Laboratory Markers of Chronic and Acute Stress: Diagnostic Value and Clinical Implications (Part 2: Neuroendocrine, Immunological and Metabolic Biomarkers of Chronic Stress in the Context of Its Influence on Cardiovascular System)

Anastasiia  Shkvarok-Lisovenko; Yevheniia  Bushman

doi:10.32345/USMYJ.4(158).2025.89-98

Anastasiia Shkvarok-Lisovenko Bogomolets National Medical University, Kyiv, Ukraine https://orcid.org/0000-0002-8308-7206
Yevheniia Bushman University of North Carolina at Charlotte, Charlotte, North Carolina, USA https://orcid.org/0000-0003-2983-6058

DOI: https://doi.org/10.32345/USMYJ.4(158).2025.89-98

Keywords: Cortisol, Oxidative Stress, Immune System, Endocrinology, Biomarkers, Chronic Stress.

Abstract

Chronic stress (CS) is a powerful factor that silently, but persistently undermines human health by dysregulating the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS). Its manifestation goes far beyond emotional experiences, shaping profound physiological changes that affect the endocrine, immune and metabolic systems. Modern biomarkers allow us both to visualize these changes and measure their intensity, making them quantifiable and clinically relevant. A comprehensive literature review was conducted, encompassing 76 English-language sources identified through PubMed, Scopus, Web of Science and Google Scholar. The analysis focused on the interplay between the hypothalamic–pituitary-adrenal (HPA) axis, the autonomic nervous system (ANS), and stress-related conditions (CS). The search strategy targeted peer-reviewed publications from 2020 to 2025 using the following keywords: “cardiovascular system“, “acute stress“, “chronic stress“, “cortisol“, “epinephrine“, “norepinephrine“, “dehydroepiandrosterone“, “dopamine“, “aldosterone“, “tumor necrosis factor alpha“, “interleukin-1“, “interleukin-6“, “C-reactive protein“, “cholesterol“, “albumin“ and “glycosylated hemoglobin“. Inclusion criteria comprised original research articles, systematic and narrative reviews, meta-analyses and clinical guidelines, while non-peer-reviewed sources and non-English publications were generally excluded. The article summarizes key laboratory markers of stress, from classical hormones (cortisol, epinephrine, ACTH) to immune and metabolic indicators (cytokines, C-reactive protein, oxidative stress markers), with particular attention to hair cortisol as an innovative tool for long-term stress assessment. Stress-related biomarkers provide an integrated view of CS pathophysiology, demonstrating how neuroendocrine, immune and metabolic dysregulation drives hypertension, cardiovascular events, insulin resistance, systemic inflammation and neuropsychiatric disturbances. Early detection and management of CS are essential to prevent cumulative damage that can progress to obesity, metabolic syndrome, atherosclerosis, neurodegeneration and increased morbidity and mortality.

References

Dhama, K., Latheef, S. K., Dadar, M., Samad, H. A., Munjal, A., Khandia, R., Karthik, K., Tiwari, R., Yatoo, Mohd. I., Bhatt, P., Chakraborty, S., Singh, K. P., Iqbal, H. M. N., Chaicumpa, W., & Joshi, S. K. (2019). Biomarkers in Stress Related Diseases/Disorders: Diagnostic, Prognostic, and Therapeutic Values. Frontiers in Molecular Biosciences, 6, 91. https://doi.org/10.3389/fmolb.2019.00091

Brenner-Fliesser, M., Houtenbos, S., Ewerton, M., Bontrup, C., Visscher, R., Taylor, W. R., Zemp, R., & Wippert, P.-M. (2024). The association of different types of stress, and stress accumulation with low back pain in call-center workers—A cross-sectional observational study. BMC Musculoskeletal Disorders, 25(1), 971. https://doi.org/10.1186/s12891-024-08087-5

Gallistl, M., Linz, R., Puhlmann, L. M. C., Singer, T., & Engert, V. (2024). Evidence for differential associations of distinct trait mindfulness facets with acute and CS. Psychoneuroendocrinology, 166, 107051. https://doi.org/10.1016/j.psyneuen.2024.107051

Probo, M., Peric, T., Fusi, J., Prandi, A., Faustini, M., & Veronesi, M. C. (2021). Hair cortisol and dehydroepiandrosterone sulfate concentrations in healthy beef calves from birth to 6 months of age. Theriogenology, 175, 89–94. https://doi.org/10.1016/j.theriogenology.2021.08.037

Choi, C. W., Hong, D., & Kim, M.-G. (2025). Light source-free smartphone detection of salivary cortisol via colorimetric lateral flow immunoassay using a photoluminescent film. Biosensors and Bioelectronics, 271, 116971. https://doi.org/10.1016/j.bios.2024.116971

Garg, R., Memon, S. S., Lila, A., Sarathi, V., Patil, P., Jamale, T., Bose, S., Karlekar, M., Patil, V., Shah, N., & Bandgar, T. (2024). Overnight 1-mg DST Serum Cortisol in Various Stages of Chronic Kidney Disease—Normative Data and Underlying Mechanisms. Journal of the Endocrine Society, 8(3), bvae002. https://doi.org/10.1210/jendso/bvae002

Peric, T., Comin, A., Corazzin, M., Montillo, M., & Prandi, A. (2020). Comparison of AlphaLISA and RIA assays for measurement of wool cortisol concentrations. Heliyon, 6(10), e05230. https://doi.org/10.1016/j.heliyon.2020.e05230

Koumbia, M., & Madoka, T. (2025). Conductive and flexible gold-coated polylactic acid nanofiber-based electrochemical aptasensor for monitoring cortisol level in sweat and saliva. Bioelectrochemistry, 163, 108908. https://doi.org/10.1016/j.bioelechem.2025.108908

Ding, Y., Tan, K., Sheng, L., Ren, H., Su, Z., Yang, H., Zhang, X., Li, J., & Hu, P. (2024). Integrated mental stress smartwatch based on sweat cortisol and HRV sensors. Biosensors and Bioelectronics, 265, 116691. https://doi.org/10.1016/j.bios.2024.116691

Pirnia, B., Soleimani, A., Farhoudian, A., & Zahiroddin, A. (2024). Prediction of suicidal thoughts and behaviors based on the diurnal cortisol pattern and THC dosage in continued cannabis users, a 5 year population-based matched cohort study. Psychiatry Research, 339, 116091. https://doi.org/10.1016/j.psychres.2024.116091

Dahl, S. R., Bakke, L. H., Thorsby, P. M., & Zykova, S. N. (2024). An LC-MS/MS assay for simultaneous determination of 13 steroid hormones and two synthetic steroids in saliva: Potential utility for paediatric population and beyond. Scandinavian Journal of Clinical and Laboratory Investigation, 84(7–8), 527–534. https://doi.org/10.1080/00365513.2024.2437620

Barrero, J. A., Duarte-Zambrano, F., Aranzález, L. H., Cruz-González, M., & Mockus, I. (2024). Salivary cortisol/DHEA ratio response to acute academic stress and its association with performance in middle-to-late adolescents. Neuro Endocrinology Letters, 45(4), 255–261.

Li, Z.-M., & Kannan, K. (2022). Determination of 19 Steroid Hormones in Human Serum and Urine Using Liquid Chromatography-Tandem Mass Spectrometry. Toxics, 10(11), 687. https://doi.org/10.3390/toxics10110687

Hoppmann, U., Engler, H., Krause, S., Rottler, E., Hoech, J., Szabo, F., Radermacher, P., & Waller, C. (2021). Systemic Catecholaminergic Deficiency in Depressed Patients with and without Coronary Artery Disease. Journal of Clinical Medicine, 10(5), 986. https://doi.org/10.3390/jcm10050986

Bergmann, M. L., & Schmedes, A. (2020). Highly sensitive LC-MS/MS analysis of catecholamines in plasma. Clinical Biochemistry, 82, 51–57. https://doi.org/10.1016/j.clinbiochem.2020.03.006

Luo, W., Van Beek, T. A., Chen, B., Zuilhof, H., & Salentijn, G. Ij. (2022). Boronate affinity paper spray mass spectrometry for determination of elevated levels of catecholamines in urine. Analytica Chimica Acta, 1235, 340508. https://doi.org/10.1016/j.aca.2022.340508

Cheuk, M., Lo, Y., & Poon, W. (2017). Determination of urine catecholamines and metanephrines by reversed-phase liquid chromatography-tandem mass spectrometry. Chinese Journal of Chromatography, 35(10), 1042. https://doi.org/10.3724/SP.J.1123.2017.06011

Kumar, D., Sinha, S. N., & Gouda, B. (2024). Novel LC-MS/MS Method for Simultaneous Determination of Monoamine Neurotransmitters and Metabolites in Human Samples. Journal of the American Society for Mass Spectrometry, 35(4), 663–673. https://doi.org/10.1021/jasms.3c00326

Seravalle, G., Facchetti, R., Cappellini, C., Annaloro, A., Gelfi, E., & Grassi, G. (2022). Elevated heart rate as sympathetic biomarker in human obesity. Nutrition, Metabolism and Cardiovascular Diseases, 32(10), 2367–2374. https://doi.org/10.1016/j.numecd.2022.07.011

Zhang, D., Wu, L., Chow, D. S.-L., Tam, V. H., & Rios, D. R. (2016). Quantitative determination of dopamine in human plasma by a highly sensitive LC–MS/MS assay: Application in preterm neonates. Journal of Pharmaceutical and Biomedical Analysis, 117, 227–231. https://doi.org/10.1016/j.jpba.2015.09.003

Battal, D., Aktaş Süküroğlu, A., Alkaş, F. B., & Ünlüsayin, İ. (2021). A Rapid, Precise, and Sensitive LC-MS/MS Method for the Quantitative Determination of Urinary Dopamine Levels via a Simple Liquidliquid Extraction Technique. Turkish Journal of Pharmaceutical Sciences, 18(6), 761–769. https://doi.org/10.4274/tjps.galenos.2021.60486

Fu, R., Jinnah, H., Mckay, J. L., Miller, A. H., Felger, J. C., Farber, E. W., Sharma, S., Whicker, N., Moore, R. C., Franklin, D., Letendre, S. L., & Anderson, A. M. (2023). Cerebrospinal fluid levels of 5-HIAA and dopamine in people with HIV and depression. Journal of NeuroVirology, 29(4), 440–448. https://doi.org/10.1007/s13365-023-01142-2

Taki, Y., Kono, T., Teruyama, K., Ichijo, T., Sakuma, I., Nagano, H., Miyagawa, H., Kono, S., Fujimoto, M., Hashimoto, N., Yokoyama, M., Kawakami, E., Miki, T., & Tanaka, T. (2024). Comparative analysis of aldosterone and renin assays for primary aldosteronism screening. Scientific Reports, 14(1), 26040. https://doi.org/10.1038/s41598-024-75645-1

Uhrová, J., Benáková, H., Vaníčková, Z., & Zima, T. (2021). Comparison of the Chemiluminescence Immunoassay LIAISON® with the Radioimmunoassay for Aldosterone and Renin Measurement. Prague Medical Report, 122(2), 80–95. https://doi.org/10.14712/23362936.2021.9

Zeng, Q., Li, J., Yang, Y., He, Y., Song, Y., Hu, J., Wang, Y., Li, Q., & Yang, S. (2025). Comparison of a chemiluminescence immunoassay with LC–MS/MS in the determination of the plasma aldosterone concentration in patients with impaired renal function. Steroids, 213, 109540. https://doi.org/10.1016/j.steroids.2024.109540

Dong, H., Hu, B., Chen, W., Wang, L., Sun, H., Zhou, J., Chen, J., Chen, B., & Du, Z. (2024). A LC-MS/MS method for the simultaneous quantitative determination of aldosterone, its precursor 18-hydroxycorticosterone and its metabolite tetrahydroaldosterone in human urine. Journal of Chromatography B, 1234, 124012. https://doi.org/10.1016/j.jchromb.2024.124012

Abukhalaf, D., Koerner, R., Patel, S., Duffy, A., & Prescott, S. (2025). Exploring stress and depressive symptoms in pregnancy and the IL-1β, IL-6, and C-reactive protein pathway: Looking for possible biomarker targets. Comprehensive Psychoneuroendocrinology, 21, 100280. https://doi.org/10.1016/j.cpnec.2024.100280

Noushad, S., Ahmed, S., Ansari, B., Mustafa, U.-H., Saleem, Y., & Hazrat, H. (2021). Physiological biomarkers of CS: A systematic review. International Journal of Health Sciences, 15(5), 46–59.

Шкварок А., Корост Я. (2025). Фізіологічні аспекти розвитку хронічного емоційного стресу в контексті впливу на серцево-судинну систему та роль визначення рівня кортизолу у волоссі як показника наявності хронічного емоційного стресу. Collection of scientific papers «ΛΌГOΣ», 411-419.

El-Farhan, N., Rees, D. A., & Evans, C. (2017). Measuring cortisol in serum, urine and saliva – are our assays good enough? Annals of Clinical Biochemistry: International Journal of Laboratory Medicine, 54(3), 308–322. https://doi.org/10.1177/0004563216687335

Russell, E., Koren, G., Rieder, M., & Van Uum, S. (2012). Hair cortisol as a biological marker of CS: Current status, future directions and unanswered questions. Psychoneuroendocrinology, 37(5), 589–601. https://doi.org/10.1016/j.psyneuen.2011.09.009

Luo, J., Wei, Z., Liu, Y., Guo, K., Zhao, X., Ren, Y., Wu, Y., & Yang, J. (2024). Role of interdependent self-construal in predicting acute salivary cortisol response, hair cortisol concentrations, and their associations. Hormones and Behavior, 166, 105650. https://doi.org/10.1016/j.yhbeh.2024.105650

Kirschbaum, C. (2024). What is hair cortisol analysis and how can it aid endocrinologists? Expert Review of Endocrinology & Metabolism, 19(6), 467–468. https://doi.org/10.1080/17446651.2024.2365786

Kern, J., Jorgensen, M. W., Boerman, J. P., Erasmus, M., Johnson, J. S., & Pempek, J. A. (2024). Effect of repeated HPA axis stimulation on hair cortisol concentration, growth, and behavior in preweaned dairy cattle. Journal of Animal Science, 102, skae171. https://doi.org/10.1093/jas/skae171

Chen, Y., Cai, W., Li, C., Su, Z., Guo, Z., Li, Z., Wang, C., & Xu, F. (2022). Sex differences in peripheral monoamine transmitter and related hormone levels in CS mice with a depression-like phenotype. PeerJ, 10, e14014. https://doi.org/10.7717/peerj.14014

Strumila, R., Lengvenyte, A., Zdanavicius, L., Badaras, R., Dlugauskas, E., Lesinskiene, S., Matiekus, E., Marcinkevicius, M., Venceviciene, L., Utkus, A., Kaminskas, A., Petrenas, T., Songailiene, J., Vitkus, D., & Ambrozaityte, L. (2024). Higher levels of plasma Adrenocorticotropic hormone (ACTH) are associated with lower suicidal ideation in depressed patients compared to controls and suicide attempters, independently from depression severity. Comprehensive Psychoneuroendocrinology, 19, 100235. https://doi.org/10.1016/j.cpnec.2024.100235

Hansen, J. L., Carroll, J. E., Seeman, T. E., Cole, S. W., & Rentscher, K. E. (2025). Lifetime CS exposures, stress hormones, and biological aging: Results from the Midlife in the United States (MIDUS) study. Brain, Behavior, and Immunity, 123, 1159–1168. https://doi.org/10.1016/j.bbi.2024.10.022

Baik, J.-H. (2020). Stress and the dopaminergic reward system. Experimental & Molecular Medicine, 52(12), 1879–1890. https://doi.org/10.1038/s12276-020-00532-4

Sproston, N. R., & Ashworth, J. J. (2018). Role of C-Reactive Protein at Sites of Inflammation and Infection. Frontiers in Immunology, 9, 754. https://doi.org/10.3389/fimmu.2018.00754

Silva, D., & Pais De Lacerda, A. (2012). High-sensitivity C-reactive protein as a biomarker of risk in coronary artery disease. Revista Portuguesa de Cardiologia (English Edition), 31(11), 733–745. https://doi.org/10.1016/j.repce.2012.09.006

Hassamal, S. (2023). CS, neuroinflammation, and depression: An overview of pathophysiological mechanisms and emerging anti-inflammatories. Frontiers in Psychiatry, 14, 1130989. https://doi.org/10.3389/fpsyt.2023.1130989

Wen, J., Wu, Y., Han, J., Tian, Y., & Man, C. (2023). Stress-induced immunosuppression affecting immune response to Newcastle disease virus vaccine through “miR-155-CTLA-4” pathway in chickens. PeerJ, 11, e14529. https://doi.org/10.7717/peerj.14529

Vedantam, D., Poman, D. S., Motwani, L., Asif, N., Patel, A., & Anne, K. K. (2022). Stress-Induced Hyperglycemia: Consequences and Management. Cureus. https://doi.org/10.7759/cureus.26714

Wazir, M., Olanrewaju, O. A., Yahya, M., Kumari, J., Kumar, N., Singh, J., Abbas Al-itbi, A. Y., Kumari, K., Ahmed, A., Islam, T., Varrassi, G., Khatri, M., Kumar, S., Wazir, H., & Raza, S. S. (2023). Lipid Disorders and Cardiovascular Risk: A Comprehensive Analysis of Current Perspectives. Cureus. https://doi.org/10.7759/cureus.51395

Jomova, K., Raptova, R., Alomar, S. Y., Alwasel, S. H., Nepovimova, E., Kuca, K., & Valko, M. (2023). Reactive oxygen species, toxicity, oxidative stress, and antioxidants: Chronic diseases and aging. Archives of Toxicology, 97(10), 2499–2574. https://doi.org/10.1007/s00204-023-03562-9

Laboratory Markers of Chronic and Acute Stress: Diagnostic Value and Clinical Implications (Part 2: Neuroendocrine, Immunological and Metabolic Biomarkers of Chronic Stress in the Context of Its Influence on Cardiovascular System)

Abstract

References

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