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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Chronic stress activation may compromise the immune functional balance and lead to dysregulation of inflammatory status and cell-mediated immunity.
“However, chronic stress activation may compromise the immune functional balance through setting different internal set-points and lead to a dysregulation of the inflammatory status and the cell-mediated immunity, together with other stress-related neurobiological and neuroendocrine responses [8,9,10].”
Cites
Protective and Damaging Effects of Stress Mediators
McEwen, B. S. (1998) · New England Journal of Medicine · doi:10.1056/nejm199801153380307 · Cited by 6,733 · see citing works
Effects of stress throughout the lifespan on the brain, behaviour and cognition
Lupien, S. J., McEwen, B. S., Gunnar, M. R., & Heim, C. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2639 · Cited by 6,256 · see citing works
Physiology and neurobiology of stress and adaptation: central role of the brain
McEwen, B. S. (2007) · Physiological Reviews · doi:10.1152/physrev.00041.2006 · Cited by 4,981 · see citing works
The concept of allostasis in biology and biomedicine
McEwen, B. S., & Wingfield, J. C. (2003) · Hormones and Behavior · doi:10.1016/s0018-506x(02)00024-7 · Cited by 3,302 · see citing works
Stress and disorders of the stress system
Chrousos, G. P. (2009) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2009.106 · Cited by 3,215 · see citing works
Self-citationMiller, G. E., Chen, E., & Zhou, E. S. (2007) · Psychological Bulletin · doi:10.1037/0033-2909.133.1.25 · Cited by 2,467 · see citing works
Stress revisited: a critical evaluation of the stress concept
Koolhaas, J. M., Bartolomucci, A., Buwalda, B., de Boer, S. F., Flügge, G., Korte, S. M., Meerlo, P., Murison, R., Olivier, B., Palanza, P., et al. (2011) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2011.02.003 · Cited by 1,626 · see citing works
Stressed or Stressed out: What Is the Difference?
McEwen, B. S. (2005) · Journal of Psychiatry and Neuroscience · doi:10.1139/jpn.0540 · Cited by 593 · see citing works
Turner, A. I., Smyth, N., Hall, S. J., Torres, S. J., Hussein, M., Jayasinghe, S. U., Ball, K., & Clow, A. J. (2020) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2020.104599 · Cited by 503 · see citing works
Agorastos, A., Pervanidou, P., Chrousos, G. P., & Baker, D. G. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00118 · Cited by 385 · see citing works
Self-citationHypothalamic-pituitary-adrenocortical axis regulation
Jacobson, L. (2005) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2005.01.003 · Cited by 248 · see citing works
Charmandari, E., Chrousos, G. P., Lambrou, G. I., Pavlaki, A., Koide, H., Ng, S. S. M., & Kino, T. (2011) · PLoS ONE · doi:10.1371/journal.pone.0025612 · Cited by 139 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Mentis, A.-F. A., Lee, D., & Roussos, P. (2024) · Molecular Psychiatry · doi:10.1038/s41380-023-02047-6 · Cited by 75 · see citing works
Algaidi, S. A. (2025) · Brain Research · doi:10.1016/j.brainres.2025.149461 · Cited by 40 · see citing works
Testosterone and cortisol responses to acute and prolonged stress during officer training school
Zueger, R., Annen, H., & Ehlert, U. (2023) · Stress · doi:10.1080/10253890.2023.2199886 · Cited by 25 · see citing works
Gonzalez-Gomez, R., Cruzat, J., Hernández, H., Migeot, J., Legaz, A., Santamaria-García, H., Fittipaldi, S., Maito, M. A., Medel, V., Tagliazucchi, E., et al. (2025) · eClinicalMedicine · doi:10.1016/j.eclinm.2025.103187 · Cited by 19 · see citing works
Koureta, A., Asimakopoulos, L. O., Bozikas, V. P., & Agorastos, A. (2023) · Brain Sciences · doi:10.3390/brainsci13030448 · Cited by 12 · see citing works
Self-citationMatthaeus, H., Heim, C., Voelkle, M. C., & Singer, T. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1277929 · Cited by 6 · see citing works
Demori, I., Siriya, S., & Burlando, B. (2025) · Applied Sciences · doi:10.3390/app151910483 · Cited by 2 · see citing works
Romance Fraud: Its Repercussions on Victims’ Wellbeing
Gauci, C., & Vella, M. G. (2025) · Women & Criminal Justice · doi:10.1080/08974454.2025.2600304 · Cited by 2 · see citing works
- Authors
- Agorastos, A., & Chrousos, G. P.
- Affiliations
- Aristotle University of Thessaloniki (GR)
- National and Kapodistrian University of Athens (GR)
- Corresponding author
- Agorastos, Agorastos
- Venue
- Molecular Psychiatry
- Published
- 2021-07-21
- Volume
- 27
- Issue
- 1
- Pages
- 502-513
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- OpenAlex
- W3186176846
- Cited by
- 462
- References
- 12
- Citations by year
- 2026: 107 · 2025: 149 · 2024: 109 · 2023: 68 · 2022: 23 · 2021: 4 · 2020: 1
- FWCI
- 6.20
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- stress, neuroendocrinology, stress system, homeostatic balance, stress reactivity, glucocorticoid signaling, chronic stress, acute stress, maladaptive stress response, stressors, mental health, physical health
- MeSH terms
- Chronic Disease, Glucocorticoids, Humans, Neuroendocrinology, Neurosecretory Systems, Stress, Physiological, Stress, Psychological
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
