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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
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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 HPA axis is a neuroendocrine system involved in maintaining homeostasis in mammalian organisms under physiological conditions and stress, and cortisol is the principal hormone of HPA axis in humans (7, 8).”
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A potential impact of Helicobacter pylori -related galectin-3 in neurodegeneration
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“Several hormones and neuropeptides mediate signaling between gut and the brain, under the regulation of the hypothalamicpituitary-adrenal axis and the autonomic nervous system (Tsigos and Chrousos, 2002).”
Işık, Ü., Bi̇lgi̇ç, A., Toker, A., & Kılınç, İ. (2018) · Psychiatry Research · doi:10.1016/j.psychres.2017.12.076 · Cited by 32
“Cortisol secretion has a diurnal variation and is characterized by high levels during awakening, a further increase during the morning, and a gradual decrease throughout the day until midnight (Tsigos and Chrousos, 2002).”
Zoeram, S. B., Salmani, M. E., Lashkarbolouki, T., & Goudarzi, I. (2018) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2018.11.009 · Cited by 33
Sex-biased transcriptomic response of the reproductive axis to stress
Calisi, R. M., Austin, S. H., Lang, A. S., & MacManes, M. D. (2018) · Hormones and Behavior · doi:10.1016/j.yhbeh.2017.11.011 · Cited by 31
“, 2004) which can affect the stress response (Tsigos and Chrousos, 2002).”
Hoyt, M. A., Mazza, M. C., Ahmad, Z. N., Darabos, K., & Applebaum, A. J. (2020) · International Journal of Behavioral Medicine · doi:10.1007/s12529-019-09842-y · Cited by 34
The longitudinal association of changes in diurnal cortisol features with fasting glucose: MESA
Dias, J. P., Joseph, J. J., Kluwe, B., Zhao, S., Shardell, M. D., Seeman, T. E., Needham, B. L., Wand, G. S., Kline, D., Brock, G. N., et al. (2020) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2020.104698 · Cited by 30
“Second, activation of the HPA axis with greater cortisol burden or exposure due to inflammatory, traumatic, or psychological stresses and/or depression which are more prevalent in diabetes (Roy et al., 1987; Chrousos, 1995; Tsigos and Chrousos, 2002; Kyrou et al., 2006; Mezuk et al., 2008; Joseph and Golden, 2017).”
BackgroundWolkow, A. P., Aisbett, B., Reynolds, J., Ferguson, S. A., & Main, L. C. (2015) · International Archives of Occupational and Environmental Health · doi:10.1007/s00420-015-1085-3 · Cited by 36
Bahí, A., & Dreyer, J. (2013) · Psychopharmacology · doi:10.1007/s00213-013-3243-1 · Cited by 32
“As a matter of fact, several studies demonstrate that alcohol actually induces the stress response by stimulating hormone release by the hypothalamus, pituitary, and adrenal glands (Krishnan et al. 1991; Tsigos and Chrousos 2002; Wand and Dobs 1991).”
BackgroundDefensive responses of Brandt's voles (Lasiopodomys brandtii) to chronic predatory stress
Hegab, I. M., Shang, G., Ye, M., Jin, Y., Wang, A., Yin, B., Yang, S., & Wei, W. (2013) · Physiology & Behavior · doi:10.1016/j.physbeh.2013.12.001 · Cited by 32
Mind over matter: psychological factors and the menstrual cycle
Edozien, L. C. (2006) · Current Opinion in Obstetrics & Gynecology · doi:10.1097/01.gco.0000233942.67049.ad · Cited by 32
Finy, M. S., Bresin, K., Korol, D. L., & Verona, E. (2014) · Development and Psychopathology · doi:10.1017/s0954579414000212 · Cited by 36
“…abnormalities in HPA axis activity have been associated with numerous mental disorders and problematic behaviors (Bale, 2006; Chrousos & Gold, 1992; Dorn & Chrousos, 1993; Holsboer, 1989; Raison & Miller, 2003; Stansbury & Gunnar, 1994; Stratakis & Chrousos, 1995; Tsigos & Chrousos, 1994, 2002).”
BackgroundNyberg, C. H. (2011) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2011.06.002 · Cited by 33
“By extension, the HPA axis also serves as a key mechanism of developmental plasticity, modulating competing life history domains of growth (Sloboda et al., 2009; Tsigos and Chrousos, 2002), maintenance (i.”
BackgroundHudson, B. F., Davidson, J., & Whiteley, M. S. (2015) · International Journal of Nursing Studies · doi:10.1016/j.ijnurstu.2015.07.009 · Cited by 32
Najafi, P., & Moghadasi, M. (2016) · Complementary Therapies in Clinical Practice · doi:10.1016/j.ctcp.2016.11.006 · Cited by 32
Modelling cholesterol effects on the dynamics of the hypothalamic–pituitary–adrenal (HPA) axis
Marković, V. M., Čupić, Ž., Maćešić, S., Stanojević, A., Vukojević, V., & Kolar-Anić, L. (2016) · Mathematical Medicine and Biology · doi:10.1093/imammb/dqu020 · Cited by 31
“…complex, exhibiting ultradian oscillations that are superimposed on the circadian ones.1 In humans, the period of cortisol ultradian oscillations can be in the range between 20 and 120 min, while the circadian period is ∼24 h (Tsigos & Chrousos, 2002; Hartmann et al., 1997; Gavrila et al., 2003).”
BackgroundBay, E., Sikorskii, A., & Gao, F. (2009) · Biological Research For Nursing · doi:10.1177/1099800408326453 · Cited by 43
“…secretion is pulsatile and rhythmic in response to day-to-day stress, with higher levels in the early morning and lower levels toward bedtime (Tsigos & Chrousos, 2002), in response to chronic stress, cortisol can show patterns of sustained hypersecretion, hyposecretion, or dysregulation…”
BackgroundWass, S. V. (2021) · Developmental Review · doi:10.1016/j.dr.2021.100978 · Cited by 36
Yang, K., Jian, S., Wen, C., Guo, D., Liao, P., Wen, J., Kuang, T., Han, S., Liu, Q., & Deng, B. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.847966 · Cited by 35
Miller, S. L., Serpell, J. A., Dalton, K. R., Waite, K. B., Morris, D. O., Redding, L. E., Dreschel, N. A., & Davis, M. F. (2022) · Frontiers in Veterinary Science · doi:10.3389/fvets.2022.844252 · Cited by 45
“Cortisol mobilizes and mediates internal coping responses by initiating functional changes within various physiological processes and pathways across different brain and body systems [(65, 66, 68) as cited in (40, 62, 63)].”
BackgroundCortisol sensing by optical sensors
Santonocito, R., Puglisi, R., Cavallaro, A., Pappalardo, A., & Sfrazzetto, G. T. (2023) · The Analyst · doi:10.1039/d3an01801f · Cited by 34
Ma, X., Park, H.-S., Shin, Y.-J., Kim, J.-K., Hong, J. K., Han, S.-W., Yoon, I., & Kim, D. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03211-7 · Cited by 31
“Excessive exposure to stressors, such as social defeat and pathogens, triggers the adrenal release of glucocorticoids, which can lead to anxiety and/or depression and subsequently induce systemic inflammation, including neuroinflammation [4, 5].”
BackgroundPrevalensi dan Determinan Sindrom Metabolik pada Kelompok Eksekutif di Jakarta dan Sekitarnya
Kamso, S., Purwantyastuti, P., Lubis, D. U., Juwita, R., Robbi, Y. K., & Besral, B. (2011) · Kesmas National Public Health Journal · doi:10.21109/kesmas.v6i2.110 · Cited by 31
Todkar, A., Granholm, L., Aljumah, M., Nilsson, K. W., Comasco, E., & Nylander, I. (2016) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2015.00090 · Cited by 31
“8:90. doi: 10.3389/fnmol.2015.00090 HPA Axis Gene Expression and DNA Methylation Profiles in Rats Exposed to Early Life Stress, Adult Voluntary Ethanol Drinking and Single Housing Aniruddha Todkar1, Linnea Granholm2, Mujtaba Aljumah1, Kent W. Nilsson3, Erika Comasco1*† and Ingrid Nylander2*† 1…”
InfluentialChange in parent-child conflict and the HPA-axis: Where should we be looking and for how long?
Kuhlman, K. R., Repetti, R. L., Reynolds, B. M., & Robles, T. F. (2016) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2016.02.029 · Cited by 31
“Among healthy individuals, cortisol is highest in the morning and continues to decline across the day (Tsigos and Chrousos, 2002).”
Sun, Y., Li, W., Chen, Y., Yao, Y., & Pan, Y. (2016) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s99644 · Cited by 32
Mikkelsen, S., Forman, J. L., Fink, S., Vammen, M. A., Thomsen, J. F., Grynderup, M. B., Hansen, Å. M., Kærlev, L., Kolstad, H. A., Rugulies, R., et al. (2017) · International Archives of Occupational and Environmental Health · doi:10.1007/s00420-017-1241-z · Cited by 31
“…secretion have been associated with a number of different somatic and mental disorders (Chrousos and Kino 2007; Kudielka and Wust 2010; McEwen 1998; Tsigos and Chrousos 2002), for example hypertension (Wirtz et al. 2007), ischaemic heart disease (Bhattacharyya et al. 2008; Kumari et al. 2011;…”
BackgroundCorticotropin-Releasing Hormone Family and Their Receptors in the Cardiovascular System
Takefuji, M., & Murohara, T. (2018) · Circulation Journal · doi:10.1253/circj.cj-18-0428 · Cited by 33
González‐Castro, T. B., Escobar-Chan, Y. M., Fresán, A., López‐Narváez, M. L., Tovilla‐Zárate, C. A., Juárez‐Rojop, I. E., Blé‐Castillo, J. L., Mendoza, A. D. G., & Vázquez, P. I. A. (2019) · Journal of Health Psychology · doi:10.1177/1359105319876326 · Cited by 34
“, 2002), alterations in corticotrophin-releasing hormone levels (Chiodini et al., 2005; Strachan et al., 2011; Tsigos and Chrousos, 2002), and neurotrophins (Zhou et al.”
BackgroundVasconcelos, M., Stein, D. J., Gallas‐Lopes, M., Landau, L. J. B., & de Almeida, R. M. M. (2020) · Trends in Psychiatry and Psychotherapy · doi:10.1590/2237-6089-2018-0027 · Cited by 36
Psychological Stress Detection According to ECG Using a Deep Learning Model with Attention Mechanism
Zhang, P., Li, F., Du, L., Zhao, R., Chen, X., Yang, T., & Fang, Z. (2021) · Applied Sciences · doi:10.3390/app11062848 · Cited by 33
“This change strengthens the human body’s functions, making it easier to meet challenges [6].”
The second brain: The connection between gut microbiota composition and multiple sclerosis
Farshbafnadi, M., Agah, E., & Rezaei, N. (2021) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2021.577700 · Cited by 31
The Gut Microbiota-Brain Axis: A New Frontier on Neuropsychiatric Disorders
Queiroz, S. A. L., Ton, A. M. M., Pereira, T. D. M. C., Campagnaro, B. P., Martinelli, L., Picos, A., Campos‐Toimil, M., & Vasquez, E. C. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.872594 · Cited by 34
Nazzari, S., Grumi, S., Mambretti, F., Villa, M., Giorda, R., Provenzi, L., MOM-COPE Study Group, Borgatti, R., Biasucci, G., Decembrino, L., et al. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02160-0 · Cited by 36
“The hypothalamic–pituitary–adrenal (HPA) axis is key in regulating the mobilization of energy in the organism [14].”
BackgroundNeuropathic Pain, Depression, and Cardiovascular Disease: A National Multicenter Study
Cragg, J. J., Noonan, V. K., Noreau, L., Borisoff, J., & Kramer, J. K. (2015) · Neuroepidemiology · doi:10.1159/000377726 · Cited by 32
Newby, E. A., Myers, D. A., & Ducsay, C. A. (2015) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00126.2015 · Cited by 37
Early deprivation reduced anxiety and enhanced memory in adult male rats
Zhang, X., Wang, B., Jin, J., An, S., Zeng, Q., Duan, Y., Yang, L., Ma, J., & Cao, X. (2014) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2014.08.005 · Cited by 31
Spoon, T. R., & Romano, T. A. (2011) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2011.08.003 · Cited by 31
“…production, cell trafficking and migration, antibody secretion, gene expression, phagocytosis, and respiratory burst activity (Elenkov et al., 2000; Elenkov and Chrousos, 2002; Elenkov, 2004; Madden, 2003; Mignini et al., 2003; Moynihan, 2003; Padgett and Glaser, 2003; Tsigos and Chrousos, 2002).”
Background
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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