Adrenal Insufficiency, HPA Dysfunction and Fatigue

Adrenal Insufficiency, HPA Dysfunction and Fatigue

Ignored by mainstream medicine, adrenal fatigue is a common problem I see every day at the office. The paramount symptom is fatigue unrelieved by sleep. Other symptoms include craving for salty foods, hypoglycemic episodes, decreased libido, stress intolerance, light headed upon standing (postural hypotension), depression, loss of memory and cognitive decline, allergies, sinus problems, and prolonged recovery from flu-like illnesses. The basic underlying cause is low cortisol output by the adrenal glands. Header Photo courtesy of wikimedia commons: Sleepy Men.

A Self-Help Book for Chronic Burn-Out called Adrenal Fatigue

The definitive book on adrenal fatigue is by James L Wilson, PhD, a self-help guide for all of us chronically stressed out members of the “rat race” suffering from this new 21st century epidemic. In his book, Wilson outlines how to diagnose and treat adrenal fatigue, a syndrome not yet recognized by mainstream medicine and it should be.  Dr. Wilson’s book describes findings of adrenal fatigue on physical examination such as the unstable pupil, blood pressure reduction upon standing, and Sergent’s white line test. (1)

Cortisol Testing

Chapter eleven of Wilson’s book covers the different cortisol testing methods available for cortisol in saliva, blood, and urine, as well as the ACTH stimulation test.  Wilson favors the 4-sample salivary cortisol test as the easiest and most convenient method, with the added advantage that salivary testing can done at home without a doctor’s prescription. Another chapter in the book covers treatment and recovery from adrenal fatigue with modification of diet and lifestyle, and diet, avoiding food allergies, and the use of hormone supplements and dietary supplements.  Dr. Wilson also discusses the use of Cortef (cortisol) vs. adrenal cortical extracts.(34-38)

Results from Years of Chronic Stress

Adrenal fatigue is the net result of years of continuous high cortisol output by the adrenals caused by chronic stress from job, family, illness, injury, and poor diet and lifestyle associated with high-tech modern living. After years of chronic stress, the two small triangular supra-renal glands poop out, and we become another casualty of adrenal fatigue, the 21st century epidemic. Since mainstream doctors can’t seem to help, either ignoring the syndrome, or prescribing anti-depressants for it, this self-help book may be a life-saver. In 2001, Dr. James L Wilson defines adrenal fatigue, writing:

Adrenal Fatigue is a collection of signs and symptoms that results from low function of the adrenal glands. The paramount symptom is fatigue that is not relieved by sleep.  The syndrome may be caused by intense or prolonged stress, or after acute or chronic infections, especially respiratory infections such as influenza, bronchitis, or pneumonia…. People suffering from Adrenal Fatigue often have to use coffee, colas and other stimulants to get going in the morning and to prop themselves up during the day. (1)

Symptoms and Conditions Associated with Adrenal Fatigue:

Anxiety, Asthenia – lack of, or loss of strength, generalized weakness, Asthma, Autoimmune problems, Bronchitis – recurrent, chronic, Chemical Sensitivity, Chronic fatigue syndrome (CFS), Chronic infections, Chronically run down – with early morning fatigue and low blood pressure, Chronic mental and/or physical exhaustion, Cravings for carbohydrates, sweets or salt, Depression, Fatigue – severe, disabling early morning fatigue, Feeling tired despite sufficient hours of sleep, Fibromyalgia, Hair loss, Hypoglycemia, Immune System dysfunction – frequent illnesses, Insomnia – or non-restful sleep, Low Blood Pressure, Nervous breakdown (nervous exhaustion), Pneumonia, Respiratory infections – recurrent, chronic or slow recovery from, Rheumatoid arthritis, Reliance on stimulants like caffeine, Slow recovery following acute infectious diseases, especially influenza, pneumonia, or other respiratory infections, Weight gain. (1)

The Important Role of Cortisol

Cortisol is the stress hormone, and is produced in response to stress. Cortisol is important for blood sugar regulation; it mobilizes glycogen in the liver to maintain blood glucose levels.  Symptoms of hypoglycemia are common in low cortisol adrenal fatigue.  Also, low blood pressure or inability to maintain blood pressure upon standing is also a common symptom (postural hypotension).  Another physical exam finding is an unstable pupil response to light. The pupil at first contracts and then after a few seconds opens and closes.

The Adrenal Glands Make the Cortisol

The two small triangular adrenal glands are located just above the kidneys and secrete the hormone cortisol in response to stress, physical, emotional, or traumatic stress.  The cortex of the adrenal glands make the hormone cortisol in response to ACTH secretion by the pituitary. The cortex also makes the mineralcorticoid aldosterone, involved in maintaining blood pressure, sodium and potassium levels. The adrenal medulla secretes catecholamines, epipinephrine, and noreinephrine following activation of the sympathetic nervous system in a “fight or flight ” response to a perceived threat.

Cortisol, the Stress Hormone

Cortisol is a steroidal hormone, and like all the others it is made from cholesterol.  Cholesterol, in turn, is made from Vitamin B5 and Acetyl CoA.  The manufacture of steroidal hormones can be best understood by referring to a steroidal pathway chart.

4 Sample Salivary Cortisol Test

Although cortisol can be measured in a blood sample, the best way to measure cortisol levels is with four saliva samples taken throughout the day. There are literally hundreds of medical research studies validating the usefulness of salivary cortisol measurements.  A 2008 study by Dr Urs Nater showed that low early morning salivary cortisol is associated with chronic fatigue syndrome in women, but not in males.(8-15)

Diagnosis with Salivary Cortisol Test

Four salivary cortisol samples are taken at 8 AM, Noon, 4 PM and Midnight. The four results are plotted on a chart with the normal channel drawn as dotted lines.  If the four samples fall within the normal channel, this is considered a normal cortisol response. If the four salivary cortisol samples all fall below the normal channel, this is a “flat line pattern” indicating adrenal fatigue, a pattern identified in childhood trauma and breast cancer survivors. If the AM samples are low and the evening samples are high, this indicates a reversed pattern usually associated with insomnia, and treatment is phosphatidylserine.(91-97)

Nutritional Supplement Program for Adrenal Fatigue and Recovery

The keystone of the treatment program is a nutritional supplement program to restore adrenal function that includes vitamin C, B5, magnesium, biotin and adaptogenic herbs.  Phosphatidylserine is useful to correct the reversed pattern of high cortisol at night which may cause insomnia.  Recovery takes about 6 weeks. (71-74)(85-87)(98)

Cortef for Severe Cases of Adrenal Fatigue

In very severe cases of adrenal failure, Cortef tablets are available and produce a dramatic improvement in clinical condition.  See the book, Safe Uses of Cortisol by William MCK Jefferies MD. Cortef is the name for bio-identical cortisol which is widely available at the local drug store.  Synthetic forms of cortisol such as prednisone are not recommended as they can be associated with adverse side effects. (14-15)

Other Useful Treatments Routinely Used

Avoid excess caffeine, refined carbohydrates, alcohol and sugar. Get plenty of sleep.  Take steps to reduce stress with gentle exercise, meditation, and yoga. Bio-identical hormones may be useful, as determined by lab profile. (98)

Jacob Teitelbaum MD

Another excellent book is From Fatigued to Fantastic by Jacob Teitelbaum MD, which covers adrenal fatigue and other related conditions causing chronic fatigue.(15)

Cortisol’s Relation to Thyroid Function – Avoiding A Common Pitfall

Low cortisol adrenal fatigue will place the body into a protective state in which metabolic rate is reduced to cope with the low cortisol production.  The body accomplishes this reduction in metabolic rate by reducing thyroid function, usually by shunting thyroid hormone production into the reverse T3 pathway.  This, in essence, inactivates the thyroid hormone and creates a functional low thyroid state.  Thyroid labs will show a low thyroid state, and giving thyroid hormone in this scenario is a common pitfall to be avoided.  Giving thyroid hormone to a patient with low cortisol adrenal fatigue will only make the patient feel worse.(44-51)

The low adrenal function must be addressed first before attempting to raise thyroid levels.  This is done with a salivary cortisol test (4 samples) and a nutritional supplement program over 6 weeks as described above. In the event the patient is already taking thyroid hormone medication which doesn’t seem to be working or is not tolerated, then the most likely issue is low cortisol adrenal fatigue.  Once this is addressed, the patient will be able to tolerate thyroid medication.(44-51)

The HPA in Adrenal Fatigue and Fibromyalgia

Dr. Kent Holtorf explains that adrenal fatigue is commonly associated with fibromyalgia with underlying dysfunction of the HPA, the hypothalamic pituitary axis.  Dr Kent Holtorf goes on to say that hypothalamic-pituitary dysfunction results in low pituitary hormone output including low TSH, low Growth Hormone, low ACTH, etc, which may not be detected with conventional testing. Associated symptoms include insomnia. immune dysfunction with chronic infections, autonomic nervous system dysfunction, and gastrointestinal distress. Dr. Holtorf’s multifaceted treatment approach includes low dose cortisol (5-15 mg per day).  This was originally advocated by William McJefferies MD, and more recently by Jacob Teitelbaum MD.  The low dose cortisol is only one part of a multi-faceted treatment approach.  (2) (14-15)(98)

In 2007, Dr. Kent Holtorf MD writes:

There is controversy regarding the incidence and significance of hypothalamic-pituitary-adrenal (HPA) axis dysfunction in chronic fatigue syndrome (CFS) and fibromyalgia (FM). Studies…have demonstrated that HPA axis dysfunction of central origin is present in a majority of these patients… Because treatment with low physiologic doses of cortisol (<15 mg) has been shown to be safe and effective and routine dynamic ACTH testing does not have adequate diagnostic sensitivity, it is reasonable to give a therapeutic trial of physiologic doses of cortisol to the majority of patients with CFS and FM, especially to those who have symptoms that are consistent with adrenal dysfunction, have low blood pressure or have baseline cortisol levels in the low or low-normal range.(14)

Food Sensitivities

We have found that many patients with Chronic Fatigue/ Fibromyalgia Syndrome have in addition to all the above, additional problems with gluten sensitivity, leaky gut and other food sensitivities.  There may be malabsorption of vitamins minerals and amino acids. There may also be leakage of LPS (lipo-saccharides from enteric bacteria) into the blood stream.

Adrenal Fatigue Does Not Exist !

For those who claim that adrenal fatigue does not exist, I would simply point to the life work of Dr. Hans Selye, endocrinologist working with stress in mice in 1936, first described the three stages of adaptation, initial brief alarm reaction, followed by a prolonged period of resistance and a terminal stage of exhaustion and death. Over his 80 year carreer devoted to the endocrinology of stress, Dr. Hans Selye wrote over 1500 scientific articles, 32 books, and trained 40 PhD students, one of whom won a Nobel Prize. Dr. Hans Selye’s animal studies on restraint stress defined the field for over 80 years. (65-70)

In 2014, Dr. Mark Jackson writes:

Selye’s notion of biological stress and its impact on health was adopted and adapted by researchers in a variety of adjacent fields, including military medicine, veterinary medicine, clinical allergy, sociobiology, population studies, cybernetics, and psychiatry. (65)

Conclusion: Adrenal Insufficiency may be unmasked by use of thyroid hormone. HPA dysfunction may be associated with chronic fatigue. Four sample salivary cortisol is a useful test for HPA dysfunction.

Natural Thyroid Toolkit

If you liked this article, you might like my new book, Natural Thyroid Toolkit available on Amazon. If you purchase a book, remember to  leave a favorable review. That would be much appreciated. See the book cover, left image.

Articles with related Interest

The Non-Mystery of Chronic Fatigue Syndrome

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Jeffrey Dach MD
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Heart Book by Jeffrey Dach

References

1) Wilson, James L., Jonathan V. Wright, and Jonathan V. Wright. Adrenal fatigue: The 21st century stress syndrome. Vol. 4. Petaluma: Smart Publications, 2001.

2) Jefferies, William McK. Safe Uses of Cortisol. Charles C Thomas Publisher, 2004.

3) Guilliams, Thomas G. “Adrenal stress: Measuring and treating.” The Standards 30 (2000): 1-7.

4) Haussmann, Mark F., Carol M. Vleck, and Eugenia S. Farrar. “A laboratory exercise to illustrate increased salivary cortisol in response to three stressful conditions using competitive ELISA.” Advances in physiology education 31.1 (2007): 110-115.6)

5) Randall, Michael. “The physiology of stress: Cortisol and the hypothalamic-pituitary-adrenal axis.” Dartmouth Undergraduate Journal of Science 13.1 (2010): 22-24.

7) Edwards, Lena D., Andrew H. Heyman, and Sahar Swidan. “Hypocortisolism: An evidence-based review.” Integrative Medicine 10.4 (2011): 30.

8) Nater, Urs M., et al. “Attenuated morning salivary cortisol concentrations in a population-based study of persons with chronic fatigue syndrome and well controls.” The Journal of Clinical Endocrinology & Metabolism 93.3 (2008): 703-709.

Results: There was a significant interaction effect, indicating different profiles of cortisol concentrations over time between groups, with the CFS group showing an attenuated morning cortisol profile. Notably, we observed a sex difference in this effect. Women with CFS exhibited significantly attenuated morning cortisol profiles compared with well women.In contrast, cortisol profiles were similar in men with CFS and male controls.

9) Portella, Maria J., et al. “Enhanced early morning salivary cortisol in neuroticism.” American Journal of Psychiatry 162.4 (2005): 807-809.

9A) Nijhof, Sanne L., et al. “The role of hypocortisolism in chronic fatigue syndrome.” Psychoneuroendocrinology 42 (2014): 199-206.

Background: There is accumulating evidence of hypothalamic-pituitary-adrenal (HPA) axis hypofunction in chronic fatigue syndrome (CFS). However, knowledge of this hypofunction has so far come exclusively from research in adulthood, and its clinical significance remains unclear. The objective of the current study was to assess the role of the HPA-axis in adolescent CFS and recovery from adolescent CFS.

Method: Before treatment, we compared the salivary cortisol awakening response of 108 diagnosed adolescent CFS patients with that of a reference group of 38 healthy peers. Salivary cortisol awakening response was measured again after 6 months of treatment in CFS patients.

Results: Pre-treatment salivary cortisol levels were significantly lower in CFS-patients than in healthy controls. After treatment recovered patients had a significant rise in salivary cortisol output attaining normalization, whereas non-recovered patients improved slightly, but not significantly. The hypocortisolism found in CFS-patients was significantly correlated to the amount of sleep. Logistic regression analysis showed that an increase of one standard deviation in the difference between pre- and post-treatment salivary cortisol awakening response was associated with a 93% higher odds of recovery (adjusted OR 1.93 (1.18 to 3.17), p=0.009). Pre-treatment salivary cortisol did not predict recovery.

Conclusions: Hypocortisolism is associated with adolescent CFS. It is not pre-treatment cortisol but its change to normalization that is associated with treatment success. We suggest that this finding may have clinical implications regarding the adaptation of future treatment strategies.\

9C) Nater, Urs M., et al. “Alterations in diurnal salivary cortisol rhythm in a population-based sample of cases with chronic fatigue syndrome.” Psychosomatic medicine 70.3 (2008): 298-305.

Results: People with CFS demonstrated lower salivary cortisol concentrations in the morning and higher salivary cortisol concentrations in the evening compared with both ISF and NF groups indicating a flattening of the diurnal cortisol profile. Mean plasma IL-6 concentrations were highest in CFS compared with the other groups, although these differences were no longer significant after controlling for BMI. Attenuated decline of salivary cortisol concentrations across the day and IL-6 concentration were associated with fatigue symptoms in CFS.

Conclusions: These results suggest an altered diurnal cortisol rhythm and IL-6 concentrations in CFS cases identified from a population-based sample.

9D) Gaab, Jens, et al. “Low-dose dexamethasone suppression test in chronic fatigue syndrome and health.” Psychosomatic Medicine 64.2 (2002): 311-318.

Objective: Subtle dysregulations of the hypothalamus-pituitary-adrenal axis in chronic fatigue syndrome have been described. The aim of this study was to examine the negative feedback regulations of the hypothalamus-pituitary-adrenal axis in chronic fatigue syndrome.

Methods: In 21 patients with chronic fatigue syndrome and 21 healthy control subjects, awakening and circadian salivary free cortisol profiles were assessed over 2 consecutive days and compared with awakening and circadian salivary free cortisol profiles after administration of 0.5 mg of dexamethasone at 11:00 PM the previous day.

Results: Patients with chronic fatigue syndrome had normal salivary free cortisol profiles but showed enhanced and prolonged suppression of salivary free cortisol after the administration of 0.5 mg of dexamethasone in comparison to the control subjects.

Conclusions: Enhanced negative feedback of the hypothalamus-pituitary-adrenal axis could be a plausible explanation for the previously described alterations in hypothalamus-pituitary-adrenal axis functioning in chronic fatigue syndrome. Because similar changes have been described in stress-related disorders, a putative role of stress in the pathogenesis of the enhanced feedback is possible.

9E) Di Giorgio, Annabella, et al. “24-hour pituitary and adrenal hormone profiles in chronic fatigue syndrome.” Psychosomatic Medicine 67.3 (2005): 433-440.

Conclusions: Patients with CFS demonstrated subtle alterations in HPA axis activity characterized by reduced ACTH over a full circadian cycle and reduced levels during the usual morning physiological peak ACTH secretion. This provides further evidence of subtle dysregulation of the HPA axis in CFS. Whether this dysregulation is a primary feature of the illness or instead represents a biologic effect secondary to having the illness itself remains unclear.

 

10) McBurnett, Keith, et al. “Low salivary cortisol and persistent aggression in boys referred for disruptive behavior.” Archives of general psychiatry 57.1 (2000): 38-43.

11) Kos-Kudla, B. “Iatrogenic adrenal cortex failure in patients with steroid dependent asthma in relation to different methods of glucocorticoid treatment.” Endocrine regulations 32 (1998): 99-106.

12) Klein, Laura Cousino, et al. “Sex Differences in Salivary Cortisol Levels Following Naltrexone Administration 1.” Journal of Applied Biobehavioral Research 5.2 (2000): 144-153.

13) Roberts, Amanda DL, et al. “Salivary cortisol response to awakening in chronic fatigue syndrome.” The British Journal of Psychiatry 184.2 (2004): 136-141.

Background There is accumulating evidence of hypothalamic—pituitary — adrenal (HPA) axis disturbances in chronic fatigue syndrome (CFS). The salivary cortisol response to awakening has been described recently as a non-invasive test of the capacity of the HPA axis to respond to stress. The results of this test correlate closely with those of more invasive dynamic tests reported in the literature; furthermore, it can be undertaken in a naturalistic setting. Aims To assess the HPA axis using the salivary cortisol response to awakening in CFS. Method We measured salivary cortisol upon awakening and 10, 20, 30 and 60 min afterwards in 56 patients with CFS and 35 healthy volunteers. Results Patients had a lower cortisol response to awakening, measured by the area under the curve. Conclusions This naturalistic test of the HPA axis response to stress showed impaired HPA axis function in CFS.

14) Holtorf, Kent. “Diagnosis and treatment of hypothalamic-pituitary-adrenal (HPA) axis dysfunction in patients with chronic fatigue syndrome (CFS) and fibromyalgia (FM).” Journal of Chronic Fatigue Syndrome 14.3 (2007): 59-88.

15) Teitelbaum, Jacob. From Fatigued to Fantastic!: A Proven Program to Regain Vibrant Health, Based on a New Scientific Study Showing Effective Treatment for Chronic Fatigue and Fibromyalgia. Penguin, 2001.

16-28) deleted

29) Tsigos, Constantine, and George P. Chrousos. “Hypothalamic–pituitary–adrenal axis, neuroendocrine factors and stress.” Journal of psychosomatic research 53.4 (2002): 865-871.

30) Raison, Charles L., and Andrew H. Miller. “When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders.” American Journal of Psychiatry 160.9 (2003): 1554-1565.

31-33) deleted

34) Sad, Eduardo F., et al. “Salivary cortisol in critical care patients.” Chest 132.4 (2007): 555A.

CONCLUSION: We conclude that salivary cortisol, a broadly available method but still not routinely used, can be a better method to assess hypothalamic-pituitary-adrenal axis in critical care patients, in which serum total cortisol is greatly influenced by low levels of protein, a common complication of these patients.  CLINICAL IMPLICATIONS: Salivary cortisol can become a good , easy and confiable test for the diagnosis of adrenal insufficiency in critical care patients. It is still necessary to determine normal salivary cortisol levels in these patients to establish this criteria.

(35) Vining, Ross F., et al. “Salivary cortisol: a better measure of adrenal cortical function than serum cortisol.” Annals of clinical biochemistry 20.6 (1983): 329-335.

“Salivary cortisol is a more appropriate measure for the clinical assessment of adrenocortical function than is serum cortisol.”

(36) Laudat, M. H., et al. “Salivary cortisol measurement: a practical approach to assess pituitary-adrenal function.” The Journal of Clinical Endocrinology & Metabolism 66.2 (1988): 343-348.

(37) Nicolson, Nancy A., and Rob van Diest. “Salivary cortisol patterns in vital exhaustion.” Journal of Psychosomatic Research 49.5 (2000): 335-342.

(38) Roberts, Amanda DL, et al. “Salivary cortisol response to awakening in chronic fatigue syndrome.” The British Journal of Psychiatry 184.2 (2004): 136-141.

(39) Papadopoulos, Andrew S., and Anthony J. Cleare. “Hypothalamic–pituitary–adrenal axis dysfunction in chronic fatigue syndrome.” Nature Reviews Endocrinology 8.1 (2012): 22-32.

In conclusion, this study provides evidence that there may be impaired adrenal cortical function in CFS on some measures and that low-dose hydrocortisone therapy is associated with a reversal of this HPA axis dysfunction.”

(40) Schuder, Suzie E. “Stress‐induced hypocortisolemia diagnosed as psychiatric disorders responsive to hydrocortisone replacement.” Annals of the New York Academy of Sciences 1057.1 (2005): 466-478.

“By correcting underlying hormonal insufficiencies, many patients improved, with some patients having a total reversal of psychiatric symptoms.”

(41) Cleare, Anthony J. “The neuroendocrinology of chronic fatigue syndrome.” Endocrine reviews 24.2 (2003): 236-252.

(42 ) Kaufman, Eliaz, and Ira B. Lamster. “The diagnostic applications of saliva—a review.” Critical Reviews in oral biology & medicine 13.2 (2002): 197-212.

Autoimmunity

43) De Bellis, Annamaria, et al. “Hypothalamic-Pituitary autoimmunity and related impairment of hormone secretions in chronic fatigue syndrome.” The Journal of Clinical Endocrinology & Metabolism 106.12 (2021): e5147-e5155.

Context: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe chronic illness that reduces the quality of life. A potential role of neuroendocrine autoimmune dysfunction has been hypothesized.

Objective: This work aims to investigate the occurrence of antipituitary (APA) and antihypothalamic (AHA) antibodies and possible related hypothalamic/pituitary dysfunctions in ME/CSF patients.

Methods: This is a case-control study conducted in a university hospital setting (Stanford, California, USA; and Naples, Italy). Thirty women with ME/CSF (group 1) diagnosed according to Fukuda, Canadian, and Institute of Medicine criteria, at Stanford University, were enrolled and compared with 25 age-matched healthy controls. APA and AHA were detected by immunofluorescence; moreover, we investigated hormonal secretions of anterior pituitary and respective target glands. APA and AHA titers both were assessed and the prevalence of pituitary hormone deficiencies was also investigated.

Results: Patients in group 1 showed a high prevalence of AHA (33%) and APA (56%) and significantly lower levels of adrenocorticotropin (ACTH)/cortisol, and growth hormone (GH) peak/insulin-like growth factor-1 (IGF-1) vs controls (all AHA/APA negative). Patients in group 1A (13 patients positive at high titers, ≥ 1:32) showed ACTH/cortisol and GH peak/IGF-1 levels significantly lower and more severe forms of ME/CFS with respect to patients in group 1B (7 positive at middle/low titers, 1:16-1:8) and 1C (10 antibody-negative patients).

Conclusion: Both AHA and/or APA at high titers were associated with hypothalamic/pituitary dysfunction, suggesting that hypothalamic/pituitary autoimmunity may play an important role in the manifestations of ME/CFS, especially in its more severe forms.

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     Thyroxine unmasks Addison’s disease.”

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44) Shaikh, M. G., P. Lewis, and J. M. W. Kirk. “Thyroxine unmasks Addison’s disease.” Acta Pædiatrica 93.12 (2004): 1663-1665.

We present the first report of a child who presented clinically and biochemically with hypothyroidism, in whom thyroxine replacement therapy unmasked Addison’s disease by precipitating an acute adrenal crisis. Following steroid replacement therapy her “hypothyroidism” resolved

45) Sabih, Durr E., and Mohammad Inayatullah. “Managing thyroid dysfunction in selected special situations.” Thyroid Research 6 (2013): 1-7.

Addison’s disease

Increased TSH levels, with normal or reduced T4 levels are often found [73]. Clinical symptoms of tiredness and an elevated TSH with low T4 will prompt a diagnosis of hypothyroidism and prescription of thyroxine as replacement therapy. Thyroxine replacement alone in these patients is dangerous and may precipitate an adrenal crisis [74, 75]. Corticosteroid therapy will often correct the thyroid biochemical imbalance too [76]. If thyroxine replacement is deemed necessary it should follow steroid replacement.

Screening all patients of hypothyroidism for adrenal deficiency is not recommended [77], but those patients who are suspected to be hypothyroid because of raised TSH and get worse after thyroxine therapy should be reevaluated clinically as well as biochemically for a possible coexisting adrenal insufficiency.

No peripheral deiodination of T4 occurs in the heart muscle and the myocyte relies entirely on circulating T3 for its actions. Thyroid hormone effects include reduction in systemic vascular resistance, increased resting heart rate, left ventricular contractility and blood volume, it also increases erythropoietin production and red cell mass [20].

46) Davis, Julian, and Michael Sheppard. “Acute adrenal crisis precipitated by thyroxine.” British Medical Journal (Clinical research ed.) 292.6535 (1986): 1595.

Adrenal insufficiency is often associated with raised serum TSH and normal or low thyroxine concentrations, abnormalities which may be completely reversible with corticosteroid treatment alone, even in the presence of thyroid autoantibodies. 3   Corticosteroid deficiency may impair thyroid function, leading to a rise in serum TSH, but it may also promote pituitary TSH secretion directly.4 Therefore a raised TSH level alone may not necessarily imply hypothyroidism in patients with adrenal insufficiency; even true biochemical and clinical hypothyroidism may not be permanent. 5 Treatment with thyroxine as well as corticosteroids may be indicated in some patients, but perhaps only temporarily.

47) Graves, L. I. I. I., Robert M. Klein, and Anne D. Walling. “Addisonian crisis precipitated by thyroxine therapy: a complication of type 2 autoimmune polyglandular syndrome.” SOUTHERN MEDICAL JOURNAL-BIRMINGHAM ALABAMA- 96.8 (2003): 824-827.

48) Patel, Dhruvkumar M., et al. “Adrenocortical Crisis Triggered by Levothyroxine in an Unrecognized Autoimmune Polyglandular Syndrome Type-2: A Case Report with Review of the Literature.” Current Drug Safety 16.1 (2021): 101-106.

49) Rajput, Rajesh, et al. “Reversible thyrotropin elevation in case of primary Addison’s disease.” Thyroid Research and Practice 18.1 (2021): 31-33.

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50) Gharib, Hossein, et al. “Reversible hypothyroidism in Addison’s disease.” The Lancet 300.7780 (1972): 734-736.

Four patients with Addison’s disease are described in whom reduced thyroid function was demonstrated at the time of diagnosis of adrenocortical insufficiency. Replacement therapy consisting of physiological doses of adrenal steroids alone led to complete recovery of thyroid function in these patients, suggesting that hypothyroidism occurring in association with adrenal insufficiency may be reversible. The reason for the improvement in thyroid function after treatment with adrenal steroids is unknown.

 

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51) Murray, Jonathan Stephen, Rubaraj Jayarajasingh, and Petros Perros. “Deterioration of symptoms after start of thyroid hormone replacement.” BMJ 323.7308 (2001): 332-333.

A 26 year old woman with type 1 diabetes, presented with a five week history of lethargy, nausea, feeling lightheaded on standing, occasional vomiting, and four unexplained severe hypoglycaemic episodes. The hypoglycaemic episodes occurred unexpectedly (no change in dietary intake, amount of physical exertion, amount of alcohol ingestion, or dose or timing of insulin therapy).

Thyroid function tests showed a serum concentration of thyroid stimulating hormone of 37.30 mU/l (reference range 0.5-5.7 mU/l) and free thyroxine 12.7 pmol/l (9-22 pmol/l). The patient was started on 25 μg thyroxine daily. This resulted in an immediate exacerbation of symptoms, which prompted a referral to an endocrinologist. On examination she was pigmented and had orthostatic hypotension (92/50 mm Hg supine, 86/60 mm Hg standing). She was hyponatraemic (serum sodium 121 mmol/l) and hyperkalaemic (serum potassium 5.5 mmol/l). Basal serum cortisol was undetectable (<20 nmol/l) and failed to respond to stimulation with synthetic adrenocorticotrophin (short Synacthen (tetracosactide) test). Random plasma concentration of adrenocorticotrophin was raised (328 pmol/l (0-l0.3 pmol/l)), ambulant plasma aldosterone concentration was low (55 pmol/l (reference range 100-450 pmol/l)), and plasma renin activity was correspondingly raised (19.7 pmol/ml per hour (1.1-2.7 pmol/ml per hour)). Adrenal and thyroid microsomal antibodies were positive. The patient’s condition improved dramatically with glucocorticoid and mineralocorticoid replacement therapy.

Four weeks later the results of her thyroid function tests still showed hypothyroidism (free thyroxine 9 pmol/l, thyroid stimulating hormone 34.5 mU/l) despite receiving adequate glucocorticoid replacement therapy (random cortisol in early afternoon 376 nmol/l). It was concluded that she had permanent hypothyroidism, and thyroxine therapy was continued, with appropriate adjustment in the dose.

It is both unrealistic and unnecessary to screen every patient with a raised serum concentration of thyroid stimulating hormone for Addison’s disease. In our experience, however, most patients presenting in this manner have additional clinical features that should alert the clinician to this possibility. They include skin and mucosal pigmentation, postural hypotension, weight loss, and hyperkalaemia. Failure to reach a correct diagnosis in patients with a raised serum concentration of thyroid stimulating hormone who have Addison’s disease (even in patients with only borderline adrenal failure, as in case 2) can lead to an adrenal crisis if thyroxine is introduced before glucocorticoid replacement.10 It is imperative that Addison’s disease be excluded when a patient’s clinical state deteriorates shortly after the introduction of thyroxine.

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Autoimmunity

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52) Kasperlik‐Załuska, A. A., et al. “Secondary adrenal insufficiency associated with autoimmune disorders: a report of twenty‐five cases.” Clinical endocrinology 49.6 (1998): 779-783.

Among a group of 102 patients with secondary adrenal failure of unknown origin diagnosed at the Department of Endocrinology of the Centre for Postgraduate Medical Education (Warsaw, Poland) we have identified a group with associated autoimmune disorders. Thyroid abnormalities occurred most frequently. Other diseases included insulin-dependent diabetes mellitus, pernicious anaemia, vitiligo, premature ovarian failure and autoimmune thrombocytopaenia. There were 23 women and one man aged 17–72 years at the time of investigation.

Our own observations on patients with secondary adrenal failure associated with an autoimmune disease (Kasperlik- Załuska et al., 1993) and some case reports (Kojima et al., 1982; Roosens et al., 1992; Okuno et al., 1993; Thodou et al., 1995) support the suggestion of an autoimmune origin of this isease. Lymphocytic hypophysitis of autoimmune aetiology was described by several authors as the cause of isolated pituitary hormone deficiency or panhypopituitarism (Goudie & Pinkerton, 1962; Raczyn´ska et al., 1974; Pestell et al., 1990; Jenkins et al., 1995; Powrie et al., 1995; Thodou et al., 1995).

Sometimes the lymphocytic infiltration can cause pituitary expansion mimicking the features of a pituitary tumour, with visual deterioration due to chiasmal compression (Pestell et al., 1990), severe headaches (Jenkins et al., 1995), nausea and vomiting (Powrie et al., 1995) and even visual loss (Thodou et al., 1995). No such dramatic features were observed in our patients. The largest series containing 16 patients with lymphocytic hypophysitis, was described by Thodou et al. (1995) and compared with the published literature. In conclusion, the co-existence of rare disorders such as isolated ACTH deficiency, pernicious anaemia, thyroid autoimmunity, IDDM, premature ovarian failure, vitiligo, thrombocytopaenia and Addison’s disease suggest a possibility of a common autoimmune mechanism.

53) Kasperlik-Zaluska, A. A., et al. “Association of Addison’s disease with autoimmune disorders–a long-term observation of 180 patients.” Postgraduate Medical Journal 67.793 (1991): 984-987.

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54) Pazderska, Agnieszka, and Simon HS Pearce. “Adrenal insufficiency–recognition and management.” Clinical Medicine 17.3 (2017): 258.

Hyponatraemia is present in more than 90% of patients with primary adrenal failure at diagnosis; hyperkalaemia is less frequent (50%). Other laboratory abnormalities include moderate renal impairment, hypercalcaemia or hypoglycaemia, mild normochromic anaemia, eosinophilia and lymphocytosis.8 Moderate serum thyroid-stimulating hormone (TSH) elevation with normal free thyroxine (T4) is common at presentation and reflects lack of glucocorticoid inhibition on TSH release rather than hypothyroidism.9 This is important to recognise as commencing thyroid hormone treatment without replacing glucocorticoids can precipitate adrenal crisis.

 

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55) Osman, I. A., and Peter Leslie. “Addison’s disease. Adrenal insufficiency should be excluded before thyroxine replacement is started.” BMJ: British Medical Journal 313.7054 (1996): 427.

56) Banitt PF, Munson AK. Addisonian crisis after thyroid replacement. Hosp Pract 1986;21:132, 134

57) Stryker, Timothy D., and Mark E. Molitch. “Reversible hyperthyrotropinemia, hyperthyroxinemia, and hyperprolactinemia due to adrenal insufficiency.” The American journal of medicine 79.2 (1985): 271-276.

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58) Lewis, Alexander, et al. “Diagnosis and management of adrenal insufficiency.” Clinical Medicine 23.2 (2023): 115-118.

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ADRENAL Fatigue Does Not Exist

59)  Libianto, Renata, Jun Yang, and Peter J. Fuller. “Adrenal disease: An update.” Australian Journal of General Practice 50.1/2 (2021): 9-14.

60) Irwig, Michael S., et al. “Off-label use and misuse of testosterone, growth hormone, thyroid hormone, and adrenal supplements: risks and costs of a growing problem.” Endocrine Practice 26.3 (2020): 340-353.

Adrenal supplements are used to treat common nonspecific symptoms due to “adrenal fatigue,” an entity that has not been recognized as a legitimate medical diagnosis.

61) McDermott, Michael T. “Adrenal Fatigue.” Management of Patients with Pseudo-Endocrine Disorders: A Case-Based Pocket Guide (2019): 127-137.

62) Mullur, Rashmi S. “Making a difference in adrenal fatigue.” Endocrine Practice 24.12 (2018): 1103-1105.

63) Ross, I. L., J. Jones, and M. Blockman. “We are tired of’adrenal fatigue’.” SAMJ: South African Medical Journal 108.9 (2018): 724-725.

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64) Cadegiani, Flavio A., and Claudio E. Kater. “Adrenal fatigue does not exist: a systematic review.” BMC endocrine disorders 16.1 (2016): 1-16.

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REPLY TO : Cadegiani

October 4, 2017 Current Controversy: Does Adrenal Fatigue Exist? Defending an integrative approach to HPA axis dysfunction Sarah Bedell Cook ND

October 4, 2017 Current Controversy: Does Adrenal Fatigue Exist? Defending an integrative approach to HPA axis dysfunction

Sarah Bedell Cook ND

Introduction

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

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

Nutrition

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

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.

Conclusion

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.

Clinical Implications

“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

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Hans Selye

65) Jackson, Mark, Edmund Ramsden, and David Cantor. “Evaluating the role of Hans Selye in the modern history of stress.” Stress, shock, and adaptation in the twentieth century (2014).

He describes in this report three stages of adaptation, including an initial brief alarm reaction, followed by a prolonged period of resistance and a terminal stage of exhaustion and death….Selye’s notion of biological stress and its impact on health was adopted and adapted by researchers in a variety of adjacent fields, including military medicine, veterinary medicine, clinical allergy, sociobiology, population studies, cybernetics, and psychiatry.7

66) Szabo, Sandor, et al. ““Stress” is 80 years old: From Hans Selye original paper in 1936 to recent advances in GI ulceration.” Current pharmaceutical design 23.27 (2017): 4029-4041.

67) Szabo, Sandor, Yvette Tache, and Arpad Somogyi. “The legacy of Hans Selye and the origins of stress research: a retrospective 75 years after his landmark brief “letter” to the editor# of nature.” Stress 15.5 (2012): 472-478.

Hans Selye’s single author short letter to Nature (1936, 138(3479):32) inspired a huge and still growing wave of medical research. His experiments with rats led to recognition of the “general adaptation syndrome”, later renamed by Selye “stress response”: the triad of enlarged adrenal glands, lymph node and thymic atrophy, and gastric erosions/ulcers.

Selye was internationally recognized as a world authority in endocrinology, steroid chemistry, experimental surgery, and pathology. He wrote over 1500 original and review articles, singly authored 32 books, and trained 40 PhD students, one of whom (Roger Guillemin) won a Nobel Prize for isolating the hypothalamic releasing factors/hormones. Here, we consider the main implications of his first article launching the biological stress concept and the key ideas and problems that occupied him. Selye considered “Stress in health and disease is medically, sociologically, and philosophically the most meaningful subject for humanity that I can think of”.

68) Selye, Hans. “A syndrome produced by diverse nocuous agents.” Nature 138.3479 (1936): 32-32.

69) Selye, Hans. “Stress and the general adaptation syndrome.” British medical journal 1.4667 (1950): 1383.

70) Selye, Hans. “The Evolution of the Stress Concept: The originator of the concept traces its development from the discovery in 1936 of the alarm reaction to modern therapeutic applications of syntoxic and catatoxic hormones.” American scientist 61.6 (1973): 692-699.

 

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Adrenal Fatigue Does Exist

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71) Simpson, Kathryn. Overcoming Adrenal Fatigue: How to Restore Hormonal Balance and Feel Renewed, Energized, and Stress Free. New Harbinger Publications, 2011.

72) Meletis, Chris D., and Wayne A. Centrone. “Adrenal Fatigue: Enhancing Quality of Life for Patients with a Functional Disorder.” Alternative & Complementary Therapies 8.5 (2002): 267-272.

73) Head, Kathleen A., and Kelly, Gregory S. “Nutrients and botanicals for treatment of stress: adrenal fatigue, neurotransmitter imbalance, anxiety, and restless sleep.” Altern Med Rev 14.2 (2009): 114-40.

74) Wilson, James L. “Clinical perspective on stress, cortisol and adrenal fatigue.” Advances in Integrative Medicine 1.2 (2014): 93-96.

As a physician, I have seen many people so depleted by adrenal fatigue they were unable to work or do anything beyond menial house chores, including several whose adrenal fatigue was so severe that they were unable to even dress themselves. In the face of light or moderate intermittent stress, the HPA axis walks the cortisol tightrope walk to maintain balance (homeostasis) while helping the body adapt to the stresses being experienced. With chronic and/or severe stress, this balance can be upset, resulting in either adrenal fatigue or metabolic syndrome.

In adrenal fatigue cortisol levels are no longer able to rise adequately to meet the demand and people begin noticing signs and symptoms that give them a clue something is not right. In a nutshell, adrenal fatigue is the persistent suboptimal functioning of the adrenal glands, especially under stress. A more formal and elegant definition was put forth by Charles Sajous, an eminent physician early in the last century who, in 1930, wrote: “Functional hypoadrenia [the term used for adrenal fatigue

Unique fatigue pattern of adrenal fatigue

There are many signs and symptoms of adrenal fatigue, yet there is no single pathognomonic indicator, except possibly its unique pattern of fatigue.  Although fatigue is a common complaint heard by physicians – 85% of patients complain of fatigue as one of their major symptoms – there seems to be no other fatigue pattern like it.

Early morning fatigue even with sufficient sleep [17] – need caffeine or other stimulants to get going [18] and some do not actually feel fully awake until after noon

The distinctive pattern of fatigue when combined with the symptoms below forms a syndrome that healthcare professionals can readily learn to recognise.

Needs caffeine or other stimulants to get going and often to keep going during the day.

Decreased stamina and energy – feels run down and exhausted much of the day [21].

Decreased productivity [22].

Decreased resilience – takes longer to recover from illness and rebound from stress [14].

Craves salt or salty foods [22].

Hypoglycemia and its symptoms,

There are many causes of adrenal fatigue but by far the most common is any type of stress that is chronic, prolonged or severe [24]. In modern life, there are often multiple stresses occurring in tandem. The patient may be unaware of some of these stresses but their adrenals, being the glands of stress, have to compensate for each and every stress – physical, biochemical, hormonal, thermal, internal, external, emotional, mental, or toxic in origin, including overuse of drugs, alcohol and sugar.

An unhealthy lifestyle is how many people slip into adrenal fatigue. Although lifestyle modification alone is insufficient for full recovery, it constitutes an important leg in the triad of the therapeutic protocol for adrenal fatigue.

  1. Look for ways to decrease the stress load: mental, emotional, physical.
  2. Minimise commitments.
  3. Create a minimum of 2 h of free (uncommitted) time every day.
  4. Eliminate or minimise emotional stressors. Creating a Good for Me, Bad for Me chart is the best place to begin.

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HPA Dysfunction Chronic Fatigue

75) Papadopoulos, Andrew S., and Anthony J. Cleare. “Hypothalamic–pituitary–adrenal axis dysfunction in chronic fatigue syndrome.” Nature Reviews Endocrinology 8.1 (2012): 22-32.

76) Demitrack, Mark A., et al. “Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome.” The Journal of Clinical Endocrinology & Metabolism 73.6 (1991): 1224-1234.

77) Van Den Eedea, Filip, et al. “Hypothalamic-Pituitary-Adrenal Axis Function in Chronic Fatigue Syndrome.” Neuropsychobiology 55 (2007): 112-120.

78) Tanriverdi, Fatih, et al. “The hypothalamo–pituitary–adrenal axis in chronic fatigue syndrome and fibromyalgia syndrome.” Stress 10.1 (2007): 13-25.

79) Demitrack, MARK A., and LESLIE J. Crofford. “Evidence for and pathophysiologic implications of hypothalamic‐pituitary‐adrenal axis dysregulation in fibromyalgia and chronic fatigue syndrome.” Annals of the New York Academy of sciences 840.1 (1998): 684-697.

80) Cleare, A. J., et al. “Hypothalamo-pituitary-adrenal axis dysfunction in chronic fatigue syndrome, and the effects of low-dose hydrocortisone therapy.” The Journal of Clinical Endocrinology & Metabolism 86.8 (2001): 3545-3554.

Thirty-two patients were treated with a low-dose hydrocortisone regime in a double-blind, placebo-controlled crossover design, with 28 days on each treatment. They underwent repeated 24-h urinary free cortisol collections, a human CRH test, and an insulin stress test after both active and placebo arms of treatment. Looking at all subjects, 24-h urinary free cortisol was higher after active compared with placebo treatments, but 0900-h cortisol levels and the ACTH and cortisol responses to human CRH and the insulin stress test did not differ. However, a differential effect was seen in those patients who responded to active treatment (defined as a reduction in fatigue score to the median population level or less). In this group, there was a significant increase in the cortisol response to human CRH, which reversed the previously observed blunted responses seen in these patients. We conclude that the improvement in fatigue seen in some patients with chronic fatigue syndrome during hydrocortisone treatment is accompanied by a reversal of the blunted cortisol responses to human CRH.

81) Cleare, Anthony J. “The HPA axis and the genesis of chronic fatigue syndrome.” Trends in Endocrinology & Metabolism 15.2 (2004): 55-59.

This article presents the case that there is no specific change to the HPA axis in CFS and that the observed changes are of multifactorial aetiology, with some factors occurring as a consequence of the illness. Nevertheless, the HPA axis might play a role in exacerbating or perpetuating symptoms late on in the course of the illness.

82) Tomas, Cara, Julia Newton, and Stuart Watson. “A review of hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome.” International Scholarly Research Notices 2013 (2013).

Hypothalamic-pituitary-adrenal (HPA) axis dysfunction has been found in a high proportion of chronic fatigue syndrome (CFS) patients and includes enhanced corticosteroid-induced negative feedback, basal hypocortisolism, attenuated diurnal variation, and a reduced responsivity to challenge. A putative causal role for genetic profile, childhood trauma, and oxidative stress has been considered. In addition, the impact of gender is demonstrated by the increased frequency of HPA axis dysregulation in females. Despite the temporal relationship, it is not yet established whether the endocrine dysregulation is causal, consequent, or an epiphenomenon of the disorder. Nonetheless, given the interindividual variation in the effectiveness of existing biological and psychological treatments, the need for novel treatment strategies such as those which target the HPA axis is clear.

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Adrenal Insufficiency

83) Giebels, V., et al. “Severe fatigue in patients with adrenal insufficiency: physical, psychosocial and endocrine determinants.” Journal of Endocrinological Investigation 37 (2014): 293-301.

84) King, Mitchell S. “Adrenal insufficiency: an uncommon cause of fatigue.” The Journal of the American Board of Family Practice 12.5 (1999): 386-390.

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85) Anderson, D. “Assessment and nutraceutical management of stress-induced adrenal dysfunction.” Integrative Medicine 7.5 (2008): 18-25.

86) Kariatsumari, Bob. “Understanding Adrenal Fatigue: Nutritional and lifestyle strategies to effectively restore proper adrenal function.” Nutritional Perspectives: Journal of the Council on Nutrition 42.1 (2019).

Abstract: The human body will respond to many forms of stress with various complex mechanisms. One of these mechanisms is through the hypothalamic-pituitary-adrenal axis (HPA axis). The end result of this process is increased cortisol production and secretion by the adrenal glands. However, with the situation of continual chronic stress the adrenal glands become overwhelmed with the demand to manage the stress eventually leading to a condition termed adrenal fatigue. The adrenal glands become unable to properly respond to stress and therefore unable to produce and secrete cortisol. Adrenal fatigue is most often associated with low cortisol, postural hypotension and many other specific signs and symptoms. Testing of low cortisol to determine the possibility of adrenal fatigue, can be accurately measured with saliva cortisol testing multiple times throughout the day. There are multiple strategies for managing adrenal fatigue found to be effective through previous research. These include nutritional strategies of; Vitamins C, B1, B5 and E, magnesium, zinc, adrenal glandular, ashwagandha, panax ginseng, and licorice. There are also lifestyle strategies of; stress management, dietary modifications, proper exercise, reducing caffeine and proper sleep.

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87) Teitelbaum, Jacob, and Sarah Goudie. “An open-label, pilot trial of HRG80™ red ginseng in chronic fatigue syndrome, fibromyalgia, and post-viral fatigue.” Pharmaceuticals 15.1 (2022): 43.

88) Sharpley, Christopher F., et al. “The association between cortisol: C-reactive protein ratio and depressive fatigue is a function of CRP rather than cortisol.” Neuropsychiatric Disease and Treatment 15 (2019): 2467-2475.

Purpose: Hormonal and inflammatory factors have been suggested as potentially influencing depressive state and depressive symptoms, but rarely compared for their relative contribution to these states and to specific depressive symptoms. This study examined cortisol:C-reactive protein (CRP) ratio, plus cortisol and CRP separately, as correlates of global depression and fatigue-related depression.
Patients and methods: One hundred and twenty-six community volunteers from rural Australia provided saliva and serum samples, and also completed a depression inventory.
Results: There was a significant correlation between cortisol:CRP ratio and depression related fatigue, and this resolved to the effects of CRP rather than cortisol. Most of the variance in this association came from patients who were “depressed”, and there were no significant gender associations.
Conclusion: Inflammation, rather than HPA-axis activity, was associated with depression related fatigue, supporting a model that places inflammation as a contributor to one of the major symptoms and predictors of depression. Individualization of therapy for depression related fatigue in chronically stressed or physically ill patients might benefit from future research into cytokine therapy.

89) Hinchado, María Dolores, et al. “Synbiotic Supplementation Improves Quality of Life and Inmunoneuroendocrine Response in Patients with Fibromyalgia: Influence of Codiagnosis with Chronic Fatigue Syndrome.” Nutrients 15.7 (2023): 1591.

90) Takeshita, Kaori, et al. “Clinical investigation of a unique type of hypothalamic adrenal insufficiency.” Medicine 101.41 (2022): e30597.

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91) Bush, Bradley, and T. Hudson. “The role of cortisol in sleep.” Natural Medicine Journal 2.6 (2010): 2010-06.

92) Tori Hudson, N. D., and N. D. Bradley Bush. “The Role of Cortisol in Sleep.” Nat Medi J 2 (2010): 6.

93) Monteleone, Palmiero, et al. “Blunting by chronic phosphatidylserine administration of the stress-induced activation of the hypothalamo-pituitary-adrenal axis in healthy men.” European Journal of Clinical Pharmacology 42 (1992): 385-388.

94) Starks, Michael A., et al. “The effects of phosphatidylserine on endocrine response to moderate intensity exercise.” Journal of the International Society of Sports Nutrition 5.1 (2008): 11.

95) Hellhammer, Juliane, et al. “A soy-based phosphatidylserine/phosphatidic acid complex (PAS) normalizes the stress reactivity of hypothalamus-pituitary-adrenal-axis in chronically stressed male subjects: a randomized, placebo-controlled study.” Lipids in health and disease 13 (2014): 1-11.

96) Suzuki, Akiko, et al. “Long term effects of childhood trauma on cortisol stress reactivity in adulthood and relationship to the occurrence of depression.” Psychoneuroendocrinology 50 (2014): 289-299.

97) Kamen, Charles, et al. “Effects of childhood trauma exposure and cortisol levels on cognitive functioning among breast cancer survivors.” Child abuse & neglect 72 (2017): 163-171.

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REPLY TO : Cadegiani

October 4, 2017 Current Controversy: Does Adrenal Fatigue Exist? Defending an integrative approach to HPA axis dysfunction Sarah Bedell Cook ND

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98) October 4, 2017 Current Controversy: Does Adrenal Fatigue Exist? Defending an integrative approach to HPA axis dysfunction

Sarah Bedell Cook ND

Introduction

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

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

Nutrition

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

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.

Conclusion

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.

Clinical Implications

“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

Jeffrey Dach MD
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