Holistic Performance Institute Position Stand: Adrenal Fatigue

Transcription

1 Holistic Performance Institute Position Stand: Adrenal Fatigue Cliff Harvey. Journal of Holistic Performance ISSN: Published: 7th September 2016 Abstract Adrenal fatigue is a common diagnosis amongst alternative and complementary medicine practitioners but its diagnostic criteria, aetiology, scientific rationale and treatment methods are not well described in the literature. A review of the relevant literature was conducted to formulate a position statement for clinical practice on the topic of adrenal fatigue. This review shows that the diagnostic criteria are likely to provide a finding of adrenal fatigue in most clients due to the large number of signs, symptoms and comorbidities suggested as being a part of the complex of adrenal fatigue. These signs and symptoms are not however suggestive of defined hypoadrenia and a diagnosis of adrenal fatigue is therefore problematic. There are significant variations in individual characteristics of fatigue. While there may be some hypothalamo-pituitary axis and biochemical dysfunction present, overall baseline and total cortisol levels do not appear to be significantly different between those with CFS and controls. There may be subtle and individualdependent differences in cortisol response, and metabolism and clearance. However, the causative, corollary or resultant nature of these and other findings are yet to be properly elucidated. The position of the Holistic Performance Institute is that until there can be proper reliability and validity testing of adrenal fatigue questionnaires, and a definitive and validated diagnostic protocol for the condition, the diagnosis of adrenal fatigue should be avoided. We further caution that this diagnosis by alternative practitioners who may not be qualified and registered should be avoided, and that misleading diagnoses may put patients at risk due to the non-detection of other conditions. 1

2 Introduction This questionnaire has not been validated against any known markers of adrenal Fatigue is a common presenting symptom of insufficiency. A common criticism of the clients and patients seeking treatment through questionnaire is that it is so broad as to orthodox and complementary avenues. encourage an Adrenal Fatigue diagnosis in Adrenal fatigue syndrome (AFS) is a common diagnosis in the natural and complementary health fields. It has been stated that around 80% of people in the western world will suffer most people. A veritable catch-all of symptoms can be found in relation to AFS including psychological disorders, subjective symptoms (such as brain-fog ), the use of coffee, tea and from Adrenal Fatigue 1 however, this alcohol, physical signs such as dark-circles contention lacks supporting evidence and under the eyes, dry skin, and other medical better-defined and accepted disorders conditions. The questionnaire lists over 90 characterised by fatigue, which might indicate true population prevalence of AFS show a much lower prevalence. For example, fibromyalgia in the general population affects around 2% of people and fewer still exhibit chronic fatigue syndrome (CFS). 2 This makes the contention of a pandemic of AFS unlikely. Many complementary practitioners consider signs, symptoms and comorbidities that could, in the opinion of AFS adherents, indicate the presence of AFS. This plethora of symptoms and co-morbidities makes a diagnosis of AFS likely, despite there being little evidence for it. More worryingly, a false diagnosis could be extremely dangerous in cases where there is an underlying and more serious condition. These could include a range of fatigue-inducing that daily life can wear down one s adrenals disease ranging from diabetes and metabolic and that this leads to a depletion of adrenal hormone reserve and a life-affecting reduction in adrenal hormones, especially cortisol. It has disorder to cardiovascular disease, cancer and diagnosable (i.e. actual) adrenal insufficiency. been suggested that the hyperadrenia (over In a 2012 editorial in the Journal of production or excretion of cortisol and other stress hormones) related to acute and chronic stress may eventually lead to hypoadrenia, matching the exhaustion / fatigue phase of the Orthomolecular Medicine, Jonathon Prousky likens Adrenal fatigue, or Mild Adrenocortical Deficiency (MAD) to psychiatric disorders i.e. they can be seen in symptoms and effects general adaptation syndrome. 3 However, many observed by treating those symptoms. 5 However, a flaw in this argument is that there is people presenting purported symptoms of a claimed pathological aetiology (reduced adrenal fatigue show normal cortisol levels and cortisol) in AFS, which cannot be reliably this contention lacks reliable verification in studies, and the diagnosis of adrenal fatigue is demonstrated in cohorts with supposed not one that is defined nor recognised. 4 Adrenal Fatigue. Therefore, the basis for the diagnosis loses its veracity, and further, there is The diagnosis of adrenal fatigue is often made primarily by an Adrenal Fatigue Questionnaire (example: a grave risk of causing harm due to people not seeking an accurate diagnosis of other potential problems which may be causing the presenting symptoms. It is also contentious to justify a condition based upon treatments that are 2

3 related to an improvement in symptoms when these have not been validated in controlled trials to adjust for the placebo effect. Notwithstanding that many clinical interventions are likely to promote an improvement in symptoms for many people, despite not having anything to do with a validation of a purported disease or disorder. An exploration of the published literature is itself limited by the near dearth of research addressing Adrenal Fatigue and its proper description, definition and diagnosis. Because of this lack of evidence there is no credible and validated basis for which to diagnose AFS and treat on this basis. Because of the paucity of literature concerning AFS, a broad search, inclusive of the term adrenal fatigue was conducted in Medline complete, CINAHL, Alt Health Watch, EBSCO Psychology and Behavioural Sciences Database and Sport Discus and in addition searched for tangential literature for chronic fatigue and related disorders in order to summarise the available information which may influence our position on the topic of AFS. The common term for chronic states of fatigue is Chronic Fatigue Syndrome (CFS) and this is far better elucidated in the literature than the topic of AFS. In fact, almost the entirety of the available, published evidence is related to CFS and not AF. Chronic fatigue syndrome has no clear aetiology. Some neuroendocrine disturbances and reduced hypothalamicpituitary-adrenal (HPA) axis function have been observed in people with CFS but it is unclear as to whether these dysfunctions are causative, resultant or corollary to the condition. The HPA axis and fatigue The HPA axis plays a major role in the regulation of responses to stress and CFS, fibromyalgia syndrome (FMS), chronic pelvic pain and post-traumatic stress disorder (and perhaps chronic back pain) are characterized by alterations in HPA axis activity. However, the role of the HPA axis alterations in these stressrelated disorders is not clear. Most studies have shown that the HPA axis is underactive in the stress-related disorders, but contradictory results have also been reported, which may be due to the patients selected for studies, the methods used for the investigation of the HPA axis, the stage of the syndrome when the tests have been done and the interpretation of the results. 6 While both CFS and FMS patients are shown to have central HPA dysfunction, the dysfunction in CFS is at the pituitaryhypothalamic level while the dysfunction in FMS is more related to dysfunction at the hypothalamic and supra-hypothalamic levels. 7 However, even if the HPA axis dysfunctions are secondary to other factors, they are probably a relevant factor in symptom propagation in CFS. 8 Hypothalamic-pituitary-adrenal axis dysfunction has been found in a high proportion of CFS patients and may include enhanced corticosteroid-induced negative feedback, basal hypocortisolism, attenuated diurnal variation, and a reduced responsivity to challenge. Given the inter-individual 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. 9 It has been hypothesised that HPA axis hypofunction in CFS reflects a fundamental, persistent dysregulation of the stress system. As a result, a disturbed balance between glucocorticoid and inflammatory 3

4 signalling pathways may give rise to a AFS, CFS and cortisol pathological cytokine-induced sickness A key tenet of Adrenal Fatigue is that there is response that may be a common pathway persistent suppression of cortisol production underlying CFS symptoms, especially and / or release. Interestingly a significant effort/stress intolerance and pain correlation has been observed between a higher hypersensitivity. 10 HPA axis changes seem score on the Adrenal Fatigue Severity clinically relevant, as they are associated with Questionnaire with higher, not lower, levels of worse symptoms and/or disability and with cortisol and ACTH. Significant decreases in the poorer outcomes to standard treatments for levels of cortisol (p=0.001) and ACTH CFS. Low activity levels, depression and earlylife stress appear to reduce cortisol levels, (p=0.001) were found in the participants with moderate to high physical activity compared to whereas the use of psychotropic medication can those with mild or sedentary activity. The increase cortisol. HPA-axis dysregulation and decrement in adrenal hormonal levels hypocortisolism are extremely important positively correlated (p=0.01, r= 0.976) with conditions that have not received appropriate improvements in the adrenal fatigue status and attention until recently and hypocortisolism severity index, especially in the physically active may be a fairly common phenomenon participants. 13 So higher stress was related to associated with stress. 11 Of additional interest is higher cortisol, which we would expect, and this the observation that psychological symptoms, was mitigated by exercise as were indicators of particularly disturbances in mood and anxiety, AFS. This is in contrast to what is commonly are equally prominent in this condition. At this reported for AFS, i.e. that there is persistent time, several reports have provided replicated hypoadrenia and that this is worsened by evidence of disruptions in the integrity of the intense exercise. hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. It is notable that the pattern of the alteration in the stress response apparatus is not reminiscent of the Some studies have shown a degree of cortisol suppression in those with CFS. Cortisol levels have been demonstrated to be lower in well-understood hypercortisolism of adolescent CFS-patients than in healthy melancholic depression but, rather, suggests a sustained inactivation of central nervous system components of this system. Recent work controls 14, with this mild hypocortisolism significantly correlated to the amount of sleep. Most studies though show little difference in also implicates alterations in central baseline cortisol between those with and serotonergic tone in the overall without CFS, change from baseline in response pathophysiology of this finding. The to stress is reduced in those with CFS 15 and implications of these observations are far from morning, waking CFS may be reduced, clear, but they highlight the fact that, though chronic fatigue syndrome overlaps with the compared to healthy controls. 16 It has also been demonstrated that in CFS urinary free cortisol well-described illness category of major and cortisone concentrations show normal depression, these are not identical clinical conditions. 12 diurnal rhythm, but levels were lower across the cycle in CFS. Urinary cortisol metabolites also show a normal diurnal rhythm, and levels of 4

5 these are not significantly different between CFS and other hormones CFS and controls at any time. 17 This is in The effects on the HPA axis in CFS are contrast to the often reported variations in daily inconsistent. It has been suggested that many cortisol response observed for those purported other factors may be contributing to HPA axis to be suffering from AFS (and for which there is alterations in chronic fatigue syndrome, no data that we are aware of from peerreviewed research.) Little effect has been including sleep disturbance, inactivity, altered circadian rhythmicity, illness chronicity, observed on daily cortisol levels as a result of concomitant medication and comorbid stress tests in those with CFS. 18 And there psychiatric disturbance. These sources of appears to be no significant difference was heterogeneity need to be considered in future found between patients with CFS and controls studies, and may explain the inconsistent for basal levels of morning cortisol and 24-h findings to date. 23 Patients with CFS have urinary free cortisol. 19 Likewise total urinary demonstrated subtle alterations in HPA axis cortisol and cortisol metabolites are not activity characterized by reduced ACTH over a significantly different between CFS patients full circadian cycle and reduced levels during and controls. 20 The findings of normal urinary the usual morning physiological peak ACTH cortisol metabolite excretion in patients with secretion. 24 Reduced ACTH levels have been CFS is at variance with earlier reports that CFS observed in CFS patients during the 8 am to 10 is a hypocortisolaemic state. If serum and saliva am period as well, however, no significant cortisol levels are lower in CFS, this would abnormalities in the levels of cortisol, GH, and suggest that metabolic clearance of cortisol is PRL in patients with CFS were observed over faster in patients with CFS than controls. These the full cycle compared with control subjects. 25 results in totality do not lend support to the In other studies there has been observed theory that patients with chronic fatigue elevated evening ACTH and reduced evening syndrome have a low adrenal reserve but there cortisol. 26 And yet others, in response to various may be some minor variations in cortisol biochemical stressors; human corticotropinreleasing hormone (CRH), insulin stress test, response and metabolism. However, it is unclear whether these responses are corollary, and D-fenfluramine (a stimulant anorectic) causative or resultant from the fatigue, and baseline cortisol concentrations were from other factors likely to be causing fatigue significantly raised in the chronic fatigue (such as the observed correlation between syndrome group for the CRH test only. Baseline cortisol dysfunctions and sleep). Despite this ACTH concentrations did not differ between there is some evidence that while pre-treatment groups for any test. ACTH responses to human salivary cortisol levels do not predict treatment CRH, the insulin stress test, and D- outcomes, normalization of cortisol is fenfluramine were similar for patient and associated with treatment success. 21 Patients control groups. Cortisol responses to the insulin with chronic fatigue syndrome have also stress test did not differ between groups, but demonstrated enhanced suppression of salivary there was a trend for cortisol responses both to free cortisol after the administration of 0.5 mg human CRH and D-fenfluramine to be lower in of dexamethasone in comparison to the control the chronic fatigue syndrome group. 27 The subjects. 22 5

6 release of ACTH (but not cortisol) in response to opiate drugs may also be blunted in CFS subjects compared with controls. 28 Release of ACTH (but not cortisol) in response to ipsapirone challenge was significantly blunted in patients with CFS. 29 Significantly lower ACTH response levels have been observed in response to a psychosocial stress test and exercise test, with no differences in plasma total cortisol responses. Also, salivary-free cortisol responses did not differ between groups in the psychosocial stress test and the exercise suggesting that CFS patients are capable of mounting a sufficient cortisol response under different types of stress but that on a central level subtle dysregulations of the HPA axis exist. 30 Morphological changes have also been noted in some with CFS. Right and left adrenal gland bodies were reduced by over 50% in CFS subjects in one study. 31 DHEA and DHEAS are significantly lower in the CFS compared to healthy controls. 32 When CFS has been compared to diagnosed adrenal insufficiency (AI) and a control group (C) without CFS or AI it has been found that in some subjects cortisol response is preserved, while in others it is similar to one found in secondary adrenal insufficiency. 33 CFS patients do not show an exaggerated secretion of LPS-induced cytokines. Although cortisol responses to stress were normal, pro-inflammatory cytokine levels in CFS patients were significantly attenuated. Possible intracellular mechanisms, such as for example an enhanced sensitivity to inhibitory effects of glucocorticoids, a diminished responsivity to catecholaminergic stimulation, and a disruption of intracellular activation are discussed. Basal levels of stimulated proinflammatory Il-6 levels are generally related to fatigue scores. However, in CFS patients this association is of greater magnitude and can also be observed for TNF-alpha. 34 Conclusion There are significant variations in individual characteristics of chronic fatigue. It is likely that there is some dysfunction of the HPA axis present, especially with respect to ACTH and possibly DHEA. Baseline and total cortisol levels do not appear to be significantly different between those with CFS and controls but there may be subtle and individual-dependent differences in cortisol response, and metabolism and clearance. However, the causative, corollary or resultant nature of these and other findings are yet to be properly elucidated There is an almost complete lack of research on the condition characterised as Adrenal Fatigue Syndrome and until there can be proper validation testing of questionnaires, and a definitive and validated diagnostic protocol for the condition, this diagnosis should not be used. We further caution that diagnosis by alternative practitioners who are not qualified and registered should be avoided and that misleading diagnoses may put patients at risk due to the non-detection of other conditions. We believe that there are return to play / return to life strategies that are evidence-based, for our clients presenting with fatigue, that do not rely on the diagnosis of a pseudocondition that is yet to be described properly and using these strategies offers better potential for positive treatment outcomes. 6

7 References 1. Warren B. View BePure 2016 [Available from: 2. Goldenberg DL. Fibromyalgia, chronic fatigue syndrome, and myofascial pain. Current Opinion In Rheumatology. 1996;8(2): Anderson DC. Assessment and nutraceutical management of stress-induced adrenal dysfunction. Integrative Medicine: A Clinician's Journal. 2008;7(5): p. 4. Shah R, Greenberger PA. Chapter 29: Unproved and controversial methods and theories in allergyimmunology. Allergy And Asthma Proceedings: The Official Journal Of Regional And State Allergy Societies. 2012;33 Suppl 1:S100-S2. 5. Prousky JE. Mild Adrenocortical Deficiency (a.k.a. Adrenal Fatigue): A Real Diagnosis? Journal of Orthomolecular Medicine //. 6. Tanriverdi F, Karaca Z, Unluhizarci K, Kelestimur F. The hypothalamo-pituitary-adrenal axis in chronic fatigue syndrome and fibromyalgia syndrome. Stress (Amsterdam, Netherlands). 2007;10(1): Holtorf K. 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. 2007;14(3): p. 8. Van Den Eede F, Moorkens G, Van Houdenhove B, Cosyns P, Claes SJ. Hypothalamic-pituitaryadrenal axis function in chronic fatigue syndrome. Neuropsychobiology. 2007;55(2): Tomas C, Newton J, Watson S. A review of hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome. ISRN Neuroscience. 2013;2013: Van Houdenhove B, Van Den Eede F, Luyten P. Does hypothalamic-pituitary-adrenal axis hypofunction in chronic fatigue syndrome reflect a 'crash' in the stress system? Medical Hypotheses. 2009;72(6): Edwards LD, Heyman AH, Swidan S. Hypocortisolism: An Evidence-based Review. Integrative Medicine: A Clinician's Journal. 2011;10(4):30-7 8p. 12. Demitrack MA. Neuroendocrine correlates of chronic fatigue syndrome: a brief review. Journal Of Psychiatric Research. 1997;31(1): Alghadir AH, Gabr SA. Physical activity and environmental influences on adrenal fatigue of Saudi adults: biochemical analysis and questionnaire survey. Journal of Physical Therapy Science. 2015;27(7): DISTURBED ADRENAL FUNCTION IN ADOLESCENTS WITH CHRONIC FATIGUE SYNDROME. Archives of Disease in Childhood. 2003;88:A Scott LV, Medbak S, Dinan TG. The low dose ACTH test in chronic fatigue syndrome and in health. Clinical Endocrinology. 1998;48(6): Roberts ADL, Wessely S, Chalder T, Papadopoulos A, Cleare AJ. Salivary cortisol response to awakening in chronic fatigue syndrome. The British Journal Of Psychiatry: The Journal Of Mental Science. 2004;184: Jerjes WK, Peters TJ, Taylor NF, Wood PJ, Wessely S, Cleare AJ. Diurnal excretion of urinary cortisol, cortisone, and cortisol metabolites in chronic fatigue syndrome. Journal Of Psychosomatic Research. 2006;60(2): Kempke S, Luyten P, De Coninck S, Van Houdenhove B, Mayes LC, Claes S. Effects of early childhood trauma on hypothalamic pituitary adrenal (HPA) axis function in patients with Chronic Fatigue Syndrome. Psychoneuroendocrinology. 2015;52: Inder WJ, Prickett TCR, Mulder RT. Normal opioid tone and hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome despite marked functional impairment. Clinical Endocrinology. 2005;62(3): Jerjes WK, Taylor NF, Peters TJ, Wessely S, Cleare AJ. Urinary cortisol and cortisol metabolite excretion in chronic fatigue syndrome. Psychosomatic Medicine. 2006;68(4): Nijhof SL, Rutten JMTM, Uiterwaal CSPM, Bleijenberg G, Kimpen JLL, Putte EMvd. The role of hypocortisolism in chronic fatigue syndrome. Psychoneuroendocrinology. 2014;42: Gaab J, Hüster D, Peisen R, Engert V, Schad T, Schürmeyer TH, et al. Low-dose dexamethasone suppression test in chronic fatigue syndrome and health. Psychosomatic Medicine. 2002;64(2): Hudson M, Cleare AJ. The 1microg short Synacthen test in chronic fatigue syndrome. Clinical Endocrinology. 1999;51(5): Di Giorgio A, Hudson M, Jerjes W, Cleare AJ. 24-hour pituitary and adrenal hormone profiles in chronic fatigue syndrome. Psychosomatic Medicine. 2005;67(3): Di Giorgio A, Hudson M, Jerjes W, Cleare AJ. 24-hour pituitary and adrenal hormone profiles in chronic fatigue syndrome. Psychosomatic Medicine. 2005;67(3): p. 26. Demitrack MA, Dale JK, Straus SE, Laue L, Listwak SJ, Kruesi MJ, et al. Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. The Journal Of Clinical Endocrinology And Metabolism. 1991;73(6):

8 27. Cleare AJ, Miell J, Heap E, Sookdeo S, Young L, Malhi GS, et al. Hypothalamo-pituitary-adrenal axis dysfunction in chronic fatigue syndrome, and the effects of low-dose hydrocortisone therapy. The Journal Of Clinical Endocrinology And Metabolism. 2001;86(8): Scott LV, Burnett F, Medbak S, Dinan TG. Naloxone-mediated activation of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome. Psychological Medicine. 1998;28(2): Dinan TG, Majeed T, Lavelle E, Scott LV, Berti C, Behan P. Blunted serotonin-mediated activation of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome. Psychoneuroendocrinology. 1997;22(4): Gaab J, Hüster D, Peisen R, Engert V, Heitz V, Schad T, et al. Hypothalamic-pituitary-adrenal axis reactivity in chronic fatigue syndrome and health under psychological, physiological, and pharmacological stimulation. Psychosomatic Medicine. 2002;64(6): Scott LV, Teh J, Reznek R, Martin A, Sohaib A, Dinan TG. Small adrenal glands in chronic fatigue syndrome: a preliminary computer tomography study. Psychoneuroendocrinology. 1999;24(7): Scott LV, Salahuddin F, Cooney J, Svec F, Dinan TG. Differences in adrenal steroid profile in chronic fatigue syndrome, in depression and in health. Journal Of Affective Disorders. 1999;54(1-2): Zarković M, Pavlović M, Pokrajac-Simeunović A, Cirić J, Beleslin B, Penezić Z, et al. [Disorder of adrenal gland function in chronic fatigue syndrome]. Srpski Arhiv Za Celokupno Lekarstvo. 2003;131(9-10): Gaab J, Rohleder N, Heitz V, Engert V, Schad T, Schürmeyer TH, et al. Stress-induced changes in LPS-induced pro-inflammatory cytokine production in chronic fatigue syndrome. Psychoneuroendocrinology. 2005;30(2):