The human stress response
Open accessAbstract
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.
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Circulating glucocorticoids such as cortisol fluctuate with circadian and ultradian periodicity, reaching maximal values during the waking period and progressively decreasing during the day before rising again at night.
“circulating levels of glucocorticoids such as cortisol (CORT) fluctuate with circadian and ultradian periodicity, reaching maximal values during the waking period and progressively decreasing during the day before rising again at night ( 1 ).”
From Dynamic modulation of glucose utilisation by glucocorticoid rhythms in health and disease (2020) · cites this paper as [1]
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- Authors
- Russell, G., & Lightman, S.
- Affiliations
- University of Bristol (GB)
- Corresponding author
- Russell, Georgina
- Lightman, Stafford
- Venue
- Nature Reviews Endocrinology
- Published
- 2019-06-27
- Volume
- 15
- Issue
- 9
- Pages
- 525-534
- ISSN
- 1759-5029 (ISSN-L)
- 1759-5037
- OpenAlex
- W2954122547
- Cited by
- 1,032
- References
- 23
- Citations by year
- 2026: 158 · 2025: 246 · 2024: 199 · 2023: 148 · 2022: 103 · 2021: 117 · 2020: 56 · 2019: 5
- FWCI
- 8.14
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- Nature Reviews Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (acceptedVersion, other-oa)
- Funders
- Medical Research Council (MR/J012548/1)
- Engineering and Physical Sciences Research Council (EP/N014391/1)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- stress response, hypothalamic-pituitary-adrenal axis, cortisol, circadian rhythm, ACTH, corticotropin-releasing factor, vasopressin, chronic stress, acute stress, fight-or-flight response, homeostasis, metabolic syndrome, obesity, mental illness, cardiovascular disease, infection susceptibility
- MeSH terms
- Circadian Rhythm, Humans, Hypothalamo-Hypophyseal System, Pituitary-Adrenal System, Stress, Physiological, Stress, Psychological, Hormone Replacement Therapy
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