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      Adrenal fatigue does not exist: a systematic review

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          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.

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          Most cited references103

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          Long-term side effects of glucocorticoids.

          Glucocorticoids represent the standard therapy for reducing inflammation and immune activation in various diseases. However, as with any potent medication, they are not without side effects. Glucocorticoid-associated side effects may involve most major organ systems. Musculoskeletal, gastrointestinal, cardiovascular, endocrine, neuropsychiatric, dermatologic, ocular, and immunologic side effects are all possible.
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            Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease.

            Glucocorticoids have adverse systemic effects, including obesity, hypertension, and hyperglycemia, that may predispose to cardiovascular disease. The effect of glucocorticoid use on cardiovascular disease has not been quantified. To test the hypothesis that users of exogenous glucocorticoids have an increased risk for cardiovascular disease. A cohort study using a record linkage database. Tayside, Scotland, United Kingdom. 68,781 glucocorticoid users and 82,202 nonusers without previous hospitalization for cardiovascular disease who were studied between 1993 and 1996. The average daily dose of glucocorticoid exposure during follow-up was categorized as low (inhaled, nasal, and topical only), medium (oral, rectal, or parenteral or =7.5 mg of prednisolone equivalent). Poisson regression model, sensitivity analysis, and propensity score methods were used to investigate the association between glucocorticoid exposure and cardiovascular outcome. 4383 cardiovascular events occurred in 257,487 person-years of follow-up for a rate of 17.0 (95% CI, 16.5 to 17.5) per 1000 person-years in the comparator group, and 5068 events occurred in 212,287 person-years for a rate of 23.9 (CI, 23.2 to 24.5) per 1000 person-years in the group exposed to glucocorticoids (22.1, 27.2, and 76.5 in low, medium, and high groups, respectively). The absolute risk difference was 6.9 (CI, 6.0 to 7.7) per 1000 person-years (5.1, 10.1, and 59.4, respectively). After adjustment for known covariates, the relative risk for a cardiovascular event in patients receiving high-dose glucocorticoids was 2.56 (CI, 2.18 to 2.99). Because the data were observational, residual confounding cannot be excluded. Treatment with high-dose glucocorticoids seemed to be associated with increased risk for cardiovascular disease.
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              The cortisol awakening response: more than a measure of HPA axis function.

              In most healthy people morning awakening is associated with a burst of cortisol secretion: the cortisol awakening response (CAR). It is argued that the CAR is subject to a range physiological regulatory influences that facilitate this rapid increase in cortisol secretion. Evidence is presented for reduced adrenal sensitivity to rising levels of ACTH in the pre-awakening period, mediated by an extra-pituitary pathway to the adrenal from the suprachiasmatic nucleus (SCN). A role for the hippocampus in this pre-awakening regulation of cortisol secretion is considered. Attainment of consciousness is associated with 'flip-flop' switching of regional brain activation, which, it is argued, initiates a combination of processes: (1) activation of the hypothalamic pituitary adrenal (HPA) axis; (2) release of pre-awakening reduced adrenal sensitivity to ACTH; (3) increased post-awakening adrenal sensitivity to ACTH in response to light, mediated by a SCN extra-pituitary pathway. An association between the CAR and the ending of sleep inertia is discussed.
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                Author and article information

                Contributors
                flaviounb@gmail.com
                kater@unifesp.br
                Journal
                BMC Endocr Disord
                BMC Endocr Disord
                BMC Endocrine Disorders
                BioMed Central (London )
                1472-6823
                24 August 2016
                24 August 2016
                2016
                : 16
                : 1
                : 48
                Affiliations
                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
                Article
                128
                10.1186/s12902-016-0128-4
                4997656
                27557747
                3060787d-7c66-434c-ab0e-e7187e6e4833
                © The Author(s). 2016

                Open AccessThis 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.

                History
                : 25 June 2016
                : 11 August 2016
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2016

                Endocrinology & Diabetes
                adrenal depletion,adrenal fatigue,cortisol,adrenal insufficiency,burnout,fatigue

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