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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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“Activity of SNS and PNS can be monitored through some physiological signals, such as heart rate, heart rate variability (HRV), blood pressure and so on.”
BackgroundInfluentialThe Potential Influence of the Bacterial Microbiome on the Development and Progression of ADHD
Bull-Larsen, S., & Mohajeri, M. H. (2019) · Nutrients · doi:10.3390/nu11112805 · Cited by 111
“It is of great importance to understand to what extent the HPA axis plays a role in the pathogenesis of ADHD, as it influences pathways in the body that are often deviating in ADHD patients [39,40] as for example: Circadian rhythm [41], sleep [42], and emotions [43].”
BackgroundThe Sirt1 deacetylase modulates the insulin-like growth factor signaling pathway in mammals
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GABRA6 gene polymorphism and an attenuated stress response
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“, 2000; Carrasco and Van de Kar, 2003) and thyroid (Tsigos and Chrousos, 2002) systems, which have consistently been found to be dysregulated in depression (Brown and Gershon, 1993; Jackson, 1998; Anand and Charney, 2000).”
BackgroundPeriodontal diseases and stress: a brief review
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“In addition, these inflammatory cytokines can practically interact with every pathophysiologic target relevant to depression, including neurotransmitter metabolism, neuroendocrine function and synaptic plasticity (Maes, 1999; Tsigos and Chrousos, 2002) being correlated in humans, for instance IL-1b, with anhedonia (De…”
Neurobiology of depression: A neurodevelopmental approach
Lima‐Ojeda, J. M., Rupprecht, R., & Baghai, T. C. (2017) · The World Journal of Biological Psychiatry · doi:10.1080/15622975.2017.1289240 · Cited by 113
Exploring the multifaceted neuroprotective actions of gallic acid: a review
Shabani, S., Rabiei, Z., & Amini-Khoei, H. (2020) · International Journal of Food Properties · doi:10.1080/10942912.2020.1753769 · Cited by 113
Stress during gestation induces lasting effects on emotional reactivity of the dam rat
Darnaudéry, M., Dutriez-Casteloot, I., Viltart, O., Morley‐Fletcher, S., & Maccari, S. (2004) · Behavioural Brain Research · doi:10.1016/j.bbr.2003.12.001 · Cited by 104
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“Works based on the evolutionary account explain that the “fight-or-flight” response to stress characterizes the primary biological response to stress for both males and females, particularly by activating the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic division of the autonomic nervous system [28].”
BackgroundChronic stress and endothelial dysfunction: mechanisms, experimental challenges, and the way ahead
Sher, L. D., Geddie, H., Olivier, L., Cairns, M., Truter, N., Beselaar, L., & Essop, M. F. (2020) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00244.2020 · Cited by 111
Diurnal cortisol and survival in epithelial ovarian cancer
Schrepf, A., Thaker, P. H., Goodheart, M. J., Bender, D., Slavich, G. M., Dahmoush, L., Penedo, F. J., DeGeest, K., Méndez, L., Lubaroff, D. M., et al. (2015) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2015.01.010 · Cited by 110
Preterm behavioral epigenetics: A systematic review
Provenzi, L., Guida, E., & Montirosso, R. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.08.020 · Cited by 111
“These receptors are key regulators of the stress reactivity in mammalians, since they regulate through feedback mechanisms the hypothalamic-pituitary-adrenal (HPA) axis (Tsigos and Chrousos, 2002).”
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“Many mechanisms have been described in which the end product of the HPA axis, Cort, feeds back to limit HPA axis activity (Raubenheimer et al., 2006; Sapolsky and McEwen, 1985; Smith and Vale, 2006; Tsigos and Chrousos, 2002).”
BackgroundYang, Z., Wu, H., Lee, P. H., Tsetsos, F., Davis, L. K., Yu, D., Lee, S., Dalsgaard, S., Haavik, J., Barta, C., et al. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2020.12.028 · Cited by 105
“The HPA axis plays a critical role in human stress response through the regulation of cortisol secretion (54).”
Stress: Neurobiology, consequences and management
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“[23] Glucocorticoids directly inhibit pituitary gonadotropin, growth hormone, and thyrotropin secretion and make the target tissues of sex steroids and growth factors resistant to these substances.”
InfluentialDai, X., Liu, C.-L., Wáng, Y. X. J., Gao, L., Gong, H., Zhou, R.-L., & Wu, B. (2015) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s78335 · Cited by 99
The Oral-Microbiome-Brain Axis and Neuropsychiatric Disorders: An Anthropological Perspective
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“Cortisol is a primary regulatory factor in numerous host systems, including immune response, host growth, and development (53).”
BackgroundAn insula hierarchical network architecture for active interoceptive inference
Fermin, A. S. R., Friston, K., & Yamawaki, S. (2022) · Royal Society Open Science · doi:10.1098/rsos.220226 · Cited by 101
Stress-Activity Mapping: Physiological Responses During General Duty Police Encounters
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Overcrowded classrooms – The Achilles heel of South African education?
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Corticosteroid Binding Globulin: A New Target for Cortisol-Driven Obesity
Ousova, O., Guyonnet‐Dupérat, V., Iannuccelli, N., Bidanel, J. P., Milan, D., Genêt, C., Llamas, B., Martine Yerle, B., Gellin, J., Chardon, P., et al. (2004) · Molecular Endocrinology · doi:10.1210/me.2004-0005 · Cited by 99
“If not, as in case of chronic stress, sustained high cortisol levels have deleterious effects on the organism (3, 4).”
Effects of Chronic Social Isolation on Wistar Rat Behavior and Brain Plasticity Markers
Djordjevic, J., Djordjevic, A. D., Adžić, M., & Radojcic, M. B. (2012) · Neuropsychobiology · doi:10.1159/000338605 · Cited by 102
Nicotine modulation of fear memories and anxiety: Implications for learning and anxiety disorders
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“On the one hand, the limbic cortical regions, including the amygdala and hippocampus, process and integrate sensory and emotional information to control internal bodily responses through the modulation of the hypothalamic–pituitary– adrenal (HPA) axis, a neuroendocrine system responsible for stress response ([86]; Fig…”
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“The proinflammatory cytokine IL-1, 6, and tumour necrosis factor (TNF)-α are upregulated in psoriatic lesions and are well-known activators of the HPA axis (4).”
BackgroundEffects of increasing tryptophan intake on growth and physiological changes in nursery pigs1
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“…stress was maximal when daily total Trp intake was 10.8 g. Key words: growth, nursery pigs, serotonin, stress, tryptophan INTRODUCTION Stress can be triggered by both external and internal biological changes such as diet, environment, infection, and psychological events (Tsigos and Chrousos, 2002).”
BackgroundInfluentialKibirige, D., Lumu, W., Jones, A. G., Smeeth, L. L., Hattersley, A. T., & Nyirenda, M. (2019) · Clinical Diabetes and Endocrinology · doi:10.1186/s40842-019-0077-8 · Cited by 98
“the expression of the glucocorticoid receptors, dampening of the hypothalamic negative feedback mechanism and increased production of stress hormones (glucocorticoids) by the adrenal glands [53, 54].”
BackgroundDisease burden of adverse childhood experiences across 14 states
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“Much of the body’s stress response is mediated through hormones including adrenaline and cortisol, which exert their effects on virtually all of the body’s organ systems [9, 10].”
BackgroundEpigenetics in depression and gut-brain axis: A molecular crosstalk
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“This pathophysiological mechanism has also been proposed in patients with atypical depression [17, 75].”
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“, PGV [142, 143]).”
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“Several studies report that chronic stress alters HPA axis activity, which contributes to the development of psychiatric disorders such as depression, anxiety, and burnout (Chrousos, 2009; Miller et al., 2007; Tsigos and Chrousos, 2002).”
CRH, Stress, and Major Depression: A Psychobiological Interplay
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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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