    Ixart, G., Barbanel, G., Nouguier-Soule, J. & Assenmacher, I. A quantitative study of the pulsatile parameters of CRH-41 secretion in unanesthetized free-moving rats. Exp. Brain Res. 87, 153–158 (1991).

    CAS  PubMed  Google Scholar 

  81. 81.

    Spiga, F. et al. ACTH-dependent ultradian rhythm of corticosterone secretion. Endocrinology 152, 1448–1457 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Spiga, F., Liu, Y., Aguilera, G. & Lightman, S. L. Temporal effect of adrenocorticotrophic hormone on adrenal glucocorticoid steroidogenesis: involvement of the transducer of regulated cyclic AMP-response element-binding protein activity. J. Neuroendocrinol. 23, 136–142 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Lim, C. & Allada, R. Emerging roles for post-transcriptional regulation in circadian clocks. Nat. Neurosci. 16, 1544–1550 (2013).

    CAS  PubMed  Google Scholar 

  84. 84.

    Liston, C. et al. Circadian glucocorticoid oscillations promote learning-dependent synapse formation and maintenance. Nat. Neurosci. 16, 698–705 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Lightman, S. L. & Conway-Campbell, B. L. The crucial role of pulsatile activity of the HPA axis for continuous dynamic equilibration. Nat. Rev. Neurosci. 11, 710–718 (2010).

    CAS  PubMed  Google Scholar 

  86. 86.

    Stavreva, D. A. et al. Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription. Nat. Cell Biol. 11, 1093–1102 (2009).

    CAS  PubMed  Google Scholar 

  87. 87.

    Conway-Campbell, B. L., Pooley, J. R., Hager, G. L. & Lightman, S. L. Molecular dynamics of ultradian glucocorticoid receptor action. Mol. Cell. Endocrinol. 348, 383–393 (2012).

    CAS  PubMed  Google Scholar 

  88. 88.

    George, C. L., Lightman, S. L. & Biddie, S. C. Transcription factor interactions in genomic nuclear receptor function. Epigenomics 3, 471–485 (2011).

    CAS  PubMed  Google Scholar 

  89. 89.

    So, A. Y., Chaivorapol, C., Bolton, E. C., Li, H. & Yamamoto, K. R. Determinants of cell- and gene-specific transcriptional regulation by the glucocorticoid receptor. PLOS Genet. 3, e94 (2007).

    PubMed  PubMed Central  Google Scholar 

  90. 90.

    Zalachoras, I., Houtman, R. & Meijer, O. C. Understanding stress-effects in the brain via transcriptional signal transduction pathways. Neuroscience 242, 97–109 (2013).

    CAS  PubMed  Google Scholar 

  91. 91.

    Sarabdjitsingh, R. A. et al. Stress responsiveness varies over the ultradian glucocorticoid cycle in a brain-region-specific manner. Endocrinology 151, 5369–5379 (2010).

    CAS  PubMed  Google Scholar 

  92. 92.

    Sarabdjitsingh, R. A. et al. Ultradian corticosterone pulses balance glutaminergic transmission and synaptic plasticity. Proc. Natl Acad. Sci. USA 111, 14265–14270 (2014).

    CAS  PubMed  Google Scholar 

  93. 93.

    Kalafatakis, K. et al. Ultradian rhythmicity of plasma cortisol is necessary for normal emotional and cognitive responses in man. Proc. Natl Acad. Sci. USA 115, E4091–E4100 (2018).

    CAS  PubMed  Google Scholar 

  94. 94.

    Gjerstad, J. K., Lightman, S. L. & Spiga, F. Role of glucocorticoid negative feedback in the regulation of HPA axis pulsatility. Stress 21, 403–416 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Bornstein, S. R., Engeland, W. C., Ehrhart-Bornstein, M. & Herman, J. P. Dissociation of ACTH and glucocorticoids. Trends Endocrinol. Metab. 19, 175–180 (2008).

    CAS  PubMed  Google Scholar 

  96. 96.

    Silverman, M. N., Miller, A. H., Biron, C. A. & Pearce, B. D. Characterization of an interleukin-6- and adrenocorticotropin-dependent, immune-to-adrenal pathway during viral infection. Endocrinology 145, 3580–3589 (2004).

    CAS  PubMed  Google Scholar 

  97. 97.

    Franchimont, D. et al. Adrenal cortical activation in murine colitis. Gastroenterology 119, 1560–1568 (2000).

    CAS  PubMed  Google Scholar 

  98. 98.

    Viblanc, V. A. et al. An integrative appraisal of the hormonal and metabolic changes induced by acute stress using king penguins as a model. Gen. Comp. Endocrinol. 269, 1–10 (2018).

    CAS  PubMed  Google Scholar 

  99. 99.

    Cruz-Topete, D. & Cidlowski, J. A. One hormone, two actions: anti- and pro-inflammatory effects of glucocorticoids. Neuroimmunomodulation 22, 20–32 (2015).

    CAS  PubMed  Google Scholar 

  100. 100.

    Biddie, S. C., Conway-Campbell, B. L. & Lightman, S. L. Dynamic regulation of glucocorticoid signalling in health and disease. Rheumatology 51, 403–412 (2012).

    CAS  PubMed  Google Scholar 

  101. 101.

    Miller, G. E., Cohen, S. & Ritchey, A. K. Chronic psychological stress and the regulation of pro-inflammatory cytokines: a glucocorticoid-resistance model. Health Psychol. 21, 531–541 (2002).

    PubMed  Google Scholar 

  102. 102.

    Oster, H. et al. The functional and clinical significance of the 24-hour rhythm of circulating glucocorticoids. Endocr. Rev. 38, 3–45 (2017).

    PubMed  Google Scholar 

  103. 103.

    Keller, M. et al. A circadian clock in macrophages controls inflammatory immune responses. Proc. Natl Acad. Sci. USA 106, 21407–21412 (2009).

    CAS  PubMed  Google Scholar 

  104. 104.

    Boivin, D. B. et al. Circadian clock genes oscillate in human peripheral blood mononuclear cells. Blood 102, 4143–4145 (2003).

    CAS  PubMed  Google Scholar 

  105. 105.

    Koo, J. W., Russo, S. J., Ferguson, D., Nestler, E. J. & Duman, R. S. Nuclear factor-kappaB is a critical mediator of stress-impaired neurogenesis and depressive behavior. Proc. Natl Acad. Sci. USA 107, 2669–2674 (2010).

    CAS  PubMed  Google Scholar 

  106. 106.

    Pace, T. W., Hu, F. & Miller, A. H. Cytokine-effects on glucocorticoid receptor function: relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression. Brain Behav. Immun. 21, 9–19 (2007).

    CAS  PubMed  Google Scholar 

  107. 107.

    Pace, T. W. et al. Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. Am. J. Psychiatry 163, 1630–1633 (2006).

    PubMed  Google Scholar 

  108. 108.

    Cohen, S. et al. Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk. Proc. Natl Acad. Sci. USA 109, 5995–5999 (2012).

    CAS  PubMed  Google Scholar 

  109. 109.

    Spiegel, K., Leproult, R. & Van Cauter, E. Impact of sleep debt on metabolic and endocrine function. Lancet 354, 1435–1439 (1999).

    CAS  PubMed  Google Scholar 

  110. 110.

    Hauner, H., Schmid, P. & Pfeiffer, E. F. Glucocorticoids and insulin promote the differentiation of human adipocyte precursor cells into fat cells. J. Clin. Endocrinol. Metab. 64, 832–835 (1987).

    CAS  PubMed  Google Scholar 

  111. 111.

    Dallman, M. F. et al. Glucocorticoids, chronic stress, and obesity. Prog. Brain Res. 153, 75–105 (2006).

    CAS  PubMed  Google Scholar 

  112. 112.

    Tsigos, C. et al. Dose-dependent effects of recombinant human interleukin-6 on glucose regulation. J. Clin. Endocrinol. Metab. 82, 4167–4170 (1997).

    CAS  PubMed  Google Scholar 

  113. 113.

    McEwen, B. S. Sleep deprivation as a neurobiologic and physiologic stressor: allostasis and allostatic load. Metabolism 55, S20–S23 (2006).

    CAS  PubMed  Google Scholar 

  114. 114.

    Zhu, B., Shi, C., Park, C. G., Zhao, X. & Reutrakul, S. Effects of sleep restriction on metabolism-related parameters in healthy adults: a comprehensive review and meta-analysis of randomized controlled trials. Sleep Med. Rev. 45, 18–30 (2019).

    PubMed  Google Scholar 

  115. 115.

    Gavrila, A. et al. Diurnal and ultradian dynamics of serum adiponectin in healthy men: comparison with leptin, circulating soluble leptin receptor, and cortisol patterns. J. Clin. Endocrinol. Metab. 88, 2838–2843 (2003).

    CAS  PubMed  Google Scholar 

  116. 116.

    Knutson, K. L. & Van Cauter, E. Associations between sleep loss and increased risk of obesity and diabetes. Ann. NY Acad. Sci. 1129, 287–304 (2008).

    PubMed  Google Scholar 

  117. 117.

    Adam, T. C. & Epel, E. S. Stress, eating and the reward system. Physiol. Behav. 91, 449–458 (2007).

    CAS  PubMed  Google Scholar 

  118. 118.

    Young, E. A., Carlson, N. E. & Brown, M. B. Twenty-four-hour ACTH and cortisol pulsatility in depressed women. Neuropsychopharmacology 25, 267–276 (2001).

    CAS  PubMed  Google Scholar 

  119. 119.

    Heuser, I., Yassouridis, A. & Holsboer, F. The combined dexamethasone/CRH test: a refined laboratory test for psychiatric disorders. J. Psychiatr. Res. 28, 341–356 (1994).

    CAS  PubMed  Google Scholar 

  120. 120.

    Ising, M. et al. The combined dexamethasone/CRH test as a potential surrogate marker in depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 29, 1085–1093 (2005).

    CAS  PubMed  Google Scholar 

  121. 121.

    Krishnan, V. & Nestler, E. J. The molecular neurobiology of depression. Nature 455, 894–902 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Miller, A. H. Depression and immunity: a role for T cells? Brain Behav. Immun. 24, 1–8 (2010).

    CAS  PubMed  Google Scholar 

  123. 123.

    Koo, J. W. & Duman, R. S. IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc. Natl Acad. Sci. USA 105, 751–756 (2008).

    CAS  PubMed  Google Scholar 

  124. 124.

    Horowitz, M. A., Zunszain, P. A., Anacker, C., Musaelyan, K. & Pariante, C. M. Glucocorticoids and inflammation: a double-headed sword in depression? How do neuroendocrine and inflammatory pathways interact during stress to contribute to the pathogenesis of depression? Mod. Trends Pharmacopsychiatry 28, 127–143 (2013).

    CAS  PubMed  Google Scholar 

  125. 125.

    Munhoz, C. D. et al. Chronic unpredictable stress exacerbates lipopolysaccharide-induced activation of nuclear factor-kappaB in the frontal cortex and hippocampus via glucocorticoid secretion. J. Neurosci. 26, 3813–3820 (2006).

    CAS  PubMed  Google Scholar 

  126. 126.

    Pariante, C. M. Glucocorticoid receptor function in vitro in patients with major depression. Stress 7, 209–219 (2004).

    CAS  PubMed  Google Scholar 

  127. 127.

    Kenis, G. & Maes, M. Effects of antidepressants on the production of cytokines. Int. J. Neuropsychopharmacol. 5, 401–412 (2002).

    CAS  PubMed  Google Scholar 

  128. 128.

    Bjornsdottir, S. et al. Drug prescription patterns in patients with Addison’s disease: a Swedish population-based cohort study. J. Clin. Endocrinol. Metab. 98, 2009–2018 (2013).

    PubMed  Google Scholar 

  129. 129.

    Dunlop, D. Eighty-six cases of Addison’s disease. BMJ 2, 887–891 (1963).

    CAS  PubMed  Google Scholar 

  130. 130.

    Giordano, R. et al. Metabolic and cardiovascular profile in patients with Addison’s disease under conventional glucocorticoid replacement. J. Endocrinol. Invest. 32, 917–923 (2009).

    CAS  PubMed  Google Scholar 

  131. 131.

    Johannsson, G. et al. Adrenal insufficiency: review of clinical outcomes with current glucocorticoid replacement therapy. Clin. Endocrinol. 82, 2–11 (2015).

    CAS  Google Scholar 

  132. 132.

    Lovas, K., Loge, J. H. & Husebye, E. S. Subjective health status in Norwegian patients with Addison’s disease. Clin. Endocrinol. 56, 581–588 (2002).

    Google Scholar 

  133. 133.

    Feek, C. M. et al. Patterns of plasma cortisol and ACTH concentrations in patients with Addison’s disease treated with conventional corticosteroid replacement. Clin. Endocrinol. 14, 451–458 (1981).

    CAS  Google Scholar 

  134. 134.

    Isidori, A. M. et al. Effect of once-daily, modified-release hydrocortisone versus standard glucocorticoid therapy on metabolism and innate immunity in patients with adrenal insufficiency (DREAM): a single-blind, randomised controlled trial. Lancet Diabetes Endocrinol. 6, 173–185 (2018).

    CAS  PubMed  Google Scholar 

  135. 135.

    Bancos, I. et al. Primary adrenal insufficiency is associated with impaired natural killer cell function: a potential link to increased mortality. Eur. J. Endocrinol. 176, 471–480 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Bjanesoy, T. E. et al. Altered DNA methylation profile in Norwegian patients with autoimmune Addison’s disease. Mol. Immunol. 59, 208–216 (2014).

    CAS  PubMed  Google Scholar 

  137. 137.

    Langenheim, J., Ventz, M., Hinz, A. & Quinkler, M. Modified-release prednisone decreases complaints and fatigue compared to standard prednisolone in patients with adrenal insufficiency. Horm. Metab. Res. 45, 96–101 (2013).

    CAS  PubMed  Google Scholar 

  138. 138.

    Mallappa, A. et al. A phase 2 study of Chronocort, a modified-release formulation of hydrocortisone, in the treatment of adults with classic congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 100, 1137–1145 (2015).

    CAS  PubMed  Google Scholar 

  139. 139.

    Lovas, K. & Husebye, E. S. Continuous subcutaneous hydrocortisone infusion in Addison’s disease. Eur. J. Endocrinol. 157, 109–112 (2007).

    PubMed  Google Scholar 

  140. 140.

    Venneri, M. A. et al. Circadian rhythm of glucocorticoid administration entrains clock genes in immune cells: a DREAM trial ancillary study. J. Clin. Endocrinol. Metab. 103, 2998–3009 (2018).

    PubMed  Google Scholar 

  141. 141.

    Oksnes, M. et al. Continuous subcutaneous hydrocortisone infusion versus oral hydrocortisone replacement for treatment of Addison’s disease: a randomized clinical trial. J. Clin. Endocrinol. Metab. 99, 1665–1674 (2014).

    PubMed  Google Scholar 

  142. 142.

    Riedel, M., Wiese, A., Schurmeyer, T. H. & Brabant, G. Quality of life in patients with Addison’s disease: effects of different cortisol replacement modes. Exp. Clin. Endocrinol. 101, 106–111 (1993).

    CAS  PubMed  Google Scholar 

  143. 143.

    van Staa, T. P. et al. Use of oral corticosteroids in the United Kingdom. QJM 93, 105–111 (2000).

    PubMed  Google Scholar 

  144. 144.

    Overman, R. A., Yeh, J. Y. & Deal, C. L. Prevalence of oral glucocorticoid usage in the United States: a general population perspective. Arthritis Care Res. 65, 294–298 (2013).

    Google Scholar 

  145. 145.

    Curtis, J. R. et al. Population-based assessment of adverse events associated with long-term glucocorticoid use. Arthritis Rheum. 55, 420–426 (2006).

    PubMed  Google Scholar 

  146. 146.

    McDonough, A. K., Curtis, J. R. & Saag, K. G. The epidemiology of glucocorticoid-associated adverse events. Curr. Opin. Rheumatol. 20, 131–137 (2008).

    PubMed  Google Scholar 

  147. 147.

    Leung, D. Y. & Bloom, J. W. Update on glucocorticoid action and resistance. J. Allergy Clin. Immunol. 111, 3–22 (2003).

    CAS  PubMed  Google Scholar 

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Glossary

Zeitgebers

Cues that entrain or synchronize the body’s 24-h cycle

Ultradian rhythms

Biological rhythms that occur with a frequency of <24 h.

Circadian clock

A biochemical oscillator with phases synchronized with solar time.

Indirect projections

Neural pathways involving at least one relay.

Hypophyseal portal system

The microcirculation that allows transport of hypothalamic hormones to the pituitary gland.

Irradiance threshold

The threshold power of (solar) electromagnetic radiation needed to exert an effect.

Stereotypic behaviours

Repetitive body movements that serve no biological function.

Goal-directed behaviours

Behaviours engaged for a specific functional purpose.

Circadian rhythm

Any biological process that displays an oscillation of approximately 24 h.

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Russell, G., Lightman, S. The human stress response. Nat Rev Endocrinol 15, 525–534 (2019). https://doi.org/10.1038/s41574-019-0228-0

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