Adrenal Fatigue, Adrenal Insufficiency, or A Misnamed State of Hypofunction?

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CaptureDr Carrie Decker ND, explores the terminology and the accuracy of the ubiquitous moniker of adrenal fatigue.

“I’m so exhausted all the time, I think I have adrenal failure.” “My friend told me her naturopath said that her adrenals crashed and I think mine have too.” “I took a test and my cortisol was low and my chiropractor told me I have adrenal fatigue.”

If you have been practicing or following the field of integrative and holistic medicine for any amount of time, you inevitably have heard at least one of these statements from your patients. More often than not it comes from someone who appears to have some degree of fatigue, perhaps not more than your own, and the statement also vaguely includes something about what they read online or a quiz they took to assess their fatigue. Not only is the term adrenal insufficiency commonly misused, many walking, coherent, and healthy looking individuals often come in their physician’s office claiming to have a state of adrenal failure.

It is unfortunate that holistic health professionals are often to blame for the incorrectly termed state of health that these patients are experiencing. Although we want to convey the message that factors of stress in a patient’s life has also taxed their adrenals, it really only is very few that have a medically diagnosable condition of adrenal insufficiency. How is it that the terminology which many have come to utilise for stressors on adrenal function somehow is far different than what we utilise to describe thyroid function, where terms such as hypothyroidism or even subclinical hypothyroidism far better reflect the state of health of our other most commonly Googled gland?

The term “adrenal fatigue” actually was first coined by a chiropractor, James Wilson, in 1998, and written about in his publication “Adrenal Fatigue, the 21st Century Stress Syndrome.”[i] Somehow, this 21st century which we are now fully immersed in was felt to be more demanding on our health and function than the stressors of world and civil wars, migrating to different continents, and the great depression that our grandparents and great-grand parents experienced before this. So, what do we really mean to say when we discuss the impact of chronic stressors on our health, vitality, and zest for living? And is it the visible stressors of jobs, family, finances, and health which are to blame for our state of fatigue, or is it a toxic environment which we must continuously detoxify from in our bodies?

The medical condition of adrenal insufficiency

Primary adrenal insufficiency, or Addison’s disease, is a medical condition that has been shown in various population studies to affect between 39 to 140 individuals per million people.[ii] In this day and age, the most common cause of primary adrenal insufficiency is autoimmune destruction of the adrenal cortex, whereas in Thomas Addison’s day, the physician for whom it was named, it was destruction due to tuberculosis.[iii] Patients who experience autoimmune adrenal destruction and related insufficiency just like many other autoimmune diseases are most often female. The primary features of course include fatigue in the majority (84 – 95%), but symptoms of weight loss, skin hyperpigmentation, postural hypotension, salt cravings, nausea, vomiting, abdominal pain, muscle and joint pain also commonly are present.[iv]

Diagnosis requires the demonstration of low cortisol secretion, determining if low cortisol secretion is accompanied by corticotropin (ACTH) deficiency, and finally, determining if the dysfunctional state is due to an adrenal infiltrative process or a tumour in the pituitary gland. Assessment of mineralocorticoid secretion in patients without ACTH deficiency also should take place. In individuals with true adrenal insufficiency there are stages of adrenal destruction, and labs will vary as the body responds in attempts to compensate. Although adrenal insufficiency is not diagnosed by cortisol measurements alone, a morning serum total cortisol of 3 mcg/dL (80 nmol/L) or salivary level of 1.8 ng/mL (5 nmol/L) are strongly suggestive.[v]

However, given the normal range of serum total cortisol which is 10 – 20 mcg/dL, and normal salivary morning level of 5.6 ng/mL, there obviously is a broad range between the very low levels which predict adrenal insufficiency and that which is considered to be normal. Why, we must wonder, is there such a broad un-defined gap between normal and abnormal? Even for thyroid hormones, although laboratory ranges and physician “normal ranges” vary somewhat, they definitely fall within a much smaller range.

There actually is a reasonable answer, believe it or not. Primary differences between thyroid hormones such as triiodothyronine or thyroxine and cortisol are the hormone half-lives and the wide diurnal range of normal cortisol levels. These differences make cortisol a much more challenging marker to pinpoint, hence the sampling on multiple days or usage of tests commonly known as adrenal stress indices or salivary cortisol rhythm (SCR) by integrative and functional medicine practitioners.

In addition to this, activities such as exercise and stressful events (going for a blood draw!), as well as being on medications including hormone therapy, inhaled and oral corticosteroids all can affect cortisol levels. Because of this, testing is wrought with measurements which although “correct” from a laboratory perspective may be falsely elevated.

A recent systemic review evaluated 58 studies that assessed various markers of cortisol secretion and adrenal function in individuals that were healthy, healthy with “burnout” or diagnosed with some form of disease (often being chronic fatigue syndrome [CFS], but also conditions such as breast cancer).[vi] This review initially drew from 3,470 articles that were on the topic of adrenal fatigue, exhaustion, or burnout, however only these 58 met all inclusion criteria for assessment.

From this very comprehensive review, it was deemed that there was no data to substantiate the existence of adrenal fatigue, that is, no consistent patterns in the cortisol awakening response, direct awakening cortisol, or SCR were observed in patients describing a fatigued or burnout state. As an example, the assessment of the salivary cortisol rhythm found no difference between fatigued and healthy individuals in 61.5% of the studies in which it was assessed, while in 26.9% of studies there was an impaired circadian cortisol decrease, and the remaining 11.6% showed a pronounced decrease in cortisol levels. In terms of the cortisol awakening response and direct awakening cortisol, the majority (>50%) of the studies in which these parameters were assessed had normal findings. Finally, the area under the curve describing the SCR was assessed in a smaller faction of the studies (13) and again, in the majority (61.5%) of the studies this was a normal finding.

The gray is wide, and what do we call it?

This brings us to the dilemma those of us who practice functional medicine face. What is the appropriate terminology to describe the state of sub-optimal function, fatigue, and exhaustion which we associate with chronic stress taxing the adrenals? This of course assumes all the other high-hitting items which are common causes of fatigue such as anemia, hypothyroidism, sleep apnea, and autoimmunity are ruled out. In the traditional physician’s office, this patient is often offered an anti-depressant and psychotherapy, support for sleep if indicated, and told to follow up in a year or if a new problem arises.

Is burnout an appropriate medical term? Of course, we would need to dress this up for the use of diagnosis codes, but perhaps “Fatigue, attributed to excessive physical, mental, or emotional exertion” would do the job. There actually are a good many studies in which burnout is the terminology used to describe the presentation of this state, but again, no standardised clinical marker exists.[vii]

A description such as “Stress-associated fatigue syndrome” may capture what we are attempting to define. Much like irritable bowel syndrome, this would be a diagnosis of exclusion, with other possible causes of fatigue ruled out. And then, similarly to other syndrome-type diagnosis, a list of inclusion criteria would be applied. For example, the patient must present with 3 of the 5 following criteria:

  • Fatigue, defined by a low level of energy which limits the ability to perform the typical activities of daily living more than 50% of the time.
  • Sleeping excessively or being unable to sleep.
  • Frequent infections or difficulty in recovering from illness.
  • Mood changes including mild to moderate depression, anxiety, panic attacks, or general apathy.
  • Any one of the following symptoms: weight loss, skin hyperpigmentation, postural hypotension, salt cravings, nausea, vomiting, abdominal pain, muscle or joint pain.

The verbiage surrounding the diagnosis also should include the clause “Symptoms must be preceded by a state of chronic stress due to illness, work, emotional trauma, challenges of physical or mental endurance, and/or disrupted sleep.” Testing of SCR also should be performed primarily to rule out true adrenal insufficiency, but it should be noted that as the comprehensive review showed, there may be no variation from normal in individuals who experience burnout-type fatigue. Elevations of cortisol in the evening would not lead to exclusion from the diagnosis, as this is often expected and further contributes to fatigue due to disrupted sleep.

Cortisol does not act alone!

We all know from even the most basic courses in biochemistry and physiology that in the body, the levels of every hormone, neurotransmitter, protein, and metabolic intermediary are dependent on many, many things. Cortisol of course is no different. The function of each of the glands along hypothalamic-pituitary-adrenal (HPA) axis impact our levels of cortisol, while factors such as thyroid function, insulin levels, obesity, and inflammation also have an effect.

For review, the hypothalamus secretes corticotropin releasing hormone (CRH), which stimulates the anterior pituitary to release adrenocorticotropic hormone (ACTH), which subsequently stimulates the adrenal cortex to produce and release cortisol. There is a negative feedback loop by the secretion of cortisol on the both the pituitary and hypothalamus secretion of ACTH and CRH respectfully. GABAergic inputs also play a role in the inhibition of the HPA axis response to stress, while glutamate has an activating effect.[viii] The release of CRH is stress-dependent and the HPA axis also has a diurnal rhythm.[ix]

The HPA axis response is different with acute and chronic stress, even with different pathways in the brain serving to mediate it.[x],[xi] In the chronic stress state, the HPA axis function and responsiveness to stress change, and with repeated stressful stimuli, the glucocorticoid burden accumulates. The adrenals often increase in size and become more sensitive to ACTH; thus the cortisol response to subsequent stressors is amplified.[xii],[xiii] Making things worse, the basal cortisol levels that exist even at the lowest point of the circadian rhythm are also elevated, possibly due to loss of normal negative feedback by cortisol or the reduction of glucocorticoid receptors. This, of course, for many then contributes to disrupted sleep, and further dysregulation of the parasympathetic nervous system which also helps to keep things in check.

Although the way the HPA axis adapts to chronic stressors seemingly only worsens the situation for us, it is important to remember the stressors in life in more primitive settings were things like the threat of attack by animals or other tribes, settings in which survival would improve if the body became more vigilant and had a more rapid response. Interestingly, one novel study in which mice were subject to chronic psycho-social housing-related stressors (which in some ways may be more like our day-to-day stress) found that the adrenal cortisol response and glucocorticoid sensitivity were decreased, accompanied by adrenal-associated increases in proinflammatory cytokines and colonic inflammation.[xiv] A similar study looked at the behaviors and physiological responses of different subsets of mice groups subject to social stressors, and found that the more dominant rats had increases in CRH response to stressors, while the more submissive rats had either a downregulation of the glucocorticoid receptor expression or a blunted CRH and HPA axis response.[xv]

So, what do we do for this dysregulated state of adrenal function and presentation of fatigue?

One of the reasons we diagnose is so that we can apply standardised and evidence-based treatment. The authors of the systemic review on adrenal fatigue6 describe how the standard treatment for individuals with suspected adrenal fatigue is corticosteroids, as recommended by the medical society The American Academy of Anti-Aging Medicine. But is this the correct treatment course?

Anyone who has ever been on a corticosteroid will probably report they had a significant boost in energy levels, despite what the treatment was for. But the reason we don’t dote out steroids like holiday candy and that they are a regulated substance is that there is a significant potential for harm, particularly when they are used on a long-term basis. Osteoporosis, gastritis, weight gain, diabetes, insomnia, viral reactivation, psychosis, just to name a few, are things we would not wish upon ourselves or our patients. Excess cortisol can also adversely impact thyroid function,[xvi] further messing up our body’s regulation of the endocrine system.

As integrative and holistic medicine practitioners, we often stand at a draw with others in the medical community, as not only are our diagnoses “suspect,” but the treatments we employ lack the assessment with well-designed, double-blind, placebo-controlled clinical studies. This is in part due to the lack of financial interest in demonstrating the effectiveness of substances such as botanicals, nutritional supplements, homeopathics and glandulars, which many of us will attest to having used very effectively to help address patients with stress-associated fatigue syndrome. But perhaps we can be grateful as if they did perform such investigations and found there to be dramatic results the use of these substances would be further limited to holistic providers!

As holistic providers, we also are well aware that you cannot treat the symptom without addressing the cause, and much of our time spent helping depleted people heal involves improving diet, aiding patients to recognise and remove contributing stressors, and supporting nutritional deficiencies. Each of these things has a much greater impact on overall health than a corticosteroid treatment, and it would be incredibly difficult to design a clinical study including all of these things particularly as our treatments are so often individualised!

Despite the lack of a medical diagnosis to appropriately apply to this state of “adrenal fatigue” the one thing that is important to remember is the tremendous overlap of conditions which may present with such fatigue. It is appropriate, and recommended, to demonstrate with the appropriate laboratory testing that there is not another contributing cause. From this, we then can move forth with our holistic approaches to support a patient to recover from fatigue. But do use caution and avoid the incorrect labeling of this fatigue particularly as adrenal failure as not only does it confuse patients, but also leads to a reduction in our credibility with others in the medical profession!

References

[i] Wilson JL. Adrenal Fatigue the 21st Century Stress Syndrome. 1st ed. 2001.

[ii] Løvås K, et al. High prevalence and increasing incidence of Addison’s disease in western Norway. Clin Endocrinol (Oxf). 2002 Jun;56(6):787-91. View Abstract

[iii] Kasperlik-Zaluska AA, et al. Association of Addison’s disease with autoimmune disorders–a long-term observation of 180 patients. Postgrad Med J. 1991 Nov;67(793):984-7. View Full Paper

[iv] Bancos I, et al. Diagnosis and management of adrenal insufficiency. Lancet Diabetes Endocrinol. 2015 Mar;3(3):216-26. View Abstract

[v] Deutschbein T, et al. Diagnosis of secondary adrenal insufficiency: unstimulated early morning cortisol in saliva and serum in comparison with the insulin tolerance test. Horm Metab Res. 2009;41(11):834. View Abstract

[vi] Cadegiani FA, Kater CE. Adrenal fatigue does not exist: a systematic review. BMC Endocr Disord. 2016 Aug 24;16(1):48. View Full Paper

[vii] Kakiashvili T, Leszek J, Rutkowski K. The medical perspective on burnout. Int J Occup Med Environ Health. 2013;26(3):401–12. View Full Paper

[viii] Herman JP, Mueller NK, Figueiredo H. Role of GABA and glutamate circuitry in hypothalamo-pituitary-adrenocortical stress integration. Ann N Y Acad Sci. 2004 Jun;1018:35-45. View Abstract

[ix] Kalsbeek A, et al. Circadian rhythms in the hypothalamo-pituitary-adrenal (HPA) axis. Mol Cell Endocrinol. 2012;349:20–29. View Abstract

[x] Herman JP, et al. Regulation of the Hypothalamic-Pituitary-Adrenocortical Stress Response. Compr Physiol. 2016 Mar 15;6(2):603-21. View Full Paper

[xi] Flak JN, et al. Role of paraventricular nucleus-projecting norepinephrine/epinephrine neurons in acute and chronic stress. Eur J Neurosci. 2014;39:1903–1911. View Full Paper

[xii] Ulrich-Lai YM, Figueiredo HF, Ostrander MM, Choi DC, Engeland WC, Herman JP. Chronic stress induces adrenal hyperplasia and hypertrophy in a subregion-specific manner. Am J Physiol Endocrinol Metab. 2006;291:E965–973. View Full Paper

[xiii] Lilly MP, Engeland WC, Gann DS. Responses of cortisol secretion to repeated hemorrhage in the anesthetized dog. Endocrinology. 1983;112:681–688. View Abstract

[xiv] Reber SO, et al. Adrenal insufficiency and colonic inflammation after a novel chronic psychosocial stress paradigm in mice: implications and mechanisms. Endocrinology. 2007;148:670–682. View Abstract

[xv] Albeck DS, et al. Chronic social stress alters levels of corticotropin-releasing factor and arginine vasopressin mRNA in rat brain. J Neurosci. 1997;17:4895–4903. View Full Paper

[xvi] Holtorf K. Peripheral thyroid hormone conversion and its impact on TSH and metabolic activity. Journal of Restorative Medicine. 2014 Apr 1;3(1):30-52. View Full Paper

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