The Link Between Cortisol, Inflammation, and Disease

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By Vijay Kumar MalesuReviewed by Lily Ramsey, LLM

Cortisol and Inflammatory Response
Chronic Disease Connections
Research Findings
Managing Cortisol and Inflammation
Conclusion

Cortisol, the primary glucocorticoid hormone, plays a central role in the body’s stress response and immune regulation. Released by the adrenal cortex via the hypothalamic-pituitary-adrenal (HPA) axis, cortisol helps maintain homeostasis during stress by modulating metabolism, inflammation, and immune activity. In acute stress, cortisol enhances immune surveillance by mobilizing immune cells and promoting inflammatory responses.

However, chronic stress leads to sustained cortisol elevation, suppressing immune function by inhibiting T-cell activity, reducing cytokine production, and impairing antibody responses. This dysregulation increases susceptibility to infections, delays wound healing and contributes to chronic inflammatory diseases.

Moreover, prolonged cortisol exposure alters immune signaling pathways, leading to immune exhaustion and a heightened risk of autoimmune disorders. Understanding cortisol’s dual impact on immunity highlights the importance of stress management strategies in preventing immune dysfunction.1

This article explores the relationship between cortisol, the body’s primary stress hormone, and inflammation, highlighting their impact on chronic diseases.

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Cortisol and Inflammatory Response

Cortisol, a glucocorticoid hormone produced by the adrenal glands, plays a crucial role in modulating the body’s inflammatory response. Under normal conditions, it helps regulate the immune system by suppressing excessive inflammation.

It does so by inhibiting the production of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Cortisol binds to glucocorticoid receptors (GRs) in immune cells, leading to the downregulation of inflammatory gene expression. Additionally, it interferes with the nuclear factor-kappa B (NF-κB) pathway, a key driver of inflammation, thereby maintaining immune balance.2

However, in cases of prolonged stress and chronic cortisol exposure, the immune response may become dysregulated. One widely accepted theory, the glucocorticoid resistance model, suggests that continuous high levels of cortisol can reduce the sensitivity of immune cells to its anti-inflammatory effects.

This results in persistent inflammation despite the presence of cortisol. On the other hand, an emerging pro-inflammatory cortisol model proposes that, under specific conditions, cortisol may directly enhance inflammation instead of suppressing it.

Studies indicate that stress-related cortisol levels can, in some cases, amplify inflammatory signaling, potentially worsening conditions like depression and autoimmune diseases.2

The impact of cortisol dysregulation on health is significant. In autoimmune diseases such as rheumatoid arthritis and lupus, an inadequate cortisol response fails to control inflammation, exacerbating symptoms.

Similarly, in major depressive disorder (MDD), chronic stress and elevated cortisol levels are associated with increased inflammation, which has been linked to depressive symptoms. Moreover, metabolic disorders such as obesity and insulin resistance are influenced by chronic low-grade inflammation driven by cortisol imbalance.2

How Does Cortisol Affect The Body?

Chronic Disease Connections

Chronic diseases are increasingly linked to disruptions in cortisol regulation, inflammation, and immune responses. Cortisol, a vital hormone for stress management, is tightly controlled by the HPA axis. However, chronic stress and dysregulated cortisol can lead to widespread health issues.

One major consequence of prolonged cortisol imbalance is persistent inflammation. Under normal conditions, cortisol suppresses excessive immune activity. However, chronic stress can induce cortisol resistance, where cells fail to respond adequately, leading to unchecked inflammation. This inflammatory state contributes to cardiovascular diseases by promoting arterial plaque buildup, hypertension, and metabolic disturbances.3

Autoimmune disorders are also closely connected to cortisol dysregulation. An overactive immune system, coupled with insufficient cortisol regulation, increases the risk of conditions like rheumatoid arthritis and lupus. Persistent inflammation and immune overactivity further damage tissues, exacerbating these diseases.3

Mental health is another critical area affected by cortisol imbalance. Excessive or insufficient cortisol levels are associated with anxiety, depression, and cognitive decline. Chronic stress can impair neuroplasticity, increase neuroinflammation, and elevate the risk of neurodegenerative diseases.3

Understanding the interplay between cortisol, inflammation, and disease progression is essential for developing targeted interventions. Managing stress, improving lifestyle factors, and exploring pharmacological approaches can help mitigate these risks and improve overall health.3

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Research Findings

The relationship between cortisol, inflammation, and disease has been explored in various studies, particularly in the context of chronic conditions such as osteoarthritis (OA). Research has established that cortisol, a key hormone regulated by the HPA axis, plays a critical role in modulating inflammation and pain.

Its levels fluctuate throughout the day, peaking in the morning and declining gradually. However, in individuals experiencing chronic pain, dysregulation of the HPA axis can lead to abnormal cortisol patterns, which may contribute to disease progression and symptom severity.3,4

A study on women with OA investigated the association between disease-related pain and cortisol levels. The findings revealed that women with more severe pain had significantly higher cortisol levels throughout the day.

Specifically, for every unit increase in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale score, cortisol levels increased by approximately 9%. This suggests a direct correlation between pain severity and cortisol production. Interestingly, despite this elevation, the diurnal pattern of cortisol decline remained unchanged, indicating that while pain influences overall cortisol levels, it does not necessarily disrupt the natural rhythm of cortisol secretion.4

Following a 45-minute laboratory pain-testing session, healthy and temporomandibular disorder (TMD) participants exhibited a flattened morning salivary cortisol pattern associated with pain catastrophizing. Although cortisol levels and hypercortisolism did not differ between groups, only the TMD masseter demonstrated hyperalgesia, suggesting catastrophizing-driven cortisol alterations may substantially heighten vulnerability and maintain persistent pain.5

Further analysis explored whether daily experience variables (such as stress, fatigue, and pain catastrophizing) mediated the relationship between OA pain and cortisol levels. Contrary to expectations, none of these factors showed significant mediation effects. This raises questions about the underlying mechanisms driving cortisol elevation in chronic pain conditions.

Given that cortisol also regulates metabolic and inflammatory pathways, researchers suggest that additional mediators, such as pro-inflammatory cytokines or metabolic dysregulation, could play a role in linking pain with HPA axis activity.4,5

Ashwagandha: What Does the Science Say?

Managing Cortisol and Inflammation

Chronic stress is a key factor in pain and inflammation, yet it is often overlooked in rehabilitation. The body’s stress response triggers cortisol release, regulating energy and inflammation. While short-term stress aids survival, prolonged stress disrupts cortisol function, leading to widespread inflammation and chronic pain conditions like fibromyalgia and musculoskeletal disorders.6

To manage stress-related pain, a lifestyle approach includes regular exercise, balanced nutrition (anti-inflammatory diet), quality sleep, and relaxation techniques (breathing exercises, meditation).

Medical strategies involve corticosteroids for inflammation control, adaptogens (e.g., ashwagandha) for cortisol balance, and medications such as Selective Serotonin Reuptake Inhibitors (SSRIs) for stress-related pain. Therapeutic interventions like cognitive-behavioral therapy (CBT) address maladaptive thinking, mindfulness-based stress reduction (MBSR) enhances emotional regulation, and graded exposure therapy reduces pain-related fear responses.6

Screening tools like the Pain Catastrophizing Scale and Perceived Stress Scale help identify patients who may benefit from stress management. Addressing both pain-related and non-pain-related stressors in physical therapy enhances recovery, prevents chronic disability, and improves quality of life. A multidisciplinary approach integrating lifestyle, medical, and therapeutic strategies is crucial for long-term pain relief and inflammation management.6

Conclusion

While cortisol is essential for immune modulation, prolonged stress-induced dysregulation leads to persistent inflammation, contributing to autoimmune disorders, cardiovascular diseases, and mental health conditions. Research highlights the association between elevated cortisol levels and increased pain severity in OA, reinforcing its broader implications for chronic inflammatory conditions.

From a healthcare perspective, integrating stress management into clinical practice is crucial. Lifestyle modifications, including regular exercise, anti-inflammatory diets, and mindfulness alongside medical interventions such as corticosteroids and adaptogens, can help restore cortisol balance. Additionally, CBT and MBSR offer effective therapeutic avenues for mitigating stress-related inflammation.

A multidisciplinary approach that combines lifestyle, medical, and psychological interventions can enhance patient outcomes, prevent disease progression, and improve quality of life. Future research should focus on targeted therapies to optimize cortisol regulation and reduce inflammation-related health risks.

References

Alotiby, A. (2024). Immunology of stress: a review article. Journal of Clinical Medicine, 13(21), 6394. https://doi.org/10.3390/jcm13216394
Amasi-Hartoonian, N., Sforzini, L., Cattaneo, A., & Pariante, C. M. (2022). Cause or consequence? Understanding the role of cortisol in the increased inflammation observed in depression. Current opinion in endocrine and metabolic research, 24, 100356. https://doi.org/10.1016/j.coemr.2022.100356
Knezevic, E., Nenic, K., Milanovic, V., & Knezevic, N. N. (2023). The role of cortisol in chronic stress, neurodegenerative diseases, and psychological disorders. Cells, 12(23), 2726.
Carlesso, L. C., Sturgeon, J. A., & Zautra, A. J. (2016). Exploring the relationship between disease-related pain and cortisol levels in women with osteoarthritis. Osteoarthritis and cartilage, 24(12), 2048-2054. https://doi.org/10.1016/j.joca.2016.06.018
Quartana, P. J., Buenaver, L. F., Edwards, R. R., Klick, B., Haythornthwaite, J. A., & Smith, M. T. (2010). Pain catastrophizing and salivary cortisol responses to laboratory pain testing in temporomandibular disorder and healthy participants. The Journal of Pain, 11(2), 186-194
Hannibal, K. E., & Bishop, M. D. (2014). Chronic stress, cortisol dysfunction, and pain: a psychoneuroendocrine rationale for stress management in pain rehabilitation. Physical therapy, 94(12), 1816-1825.

[Further Readng: Inflammation]

Last Updated: Mar 10, 2025