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.
“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
The “Physiology of the stress response” section (page unavailable) says glucocorticoids act through glucocorticoid receptors and affect neuronal cells. It does not describe mineralocorticoid receptors or compare the two receptors’ affinities, so those parts of the claim are unsupported by our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredSuch distorted beliefs engender misdirected coping behavior and have profound physiological consequences, including dysregulation of cerebral control over endocrine and autonomic nervous system processes.
“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
The HPA axis: pathophysiology section describes prolonged stress-system activation, including HPA-axis hyperactivation, and its behavioral, neuroendocrine, autonomic, and physical consequences. The paper does not establish that distorted beliefs cause misdirected coping or this physiological dysregulation; it supports the HPA-axis example, not that proposed causal chain. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe HPA axis coordinates the adaptive responses of the organism to stressors of any kind.
“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]
There is an excitatory reciprocal interaction between the HPA axis and the brainstem sympathetic locus coeruleus-norepinephrine system: CRH activates the LC, and NE activates hypothalamic CRH.
“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]
Cortisol exhibits complex dynamic behavior with two characteristic frequencies: ultradian oscillations, with a period of 20-120 min, superimposed on circadian oscillations, with a period of about 24 h.
“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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“Whereas anxiety in general is associated with raised cortisol, PTSD is associated with reduced cortisol (Tsigos and Chrousos, 2002).”
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“…consistent biological correlates of severe depression (see Pariante & Lightman, 2008; Stetler & Miller, 2011) and may be linked to serotonergic or noradrenergic dysfunction (given the important role of these neurotransmitters in HPA activation/regulation; see Dinan, 1996; Tsigos & Chrousos, 2002).”
The Effect of Music on the Human Stress Response
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“In particular, given the reduced cortisol levels found among some victims with PTSD, it has been suggested that a downregulated glucocorticoid system may result in elevations in leukocyte and other immune inflammatory activities (55).”
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“Furthermore, glucocorticoids antagonize the anabolic actions of growth and thyroid hormones, insulin and sex steroids on their target tissues (Figure 2) [18].”
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“During pregnancy, in addition to hypothalamic CRH, the placenta also generates and releases CRH into the blood stream, causing hyperactivation of the HPA axis, and a considerable rise in the ratio of free/ bound cortisol, reaching values comparable to those found in Cushing’s disease.(40,41) The production of placenta…”
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“Opposing effects of estradiol may also occur due to different signaling mechanisms of ERα and ERβ (Tsigos and Chrousos, 2002).”
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“This negative feedback mechanism (see below) is essential for keeping the balance of the HPA axis activity during basal conditions and in response to stress (Tsigos and Chrousos, 2002).”
BackgroundSignalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis
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“…axis Additional support for the role of sex hormones in influencing inflammatory activity and risk for MDD comes from research demonstrating links between an imbalance of the HPA axis and pathologies related to inflammation in humans (Tsigos and Chrousos 2002; Yudkin et al. 2000).”
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“Symptomatically, disruptions as a result of proinflammatory cytokines may be experienced as fatigue, loss of appetite and libido as well as hypersensitivity to pain ( 48 ).”
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The role of Interleukin 6 in the pathophysiology of rheumatoid arthritis
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“Hypothalmic pituitary adrenal (HPA) axis abnormality has been linked to the development of fatigue in many diseases [Tsigos and Chrousos, 2002].”
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“Possibilities include increased activity of the hypothalamic pituitary axis[23], increased sympathetic outflow[24] or altered behaviors causing insulin resistance and central obesity[25].”
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“, 1997) fibromyalgia, chronic fatigue syndrome, and rheumatoid arthritis (Tsigos and Chrousos, 2002).”
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An assessment of cortisol analysis in hair and its clinical applications
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“Sensory systems perceive the stimuli called stressors and carry them into the limbic system, which controls the HPA axis (Tsigos and Chrousos, 2002).”
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“In the presence of an environmental stressor, the body responds with major modifications of the normal homeostasis, including alterations of the hypothalamicpituitary-adrenal (HPA) axis, the major neuroendocrine system activated by stressful experiences [4, 5].”
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“Physiologically normal HPA axis function depends on the balanced activation of two corticosteroid receptors with opposing effects: mineralocorticoid and glucocorticoid receptors [36,39].”
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“Other body processes regulated by the HPA-axis are immune functions, emotions and mood (Tsigos and Chrousos, 2002).”
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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.”
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“effects of PYY(3-36) and PYY(1-36) on gastric emptying in rats.”
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“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 · see citing works
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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 ).”
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“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).”
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“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.
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“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
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“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…”
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“, physical ormental).(60,61) The HPA is influenced by the GI system through a complex neural-immunoregulatory mechanism.”
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“and may open exciting new research avenues, e.g. on possible benefits of experimental substances such as CRH agonists/antagonists [”
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“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).”
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“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.”
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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).”
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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 · see citing works
- 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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