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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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“In addition, in the general population, CRH and neuroendocrine hormones mediated by CRH have been associated with fatigue [21] and anxiety [22].”
BackgroundThe ethological relevance of predator odors to induce changes in prey species
Hegab, I. M., Kong, S., Yang, S., Mohamaden, W. I., & Wei, W. (2014) · acta ethologica · doi:10.1007/s10211-014-0187-3 · Cited by 54
“…substrates of defensive responses and utilized predator exposures as a means to address the impact of threatening and stressful factors on regional brain activity and plasticity, as well as to examine the functioning of various endocrine systems (Perrot-Sinal et al. 1999; Tsigos and Chrousos 2002).”
BackgroundThe role of Thyrotropin Releasing Hormone in aging and neurodegenerative diseases
Daimon, C. M., Chirdon, P., Maudsley, S. R., & Martin, B. (2013) · American Journal of Alzheimer s Disease & Other Dementias® · doi:10.7726/ajad.2013.1003 · Cited by 50
“Additionally, corticotrophin releasing hormone (CRH) has demonstrated a capacity to decrease TRH levels in multiple regions of the brain (Tsigos and Chrousos, 2002).”
BackgroundRelationship between hair and salivary cortisol and pregnancy in women undergoing IVF
Massey, A. J., Campbell, B. K., Raine‐Fenning, N., Pincott‐Allen, C., Perry, J., & Vedhara, K. (2016) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2016.08.027 · Cited by 53
Psychophysiological response in parachute jumps, the effect of experience and type of jump
Clemente‐Suárez, V. J., Robles‐Pérez, J. J., & Fernández‐Lucas, J. (2017) · Physiology & Behavior · doi:10.1016/j.physbeh.2017.06.006 · Cited by 51
Role of gut microbiota in brain function and stress-related pathology
Sudo, N. (2019) · Bioscience of Microbiota Food and Health · doi:10.12938/bmfh.19-006 · Cited by 55
Is there a relationship between PTSD and complicated obesity? A review of the literature
Aaseth, J., Roer, G. E., Lien, L., & Bjørklund, G. (2019) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2019.108834 · Cited by 51
Yüce, U. Ö., & Taşçı, S. (2021) · Complementary Therapies in Medicine · doi:10.1016/j.ctim.2021.102708 · Cited by 51
Moreira, R. O., Marca, K. F., Appolinário, J. C., & Coutinho, W. F. (2007) · Eating and Weight Disorders - Studies on Anorexia Bulimia and Obesity · doi:10.1007/bf03327770 · Cited by 51
Patani, A., Balram, D., Yadav, V. K., Lian, K.-Y., Patel, A., & Sahoo, D. K. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1271521 · Cited by 58
“Stress hormones induce the disruption of tight junctions, consequently leading to increased permeability of the intestinal barrier (192).”
BackgroundMachine learning-based detection of acute psychosocial stress from body posture and movements
Richer, R., Koch, V., Abel, L., Hauck, F., Kurz, M., Ringgold, V., Müller, V., Küderle, A., Schindler‐Gmelch, L., Eskofier, B. M., et al. (2024) · Scientific Reports · doi:10.1038/s41598-024-59043-1 · Cited by 59
Shin, A. C., MohanKumar, S. M. J., Sirivelu, M. P., Claycombe, K., Haywood, J. R., Fink, G. D., & MohanKumar, P. S. (2010) · International Journal of Obesity · doi:10.1038/ijo.2010.34 · Cited by 52
Uysal, N., Şişman, A. R., Dayı, A., Özbal, S., Çeti̇n, F., Baykara, B., Aksu, İ., Taş, A., Cavus, S. A., Arda, S. G., et al. (2012) · Neuroscience Letters · doi:10.1016/j.neulet.2012.02.049 · Cited by 51
Expression and Function of Endocannabinoid Receptors in the Human Adrenal Cortex
Ziegler, C. G., Mohn, C. E., Lamounier‐Zepter, V., Rettori, V., Bornstein, S., Krug, A. W., & Ehrhart‐Bornstein, M. (2009) · Hormone and Metabolic Research · doi:10.1055/s-0029-1241860 · Cited by 50
Klatzkin, R. R., Lindgren, M. E., Forneris, C. A., & Girdler, S. S. (2010) · Biological Psychology · doi:10.1016/j.biopsycho.2010.01.018 · Cited by 54
“N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript However, it must be acknowledged that β-endorphin concentrations, also reflecting HPA-axis activity (Tsigos and Chrousos 2002), did not differ as a function of either PMDD or prior MDD status.”
BackgroundOf depression and immunity: does sex matter?
Pitychoutis, P. M., & Papadopoulou‐Daifoti, Z. (2010) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145710000465 · Cited by 51
García-Manzanares, N., Monseny, R., Ortega, L., Montalvo, I., Franch, J., Gutiérrez‐Zotes, A., Reynolds, R. M., Walker, B. R., Vilella, E., & Labad, J. (2013) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2013.09.023 · Cited by 50
“, 2006), and can induce activation of the hypothalamic—pituitary—adrenal (HPA) axis (Tsigos and Chrousos, 2002).”
BackgroundPeckins, M. K., Susman, E. J., Negriff, S. L., Noll, J. G., & Trickett, P. K. (2015) · Development and Psychopathology · doi:10.1017/s0954579415000875 · Cited by 49
“…repeated activation of the SRS, as is the case with exposure to acute and chronic stressors such as maltreatment, to be associated with future dysfunction (i.e., hypo- or hyperactivity) of the SRS (McEwen, 2007) and declines in mental and physical health (for review, see Tsigos & Chrousos, 2002).”
BackgroundInfluentialMychasiuk, R., Muhammad, A., & Kolb, B. E. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2016.02.053 · Cited by 53
Peeters, B. W. M. M., Tonnaer, J. A. D. M., Groen, M. B., Broekkamp, C. L. E., van der Voort, H. A. A., Schoonen, W. G. E. J., Smets, R. J. M., Vanderheyden, P., Gebhard, R., & Ruigt, G. S. F. (2004) · Stress · doi:10.1080/10253890400019672 · Cited by 50
“In addition, glucocorticoids have strong anti-inflammatory and immuno-suppressive properties (Adcock, 2003; Pelaia et al., 2003) and various actions in the central nervous system have been described (Tsigos and Chrousos, 2002).”
BackgroundZimmer, K. E., Gutleb, A. C., Lyche, J. L., Dahl, E., Oskam, I. C., Krogenæs, A., Skaare, J. U., & Ropstad, E. (2009) · Journal of Toxicology and Environmental Health · doi:10.1080/15287390802539004 · Cited by 50
“In addition to the well-known effects on the immune system and metabolism, chronic elevated cortisol levels suppress the actions of other hormones such as reproductive, thyroid, and growth hormones ( O'Connor et al, 2000 ; Tsigos & Chrousos, 2002 ).”
BackgroundAssociations between waist circumference and depressive disorders
Hach, I., Ruhl, U. E., Klotsche, J., Klose, M., & Jacobi, F. (2006) · Journal of Affective Disorders · doi:10.1016/j.jad.2006.01.023 · Cited by 50
“Thus, we cannot confirm the theory that the WC might be a suitable measure for permanent mental strain and an increased risk for mental disorders (Bojer, 2000; Tsigos, 2002; Young et al., 2001).”
BackgroundPollitt, R. A., Daniel, M., Kaufman, J. S., Lynch, J. W., Salonen, J. T., & Kaplan, G. A. (2005) · Journal of Behavioral Medicine · doi:10.1007/s10865-005-2563-y · Cited by 50
“…of glucocorticoids, leading to increased release of insulin and hyperlipidemia, hypercholesterolemia, hypertension, hypertrophy of the adrenal gland, and injury to the intima and vascular endothelial cells (Bjorntorp, 1997; Checkley, 1996; Cohen and Rodriguez, 1995; Tsigos and Chrousos, 2002).”
BackgroundPeriodontal diseases and depression: A pre‐clinical in vivo study
Martínez, M., Martín‐Hernández, D., Virto, L., MacDowell, K. S., Montero, E., Bris, Á. G., Marín, M. J., Ambrosio, N., Herrera, D., Leza, J. C., et al. (2021) · Journal Of Clinical Periodontology · doi:10.1111/jcpe.13420 · Cited by 56
Mero, A. A., Tornberg, J., Mäntykoski, M., & Puurtinen, R. (2015) · SpringerPlus · doi:10.1186/s40064-015-1093-5 · Cited by 49
The Hypothalamic-Pituitary-Adrenal Axis, Obesity, and Chronic Stress Exposure: Foods and HPA Axis
Rutters, F., la Fleur, S. E., Lemmens, S. G. T., Born, J. R., Martens, M. J. I., & Adam, T. C. (2012) · Current Obesity Reports · doi:10.1007/s13679-012-0024-9 · Cited by 50
“The HPA axis is one of the neuro-endocrine axes that plays an important role in the regulation of the stress-response, by regulating the secretion of glucocorticoids: cortisol in humans and corticosterone in animals [3].”
BackgroundThe biopsychosocial model of pain and contemporary osteopathic practice
Penney, J. N. (2010) · International journal of osteopathic medicine · doi:10.1016/j.ijosm.2010.01.004 · Cited by 49
Long Work Hours and Obesity in Korean Adult Workers
Jang, T. W., Kim, H., Lee, H., Myong, J., & Koo, J. (2013) · Journal of Occupational Health · doi:10.1539/joh.13-0043-oa · Cited by 48
Frigerio, A., Ceppi, E., Rusconi, M., Giorda, R., Raggi, M. E., & Fearon, P. R. M. (2009) · Journal of Child Psychology and Psychiatry · doi:10.1111/j.1469-7610.2009.02126.x · Cited by 49
Zilioli, S., Imami, L., & Slatcher, R. B. (2016) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2016.09.025 · Cited by 51
“The steroid hormone cortisol is the end product of the hypothalamic-pituitary adrenal (HPA) axis, a neuroendocrine system responsible for coordinating biological responses to stress (Tsigos and Chrousos, 2002).”
Rao, R., & Androulakis, I. P. (2017) · Endocrinology · doi:10.1210/en.2017-00544 · Cited by 49
Academic stress-induced changes in Th1- and Th2-cytokine response
Assaf, A. M., Al-Abbassi, R., & Al-Binni, M. A. (2017) · Saudi Pharmaceutical Journal · doi:10.1016/j.jsps.2017.09.009 · Cited by 50
“…receptors on different types of cells including the immune cells modulating cytokine production (Chrousos, 2000; Glaser and Kiecolt-Glaser, 2005; Hänsel et al., 2010; Miller et al., 2011; Smith and Vale, 2006; Stephens and Wand, 2012; Tsigos and Chrousos, 2002; Webster Marketon and Glaser, 2008).”
BackgroundZhao, Y., Pan, Y., Tang, M., & Lin, W. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00511 · Cited by 48
“By combining with the GR, glucocorticoids exert a feedback inhibition effect on numerous pathways (Pariante and Miller, 2001; Tsigos and Chrousos, 2002).”
BackgroundPavlov, D., Bettendorff, L., Вячеславовна, Г. А., Olkhovik, A., Kalueff, A. V., Ponomarev, E. D., Inozemtsev, A. N., Chekhonin, V. P., Lesch, K., Anthony, D. C., et al. (2018) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2018.11.014 · Cited by 50
“These inter-connected processes result in aberrant hippocampus activity and the activity of other limbic structures, including prefrontal cortex and amygdala resulting in the behavioural, vegetative and hormonal features of depressive disorder (Tsigos and Chrousos, 2002; Buwalda et al., 2005; Mahar et al., 2014; Chesn…”
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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