Blood biomarkers assess adrenal hypofunction. Serum cortisol is best to evaluate adrenal function, especially low cortisol, which salivary testing may not detect. DHEA-S, cortisol:DHEA-S ratio, sodium:potassium ratio, aldosterone, glucose, and ACTH.
Adrenal fatigue occurs at the stage of adrenal dysfunction associated with severe maladaptation to stress. It can occur when the amount or intensity of stress outweighs the body’s ability to deal with and recover from that stress. Over time, adrenal, thyroid, pituitary, and hypothalamic functions can become compromised. At the same time, the excess cortisol leading up to adrenal fatigue can contribute to obesity and gastrointestinal dysfunction leading to inflammation, infection, and dysbiosis (Raymond 2021).
Other signs along the spectrum of adrenal dysfunction include mood changes, cognitive dysfunction, difficulty concentrating, decreased productivity, lethargy, decreased tolerance, insomnia, and orthostatic hypotension (Anderson 2008).
Along with a complete history, a biochemical assessment of cortisol, DHEA/DHEA-S, the cortisol:DHEA-S ratio, and the sodium:potassium ratio can help evaluate adrenal status. Elevated ACTH, aldosterone, and glucose may also be signs of ongoing stress. It should be noted that drawing blood can induce stress and even acutely increase cortisol (Anderson 2008).
Adrenal fatigue is not the same as adrenal insufficiency, a less common endocrine disease associated with a primary failure of the adrenal gland to produce cortisol and aldosterone. Secondary adrenal insufficiency may be due to a lack of ACTH release. Adrenal insufficiency can be fatal and is associated with weight loss, hypotension, fatigue, anorexia, and depression (Mahzari 2022).
Adrenal Fatigue and the Stress Response
Both cortisol and DHEA can increase early in the stress response but return to baseline reasonably quickly. Symptoms may not be present at this stage. However, if the stress continues, the adaptation phase will be characterized by persistently high cortisol, declining DHEA, and mood changes, including anxiety.
Adrenal fatigue occurs in what is traditionally called the Exhaustion Stage of the stress response, where dysfunction progresses toward adrenal hypofunction with low cortisol and low DHEA. This phase can be characterized by low energy, fatigue, weakness, and moodiness. Additional consequences include severe fatigue, hormone imbalance, hair loss, muscle and bone loss, immune dysfunction, arthritis, weight gain, insomnia, anxiety, and depression. Poor diet, toxin exposure, hormone imbalances, and poor dietary choices contribute to adrenal dysfunction and, eventually, adrenal fatigue (Noland 2020).
Stage 1 Arousal: Cortisol and DHEA become elevated but return to baseline
Stage 2 Adaptation: Cortisol becomes chronically elevated, and DHEA declines
Stage 3 Exhaustion: Cortisol and DHEA are decreased due to insufficient adrenal function
Assess Adrenal Dysfunction
Cortisol
Measuring plasma cortisol is best for evaluating adrenal activity. Very low cortisol suggests adrenal hypofunction or adrenal fatigue. Cortisol follows a diurnal pattern and, under normal circumstances, peaks in the morning between 6 am and 8 am and falls throughout the day to a nadir at midnight. Measurements are commonly taken at 8 am and again at 4 pm when levels should be one-third to two-thirds the morning value. Cortisol that does not decline may indicate Cushing syndrome, and persistently low cortisol may indicate adrenal hypofunction or Addison’s disease. Although salivary cortisol is convenient and can assess high cortisol levels, it is not as sensitive as blood testing to identify low cortisol levels (Pagana 2021).
Cortisol and glucose levels are both altered during stress as cortisol increases glucose levels by increasing protein catabolism and gluconeogenesis and decreasing insulin sensitivity. Hypoglycemia can trigger cortisol release and should be prevented to avoid a vicious cycle (Anderson 2008).
Additional cortisol biomarkers in adults include free serum 8 am cortisol, 24-hour urinary cortisol, and salivary cortisol, which can be checked 3-4 times during the day but may not be accurate or detect very low levels (Pagana 2021). More advanced testing of steroid intermediates may be indicated in congenital adrenal hyperplasia, characterized by low cortisol (Rege 2019).
ACTH Stimulation Test
Although primary adrenal insufficiency is rare, it should be assessed if suspected. ACTH stimulation is traditionally used for its diagnosis, and it measures the cortisol response to ACTH administration and is used to identify adrenal insufficiency. Serum cortisol is measured in the morning, followed by measurements 30 and 60 minutes after ACTH administration. Higher cortisol cutoff values have better sensitivity. Individuals on prescribed corticosteroid replacement are expected to have lower basal cortisol (Mahzari 2022).
DHEA-S
DHEA-S is the active sulfated form of DHEA and the most abundant steroid in circulation. Significant stress or injury will decrease the adrenal production of DHEA-S while the production of catabolic cortisol increases. Researchers suggest that DHEA supplementation may restore the balance of cortisol to DHEA-S and improve healing, bone remodeling, well-being, and mood, as seen with adrenal hypofunction, aging, and menopause. Research in older individuals demonstrates that an oral dose of 50 mg/day restored serum DHEA and DHEAS to levels seen in 30-year-olds (Bentley 2019). DHEA-S should only be supplemented after a deficiency has been confirmed, as adverse side effects can occur with excess DHEA (Anderson 2008).
Cortisol:DHEA-S Ratio
Under normal circumstances, circulating DHEA-S is approximately 5 to 10 times higher than circulating cortisol (Ritsner 2005). Stress can alter the cortisol:DHEA-S ratio as the body shifts the use of cholesterol-based pregnenolone from DHEA to cortisol, and the ratio shifts higher, especially in acute situations. However, prolonged stress and the advent of adrenal fatigue will decrease both cortisol and DHEA-S, reducing its effect on the ratio.
Sodium:Potassium Ratio
Stress-induced Increases in aldosterone will affect sodium-potassium balance by causing sodium and water retention and potassium excretion. An increase in the plasma sodium:potassium ratio is associated with a significantly increased risk of hypertension and markers of inflammation and oxidation (Ekun 2020).
Increased serum sodium:potassium ratio, especially above 34, suggests a potassium depletion, while below 28 suggests sodium depletion and insufficiency of magnesium and vitamin E (Wardle 2019). Elevated sodium:potassium ratio may indicate acute stress, while decreased sodium:potassium ratio may occur with chronic stress and adrenal hypofunction.
Hormonal facilitation of the stress response involves the adrenal cortex, which releases glucocorticoids and mineralocorticoids/corticosteroids that have profound effects on physiology (Singh 2016):
|
Cortisol (glucocorticoid) |
Aldosterone (mineralocorticoid) |
|
Mobilizes free fatty acids Mobilizes protein and amino acids Initiates gluconeogenesis Increases serum glucose levels Promotes muscle wasting Damages antibodies Impairs immune system Depletes micronutrients Causes beta cell depletion Decreases insulin production Increases arterial blood pressure |
Promotes sodium retention Enhances potassium elimination Increases osmotic retention of water Increases blood pressure by increasing blood volume
|
Aldosterone
Although not commonly thought of as a stress hormone, the adrenal mineralocorticoid aldosterone increases in response to stress and HPA activation. Research suggests that elevated aldosterone may be associated with an increased risk of metabolic dysfunction and cardiovascular risk via several different actions as it (Kubzansky 2010):
- Increases water and sodium retention
- Facilitates potassium excretion
- Increases risk of hypertension
- Increases pro-inflammatory mediators
- Decreases adiponectin and insulin sensitivity
- Activates the mineralocorticoid receptor (MR)
- Levels increase with sodium intake
- Levels increase with stress
- Increased aldosterone may contribute to mood disorders, including anxiety and depression
Adrenocorticotropic hormone (ACTH, Corticotropin)
Stress can interfere with the normal diurnal cycle of ACTH, which follows the same pattern as cortisol. Measuring ACTH helps assess the overproduction of cortisol and Cushing syndrome and the underproduction of cortisol and Addison disease. ACTH is produced by the anterior pituitary in response to CRH from the hypothalamus. The ACTH then stimulates the adrenal cortex to produce cortisol. If cortisol remains low while ACTH is high, adrenal hypofunction is likely. A low ACTH likely reflects hypopituitarism (Pagana 2021).
Address Adrenal Dysfunction
Once identified, adrenal fatigue must be addressed. A nutrient-dense, balanced diet, physical activity, adequate sleep, and relaxation techniques are especially important to recovery.
Micronutrients are essential in maintaining optimal adrenal function and include vitamin B6, pantothenic acid, folate, vitamin C, vitamin D, magnesium, zinc, and omega-3 fatty acids (Noland 2020). Vitamin A, carotenoids, vitamin E, calcium, copper, manganese, selenium, molybdenum, chromium, and iodine are also essential to adrenal function (Anderson 2008).
Botanicals with anti-stress effects can be helpful, including chamomile, ginseng, ginkgo biloba, holy basil, rhodiola, cordyceps, and lavender essential oil (Anderson 2008, Raymond 2021).
Physical activity helps improve resilience to physical, emotional, and psychological stress and can help blunt the cortisol response to stress. Cortisol levels were significantly increased early in adrenal fatigue and correlated with the severity of fatigue in a cross-sectional study of 160 young adults. Results indicate that moderate and vigorous physical activity significantly decreases the severity of adrenal fatigue and cortisol and ACTH levels. Extremely high levels of physical activity are not recommended due to immunosuppressive effects (Alghadir 2015).
Stress management is vital as well. Significant sources of stress should be identified and addressed, including structural or physical stress; mental, emotional, and spiritual stress; chemical/toxic stress; and electromagnetic stress. Each stressor can be addressed accordingly by incorporating nutrition support, hormonal support, moderate exercise, yoga, and relaxation techniques (Anderson 2008).
Optimal Takeaways
- Adrenal fatigue may be characterized by
- Decreased cortisol and DHEA-S with an initial increase in cortisol:DHEA-S ratio, which may decrease as both cortisol and DHEA-S decrease with adrenal hypofunction.
- Increased aldosterone
- Increased ACTH with low cortisol
- Healthy lifestyle and nutrition habits can help reduce stress-related adrenal dysfunction
- Nutrition and supplement support may be indicated
- Stress management is essential to addressing adrenal fatigue
Want to learn more?
Stress Biomarkers and Physiological Consequences
References
Alghadir, Ahmad H, and Sami A Gabr. “Physical activity and environmental influences on adrenal fatigue of Saudi adults: biochemical analysis and questionnaire survey.” Journal of physical therapy science vol. 27,7 (2015): 2045-51. doi:10.1589/jpts.27.2045
Anderson, D. "Assessment and nutraceutical management of stress-induced adrenal dysfunction." Integrative Medicine 7.5 (2008): 18-25. http://imjournal.com/resources/web_pdfs/popular/1008_anderson.pdf
Ekun, Oloruntoba A et al. “Assessment of Plasma Sodium to Potassium Ratio, Renal Function, Markers of Oxidative Stress, Inflammation, and Endothelial Dysfunction in Nigerian Hypertensive Patients.” International journal of hypertension vol. 2020 6365947. 7 Dec. 2020, doi:10.1155/2020/6365947
Kubzansky, Laura D, and Gail K Adler. “Aldosterone: a forgotten mediator of the relationship between psychological stress and heart disease.” Neuroscience and biobehavioral reviews vol. 34,1 (2010): 80-6. doi:10.1016/j.neubiorev.2009.07.005
Mahzari, Moeber et al. “Variations in cortisol response in patients with known and suspected adrenal insufficiency.” Medicine vol. 101,52 (2022): e32557. doi:10.1097/MD.0000000000032557
Noland, Diana, Jeanne A. Drisko, and Leigh Wagner, eds. Integrative and functional medical nutrition therapy: principles and practices. Springer Nature, 2020.
Raymond, Janice L., et al. Krause and Mahan's Food & the Nutrition Care Process. Elsevier, 2021.
Rege, Juilee et al. “Steroid biomarkers in human adrenal disease.” The Journal of steroid biochemistry and molecular biology vol. 190 (2019): 273-280. doi:10.1016/j.jsbmb.2019.01.018
Ritsner, Michael et al. “Cortisol/dehydroepiandrosterone ratio and responses to antipsychotic treatment in schizophrenia.” Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology vol. 30,10 (2005): 1913-22. doi:10.1038/sj.npp.1300747
Singh, K. "Nutrient and stress management." J Nutr Food Sci 6.4 (2016): 528.
Wardle, Jon, and Jerome Sarris. Clinical naturopathy: an evidence-based guide to practice. Elsevier Health Sciences, 2019. 3rd edition.