Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Expert Review
  • Published:

The neuroendocrinology of stress: the stress-related continuum of chronic disease development

Abstract

Stress is defined as a state of threatened homeodynamic balance by a wide range of intrinsic or extrinsic, real or perceived challenges or stimuli, defined as stressors. To preserve this optimal homeodynamic state within a physiologic range, organisms have developed a highly sophisticated system, the stress system, which serves self-regulation and adaptability of the organism by energy redirection according to the current needs. Repeated, ephemeral, and motivating stress states lead to adaptive responses and response habituations, being fairly beneficial; in contrast, inadequate, aversive, excessive, or prolonged stress may surpass the regulatory capacity and adjustive resources of the organism and produce maladaptive responses and a chronically altered homeodynamic state associated with compromised mental and physical health and life expectancy. Neuroendocrine responses to stress depend on developmental timing, duration, time of day and nature of stressors leading to a vulnerable phenotype with disrupted stress reactivity (i.e., hyper- or hypoactivation of the stress system), impaired glucocorticoid signaling, and accumulated cacostatic load with cumulatively elevated long-term risk of mental and physical morbidity. This article offers a brief overview on the organization and physiology of the human stress system and its (re)activity, refreshes the plethora of somatic effects of acute and chronic stress and discusses a conceptual model of acute and chronic stress pathophysiology as a continuum in chronic disease development.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Conceptional model of stress, homeodynamic (homeostatic) balance, and adaptive responses.
Fig. 2: Structural components and regulation of the central and peripheral stress system.
Fig. 3: Physiologic human cortisol levels and target tissue sensitivity along 24 h.
Fig. 4
Fig. 5: Hypothetical graphical models of the effects of adaptive, traumatic, and chronic stress-system activation on cortisol levels over time.

Similar content being viewed by others

References

  1. Chrousos GP, Gold PW. The concepts of stress and stress system disorders. Overv Phys Behav Homeost JAMA. 1992;267:1244–52.

    CAS  Google Scholar 

  2. Chrousos GP. Stress and disorders of the stress system. Nat Rev Endocrinol. 2009;5:374–81.

    Article  CAS  PubMed  Google Scholar 

  3. McEwen BS. Protective and damaging effects of stress mediators. N. Engl J Med. 1998;338:171–9.

    Article  CAS  PubMed  Google Scholar 

  4. Ulrich-Lai YM, Herman JP. Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci. 2009;10:397–409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Elenkov IJ, Chrousos GP. Stress system organization, physiology and immunoregulation. Neuroimmunomodulation. 2006;13:257–67.

    Article  CAS  PubMed  Google Scholar 

  6. Joels M, Baram TZ. The neuro-symphony of stress. Nat Rev Neurosci. 2009;10:459–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. McEwen BS. Stressed or stressed out: what is the difference? J Psychiatry Neurosci. 2005;30:315–8.

    PubMed  PubMed Central  Google Scholar 

  8. McEwen BS, Wingfield JC. The concept of allostasis in biology and biomedicine. Horm Behav. 2003;43:2–15.

    Article  PubMed  Google Scholar 

  9. Koolhaas JM, Bartolomucci A, Buwalda B, de Boer SF, Flügge G, Korte SM, et al. Stress revisited: a critical evaluation of the stress concept. Neurosci Biobehav Rev. 2011;35:1291–301.

    Article  CAS  PubMed  Google Scholar 

  10. Agorastos A, Nicolaides NC, Bozikas VP, Chrousos GP, Pervanidou P. Multilevel interactions of stress and circadian system: implications for traumatic stress. Front Psychiatry. 2019;10:1003.

    Article  PubMed  Google Scholar 

  11. Thayer JF, Sternberg E. Beyond heart rate variability: vagal regulation of allostatic systems. Ann N. Y Acad Sci. 2006;1088:361–72.

    Article  CAS  PubMed  Google Scholar 

  12. Nicolaides NC, Kyratzi E, Lamprokostopoulou A, Chrousos GP, Charmandari E. Stress, the stress system and the role of glucocorticoids. Neuroimmunomodulation. 2015;22:6–19.

    Article  CAS  PubMed  Google Scholar 

  13. Chrousos GP, Charmandari E, Kino T. Glucocorticoid action networks—an introduction to systems biology. J Clin Endocrinol Metab. 2004;89:563–4.

    Article  CAS  PubMed  Google Scholar 

  14. Gamble KL, Berry R, Frank SJ, Young ME. Circadian clock control of endocrine factors. Nat Rev Endocrinol. 2014;10:466–75.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Gan EH, Quinton R. Physiological significance of the rhythmic secretion of hypothalamic and pituitary hormones. Prog Brain Res. 2010;181:111–26.

    Article  CAS  PubMed  Google Scholar 

  16. Nader N, Chrousos GP, Kino T. Circadian rhythm transcription factor CLOCK regulates the transcriptional activity of the glucocorticoid receptor by acetylating its hinge region lysine cluster: potential physiological implications. FASEB J. 2009;23:1572–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Charmandari E, Chrousos GP, Lambrou GI, Pavlaki A, Koide H, Ng SS, et al. Peripheral CLOCK regulates target-tissue glucocorticoid receptor transcriptional activity in a circadian fashion in man. PLoS ONE. 2011;6:e25612.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Jacobson L. Hypothalamic-pituitary-adrenocortical axis regulation. Endocrinol Metab Clin North Am. 2005;34:271–92.

    Article  CAS  PubMed  Google Scholar 

  19. Charmandari E, Tsigos C, Chrousos G. Endocrinology of the stress response. Annu Rev Physiol. 2005;67:259–84.

    Article  CAS  PubMed  Google Scholar 

  20. ter Heegde F, De Rijk RH, Vinkers CH. The brain mineralocorticoid receptor and stress resilience. Psychoneuroendocrinology. 2015;52:92–110.

    Article  PubMed  Google Scholar 

  21. Wingenfeld K, Otte C. Mineralocorticoid receptor function and cognition in health and disease. Psychoneuroendocrinology. 2019;105:25–35. https://doi.org/10.1016/j.psyneuen.2018.09.010.

  22. Kino T, Chrousos GP. Circadian CLOCK-mediated regulation of target-tissue sensitivity to glucocorticoids: implications for cardiometabolic diseases. Endocr Dev. 2011;20:116–26.

    Article  CAS  PubMed  Google Scholar 

  23. Turner AI, Smyth N, Hall SJ, Torres SJ, Hussein M, Jayasinghe SU, et al. Psychological stress reactivity and future health and disease outcomes: a systematic review of prospective evidence. Psychoneuroendocrinology. 2020;114:104599.

    Article  PubMed  Google Scholar 

  24. Fries E, Hesse J, Hellhammer J, Hellhammer DH. A new view on hypocortisolism. Psychoneuroendocrinology. 2005;30:1010–6.

    Article  CAS  PubMed  Google Scholar 

  25. McEwen BS. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev. 2007;87:873–904.

    Article  PubMed  Google Scholar 

  26. Lupien SJ, McEwen BS, Gunnar MR, Heim C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci. 2009;10:434–45.

    Article  CAS  Google Scholar 

  27. Miller GE, Chen E, Zhou ES. If it goes up, must it come down? Chronic stress and the hypothalamic-pituitary-adrenocortical axis in humans. Psychol Bull. 2007;133:25–45.

    Article  PubMed  Google Scholar 

  28. Juruena MF, Eror F, Cleare AJ, Young AH. The role of early life stress in HPA axis and anxiety. Adv Exp Med Biol. 2020;1191:141–53.

    Article  CAS  PubMed  Google Scholar 

  29. Heim C, Ehlert U, Hellhammer DH. The potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders. Psychoneuroendocrinology. 2000;25:1–35.

    Article  CAS  PubMed  Google Scholar 

  30. Raison CL, Miller AH. When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. Am J Psychiatry. 2003;160:1554–65.

    Article  PubMed  Google Scholar 

  31. Herane-Vives A, Papadopoulos A, de Angel V, Chua KC, Soto L, Chalder T, et al. Cortisol levels in chronic fatigue syndrome and atypical depression measured using hair and saliva specimens. J Affect Disord. 2020;267:307–14.

    Article  CAS  PubMed  Google Scholar 

  32. Tak LM, Cleare AJ, Ormel J, Manoharan A, Kok IC, Wessely S, et al. Meta-analysis and meta-regression of hypothalamic-pituitary-adrenal axis activity in functional somatic disorders. Biol Psychol. 2011;87:183–94.

    Article  PubMed  Google Scholar 

  33. Herane-Vives A, Young AH, Wise T, Aguirre J, de Angel V, Arnone D, et al. Comparison of short-term (saliva) and long-term (hair) cortisol levels in out-patients with melancholic and non-melancholic major depression. BJPsych Open. 2020;6:e41.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Rohleder N. Stress and inflammation - The need to address the gap in the transition between acute and chronic stress effects. Psychoneuroendocrinology. 2019;105:164–71.

    Article  PubMed  Google Scholar 

  35. Zannas AS, Chrousos GP. Epigenetic programming by stress and glucocorticoids along the human lifespan. Mol Psychiatry. 2017;22:640–6.

    Article  CAS  PubMed  Google Scholar 

  36. Agorastos A, Pervanidou P, Chrousos GP, Baker DG. Developmental trajectories of early life stress and trauma: a narrative review on neurobiological aspects beyond stress system dysregulation. Front Psychiatry. 2019;10:118.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Youngoung ES, Doom JR, Farrell AK, Carlson EA, Englund MM, Miller GE, et al. Life stress and cortisol reactivity: An exploratory analysis of the effects of stress exposure across life on HPA-axis functioning. Dev Psychopathol. 2020;33:1–12.

    Google Scholar 

  38. Desantis AS, Kuzawa CW, Adam EK. Developmental origins of flatter cortisol rhythms: socioeconomic status and adult cortisol activity. Am J Hum Biol. 2015;27:458–67.

    Article  PubMed  Google Scholar 

  39. Kajantie E, Feldt K, Räikkönen K, Phillips DI, Osmond C, Heinonen K, et al. Body size at birth predicts hypothalamic-pituitary-adrenal axis response to psychosocial stress at age 60 to 70 years. J Clin Endocrinol Metab. 2007;92:4094–100.

    Article  CAS  PubMed  Google Scholar 

  40. Maercker A, Michael T, Fehm L, Becker ES, Margraf J. Age of traumatisation as a predictor of post-traumatic stress disorder or major depression in young women. Br J Psychiatry. 2004;184:482–7.

    Article  PubMed  Google Scholar 

  41. Chrousos GP, Kino T. Glucocorticoid signaling in the cell. Expanding clinical implications to complex human behavioral and somatic disorders. Ann N. Y Acad Sci. 2009;1179:153–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tsigos C, Stefanaki C, Lambrou GI, Boschiero D, Chrousos GP. Stress and inflammatory biomarkers and symptoms are associated with bioimpedance measures. Eur J Clin Invest. 2015;45:126–34.

    Article  CAS  PubMed  Google Scholar 

  43. Cohen S, Janicki-Deverts D, Miller GE. Psychological stress and disease. JAMA. 2007;298:1685–7.

    Article  CAS  PubMed  Google Scholar 

  44. Liu YZ, Wang YX, Jiang CL. Inflammation: the common pathway of stress-related diseases. Front Hum Neurosci. 2017;11:316.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Glaser R, Kiecolt-Glaser JK. Stress-induced immune dysfunction: implications for health. Nat Rev Immunol. 2005;5:243–51.

    Article  CAS  PubMed  Google Scholar 

  46. Stojanovich L. Stress and autoimmunity. Autoimmun Rev. 2010;9:A271–6.

    Article  CAS  PubMed  Google Scholar 

  47. Geiker NRW, Astrup A, Hjorth MF, Sjodin A, Pijls L, Markus CR. Does stress influence sleep patterns, food intake, weight gain, abdominal obesity and weight loss interventions and vice versa? Obes Rev. 2018;19:81–97.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Agorastos Agorastos.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Agorastos, A., Chrousos, G.P. The neuroendocrinology of stress: the stress-related continuum of chronic disease development. Mol Psychiatry 27, 502–513 (2022). https://doi.org/10.1038/s41380-021-01224-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-021-01224-9

This article is cited by

Search

Quick links