Adrenal fatigue does not exist: a systematic review

Study selection

In total, 3,470 articles were identified. A summary of the study selection is shown in Fig. 1. The search for “adrenal” + “burnout” yielded 56 studies; “adrenal” + “exhaustion” yielded 446 articles; “adrenal” + “fatigue” yielded 1,353 articles; “fatigue” + “cortisol” yielded 1,128 articles; “cortisol” + “burnout” yielded 102 articles; “cortisol” + “vitality” yielded 37 articles; “adrenal” + “vitality” yielded 53 articles; “hypoadrenia” yielded 9 articles articles (“hypoadrenocorticism” yielded 1,302 articles but is used to refer to hypocortisolism in animals, and therefore, was not included here); and “cortisol” + “exhaustion” yielded 286 articles. Twelve studies were excluded because they were written in languages other than English, 1,989 were excluded because there was no relation with the purpose of the systematic review, whereas 905 articles of interest were duplicates. Of the 564 remaining studies, 504 had only descriptive characteristics or contained results already presented in another study (in which tests were performed), and therefore were excluded. Two studies were excluded because despite of the correlation between cortisol profile and burnout or multiple sclerosis, they did not perform correlation between fatigue and cortisol, but other aspects, as depression and pain [19, 20]. For the systematic review, we analyzed all the included and not excluded studies, which represent a total of 58 articles (1.67 % of the original search) (Table 1).

First Author & Reference	Year of Publication	Number of Patients	Population	Questionnaire	Tests	Results	Comments
McLennan [21]	2016	257	H/B	Maslach	HCC	Nl
Schmidt [69] (part 1)	2016	265	Breast Cancer	FAQ	DAC, CAR, SCR, NSC	↑NSC, ↑AUC, Nl CAR, Nl DAC, ↓SCR	Pts. mostly on chemotherapy (ChTx); schemes not specified. No controls, only correlation between fatigue levels and tests. ChTx related to worse fatigue. Initial tests performed during, w/ or w/o ChTx.
Schmidt [69] (part 2)	2016	265	Breast Cancer	FAQ	DAC, CAR, SCR, NSC	↑AUC, ↑CAR, ↑NSC, ↑SCR, Nl DAC	Second test of the study, performed after 14 weeks of procedures.
Sjors [25]	2015	220	H/B	SMBQ	DAC, CAR	↓CAR, ↑DAC	Results normalized after adjustment of anti-depressive use; SCR results not provided
Oosterholt [28]	2015	91	H/B	Maslach	DAC, CAR, SCR, AUC, CAR 60 min	Nl SCR, ↓CAR, Nl AUC, Nl CAR 60 min, ↓DAC	Control of variations did not change results
De Vente [22]	2015	95	H/B	Acute Psychosocial Stressor diagnosis	MSC, MST	Nl MSC, Nl MST	MST: Nl (women), reduced (men); MSC: Nl (men), reduced (women). Mental arithmetic and public speech stressors also performed
Lennartsson [24]	2015	56	H/B	DCSRD; exclusion w/ SEQ	DHEA-S; ACTH; ACTH and DHEA-S post-TSST (TSST stress test performed)	↓DHEA-S, ↓post-TSST DHEA-S, Nl ACTH, Nl post-TSST ACTH
Tao [23]	2015	171	H/B	Maslach	MSC, ACTH	↑ACTH, ↑MSC
Jonsson [29]	2015	51	H/B	SMBQ	MSC, MST	Nl MSC, ↓MST
Lennartsson [27]	2015	56	H/B	DCSRD and SMBQ	MSC, MST, ACTH, ACTH post-TSST (TSST stress test performed)	Nl MSC, Nl MST, Nl ACTH, Nl post-TSST ACTH	Severe BO: lower ACTH, cortisol response to TSST vs controls, whereas low BO: higher ACTH, cortisol responses vs controls
Schmaling [26]	2015	62	Healthy	ADAS	AUC, SCR	↓AUC, ↓SCR	31 couples studied, one of which had chronic fatigue (but not CFS)
Sveinsdottir [68]	2015	1150	Chronic Lombalgia	CFQ	DAC, CAR, SCR, NSC	Nl DAC, Nl CAR, Nl NSC, Nl SCR	**Colocar como SAUDÁVEL – porque é só lombalgia (increased CAR in Low back pain)
Powell [67]	2015	76	Multiple Sclerosis	CFQ	DAC, CAR, SCR	↓DAC, ↑CAR, Nl SCR	Sleep disorders excluded; adjusted for depressive symptoms; NSC not published. Multiple sclerosis had increased awakening cortisol and decreased CAR
Cruz [70]	2015	43	Breast cancer	BFI and CFQ	MSC, DHEA-S	Nl MSC, Nl DHEA-S	Pts undergoing ChTx included anthracyclines
Marchand [31]	2014	1043	H/B	Maslach	DAC, CAR, SCR, NSC	↑DAC, ↓CAR, ↑SCR, ↓NSC	Only BO; Groups of severe distress or depression not included
Aggarwal [30]	2014	227	Healthy	CFQ	MSC, NSC, 0.25 mg DST, DHEA-S	Nl MSC, Nl NSC, Nl 0.25 mg DST, ↓DHEA-S	Evaluation of chronic, widespread pain, chronic orofacial pain, chronic fatigue (but not CFS), irritable bowel syndrome
Tell D [71]	2014	130	Breast cancer	MFI	DAC, CAR, SCR, NSC	↓CAR, ↓SCR, ↑DAC, ↑NSC	Post-surgery breast cancer, regardless of ChTx. Not adjusted to sleeping patterns
Wolfram [32]	2013	53	H/B	Maslach	MSC, 1 mcg CST, DST/CRH test (1.5 mg DST + 100 mcg CRH)	Nl MSC, ↓post-1 mcg ACTH, Nl ACTH and cortisol DST-CRH	High over-commitment present blunted serum and salivary cortisol and ACTH responses to DST-CRH test
Klaassen [33]	2013	27	Healthy	MP (Beck & Luine, 2010) and Stress Tasks (Wang, 2006)	MSC, post-stress	Nl MSC, Nl post-stress	A complex test sequence was performed but not reproduced
Eek [34]	2012	581	Healthy	SOFI-20	DAC, CAR, NSC, SCR, MSC	Nl DAC, Nl CAR, Nl NSC, Nl SCR, Nl MSC	Women: reduced awakening, increased CAR, increased SCR; Men: increased awakening and reduced CAR – when fatigued
Sjors [35]	2012	247	H/B	DCSRD and SMBQ	DAC, 15 min CAR	Nl DAC, Nl 15 min CAR
Rahman [54]	2011	30	CFS	Previous Dx – No questionnaire	MSC, SCR, NSC	Nl MSC, Nl SCR, Nl NSC
Moya-Albiol [37]	2010	64	H/B	Maslach	DAC, CAR	Nl DAC, Nl CAR
Kumari [38]	2009	4,299	Healthy	SF-36	DAC, CAR, NSC, SCR	↓DAC, ↓CAR, ↑NSC, ↓SCR	Adjusted for WC, BMI, sleep duration, CVD medication, depressive symptoms, smoking, alcohol intake provides Nl awakening but lower SCR
Osterberg [39]	2009	304	H/B	Maslach	DAC, CAR, NSC, SCR	Nl DAC, Nl CAR, ↓NSC, ↑SCR	0.5 mg DST was not compared to controls
Wingenfeld [41]	2009	279	H/B	Maslach and Maastricht	AUC, SCR	Nl AUC, Nl SCR	DAC and CAR not done; conclusions different from results. For AUC, Low BO: Nl, moderate: increased, severe: decreased
Rydstedt [40]	2009	76	Healthy	NRWS	DAC, NSC	Nl DAC, Nl NSC
Papadopoulos [55]	2009	38	CFS	CFQ and SF-36	MSC, AUC, morning AUC, 0,5 mg DST	↑MSC, ↑AUC, ↑MAUC, Nl 0.5 mg DST	Data on absolute cortisol levels at each point not published. DST reduction evaluated by percent reduction.
Bay [72]	2009	75	Post traumatic brain injury	POMS	AUC	Nl AUC	Correlation between brain injury-related fatigue level and cortisol AUC. Basal and NSC results not reported; SCR not evaluated.
Sudhaus [73]	2009	43	Chronic Lombalgia	MFI	DAC, CAR, MAUC	↓CAR, Nl DAC, Nl MAUC (correlation between fatigue levels among low back pain subjects)
Lindeberg [36]	2008	78	Healthy	SF-36	DAC, CAR, NSC, SCR	Nl DAC, ↓CAR, Nl NSC, ↓SCR
Sertoz [42]	2008	72	H/B	Maslach	Basal and post 1.0 mcg DST cortisol	Nl basal cortisol and 1.0 mg DST
Bellingrath [43]	2008	101	H/B	Maslach and Maastricht	DAC, CAR, NSC, SCR, 0.25 mg DST	Nl DAC, Nl CAR, Nl NSC, Nl SCR, ↓0.25 mg DST
Nater [57]	2008	185	CFS	SF-36 and MFI	DAC, CAR, MAUC	Nl DAC, Nl CAR, ↓MAUC
Torres-Harding [56]	2008	108	CFS	FSE	AUC, SCR	Nl AUC, Nl SCR	Multiple psychological tests performed. Data on NSC, basal and CAR not published.
Sonnenschein [45]	2007	42	H/B	Maslach	CAR, 0.5 mg DST, DHEA-S	Nl CAR, Nl 0.5 mg DST, Nl DHEA-S	Adjusted for depression, sleep quality. Awakening levels and each level graphics not available
Harris [44]	2007	44	Healthy	SF-36	DAC, CAR, NSC, SCR	Nl DAC, Nl CAR, Nl NSC, Nl SCR	Other aspects also correlated: complains, job stress and demand, QOL and coping. Adjusted for coffee and tobacco.
Langelaan [46]	2006	55	H/B	Maslach	DAC, CAR, 0.5 mg DST, DHEA-S	Nl DAC, Nl CAR, Nl 0.5 mg DST, Nl DHEA-S	Engaged work also compared and had stronger suppression in DST
Mommersteeg [47]	2006	109	Healthy	NC-WHO	DAC, CAR, 0.5 mg DST, SCR, AUC, NSC	Nl DAC, Nl CAR, Nl NSC, Nl SCR, Nl 0.5 mg DST, Nl AUC
Barroso [74]	2006	40	HIV	HRFS	MSC, NSC	↓MSC, ↑NSC
Jerjes [58]	2006	80	CFS	CFQ	UFC, TCM	↓UFC, Nl TCM
Grossi [48]	2005	64	H/B	SMBQ	DAC, CAR	↓DAC, ↑CAR	Groups were high x moderate x low BO score; correlation was significant
Segal [59]	2005	40	CFS	No questionnaire	MSC, 1 mcg CST	↓ MSC, ↓1 mcg CST	DHEA-S collected only in CFS. No questionnaires used.
Jerjes [60]	2005	35	CFS	CFQ	MSC, SCR, NSC, AUC	↓MSC, ↓SCR, ↓AUC ↓, Nl NSC
Bower [75]	2005	29	Breast cancer	SF-36	DAC, AUC, SCR, NSC	↑AUC, ↓SCR, Nl DAC, ↑NSC	Post-ChTx (regardless of time) complete cancer remission and exclusion of other disorders
McLean [76]	2005	55	Fybro-mialgia	SF-36	DAC, 60 min CAR, SCR, AUC, NSC	Nl DAC, Nl 60 min CAR, Nl SCR, Nl AUC, Nl NSC (correlation between fatigue levels among FMG subjects)	FMG subjects presented Nl DAC and CAR, as controls.
Roberts [62]	2004	92	CFS	CFQ and SF-36	DAC, CAR, MAUC	Nl DAC, ↓CAR, ↓MAUC
Crofford [61]	2004	72	CFS/FMG	POMS	ACTH, MSC, SCR, NSC, AUC	Nl ACTH, Nl SCR, Nl NSC, ↓AUC, Nl MSC	Tests performed in: CFS, FMG and CFS + FMG; FMG w/o fatigue had Nl AUC and increased BMC levels
Moch [50]	2003	16	H/B	Maslach	UFC, DHEA-S, ACTH, MSC	↓UFC, Nl DHEA-S, Nl ACTH, ↓MSC	Only women; longitudinal evaluation – Nl initial cortisol.
De Vente [49]	2003	45	H/B	Maslach	DAC, MSC, post-TSST	↑DAC, ↑MSC, Nl post-TSST
Gaab [63]	2002	42	CFS	MFI	DAC, CAR, SCR, 0.5 mg DST	↓0.5 mg DST, Nl AUC, Nl CAR, Nl DAC, Nl SCR, Nl NSC	CAR also performed at 15, 45 and 60 min.
Dekkers [77]	2000	53	Rheumatoid Arthritis	MFI	DAC, CAR, SCR, AUC	Nl AUC, Nl SCR Nl, ↓DAC, ↑CAR	5/25 subjects with RA taking prednisone (5–10 mg/d); RS subjects had smaller SCR, increased AM cortisol and decreased CAR. 15 and 45 min CAR also performed.
Melamed [51]	1999	111	H/B	SMBQ and Maastricht	MSC and 4 PM cortisol	↑MSC, Nl 4 PM cortisol
Pruessner [52]	1999	66	Healthy	Maslach	DAC, CAR, 0.5 mg DST	↓DAC, ↓CAR, ↓0.5 mg DST	15 min and 60 min CAR also performed
Strickland [65]	1998	74	CFS	Not specified/detailed	MSC, NSC	↓NSC, Nl MSC	Adjusted for depression
Young [66]	1998	45	CFS	NC-WHO	UFC, SCR, MSC, AUC	Nl UFC, Nl SCR, Nl MSC, Nl AUC
Scott [64]	1998	28	CFS	Not specified (not detailed)	MSC, ACTH, 100 mcg CRH cortisol stimulation	Nl MSC, Nl ACTH, CRH stim test: ↓cortisol, ↓ACTH
Raikkonen [53]	1996	22	Healthy	Not assessed	1 mcg CST, DST (non specified), OGTT, MSC, ACTH, cortisol/ACTH ratio	↑Cortisol/ACTH ratio; ↑CST, Nl DST, Nl OGTT, Nl MSC, Nl ACTH	Full article not assessed – not in PUBMED or other database

Questionnaires: SMBQ shirom-melamed burnout questionnaire, BFI brief fatigue inventory, CFQ chalder fatigue questionnaire, Maslach maslach burnout inventory, SF-36 short form health survey 36, NC-WHO neurasthenia criteria, DCSRD diagnosis criteria of stress-related exhaustion disorder, SEQ stress-energy questionnaire, ADAS, abbreviated dyadic adjustment scale, MFI multidimensional fatigue inventory, FAQ fatigue assessment questionnaire, MP memory performance, POMS profile of mood states, Stress Tasks, FSE fatigue severity scale, SOFI Swedish occupational fatigue inventory, Maastricht Maastricht vital exhaustion questionnaire, NRWS need for recovery from work scale, HRFS HIV-related fatigue scale, WC waist circumference

Other abbreviations: CFS chronic fatigue syndrome, H/B healthy/burnout, 24 h-UFC 24-h urinary free cortisol, FMG fibromyalgia; ↑: Increased or elevated; ↓: Decreased or reduced; →: Unchanged; Nl: Normal

Study characteristics

Among the 58 studies included, 33 (56.9 % of the selected studies) were performed in healthy subjects [21–53], since we considered “burnout” not an actual disorder but instead a stressful condition presented by some groups of health workers. Despite the several studies describing cortisol impairment in Chronic Fatigue Syndrome (CFS), only 13 (22.4 %) studies performed an actual assessment of the hypothalamic–pituitary–adrenal (HPA) axis [54–66]. Twelve studies (20.7 %) were found in which tests for cortisol profiling were performed for other diseases [67–77]. However, for analysis purposes, one study [69] was divided into two studies as it performed two distinct protocols at different moments. Among these, five were done performed in patients with a diagnosis of breast cancer who had undergone or were undergoing chemotherapy. One study tested patients with fibromyalgia, two studies compared patients with chronic lower pain, one with rheumatoid arthritis, one with post brain injury, two with multiple sclerosis, and one involved patients with human immunodeficiency virus (HIV) and CFS. One study evaluated both patients with fibromyalgia and patients with CFS in different groups.

The median number of tested subjects in the 58 studies was 72 (range: 16–4,299). The median numbers of participants in articles involving healthy individuals, patients with CFS, or patients with other diseases were 76 (16–4,299), 45 (28–185), and 65 (29–1150), respectively. The largest number of healthy subjects included groups of workers whose cortisol results were compared to exhaustion and fatigue status, in an attempt to discriminate correlations between cortisol and energy levels. One study involving 4,299 individuals was responsible for more subjects than the sum of all the other studies.

Methods used to evaluate fatigue in the general study population

Another method that became widely used to evaluate exhaustion/burnout/fatigue states is the salivary cortisol rhythm (SCR), which evaluates the change in cortisol levels between morning, afternoon, and late night. A total of 26 studies evaluated SCR (44.8 %). Some heterogeneity in the method was found between studies, but in general, salivary cortisol was collected at 8 AM, 4 PM, and 10–11 PM. While the SCR is considered as another fatigue marker [82, 83], like the CAR, there is no justification for considering this as an etiology for “adrenal fatigue”. Sixteen (61.5 %) studies showed no difference between fatigued and control patients, whereas seven (26.9 %) demonstrated an impaired decrease in the circadian SCR. The remaining three (11.6 %) studies disclosed a more pronounced decrease in cortisol level.

The direct awakening cortisol (DAC) level, collected at the exact moment of waking, was used in 29 studies (50.0 %). Unlike CAR, DAC reflects sleep quality rather than being a possible identifying factor of fatigue [84–86], even though a poor quality sleep plays an important role in the fatigue process [87–89]. In studies that employed DAC, inconsistent results were observed: normal results were found in nineteen (65.5 %) studies, elevated levels were shown in four (13.8 %), and reduced levels in six (20.7 %).

The DAC, CAR and SCR methods were by far the most commonly elected ones for examining the correlation between cortisol profile and fatigue status. However, a few other studies analyzed other aspects of cortisol release.

The dexamethasone (Dex) suppression test (DST) was also used in nine (15.3 %) studies. The DST identifies autonomous hypercortisolism, as cortisol production is normally suppressed by Dex. DSTs have also been used to investigate hypocortisolism, based on the supposed assumption that it promotes “oversuppression” of cortisol in low cortisol states, indicating that lower levels of cortisol would disclose a more prolonged suppression than controls [55, 90–93], although many studies do not show correlation between DST and fatigue [47, 55, 94, 95]. In six studies, a lower Dex dose (0.5 mg) was used in an attempt to improve the test sensitivity. Among these, four studies (66.7 %) showed the same results for both groups, whereas in two others (33.3 %), the test resulted in lower and prolonged suppression of cortisol levels in fatigued subjects. Moreover, an even lower Dex dose (0.25 mg) was performed in two studies and resulted in reduced cortisol in one study and normal levels in the group with exhaustion. In one study, Dex dose was not specified, but levels were not different among exhausted and control groups. As a whole, the DST was used in nine studies, and no significant differences were observed between fatigued and non-fatigued groups in six of these studies (66.7 %), whereas reduced levels were observed in three studies (33.3 %).

Adrenocorticotropic hormone (ACTH) is a pituitary peptide hormone that stimulates cortisol production by the adrenocortical zona fasciculata. Elevated ACTH occurs early in primary adrenal insufficiency, whereas inappropriate (normal) ACTH levels in the presence of low serum cortisol are found in secondary adrenal failure. Although, normal ACTH levels with normal cortisol levels does not exclude the possibility of relative adrenocortical failure. Six (10.3 %) studies employed the morning ACTH levels to compare fatigued and non-fatigued patients; no significant differences for ACTH, as well as for cortisol, were found in five studies (83.3 %), meanwhile one showed elevated ACTH levels in burnout patients (16.7 %).

On the other hand, three studies (5.2 %) used the low-dose cosyntropin (a synthetic _1-24ACTH) stimulation test (CST), in which 1 μg of cosyntropin is used instead of the classic 250 μg dose, based on the premise that the CST is more accurate and sensitive for verifying the adrenocortical cortisol reserve [96], even though most findings indicate that both doses have similar accuracy [97, 98]. Surprisingly, one of three (33.3 %) studies disclosed a paradoxically higher cortisol increase compared to controls, while in two (66.7 %) lower levels were observed. Conversely, impaired cortisol and ACTH responses was observed in the fatigued group in a single study in which corticotropin-releasing hormone (CRH) was used to stimulate the HPA axis.

Three (5.2 %) studies measured 24 h-urinary free cortisol (UFC) in an attempt to correlate cortisol excretion rates with intensity of fatigue. Although the 24 h-UFC reflects the total cortisol produced per day, it was initially conceived to investigate cortisol excess syndromes, although diminished levels could hypothetically imply subnormal adrenal function, despite of lack of any evidence. One of these studies (33.3 %) found no correlation between 24 h-UFC and energy status, whereas two studies (66.7 %) showed reduced values in fatigued patients.

Thirteen studies (22.4 %) estimated total cortisol release (AUC) by calculating the areas under the curves for the whole day salivary cortisol collection by using three or more daily salivary cortisol levels over four or more days. Assessment of the total 24 h cortisol release by this method would complement the SCR, since the lack of the expected decrease throughout the day observed in some studies can be due either to a non-elevated morning serum cortisol (MSC) level or to a full day elevated cortisol, although three daily levels of cortisol is probably too few for a minimally precise AUC; herein, findings are conflicting. AUC was elevated in two (15.4 %) studies, normal in eight (61.5 %), and reduced in another three (23.1 %).

Twenty-two studies (37.9 %) compared baseline MSC between controls and fatigued patients; traditionally [98], this is the initial cortisol assessment to investigate possible hypocortisolism. Basal MSC was not different between individuals in fourteen (63.6 %) of these studies, was significantly reduced in fatigued patients in three (23.1 %), and was elevated in two (15.4 %).

Twenty-two articles (37.9 %) correlated late night salivary cortisol (11 PM NSC) and fatigue status. The NSC was initially validated to assess cortisol excess, as physiologically, one expects lower cortisol levels at the end of the day; although, NSC has been extended to investigate hypocortisolism in these studies, despite of lack of validation. Three studies (13.6 %) showed a lower cortisol level in fatigued subjects compared to controls, thirteen (59.1 %) found no differences, and six (27.3 %) showed increased levels in fatigued subjects.

Six studies (10.3 %) investigated the correlation between dehydroepiandrosterone sulfate (DHEA-S) levels and fatigue status. Reduced DHEA-S levels are usually found in hypocortisolism and are a potential marker of fatigue, although there is still not enough evidence to corroborate this affirmation. Four studies (66.7 %) found no correlation with DHEA-S, whereas two (33.3 %) found lower levels in chronic exhausted patients.

The morning estimated total cortisol release (MAUC) is obtained by calculating the area under the curves for the period between the awakening moment and 1 hour later, and is based on determining three or more salivary cortisol levels during this period of the day, although this method has also not been validated by any indexed study. A total of four studies (6.9 %) among the selected studies reported the MAUC. Two of these studies (50.0 %) showed reduced MAUC levels in fatigued subjects, one demonstrated increased results (25.0 %), and one demonstrated no differences (25.0 %).

Mental stress tests (MST) have been performed in some studies in order to identify possible differences in cortisol and ACTH release between fatigued and non-fatigued individuals. The most employed test was the Trier Social Stress Test (TSST), which has been already validated as a stress trigger test [99–102], and requires complete HPA axis integrity for a proper response. Other types of MSTs have also been proposed and validated [103, 104]. MSTs were performed in five different studies in order to correlate cortisol and ACTH responses and burnout status. No difference was seen in four studies (80.0 %), whereas in one (20.0 %), cortisol and ACTH responses were impaired in exhausted individuals.

Some other tests were performed in a smaller number of the selected studies, as follows: two studies performed a 60 min CAR (both showed normal results among fatigued and non-fatigued subjects); one study performed a 15 min CAR (and showed normal results); two studies performed the ACTH MST (both used the TSST and found normal results); one study performed the DHEA-S MST (which also used the TSST and demonstrated normal results); one study performed the cortisol post Oral Glucose Tolerance Test (OGTT) (and found no differences among fatigued and non-fatigued subjects); one study calculated cortisol/ACTH ratio (and found an increased ratio among exhausted subjects); one study evaluated the 4 PM cortisol level (and found no significant differences between exhausted subjects and controls); one study used 1.5 mg-Dex followed by 0.1 mg-CRH to stimulate cortisol and ACTH (and showed normal responses); one study stimulated ACTH and cortisol with 0.1 mg of CRH (and found reduced levels of both hormones in fatigued subjects compared to controls); and finally, one study evaluated the multiple urinary cortisol metabolites and calculated the Total Cortisol Metabolites (TCM) (and found no differences between fatigued subjects and controls).

Finally, we were not able to find studies in which the gold standard test for assessing the integrity and functionality of the HPA axis—the insulin tolerance test (ITT)—were performed. The same was true for the lipopolysaccharides (LPS) stimulation test. Both tests stimulate hypothalamic CRH secretion, leading to a complete evaluation of the HPA axis.

Fatigue in burnout syndrome

Fatigue in chronic fatigue syndrome

Fatigue in other disorders

Questionnaires for fatigue assessment