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Adrenal Fatigue: Myth or Metaphor?

"Hi Mrs. Jones, your four-point salivary Cortisol test showed a normal but blunted response. Your 24-hour urine hormone tests showed that your allo-tetrahydrocortisol and your tetrahydrocortisone were low, tetrahydrocortisol was high, and your cortisone was average. Ragland's test for postural hypotension and Rogoff's sign of back tenderness were positive. Oh, and by the way, your serum morning Cortisol was normal." I scratched my head and furrowed my eyebrow like I was deep in thought. She looked at me with bewildered eyes. We both appeared to be confused. I paused for a moment and then stammered, "I think you have adrenal fatigue." I then continued, "Here take these supplements to help build up and nourish your adrenal glands. I think they will improve your energy, make you feel better and improve your response to stress." She asked, "What is adrenal fatigue?" I then went into a long ardent and zealous lecture of what the adrenal glands are, what they do, how they modulate the stress response, why they appear to get run down and how I think we can improve them. My impassioned narrative was full of medical metaphors, similes and hyperboles. We both then nodded, smiled at each other and shook hands. She left with her supplements, and I reflected back in my chair.

According to my old physiology book and Wikipedia, the adrenal glands are a pair of small acorn-shaped organs located on the top of each kidney. They measure 3 by 5 and 1 centimeter in size and weigh a combined weight of 7 to 10 grams. Histologically, they consist of two different and distinct tissues: an outer cortex and inner medulla. The outer cortex consists of three layers: the zona glomerulosa, zona fasciculata, and zona reticularis. The zona glomerulosa secretes mineralocorticoids, mainly as aldosterone, that regulate blood pressure and fluid volume. The zona fasciculata secretes glucocorticoids, mainly as Cortisol, that regulate immunologic, inflammatory, metabolic and homeostatic mechanisms. The zona reticularis secretes sex hormones, including dehydroepiandrosterone. The zona fasciculata accounts for 80% of the size of the adrenal cortex. The inner medulla consists of chromaffin cells that produce adrenaline (epinephrine) and noradrenaline (norepinephrine) that regulate the "flight or fight" response to stress. The adrenal glands, along with the sympathetic part of the nervous system, are the considered to be the main part of the body that deals with stress.

The function of the adrenal glands, particularly the outer cortex, is under the control of the pituitary gland and hypothalamus in the brain. The HPA axis refers to inter-relationship and feedback mechanisms of these three regions. The hypothalamus secretes corticotrophin releasing hormone (CRH) that stimulates the pituitary gland to secrete adrenocorticotropin hormone (ACTH). The ACTH in turn stimulates the adrenal glands to produce Cortisol and other hormones. The HPA axis helps to maintain a homeostatic balance of adrenal hormones in response to everyday life and response to acute and chronic stress.

Addison's disease is a condition marked by adrenal hormone insufficiency. It was first described in 1849 by the English physician Dr. Thomas Addison. Early symptoms of Addison's disease include fatigue, weakness, depression, increase thirst, frequent urination and craving for salt. The most common cause of Addison's disease is an autoimmune condition. The incidence of Addison's disease is reported to be about 1/100,000 people. Conversely, Cushing's disease is a condition marked by adrenal hormone excess. It is most commonly caused by a pituitary adenoma. The incidence of Cushing's disease is reported to 2-3/1,000,000 people. Both diseases are relatively rare.

The American physician Dr. John W. Tintera first described hypo-adrenocortical syndrome in 1949. I read his book called Hypoadrenocorticism, a collection of papers in which he describes a constellation of symptoms that are a result of a hypo-functioning adrenal gland system. Interestingly, he strongly associated hypo-adrenalism with hypoglycemic symptoms. Hypo-adrenia, subclinical Addison's disease, adrenal neurasthenia, adrenal exhaustion and adrenal fatigue are colloquial terms used to describe low-functioning adrenal glands. I learned that adrenal exhaustion was a syndrome marked by undiagnosed fatigue, malaise, unusual tiredness, depression, anxiety, muscle and body aches, low or high blood pressure, dizziness and lightheadedness, inability to concentrate, hair loss, headaches, allergies, shortness of breath, heart palpitations, poor digestion, hypoglycemia, weight gain, weight loss, urinary irritation and many other symptoms too numerous to list here. (1) I further learned that hypo-adrenia was caused by heavy acute stress and/or chronic stress on the body. The term adrenal fatigue was popularized by the American chiropractor Dr. James L. Wilson who wrote a book called Adrenal Fatigue: The 21st Century Stress Syndrome in 2001.

Fatigue is a subjective feeling of lack of energy, unusual tiredness, weakness, and poor vitality. It is one of the most common complaints encountered in family practice. The causes of fatigue can be many, including infection, anemia (including iron and vitamin B12 deficiency), endocrine dysfunction (including diabetes), hypothyroidism, sleep disturbance, medication side effects, asthma and chronic obstructive lung disease, anxiety, depression and other neurological issues and prolonged periods of excessive stress. Other illnesses associated with fatigue include cancer and Lyme's disease, malignancy, fibromyalgia, and chronic fatigue syndrome. (2,3) Often the causes of unexplained fatigue are rooted in diet, lifestyle, and stress-related consequences. The diagnosis of fatigue can be complex and almost always involves blood and other lab tests. Routine lab tests are used to evaluate fatigue and rule out certain relatively common diseases that may cause this symptom. Common lab tests routinely done for evaluation of unusual fatigue include CBC or complete blood count, blood chemistry including ferritin, vitamin B12, liver enzymes and bilirubin, electrolytes including sodium, potassium, calcium and magnesium, kidney function including BUN and creatinine, protein including albumin and globulin, uric acid, thyroid hormone levels and possibly inflammatory markers including CRP or c-reactive protein and ESR or erythrocyte sedimentation rate, possibly autoimmune markers and other markers of inflection and inflammation. It is important to note there are many other causes and many other lab tests that are further used to evaluate fatigue that are too numerous to list here. (2,3)

Is adrenal fatigue a real disease or a symptom of other disease and illness? Modern medicine uses diagnostic tests to evaluate and diagnose disease. Serum levels of cortisol are used to evaluate adrenal function. Morning levels of cortisol are considerably higher than at any time during the day or night. The diurnal pattern of cortisol reflects a normal pattern that is highest in the morning from about 6 to 8 am. From there levels normally decrease through the day and are at their lowest levels usually at night. Low levels of cortisol would possibly indicate Addison's disease and high levels of cortisol could possibly indicate Cushing's disease. I have noticed that the lab values of morning cortisol are quite broad and they only very rarely show abnormal levels. I still order baseline cortisol levels in individuals with suspected adrenal disease.

I have also used other tests to evaluate adrenal function including urine hormone and salivary cortisol tests. Urine tests evaluate levels of cortisol, cortisone, precursor pregnanetriol, dehydroepiandosterone, sex hormones including estrogens, progesterone and testosterone and various cortisol metabolites including tetrahydrocortisone, all-tetrahydrocortisol, tetrahydrocortisol and other byproducts. Four point salivary cortisol levels are measured first thing in the morning upon awakening between 6 and 8 am, lunch time at 12 pm, late afternoon between 4 and 6 pm and at bedtime between 10 to 12 pm. A graphic representation of the diurnal rhythm of salivary cortisol is then produced and compared to a normal rhythm in healthy individuals. I find that both urine and saliva tests are useful and interesting, but they can also be complicated, confusing and expensive for some patients.

I then searched out adrenal fatigue and allied synonyms on medical databases. I looked at various published studies and found different studies on the same topic to be contradictory and inconclusive. I came across a systematic review of adrenal fatigue published in 2016 that looked at 3470 studies found on PubMed, Medline and Cochrane databases. (4) The researchers concluded that most of these studies had poor study design, poor quality assessment, unsubstantiated methodology, false premises, and inappropriate and/or invalid conclusions. Fifty-eight/3470 studies were selected and met the inclusion criteria for this review. Thirty-three studies were on healthy individuals and 25 studies were symptomatic individuals. Methods used to evaluate adrenal fatigue included salivary cortisol rhythm, direct awakening cortisol, cortisol awakening response, morning serum cortisol, night salivary cortisol, area under curve measurement, dexamethasone suppression test, dehydroepiandosterone sulfate or DHEA-S, adrenocorticotropic hormone or ACTH, mental stress test, 24-hour urinary free cortisol, cosyntrophin stimulation test, morning area under curve, corticotrophin releasing hormone, total urinary cortisol metabolites and oral glucose tolerance test. (4)

Twenty-six studies utilized the salivary cortisol rhythm (SCR) to evaluate adrenal fatigue: 16/26 studies (61.5%) showed no difference between fatigued and controlled patients, (4) 7/26 studies (26.9%) showed impaired circadian rhythm, and 3/26 studies (11.6%) showed a pronounced decrease in cortisol levels. Twenty-nine studies utilized direct awakening cortisol (DAC) to evaluate adrenal fatigue: 19/29 studies (65.5%) showed normal DAC, 6/29 studies (20.7%) showed a decrease in (CAR) and 4/29 studies (13.8%) showed an increase in DAC. (4) Nine studies utilized the dexamethasone suppression test (DST) to evaluate adrenal fatigue (4): 6/9 studies (66.6%) showed no significant difference between fatigued and non-fatigued individuals, and 3/9 studies (33.3%) showed a decreased cortisol response from the DST. Six studies (10.3%) utilized adrenocorticotropic hormone or ACTH levels to evaluate adrenal fatigue (4): 5/6 studies (83.3%) showed no significant difference between fatigued and non-fatigued individuals in terms of ACTH levels, and 1/6 studies (16.7%) showed an increase in ACTH levels in burnout patients. Three studies (5.2%) utilized 24-hour urinary free cortisol (UFC) levels to evaluate adrenal fatigue (4): 1/3 study (33.3%) showed no correlation between UFC with fatigue and energy status. 2/3 studies (66.6%) showed a decrease in UFC in fatigued patients. Thirteen studies (22.4%) utilized area under the curve (AUC) in diurnal salivary cortisol levels to evaluate adrenal fatigue (4): 8/13 studies (61.5%) showed a normal AUC, 2/13 studies (15.4%) showed an increased AUC, and 3/13 studies (23.1%) showed decreased AUC in fatigued individuals. Twenty-two studies (37.9%) utilized morning serum cortisol (MSC) to evaluate adrenal fatigue (4):14/22 studies (63.6%) showed no difference in MSC between fatigued and non-fatigued individuals, 3/22 studies (23.1%) showed a decrease in MSC, and 2/22 studies (15.4%) showed an increase in MSC. Twenty-two studies (37.9%) utilized late night cortisol (LNC) levels to evaluate adrenal fatigue (4):13/22 studies (59.1%) showed no difference in LNC in fatigued individuals, 3/22 studies (13.6%) showed a decrease in LNC, and 6/22 studies (27.3%) showed an increase in LNC levels. Six studies (10.3%) utilized dehydroepiandrosterone sulfate or DHEA-S levels to evaluate adrenal fatigue (4): 4/6 studies (66.7%) showed no correlation between fatigued and non-fatigued individuals while 2/6 studies (33.3%) showed a decrease in DHEA-S levels in fatigued individuals. Four studies (6.9%) utilized the morning total cortisol release or morning area under the curve or MAUC to evaluate adrenal fatigue (4): 2/4 studies (50%) showed a decrease MAUC, while 1/4 studies (25%) showed an increase in MAUC, and 1/4 studies (25%) showed no difference in MAUC in fatigued versus non-fatigued patients. Five studies (8.7%) utilized Mental Stress Tests to evaluate adrenal fatigue (4): 4/5 studies (80%) showed no difference between fatigued and non-fatigued individuals while 1/5 studies (20%) showed a correlation between burnout status and Cortisol and ACTH responses. This paper also pointed out that none of the 58 studies utilized the insulin tolerance test (ITT) which is considered by specialists to be the gold standard test to evaluate the hypothalamic-pituitary-adrenal or HPA axis. (4) The researchers concluded in this review that there is "no substantiation that adrenal fatigue is an actual medical condition" and is "not recognized by endocrine societies." (4)

The clinical diagnosis of adrenal fatigue through objective testing is unclear and disputable. (5,6) Lab tests used to diagnosis this condition are not straightforward and still controversial. (7,8) Urine and saliva tests may still be useful and may reveal some results that are important with regards to adrenal function. However, their clinical relevance may be overstated for practical purposes. These tests can be helpful, but I feel that they only help to confirm the physician's intuition of what is wrong with the patient. The evidence of the effects of stress on the body leading to fatigue and burnout is fairly well documented. (9) Symptoms of burnout are eerily similar to the symptoms of adrenal fatigue. (10) These include unexplained fatigue, malaise, listlessness, anxiety, depression, inability to cope, and many other symptoms too numerous to list here. It doesn't take a rocket scientist to see that adrenal fatigue could be easily diagnosed as clinical burnout.

Here is a classic example of that old adage that you may be smart, but you still can't see what is right under your nose. Mainstream medicine admonishes many alternative practitioners for their belief in the concept of adrenal fatigue. While I agree the objective lab testing of this condition is controversial, clearly something is going on. (11,12) Adrenal fatigue may be a synonym for stress-induced burnout. Burnout is a fairly well documented clinical disorder. There are no objective lab tests that clearly diagnose burnout, but subjective symptoms are revealing (13,14) Few would dispute that physicians have one of the highest rates of work-related burnout. Many mainstream physicians are overworked, highly stressed, and burned out. (15) Therefore, it is fair to say that many physicians suffer with adrenal fatigue or something similar to that.

I feel that naturopathic medicine has much to offer to help the body effectively deal with the deleterious effects of stress and burnout. Dietary and lifestyle factors are fundamental and important for optimal health and vitality. Few would dispute a healthy diet rich in good quality protein, whole grains and ample fruits and vegetables is important for proper energy production. Daily exercise and good quality sleep are also vitally important. Also there are many nutritional supplements that can help improve energy and help the body deal with stress. All vitamins and minerals are probably important for proper biochemical reactions and energy production in the human body. B-vitamins play an especially important role in energy production and have been used to help improve symptoms of burnout. (16) Iron may be important especially when diagnosed as low and anemic. Substances that help improve mitochondrial function can help improve energy production including co-enzyme Q10, l-carnitine, l-cysteine, alpha-lipoic acid and other nutrients. (17)

Adaptogenic botanical medicines may be beneficial in treating fatigue and burnout. An adaptogen is a substance, primarily used in natural medicine, that helps the body adapt and deal with stress. It helps to nourish and balance the parts of the body that respond to stress. It helps to promote balance and homeostasis. Popular examples of adaptogenic herbs include Korean ginseng, Eleuthero or Siberian ginseng, American ginseng, maca, rhodiola, ashwaghanda, holy basil, cordyceps, astragalus, licorice, and other herbs. Adrenal cortex glandular extracts usually derived from bovine and porcine animal sources have been used to treat stress-induced fatigue and exhaustion. And although the medical databases seem to have only scant information on these substances, they are quite popular and widely used. Also liver extracts have been used for fatigue and exhaustion especially as a nutritional source of iron and B-vitamins. Relaxing and sedating botanical medicines can useful in treating nervous exhaustion, anxiety, insomnia and some the neurological signs of burnout. Examples of nervines and relaxants include kava kava, passionflower, valerian, hops, scullcap, magnolia, chamomile and other herbs. Hormones such as melatonin and amino acids such as 5-hydroxy tryptophan, L-theanine, and gamma aminobutyric acid can be useful in treating insomnia, depression, and anxiety associated with stress and burnout. Other possibly beneficial tools would include acupuncture and counseling.

I believe that adrenal fatigue is an example of a medical metaphor. A metaphor is a figure of speech used to describe and explain something. A medical metaphor is used to explain and conceptualize something that is complicated and abstract. (18,19) It helps to make something easier for the patient to understand. The adrenal glands, along with the sympathetic nervous system, are the main part of the body that deals with stress. The cumulative effects of stress and burnout can cause depleting fatigue. Whether the adrenal glands are really fatigued or not is controversial and debatable. Current objective lab testing of adrenal fatigue is still not clear and straightforward. However, awareness of the effects of stress and fatigue on the body is important to help alleviate suffering, promote homeostasis, and facilitate healing. Naturopathic medicine can offer some useful, practical and effective treatments that can help treat adrenal fatigue, burnout, or whatever stress-induced illness you call it.

References

(1.) Tintera JW. Hypoadrenocorticism. Adrenal Metabolic Research Society of the Hypoglycemic Foundation Inc., Troy New York, 9th printing, Nov. 1980.

(2.) Ponk D, Kirlew M. Top 10 differential diagnosis in family medicine. Fatigue. Can Fam Practice. 2007 May; 53(5); 892.

(3.) Rosenthal T, et al. Fatigue: An Overview. Am Fam Physician. 2008 No. 15;78(10): 1173-1179.

(4.) Cardegiani FA, Kater CE. Adrenal Fatigue does not exist: a systematic review. BMC Endocrin Disorder. 2016 Aug 24:16(1):48.

(5.) Ross IL, et al. We are tired of "adrenal fatigue." SAMJ. 2018;108 (9).

(6.) Mullur RS. Making a Difference in Adrenal Fatigue. Endocr Pract. 2018 Oct 5. doi: 10.4158/EP-2018-0373.

(7.) Blair J, et al. Salivary cortisol and cortisone. Curr Opin Endocrinol Diabetes Obese. 2017 Jun; 24(3): 161-168.

(8.) Bozovic E, et al. Salivary cortisol levels as a biological marker of stress reaction. Med Arch. 2013; 67(5)374-7.

(9.) Dike D. Physician Burnout: Its Origin, Symptoms, and Five Main Causes. Family Pract Manag. 2015 Sep-Oct; 22(5): 42-47.

(10.) De Vente W, et al. Burnout is Associated with Reduced Parasympathetic Activity and Reduced HPA Axis Responsiveness, Predominantly in Males. Biomed Res Int. 2015; 431725.

(11.) Oosterholt BG, et al. Burnout and Cortisol: evidence for a lower cortisol awakening response in both clinical and non-clinical burnout. J Psychosom Res. 2015 May; 78(5):455-51.

(12.) Mommersteeg PM, et al. Clinical burnout is not reflected in cortisol awakening response, the day curve or the response to a low-dose dexamethasone. Psychoneuroendocrinology. 2006 Feb;31(2):216-25.

(13.) Osterberg K. Cognitive performance in patients with burnout, in relation to diurnal salivary cortisol. Stress. 2009 Jan; 12(1): 70-81.

(14.) Danhof-Pont MB, et al. Biomarkers in burnout: a systematic review. J Psychosom Res. 2011 Jun; 70(6): 505-24.

(15.) Collier R. Physician burnout a major concern. CMAJ. October 02, 2017;189(89): e 1237.

(16.) Stough Con, et al. Reducing occupation stress with a B-vitamin focused intervention: a randomized clinical trial: study protocol. Nutr J. 2014; 13: 122.

(17.) Nicolson GL. Mitochondrial Dysfunction and Chronic Disease: Treatment With Natural Supplements Integr Med (Encinitas). 2014 Aug; 13(4): 35-43.

(18.) Coulehan J. Metaphor and medicine: narrative in clinical medicine. Yale J Biol Med. 2003; 76(2): 87-95.

(19.) Kotei C Metaphors in Medicine. October 26, 2017.

by Dr. Douglas Lobay, BSc, ND

Douglas G. Lobay is a practicing naturopathic physician in Kelowna, British Columbia. Dr. Lobay graduated with a bachelor of science degree from the University of British Columbia in 1987. He then attended Bastyr College of Health Sciences in Seattle, Washington, and graduated with a doctorate of naturopathic medicine in 1991. While attending Bastyr College, he began researching the scientific information on the use of food, nutrition, and natural healing. Dr. Lobay enjoys research, writing, and teaching others about good health and good nutrition. He is the author of four books and numerous articles in magazines. He also enjoys hockey, skiing, hiking, tennis, and playing guitar.
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