Psychosomatics 44:113-119, April 2003
© 2003 The Academy of Psychosomatic Medicine
Assessment of Cortisol Response With Low-Dose and High-Dose ACTH in Patients With Chronic Fatigue Syndrome and Healthy Comparison Subjects
Jens Gaab, Ph.D.,
D. Hüster, M.Sc.,
R. Peisen, M.Sc.,
V. Engert, B.Sc.,
V. Heitz, B.Sc.,
T. Schad, B.Sc.,
Th. Schürmeyer, Ph.D., M.D., and
U. Ehlert, Ph.D.
Received March 6, 2002; revision received July 27, 2002; accepted Aug. 1, 2002. From the Center for Psychobiological and Psychosomatic Research, University of Trier, Trier, Germany. Address reprint requests to Dr. Gaab, Institute for Psychology, Clinical Psychology II, University of Zurich, Zürichbergstr. 43, CH-8044 Zurich; jgaab{at}klipsy.unizh.ch (e-mail).
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ABSTRACT
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A reduced secretion of cortisol has been proposed as a possible explanation of the symptoms in chronic fatigue syndrome. However, the evidence of hypocortisolism in chronic fatigue syndrome is conflicting. In order to simultaneously assess possible alterations in adrenocortical sensitivity and secretory adrenal reserve, the authors administered both low-dose and high-dose ACTH to a group of 18 chronic fatigue syndrome patients and 18 age- and gender-matched healthy comparison subjects. No response differences for salivary and plasma cortisol were detectable after administration of either low-dose or high-dose ACTH, indicating that primary adrenal insufficiency is unlikely to play a significant role in the etiology of chronic fatigue syndrome.
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INTRODUCTION
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Chronic fatigue syndrome is characterized by persistent or relapsing debilitating mental and physical fatigue, which is exacerbated by minor exertion. Patients typically experience an array of other symptoms, including myalgia, arthralgia, cognitive disturbances, and sleep disturbances.1
Several studies have addressed possible hypothalamic-pituitary-adrenal (HPA) axis dysfunctions in chronic fatigue syndrome patients, since there are clinical similarities between chronic fatigue syndrome and states of glucocorticoid deficiencies as well as early observations of reduced adrenocortical activity in chronically fatigued patients.2 In a comprehensive series of tests, Demitrack et al.3 found evidence for adrenal hyperresponsivity with reduced secretory capacity to increasing doses of exogenous ACTH. In a recent study,4 we found reduced ACTH response levels with three different neuroendocrine stress tests, with normal salivary free and plasma total cortisol responses. Calculating the ACTH-cortisol ratios, we found significantly lower values for chronic fatigue syndrome patients relative to healthy comparison subjects. The magnitude of this difference in adrenal sensitivity was 28%.4
Two studies5,6 have used a low-dose ACTH test. One of these reported reduced adrenocortical responsiveness,5 with a subgroup of patients showing reduced adrenal gland size.6 However, a subsequent study that used a similar low-dose ACTH test7 reported no basal or reactive differences between chronic fatigue syndrome patients and healthy comparison subjects.
The standard 250-µg ACTH test has been criticized for being insensitive to subtle hypoadrenocortical states8 and for its low reliability in comparison to the insulin tolerance test.9 It has been shown that in healthy comparison subjects, as little as 0.5–1.0 µg of exogenous ACTH produces an equivalent response comparable to the standard 250-µg ACTH test.10–14 Since the cortisol rise after the low-dose ACTH test has been reported to be of shorter duration than after the standard dose,13 and repeated stimulation with low doses of ACTH did not attenuate subsequent cortisol responses,10,11 we administered both low-dose and high-dose ACTH in order to assess subclinical hypoadrenocortisol states as well as possible changes in maximal adrenal secretory capacity in chronic fatigue syndrome patients.
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METHOD
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Subjects
Patients were contacted through a German chronic fatigue syndrome self-help organization. Those who expressed interest (N=128) received a postal screening questionnaire containing all chronic fatigue symptoms required by the U.S. and U.K. definitions.15,16 Patients who returned the questionnaire and fulfilled the symptom requirements (N=68) were interviewed by telephone and asked to disclose any diagnosed medical illnesses and psychiatric disorders. Patients were only excluded from participating in the study if they had received a medical or psychiatric diagnosis defined as an exclusion criterion by the U.S. definition.15,16 Selection criteria were fulfillment of U.S.- and U.K.-defined chronic fatigue syndrome criteria as determined by a screening questionnaire; acute onset of chronic fatigue syndrome; age between 30 and 50; no current antidepressant, anxiolytic, antibiotic, antihypertensive, or steroid medications; and no medical cause for the chronic fatigue according to routine laboratory test results. Twenty-three patients were admitted to a general hospital for 1 week. All selected patients (10 men and 13 women) were medically examined according to recommendation15 by the same physician (Th.S.). Patients were also interviewed by one trained psychologist (J.G.) who used a computer-aided standardized and structured diagnostic interview in accordance with DSM-IV17 and a semistructured chronic fatigue syndrome interview, which contained the severity and course of all symptoms required by the U.S. and U.K. definitions.15,16 Two female patients were excluded from the study because of thyroid hormone levels indicative of thyroid hypofunction and primary adrenal insufficiency. Urine toxicology screens were not performed, but participants were asked to report any substance and medication abuse in the last 2 years during the standardized diagnostic interview. All patients fulfilled U.S. and U.K. consensus criteria for chronic fatigue syndrome. Patients were matched by age and sex with healthy volunteer comparison subjects, who had been randomly recruited by telephone from a larger cohort of subjects interested in participating in research projects. These subjects were medication-free and underwent comprehensive medical examination for past and current health problems. All participants were recruited for a study on possible neuroendocrine dysregulations in patients with chronic fatigue syndrome. In addition, all participants received a letter containing a short description of the theoretical background and the planned procedures. Comparison subjects received a payment of 50 Euro.
For better characterization of the patient group, all subjects completed a battery of questionnaires, including German versions of the Multidimensional Fatigue Inventory18 and the Hospital Anxiety and Depression Scale.19
All subjects provided written informed consent before participation in the study, and ethical committee approval for the study was obtained.
Test Protocol
Unlike the chronic fatigue syndrome patients, the comparison subjects did not stay in the hospital but rather reported to the laboratory for administration of low-dose and high-dose ACTH. Chronic fatigue syndrome patients were free to plan their own daily activities except for the time of the ACTH testing. From self-report diaries, chronic fatigue syndrome patients reported an average of 5.3 hours of rest (range=1–16 hours) on the testing day. Each subject arrived at the laboratory 60 minutes before ACTH testing. They were taken into a separate room, and a venous catheter was inserted and kept patent with a lock. All subjects were required to rest for at least 45 minutes. A baseline sample was collected immediately before testing began. At all time points, blood and saliva samples were taken. The ACTH testing started at 2:00 p.m. After a baseline sample of ACTH and plasma total and salivary free cortisol was taken, subjects received an intravenous bolus injection of 1.25 µg ACTH (Synacthen, Ciba, Wehr, Germany) prepared as follows: 0.1 ml ACTH (25 µg) was drawn off the standard 250-µg dose by using a graded 1-ml syringe and diluted with 0.9 ml NaCl saline. After adequate dispersion, half of the resulting 1 ml was again diluted to 1 ml with 0.5 NaCl, resulting in 12.5 µg ACTH. We used as the bolus low-dose injection 0.1 ml of this dilution, which contained 1.25 µg ACTH. Samples were obtained 10, 20, 30, 45, and 60 minutes after the injection. The remaining 225 µg was then used as the bolus high-dose injection. This procedure was used because it enables two doses to be obtained from one ACTH test and also because it seemed to be the least susceptible to measurement errors. Again, plasma total and salivary free cortisol samples were taken 10, 20, 30, 45, and 60 minutes after injection of high-dose ACTH.
Sampling Methods and Biochemical Analyses
Ethylenediamine tetraacetate blood samples were spun immediately at 4°C and stored at 20°C until assayed. Saliva was collected by the subjects by using Salivette collection devices (Sarstedt, Rommelsdorf, Germany) and stored at room temperature until completion of the session. It was then stored at –20°C until biochemical analysis.
Plasma cortisol was measured with two-site commercial chemiluminescence assays (CLIA, Nichols Institute Diagnostics, Bad Nauheim, Germany). The free cortisol concentration in saliva was determined by using a time-resolved immunoassay with fluorometric detection, as described in detail elsewhere.20 Inter- and intraassay coefficients of variance were below 10% for all analytes.
Statistical Analysis
Chi-square analyses were used to test significant differences in discrete variables, and analysis of variance and analysis of covariance (ANCOVA) for repeated measures were computed to analyze endocrine. All reported results were corrected by Greenhouse-Geisser procedure when assumptions of sphericity were violated. For all endocrine parameters, areas under the total response curve, expressed as area under all samples, were calculated by using the trapezoidal method. Data were tested for normal distribution and homogeneity of variance by using Kolmogorov-Smirnov and Levene's test before statistical procedures were applied. The optimal total sample size of N=40 to detect an expected effect size of 0.35 with a power  0.90 and alpha=0.05 was calculated a priori with the statistical software G-Power.21 For all analyses, the significance level was alpha=5%.
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RESULTS
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Group Characteristics
The two groups had similar gender ratios (chronic fatigue group: 10 men and eight women, comparison group: 11 men and seven women;  2=1.69, df=1, p=0.64). The two groups did not differ significantly in mean age and body mass index (Table 1). Sixteen chronic fatigue syndrome patients reported an infectious onset of their symptoms. All patients reported an acute onset of their chronic fatigue syndrome symptoms (within 3 months). Mean duration of symptoms was 67.4 months (range=17–168). All patients had been drug-free for a minimum of 1 month with the exception of four female subjects in each group who had been using monophasic oral contraceptives. One patient fulfilled criteria for a current episode of major depression. Since the exclusion of these subjects did not alter the results, they were included in the reported analysis. Seven patients reported a history of major depression, and four reported a history of anxiety disorder. None of the comparison subjects reported any current or lifetime psychiatric disorder. As expected, chronic fatigue syndrome patients exhibited significantly higher scores in the questionnaires employed (Table 1).
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TABLE 1. Clinical Characteristics of Chronic Fatigue Patients and Healthy Comparison Subjects Administered Low-Dose and High-Dose ACTH for Assessment of Cortisol Response
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ACTH Testing
Both low and high doses of ACTH caused significant endocrine responses for plasma cortisol (F=190.21, df=4.46, 142.61, p 0.001) and salivary cortisol (F=121.70, df=3.00, 96.11, p0.001). ANCOVA revealed no significant group effects (F=0.04, df=1, 32, p=0.84) and no significant response differences over time between the groups (F=0.44, df=4.46, 142.6, p=0.82) for plasma cortisol (Figure 1). There were also no significant effects for group (F=0.38, df=1, 32, p=0.54) or interaction (F=0.65, df=3.00, 96.11, p=0.58) for salivary cortisol response to either low-dose or high-dose ACTH (Figure 1).
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FIGURE 1. Plasma and Salivary Cortisol Response to Low-Dose and High-Dose ACTH Administration in 18 Patients With Chronic Fatigue Syndrome and 18 Age- and Gender-Matched Healthy Comparison Subjects
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These results were confirmed through the comparison of both areas under the total response curve, with comparable area under the total response curve for plasma cortisol (t=0.33, df=33, p=0.76) and salivary cortisol (t=0.51, df=33, p=0.62) (Figure 2). Using reference values for the low- and high-dose ACTH test developed by Gonzálbez et al.,22 we calculated the number of cases below and above the cutoff score, which represented the fifth percentile (Table 2). The number of subjects below the cutoff score did not differ significantly between the groups.
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FIGURE 2. Areas Under the Plasma and Salivary Cortisol Response Curves for 18 Patients With Chronic Fatigue Syndrome and 18 Age- and Gender-Matched Healthy Comparison Subjects Given Low-Dose (1.25 µg) and High-Dose (225 µg) ACTH
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TABLE 2. Plasma Cortisol Response Relative to Standard Reference Values for Chronic Fatigue Patients and Healthy Comparison Subjects Administered Low-Dose and High-Dose ACTH
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Discussion
Employing both a low and a high dose of ACTH, we found no significant differences in cortisol response between chronic fatigue syndrome patients and healthy matched comparison subjects. In both cortisol parameters, reflecting the total and the free biological active cortisol response, chronic fatigue syndrome patients had a nearly identical response to that of the comparison subjects. These results were confirmed by the area under the total response curve, which was comparable in both parameters for both groups. Employing recently developed reference values for the low- and the high-dose ACTH test,22 we detected no statistical differences between the groups in the number of subjects below and above the cutoff scores.
In both groups, administration of a low dose and a subsequent high dose of ACTH produced a profound adrenocortical response. We did not use the exact amount of ACTH for either the standard low-dose or the standard high-dose ACTH test. However, given that the endocrine responses in both groups were comparable to the mean endocrine responses observed in previous studies that used 1 µg and 250 µg,13,22 we are confident that these methodological differences did not significantly influence the results.
Three studies have assessed adrenocortical function with exogenous ACTH administration in chronic fatigue syndrome patients. Demitrack et al.3 performed a placebo-controlled ACTH dose-response study with doses of 0.003, 0.01, 0.1, and 1 µg/kg ACTH given in a randomized fashion on separate days. Chronic fatigue syndrome patients showed exaggerated responses to the lowest doses and reduced responses to the maximal doses, incompatible with a diagnosis of primary adrenal insufficiency but indicative of secondary adrenal insufficiency and hyperresponsive adrenal ACTH receptors. Two recent studies have produced conflicting results. While Scott et al.5 reported a reduced maximum plasma cortisol increase from baseline in chronic fatigue syndrome patients, Hudson and Cleare7 could not find significant differences in the same parameter between chronic fatigue syndrome patients and a group of closely matched comparison subjects. Since significant gender differences in HPA axis reactivity have been observed,23 it is important to note that in contrast to the latter studies,5,7 gender ratio for chronic fatigue syndrome patients was not equally distributed in the study by Demitrack et al.3
The low-dose ACTH test has been demonstrated to be capable of detecting secondary adrenocortical insufficiency with a higher sensitivity than the standard ACTH test.24 Several neuroendocrine stimulation studies have demonstrated a central dysregulation of the HPA axis in chronic fatigue syndrome patients with abnormal ACTH but normal cortisol responses.25 In addition, in a previous study we observed an enhanced adrenocortical sensitivity in chronic fatigue syndrome patients, which compensated for the observed reduced absolute ACTH response levels and thus resulted in normal cortisol responses.4
Our finding of similar cortisol responses to both low and high doses of ACTH is discrepant to findings of enhanced adrenocortical sensitivity and reduced maximal secretory capacity.3 However, with regard to the low-dose ACTH test, it needs to be questioned whether the dose of 1 µg (or 1.25 µg used in this study) is comparable to the ACTH release under "physiological" circumstances. For this to be ascertained, the amount of ACTH used in the low-dose ACTH test needs to be compared with the amount of ACTH released under central stimulation of the HPA axis. With an assumed total blood volume of 7000 ml, the injection of 1.25 µg (1,250,000 pg) ACTH results in a concentration of approximately 1,250,000 pg/7000 ml=178.57 pg/ml ACTH. This amount is in the range of the ACTH response of chronic fatigue syndrome patients seen in the insulin tolerance test, which evokes a profound physiological stress response.4 However, under nonpharmacological stress conditions, ACTH responses seldom exceed 70 pg/ml in healthy subjects and 40 pg/ml ACTH in chronic fatigue syndrome patients.4 In this study, we observed clearly reduced ACTH response levels in chronic fatigue syndrome patients relative to healthy gender-matched comparison subjects, which did not lead to differences in the cortisol responses indicative of an enhanced adrenocortical sensitivity to ACTH. In this regard, it is noteworthy that the previously reported enhanced adrenocortical sensitivity in chronic fatigue syndrome patients has been observed with ACTH doses well below the dose used in the low-dose ACTH and in the range of nonpharmacological stress.3 Therefore, our results do not necessarily speak against an enhanced adrenocortical sensitivity in chronic fatigue syndrome patients under physiological circumstances, since it is possible that these differences are masked by supraphysiological ACTH concentrations achieved with the low and the standard ACTH tests.
Using both a hypothalamic and pituitary challenge in the same patient group, Cleare et al.26 reported reduced cortisol responses to hCRH and d-fenfluramine challenge when covarying for the observed ACTH responses. This finding of impaired adrenocortical reactivity differs from our findings of normal cortisol responses to the low- and high-dose ACTH test and the results of previous studies.4 Several methodological differences may account for the discrepancies in these studies, such as the use of centrally acting pharmacological challenge tests, the time of challenge testing, the testing procedure, and differences in patient characteristics.
Patients for this study were recruited through a self-help organization. It is possible that this constitutes a selection bias and that our study group therefore differs from those used in other studies. Only one patient fulfilled criteria for a psychiatric disorder, which is unusually low for an unselected sample. Although we did not select for patients without psychiatric comorbidity, this could be the result of a selection bias. Given that self-help groups advocate a somatic etiology of chronic fatigue syndrome, it is possible that differences in the attribution of symptoms experienced partly explains the low number of psychiatric disorders in our patient group, since an attribution to a biological cause seems to protect against psychological distress.27,28 In order to control for possible gender differences in neuroendocrine reactivity,23 we tried to obtain an equal gender ratio. However, the majority of studies report a female predominance in chronic fatigue syndrome.29 Although we did not observe a gender difference in the endocrine reactivity (data not shown), psychobiological gender differences could be involved in the etiology and the maintenance of the syndrome.30
We observed comparable cortisol responses after the administration of the high dose of 225 µg ACTH. Since repeated stimulation with a low dose of ACTH did not result in attenuated or enhanced cortisol responses to either low (90 ng/1.73 m2) or high (500 ng/1.73 m2) doses of ACTH,11 it is unlikely that normal cortisol responses were primed by the previous adrenocortical stimulation.
Mild hypocortisolism has been proposed as a possible neuroendocrine substrate of chronic fatigue syndrome symptoms and a cause of reported physiological abnormalities.31 Also, substitution with very low doses of hydrocortisone has been shown to be of benefit in chronic fatigue syndrome patients.32 However, with the exception of 24-hour urinary free cortisol, no consistent evidence for basal or reactive hypocortisolism has been reported. Future studies are needed to elucidate the role, if any, of cortisol in the pathophysiology of chronic fatigue syndrome. For example, recent studies have suggested enhanced sensitivity of peripheral blood mononuclear cells and of glucocorticoid receptors on the levels of the pituitary to glucocorticoids.33,34 With regard to the observed normal glucocorticoid levels, this would imply different physiological consequences than those proposed assuming a role of hypocortisolism in chronic fatigue syndrome.
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ABSTRACT
INTRODUCTION
