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High Nocturnal Melatonin in Adolescents with Chronic Fatigue Syndrome¹

Departments of Pediatric Immunology (L.K., A.K., W.K., C.J.H.) and Psychology (G.S.), Wilhelmina Children Hospital of the University Medical Center Utrecht, 3584 EA Utrecht, The Netherlands

Address correspondence and requests for reprints to: Prof. Dr. Cobi J. Heijnen, Department of Immunology, Wilhelmina Children Hospital of the University Medical Center Utrecht, Lundlaan 6, Room KC 03.068.0, 3584 EA Utrecht, The Netherlands. E-mail: c.heijnen{at}wkz.azu.nl

	Abstract

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Decreased quality of sleep is frequently reported by chronic fatigue syndrome (CFS) patients. The pineal hormone melatonin is involved in regulation of sleep. We analyzed the nocturnal rise in melatonin in13 adolescent CFS patients and 15 healthy age-matched controls. Saliva samples were collected at hourly intervals between 1700 and 0200 h. Nocturnal saliva melatonin levels were significantly higher in CFS patients, compared with controls, at midnight, 0100 h, and 0200 h (P < 0.001). No differences were observed in timing of melatonin increase in saliva between patients and controls. Time of sleep onset and duration of sleep did not differ significantly between patients and controls. However, all CFS patients and only one of the controls in our study group reported unrefreshing sleep. Our data demonstrate that sleep problems in adolescents with CFS are associated with increased melatonin levels during the first part of the night. Based on these data, we suggest that there is no indication for melatonin supplementation in adolescents with CFS.

	Introduction

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CHRONIC FATIGUE syndrome (CFS) is a disease characterized by debilitating fatigue of at least 6 months that has reduced the activity level of the individual by more than 50% and that is not attributable to known clinical conditions. In addition to the persistent or relapsing fatigue, at least four minor criteria should be fulfilled, including unrefreshing sleep, postexertion malaise, joint pain, headache, muscle pain, adenopathy, sore throat, and/or impaired cognition (Centers for Disease Control, Atlanta, GA; Ref. 1).

One of the most common complaints of CFS patients is impairment of sleep (2). The pineal hormone melatonin is an important regulator of circadian rhythms and thereby contributes to the regulation of sleep onset. In humans, melatonin levels start to increase after the onset of darkness and decrease again during the second half of the night (3). Melatonin is important for the synchronization of circadian rhythms based on the environmental light-dark cycle. Bright light inhibits melatonin secretion (3).

It has been suggested that the sleep disorders reported by CFS patients may result from melatonin-insufficiency (4). Based on these suggestions, melatonin is frequently used by CFS patients for reduction of sleep disturbances. The present study was designed to test the hypothesis that sleep disturbances in CFS patients are associated with disturbed melatonin secretion patterns. Therefore, we examined saliva melatonin levels in samples obtained from adolescent CFS patients and age- and sex-matched controls. In addition, we analyzed subjective sleep quality in CFS patients and controls by use of a sleep questionnaire.

	Subjects and Methods

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Adolescents diagnosed with CFS, according to the criteria defined by the Centers for Disease Control and Prevention, with a substantial decrease in activity level and no primary psychological morbidity, were asked to enter our study. The CFS patients included in our study did not take any medication at the time of the study or within 6 weeks before the study. Patients with a psychiatric history were excluded. Control subjects were recruited by asking patients to suggest healthy friends of the same sex and similar age. The experimental protocol was approved by the medical ethical committee of the University Medical Center Utrecht. Written informed consent was obtained from parents and from the children.

Sleep

The sleep questionnaire asked for time of sleep onset and duration of sleep on a weekday. Sleep quality and sleep problems were determined by asking whether "restless sleep", "unrefreshing sleep", and "nocturnal wake-ups" occurred "never", "sometimes", "often", or "always". Scores "often" or "always" were regarded as a positive answer; "never " or "sometimes", as a negative answer.

Saliva sample collection

Saliva samples were collected at home on a regular weekday by chewing on acidified cotton (Salivette, Sarstedt, Denmark) in dim light (<100 lux), as described (5). Patients went to bed at their regular time and stayed in bed for the remainder of the sampling time. Subjects did not smoke, did not eat or drink from 15 min before till the end of each sampling, and did not brush their teeth on the day of the test. In addition, subjects did not consume substances containing melatonin or melatonin precursors, e.g. caffeine, alcohol, banana, kiwi, tomato, artificial colorant, and nuts on the day of the test. Samples were collected at hourly intervals between 1700 and 0200 h. Samples were stored at -20 C, and frozen samples were transported to the lab. Saliva was collected by centrifugation, and melatonin levels were determined by RIA (Buhlmann Laboratories, Allschwil, Switzerland).

Data analysis

Data from the sleep questionnaire were analyzed by two-sided Student’s t test or Fischer exact test. Saliva melatonin data were analyzed by two-way ANOVA, followed by Bonferroni post-tests. P < 0.05 was considered statistically significant. Data are depicted as mean and SEM.

	Results

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Subject characteristics

We investigated 13 adolescents [3 males, 10 females; age, 10–17 yr (median, 15 yr)] with CFS and 15 healthy subjects [3 males, 12 females; age, 9–17 yr (median, 14 yr)]. Mean duration of disease was 6–72 months (median, 13 months).

All CFS patients (n = 13) reported unrefreshing sleep, in contrast to 1 out of 15 control individuals (P < 0.001). CFS patients also reported nocturnal wake-ups and restless sleep more often than controls (Table 1). Time of sleep onset and total duration of sleep were similar in CFS and healthy subjects (Table 1).

We examined melatonin levels in saliva samples taken at hourly intervals between 1700 and 0200 h. Both in CFS patients and in healthy subjects, saliva melatonin levels started to rise at 2200 h and increased further until the last time point tested, which was 0200 h. Surprisingly, however, the level of melatonin in saliva from CFS patients was significantly higher than in saliva samples of healthy subjects (Fig. 1). Two-way repeated-measures ANOVA: time: F(8,108) = 33.19, P < 0.001; group: F(1,108) = 37.84, P < 0.001. Bonferroni post tests revealed that saliva melatonin was significantly higher in CFS patients at midnight (P < 0.01), 0100 h (P < 0.001), and 0200 h (P < 0.001).

View larger version (16K): [in this window] [in a new window]   Figure 1. Saliva melatonin levels in CFS patients and healthy controls were determined as described (5 ). , Controls; •, CFS patients. Data represent mean and SEM.

	Discussion

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Sleep disturbances were frequently reported by the CFS patients in our study group and led us to investigate saliva melatonin. The most prominent finding of our study is that adolescents with CFS display increased nocturnal saliva melatonin.

Abnormalities in melatonin have also been reported for patients with delayed-sleep-phase syndrome. Delayed-sleep-phase syndrome patients also complain of unrefreshing sleep. In these patients, the onset of the rise of melatonin is delayed, but normal levels are obtained. Treatment with melatonin results in a shift of sleep onset to an earlier time point and also normalization of the sleep pattern in delayed-sleep-phase syndrome patients (6). It is interesting that CFS patients, in our study, do not report delayed onset or decreased duration of sleep, but rather, decreased quality of sleep. In line with the similar time of sleep onset, the time of onset of the melatonin increase is similar in CFS patients and control individuals in our study.

Based on poor quality of sleep in CFS, we would have expected decreased, rather than increased, melatonin levels in CFS patients. Decreased nocturnal melatonin levels have been reported in adults with fibromyalgia syndrome, who also report sleep problems (7). More recently, however, Korszun et al. (4) reported significantly increased plasma melatonin levels in adult women with fibromyalgia. In the same study, no abnormalities were observed in plasma melatonin levels in adult women with CFS, when compared with controls. The reason for the discrepancy with our observations is unclear. It is possible that the differences in age and/or duration of the disease, which will be shorter in adolescents than in adults, are involved.

Increased levels of melatonin, during the night, have also been reported in patients with hypothalamic amenorrhea, a syndrome that is associated with dysregulation of the hypothalamus-pituitary-adrenal axis (8). However, we do not have evidence that the activity of the hypothalamus-pituitary-adrenal axis is disturbed in adolescents with CFS (9).

Administration of antidepressant drugs that inhibit noradrenaline uptake results in increased nocturnal melatonin levels without changes in timing of the nocturnal rise in melatonin (10). Thus, it is possible that putative increases in central noradrenaline are responsible for high nocturnal melatonin levels in CFS patients.

In conclusion, we demonstrate here that nocturnal melatonin levels are increased in adolescents with CFS. In addition, all patients in our study group reported unrefreshing sleep. Melatonin administration has been suggested as a possible therapy for CFS patients with sleep disturbances. However, our present findings suggest that high melatonin levels are already present in these patients. Moreover, we do not have evidence for a delay in the increase in melatonin and sleep onset. Therefore, we conclude that there is no rationale for melatonin administration in CFS.

	Acknowledgments

 
The excellent assistance of Marijke Tersteeg is gratefully acknowledged.

	Footnotes

 
¹ Supported by the ME fonds, Stichting De Drie Lichten, Scholten-Cordes Fonds, Lameris Foundation, and Buwalda Stichting, The Netherlands.

Received May 8, 1999.

Revised July 7, 2000.

Accepted July 11, 2000.

	References

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