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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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“The first acute response to a stressor involves the activation of the hypothalamic-pituitaryadrenal axis, represented mainly by elevated adrenocorticotropic hormone (ACTH) levels [33,34].”
BackgroundHegab, I. M., Wang, A., Yin, B., Yang, S., & Wanhong, W. (2013) · European Journal of Wildlife Research · doi:10.1007/s10344-013-0790-z · Cited by 28
“…assumed that behavioral outcomes of preys under predation risk are controlled mainly by endocrine changes in hypothalamic–pituitary–adrenal axis (HPA) which in turn facilitate the display of the behavioral responses (Blanchard et al. 1998; Tsigos and Chrousos 2002; Figueiredo et al. 2003).”
BackgroundGarcía‐Gutiérrez, M. S., & Manzanares, J. (2009) · Journal of Psychopharmacology · doi:10.1177/0269881109106910 · Cited by 30
“Alterations in the hypothalamic–pituitary– adrenal (HPA) axis are closely related to anxiety- and mood-related behaviours in animals and humans (Arborelius et al., 1999; Tsigos and Chrousos, 2002).”
BackgroundSwart, P., Swart, A. C., Louw, A., & van der Merwe, K. J. (2003) · BioEssays · doi:10.1002/bies.10285 · Cited by 28
Effects of the cortisol stress response on the psychotherapy outcome of panic disorder patients
Wichmann, S., Kirschbaum, C., Lorenz, T., & Petrowski, K. (2016) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2016.11.030 · Cited by 30
Tsai, J., & Shen, J. (2017) · Psychiatric Quarterly · doi:10.1007/s11126-017-9508-9 · Cited by 28
Minias, P., Włodarczyk, R., & Meissner, W. (2017) · Functional Ecology · doi:10.1111/1365-2435.12991 · Cited by 28
Exercise, the diurnal cycle of cortisol and cognitive impairment in older adults
Tortosa‐Martínez, J., Manchado, C., Cortell-Tormo, J. M., & Chulvi‐Medrano, I. (2018) · Neurobiology of Stress · doi:10.1016/j.ynstr.2018.08.004 · Cited by 28
Choudhury, B. K., Shi, X.-Z. P., & Sarna, S. K. (2009) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.90673.2008 · Cited by 28
“Peripheral inflammation activates the hypothalamus-pituitaryadrenal gland axis that plays a critical role in the course of the inflammatory response (25, 33, 45).”
BackgroundRegulatory interactions of stress and reward on rat forebrain opioidergic and GABAergic circuitry
Christiansen, A. M., Herman, J. P., & Ulrich‐Lai, Y. M. (2011) · Stress · doi:10.3109/10253890.2010.531331 · Cited by 27
Ram, S., Howland, M. A., Sandman, C. A., Davis, E. P., & Glynn, L. M. (2018) · Clinical Psychological Science · doi:10.1177/2167702618811079 · Cited by 28
The capacity for acute exercise to modulate emotional memories: A review of findings and mechanisms
Keyan, D., & Bryant, R. A. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.09.033 · Cited by 27
Isaksson, J., Lindblad, F., Valladares, E., & Högberg, U. (2015) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2015.09.016 · Cited by 27
Bagosi, Z., Csabafi, K., Palotai, M., Jászberényi, M., Földesi, I., Gardi, J., Szabó, G., & Telegdy, G. (2013) · Neuropeptides · doi:10.1016/j.npep.2013.07.001 · Cited by 27
“CRF is the principal activator of the hypothalamic-pituitary adrenal (HPA) axis (Carrasco and Van de Kar, 2003; Tsigos and Chrousos, 2002).”
BackgroundMolecular genetics of the stress‐responsive adrenocortical axis
Redei, E. E. (2008) · Annals of Medicine · doi:10.1080/07853890701724863 · Cited by 26
“If not, as in situations of chronic stress, sustained high cortisol levels have deleterious effects on the organism (13,21).”
BackgroundKoizumi, M., & Yada, T. (2008) · Journal of Endocrinology · doi:10.1677/joe-07-0462 · Cited by 27
“2002, Tsigos & Chrousos 2002, Kyrou et al .”
BackgroundGerwin, R. D. (2010) · Springer eBooks · doi:10.1007/978-3-642-05468-6_2 · Cited by 27
“1998), decreased thyroid release of T4, and inhibition of 50-deiodinase I (Feelders et al. 1999; Michalaki et al. 2001; Tsigos and Chrousos 2002).”
BackgroundRole of shame and body esteem in cortisol stress responses
Lupis, S. B., Sabik, N. J., & Wolf, J. M. (2015) · Journal of Behavioral Medicine · doi:10.1007/s10865-015-9695-5 · Cited by 37
“Symptoms of allostatic load, in turn, are associated with a host of negative physiological and mental health outcomes (Goldstein & McEwen, 2002; McEwen & Seeman, 1999; Tsigos & Chrousos, 2002).”
BackgroundAssessing the neuroendocrine stress response in the functional neuroimaging context
King, A. P. J., & Liberzon, I. (2009) · NeuroImage · doi:10.1016/j.neuroimage.2009.05.055 · Cited by 28
“of thyroid gland (thyroid stimulating hormone (TSH) regulating thyroxin), gonads (gonadotropins regulating sex steroids), and liver (growth hormone (GH) regulating production of insulin-like growth factor I (IGF-I)) (Tsigos and Chrousos, 2002).”
InfluentialIversen, M. H., & Eliassen, R. A. (2009) · Journal of the World Aquaculture Society · doi:10.1111/j.1749-7345.2009.00244.x · Cited by 27
Tsai, P., Chang, N., Chang, W., Lee, P., & Wang, M.-Y. (2007) · The Journal of Alternative and Complementary Medicine · doi:10.1089/acm.2007.6289 · Cited by 27
“21,22 The question of whether or not BP biofeedback has an effect on the HPA axis remained to be studied.”
Aghajanian, S., Shafiee, A., Athar, M. M. T., Mohammadifard, F., Goodarzi, S., Abianeh, F. E., & Elsamadicy, A. A. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm13113247 · Cited by 28
“Furthermore, depressive symptoms can influence patients’ adherence to prescribed medical regimens, affecting their biological milieu through neuroendocrine and inflammatory mechanisms [38,39].”
BackgroundNeigh, G. N., Karelina, K., Zhang, N., Glasper, E. R., Owens, M. J., Plotsky, P. M., Nemeroff, C. B., & DeVries, A. C. (2009) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2009.85 · Cited by 26
“Given the established role of HPA axis pathology in depressive and anxiety disorders (Tsigos and Chrousos, 2002), and the increased incidence of affective disorders in CA/CPR survivors (Ladwig et al, 1999; Wachelder et al, 2009), we sought to establish whether CA/CPR caused long-term changes in the…”
BackgroundPhysiologische Wirkmechanismen des Sports unter Stress
Gerber, M. (2017) · Springer eBooks · doi:10.1007/978-3-662-49322-9_10 · Cited by 26
Role of the PACAP system of the extended amygdala in the acoustic startle response in rats
Seiglie, M. P., Huang, L., Cottone, P., & Sabino, V. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2019.107761 · Cited by 26
“However, hyperactivation of these fundamental arousal and emotional systems may be key to the pathogenesis of conditions involving abnormal responses to stressors [5, 6].”
BackgroundWang, S., Shi, W., Zhang, G., Zhang, X., Ma, C., Zhao, K., Cong, B., & Li, Y. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00511 · Cited by 26
Towards early detection of neurodegenerative diseases: A gut feeling
Makdissi, S., Parsons, B., & Cara, F. D. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1087091 · Cited by 28
“Vagal afferent signaling has been implicated modulating mood and affect, including distinct forms of anxiety and fear and are involved in the activation/regulation of the Hypothalamic Pituitary Adreno axis, which coordinates the adaptive responses to stressors of any kind (Tsigos and Chrousos, 2002; Howland, 2014).”
BackgroundThe Hypothalamic-Pituitary-Gonadal Axis in Men with Schizophrenia
Matuszewska, A., Kowalski, K., Jawień, P., Tomkalski, T., Gaweł-Dąbrowska, D., Merwid‐Ląd, A., Szeląg, E., Błaszczak, K., Wiatrak, B., Danielewski, M., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24076492 · Cited by 30
“GnRH release is regulated by the CNS and ANS [30,31].”
BackgroundFucoidan prevents depression-like behavior in rats exposed to repeated restraint stress
Lee, B., Shim, I., Lee, H., & Hahm, D. (2012) · Journal of Natural Medicines · doi:10.1007/s11418-012-0712-5 · Cited by 26
“ability to appropriately regulate physiological and behavioral responses to subsequent stressors [10].”
BackgroundMa, Y., Matsuwaki, T., Yamanouchi, K., & Nishihara, M. (2013) · Brain Research · doi:10.1016/j.brainres.2013.02.042 · Cited by 26
Anxiolytic medication is an independent risk factor for 30-day morbidity or mortality after surgery
Ward, N., Roth, J. S., Lester, C., Mutiso, L. A., Lommel, K. M., & Davenport, D. L. (2015) · Surgery · doi:10.1016/j.surg.2015.03.050 · Cited by 26
Konishi, M., Takahashi, M., Endo, N., Numao, S., Takagi, S., Miyashita, M., Midorikawa, T., Suzuki, K., & Sakamoto, S. (2012) · Journal of Sports Sciences · doi:10.1080/02640414.2012.733824 · Cited by 26
“…hypothalamic-pituitary-adrenocortical axis by sleep deprivation may contribute to the reduction of heart rate during exercise tolerance testing because activation of the hypothalamic-pituitary-adrenocortical axis leads to sympathetic activation, which increases heart rate (Tsigos & Chrousos, 2002).”
BackgroundAssessing stress in Western Hudson Bay polar bears using hair cortisol concentration as a biomarker
Mislan, P., Derocher, A. E., Louis, V. L. S., Richardson, E. S., Lunn, N. J., & Janz, D. M. (2016) · Ecological Indicators · doi:10.1016/j.ecolind.2016.06.034 · Cited by 28
Everyday Support to Aging Parents: Links to Middle-Aged Children’s Diurnal Cortisol and Daily Mood
Bangerter, L. R., Liu, Y., Kim, K., Zarit, S. H., Birditt, K. S., & Fingerman, K. L. (2016) · The Gerontologist · doi:10.1093/geront/gnw207 · Cited by 26
“Cortisol secretion follows a diurnal cycle with a large increase released into the bloodstream after awakening and a steady decline throughout the day with lowest levels during the first half of the night (Tsiqos & Chrousos, 2002).”
Ho, R., Wan, A. H. Y., Chan, J. S. M., Ng, S., Chung, K., & Chan, C. (2017) · BMC Complementary and Alternative Medicine · doi:10.1186/s12906-017-1898-6 · Cited by 26
Wass, S. V. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.03.029 · Cited by 29
Precision medicine in perinatal depression in light of the human microbiome
Bernabé, B. P., Maki, P. M., Dowty, S. M., Salas, M. L. C., Cralle, L. E., Shah, Z., & Gilbert, J. A. (2020) · Psychopharmacology · doi:10.1007/s00213-019-05436-4 · Cited by 26
“…(in a sex-dependent manner due to the cross-reactivity of female gonadal hormones (Oyola and Handa 2017)), which modulates immune responses (Tsigos and Chrousos 2002) and regulates the gut-epithelial barrier (Farhadi et al. 2003; Maes et al. 2008), as well as enteroendocrine and gut…”
BackgroundFibromyalgia: a rheumatologic diagnosis?
Endresen, G. K. M. (2007) · Rheumatology International · doi:10.1007/s00296-007-0402-x · Cited by 26
“IBS and premenstrual syndrome remain unclear [27, 31, 32, 43–47].”
BackgroundPhysiological restitution after night‐call duty in anaesthesiologists: impact on metabolic factors
Malmberg, B., Persson, R., Jönsson, B., Erfurth, E. M., Flisberg, P., Ranklev, E., & Ørbæk, P. (2007) · Acta Anaesthesiologica Scandinavica · doi:10.1111/j.1399-6576.2007.01350.x · Cited by 26
“In comparison to cortisol, TSH is more easily affected in this respect (12, 29).”
BackgroundNakamura, K., Fujiwara, Y., Mizutani, R., Sanbe, A., Miyauchi, N., Hiroyama, M., Yamauchi, J., Yamashita, T., Nakamura, S., Mori, T., et al. (2008) · Endocrinology · doi:10.1210/en.2007-1528 · Cited by 25
Underlying mechanisms of mindfulness meditation: Genomics, circuits, and networks
Gu, Y., & Zhu, Y. (2022) · World Journal of Psychiatry · doi:10.5498/wjp.v12.i9.1141 · Cited by 36
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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