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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.

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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.

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Correspondence to Agorastos Agorastos.

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Agorastos, A., Chrousos, G.P. The neuroendocrinology of stress: the stress-related continuum of chronic disease development. Mol Psychiatry (2021). https://doi.org/10.1038/s41380-021-01224-9

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