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Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress
Abstract
The stress system coordinates the adaptive responses of the organism to stressors of any kind.(1). The main components of the stress system are the corticotropin-releasing hormone (CRH) and locus ceruleus-norepinephrine (LC/NE)-autonomic systems and their peripheral effectors, the pituitary-adrenal axis, and the limbs of the autonomic system. Activation of the stress system leads to behavioral and peripheral changes that improve the ability of the organism to adjust homeostasis and increase its chances for survival. The CRH and LC/NE systems stimulate arousal and attention, as well as the mesocorticolimbic dopaminergic system, which is involved in anticipatory and reward phenomena, and the hypothalamic beta-endorphin system, which suppresses pain sensation and, hence, increases analgesia. CRH inhibits appetite and activates thermogenesis via the catecholaminergic system. Also, reciprocal interactions exist between the amygdala and the hippocampus and the stress system, which stimulates these elements and is regulated by them. CRH plays an important role in inhibiting GnRH secretion during stress, while, via somatostatin, it also inhibits GH, TRH and TSH secretion, suppressing, thus, the reproductive, growth and thyroid functions. Interestingly, all three of these functions receive and depend on positive catecholaminergic input. The end-hormones of the hypothalamic-pituitary-adrenal (HPA) axis, glucocorticoids, on the other hand, have multiple roles. They simultaneously inhibit the CRH, LC/NE and beta-endorphin systems and stimulate the mesocorticolimbic dopaminergic system and the CRH peptidergic central nucleus of the amygdala. In addition, they directly inhibit pituitary gonadotropin, GH and TSH secretion, render the target tissues of sex steroids and growth factors resistant to these substances and suppress the 5' deiodinase, which converts the relatively inactive tetraiodothyronine (T(4)) to triiodothyronine (T(3)), contributing further to the suppression of reproductive, growth and thyroid functions. They also have direct as well as insulin-mediated effects on adipose tissue, ultimately promoting visceral adiposity, insulin resistance, dyslipidemia and hypertension (metabolic syndrome X) and direct effects on the bone, causing "low turnover" osteoporosis. Central CRH, via glucocorticoids and catecholamines, inhibits the inflammatory reaction, while directly secreted by peripheral nerves CRH stimulates local inflammation (immune CRH). CRH antagonists may be useful in human pathologic states, such as melancholic depression and chronic anxiety, associated with chronic hyperactivity of the stress system, along with predictable behavioral, neuroendocrine, metabolic and immune changes, based on the interrelations outlined above. Conversely, potentiators of CRH secretion/action may be useful to treat atypical depression, postpartum depression and the fibromyalgia/chronic fatigue syndromes, all characterized by low HPA axis and LC/NE activity, fatigue, depressive symptomatology, hyperalgesia and increased immune/inflammatory responses to stimuli.
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“In the brain, glucocorticoids interact with high-affinity mineralocorticoid receptors and lower affinity glucocorticoid receptors (Herman et al., 2016;Smith and Vale, 2006;Tsigos and Chrousos, 2002).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Tsigos and Chrousos, 2002
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In the citing paper
“Such beliefs engender misdirected coping behavior and have profound physiological consequences, including a dysregulation of cerebral control over endocrine and autonomic nervous system processes (e.g., aberrant activation of the hypothalamic-pituitary axis; HPA; Tsigos and Chrousos, 2002).”
From Allostatic Self-efficacy: A Metacognitive Theory of Dyshomeostasis-Induced Fatigue and Depression (2016) · cites this paper as Tsigos and Chrousos, 2002
Experimental — accuracy not yet measuredIn the citing paper
“The vagal afferent pathways are involved in the activation/regulation of the HPA axis (29), which coordinates the adaptive responses of the organism to stressors of any kind (30).”
From Vagus Nerve as Modulator of the Brain–Gut Axis in Psychiatric and Inflammatory Disorders (2018) · cites this paper as [30]
In the citing paper
“An important interplay is also the excitatory reciprocal interaction between the HPA axis and the brainstem sympathetic locus coeruleus (LC)-norepinephrine (NE) system: CRH activates the LC; in turn, NE, a known wake-promoting neurotransmitter, activates hypothalamic CRH [9, 10].”
From Impact of Sleep and Its Disturbances on Hypothalamo-Pituitary-Adrenal Axis Activity (2010) · cites this paper as [9]
In the citing paper
“acteristic frequencies: ultradian oscillations, with a period of 20-120 min [4-6] superimposed on circadian oscillations, with a period of about 24 h.”
From Predictive modeling of the hypothalamic-pituitary-adrenal (HPA) axis response to acute and chronic stress (2011) · cites this paper as [5]
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Bucci, M., Marques, S. S., Oh, D., & Harris, N. B. (2016) · Advances in Pediatrics · doi:10.1016/j.yapd.2016.04.002 · Cited by 295
“Physiologically normal HPA axis function depends on the balanced activation of two corticosteroid receptors with opposing effects: mineralocorticoid and glucocorticoid receptors [36,39].”
BackgroundInfluentialInterplay between the gut-brain axis, obesity and cognitive function
Agustí, A., García-Pardo, M. P., López-Almela, I., Campillo, I., Maes, M., Romaní-Pérez, M., & Sanz, Y. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00155 · Cited by 294
“Other body processes regulated by the HPA-axis are immune functions, emotions and mood (Tsigos and Chrousos, 2002).”
BackgroundEvaluation of respiratory status in patients with myopathy
Ghaedrahmati, M., Kazemi, A., Kheirabadi, G., Ebrahimi, A., & Bahrami, M. (2017) · Journal of Education and Health Promotion · doi:10.4103/jehp.jehp_916 · Cited by 286
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Structural and functional evolution of vertebrate neuroendocrine stress systems
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Relationship between Cortisol Responses to Stress and Personality
Oswald, L. M., Zandi, P. P., Nestadt, G., Potash, J. B., Kalaydjian, A., & Wand, G. S. (2006) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301012 · Cited by 294
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On the biology of technostress
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“As a correlative, the basic functioning of the HPA system can be described as follows (e.g., Tsigos & Chrousos, 2002): In a stress situation, specific brain areas become activated.”
BackgroundRole of the gut-brain axis in energy and glucose metabolism
Wachsmuth, H. R., Weninger, S. N., & Duca, F. A. (2022) · Experimental & Molecular Medicine · doi:10.1038/s12276-021-00677-w · Cited by 269
“effects of PYY(3-36) and PYY(1-36) on gastric emptying in rats.”
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“For instance, the stress response can cause hypercortisolemia (an excess excretion of CRH and cortisol) [18, 21] and a substantial body of research suggests that this excess secretion of cortisol increases vulnerability to depression [22].”
BackgroundThe hypothalamic-pituitary-adrenal-axis in the regulation of energy balance
Nieuwenhuizen, A. G., & Rutters, F. (2007) · Physiology & Behavior · doi:10.1016/j.physbeh.2007.12.011 · Cited by 271
“CRH may act through activation of the central sympathetic system, both in the hypothalamus as well as in the locus ceruleus of the brain stem [1].”
BackgroundInfluentialStress, Endocrine Physiology and Pathophysiology -- Endotext
DeGroot, L. J., Chrousos, G. P., Dungan, K., Grossman, A. B., Jm, H., Koch, C., Korbonits, M., McLachlan, R., New, M., Purnell, J. Q., et al. (2000) · Europe PMC (PubMed Central) · Cited by 260
Self-citationStress, hypothalamic–pituitary–adrenal axis, hypothalamic–pituitary–gonadal axis, and aggression.
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“These glucocorticoids exert the physiological effects of the HPA axis as well as feedback negatively to inhibit further activation of the axis (Tsigos and Chrousos 2002 ).”
BackgroundRole of kappa-opioid receptors in stress and anxiety-related behavior
Veer, A. V., & Carlezon, W. A. (2013) · Psychopharmacology · doi:10.1007/s00213-013-3195-5 · Cited by 262
“Several mediators have been implicated in the stress response , including the CRF, catecholamine, serotonin, and vasopressin systems (see Carrasco and Van de Kar 2003; Tsigos and Chrousos 2002).”
Bradley, A. J., & Dinan, T. G. (2010) · Journal of Psychopharmacology · doi:10.1177/1359786810385491 · Cited by 267
“For detailed reviews of the function of the stress axes and the central role of the brain the reader is referred to Tsigos and Chrousos (2002) and McEwen and Gianaros (2010).”
BackgroundEarly-life stress and HPA axis trigger recurrent adulthood depression
Juruena, M. F. (2013) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2013.10.020 · Cited by 270
“In addition to melancholic depression, a spectrum of other conditions may be associated with increased and prolonged activation of the HPA axis, including anorexia nervosa with or without malnutrition, obsessive–compulsive disorder, panic anxiety, chronic active alcoholism, alcohol and narcotic withdrawal, poorly cont…”
BackgroundThe Stress and Migraine Interaction
Sauro, K. M., & Becker, W. J. (2009) · Headache The Journal of Head and Face Pain · doi:10.1111/j.1526-4610.2009.01486.x · Cited by 252
“Stress-related activation of these 2 systems results in increased arousal, as well as stimulation of the dopamine and b-endorphin systems.(29,30) The activation of these systems in response to stress is intended to be short-lived; otherwise, the anti-reproductive, immunosuppressive, and other effects of their activati…”
BackgroundExercise influence on the microbiome–gut–brain axis
Dalton, A., Mermier, C. M., & Zuhl, M. (2019) · Gut Microbes · doi:10.1080/19490976.2018.1562268 · Cited by 273
“, physical ormental).(60,61) The HPA is influenced by the GI system through a complex neural-immunoregulatory mechanism.”
BackgroundFibromyalgia: A Stress Disorder?
Houdenhove, B. V., & Egle, U. T. (2004) · Psychotherapy and Psychosomatics · doi:10.1159/000078843 · Cited by 260
“and may open exciting new research avenues, e.g. on possible benefits of experimental substances such as CRH agonists/antagonists [”
BackgroundPetrik, D., Lagace, D. C., & Eisch, A. J. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.09.003 · Cited by 241
“In addition, the gastrointestinal, cardiovascular, endocrine, and immune systems are also notably affected (e.g. O’Mahony et al., 2011; Savignac et al., 2011; Tsigos and Chrousos, 2002).”
BackgroundEffects of psychological stress on male fertility
Nargund, V. H. (2015) · Nature Reviews Urology · doi:10.1038/nrurol.2015.112 · Cited by 261
Technostress from a Neurobiological Perspective
Riedl, R., Kindermann, H., Auinger, A., & Javor, A. (2012) · Business & Information Systems Engineering · doi:10.1007/s12599-012-0207-7 · Cited by 277
“We outline the major system, the hypothalamic-pituitaryadrenal (HPA) axis (e.g., Tsigos and Chrousos 2002), in the following to provide a conceptual basis for the remainder of this article.”
BackgroundBeyond the Hippocampus and the SVZ: Adult Neurogenesis Throughout the Brain
Jurkowski, M. P., Bettio, L. E. B., Woo, E. K., Patten, A. R., Yau, S., & Gil‐Mohapel, J. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.576444 · Cited by 278
“For example, methamphetamine was shown to induce a low level of neurogenesis in the striatum of rats (Tulloch et al., 2014).”
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Bienvenu, O. J., Colantuoni, E., Méndez-Téllez, P. A., Dinglas, V. D., Shanholtz, C. B., Husain, N., Himmelfarb, C. D., Herridge, M. S., Pronovost, P. J., & Needham, D. M. (2011) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201103-0503oc · Cited by 236
Stress, alcohol and drug interaction: an update of human research
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“Moreover, excess cortisol exposure is related to a variety of medical conditions, including hypertension, atherosclerosis, obesity, insulin resistance, dyslipidemia, bone demineralization and impaired immunity (McEwen 1998; Tsigos & Chrousos 2002).”
BackgroundImmune, health and endocrine characteristics of depressed postpartum mothers
Groer, M. E., & Morgan, K. H. (2007) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2006.11.007 · Cited by 233
Regulation of anxiety during the postpartum period
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A prescription for “nature” – the potential of using virtual nature in therapeutics
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“The HPA axis regulates stress hormone (cortisol) secretion, and its dysregulation is associated with a wide range of disease outcomes and immune system malfunction.(88) Several studies have provided evidence for this theory;(89) however, the complexity and sensitivity of the stress regulation physiology are often a me…”
BackgroundPain processing in dementia and its relation to neuropathology
Scherder, E., Sergeant, J. A., & Swaab, D. F. (2003) · The Lancet Neurology · doi:10.1016/s1474-4422(03)00556-8 · Cited by 226
Metadata
- Authors
- Tsigos, C., & Chrousos, G. P.
- Affiliations
- National and Kapodistrian University of Athens (GR)
- National Institutes of Health (US)
- Corresponding author
- Chrousos, George P
- ORCID
- Chrousos, George P
- Venue
- Journal of Psychosomatic Research
- Publisher
- Elsevier BV
- Published
- 2002-10
- Volume
- 53
- Issue
- 4
- Pages
- 865-871
- ISSN
- 0022-3999 (ISSN-L)
- OpenAlex
- W1971639265
- Cited by
- 2,822
- References
- 49
- Citations by year
- 2026: 86 · 2025: 126 · 2024: 153 · 2023: 137 · 2022: 143 · 2021: 180 · 2020: 150 · 2019: 130 · 2018: 150 · 2017: 162 · 2016: 149 · 2015: 146 · 2014: 142 · 2013: 145 · 2012: 130
- FWCI
- 3.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Psychosomatic Research (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
- H, hypothalamic-pituitary-adrenal axis, stress response, locus coeruleus-norepinephrine system, beta-endorphin, glucocorticoids, catecholamines, amygdala, hippocampus, somatostatin, insulin resistance, metabolic syndrome X, bone loss, osteoporosis
- MeSH terms
- Autonomic Nervous System, Corticotropin-Releasing Hormone, Glucocorticoids, Humans, Hypothalamo-Hypophyseal System, Pituitary-Adrenal System, Stress, Physiological, Feedback, Physiological
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