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Stress and disorders of the stress system

Nature Reviews Endocrinology volume 5, pages 374–381 (2009)Cite this article

Abstract

All organisms must maintain a complex dynamic equilibrium, or homeostasis, which is constantly challenged by internal or external adverse forces termed stressors. Stress occurs when homeostasis is threatened or perceived to be so; homeostasis is re-established by various physiological and behavioral adaptive responses. Neuroendocrine hormones have major roles in the regulation of both basal homeostasis and responses to threats, and are involved in the pathogenesis of diseases characterized by dyshomeostasis or cacostasis. The stress response is mediated by the stress system, partly located in the central nervous system and partly in peripheral organs. The central, greatly interconnected effectors of this system include the hypothalamic hormones arginine vasopressin, corticotropin-releasing hormone and pro-opiomelanocortin-derived peptides, and the locus ceruleus and autonomic norepinephrine centers in the brainstem. Targets of these effectors include the executive and/or cognitive, reward and fear systems, the wake–sleep centers of the brain, the growth, reproductive and thyroid hormone axes, and the gastrointestinal, cardiorespiratory, metabolic, and immune systems. Optimal basal activity and responsiveness of the stress system is essential for a sense of well-being, successful performance of tasks, and appropriate social interactions. By contrast, excessive or inadequate basal activity and responsiveness of this system might impair development, growth and body composition, and lead to a host of behavioral and somatic pathological conditions.

Key Points

  • Stress occurs when homeostasis is threatened or perceived to be so

  • The stress response is mediated by the stress system, which is located in both the central nervous system and peripheral organs

  • The main central effectors of the stress system are highly interconnected, and include hypothalamic corticotropin-releasing hormone and brainstem-derived norepinephrine

  • Malfunction of the stress system is associated with behavioral and somatic disorders

  • Stress is a major contributor to psychosocial and physical pathological conditions in humans

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Figure 1: Homeostatic systems exert their effects in an inverse, U-type dose response.2
Figure 2: Chronic stress can lead to development of the metabolic syndrome.35

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References

  1. Raisman, G. An urge to explain the incomprehensible: Geoffrey Harris and the discovery of the neural control of the pituitary gland. Ann. Rev. Neurosci. 20, 533–566 (1997).

    Article  CAS  Google Scholar 

  2. Chrousos, G. P. & Gold, P. W. The concepts of stress and stress system disorders: overview of physical and behavioral homeostasis. JAMA 267, 1244–1252 (1992).

    Article  CAS  Google Scholar 

  3. Charmandari, E., Tsigos, C. & Chrousos, G. P. Neuroendocrinology of stress. Ann. Rev. Physiol. 67, 259–284 (2005).

    Article  CAS  Google Scholar 

  4. Chrousos, G. P., Loriaux, D. L. & Gold, P. W. (eds) Mechanisms of Physical and Emotional Stress (Advances in Experimental Medicine and Biology, Vol. 245) (Plenum Press, New York, 1988).

    Book  Google Scholar 

  5. Chrousos, G. P. et al. (eds) Stress: Basic Mechanisms and Clinical Implications (Annals of the New York Academy of Sciences, Vol. 771) (New York Academy of Sciences, New York, 1996).

    Google Scholar 

  6. Chrousos, G. P. The hypothalamic–pituitary–adrenal axis and immune-mediated inflammation. N. Engl. J. Med. 332, 1351–1362 (1995).

    Article  CAS  Google Scholar 

  7. Chrousos, G. P. 1997 Hans Selye memorial lecture: stressors, stress and neuroendocrine integration of the adaptive response. Ann. NY Acad. Sci. 851, 311–335 (1998).

    Article  CAS  Google Scholar 

  8. Chrousos, G. P. The stress response and immune function: clinical implications; the 1999 Novera H. Spector lecture. Ann. NY Acad. Sci. 917, 38–67 (2000).

    Article  CAS  Google Scholar 

  9. Karalis, C. et al. Autocrine or paracrine inflammatory actions of corticotropin releasing hormone in vivo . Science 254, 421–423 (1991).

    Article  CAS  Google Scholar 

  10. Papanicolaou, D. A., Wilder, R. L., Manolagas, S. C. & Chrousos, G. P. The pathophysiologic roles of interleukin-6 in humans. Ann. Intern. Med. 128, 127–137 (1998).

    Article  CAS  Google Scholar 

  11. Vale, W., Spiess, J., Rivier, C. & Rivier, J. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and β-endorphin. Science 213, 1394–1397 (1981).

    Article  CAS  Google Scholar 

  12. Chrousos, G. P. Organization and integration of the endocrine system: the sleep and wakefulness perspective. Sleep Med. Clin. 2, 125–145 (2007).

    Article  Google Scholar 

  13. Makino, S. et al. Psychological stress increased corticotropin-releasing hormone mRNA and content in the central nucleus of the amygdala but not in the hypothalamic paraventricular nucleus in the rat. Brain Res. 850, 136–143 (1999).

    Article  CAS  Google Scholar 

  14. LeDoux, J. E. Emotion and the amygdala. In The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction (Ed. Aggleton, J. P.) 339–351 (Wiley-Liss, New York, 1992).

    Google Scholar 

  15. Morgan, M., Romanski, L. & LeDoux, J. Extinction of emotional learning: contribution of medial prefrontal cortex. Neurosci. Lett. 163, 109–113 (1993).

    Article  CAS  Google Scholar 

  16. Morgan, M. & LeDoux, J. E. Differential contribution of dorsal and ventral medial prefrontal cortex to the acquisition and extinction of conditioned fear. Behav. Neurosci. 109, 681–688 (1995).

    Article  CAS  Google Scholar 

  17. Sullivan, R. M. & Gratton, A. Lateralized effects of medial prefrontal cortex lesions on neuroendocrine and autonomic stress responses in rats. J. Neurosci. 19, 2834–2840 (1999).

    Article  CAS  Google Scholar 

  18. Fuster, J. M. The prefrontal cortex. An update: time is of the essence. Neuron 30, 319–333 (2001).

    Article  CAS  Google Scholar 

  19. Kalivas, P. W. & Volkow, N. D. The neural basis of addiction: a pathology of motivation and choice. Am. J. Psychiatry 162, 1403–1413 (2005).

    Article  Google Scholar 

  20. McEwen, B. S. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol. Rev. 87, 873–904 (2007).

    Article  Google Scholar 

  21. Vgontzas, A. N. et al. Sleep deprivation effects on the activity of the hypothalamic–pituitary–adrenal and growth axes: potential clinical implications. Clin. Endocrinol. (Oxf.), 51, 205–215 (1999).

    Article  CAS  Google Scholar 

  22. Vgontzas, A. N. et al. Circadian interleukin-6 secretion and quality and depth of sleep. J. Clin. Endocrinol. Metab. 84, 2603–2607 (1999).

    Article  CAS  Google Scholar 

  23. Vgontzas, A. N. et al. Impaired nighttime sleep is associated with elevated plasma IL-6 and cortisol levels in healthy old vs. young adults: physiologic and therapeutic implications. J. Clin. Endocrinol. Metab. 88, 2087–2095 (2003).

    Article  CAS  Google Scholar 

  24. Vgontzas, A. et al. Adverse effects of modest sleep restriction on sleepiness, performance, and inflammatory cytokines. J. Clin. Endocrinol. Metab. 89, 2119–2126 (2004).

    Article  CAS  Google Scholar 

  25. Vgontzas, A. N. et al. Daytime napping after a night of sleep loss decreases sleepiness, improves performance, and causes beneficial changes in cortisol and interleukin-6 secretion. Am. J. Physiol. Endocrinol. Metab. 292, E253–E261 (2007).

    Article  CAS  Google Scholar 

  26. Vgontzas, A. N. & Chrousos, G. P. Sleep, the hypothalamic–pituitary–adrenal axis, and cytokines: multiple interactions and disturbances in sleep disorders. Endocrinol. Metab. Clin. North Am. 31, 15–36 (2002).

    Article  CAS  Google Scholar 

  27. Chrousos, G. P., Torpy, D. & Gold, P. W. Interactions between the hypothalamic–pituitary–adrenal axis and the female reproductive system: clinical implications. Ann. Intern. Med. 129, 229–240 (1998).

    Article  CAS  Google Scholar 

  28. Taché, Y. & Bonaz, B. Corticotropin-releasing factor receptors and stress-related alterations of gut motor function. J. Clin. Invest. 117, 33–40 (2007).

    Article  Google Scholar 

  29. Elenkov, I. J., Papanicolaou, D. A., Wilder, R. L. & Chrousos, G. P. Modulatory effects of glucocorticoids and catecholamines on human interleukin-12 and interleukin-10 production: clinical implications. Proc. Assoc. Am. Phys. 108, 374–381 (1996).

    CAS  PubMed  Google Scholar 

  30. Elenkov, I. J. & Chrousos, G. P. Stress hormones, TH1/TH2-patterns, pro/anti- inflammatory cytokines and susceptibility to disease. Trends Endocrinol. Metab. 10, 359–368 (1999).

    Article  CAS  Google Scholar 

  31. Elenkov, I. J. et al. Low versus high baseline epinephrine output shapes opposite innate cytokine profiles: presence of Lewis- and Fischer-like neurohormonal-immune phenotypes in humans. J. Immunol. 181, 1737–1745 (2008).

    Article  CAS  Google Scholar 

  32. Theoharides, T. C. et al. Corticotropin-releasing hormone induces skin mast cell degranulation and increased vascular permeability, a possible explanation for its proinflammatory effects. Endocrinology 139, 403–413 (1998).

    Article  CAS  Google Scholar 

  33. Theoharides, T. C. et al. Stress-induced intracranial mast cell degranulation. A corticotropin-releasing hormone-mediated effect. Endocrinology 136, 5745–5750 (1995).

    Article  CAS  Google Scholar 

  34. Franchimont, D., Kino, T., Galon, J., Meduri, G. U. & Chrousos, G. P. Glucocorticoids and inflammation revisited. NIH Clinical Staff Conference. Neuroimmunomodulation 10, 247–260 (2003).

    Article  CAS  Google Scholar 

  35. Chrousos, G. P. & Kino, T. Intracellular glucocorticoid signaling: a formerly simple system turns stochastic. Sci. STKE 304, pe48 (2005).

    Google Scholar 

  36. Chrousos, G. P. & Kino, T. Glucocorticoid action networks and complex psychiatric and/or somatic disorders. Stress 10, 213–219 (2007).

    Article  CAS  Google Scholar 

  37. Levine, S. The pituitary–adrenal system and the developing brain. Prog. Brain Res. 32, 79–85 (1970).

    Article  CAS  Google Scholar 

  38. Newport, D. J., Stowe, Z. N. & Nemeroff, C. B. Parental depression: animal models of an adverse life event. Am. J. Psychiatry 159, 1265–1283 (2002).

    Article  Google Scholar 

  39. Szyf, M., Weaver, I. C., Champagne, F. A., Diorio, J. & Meaney, M. J. Maternal programming of steroid receptor expression in the rat. Front. Neuroendocrinol. 26, 139–162 (2005).

    Article  CAS  Google Scholar 

  40. Champagne, F. A. et al. Maternal care associated with methylation of the estrogen receptor-α1b promoter and estrogen receptor-α expression in the medial preoptic area of female offspring. Endocrinology 147, 2909–2915 (2006).

    Article  CAS  Google Scholar 

  41. Gold, P. W., Goodwin, F. & Chrousos, G. P. Clinical and biochemical manifestations of depression: relationship to the neurobiology of stress (Part I). N. Engl. J. Med. 319, 348–353 (1988).

    Article  CAS  Google Scholar 

  42. Gold, P. W., Goodwin, F. & Chrousos, G. P. Clinical and biochemical manifestations of depression: relationship to the neurobiology of stress (Part 2). N. Engl. J. Med. 319, 413–420 (1988).

    Article  CAS  Google Scholar 

  43. Gold, P. W. et al. Cardiac implications of increased arterial entry and reversible 24-h central and peripheral norepinephrine levels in melancholia. Proc. Natl Acad. Sci. USA 102, 8303–8308 (2005).

    Article  CAS  Google Scholar 

  44. Wong, M.-L. et al. Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to hypercortisolism and corticotropin releasing hormone. Proc. Natl Acad. Sci. USA 97, 325–330 (2000).

    Article  CAS  Google Scholar 

  45. Alesci, S. et al. Major depression is associated with significant diurnal elevations in plasma IL-6 levels, a shift of its circadian rhythm, and loss of physiologic complexity in its secretion: clinical implications. J. Clin. Endocrinol. Metab. 90, 2522–2530 (2005).

    Article  CAS  Google Scholar 

  46. Vgontzas, A. et al. Chronic insomnia is associated with nyctohemeral activation of the hypothalamic–pituitary–adrenal axis. J. Clin. Endocrinol. Metab. 86, 3787–3794 (2001).

    Article  CAS  Google Scholar 

  47. Vgontzas, A. N. et al. Chronic insomnia is associated with a shift of IL-6 and TNFα secretion from nighttime to daytime. Metabolism 29, 1252–1261 (2002).

    Google Scholar 

  48. Charmandari, E., Kino, T., Souvatzoglou, E. & Chrousos, G. P. Pediatric stress: hormonal mediators and human development. Hormone Res. 59, 161–179 (2003).

    Article  CAS  Google Scholar 

  49. Chrousos, G. P. The role of stress and the hypothalamic–pituitary–adrenal axis in the pathogenesis of the metabolic syndrome: neuro-endocrine and target tissue-related causes. Int. J. Obes. (London) 24, S50f–S55f (2000).

    Article  Google Scholar 

  50. Chrousos, G. P. & Tsigos, C. (Eds) Annals of the New York Academy of Sciences, Stress, Obesity, and Metabolic Syndrome, Vol. 1083 (Wiley Blackwell, Hoboken, 2006).

    Google Scholar 

  51. Vgontzas, A. N. et al. Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity. J. Clin. Endocrinol. Metab. 82, 1313–1316 (1997).

    Article  CAS  Google Scholar 

  52. Vgontzas, A. N. et al. Sleep apnea and daytime sleepiness and fatigue: relations with visceral obesity, insulin resistance, and hypercytokinemia, J . Clin. Endocrinol. Metab. 85, 1151–1158 (2000).

    Article  CAS  Google Scholar 

  53. De Bellis, M. D. et al. Hypothalamic–pituitary–adrenal dysregulation in sexually abused girls. J. Clin. Endocrinol. Metab. 78, 249–255.

  54. Pervanidou, P. et al. The natural history of neuroendocrine changes in pediatric post-traumatic stress disorder (PTSD) after motor vehicle accidents: progressive divergence of noradrenaline and cortisol concentrations over time. Biol. Psychiatry 62, 1095–1102 (2007).

    Article  CAS  Google Scholar 

  55. Pervanidou, P. et al. Elevated morning serum interleukin (IL)-6 or evening salivary cortisol concentrations predict posttraumatic stress disorder in children and adolescents six months after a motor vehicle accident. Psychoneuroendocrinology 32, 991–999 (2007).

    Article  CAS  Google Scholar 

  56. Grundy, D. et al. Fundamentals of neurogastroenterology: basic science. Gastroenterology 130, 1391–1411 (2006).

    Article  CAS  Google Scholar 

  57. Habib, K. E. et al. Oral administration of a CRH receptor antagonist significantly attenuates behavioral, neuroendocrine, and autonomic responses to stress in primates. Proc. Natl Acad. Sci. USA 10, 1073–1079 (2000).

    Google Scholar 

  58. Webster, E. L. et al. Corticotropin-releasing hormone (CRH) antagonist attenuates adjuvant-induced arthritis: evidence supporting major role for CRH in peripheral inflammation. J. Rheumatol. 29, 1252–1261 (2002).

    CAS  PubMed  Google Scholar 

  59. Gabry, K. E. et al. Marked suppression of gastric ulcerogenesis and intestinal responses to stress by a novel class of drugs. Mol. Psychiatry 7, 474–483 (2002).

    Article  CAS  Google Scholar 

  60. Grammatopoulos, D. & Chrousos, G. P. Structural and signalling diversity of corticotropin-releasing hormone (CRH) and related peptides and their receptors: potential clinical applications of CRH receptor antagonists. Trends Endocrinol. Metab. 13, 436–444 (2002).

    Article  CAS  Google Scholar 

  61. Contoreggi, C., Rice, K. C. & Chrousos, G. P. Non-peptide corticotropin-releasing hormone receptor type 1 antagonists and their applications in psychosomatic disorders. Neuroendocrinology 80, 111–123 (2004).

    Article  CAS  Google Scholar 

  62. Zoumakis, E., Grammatopoulos, D. & Chrousos, G. Corticotropin-releasing hormone antagonists. Eur. J. Endocrinol. 155 (Suppl. 1), S85–S90 (2006).

    Article  CAS  Google Scholar 

  63. Clauw, D. J. & Chrousos, G. P. Chronic pain and fatigue syndromes: overlapping clinical and neuroendocrine features and potential pathogenic mechanisms. Neuroimmunomodulation 4, 134–153 (1997).

    Article  CAS  Google Scholar 

  64. Magiakou, M. A. et al. Hypothalamic corticotropin releasing hormone suppression during the postpartum period: implications for the increase of psychiatric manifestations during this time. J. Clin. Endocrinol. Metab. 81, 1912–1917 (1996).

    CAS  PubMed  Google Scholar 

  65. Elenkov, I. J. et al. Interleukin 12, tumor necrosis factor-α and hormonal changes during late pregnancy and early postpartum: implications for autoimmune disease activity during these times. J. Clin. Endocrinol. Metab. 86, 4933–4938 (2001).

    CAS  PubMed  Google Scholar 

  66. Gold, P. W. & Chrousos, G. P. The endocrinology of melancholic and atypical depression: relation to neurocircuitry and somatic consequences. Proc. Assoc. Am. Physicians 111, 22–34 (1999).

    Article  CAS  Google Scholar 

  67. Gold, P. W., Gabry, K. E., Yasuda, M. R. & Chrousos, G. P. Divergent endocrine abnormalities in melancholic and atypical depression: clinical and pathophysiologic implications. Endocrinol. Metab. Clin. North Am. 31, 37–62 (2002).

    Article  CAS  Google Scholar 

  68. Chrousos, G. The glucocorticoid receptor gene, longevity, and the highly prevalent complex disorders of western societies. Am. J. Med. 117, 204–207 (2004).

    Article  CAS  Google Scholar 

  69. Brown, G. R. & Anderson, B. Psychiatric morbidity in adult inpatients with childhood histories of sexual and physical abuse. Am. J. Psychiatry 148, 55–61 (1991).

    Article  CAS  Google Scholar 

  70. Smith, G. D., Hart, C., Blane, D. & Hole, D. Adverse socioeconomic conditions in childhood and cause specific adult mortality: prospective observation study. BMJ 316, 1631–1635 (1998).

    Article  CAS  Google Scholar 

  71. Felitti, V. J. et al. Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. Am. J. Prevent. Med. 14, 245–258 (1998).

    Article  CAS  Google Scholar 

  72. Repetti, R. L., Taylor, S. E. & Seeman, T. E. Risky families: family social environments and the mental and physical health of offspring. Psych. Bull. 128, 330–366 (2002).

    Article  Google Scholar 

  73. Banks, J., Marmot, M., Oldfield Z. & Smith, J. P. Disease and disadvantage in the United States and in England. JAMA 295, 2037–2045 (2006).

    Article  CAS  Google Scholar 

  74. Flegal, K. M., Graubard, B. I., Williamson, D. F. & Gail, M. H. Excess deaths associated with underweight, overweight, and obesity. JAMA 298, 1861–1867 (2005).

    Article  Google Scholar 

  75. Warren, J. Presocratics: Natural Philosophers before Socrates (University of California, Berkeley, 2007).

    Google Scholar 

  76. Cannon, W. B. The Wisdom of the Body edn 2 (W. W. Norton, New York, 1939).

    Book  Google Scholar 

  77. Cannon, W. B. The Way of an Investigator (Hafner, New York, 1968).

    Google Scholar 

  78. Wolfe, E. L., Barger, A. C. & Benison, S. Walter B. Cannon: Science and Society (Harvard University Press, Cambridge, 2000).

    Google Scholar 

  79. Selye, H. A syndrome produced by diverse nocuous agents. J. Neuropsychiatry Clin. Neurosci. 138, 230–231 (1936).

    Google Scholar 

  80. Selye, H. The Stress of Life (McGraw-Hill, New York, 1956).

    Google Scholar 

  81. Landau, L. D., Pitaevskii, L. P., Lifshitz, E. M. & Kosevich, A. M. Theory of Elasticity edn 3 (Butterworth-Heinemann, Oxford, 1986).

    Google Scholar 

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Acknowledgements

This review is partially based on the Geoffrey Harris Memorial Lecture given by the author at the 10th European Congress of Endocrinology, 3–7 May 2008, Berlin, Germany.

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  1. G. P. Chrousos, First Department of Pediatrics, Aghia Sophia Children's Hospital, University of Athens, Thivon and Mikras Asias Streets, Athens 11527, Greece chrousge@med.uoa.gr

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    George P. Chrousos

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Chrousos, G. Stress and disorders of the stress system. Nat Rev Endocrinol 5, 374–381 (2009). https://doi.org/10.1038/nrendo.2009.106

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