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Adrenal Fatigue Does Not Exist: a Systematic Review Flavio A Cadegiani and Kater BMC Endocrine Disorders (2016) 16:48 DOI 10.1186/s12902-016-0128-4 RESEARCH ARTICLE Open Access Adrenal fatigue does not exist: a systematic review Flavio A. Cadegiani and Claudio E. Kater* Abstract Background: The term “adrenal fatigue” (“AF”) has been used by some doctors, healthcare providers, and the general media to describe an alleged condition caused by chronic exposure to stressful situations. Despite this, “AF” has not been recognized by any Endocrinology society, who claim there is no hard evidence for the existence. The aim of this systematic review is to verify whether there is substantiation for “AF”. Methods: A systematic search was performed at PUBMED, MEDLINE (Ebsco) and Cochrane databases, from the beginning of the data until April 22nd, 2016. Searched key words were: “adrenal” + “fatigue”, “adrenal” + “burnout”, “adrenal” + “exhaustion”, “hypoadrenia”, “burnout” + “cortisol”, “fatigue” + “cortisol”, “clinical” + “burnout”, “cortisol” + “vitalility”, “adrenal” + “vitality”,and“cortisol” + “exhaustion”. Eligibility criteria were: (1) articles written in English, (2) cortisol profile and fatigue or energy status as the primary outcome, (3) performed tests for evaluating the adrenal axis, (4) absence of influence of corticosteroid therapy, and (5) absence of confounding diseases. Type of questionnaire to distinct fatigued subjects, population studied, tests performed of selected studies were analyzed. Results: From 3,470 articles found, 58 studies fulfilled the criteria: 33 were carried in healthy individuals, and 25 in symptomatic patients. The most assessed exams were “Direct Awakening Cortisol” (n=29), “Cortisol Awakening Response” (n=27) and “Salivary Cortisol Rhythm” (n=26). Discussion: We found an almost systematic finding of conflicting results derived from most of the studies methods utilized, regardless of the validation and the quality of performed tests. Some limitations of the review include: (1) heterogeneity of the study design; (2) the descriptive nature of most studies; (3) the poor quality assessment of fatigue; (4) the use of an unsubstantiated methodology in terms of cortisol assessment (not endorsed by endocrinologists); (5) false premises leading to an incorrect sequence of research direction; and, (6) inappropriate/invalid conclusions regarding causality and association between different information. Conclusion: This systematic review proves that there is no substantiation that “adrenal fatigue” is an actual medical condition. Therefore, adrenal fatigue is still a myth. Keywords: Adrenal depletion, Adrenal fatigue, Cortisol, Adrenal insufficiency, Burnout, Fatigue Abbreviations: 24 h UFC, 24-h urinary free cortisol; ACTH, Adrenocorticotropic hormone; ADAS, Abbreviated dyadicadjustmentscale;AF,Adrenalfatigue;AUC,Estimatedcortisolrelease(areaunderthecurve);BFI,Brief fatigue inventory; CAR, Cortisol awakening response; CFQ, Chalder fatigue questionnaire; CFS, Chronic fatigue syndrome;CST,Cosyntropinstimulationtest;DAC,Direct awakening cortisol; DCSRD, Diagnosis criteria of stress-related exhaustion disorder; DHEA-S, Dehydroepiandrosterone sulfate; DST, Dexamethasone suppression test; FAQ, Fatigue assessment questionnaire; FMG, Fibromyalgia; FSE, Fatigue severity scale; H/B, Healthy/Burnout; (Continued on next page) * Correspondence: [email protected] From the Adrenal and Hypertension Unit, Division of Endocrinology and Metabolism, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM/UNIFESP), R. Pedro de Toledo 781– 13th floor, 04039-032 São Paulo, SP, Brazil © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Cadegiani and Kater BMC Endocrine Disorders (2016) 16:48 Page 2 of 16 (Continued from previous page) HRFS, HIV-related fatigue scale; Maastricht, Maastricht vital exhaustion questionnaire; Maslach, Maslach burnout inventory; MFI, Multidimensional fatigue inventory; MP, Memory performance; MSC, morning serum cortisol (& salivary); MST, Mental stress tests; NC-WHO, Neurasthenia criteria; NRWS, Need for recovery from work scale; NSC, Night salivary cortisol; POMS, Profile of mood states;SCR,Salivarycortisolrhythm;SEQ,Exclusionwith stress-energy questionnaire; SF-36, Short form health servey 36; SMBQ, Shirom-melamed burnout questionnaire; SOFI, Swedish occupational fatigue inventory; UFC, 24 h Urinary free cortisol Background patient’s condition. Second, even at low and physio- The term “adrenal fatigue” (“AF”) has been used by logical doses, corticosteroids increase the risk for several some doctors, healthcare providers, and the general disorders, such as psychiatric disorders [8–11], osteopor- media to describe an alleged condition caused by osis [12], myopathy [13], glaucoma [14], metabolic disor- chronicexposuretostressful situations. According to ders [14, 15], sleep disturbances [16] and cardiovascular this theory, chronic stress could potentially lead to diseases [17, 18]. “overuse” of the adrenal glands, eventually resulting in Therefore, is “adrenal fatigue” an actual disorder? Is their functional failure. In a recent search on Google fatigue related to depleted adrenal function? Does fa- (April 22, 2016), “adrenal fatigue” provided 640,000 re- tigued healthy subjects present relative adrenal failure? sults, and the association of the two words exhibited Is adrenal involved in the pathophysiology of fatigue in 1,540,000 findings. Despite this, “adrenal fatigue” has diseases? Which tests were performed in order to es- not been recognized by any endocrinology societies to tablish markers or triggers? The aim of this systematic date, who claim there is no evidence for the existence review was to determine the correlation between ad- of this syndrome [1]. renal status and fatigue states, including the recently Conversely, some medical societies, although unrecognized described “burnout” or “burnout syndrome”,andother by American Board of Medical Specialties and Associ- fatigue-related diseases. The primary objective was to ation of American Medical Colleges [2, 3], claim that evaluate the methodology for fatigue status assessment, adrenal fatigue is a real and underdiagnosed disease including cortisol tests, and to examine the results of [4, 5]. According to these societies, to screen for “AF” studies involving cortisol and fatigue correlation. in patients, a questionnaire developed by Dr. Wilson, whoisreportedlythefirstpersontodescribethissup- Methods posed syndrome, is recommended to be used [6]. In Search strategies addition, patients suspected of “AF” are now being The PRISMA protocol for systematic reviews was uti- tested for serum basal cortisol levels and salivary cor- lized for this study design. A systematic search was tisol rhythm. Those who present impaired results from conducted through the electronic PUBMED, MEDLINE these tests are then treated with corticosteroids, re- (Ebsco), and COCHRANE databases, from the begin- gardless of the etiology. As a result, corticosteroids ning of the data until April 22, 2016. The search strat- (mainly hydrocortisone) are probably being prescribed egy included the following keywords: (1) “adrenal + to a large number of patients, as at least 24,000 health fatigue”;(2)“adrenal + burnout”;(3)“adrenal + exhaus- providers [7] are instructed by one medical society tion”;(4)“adrenal” + “fatigue”;(5)“hypoadrenia”;(6) (The American Academy of Anti-Aging Medicine – A4M) “cortisol” + “fatigue”;(7)“cortisol” + “burnout”;(8) to prescribe corticosteroids in these cases. “clinical” + “burnout”;(9)“cortisol” + “vitality”;(10)“ad- Arguments for corticosteroid use as a treatment for renal” + “vitality”; and (11) “cortisol” + “exhaustion”, “claimed AF” include: [1] the immediate and significant where “a+b” means “a” and “b” together in the exact improvement seen in patients who are prescribed cor- expression, and “a” +”b” means that both words needed ticosteroid, and [2] the long and extensive clinical symp- to be contained in the article, but not necessarily to- tomatology of this alleged disease, which shows a slow gether. Although the terms “adrenal + fatigue” and “ad- depletion before clinical and severe hypocortisolism en- renal” + “fatigue” were searched, as articles found using sues [4–6]. Moreover, others claim that endocrinologists the first criteria were also found using the second cri- use much too strict diagnostic criteria before prescribing teria, further analysis were performed for the exact corticosteroids, and thus, many sufferers would not be expression that matched with the disease. We also receiving adequate treatment [4, 6]. However, there are analyzed articles mentioned within identified studies logical counterarguments to routine corticosteroid use whenever the alleged disorder, or a similar situation, in these patients. First, corticosteroids promote a sense were described (such as cortisol profile and exhaustion of wellbeing (usually temporary), regardless of the or fatigued patients). Cadegiani and Kater BMC Endocrine Disorders
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