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.
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Chrousos GP, Gold PW. The concepts of stress and stress system disorders. Overv Phys Behav Homeost JAMA. 1992;267:1244–52.
Chrousos GP. Stress and disorders of the stress system. Nat Rev Endocrinol. 2009;5:374–81.
McEwen BS. Protective and damaging effects of stress mediators. N. Engl J Med. 1998;338:171–9.
Ulrich-Lai YM, Herman JP. Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci. 2009;10:397–409.
Elenkov IJ, Chrousos GP. Stress system organization, physiology and immunoregulation. Neuroimmunomodulation. 2006;13:257–67.
Joels M, Baram TZ. The neuro-symphony of stress. Nat Rev Neurosci. 2009;10:459–66.
McEwen BS. Stressed or stressed out: what is the difference? J Psychiatry Neurosci. 2005;30:315–8.
McEwen BS, Wingfield JC. The concept of allostasis in biology and biomedicine. Horm Behav. 2003;43:2–15.
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.
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.
Thayer JF, Sternberg E. Beyond heart rate variability: vagal regulation of allostatic systems. Ann N. Y Acad Sci. 2006;1088:361–72.
Nicolaides NC, Kyratzi E, Lamprokostopoulou A, Chrousos GP, Charmandari E. Stress, the stress system and the role of glucocorticoids. Neuroimmunomodulation. 2015;22:6–19.
Chrousos GP, Charmandari E, Kino T. Glucocorticoid action networks—an introduction to systems biology. J Clin Endocrinol Metab. 2004;89:563–4.
Gamble KL, Berry R, Frank SJ, Young ME. Circadian clock control of endocrine factors. Nat Rev Endocrinol. 2014;10:466–75.
Gan EH, Quinton R. Physiological significance of the rhythmic secretion of hypothalamic and pituitary hormones. Prog Brain Res. 2010;181:111–26.
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.
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.
Jacobson L. Hypothalamic-pituitary-adrenocortical axis regulation. Endocrinol Metab Clin North Am. 2005;34:271–92.
Charmandari E, Tsigos C, Chrousos G. Endocrinology of the stress response. Annu Rev Physiol. 2005;67:259–84.
ter Heegde F, De Rijk RH, Vinkers CH. The brain mineralocorticoid receptor and stress resilience. Psychoneuroendocrinology. 2015;52:92–110.
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.
Kino T, Chrousos GP. Circadian CLOCK-mediated regulation of target-tissue sensitivity to glucocorticoids: implications for cardiometabolic diseases. Endocr Dev. 2011;20:116–26.
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.
Fries E, Hesse J, Hellhammer J, Hellhammer DH. A new view on hypocortisolism. Psychoneuroendocrinology. 2005;30:1010–6.
McEwen BS. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev. 2007;87:873–904.
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.
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.
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.
Heim C, Ehlert U, Hellhammer DH. The potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders. Psychoneuroendocrinology. 2000;25:1–35.
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.
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.
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.
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.
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.
Zannas AS, Chrousos GP. Epigenetic programming by stress and glucocorticoids along the human lifespan. Mol Psychiatry. 2017;22:640–6.
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.
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.
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.
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.
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.
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.
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.
Cohen S, Janicki-Deverts D, Miller GE. Psychological stress and disease. JAMA. 2007;298:1685–7.
Liu YZ, Wang YX, Jiang CL. Inflammation: the common pathway of stress-related diseases. Front Hum Neurosci. 2017;11:316.
Glaser R, Kiecolt-Glaser JK. Stress-induced immune dysfunction: implications for health. Nat Rev Immunol. 2005;5:243–51.
Stojanovich L. Stress and autoimmunity. Autoimmun Rev. 2010;9:A271–6.
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.
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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
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