Hormone Biomarkers: Cortisol Total/AM

Optimal Takeaways

Cortisol is a regulatory steroid hormone produced in the adrenal gland. It has effects throughout the body, especially during the stress response. Under normal circumstances, it is highest in the morning upon awakening and then declines during the day, with the lowest levels occurring around midnight. However, prolonged elevated cortisol can lead to elevated blood glucose, hypertension, muscle breakdown, loss of brain volume, and micronutrient depletion. Persistently low cortisol can lead to fatigue, exhaustion, and low blood pressure.

Standard Range: 4 - 22 ug/dL (110.35 - 606.94 nmol/L)

The ODX Range: 10 - 15 ug/dL (275.88 - 413.82 nmol/L)      

Low cortisol levels are seen with Addison’s disease, adrenal insufficiency, congenital adrenal hyperplasia, hypothyroidism, hypopituitarism, and liver disease. Medications that reduce cortisol include lithium, levodopa, phenytoin, androgens, and exogenous steroids (Pagana 2021). Prolonged stress and burnout can also contribute to a hypocortisolemic state and low morning cortisol (Bayes 2021) which may be a sign of HPA insufficiency (Kazlauskaite 2008).

High cortisol levels are seen with physical and emotional stress, Cushing syndrome, pregnancy, obesity, adrenal carcinoma, hyperthyroidism, and liver disease. Medications that increase cortisol include cortisone, amphetamines, spironolactone, and oral contraceptives (Pagana 2021). Elevated cortisol can also be associated with seizures, epilepsy (Cano-López, 2019), frailty (Marcos-Perez 2019), dysglycemia, higher fasting glucose, visceral adiposity, and higher hs-CRP and TSH (Alufer 2023).

Overview

Cortisol is a glucocorticoid steroid hormone produced in the adrenal cortex from cholesterol. It has profound effects throughout the body, including in the nervous, immune, cardiovascular, respiratory, reproductive, musculoskeletal, and integumentary systems. Cortisol regulates metabolism, immune function, inflammation, and the stress response. Ultimately, it puts the body on high alert. Cortisol directly affects the liver, pancreas, muscle, and adipose tissue and increases the endogenous availability of resources, including glucose, fatty acids, and amino acids. It also suppresses inflammation and the immune response (Thau 2021).

Cortisol also increases blood pressure, promotes muscle wasting, depletes micronutrients, and decreases insulin production and beta cell function (Singh 2016). Low levels can be associated with fatigue and exhaustion.

Approximately 95% of circulating cortisol is bound to corticosteroid-binding globulin and albumin. A total cortisol level will reflect bound and unbound hormones. Men can have significantly higher baseline am cortisol than women (Kamba 2016).

Measuring plasma cortisol is best for evaluating adrenal activity. Cortisol follows a diurnal pattern and, under normal circumstances, peaks in the morning and helps you wake up, usually between 6 am and 8 am. Levels fall slowly throughout the day, with the lowest occurring around midnight. Loss of this diurnal variation may be the first sign of adrenal dysfunction. Elevated cortisol that does not decline during the day may indicate adrenal hyperfunction or Cushing syndrome, while persistently low levels may indicate adrenal hypofunction or Addison’s disease. Plasma levels should be evaluated at 8 am and again at 4 pm when they should be one-third to two-thirds of the 8 am value. Late-night salivary cortisol may be used for identifying elevated cortisol and adrenal hyperfunction. However, salivary cortisol may not be accurate for evaluating low cortisol or Addison’s because salivary assays may not be sensitive enough at low cortisol levels (Pagana 2021).

It is often called the “stress hormone” and levels rise within 15 minutes of acute stress. Though stress can cause an increase in morning cortisol, prolonged stress can ultimately lead to burnout characterized by an overall reduction in cortisol and systemic inflammation, compromised immunity, increased risk of infection, dyslipidemia, and altered glucose regulation (Bayes 2021).

Elevated cortisol may represent increased stimulation of the autonomic nervous system and HPA axis, a phenomenon associated with B-cell dysfunction, impaired glucose regulation, and diabetes. In a cross-sectional population-based study of 1,071 Japanese subjects, fasting am cortisol above 11 ug/dL (304 nmol/L) or below 8 ug/dL versus midrange 8-11 ug/dL (221-304 nmol/L) was associated with decreased insulin secretion and beta cell function and future risk of diabetes (Kamba 2016).

A review of data from 4,206 African American participants in the Jackson Heart Study found that elevated morning cortisol was associated with increased fasting blood glucose and reduced beta cell function in non-diabetics and increased fasting blood glucose and hemoglobin A1C in those with T2DM. In all subjects, the highest am cortisol in the range of 13.2-16.6 ug/dL (364-458 nmol/L) was associated with a 1.26 increased risk of T2DM compared to the lowest quartile in the range of 4.8-6.4 ug/dL (132-177 nmol/L). Higher am serum cortisol was associated with male gender, smoking, alcohol consumption, and lower educational status (Ortiz 2019).

However, a low am cortisol between 4.7-5.3 ug/dL (130-146 nmol/L) can be related to HPA insufficiency according to a meta-analysis of 12 studies and should be investigated further (Kazlauskaite 2008).

Elevated cortisol can suppress inflammation and immune function by decreasing lymphocyte and eosinophil counts (Wardle 2019).

In a study of dementia-free Framingham Heart Study subjects, higher morning cortisol was associated with brain tissue depletion, cognitive impairment, memory deficits, and decreased visual perception. Those with cortisol in the highest tertile, above 15.8 ug/dL (436 nmol/L) within a range of 17.6-24.6 ug/dL (486-679 nmol/L), had the worst memory and visual perception as well as significantly lower cerebral brain volume and gray matter compared to the middle tertile of 10.8-15.8 ug/dL (298-436 nmol/L). Those in the lowest tertile, with cortisol below 10.8 ug/dL (range 7.4-9.8 ug/dL), had no brain volume or cognitive deficits (Echouffo-Tcheugui 2018).

References

Alufer, Liav et al. “Long-term green-Mediterranean diet may favor fasting morning cortisol stress hormone; the DIRECT-PLUS clinical trial.” Frontiers in endocrinology vol. 14 1243910. 14 Nov. 2023, doi:10.3389/fendo.2023.1243910

Bayes, Adam et al. “The biology of burnout: Causes and consequences.” The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry vol. 22,9 (2021): 686-698. doi:10.1080/15622975.2021.1907713

Cano-López, Irene, and Esperanza González-Bono. “Cortisol levels and seizures in adults with epilepsy: A systematic review.” Neuroscience and biobehavioral reviews vol. 103 (2019): 216-229. doi:10.1016/j.neubiorev.2019.05.023

Echouffo-Tcheugui, Justin B et al. “Circulating cortisol and cognitive and structural brain measures: The Framingham Heart Study.” Neurology vol. 91,21 (2018): e1961-e1970. doi:10.1212/WNL.0000000000006549

Kamba, Aya et al. “Association between Higher Serum Cortisol Levels and Decreased Insulin Secretion in a General Population.” PloS one vol. 11,11 e0166077. 18 Nov. 2016, doi:10.1371/journal.pone.0166077

Kazlauskaite, Rasa et al. “Corticotropin tests for hypothalamic-pituitary- adrenal insufficiency: a metaanalysis.” The Journal of clinical endocrinology and metabolism vol. 93,11 (2008): 4245-53. doi:10.1210/jc.2008-0710

Marcos-Perez, Diego et al. “Serum cortisol but not oxidative stress biomarkers are related to frailty: results of a cross-sectional study in Spanish older adults.” Journal of toxicology and environmental health. Part A vol. 82,14 (2019): 815-825. doi:10.1080/15287394.2019.1654639

Ortiz, Robin et al. “The association of morning serum cortisol with glucose metabolism and diabetes: The Jackson Heart Study.” Psychoneuroendocrinology vol. 103 (2019): 25-32. doi:10.1016/j.psyneuen.2018.12.237

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.

Singh, K. "Nutrient and stress management." J Nutr Food Sci 6.4 (2016): 528.

Thau, Lauren, et al. “Physiology, Cortisol.” StatPearls, StatPearls Publishing, 6 September 2021.

Wardle, Jon, and Jerome Sarris. Clinical naturopathy: an evidence-based guide to practice. Elsevier Health Sciences, 2019. 3rd edition.