Low-Dose Dexamethasone Suppression Test in Chronic Fatigue Syndrome and Health
Gaab, Jens PhD; Hüster, Dominik MSc; Peisen, Renate MSc; Engert, Veronika BSc; Schad, Tanja BSc; Schürmeyer, Thomas H. PhD, and; Ehlert, Ulrike PhD
From the Center for Psychobiological and Psychosomatic Research, University of Trier, Trier, Germany.
Address reprint requests to: Jens Gaab, PhD, Institute of Psychology, Clinical Psychology II, University of Zürich, Zürichbergstr. 43, CH-8044 Zürich, Switzerland. Email: email@example.com
Received for publication January 16, 2001; revision received May 21, 2001.
Objective: Subtle dysregulations of the hypothalamus-pituitary-adrenal axis in chronic fatigue syndrome have been described. The aim of this study was to examine the negative feedback regulations of the hypothalamus-pituitary-adrenal axis in chronic fatigue syndrome.
Methods: In 21 patients with chronic fatigue syndrome and 21 healthy control subjects, awakening and circadian salivary free cortisol profiles were assessed over 2 consecutive days and compared with awakening and circadian salivary free cortisol profiles after administration of 0.5 mg of dexamethasone at 11:00 PM the previous day.
Results: Patients with chronic fatigue syndrome had normal salivary free cortisol profiles but showed enhanced and prolonged suppression of salivary free cortisol after the administration of 0.5 mg of dexamethasone in comparison to the control subjects.
Conclusions: Enhanced negative feedback of the hypothalamus-pituitary-adrenal axis could be a plausible explanation for the previously described alterations in hypothalamus-pituitary-adrenal axis functioning in chronic fatigue syndrome. Because similar changes have been described in stress-related disorders, a putative role of stress in the pathogenesis of the enhanced feedback is possible.
AUC = area under curve;, CFS = chronic fatigue syndrome;, CRH = corticotropin-releasing hormone;, HPA = hypothalamus-pituitary-adrenal (axis);, PTSD = posttraumatic stress disorder;, SEM = standard error of the mean;, VAS = visual analog scale.
Chronic fatigue syndrome (CFS) is a debilitating and disabling condition characterized by persistent or relapsing mental and physical fatigue and somatic symptoms, such as myalgia, arthralgia, neuropsychological complaints, and sleep disturbances, in the absence of an established clinical condition (1). Dysregulations of the hypothalamus-pituitary-adrenal (HPA) axis have been proposed as an underlying physiological substrate, because on one hand there is symptomatic overlap between states of adrenal insufficiency and CFS and on the other hand the HPA axis is influenced by many factors known to be of relevance to the pathogenesis or maintenance of CFS, such as negative life events and chronic stress, inactivity, and sleep disturbances (2).
Evaluations of the HPA axis in CFS have led to two major assumptions. First, CFS could be the result of a moderate hypocortisolism (3, 4). Although this idea is not new (5), empirical support is inconsistent, with normal (6, 7) and reduced (8–10) basal and reactive cortisol levels. Second, the neuroendocrine alterations could be of tertiary origin, with hypofunctional corticotropin-releasing hormone (CRH) secretion being compensated on a peripheral level by sensitized adrenals (11). Being the principal modulator of the stress response, CRH not only modulates endocrine and autonomic responses but also influences nociception and behavior (12). Several syndromes marked by lethargy, pain, and fatigue, eg, postsurgery Cushing’s disease, seasonal affective disorder, and postpartum blues, have been associated with a deficiency of hypothalamic CRH secretion (13).
Enhanced negative feedback control of the HPA axis has been proposed as a putative cause of a hypofunctional HPA axis in CFS (14). Two studies have assessed negative feedback functioning in fatigued patients, but no evidence of feedback resistance was found (15, 16). Also, studies performed in patients with fibromyalgia, a syndrome closely related to CFS, have shown no escape from suppression using the standard dexamethasone suppression test (17, 18), whereas others have found escape from suppression in some patients (19, 20). However, these studies used 1 mg of dexamethasone, a dose intended to screen for nonsuppressors that is indicative of depression, which has an HPA axis profile opposite that of CFS (8, 21).
The objective of the study reported here was to explore alterations in negative feedback control of the HPA axis in patients with CFS. Assuming enhanced feedback sensitivity, we used a low dose of dexamethasone, which has been shown to be a suitable tool for such a purpose (22). Also, the low dose of dexamethasone shows an enhanced sensitivity to distinguish suppressors and nonsuppressors in depressed and healthy subjects (23). However, the information delivered by the low-dose dexamethasone test seemed to be restricted to the feedback sensitivity of the HPA axis (24).
The study was approved by the Ethical Committee of the Medical Council of Rheinland-Pfalz, Germany. Patients were contacted through a German self-help organization. Interested patients received by post a screening questionnaire, which assessed all symptoms required by the US and UK definitions of CFS (1, 25). Patients fulfilling the symptom requirements on this screening questionnaire were interviewed by telephone and asked about diagnosed medical illnesses and psychiatric disorders. Interested patients were excluded from participating in the study only if they had received a medical or psychiatric diagnosis defined as an exclusionary criterion by the US definition (1). Selection criteria for participation in the study were fulfillment of CFS symptom criteria on the screening questionnaire; acute onset of CFS; age between 30 and 50 years; no current use of antidepressant, anxiolytic, antibiotic, antihypertensive, or steroid medication; and no medical cause of the chronic fatigue on routine laboratory testing. All 23 selected patients (10 men and 13 women) were medically examined by the same physician (T.H.S.) according to the recommendations of Fukuda et al. (1) and interviewed by a trained psychologist (J.G.), who used a computer-aided standardized and structured diagnostic interview based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (26), and a semistructured CFS interview that assessed the severity and course of all symptoms required by the US and UK definitions (1, 25). Two female patients were excluded from the study because of thyroid hormone levels indicative of thyroid hypofunction and primary adrenal insufficiency. All remaining 21 patients fulfilled US and UK consensus criteria for the diagnosis of CFS (1, 25). Patients were matched for age and sex with 21 healthy volunteer control subjects, who were randomly recruited by telephone. Control subjects were not taking any medication, and they underwent comprehensive medical examination for past and current health problems. None of the control subjects showed signs of current health problems. Also, no control subjects had symptoms of fatigue or pain. For better characterization of the patient sample, all subjects completed a battery of questionnaires according to recent recommendations (27), including German versions of the Multidimensional Fatigue Inventory (28), the Sickness Impact Profile (29), the Hospital Anxiety and Depression Scale (30), the Beck Depression Inventory (31), and the Symptom Checklist 90, Revised (32). All subjects completed a visual analog scale (VAS) to assess sleep duration, sleep quality, and fatigue and pain symptoms before, during, and after sampling days. Subjects were instructed to start recording their fatigue and pain symptoms using the VAS on a Saturday.
After complete written and oral descriptions of the study were given to the subjects, written informed consent was obtained.
Cortisol Assessment and Biochemical Analysis
For assessment of salivary free cortisol levels, subjects received material and written instructions for saliva collection at home using Salivettes (Sarstedt, Rommelsdorf, Germany). Subjects were asked to obtain saliva samples on 3 consecutive days, starting on a Monday, which constituted day 3 on the VAS. For awakening salivary free cortisol profiles, samples were obtained immediately after awakening and 15, 30, 45, and 60 minutes thereafter. Subjects were free to wake up according their normal schedule, because the awakening cortisol profile does not seem to be altered by differences in time of awakening (33). Subjects were asked to remain lying in bed for the first 30 minutes and not to have breakfast or brush their teeth during the first hour after awakening to avoid false high cortisol values due to plasma exudates from minor bleeding in the oral cavity. Regardless of awakening time, subjects took saliva samples at 8:00 AM, 11:00 AM, 3:00 PM, and 8:00 PM for the assessment of the circadian salivary free cortisol profile. Subjects were asked not to eat or drink 30 minutes before they took a sample. At 11:00 PM on the second day, subjects took an oral dose of 0.5 mg of dexamethasone (Merck, Darmstadt, Germany). All saliva samples were stored in the refrigerator until completion of sampling and then sent to our laboratory. On arrival all samples were stored at −20°C. After thawing, saliva samples were centrifuged at 3000 rpm for 5 minutes, which resulted in a clear supernatant of low viscosity. Fifty microliters of saliva was used for duplicate analyses. Salivary free cortisol was analyzed by using an in-house immunoassay with time-resolved fluorescence detection (34). Intraassay and interassay coefficients of variation were below 10%. To reduce error variance caused by imprecision of the intraassay, all samples of one subject were analyzed in the same run.
Repeated-measures analyses of variance were computed to analyze endocrine data, with clinical diagnosis as the grouping variable and time as the repeated-measure factor. All reported results were corrected by means of the Greenhouse-Geisser procedure when assumptions of sphericity were violated. Correlations were computed by Pearson product-moment correlation. Psychological parameters were analyzed by Student’s t test, analysis of variance, or multivariate analysis of variance. Kolmogorov-Smirnov tests showed that salivary free cortisol data were not normally distributed. Calculating the log of cortisol values produced nearly normally distributed values. Log-transformed cortisol values were used for all statistical analyses, but means and standard deviations of untransformed values are presented. Data were also tested for homogeneity of variance using Levene’s test before statistical procedures were applied. Area under the total response curve (AUCtotal), expressed as area under all samples, was calculated for all log cortisol values using the trapezoidal method relative to the baseline. For all analyses, the significance level was α = 5%. Unless indicated, all results shown are mean ± SD.
All 21 patients with CFS (11 women and 10 men) and all 21 healthy control subjects (11 women and 10 men) confirmed taking the dexamethasone. Patients with CFS did not differ from control subjects in age (mean = 36.0 years, SD = 4.5 and mean = 35.2 years, SD = 4.5, respectively), but control subjects had a slightly higher body mass index than the patients with CFS (mean = 24.1 kg/m2, SD = 4.5 and mean = 22.4 kg/m2, SD = 2.4, respectively). Sixteen patients with CFS reported an infectious onset of their symptoms. All patients reported onset of symptoms within 3 months. Mean duration of symptoms in patients with CFS was 67.4 months (range, 17–168 months). Four female subjects in each group used monophasic oral contraceptives. One patient fulfilled criteria for a current episode of major depression. Because exclusion of these subjects did not alter the results of the analysis, they were included in the reported analysis. Seven patients reported a past episode of major depression and four reported a past episode of anxiety disorder. None of the control subjects reported any current or lifetime psychiatric disorder.
As expected, patients with CFS had significantly higher scores on all questionnaires designed to assess the different dimensions of CFS (Table 1).
Patients with CFS had higher scores for symptoms of fatigue (F (1,39) = 80.65, p < .000) and pain (F (1,39) = 27.72, p < .000) on the VAS during the sample period. Fatigue and pain severity did not change during the week in all subjects (F (6,234) = 1.06, NS and F (6,234) = 0.84, NS, respectively) and between the groups (F (4.75,185.25) = 0.68, NS and F (3.75,146.39) = 0.60, NS, respectively).
Controlling for group, associations of the AUCtotal of the salivary free cortisol profiles after awakening and during the day with self-reported sleep duration and sleep quality were assessed by partial correlation. AUCtotal of log-transformed salivary free cortisol levels after awakening were not significantly correlated with sleep duration (day 1:r = .08, day 2:r = .05, and day 3:r = −.13, all df = 39 and NS) or sleep quality (day 1:r = −.07, day 2:r = .02, and day 3:r = .11, all df = 39 and NS). Also, there was no significant association of the log AUCtotal of the circadian salivary free cortisol profile with sleep duration (day 1:r = .18, day 2:r = −.25, and day 3:r = −.20, all df = 39 and NS) or sleep quality (day 1:r = .00, day 2:r = .14, and day 3:r = −.20, all df = 39 and NS).
On days 1 and 2, waking up was followed by a significant increase of salivary free cortisol level in both groups (F (4,160) = 4.60, p = .002 and F (4,160) = 3.51, p = .009, respectively). After administration of 0.5 mg of dexamethasone, both groups had no significant endocrine response after waking up (F (4,160) = 0.77, NS). Awakening salivary free cortisol responses over time did not differ significantly between the groups on days 1 and 2 (day 1:F (2.71,108.48) = 0.94 and day 2:F (2.43,97.24) = 0.90, both NS). Because there was no significant response in salivary free cortisol on day 3, group effects were calculated. Patients with CFS had significantly lower overall salivary free cortisol levels on day 3 (F (1,40) = 22.62, p < .000) but not on day 1 and day 2 (F (1,40) = 0.37, NS and F (1,40) = 0.64, NS, respectively) (Fig. 1). These results were confirmed by group comparisons of the log AUCtotal (Table 2).
Patients with CFS did not differ in their AUCtotal on days 1 and 2, but they had a significantly reduced integrated response after taking dexamethasone. For all subjects, AUCtotal was significantly lower after the administration of dexamethasone (F (2,80) = 126.97, p < .000), with a stronger decrease in patients with CFS (F (1.39,55.49) = 12.16, p = .003).
For the circadian profile, significant changes in salivary free cortisol levels over time were found for day 1 and day 2 (F (3,120) = 78.44, p < .000 and F (3,120) = 57.09, p < .000, respectively) but again not on day 3 (F (3,120) = 2.53, p = .06). Salivary free cortisol levels over time on day 1 and day 2 were not significantly different between the two groups (F (2.54,101.56) = 0.81, p = .47 and F (2.49,99.88) = 1.66, p = .19, respectively). As in the awakening profile, CFS patients had significantly lower overall salivary free cortisol levels after the administration of dexamethasone (F (1,40) = 11.51, p = .001), with no group differences on days 1 and 2 (F (1,40) = 0.003, p = .95 and F (1,40) = 0.009, p = .92, respectively) (Fig. 2). These results were confirmed by comparing the log AUCtotal between the groups (Table 2). Again, all subjects had significantly reduced integrated cortisol levels after the administration of dexamethasone (F (2,80) = 119.27, p < .000), but CFS patients had a significantly greater reduction in their AUCtotal in comparison to the control subjects (F (1.36,54.36) = 9.93, p = .001).
This is the first study, to the best of our knowledge, to report enhanced suppression of the HPA axis in response to a low dose of dexamethasone in CFS, under both reactive and basal conditions. Like healthy control subjects, patients with CFS show normal increases in salivary free cortisol after awakening and exhibit an almost similar circadian salivary cortisol profile. After the administration of 0.5 mg of dexamethasone at 11:00 PM, both salivary free cortisol profiles were clearly suppressed and did not show any changes over time in both healthy control subjects and patients with CFS, but in the latter group overall endocrine levels were distinctively more suppressed throughout the whole testing day.
Dexamethasone bioavailability should be taken into account when interpreting cortisol suppression of dexamethasone (35). It has been shown that in depressed patients post-dexamethasone cortisol suppression is negatively correlated with dexamethasone bioavailability and that nonsuppressors have lower plasma dexamethasone levels, probably due to accelerated dexamethasone clearing (36). However, studies reporting enhanced suppression of cortisol after administration of low-dose dexamethasone have not found different dexamethasone levels in plasma or saliva, or differences in cortisol levels were not attributable to dexamethasone levels (22, 37–39). We have not assessed dexamethasone levels, but because none of our subjects reported a history of alcoholism, the results of liver function tests were normal, and groups did not differ in age or body mass index, it seems unlikely that differences in dexamethasone bioavailability account for our findings. However, future studies should address this issue.
Patients for this study were recruited through a self-help organization. It is possible that this constitutes a selection bias and therefore that our sample 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 origin of CFS, it is possible that differences in the attribution of symptoms experienced partly explains the low number of psychiatric disorders in our sample, because attribution to a biological cause seems to protect against psychological distress (40, 41).
We did not control for menstrual cycle phase in the female subjects. It has been shown that women in the luteal phase of the menstrual cycle show a significantly higher salivary free cortisol response to a psychosocial stressor in comparison to women in the follicular phase of the menstrual cycle (42). However, in the same study this effect could not be seen in the awakening salivary free cortisol profiles, with inconclusive results for the circadian salivary free cortisol profiles. To our knowledge, no study has assessed the possible impact of menstrual cycle phase on the feedback sensitivity of the HPA axis. We could therefore not rule out that our results are confounded by influences of the menstrual cycle phase on the dexamethasone-induced suppression of the HPA axis.
These results confirm those from previous studies showing that circadian salivary free cortisol profiles are normal in CFS (6). Also, we previously found normal salivary free and total plasma cortisol responses in CFS with three different centrally acting HPA axis challenge tests, so the inconspicuous salivary free cortisol profiles after awakening are not unexpected (J. Gaab et al, submitted). Awakening salivary free cortisol responses showed the same magnitude as seen in previous studies using the same protocol, with increases in endocrine parameters comparable to those obtained with a standard CRH test (43).
An exaggerated suppression of cortisol after the low-dose dexamethasone test has been observed in other conditions, including burnout syndrome (44), posttraumatic stress disorder (PTSD) (22, 37), adolescents exposed to earthquake-related trauma (38), women with a history of childhood sexual abuse (39), and chronic pelvic pain (45). However, contrary to the postulated mechanisms in CFS, PTSD has been indirectly (46) and directly (47) characterized by hypothalamic CRH hypersecretion, restrained by an enhanced negative feedback on the level of the pituitary (22). Also, the cortisol supersuppression seen in chronic pelvic pain could be the result of the reported reduced adrenocortical responsiveness (45). It seems unlikely that the latter is a likely explanation for the supersuppression found in our sample, because sensitization of the adrenals to low doses of exogenous doses of adrenocorticotropic hormone have been described (11).
It is tempting to assume an acquired nature of the observed enhanced negative feedback, as postulated for burnout syndrome, PTSD, and chronic pelvic pain, because patients with CFS report high levels of critical and stressful life events precipitating CFS (48, 49). Also, there have been reports of traumatic early life events in CFS and in the related syndrome of fibromyalgia (50), although this might not be specific to these syndromes (51). However, concurrent chronic stress is associated with elevated cortisol secretion after awakening (52) and increased cortisol responses after awakening following the low-dose dexamethasone test (44).
Recently an animal model for stress-induced negative feedback changes in PTSD has been reported (53, 54). But because the site of feedback action for dexamethasone seems to be restricted to the pituitary (55, 56), and taking into account that pituitary glucocorticoid receptors display a unique insensitivity to the effects of either high or low doses of circulating glucocorticoids (57), it remains speculative whether the observed feedback sensitization in our sample is stress-related. Effects of glucocorticoids in the central nervous system differ with regard to the site of action and the circulating levels of glucocorticoids and thus are far from uniform (14). It should also be noted that there is little evidence for a generalized pattern of glucocorticoid sensitivity in different body tissue in healthy subjects (24). Interestingly, recent studies in patients with CFS suggest that there is an increased sensitivity for glucocorticoids in purified peripheral blood mononuclear cells, but these changes were seemingly not the consequence of an altered affinity or number of glucocorticoid receptors (58).
There is a considerable comorbidity of CFS and major depression. Although the low-dose dexamethasone suppresion test will not solve the ambiguous relationship between these two syndromes (58), it may be a potentially useful tool to differentiate between them. The examination of the feedback regulation in CFS offers a fruitful approach to the understanding of observed changes of HPA axis activity and reactivity in CFS. Still, further studies are needed to examine the feedback regulation in CFS; possibly using different pharmacological agents directed at different feedback sites.
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chronic fatigue syndrome,; HPA axis,; salivary cortisol,; dexamethasone.
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