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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 seasonal affective disorder (SAD), atypical depression and PPD, the activity of the HPA axis is usually reduced, which could point to a similar pathologic mechanism in these three conditions [46].”
BackgroundThe central role of hypothalamic inflammation in the acute illness response and cachexia
Burfeind, K. G., Michaelis, K. A., & Marks, D. L. (2016) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2015.10.038 · Cited by 156
“Direct stimulation by ACTH causes production and release of cortisol from the zona fasiculata of the adrenal cortex [36].”
BackgroundMechanistic Insights into the Link between Gut Dysbiosis and Major Depression: An Extensive Review
Sonali, S., Ray, B., Hediyal, T. A., Rathipriya, A. G., Sunanda, T., Mahalakshmi, A. M., Rungratanawanich, W., Essa, M. M., Qoronfleh, M. W., Chidambaram, S. B., et al. (2022) · Cells · doi:10.3390/cells11081362 · Cited by 166
“Environmental, emotional, and physiological stress is shown to increase systemic pro-inflammatory cytokine levels, which stimulate the HPA axis by triggering the paraventricular nucleus of the hypothalamus to secrete the corticotropin-releasing hormone (CRH) [53,73].”
BackgroundExtra-adrenal glucocorticoid biosynthesis: implications for autoimmune and inflammatory disorders
Slominski, R. M., Tuckey, R. C., Manna, P. R., Jetten, A. M., Postlethwaite, A., Raman, C., & Slominski, A. T. (2020) · Genes & Immunity · doi:10.1038/s41435-020-0096-6 · Cited by 155
Interactions between Temperament, Stress, and Immune Function in Cattle
Sanchez, N. C. B., Randel, R. D., Carroll, J. A., & Welsh, T. H. (2011) · International Journal of Zoology · doi:10.1155/2011/373197 · Cited by 171
“An additional subset of vagal and sacral parasympathetic efferent nerves is activated which mediate the gut response to stress [30].”
BackgroundInfluentialMedical comorbidity in bipolar disorder: The link with metabolic-inflammatory systems
SayuriYamagata, A., Brietzke, E. M., Rosenblat, J. D., Kakar, R., & McIntyre, R. S. (2017) · Journal of Affective Disorders · doi:10.1016/j.jad.2016.12.059 · Cited by 160
“Hypercortisolemia has been shown to have several endocrine and metabolic implications including weight gain (Gregoire et al., 1991), insulin resistance (Berrettini et al., 1985; Murphy, 1991) and hypothyroidism (Tsigos and Chrousos, 2002), with strong associations to BD (Cole et al., 2002).”
Exploring metabolic dysfunction in chronic kidney disease
Slee, A. (2012) · Nutrition & Metabolism · doi:10.1186/1743-7075-9-36 · Cited by 161
Fatigue in Liver Disease: Pathophysiology and Clinical Management
Swain, M. G. (2006) · Canadian Journal of Gastroenterology · doi:10.1155/2006/624832 · Cited by 148
The lonely mouse: Verification of a separation-induced model of depression in female mice
Martin, A. L., & Brown, R. E. (2009) · Behavioural Brain Research · doi:10.1016/j.bbr.2009.10.006 · Cited by 158
Raimondi, I., Izzo, L., Tunesi, M., Comar, M., Albani, D., & Giordano, C. (2020) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2019.00435 · Cited by 150
“It regulates different body processes, such as digestion, energy, immune system, and emotions (Sudo, 2012) and it coordinates the adaptive responses to stress by the release of hormones (Tsigos and Chrousos, 2002).”
BackgroundGenes, Environment, and Time: The Vietnam Era Twin Study of Aging (VETSA)
Kremen, W. S., Thompson‐Brenner, H., Leung, Y.-M. J., Grant, M. D., Franz, C. E., Eisen, S. A., Jacobson, K. C., Boake, C., & Lyons, M. J. (2006) · Twin Research and Human Genetics · doi:10.1375/183242706779462750 · Cited by 147
Stress and central autonomic network
Lamotte, G. J., Shouman, K., & Benarroch, E. E. (2021) · Autonomic Neuroscience · doi:10.1016/j.autneu.2021.102870 · Cited by 162
Dysfunctional hippocampal activity affects emotion and cognition in mood disorders
Femenía, T., Gómez-Galán, M., Lindskog, M., & Magara, S. (2012) · Brain Research · doi:10.1016/j.brainres.2012.03.053 · Cited by 143
Wichmann, S., Kirschbaum, C., Böhme, C., & Petrowski, K. (2017) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2017.06.005 · Cited by 152
“Normative HPA-axis functioning includes the circadian ACTH and cortisol secretion as well as the temporary disruption of the diurnal hormone secretion upon acute stressors (Tsigos & Chrousos, 2002).”
Physiological effects of modulating the interleukin-6 axis
Schett, G. A. (2018) · Rheumatology · doi:10.1093/rheumatology/kex513 · Cited by 148
Riebe, C. J. N., & Wotjak, C. T. (2011) · Stress · doi:10.3109/10253890.2011.586753 · Cited by 149
Keep the Stress Away with SoDA: Stress Detection and Alleviation System
Akmandor, A. O., & Jha, N. K. (2017) · IEEE Transactions on Multi-Scale Computing Systems · doi:10.1109/tmscs.2017.2703613 · Cited by 145
“For example, excessive exposure to stress may result in depression [4], cardiovascular diseases [5], sleep disorders [6], degradation in the immune system [7], cancer [8], etc.”
BackgroundCRH-stimulated cortisol release and food intake in healthy, non-obese adults
George, S. A., Khan, S. A., Briggs, H., & Abelson, J. L. (2009) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2009.09.017 · Cited by 140
“In response to perceived threat or challenge, corticotrophin releasing hormone (CRH) is released from the hypothalamus, triggering release of adrenocorticotropic hormone (ACTH) from the pituitary, followed by glucocorticoid (GC) release from the adrenal cortex (Tsigos and Chrousos 2002).”
BackgroundAssociations between Melatonin, Neuroinflammation, and Brain Alterations in Depression
Won, E., Na, K., & Kim, Y. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms23010305 · Cited by 149
Tegethoff, M., Pryce, C. R., & Meinlschmidt, G. (2009) · Endocrine Reviews · doi:10.1210/er.2008-0014 · Cited by 147
“tity of the fetal hpa axis, which is somewhat different from the postnatal hpa axis or its better-characterized adult counterpart (22).”
BackgroundAssociation between anxiety and hypertension in adults: A systematic review and meta-analysis
Lim, L.-F., Solmi, M., & Cortese, S. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.08.031 · Cited by 134
Ovarian Dysfunction, Stress, and Disease: A Primate Continuum
Kaplan, J. R., & Manuck, S. B. (2004) · ILAR Journal · doi:10.1093/ilar.45.2.89 · Cited by 139
McCain, N. L., Gray, D. P., Walter, J. M., & Robins, J. W. (2005) · Advances in Nursing Science · doi:10.1097/00012272-200510000-00004 · Cited by 138
The Mu-Opioid Receptor Polymorphism A118G Predicts Cortisol Responses to Naloxone and Stress
Chong, R. Y., Oswald, L. M., Yang, X., Uhart, M., Lin, P., & Wand, G. S. (2005) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300856 · Cited by 140
“Chronic HPA axis dysregulation has been shown to contribute to a number of medical disorders including obesity, insulin resistance, hypertension, dyslipidemia, atherosclerosis, osteoporosis, and immune dysfunction (McEwen, 1998; Tsigos and Chrousos, 2002).”
BackgroundDavis, L., Appleby, R., Davis, P., Wetherell, M. A., & Gustafsson, H. (2018) · Journal of Sports Sciences · doi:10.1080/02640414.2018.1429176 · Cited by 138
“Thereafter, the level of cortisol steadily declines during the day with the lowest level of cortisol in the first half of the night (Tsigos & Chrousos, 2002).”
Gracely, R. H., Čeko, M., & Bushnell, M. C. (2011) · Pain Research and Treatment · doi:10.1155/2012/486590 · Cited by 157
Joca, S. R. L., Ferreira, F. R., & Guimarães, F. S. (2007) · Stress · doi:10.1080/10253890701223130 · Cited by 139
Chronic unpredictable mild stress generates oxidative stress and systemic inflammation in rats
López-López, A. L., Jaime, H. B., Villanueva, M. D. C. E., Brianza-Padilla, M., Vázquez-Palacios, G., & Aguilar, F. J. A. (2016) · Physiology & Behavior · doi:10.1016/j.physbeh.2016.03.017 · Cited by 146
Koenen, K. C., Sumner, J. A., Gilsanz, P., Glymour, M. M., Ratanatharathorn, A., Rimm, E. B., Roberts, A. L., Winning, A., & Kubzansky, L. D. (2017) · Psychological Medicine · doi:10.1017/s0033291716002294 · Cited by 136
“…stress hormone release by the hypothalamic – pituitary – adrenal (HPA) axis and the sympathetic – adrenal – medullary system is commonly observed in PTSD (Tsigos & Chrousos, 2002; de Kloet et al. 2006; Yehuda, 2006; Blechert et al. 2007), and other work has demonstrated that these disruptions…”
Zhang, J., Ronald, C. W., Kong, A. P. S., So, W. Y., Li, A. M., Lam, S. P., Li, S. X., Yu, M. W. M., Ho, C. S., Chan, M. H. M., et al. (2011) · SLEEP · doi:10.1093/sleep/34.2.225 · Cited by 137
Effects of Low- and High-Nicotine Cigarette Smoking on Mood States and the HPA Axis in Men
Mendelson, J. H., Sholar, M. B., Goletiani, N. V., Siegel, A. J., & Mello, N. K. (2005) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300753 · Cited by 135
“It is generally agreed that CRH stimulation of ACTH is one component of an integrated physiological response to ‘stress’ (Nemeroff, 1996; Tsigos and Chrousos, 2002).”
BackgroundPenninx, B. W. J. H., Beekman, A. T. F., Corsi, A. M., Bremmer, M., Hoogendijk, W. J., Guralnik, J. M., Ferrucci, L., & Bandinelli, S. (2007) · The American Journal of Geriatric Psychiatry · doi:10.1097/jgp.0b013e318033ed80 · Cited by 134
Xu, N., Tang, X.-H., Pan, W., Xie, Z.-M., Zhang, G.-F., Ji, M., Yang, J., Zhou, M.-T., & Zhou, Z. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00209 · Cited by 138
“…neuroimmune responses, and neurotransmitters/neuromodulators are involved in the pathogenesis of the comorbidity of chronic pain and depression (Tsigos and Chrousos, 2002; Jasmin et al., 2003; Schatzberg, 2004; Andre et al., 2005; Gameiro et al., 2006; Walker et al., 2014), however the…”
BackgroundEpigenetic programming of the neuroendocrine stress response by adult life stress
Dirven, B. C. J., Homberg, J. R., Kozicz, T., & Henckens, M. J. A. G. (2017) · Journal of Molecular Endocrinology · doi:10.1530/jme-17-0019 · Cited by 135
“As mentioned before, stress-related psychopathology is associated with HPA axis dysfunction (Tsigos & Chrousos 2002), which has clear clinical relevance; elevated basal cortisol has for example been shown predictive of the risk for depressive episodes (Goodyer et al.”
BackgroundMahon, P. B., Zandi, P. P., Potash, J. B., Nestadt, G., & Wand, G. S. (2012) · Psychopharmacology · doi:10.1007/s00213-012-2956-x · Cited by 140
“Dysregulation of the cortisol response to stress may be a risk factor for psychiatric illness (Holsboer 2000; Tsigos and Chrousos 2002).”
D’Mello, C., & Swain, M. G. (2011) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00184.2011 · Cited by 136
Effects of prenatal maternal stress on serotonin and fetal development
St‐Pierre, J., Laurent, L., King, S., & Vaillancourt, C. (2015) · Placenta · doi:10.1016/j.placenta.2015.11.013 · Cited by 137
The psychobiology of stress and intimate partner violence
Yim, I. S., & Kofman, Y. B. (2018) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2018.08.017 · Cited by 145
Richards, J. M., Stipelman, B. A., Bornovalova, M. A., Daughters, S. B., Sinha, R., & Lejuez, C. W. (2011) · Biological Psychology · doi:10.1016/j.biopsycho.2011.06.009 · Cited by 132
“Importantly, cortisol is not only involved in activating the physiological stress response, but also plays a regulatory role in terminating the stress response through negative feedback loop processes (Tsigos & Chrousos, 2002).”
BackgroundInfluentialPost-Traumatic Stress Disorder
Wentworth, B. A., Stein, M. B., Redwine, L. S., Xue, Y., Taub, P. R., Clopton, P., Nayak, K. R., & Maisel, A. S. (2012) · Cardiology in Review · doi:10.1097/crd.0b013e318265343b · Cited by 130
Role of glucocorticoid in developmental programming: Evidence from zebrafish
Nesan, D., & Vijayan, M. M. (2012) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2012.10.006 · Cited by 136
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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