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Circadian endocrine rhythms: the hypothalamic–pituitary–adrenal axis and its actions
Open accessAbstract
The stress system effectively restores the internal balance—or homeostasis—of living organisms in the face of random external or internal changes, the stressors. This highly complex system helps organisms to provide a series of neuroendocrine responses to stressors—the stress response—through coordinated activation of the hypothalamic–pituitary–adrenal (HPA) axis and the locus coeruleus/norepinephrine autonomic nervous systems. In addition to stressors, life is influenced by daily light/dark changes due to the 24‐h rotation of Earth. To adjust to these recurrent day/night cycles, the biological clock system employs the heterodimer of transcription factors circadian locomotor output cycle kaput/brain–muscle–arnt–like protein 1 (CLOCK/BMAL1), along with a set of other transcription factors, to regulate the circadian pattern of gene expression. Interestingly, the stress system, through the HPA axis, communicates with the clock system; therefore, any uncoupling or dysregulation could potentially cause several disorders, such as metabolic, autoimmune, and mood disorders. In this review, we discuss the biological function of the two systems, their interactions, and the clinical implications of their dysregulation or uncoupling.
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“These pathways are tightly and bi-directionally linked with HPA axis activity (Lee et al. 2013;Nicolaides et al. 2014)”
From The HPA axis in bipolar disorder: Systematic review and meta-analysis (2016) · cites this paper as Nicolaides et al. 2014
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“Furthermore, long-term activation of the stress system can increase the risk of obesity, heart disease, depression and a variety of other illnesses (Chrousos & Gold, 1992; Chrousos, 2009; Nicolaides et al., 2014).”
BackgroundAttention to Innate Circadian Rhythm and the Impact of Its Disruption on Diabetes
Lee, D. Y., Jung, I., Park, S. Y., Yu, J. H., Seo, J. A., Kim, K. J., Kim, N. H., Yoo, H. J., Kim, S. G., Choi, K. M., et al. (2024) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2023.0193 · Cited by 21
“It can activate the release of corticotropin-releasing hormone and adrenocorticotropic hormone via the PVN [30] and the sympathetic nervous system (SNS) [31].”
BackgroundRapson, A., Collman, E., Faustini, S. E., Yonel, Z., Chapple, I., Drayson, M. T., Richter, A. G., Campbell, J. P., & Heaney, J. L. J. (2019) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2019.09.018 · Cited by 21
Postoperative cognitive dysfunction: spotlight on light, circadian rhythms, and sleep
Campbell, E., & Figueiro, M. G. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2024.1390216 · Cited by 20
“Just as the SCN regulates cortisol secretion, cortisol levels in turn influence circadian rhythms through glucocorticoid response elements (GREs) located in the peripheral circadian clocks (Nicolaides et al., 2014).”
BackgroundRowe, R. K., & Griesbach, G. S. (2022) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2022.04.017 · Cited by 21
Peris-Ramos, H. C., Carreira-Míguez, M., Rodríguez-Besteiro, S., David-Fernandez, S., & Clemente‐Suárez, V. J. (2024) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph21040385 · Cited by 28
“The goal of this complex reaction is to maintain organic homeostasis through cardiovascular, metabolic, and immunological processes [2].”
BackgroundRoa, S. L. R., Martínez, E. Z., Martins, C. S., Antonini, S. R. R., de Castro, M., & Moreira, A. C. (2017) · Endocrinology · doi:10.1210/en.2016-1782 · Cited by 20
Mihailidou, C., Panagiotou, C., Kiaris, H., Kassi, E. N., & Moutsatsou, P. (2016) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2016.08.001 · Cited by 19
“GR receptoractivity ismodulatedbypost-translationalmodifications such as phosphorylation, the phosphorylation sites of human GR being located in itsN-terminal region (Ratmanet al., 2013;Nicolaides et al., 2014; Kadmiel and Cidlowski, 2013).”
BackgroundRetractedFennell, K. A., Busby, R. G. G., Li, S., Bodden, C., Stanger, S. J., Nixon, B., Short, A. K., Hannan, A. J., & Pang, T. Y. (2020) · Scientific Reports · doi:10.1038/s41598-020-72560-z · Cited by 19
Rapid volumetric brain changes after acute psychosocial stress
Uhlig, M., Reinelt, J. D., Lauckner, M. E., Kumral, D., Schaare, H. L., Mildner, T., Babayan, A., Möller, H. E., Engert, V., Villringer, A., et al. (2022) · NeuroImage · doi:10.1016/j.neuroimage.2022.119760 · Cited by 19
Biological Rhythms Advance in Depressive Disorder
Hong, W., & Zhang, Q. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-981-32-9271-0_6 · Cited by 18
Erythropoietin negatively regulates pituitary ACTH secretion
Dey, S., Scullen, T. A., & Noguchi, C. T. (2015) · Brain Research · doi:10.1016/j.brainres.2015.02.052 · Cited by 17
Transcriptome Profile in Unilateral Adrenalectomy-Induced Compensatory Adrenal Growth in the Rat
Jopek, K., Tyczewska, M., Celichowski, P., Malendowicz, L. K., & Ruciński, M. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19041111 · Cited by 17
The impact of night-shift work on platelet function in healthy medical staff
Nakao, T., Yasumoto, A., Tokuoka, S. M., Kita, Y., Kawahara, T., Daimon, M., & Yatomi, Y. (2018) · Journal of Occupational Health · doi:10.1539/joh.2018-0027-fs · Cited by 17
“To assess the platelet aggregation rate and serum concentration of eicosanoid 13 mediators, fasting venous blood was collected from each subject at the following 14 times: (1) on day-shift work without previous night-shift work (baseline), and (2) 15 after night-shift work (post-shift).”
MethodMurray, A., Tharmalingam, S., Khurana, S., Lalonde, C., Nguyen, P., & Tai, T. C. (2022) · Cells · doi:10.3390/cells11101613 · Cited by 16
“Under situations of stress, GCs are released from the adrenal gland through the activation of the hypothalamic-pituitary-adrenal (HPA) axis [16,25,26] and interact with the glucocorticoid receptor (GR), which is expressed in all tissues with notable exception of the SCN [27].”
BackgroundCircadian Biology and the Neurovascular Unit
Li, W., Tiedt, S., Lawrence, J. H., Harrington, M. E., Musiek, E. S., & Lo, E. H. (2024) · Circulation Research · doi:10.1161/circresaha.124.323514 · Cited by 17
“32,33 36 Circadian rhythms are already present and necessary during synaptogenesis: in larval zebrafish, the rate of synaptogenesis decreased during daytime (ie, when zebrafish are more active) and increased during night-time—a pattern that was preserved during constant darkness.”
BackgroundRole of 11β-hydroxysteroid dehydrogenase type 1 in the development of atopic dermatitis
Lee, N. R., Kim, B. J., Lee, C. H., Lee, Y. B., Lee, S., Hwang, H. J., Kim, E., Kim, S. H., Lee, M., Lee, S. E., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-77281-x · Cited by 17
Das, M., Minocha, T., Kumar, D., Yadav, S. K., & Haldar, C. (2022) · Photochemical & Photobiological Sciences · doi:10.1007/s43630-022-00210-6 · Cited by 15
“During prenatal days or early pregnancy, endometrial receptivity and implantation is highly coordinated process that requires synchronized timing between circadian clock systems with neuroendocrine hormones of hypothalamus–pituitary–gonadal (HPG) axis [42, 44].”
BackgroundLin, Y., Jen, H., Lin, Y., Seo, J., & Chang, W. (2022) · BioMed Research International · doi:10.1155/2022/9506583 · Cited by 14
“HPA axis stimulation has a stronger impact on hormones when it takes place in the morning than when it happens in the evening [5].”
Panagiotou, K., Stefanou, G., Kourlaba, G., Athanasopoulos, D., Kassari, P., & Charmandari, E. (2024) · Nutrients · doi:10.3390/nu16213700 · Cited by 18
“However, more clinical studies should be carried out with a variety of participants, including children and adolescents, and a longer duration of intervention in order to draw safer conclusions.”
BackgroundSelf-citationBehavioral and Transcriptomic Changes Following Brain-Specific Loss of Noradrenergic Transmission
Isingrini, E., Guinaudie, C., Perret, L. C., Guma, E., Gorgievski, V., Blum, I. D., Colby-Milley, J., Bairachnaya, M., Mella, S., Adamantidis, A., et al. (2023) · Biomolecules · doi:10.3390/biom13030511 · Cited by 17
From circadian clocks to non-alcoholic fatty liver disease
Ji, Y., Elkin, K. B., Yip, J., Guan, L., Han, W., & Ding, Y. (2019) · Expert Review of Gastroenterology & Hepatology · doi:10.1080/17474124.2019.1684899 · Cited by 14
Bao, C., Jin, D., Sun, S., Xu, L., Wang, C., Tang, W., Zhang, W., Bao, Y., Xu, D., Zhou, S., et al. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.762719 · Cited by 15
“In general, cortisol levels have a significant circadian rhythm in humans with higher levels in the morning and lower levels in the evening (19).”
BackgroundSallam, A. E.-D., Hassan, S. A., Hassaneen, E., & Ali, E. M. (2016) · Biological Rhythm Research · doi:10.1080/09291016.2016.1173361 · Cited by 14
“…these circadian and stress-related responses are achieved by two highly conserved and interrelated regulatory networks; the circadian and stress systems, which respectively consist of oscillating molecular pacemakers and the hypothalamic-pituitary-adrenal (HPA) axis (Nicolaides et al. 2014).”
BackgroundGewehr, M. C. F., Silvério, R., Neto, J. C. R., Lira, F. S., Reckziegel, P., & Ferro, E. S. (2020) · Molecules · doi:10.3390/molecules25051093 · Cited by 15
Mezhibovsky, E., Tveter, K. M., Villa-Rodríguez, J. A., Bacalia, K. M. A., Kshatriya, D., Desai, N., Cabales, A., Wu, Y., Sui, K., Duran, R. M., et al. (2023) · Journal of the Endocrine Society · doi:10.1210/jendso/bvad095 · Cited by 12
“Both BA metabolism and the HPAA are influenced by the circadian clock system which is uncoupled by HFD feeding [19-21].”
BackgroundMiller, L. A., Careaga, M. B. L., Handa, R. J., & Wu, T. J. (2022) · Neuroscience · doi:10.1016/j.neuroscience.2022.06.011 · Cited by 13
Deer, L. K., Chen, S., Thwaites, N. A., Davis, E. P., & Doom, J. R. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1111474 · Cited by 13
The Role of Circulating β-endorphin in Different Stress Models in Equines: A Review
Ferlazzo, A., Fazio, E., Cravana, C., & Medica, P. (2018) · Journal of Equine Veterinary Science · doi:10.1016/j.jevs.2018.10.012 · Cited by 13
Cardiovascular disease and depression: a bidirectional relationship and its clinical implications
Wu, J., Tian, Z., Qi, Z., Liu, X., & Yu, P. (2026) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2025.1675680 · Cited by 14
Metadata
- Authors
- Nicolaides, N. C., Charmandari, E., Chrousos, G. P., & Kino, T.
- Affiliations
- National and Kapodistrian University of Athens (GR)
- King Abdulaziz University (SA)
- National Institutes of Health (US)
- Corresponding author
- Nicolaides, Nicolas C.
- Venue
- Annals of the New York Academy of Sciences
- Publisher
- Wiley
- Published
- 2014-05
- Volume
- 1318
- Issue
- 1
- Pages
- 71-80
- ISSN
- 0077-8923 (ISSN-L)
- 1749-6632
- PMC
- PMC4104011
- OpenAlex
- W1598021542
- Cited by
- 183
- References
- 78
- Citations by year
- 2026: 11 · 2025: 17 · 2024: 15 · 2023: 16 · 2022: 12 · 2021: 16 · 2020: 18 · 2019: 12 · 2018: 13 · 2017: 14 · 2016: 20 · 2015: 17 · 2014: 2
- FWCI
- 2.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of the New York Academy of Sciences (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (ZIAHD008732)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- circadian rhythm, hypothalamic-pituitary-adrenal axis, stress response, biological clock, Clock/BMAL1, circadian gene expression, circadian dysfunction, metabolic disorders, autoimmune disease, mood disorders
- MeSH terms
- Animals, Circadian Rhythm, Gene Expression Regulation, Glucocorticoids, Humans, Hypothalamo-Hypophyseal System, Pituitary-Adrenal System, Receptors, Glucocorticoid, CLOCK Proteins, ARNTL Transcription Factors
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