Adrenal fatigue does not exist: a systematic review

Theories on adrenal impairment as the genesis for fatigue are tempting, as they allow for a treatable condition. Despite the widespread use of the term “adrenal fatigue” by the general media and certain health practitioner groups, in this systematic review, only ten citations [113‐122] were found with this exact expression, and they were all only descriptive and did not perform any test regarding the HPA axis and “adrenal fatigue”. Studies that tried to correlate the HPA axis and fatigue states used the term “burnout” instead of “adrenal fatigue” to denote adrenal depletion. Therefore, a distinction between the “general information” and the actual scientific literature regarding this condition is evident. First, this suggests that the terminology of a hypothetical adrenal depletion should be normalized, with a suitable name given for the purported condition, as “adrenal fatigue” has been already been stigmatized and lacks proper scientific support. Second, methodology employed to evaluate the proposed correlation between fatigue and adrenal function should be standardized among physicians and medical associations that claim for the existence of adrenal impairment in patients with fatigue before evident clinical hypocortisolism manifests, in order to strength eventual evidence, in case one finds actual and proper causal correlation.

No confirmed methods of clinical screening for AF are available. Indeed, the popular questionnaire developed by Dr. Wilson and published in the first book exclusively dedicated to the description of this supposedly disease [6] has not been cited in any indexed databases. Another theory, the “Thompson cortisol hypothesis” [123], suggests that cortisol is responsible for yawning and fatigue; however, again, no studies that tested this theory have been published in indexed journals. Validated surveys have been used in studies that investigate fatigue states, but they were not correlated with proper cortisol assessment methods. The TSST is the only survey to have enough credibility to be officially tested and standardized as a trigger of stress [99‐102].

Functional tests are the only methods to assess adrenal cortisol production endorsed by endocrinology societies [97]. Although, the ITT is considered the gold standard test to evaluate the entire HPA axis, neither the ITT (or the similar LPS stimulation test) was performed in any studies investigating the correlation between fatigue states and adrenocortical function. Moreover, we generally found conflicting data using most of the functional tests when trying to differentiate exhausted, fatigued, and burnout individuals from healthy patients. For example, using the low-dose CST, we found an unexpected increase in cortisol levels in fatigued subjects in the selected studies. This may have been perhaps the result of a relative secondary adrenal insufficiency, which leads to an amplified adrenal cortisol response due to an upregulation of ACTH receptors, but this sounds unjustifiable since the lack of continuous stimulation of the adrenal cortices would cause atrophy, rendering them non-responsive to a low- (and even high) dose of cosyntropin stimulation in the long run. Regardless of the theoretical explanation, CST has shown to be not a good marker of fatigue. Similarly, ACTH levels were also poorly studied and did not show significant correlations in most fatigued subjects. In addition, despite its lack of standardization, the DST was performed in nine studies, but conflicting results invalidated attempts to establish this as a new marker for fatigue states. Moreover, the 24 h-UFC has been shown to be so far inaccurate for investigation of adrenal impairment. Findings were also contradictory in the six studies that calculated cortisol AUC as well as in the four studies that performed MAUC. Therefore, the above methods cannot be used to differentiate fatigued from non-fatigued individuals.

In this review, we also examined whether cortisol markers can be used to assess cortisol impairment. The results of our review indicate that the three major tests (CAR, DAC and SCR) used to identify the underlying causes of the fatigue/exhaustion state failed to do so, since they were unable to demonstrate significant differences or proper causality. CAR and DAC frequently showed inconsistent results in studies that used heterogeneous groups of subjects. CAR and DAC are not necessarily indicatives of the etiology and pathogenesis of the fatigue status, since both can be consequences of other disorders, such as sleep disturbances. Indeed, a recent study [124] was the first to use CAR as a marker of improvement of burnout syndrome, which reinforces the use of this method for monitoring the consequences of fatigue states, but not for its etiology [77‐81].

With regards to the SCR, the results may be misleading if they are not analyzed together with the total 24 h cortisol release. This is because a non-physiological blunted rhythm can be due either to an impairment of the lowering cortisol trend throughout the day or due to a lower morning cortisol level. Despite this, studies that evaluated total 24 h cortisol by measuring serial salivary cortisol levels also showed conflicting findings. Our systematic review corroborates another systematic review [83] that shows inconsistency regarding measuring methods among across different randomized controlled trials. Similarly, baseline MSC and NSC were poor markers of fatigue status as it failed to reveal any differences in burnout/exhaustion/fatigue patients compared to healthy subjects.

Adrenal size could be considered another marker of adrenal activity, as hypertrophic/hyperplastic adrenal glands could be the result of an ACTH over-stimulation by the pituitary, as seen in subjects exposed to chronic stress [125, 126], whereas a diminished or atrophic gland may reflect adrenal insufficiency at any level of the HPA axis [98]. However, not a single study could be identified in which the adrenal size has been checked in fatigued or exhausted patients. Similarly, although DHEA-S could also be a potential marker for adrenal atrophy or dysfunction, is still uncertain whether it plays any pathophysiological role in fatigue. Finally, none of the abovementioned methods were accurate markers of fatigue, nor could they be correlated with the HPA axis dysfunction as an etiology of fatigue.

It is also important to note that once adrenal impairment is confirmed using any of these tests, the etiology should also be elucidated. As the HPA axis can be affected by several chronic and/or metabolic disorders, other primary conditions must be excluded before intrinsic disorders of the HPA axis are deemed responsible. Typical differential diagnosis of “adrenal fatigue” and related states are: (1) sleep obstructive apnea syndrome; (2) adrenal insufficiency; (3) mental illnesses; (4) excessive working (overwork); (5) night-shift workers; (6) other hormonal deficiencies; (7) liver and kidney dysfunctions; (8) heart conditions; (9) chronic pulmonary obstructive disease; (10) autoimmune diseases.

Although conflicting data were reported, patients with CFS tend to have a normal cortisol profile, and the abnormalities found can be typically be explained by a poor quality sleeping patterns. Therefore, health providers should not be concerned about adrenal function in CFS subjects once they had been already excluded to other conditions prior to the diagnosis of CFS. Similarly, studies investigating patients with the burnout syndrome were greatly inconsistent So far, HPA axis tests should not be used as markers for burnout syndrome by health practitioners. Similar conclusions can be drawn for the use of HPA axis tests as markers for fibromyalgia and other chronic diseases, which tend to demonstrate inconsistent findings, whereas studies that were performed in breast cancer subjects tended to show depletion of cortisol levels; however, studies in breast cancer were performed while administering chemotherapy, which can introduce a confounding bias.

Therefore, based on our current knowledge, cortisol tests should not yet be used in clinical practice for examining any condition, except if adrenal impairment is suspected. Moreover, glucocorticoid therapy should be avoided in patients, as it can increase the risk of cardiovascular disease or osteoporosis, even in low doses.