CORTISOL AS A KEY FACTOR IN THE DEVELOPMENT OF POST-TRAUMATIC STRESS DISORDER AND THE ROLE OF MELATONIN IN THE NEUROPROTECTION OF THIS CONDITION

Authors:

Abstract:

Cortisol is the most important glucocorticoid hormone, the stimulation of which is clearly organized by the hypothalamic-pituitary-adrenal axis, and the secretion itself is provided by the adrenal cortex. It plays a key role in various physiological processes. Cortisol dysfunction due to chronic stress has serious consequences for many body systems and is characterized by hyperactivity of the hypothalamic-pituitary-adrenal axis and disruption of the amygdala-cortico-hippocampal circuit - a trigger for post-traumatic stress disorder. Understanding the multifaceted mechanisms of the constant influence of this hormone is important, as it opens up prospects for mitigating the detrimental effects of traumatic disorders, for example, with the use of melatonin as part of adjuvant therapy. The purpose of the study was to analyze and summarize data from many years of research in the field of disorders arising from post-traumatic stress disorder, to deepen understanding of the importance of further directions and prospects for correcting body dysfunctions in this pathological condition. An analysis of modern publications from the scientometric databases Scopus, Web of Science, PubMed, and Google Scholar was conducted. The following keywords were searched in the PubMed database: “post-traumatic stress disorder”, “cortisol”, “hypothalamic-pituitary-adrenal axis”, “melatonin”, “acute and chronic stress”. Particular attention was paid to publications from the last 5 years to provide an analysis of modern scientific approaches. Additionally, classical studies were taken into account, which laid the foundation for further discoveries in this field. To gain a deeper understanding of the problem, articles were analyzed that included results from double-blind, randomized, placebo-controlled trials, data from meta-analyses and systematic reviews, and studies using biochemical methods to assess cortisol and melatonin levels. After collecting the literature, a critical analysis was conducted using statistical data processing tools. A comparative analysis method was used to evaluate the effectiveness of melatonin in regulating the hypothalamic-pituitary-adrenal axis and reducing symptoms of posttraumatic stress disorder. Particular attention was paid to studies examining the molecular mechanisms underlying cortisol's effects on the hippocampus and amygdala, as well as to works exploring the potential for neuroprotection with melatonin. We suggest that the use of exogenous melatonin can suppress cortisol secretion in patients with posttraumatic stress disorder and, as a result, reduce the frequency of side effects in the form of sleep dysfunction, but this issue requires further research.

Keywords:

post-traumatic stress disorder cortisol hypothalamic-pituitary-adrenal axis melatonin acute and chronic stress

References:

1. Alghamdi D, Alghamdi A. Corticosteroids resistance diseases review. In: Radenkovic M, editor. Updates on corticosteroids. IntechOpen; 2023. p. 1–18. doi: 10.5772/intechopen.109593.
2. Beech EL, Riddell N, Murphy MJ, Crewther SG. Sex and stress hormone dysregulation as clinical manifestations of hypothalamic function in migraine disorder: A meta-analysis. Eur J Neurosci. 2023 Jul;58(4):3150-3171. doi:10.1111/ejn.16087.
3. Brock M, Hawkins S, Starks A. Clinical and polysomnographic features of trauma-associated sleep disorder: a five-year study. J Clin Sleep Med. 2022;18(8):2045-2053. doi:10.5664/jcsm.10123.
4. Chattarji S, Tomar A, Suvrathan A, Ghosh S, Rahman MM. Repeated stress exposure leads to structural synaptic instability in the hippocampus. Transl Psychiatry. 2022;12(1):1–11. doi:10.1038/s41398-022-02107-5.
5. Chavanne AV, Robinson OJ. The overlapping neurobiology of induced and pathological anxiety: a meta-analysis of functional neural activation. Am J Psychiatry. 2020;178(2):156–164. doi:10.1176/appi.ajp.2020.19111153.
6. Choi J, Lee J, Lee H, et al. Altered amygdala-prefrontal functional connectivity in post-traumatic stress disorder: A resting-state fMRI study. Psychiatry Res Neuroimaging. 2023;324:113664. doi:10.1016/j.pscychresns.2023.113664.
7. Chrousos GP, Gold PW. The Hypothalamic–Pituitary–Adrenal Axis and Stress. In: Fink G, editor. Encyclopedia of Stress. 3rd ed. Academic Press; 2023. p. 1–6. doi:10.1016/B978-0-12-818697-4.00001-3.
8. Chudoba R, Dabrowska J. Distinct populations of corticotropin-releasing factor (CRF) neurons mediate divergent yet complementary defensive behaviors in response to a threat. Neuropharmacology. 2023;228:109461. doi:10.1016/j.neuropharm.2023.109461.
9. Daskalakis NP, Yehuda R. The hypothalamic-pituitary-adrenal axis in stress regulation. In: Fink G, editor. Encyclopedia of Stress. 3rd ed. Academic Press; 2023. p. 1–6. doi:10.1016/B978-0-12-819987-7.00001-4.
10. DeGutis J, Mercado R, Wilkins K. Less is more: smaller hippocampal subfield volumes predict greater PTSD symptom severity. Neurobiol Stress. 2023;20:100453. doi:10.1016/j.ynstr.2023.100453.
11. Domínguez-Pérez J, Peñate-Castro W. Neural mechanisms of cognitive behavioral therapy efficacy in anxiety disorders: A scoping review of fMRI-based studies that tested the dual model. Psychol Med. 2025;55(2):235-246. doi:10.1017/S0033291724006848.
12. Duek O, Spiller TR, Rubenstein A, Pietrzak RH, Harpaz-Rotem I. Exploration of a novel model of intrusive symptoms in posttraumatic stress disorder among US veterans. JAMA Netw Open. 2022 Mar 21;5(3):e223555. doi: 10.1001/jamanetworkopen.2022.3555.
13. Feder A, Costi S, Rutter SB. A randomized controlled trial of repeated ketamine administration for chronic posttraumatic stress disorder. Am J Psychiatry. 2021 Feb;178(2):193–202. doi:10.1176/appi.ajp.2020.20050596.
14. Ganguly P, Sahu A, Saha S. Comprehensive review of melatonin as a promising nutritional and nutraceutical supplement. J Nutr Biochem. 2024;113:109212. doi:10.1016/j.jnutbio.2023.109212.
15. Gobbi G, Comai S. Melatonin receptors: localization, molecular pharmacology and physiological significance. J Pineal Res. 2023;75(1):e12955. doi:10.1111/jpi.12955.
16. Hodgens A, Sharman T. Corticosteroids. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554612/
17. Huang Y, Zhang Y, Zhang L. Molecular mechanisms of glucocorticoid resistance. Endocrine Connections. 2023;12(4):e13901. doi:10.1530/ECI-23-13901.
18. International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors. Pharmacol Rev. 2021 Jun;73(2):1–24. doi: 10.1124/pr.120.019654.
19. Kredlow MA, Fenster RJ, Laurent ES, Ressler KJ, Phelps EA. Prefrontal cortex, amygdala, and threat processing: implications for PTSD. Neuropsychopharmacology. 2022;47(1):247–259. doi:10.1038/s41386-021-01155-7.
20. Mascaro L, Phillips AJK, Clark JW, Straus LD, Drummond SPA. Diurnal rhythm robustness in individuals with PTSD and insomnia and the association with sleep. J Biol Rhythms. 2021;36(3):185–195. doi:10.1177/07487304211014196.
21. Melloni RH, Gaddam S, McGinnis MY. The emerging role of rapid corticosteroid actions on excitatory and inhibitory synaptic transmission in the hypothalamus, hippocampus, and amygdala. Neuroscience. 2024;468:1-13. doi:10.1016/j.neuroscience.2024.01.012.
22. Mikkelsen MB, Tramm G, O'Toole MS. A systematic review and meta-analysis of the effect of emotion regulation on cortisol. Psychoneuroendocrinology. 2021 Feb;123:104900. doi: 10.1016/j.psyneuen.2020.104900.
23. Miethe S, Wigger J, Wartemann A, Fuchs FO, Trautmann S. Posttraumatic stress symptoms and their association with rumination, thought suppression, and experiential avoidance: a systematic review and meta-analysis. J Psychopathol Behav Assess. 2023;45(3):497-508. doi:10.1007/s10862-023-10022-2.
24. Mithoefer MC, Feduccia AA, Jerome L, Wagner M, Wymer J, Holland J, et al. MDMA-assisted therapy for moderate to severe PTSD: A randomized, placebo-controlled phase 3 trial. Nat Med. 2023;29(9):1907–1917. doi:10.1038/s41591-023-02435-4.
25. Nikolaev G, Robeva R, Konakchieva R. Membrane melatonin receptors activated cell signaling in physiology and disease. Int J Mol Sci. 2022;23(1):471. doi:10.3390/ijms23010471.
26. Poza JJ, Pujol M, Ortega-Albás JJ, Romero O, Insomnia Study Group of the Spanish Sleep Society (SES). Melatonin in sleep disorders. Neurologia. 2022;37(7):575–585. doi:10.1016/j.nrleng.2018.08.004.
27. Ravulapalli KC, Sud N. Neuropsychiatric presentations of hypocortisolaemia—a literature review. Eur Psychiatry. 2023 Jul;66(Suppl 1):S285. doi: 10.1192/j.eurpsy.2023.643.
28. Ressler KJ, Berretta S, Bolshakov VY, Rosso IM, Meloni EG, Rauch SL, Carlezon WA Jr. Post-traumatic stress disorder: clinical and translational neuroscience from cells to circuits. Nat Rev Neurol. 2022;18(5):273–288. doi:10.1038/s41582-022-00635-8.
29. Schenberg EE, Tófoli LF, Rezinovsky D, Polanczyk GV. Psilocybin-assisted therapy for PTSD: Emerging evidence and future directions. Front Psychiatry. 2022;13:888245. doi:10.3389/fpsyt.2022.888245.
30. Sic A, Bogicevic M, Brezic N, Nemr C, Knezevic NN. Chronic stress and headaches: the role of the HPA axis and autonomic nervous system. Biomedicines. 2025;13(2):463. doi:10.3390/biomedicines13020463.
31. Sohini R, Maiya GA, Padmakumar R. Effect of exercise training on cardiac autonomic function in type 2 diabetes mellitus: a systematic review and meta-analysis. Syst Rev. 2025;14(1):34. doi:10.1186/s13643-025-02772-9.
32. Sottile RJ, Vida T. A proposed mechanism for the MDMA-mediated extinction of traumatic memories in PTSD patients treated with MDMA-assisted therapy. Front Psychiatry. 2022;13:991753. doi:10.3389/fpsyt.2022.991753.
33. Weber FC, Wetter TC. The many faces of sleep disorders in post-traumatic stress disorder: an update on clinical features and treatment. Neuropsychobiology. 2022;81(2):85-94. doi:10.1159/000520963.
34. Yao D, Li C, Luo J, Liu Y, Li Z, Ma X. Melatonin alleviates PTSD-like symptoms by inhibiting oxidative stress and neuroinflammation via the SIRT1/Nrf2 pathway. Behav Brain Res. 2023;437:114147. doi:10.1016/j.bbr.2022.114147.
35. Zhao Z, Duek O, Seidemann R. Amygdala downregulation training using fMRI neurofeedback in post-traumatic stress disorder: a randomized, double-blind trial. Transl Psychiatry. 2023;13(1):1-10. doi:10.1038/s41398-023-02467-6.
36. Zou Y, Wang J, Zhang X. Chronotype, circadian rhythm, and psychiatric disorders: recent evidence and potential mechanisms. Front Neurosci. 2022;16:811771. doi:10.3389/fnins.2022.811771.

Publication:

«World of Medicine and Biology» Vol. 21 No. 94 (2025) , с. 216-221
УДК 616.89;612.8;616-091;616-092;616-008;616-03

DOI:

https://doi.org/10.26724/2079-8334-2025-4-94-216-221