The term “adrenal fatigue” has been challenged and rejected by the conventional medical community for decades. The Endocrine Society, a respected global organization of researchers and medical professionals, asserts that there is no scientific proof that adrenal fatigue exists as a medical diagnosis.1 An article on the Mayo Clinic blog warns patients that “unproven remedies for so-called adrenal fatigue may leave you feeling sicker, while the real cause—such as depression or fibromyalgia—continues to take its toll.”2
Now a systematic review, published by Cadegiani and Kater in BMC Endocrine Disorders, concludes that “there is no substantiation that ‘adrenal fatigue’ is an actual medical condition. Therefore adrenal fatigue is still a myth.”3 Secondary conclusions of the review are that cortisol profile tests should not be used to justify corticosteroid treatment and that cortisol profile tests have no clinical utility in evaluating patients with fatigue.
These conclusions raise an undeniable question: Does the bulk of scientific knowledge truly discredit the many hypothalamic-pituitary-adrenal (HPA) axis dysfunctions that integrative physicians evaluate with cortisol profile tests and treat with natural therapeutics?
Part of the challenge in deciding whether or not adrenal fatigue exists is that adrenal fatigue is a vague and ill-defined concept. Cadegiani and Kater do not even provide a clear definition in their article for the term. Instead, their conclusions appear to rely on 3 assumptions, which they imply but do not outwardly state:
- Adrenal fatigue exists only if low cortisol production correlates with fatigue status.
- Corticosteroid therapy is the only treatment option for so-called adrenal fatigue.
- Cortisol profile tests are useful only if they detect a diagnosable disease.
Here we briefly summarize the results of Cadegiani and Kater’s 2016 systematic review and then challenge each of their 3 implied assumptions. We suggest the following instead:
- Adrenal fatigue is one of several patterns of HPA axis dysfunction.
- Nutritional, herbal, and lifestyle therapies can help normalize the HPA axis without the use of corticosteroids.
- Cortisol profile tests are useful to identify subclinical patterns that guide individualized patient care.
Perhaps the controversy surrounding the term “adrenal fatigue” would dissipate if we could clarify its definition and view it as one of many manifestations of subclinical HPA axis dysfunction.
Cadegiani and Kater’s Conclusions
Cadegiani and Kater reviewed 58 studies that evaluated the correlation between cortisol profile and fatigue status. The direct awakening cortisol level, the cortisol awakening response, and the salivary cortisol rhythm were the most commonly used tests to assess cortisol profile. The studies assessed healthy individuals as well as symptomatic patients, including those with chronic fatigue syndrome (CFS), fibromyalgia, breast cancer, rheumatoid arthritis, multiple sclerosis, and human immunodeficiency virus (HIV).
Science is only beginning to unravel the mysteries of how cortisol, HPA axis dysfunction, and chronic disease interrelate.
The authors reported no consistent correlations between fatigue status and cortisol profile in the included studies. They did acknowledge that a significant number of the studies showed differences between the healthy and fatigued groups, but they attributed these differences to methodological issues. The article was a systematic review rather than a meta-analysis, so no statistical calculations were used to justify their conclusions.
It could be argued that upon closer examination, some patterns in their reviewed studies do emerge. For example, of 38 cortisol profile assessments conducted in studies comparing patients with CFS to controls, no correlation between cortisol production and CFS was detected in 26 cortisol profile tests (68%), decreased cortisol was associated with CFS in 10 tests (26%), and increased cortisol was associated with CFS in only 2 tests (5%). These results suggest that approximately 1 in 4 patients with CFS experience decreased cortisol production.
Nevertheless, Cadegiani and Kater conclude from their systematic review that cortisol does not correlate with fatigue status and, therefore, there is no justification so far for adrenal fatigue as a diagnosis. They note that adrenal fatigue requires further investigation by those who claim it exists.
Complexity of the HPA Axis
Physiology of the HPA Axis
The HPA axis can be thought of as a neuroendocrine organ—the point at which the nervous and the endocrine systems converge. The HPA axis secretes hormones on a circadian rhythm to regulate daily energetic needs. The suprachiasmatic nucleus in the hypothalamus sets this rhythm, releasing corticotropin-releasing hormone (CRH) on a 24-hour cycle. Corticotropin-releasing hormone acts on the pituitary gland to trigger release of adrenocorticotropic hormone (ACTH), which in turn acts on the adrenal cortex to trigger release of cortisol. In healthy individuals, cortisol production spikes by 38% to 70% upon waking and gradually declines throughout the day so that it reaches its lowest point around midnight.4 The daily rhythm of cortisol production exerts numerous physiologic effects, including raising morning blood glucose by stimulating gluconeogenesis.5
In addition to establishing a circadian rhythm of hormone production, the HPA axis also reacts to physical and psychological stressors. The amygdala, part of the primitive and emotional brain, initially perceives the sense of danger (ie, stress) and sends a signal to the hypothalamus. The hypothalamus activates the sympathetic nervous system (SNS), sending signals via autonomic nerves to the adrenal medulla to trigger the release of epinephrine (ie, adrenaline) into the bloodstream. As the initial flood of epinephrine subsides, the HPA axis activates to produce cortisol. Via a negative feedback mechanism, cortisol feeds back to dampen production of CRH and ACTH, and cortisol levels return to baseline. This physiologic response to stress is an evolutionary mechanism to keep us alive, but prolonged stress can disrupt healthy HPA axis function.
Hans Selye, a Hungarian endocrinologist, was the first to describe the physiologic response to stress in a series of stages.6 Selye used the term “General Adaptation Syndrome” to describe 3 stages of the stress response: alarm, resistance, and exhaustion. Epinephrine and norepinephrine are released during the alarm stage; cortisol is elevated during the resistance stage; and cortisol becomes depleted during the exhaustion stage. The progression through these stages takes several years or even decades.
In response to prolonged stress over time, a person might develop one of a number of dysfunctional cortisol patterns: a reversed diurnal rhythm, a consistently elevated cortisol, and a flat-line level of low cortisol are some examples. Any of these patterns could appear in a patient with fatigue, which may be one explanation for why Cadegiani and Kater detected no correlation between cortisol pattern and fatigue states.
HPA Axis in Chronic Disease
The many dysfunctional patterns of cortisol production make it difficult for researchers to correlate single patterns with specific diseases or symptoms, but some studies have succeeded in doing this. As the results of Cadegiani and Kater’s review show, patients with CFS are more likely to have depleted cortisol levels than they are to have elevated cortisol levels. It may turn out that the subset of CFS patients with low cortisol share common characteristics. For example, a 2009 study found that low cortisol with CFS occurred only in patients who had experienced childhood trauma.7
In contrast to CFS, insulin resistance and metabolic syndrome are more likely to occur with subclinical hypercortisolism than with cortisol depletion. It has been proposed that chronically elevated cortisol might induce insulin resistance by promoting the release of free fatty acids and by promoting central obesity.8 Small studies suggest that subclinical cortisol elevations are associated with an increased risk of metabolic syndrome.9,10
Studies assessing cortisol levels in relation to depression have produced mixed results. In a study of 104 adults caring for someone with dementia, patterns of hypercortisolism were associated with more anger and depressive symptoms.11 Another study found that mothers with depression, as well as their at-risk daughters, exhibited higher cortisol levels than controls without depression.12 In contrast, young children with depression have demonstrated a blunted cortisol response to stress.13 A 2015 study found that elevated cortisol correlated with depression at the group level but not necessarily at the individual level, emphasizing the need to evaluate each patient on an individual basis.14
Science is only beginning to unravel the mysteries of how cortisol, HPA axis dysfunction, and chronic disease interrelate. Evidence suggests that the HPA axis interacts with the nervous system and the immune system to influence the pathophysiology of inflammatory, autoimmune, metabolic, cardiovascular, psychiatric, and other chronic disorders.15 Disrupted cortisol rhythms may contribute to sleep disorders, pain, fatigue, and gastrointestinal conditions.16-20 Flattened or abnormal cortisol rhythms are associated with shorter survival in patients with breast cancer as well as those with ovarian cancer.21,22 Studies repeatedly correlate emotional, physical, chemical, and immune stressors—all of which have the physiologic potential to disrupt HPA function—with an increased risk for chronic diseases, including CFS, depression, irritable bowel syndrome (IBS), heart disease, diabetes, and periodontal disease.23-29
Integrative Therapies for the HPA Axis
Recall that the physiology of the stress response, as outlined by Selye, evolves over time, progressing from alarm to resistance to exhaustion. This sequence can take many years and only results in cortisol depletion in some individuals. Because of this, integrative therapies aim to normalize, rather than stimulate, HPA function. They aim to allow for normal HPA axis stimulation while repairing the feedback mechanisms to the hypothalamus and pituitary glands to produce healthy cortisol levels. Therapies that achieve this goal are called adaptogenic. In this section, we evaluate whether evidence supports the use of adaptogenic herbs, nutrition, exercise, and stress reduction techniques to normalize HPA function. These therapies are only a small sampling of the many therapies employed by integrative physicians to normalize HPA function.
Adaptogenic herbs are plants that help the body respond more favorably to perceived stress, normalizing the physiologic response. Examples of adaptogenic herbs include Eleutherococcus senticosus (Siberian ginseng), Panax ginseng (Korean or Chinese ginseng), Panax quinquefolia (American ginseng), and Rhodiola rosea (rhodiola). True to the definition of an adaptogen, animal studies suggest that there is a threshold level of cortisol production, below which Eleutherococcus senticosus and Panax ginseng stimulate the stress response and above which they decreases the stress response.30
In relation to symptomatic outcomes, Panax ginseng and Panax quinquefolium have been shown to improve cancer-related fatigue.31,32 Eleutherococcus senticosus has been shown to improve endurance in competitive athletes.33,34 Rhodiola has been shown to reduce fatigue under stressful situations, improve exercise performance by decreasing perceived effort, and improve attention, cognitive function, and mental performance in patients with fatigue.35-37 A systematic review of 10 controlled clinical trials concluded that rhodiola may have beneficial effects on physical performance, mental performance, and mental health.38
Consumption of sugar and refined carbohydrates produces dramatic fluctuations from hyperglycemia to hypoglycemia. The hypoglycemic state is a trigger for cortisol release, as one of cortisol’s roles is to elevate blood glucose. One study found that children who eat more sugar display an exaggerated cortisol awakening response and overall elevated cortisol levels throughout the day.39 If hypoglycemia occurs in the middle of the night, however, the spike in cortisol production may disrupt sleep but not be detected on daytime cortisol testing.
Studies have also found that the diurnal cortisol rhythm responds to diet and nutrition in adults. Women who eat more saturated fats and less monounsaturated fats display less dramatic variation in cortisol levels over the course of the day, with a flatter line of production from morning to night.40 Young adults who eat more fat and less fruits and vegetables also display a flatter cortisol pattern over the course of the day.41 Vitamin C, at a dosage of 1000 mg 3 times per day, improved salivary cortisol recovery and improved the subjective response to psychological stress.42 And a complex of soy lecithin-derived phosphatidic acid and phosphatidylserine complex has shown in 2 studies to dampen the ACTH and cortisol response to stress and decrease psychological distress.43,44
Exercise may be a profound and simple way to modulate the HPA axis. Regular exercise has been shown to protect against the physiologic effects of stress by optimizing the response of the HPA axis to perceived stress.45 Studies suggest that low-intensity exercise lowers cortisol levels, whereas moderate to high-intensity exercise elevates cortisol.46 To coincide with the healthy circadian rhythm, it makes sense to engage in high-intensity exercise in the morning and low-intensity later in the day.
Stress Reduction Techniques
Stress reduction techniques have been shown to both improve stress-related symptoms as well as improve the body’s physiologic response to perceived stress. Examples of these techniques include mindfulness-based stress reduction (MBSR), yoga, and massage.
A study evaluating the effects of MBSR in patients with cancer found that the practice had an adaptogenic effect on cortisol levels: MBSR increased cortisol in patients with low baseline levels and decreased cortisol in patients with high baseline levels.47 In a study of women with prenatal and postpartum depression, both yoga and social support interventions effectively decreased symptoms of anxiety, depression, and anger while also decreasing cortisol levels.48 In a randomized trial, 15 minutes of back massage per day improved symptoms of anxiety, blood pressure, sleep quality, and cortisol levels in caregivers for patients with cancer.49
The Role of Cortisol Profile Testing
Conventional tests to diagnose adrenal insufficiency include the ACTH stimulation test, the CRH stimulation test, and the insulin tolerance test (ITT). These provocation tests require intravenous injections of hormones and are performed by endocrinologists.
Tests that are more commonly employed to evaluate subclinical HPA dysfunction include the direct awakening cortisol level, the cortisol awakening response, and the salivary cortisol rhythm. These were the most frequently used tests in the studies reviewed by Cadegiani and Kater. One conclusion of their review was that these tests should not be used to diagnose “adrenal fatigue,” but we propose that these tests can play an important role in evaluating subclinical HPA dysfunction.
An important distinction between conventional medical testing and functional medical testing is this: conventional tests aim to diagnose disease, whereas functional tests aim to identify subclinical biochemical patterns. Cortisol profile tests provide a glimpse of the body’s biochemistry and physiology to identify subclinical patterns of HPA dysfunction. Cortisol tests can help identify which subset of patients will benefit from therapies that help normalize HPA function and which therapies will be most appropriate.
Professional medical societies and a recent systematic review have concluded that “adrenal fatigue” does not exist. This uncompromising conclusion is an oversimplification of human physiology and pathophysiology. It ignores the clinical reality that perceived stress and the body’s hormonal response to perceived stress influence disease.
Cortisol production is often disrupted in chronic disease, integrative therapies help normalize HPA function, and testing cortisol profiles can be a useful tool to identify which subset of patients might benefit from such therapies. These approaches allow clinicians to individualize therapies and prevent the progression from subclinical to clinical disease, making them consistent with the foundational principles of naturopathic medicine, functional medicine, and other integrative systems of medicine.
Just as the conclusion that “adrenal fatigue does not exist” is an oversimplification, so too is the term “adrenal fatigue” itself. Cortisol depletion is just one of many potential patterns that can manifest from HPA axis dysfunction. Perhaps if we shift the terminology away from “adrenal fatigue” and toward the more encompassing phenomenon of “HPA axis dysfunction,” we can begin to have a conversation rather than an argument.
- “Adrenal Fatigue” is not a medically recognized diagnosis
- Functional laboratory tests, including direct awakening cortisol and salivary cortisol rhythm, should not be used to justify corticosteroid therapy
- Function of the hypothalamic-pituitary-adrenal (HPA) axis can be disrupted by chronic stress or disease and can affect physiology and pathophysiology
- Functional laboratory tests can help identify patients who might benefit from herbal, nutritional, or lifestyle interventions to normalize function of the HPA axis
- Evaluation and treatment of subclinical dysfunction of the HPA axis is consistent with the paradigm and values of naturopathic medicine, functional medicine, and other integrative medical approaches