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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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Citations
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Insulin resistance possible risk factor for cognitive impairment in fibromialgic patients
Fava, A., Plastino, M., Cristiano, D., Spanò, A., Cristofaro, S., Opipari, C., Chillà, A., Casalinuovo, F., Colica, C., De Bartolo, M., et al. (2013) · Metabolic Brain Disease · doi:10.1007/s11011-013-9421-3 · Cited by 31
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“Growth axis hormones and their receptors play a significant role in regulating growth, and the pituitary gland is a principal endocrine organ that participates in this process [26,27].”
BackgroundIsaksson, J., Allen, M., Nilsson, K. W., & Lindblad, F. (2015) · Acta Paediatrica · doi:10.1111/apa.13056 · Cited by 20
“Cortisol levels are controlled through a feedback system where cortisol interacts with glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) in the brain, promoting a decrease of cortisol release through inhibition of the synthesis and release of corticotropin-releasing factor in the hypothalamus and adre…”
BackgroundWang, H., Li, F., Miao, M., Yu, Y., Ji, H., Liu, H., Huang, R., Obel, C., Zhang, J., & Li, J. (2020) · Human Reproduction · doi:10.1093/humrep/deaa035 · Cited by 19
Kell, G., Rao, A., & Katsikitis, M. (2019) · Journal of Affective Disorders · doi:10.1016/j.jad.2018.12.062 · Cited by 17
Munk, A., Reme, S. E., & Jacobsen, H. B. (2021) · Frontiers in Psychology · doi:10.3389/fpsyg.2021.630422 · Cited by 16
Intestinal microbiota modulates adrenomedullary response through Nod1 sensing in chromaffin cells
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Zemestani, M., Babamiri, M., Griffiths, M. D., & Didehban, R. (2021) · Journal of Addictive Diseases · doi:10.1080/10550887.2021.1889752 · Cited by 12
Belal, M. M., Youssef, A. R., Baker, H., Elalaky, N. A., Marey, A. A., Quaisy, M. A., & Rabea, E. M. (2024) · Irish Journal of Medical Science (1971 -) · doi:10.1007/s11845-023-03526-z · Cited by 10
Relevance of cortisol and copeptin blood concentration changes in an experimental pain model
Blum, C. A., Velly, L., Brochet, C., Ziegler, F., Tavolacci, M.-P., Hausfater, P., & Lvovschi, V. E. (2022) · Scientific Reports · doi:10.1038/s41598-022-08657-4 · Cited by 8
Influence of arginine vasopressin on the ultradian dynamics of Hypothalamic-Pituitary-Adrenal axis
Stojiljković, A. S., Čupić, Ž., Maćešić, S., Ivanović-Šašić, A., & Kolar-Anić, L. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.976323 · Cited by 9
“d1⁄2CHOL dt = k1 − (k6 + k7)1⁄2CHOL 1⁄2ACTH − k101⁄2CHOL (1)”
MethodBiobehavioral measures as outcomes: A cautionary Tale
Kovach, C. R., Woods, D. L., Devine, E. C., Logan, B. R., & Raff, H. (2014) · Research in Gerontological Nursing · doi:10.3928/19404921-20131018-01 · Cited by 4
“Salivary cortisol is frequently used as a biomarker of psychological stress (Piazza, Almeida, Dmitrieva, & Klein, 2010) and measurement of cortisol in saliva provides a reliable marker of stress resulting from both physical discomfort and emotional stress (Chrousos, 2011; Weibel, 2003; Young, Abelson, & Lightman, 2004…”
MethodBindellini, D., Michelet, R., Aulin, L. B. S., Melin, J., Neumann, U., Blankenstein, O., Huisinga, W., Whitaker, M. J., Ross, R., & Kloft, C. (2024) · Journal of Pharmacokinetics and Pharmacodynamics · doi:10.1007/s10928-024-09934-7 · Cited by 4
“This assumption overlooked the known contributions of other glucocorticoids to the feedback mechanism [ 44, 45].”
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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