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The adrenal hormone cortisol impacts nearly all of the body’s systems. Cortisol levels fluctuate throughout the day, normally peaking in the morning hours and bottoming out at night. Deviations from this diurnal pattern have been associated with signs and symptoms of adrenal dysfunction. One such dysfunctional pattern is a flat cortisol curve, in which the amount of cortisol secreted (high or low) shifts very little throughout the day. In both healthy and clinical populations, flatter diurnal cortisol slopes have been associated with risk of a shorter lifespan and with negative physical and mental health outcomes.^1-3

Mortality Risk & Cardiovascular Implications

Research continues to elucidate the heart health consequences of flattened or dysregulated cortisol slopes. Most recently, a 2022 German cohort study that included a random representative sample from the general population (n=1,090 adults) assessed salivary cortisol and cardiovascular morbidity and mortality.² Reported results indicated that a greater diurnal cortisol peak-to-bedtime ratio at baseline predicted a decreased risk of cardiovascular mortality (HR: 0.50; CI: 0.34-0.73) and a decreased risk of stroke (HR: 0.71; CI: 0.55-0.92).² In addition, an increased level of late-night salivary cortisol that reflected a dysregulated diurnal cortisol pattern was associated with a higher risk of cardiovascular mortality (HR: 1.49; CI: 1.13-1.97) and an increased risk of stroke (HR: 1.24; 1.01-1.52).²

In addition to the potential heart and health impacts of increased late-night cortisol levels, studies have also suggested that elevated morning plasma cortisol levels may be a risk factor for cardiovascular disease.⁴

Diabetes and Depression

A blunted cortisol curve may also be correlated with diabetes and higher HbA1c in individuals with diabetes.^5,6 Due to potential differences among diurnal cortisol profiles in different race populations⁷ and age groups, the 2021 CARDIA study examined the longitudinal association of diurnal cortisol curve patterns with incident diabetes over a 10-year period among African American adults (n=376; median age 39 years) and white adults (n=333, median age 40 years).⁸ Results indicated:⁸

• A robust cortisol awakening response was associated with lower odds of incident diabetes among middle-aged white participants.
• A flatter late decline slope was associated with increased odds of incident diabetes among middle-aged white participants.
• African American participants had more than double the incidence of diabetes compared to white counterparts.
• The analysis did not show a significant relationship between the measured diurnal cortisol curve features and diabetes development in African American participants. However, the higher baseline risk factors (i.e., higher fasting insulin, BMI, and waist circumference) among these adults and the unmeasured confounders, including sleep and chronic stress, may have influenced the findings.

Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been implicated in the development of major depressive disorder (MDD) in adults, and cortisol has been identified as a potential predictor of onset, relapse, and recurrence of MDD.⁹ Specific to adolescents, a 2022 meta-analysis found that elevated morning cortisol levels preceded depression in the younger population.¹⁰

Chronic Stressors & Populations

Recurrent exposure to multiple social, physical, or environmental stressors not only impacts a patient’s quality of life and wellness but may impact cortisol curves^11,12 and compound negative health effects as well as disease burden.¹³

• Exposure to traffic-related air pollution and higher NO₂ levels have been associated with higher morning salivary cortisol levels. Chronic exposure to these toxicants has also been associated with overall flatter cortisol curves.¹¹
• Sustained psychosocial stress such as racial discrimination and experiencing microaggressions may also contribute to cortisol dysregulation and a flatter diurnal cortisol slope.¹²
• Results from the 2022 Stress in America survey indicated that nearly three-quarters of adults experienced health impacts due to stress in the prior month.¹⁴ The recent 2023 Stress in America survey echoed previous findings of long-term stress sustained by the US population with a suggested connection to reported increases in chronic illnesses (from 48% in 2019 to 58% in 2023) and mental health diagnoses (from 31% in 2019 up to 50% in 2023 among young adults).¹⁵

A Functional Medicine Approach

Measuring cortisol over the course of a day may help predict health outcomes both for patients with diseases and for seemingly healthy individuals. And understanding the factors that affect cortisol secretion can inform appropriate treatment interventions. How can clinicians screen for high levels of emotional and psychological stress in their patients? What can be done to mitigate the effects of toxic stress?

The functional medicine model provides tools to connect the dots between a patient’s health journey and any adrenal dysfunction. In addition, this approach shows clinicians how to identify the sources of stress in each patient, the best practices for measuring cortisol levels, and the most appropriate personalized treatment plans that may include a range of modifiable lifestyle factors from nutrition and exercise to breathing techniques and meditation.

The importance of addressing chronic stress is growing, as more and more studies continue to link stress to disease across the lifespan. The functional medicine approach helps identify points of leverage where physicians can apply individualized interventions to help restore cortisol patterns and overall hormonal balance. Learn more at IFM’s upcoming Hormone Advanced Practice Module (APM).

Related Articles

Lifestyle Changes for Shifting Cortisol Levels

How do stress and inflammation contribute to chronic disease?

Chronic stress and hormone disruption

References

1. Imami L, Jiang Y, Murdock KW, Zilioli S. Links between socioeconomic status, daily depressive affect, diurnal cortisol patterns, and all-cause mortality. Psychosom Med. 2022;84(1):29-39. doi:1097/PSY.0000000000001004
2. Karl S, Johar H, Ladwig KH, Peters A, Lederbogen F. Dysregulated diurnal cortisol patterns are associated with cardiovascular mortality: findings from the KORA-F3 study. Psychoneuroendocrinology. 2022;141:105753. doi:1016/j.psyneuen.2022.105753
3. Adam EK, Quinn ME, Tavernier R, McQuillan MT, Dahlke KA, Gilbert KE. Diurnal cortisol slopes and mental and physical health outcomes: a systematic review and meta-analysis. Psychoneuroendocrinology. 2017;83:25-41. doi:1016/j.psyneuen.2017.05.018
4. Crawford AA, Soderberg S, Kirschbaum C, et al. Morning plasma cortisol as a cardiovascular risk factor: findings from prospective cohort and Mendelian randomization studies. Eur J Endocrinol. 2019;181(4):429-438. doi:1530/EJE-19-0161
5. Joseph JJ, Golden SH. Cortisol dysregulation: the bidirectional link between stress, depression, and type 2 diabetes mellitus. Ann N Y Acad Sci. 2017;1391(1):20-34. doi:1111/nyas.13217
6. Panagiotou C, Lambadiari V, Maratou E, et al. Insufficient glucocorticoid receptor signaling and flattened salivary cortisol profile are associated with metabolic and inflammatory indices in type 2 diabetes. J Endocrinol Invest. 2021;44(1):37-48. doi:1007/s40618-020-01260-2
7. Boileau K, Barbeau K, Sharma R, Bielajew C. Ethnic differences in diurnal cortisol profiles in healthy adults: a meta-analysis. Br J Health Psychol. 2019;24(4):806-827. doi:1111/bjhp.12380
8. Kluwe B, Ortiz R, Odei JB, et al. The association of cortisol curve features with incident diabetes among whites and African Americans: the CARDIA study. Psychoneuroendocrinology. 2021;123:105041. doi:1016/j.psyneuen.2020.105041
9. Kennis M, Gerritsen L, van Dalen M, Williams A, Cuijpers P, Bockting C. Prospective biomarkers of major depressive disorder: a systematic review and meta-analysis. Mol Psychiatry. 2020;25(2):321-338. doi:1038/s41380-019-0585-z
10.  Zajkowska Z, Gullett N, Walsh A, et al. Cortisol and development of depression in adolescence and young adulthood – a systematic review and meta-analysis. Psychoneuroendocrinology. 2022;136:105625. doi:1016/j.psyneuen.2021.10562510
11.  Hajat A, Hazlehurst MF, Golden SH, et al. The cross-sectional and longitudinal association between air pollution and salivary cortisol: evidence from the Multi-Ethnic Study of Atherosclerosis. Environ Int. 2019;131:105062. doi:1016/j.envint.2019.105062
12.  Nam S, Jeon S, Lee SJ, Ash G, Nelson LE, Granger DA. Real-time racial discrimination, affective states, salivary cortisol and alpha-amylase in Black adults. PLoS One. 2022;17(9):e0273081. doi:1371/journal.pone.0273081
13.  Guidi J, Lucente M, Sonino N, Fava GA. Allostatic load and its impact on health: a systematic review. Psychother Psychosom. 2021;90(1):11-27. doi:1159/000510696
14.  American Psychological Association. Stress in America 2022: concerned for the future, beset by inflation. Published October 2022. Accessed April 23, 2024. https://www.apa.org/news/press/releases/stress/2022/concerned-future-inflation
15.  American Psychological Association. Stress in America 2023: a nation recovering from collective trauma. Published November 2023. Accessed April 23, 2024. https://www.apa.org/news/press/releases/stress/2023/collective-trauma-recovery