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The human stress response


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.


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The authors contributed equally to all aspects of the article.

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Correspondence to Georgina Russell or Stafford Lightman.

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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).

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