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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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“However, HPA hypoactivity in humans is associated with alternative forms of depression, such as atypical, seasonal, and postpartum depression (Tsigos & Chrousos 2002).”
BackgroundCrombie, K. M., Leitzelar, B. N., Brellenthin, A. G., Hillard, C. J., & Koltyn, K. F. (2019) · Biological Psychology · doi:10.1016/j.biopsycho.2019.04.002 · Cited by 64
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“Inappropriate and maladaptive intensification or attenuation of HPA axis-mediated responses to stress can lead to chronic diseases (McEwen, 1998;Sapolsky, 1999;Tsigos and Chrousos, 2002).”
BackgroundEffects of sleep restriction periods on serum cortisol levels in healthy men
Wu, H., Zhao, Z., Stone, W. S., Huang, L., Zhuang, J., He, B., Zhang, P., & Li, Y. (2008) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2008.07.013 · Cited by 62
Real-time mental stress detection using multimodality expressions with a deep learning framework
Zhang, J., Yin, H. H., Zhang, J., Yang, G., Qin, J., & He, L. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.947168 · Cited by 74
“When people are under stress, the autonomic nervous system (ANS) is stimulated and regulates involuntary body functions (Tsigos and Chrousos, 2002).”
BackgroundGerber, M., Kalak, N., Elliot, C., Holsboer‐Trachsler, E., Pühse, U., & Brand, S. (2013) · Neuropsychobiology · doi:10.1159/000351735 · Cited by 61
Gourounti, K., Anagnostopoulos, F., & Βασλαματζής, Γ. (2011) · Women & Health · doi:10.1080/03630242.2011.574791 · Cited by 63
“Specifically, stress activates the hypothalamic-pituitary-adrenal (HPA) axis, which is involved in the excretions of corticotrophic-releasing hormone (CRH), adrenocorticotrophic hormone (ACTH) and cortisol, respectively ( Tsigos & Chrousos, 2002 ).”
BackgroundMikolajczak, M., Quoidbach, J., Vanootighem, V., Lambert, F., Lahaye, M., Fillée, C., & de Timary, P. (2009) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2009.11.003 · Cited by 62
“The hypothalamopituitary-adrenal axis (HPA axis) is a crucial system to that end: triggered by challenges, it induces a number of bio-behavioral changes that help the organism preserving homeostasis (e.g., Tsigos and Chrousos, 2002).”
Baddam, S. K. R., Canapari, C. A., van Noordt, S. J. R., & Crowley, M. J. (2018) · Medical Sciences · doi:10.3390/medsci6020046 · Cited by 68
“Hypothalamic-pituitary-adrenal (HPA) axis and the locus coeruleus-norepinephrine system are essential for the optimal functioning of the arousal system [103].”
BackgroundAgorastos, A., Heinig, A., Stiedl, O., Hager, T., Sommer, A., Müller, J. C., Schruers, K. R., Wiedemann, K., & Demiralay, C. (2019) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2018.12.017 · Cited by 61
Lundberg, S., Martinsson, M., Nylander, I., & Roman, E. (2017) · Hormones and Behavior · doi:10.1016/j.yhbeh.2016.11.016 · Cited by 63
“Dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis with either elevated or blunted release of glucocorticoids have been associated with a plethora of different disorders ranging frommood disorders tometabolic and inflammatory conditions (Heim et al., 2008; Tsigos and Chrousos, 2002).”
Gut microbiota and neuropsychiatric disorders: Implications for neuroendocrine-immune regulation
Ge, T., Yao, X., Zhao, H., Yang, W., Zou, X., Peng, F., Li, B., & Cui, R. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105909 · Cited by 62
HYDROGEN SULPHIDE‐INDUCED HYPOTHERMIA ATTENUATES STRESS‐RELATED ULCERATION IN RATS
Lou, L., Geng, B., Du, J., & Tang, C. (2007) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.2007.04812.x · Cited by 61
“All stress responses have a typical characteristic: activation of the hypothalamo–pituitary–adrenal axis accompanied by increases in plasma concentrations of ACTH and glucocorticoids.(26) Inhibition of stress responses could reduce continuous injury after stress.”
BackgroundWong, C. C. Y., & Schumann, G. (2008) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2008.0104 · Cited by 64
“Upon the activation of the HPA axis, a cascade of hormones including vasopressin, corticotrophinreleasing hormone (CRH), adrenocorticotrophic hormone and glucocorticoids are secreted (Tsigos & Chrousos 2002).”
BackgroundPerceived Psychological Stress and Serum Leptin Concentrations in Japanese Men
Otsuka, R., Yatsuya, H., Tamakoshi, K., Matsushita, K., Wada, K., & Toyoshima, H. (2006) · Obesity · doi:10.1038/oby.2006.211 · Cited by 61
“Stress has been classically known to activate the sympathoadrenal system and the hypothalamic-pituitary-adrenocortical (HPA)(1) axis (3,4), which mediates the increase of glucocorticoid level.”
BackgroundTonic and phasic co-variation of peripheral arousal indices in infants
Wass, S. V., de Barbaro, K., & Clackson, K. (2015) · Biological Psychology · doi:10.1016/j.biopsycho.2015.08.006 · Cited by 60
Real-Time Psychological Stress Detection According to ECG Using Deep Learning
Zhang, P., Li, F., Zhao, R., Zhou, R., Du, L., Zhao, Z., Chen, X., & Fang, Z. (2021) · Applied Sciences · doi:10.3390/app11093838 · Cited by 64
“including shortening the RR interval, increasing the low-frequency energy of HRV (heart rate variability), increasing the respiration rate, decreasing HRV’s high-frequency energy, and more [6].”
BackgroundWei, C., Zhang, W., Chen, J., He, Q., Cao, L., Zhang, P., Deng, C., Xiong, M., Huang, Y., Guo, H., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1175764 · Cited by 60
“Numerous autoimmune diseases are more common in women (43, 44).”
BackgroundEarly Life Stress in Depressive Patients: HPA Axis Response to GR and MR Agonist
Baes, C. V. W., Martins, C. M. S., Tofoli, S. M. D. C., & Juruena, M. F. (2014) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2014.00002 · Cited by 63
“Several studies have also demonstrated a hypoactivity of the HPA axis, a lower activity of CRH, hypocortisolism, and a decrease in activity of afferent noradrenergic pathways in depression with atypical features (73, 81, 82).”
BackgroundResultTran, T. T., Srivareerat, M., & Alkadhi, K. A. (2010) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.12.016 · Cited by 61
Monteleone, P., Scognamiglio, P., Canestrelli, B., Serino, I., Monteleone, A. M., & Maj, M. (2011) · Psychological Medicine · doi:10.1017/s0033291711000092 · Cited by 67
“Glucocorticoids participate in the control of whole-body homeostasis and the organism’s response to stress (Tsigos & Chrousos, 2002), and have a key inhibitory role in the control of HPA axis activity, favouring the termination of the stress response, which limits the duration of the total tissue…”
BackgroundHippocampal Subregions Across the Psychosis Spectrum
Vargas, T., Dean, D. J., Osborne, K. J., Gupta, T., Ristanovic, I., Ozturk, S., Turner, J. A., van Erp, T. G. M., & Mittal, V. A. (2017) · Schizophrenia Bulletin · doi:10.1093/schbul/sbx160 · Cited by 65
Mild prenatal stress in rats is associated with enhanced conditioned fear
Griffin, W. C., Skinner, H. D., Salm, A. K., & Birkle, D. L. (2003) · Physiology & Behavior · doi:10.1016/s0031-9384(03)00097-0 · Cited by 60
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Depression and Metabolic Syndrome: A Narrative Review
Al-Khatib, Y., Akhtar, M. A., Kanawati, M. A., Mucheke, R., Mahfouz, M., & Al-Nufoury, M. (2022) · Cureus · doi:10.7759/cureus.22153 · Cited by 69
“The HPA axis relies principally on the action of CRH, the locus coeruleus-norepinephrine autonomic systems, and the pituitaryadrenal axis [77].”
BackgroundCortisol Immunosensors: A Literature Review
Karachaliou, C., Koukouvinos, G., Goustouridis, D., Raptis, I., Kakabakos, S. E., Petrou, P. S., & Livaniou, E. (2023) · Biosensors · doi:10.3390/bios13020285 · Cited by 63
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“When faced with stress, the HPA axis becomes activated within the hypothalamus–pituitary–adrenal system, prompting the synthesis of CRH, 8 which further sets off a series of biochemical responses that ultimately culminate in the release of cortisol.”
Insulin reverses anxiety-like behavior evoked by streptozotocin-induced diabetes in mice
Gupta, D., Radhakrishnan, M., & Kurhe, Y. (2014) · Metabolic Brain Disease · doi:10.1007/s11011-014-9540-5 · Cited by 62
“corticosterone levels (as a marker of HPA-axis activity) are correlated with anxiety-like behavioral effects (Cruz et al. 1994; Tsigos and Chrousos 2002).”
BackgroundAltered sleep latency and arousal regulation in mice lacking norepinephrine
Hunsley, M. S., & Palmiter, R. D. (2004) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2004.05.008 · Cited by 58
Cortisol: the villain in Metabolic Syndrome?
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“The PFC plays an important role in mediating somatic responses to stress via projections to neuroendocrine and autonomic centers in the medial hypothalamus.(42) Interestingly, right/ left asymmetry of PFC activity also plays a role in regulation of stress response, which is similar to regulation of emotional responses.”
BackgroundDuval, F., Lebowitz, B. D., & Macher, J. P. (2006) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2006.8.2/fduval · Cited by 60
Role of Nitric Oxide in Stress-Induced Anxiety
Kumar, A., & Chanana, P. (2016) · Vitamins and hormones · doi:10.1016/bs.vh.2016.09.004 · Cited by 59
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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