Regulation of pituitary ACTH secretion during chronic stress
Abstract
Maintenance of adequate levels of response of the hypothalamic-pituitary-adrenal axis during chronic stress is important for survival. Three basic patterns of response can be identified depending on the type of stress: (a) desensitization of ACTH responses to the sustained stimulus, but hyperresponsiveness to a novel stress despite elevated plasma glucocorticoid levels, as occurs in physical-psychological paradigms; (b) no desensitization of ACTH response to the repeated stimulus and hyperresponsiveness to a novel stress, as occurs during repeated painful stress and insulin hypoglycemia; and (c) small and transient increases in ACTH, but sustained elevations of plasma corticosterone and diminished ACTH responses. The level of response of the pituitary corticotroph is determined by differential regulation of the hypothalamic regulators, corticotropin-releasing hormone (CRH) and vasopressin (VP), and the sensitivity of the negative glucocorticoid feedback. While osmotic stimulation increases VP expression in magnocellular neurons of the paraventricular (PVN) and supraoptic nuclei of the hypothalamus, chronic stress paradigms with high pituitary responsiveness are associated with activation of CRH and CRH/VP parvicellular neurons of the PVN, predominantly of the VP-containing population. While moderate increase of CRH output is important for stimulation of POMC transcription, the increase of the VP:CRH secretion ratio appears to be important in maintaining the secretory capacity of the pituitary corticotroph during chronic stimulation. Decreased sensitivity of the glucocorticoid feedback, probably due to interaction of glucocorticoid receptors with transcription factors induced by CRH and VP, is critical for the maintenance of ACTH responses in the presence of elevated plasma glucocorticoid levels during chronic stress. Although both CRH and VP receptors are activated and undergo regulatory variations during chronic stress, only the changes in VP receptor levels are parallel to the changes in pituitary ACTH responsiveness. The inhibitory effect of chronic osmotic stimulation on ACTH secretion in spite of high circulating levels of VP is probably the result of diminished activity of parvicellular PVN neurons and downregulation of pituitary VP receptors. Although the exact interaction between regulatory factors and the molecular mechanisms controlling the sensitivity of the corticotroph during adaptation to chronic stress remain to be determined, it is clear that regulation of the proportional secretion of CRH and VP in the PVN, modulation of pituitary VP receptors, and the sensitivity to feedback inhibition play a critical role.
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CRH and AVP are both required as stimulatory inputs to corticotrope cells for a complete ACTH response in physiologically normal and various stressful conditions.
“In essence, CRH and AVP are both required as stimulatory inputs to corticotrope cells for a complete ACTH response in physiologically normal as well as in various stressful conditions (32, 38, 48–51).”
From Influence of arginine vasopressin on the ultradian dynamics of Hypothalamic-Pituitary-Adrenal axis (2022) · cites this paper as [49]
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Schmidt, M. V., Sterlemann, V., & Müller, M. B. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1410.017 · Cited by 97 · see citing works
Wei, L., Sun, S., Zhang, J., et al. (2010) · Biochemistry and Cell Biology · doi:10.1139/o10-022 · Cited by 97 · see citing works
“Again, both hypoxic stress and high glucocorticoid levels may also be responsible for these changes and the hypothalamus–pituitary–adrenal gland (HPA) axis feedback might be involved (Khansari et al. 1990; Yang 2000; Aguilera 1994; Cai et al. 1997).”
BackgroundWalker, C., Toufexis, D. J., & Burlet, A. J. (2001) · Progress in brain research · doi:10.1016/s0079-6123(01)33008-x · Cited by 98 · see citing works
Rotondo, F., Butz, H., Syro, L. V., Yousef, G. M., Di Ieva, A., Restrepo, L. M., Quintanar-Stephano, A., Berczi, I., & Kovacs, K. (2016) · Pituitary · doi:10.1007/s11102-015-0703-0 · Cited by 93 · see citing works
The Molecular Pathogenesis of Corticotroph Tumors
Dahia, P. L. M., & Grossman, A. B. (1999) · Endocrine Reviews · doi:10.1210/edrv.20.2.0358 · Cited by 98 · see citing works
Savić, B., Murphy, D., & Japundžić‐Žigon, N. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.858941 · Cited by 102 · see citing works
“…ratio is dictated by the type of stressor, and is crucial for maintaining responsiveness of the HPA axis during chronic stress (Sawchenko and Swanson, 1982a; Swanson and Sawchenko, 1983; Whitnall et al., 1985; de Goeij et al., 1992; Aguilera, 1994; Sawchenko et al., 1996; Amaya et al., 2001).”
BackgroundMa, S., & Morilak, D. A. (2005) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2005.01372.x · Cited by 94 · see citing works
Könczöl, K., Bodnár, I., Zelena, D., Pintér, O., Papp, R. S., Palkovits, M., Nagy, G. M., & Tóth, Z. (2010) · Neurochemistry International · doi:10.1016/j.neuint.2010.04.012 · Cited by 94 · see citing works
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Psychological Stress in Children May Alter the Immune Response
Carlsson, E., Frostell, A. S., Ludvigsson, J., & Faresjö, M. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1301713 · Cited by 88 · see citing works
“The major neuroendocrine response to stress is via activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (2), where stimulation of the HPA axis increases the glucocorticoid (cortisol) secretion (3).”
BackgroundRegulation of pituitary corticotropin releasing hormone receptors
Aguilera, G., Rabadan‐Diehl, C., & Nikodémová, M. (2001) · Peptides · doi:10.1016/s0196-9781(01)00390-4 · Cited by 89 · see citing works
Self-citationRegulation of Pituitary Vasopressin V1b Receptor mRNA during Stress in the Rat
Rabadan‐Diehl, C., Lolait, S. J., & Aguilera, G. (1995) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.1995.tb00734.x · Cited by 86 · see citing works
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“showing increased expression of this gene after 14 days of repeated immobilization (33).”
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“Under chronic stress, AVP expression in the paraventricular nucleus is enhanced and AVP becomes the primary activator of corticotropin.(11) Vasopressin has been suggested to play the role of integrator between the behavioral and neuroendocrine responses to stress.”
Armando, I., Volpi, S., Aguilera, G., & Saavedra, J. M. (2007) · Brain Research · doi:10.1016/j.brainres.2007.01.037 · Cited by 86 · see citing works
“This is important to preserve homeostasis, limiting the duration and magnitude of the HPA axis response during stress (Aguilera, 1994; McEwen, 1998; Itoi et al., 1998; Ma and Aguilera, 1999a, b; Ginsberg et al., 2003).”
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Tsuda, M. C., & Ogawa, S. (2012) · PLoS ONE · doi:10.1371/journal.pone.0033028 · Cited by 86 · see citing works
“Both neuropeptides expressed in the brain are known as major regulators of HPA axis activity and have also been implicated in the expression of behavioral responses to stress [33–35].”
BackgroundSzemerszky, R., Zelena, D., Barna, I., & Bárdos, G. (2009) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2009.10.015 · Cited by 85 · see citing works
- Authors
- Aguilera, G.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Aguilera, Greti
- Venue
- Frontiers in Neuroendocrinology
- Publisher
- Elsevier BV
- Published
- 1994-12
- Volume
- 15
- Issue
- 4
- Pages
- 321-350
- ISSN
- 0091-3022 (ISSN-L)
- OpenAlex
- W2031934304
- Cited by
- 557
- References
- 0
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 14 · 2023: 16 · 2022: 11 · 2021: 12 · 2020: 11 · 2019: 14 · 2018: 11 · 2017: 17 · 2016: 21 · 2015: 19 · 2014: 14 · 2013: 18 · 2012: 18
- FWCI
- 5.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Frontiers in Neuroendocrinology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- ACTH secretion, chronic stress, hypothalamic-pituitary-adrenal axis, corticotropin-releasing factor, vasopressin, corticotrophs, glucocorticoid negative feedback, paraventricular nucleus, supraoptic nucleus, osmotic stimulation, glucocorticoid receptor, stress adaptation, corticosterone, insulin-induced hypoglycemia
- MeSH terms
- Adrenocorticotropic Hormone, Animals, Corticosterone, Corticotropin-Releasing Hormone, Glucocorticoids, Homeostasis, Humans, Hypothalamus, Pituitary Gland, Stress, Physiological, Vasopressins
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