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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 11 5315-5320
Copyright © 2003 by The Endocrine Society

Melatonin Acutely Improves the Neuroendocrine Architecture of Sleep in Blind Individuals

Stefan Fischer, Rüdiger Smolnik, Markus Herms, Jan Born and Horst L. Fehm

Departments of Neuroendocrinology (S.F., R.S., M.H., J.B., H.L.F.) and Internal Medicine (R.S., J.B., H.L.F.), University of Lübeck, D-23538 Lübeck, Germany

Address all correspondence and requests for reprints to: Jan Born, University of Lübeck, Department of Neuroendocrinology, Ratzeburger Allee 160, Hs. 23a, D-23538 Lübeck, Germany. E-mail: born{at}kfg.u-luebeck.de.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
In blind individuals, the absence of light cues results in disturbances of sleep and sleep-related neuroendocrine patterns. The Zeitgeber influence of light on the timing of sleep is assumed to be mediated by melatonin, a hormone of the pineal gland, whose secretion is inhibited by light and enhanced during darkness. Here, we investigated whether a single administration of melatonin improves sleep and associated neuroendocrine patterns in blind individuals. In a double-blind crossover study, 12 totally blind subjects received 5 mg melatonin and placebo orally 1 h before bedtime starting at 2300 h. The dose used enhanced blood melatonin concentrations to clearly supraphysiological levels. Melatonin increased total sleep time and sleep efficiency (P < 0.05, respectively) and reduced time awake (P < 0.05). The increment in total sleep time was primarily due to an increase in stage 2 sleep (P < 0.01) and a slight increase in rapid eye movement sleep (P < 0.06). Most important, melatonin normalized in parallel the temporal pattern of ACTH and cortisol plasma concentration. While after placebo, ACTH and cortisol levels did not differ between early and late sleep, melatonin induced the typical suppression of pituitary-adrenal activity during early sleep and a distinct rise during late sleep (P < 0.01, respectively). Cortisol nadir values were also decreased after melatonin (P < 0.05). We conclude from these data that in totally blind individuals the single administration of a clearly pharmacological dose of melatonin can improve sleep function by synchronizing in time the inhibition of pituitary-adrenal activity with central nervous sleep processes.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE NEUROHORMONE MELATONIN is released from the pineal gland in close association with the light-dark cycle and is involved in the regulation of sleep and circadian rhythms (1). Synthesis and secretion of melatonin is activated by darkness and suppressed by light, mediated through retinal nerve fibers that first project to the suprachiasmatic nucleus (SCN) via the retinohypothalamic tract, then to the superior cervical ganglion, and finally to the pineal gland (2). In healthy humans, melatonin secretion increases soon after the onset of darkness, peaks in the middle of the night, and then gradually declines during the second half of the night (2). The nighttime increase in endogenous melatonin secretion has been found to increase the propensity for sleep (3).

Administration of melatonin shortly before bedtime has been shown to increase total sleep time and sleep efficiency and to decrease sleep onset latency during subsequent nocturnal or daytime sleep periods in healthy young adults and in elderly subjects with insomnia (4, 5, 6), although also divergent results were reported in some cases (7, 8). Exogenously administered melatonin as well as bright light therapy have also been demonstrated to improve sleep in conditions characterized by a desynchronization of the endogenous melatonin rhythm and the sleep-wake cycle, which typically results in poor sleep. Examples of such conditions include advanced or delayed sleep phase syndromes (9, 10, 11), sleeping problems after jet-lag (12, 13), and night-shift work (14), and in blind individuals (15).

In totally blind individuals, who do not perceive any light cues, disturbances of sleep and circadian rhythms are very common. With respect to their melatonin rhythm, as a marker of the intrinsic period of the circadian oscillator, these individuals often display free-running rhythms (16, 17). Circadian rhythms of pituitary-adrenal activity have also been reported to free-run in totally blind individuals (17). In contrast, in sighted subjects, secretory patterns of ACTH and cortisol exhibit a pronounced circadian rhythm that is not only entrained to the endogenous rhythm of melatonin but also to nocturnal sleep (18). The entrainment of ACTH/cortisol secretion to sleep is enhanced due to an influence of sleep on pituitary-adrenal secretory activity, such that early sleep with its predominant periods of slow wave sleep (SWS) exerts a distinct inhibitory effect on pituitary-adrenal activity, thereby suppressing concentrations of ACTH and cortisol to a minimum (nadir) (18, 19, 20). In contrast, during late sleep, which is dominated by rapid eye movement (REM) sleep, stimulatory influences prevail so that plasma ACTH and cortisol concentrations strongly rise (19, 20, 21). Several studies in humans have suggested that in particular the effective suppression of cortisol during early SWS-rich sleep is critical for the adaptive role sleep plays for the homeostatic regulation of metabolic processes (18, 22, 23), and for acute and long-term memory function (24, 25, 26, 27). Melatonin has been shown to accelerate a reentrainment of cortisol rhythms to the sleep-wake cycle after short-term phase shifts in healthy humans (28). Here, we examined whether a similar reentraining effect is induced by a single administration of melatonin in blind individuals. Specifically, it was of interest whether melatonin apart from improving sleep, strengthens the inhibition of pituitary-adrenal activity, normally seen during early sleep, which may serve to synchronize both rhythms (18).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

We studied 12 men between the ages of 18 and 40 yr who were paid for their participation in the experiments. All of them had sustained damage of the retina and/or the tractus retinohypothalamicus, ensuring that no photic information was conveyed to the SCN and the pineal gland (29, 30). Accordingly, all of our subjects were totally blind and all reported symptoms of recurrent insomnia and daytime sleepiness in a standardized interview. Subjects were otherwise in a good state of health evidenced by physical examination and did not take any medication. After having received information about the study in Braille and in verbal form, all of the participants gave written informed consent. The experiments were approved by the ethics committee at the University of Lübeck.

Study design and procedure

In a double-blind cross-over design subjects orally received 5 mg melatonin (General Nutrition Corp., Pittsburgh, PA) and placebo 1 h before bedtime. The dose of melatonin was chosen on the basis of previous studies using the same dose, but with daily administrations over an extended period of several days, which in these experiments induced clear improvements of sleep (31) and were also found to modulate pituitary-adrenal activity (32, 33). Here, we focused on the effects of a single administration of 5 mg melatonin in blind individuals. Although this dose induces supraphysiological concentrations of plasma melatonin, the tissue concentrations reached in the relevant brain regions are difficult to predict [although central nervous effects of melatonin have also been reported with substantially lower doses (34)]. All subjects were adapted to the experimental sleep conditions by spending one night in the sleep laboratory under experimental conditions. Both experimental nights were separated by an interval of at least 1 wk for each subject. On the days of the experimental nights, subjects were not allowed to drink any beverage containing caffeine or alcohol. They were instructed to get up before 0700 h and not to take any naps during the day. Subjects arrived at the sleep laboratory around 2000 h, at which time they were prepared for polysomnographic recordings and blood sampling. At 2200 h, 5 mg melatonin or placebo was administered orally. At 2230 h, the first blood sample was drawn. Bedtime started at 2300 h. Sleep was recorded polysomnographically and blood samples for determination of plasma melatonin, ACTH, cortisol, and GH were collected every 30 min until subjects were awakened at 0630 h. Blood was sampled via an iv forearm catheter connected to a long thin tube that allowed blood collection from an adjacent room without disturbing the subject’s sleep. To prevent clotting, approximately 250 ml saline solution (0.9%) were infused throughout the study period. Blood samples were immediately centrifuged, and plasma was stored at -20 C. Upon awakening, sleep quality for the previous night and current mood were assessed using an adjective check list.

Dependent variables and statistical analyses

Sleep stages were scored visually by two independent experimenters from electroencephalographic, electrooculographic, and electromyographic recordings according to standardized criteria (35). For each experimental night, total sleep time, sleep efficiency (total sleep time divided by total time in bed), and the number of awakenings were determined. Time spent awake and in sleep stages 1–4 and in REM sleep was also determined. SWS was calculated by adding time spent in sleep stages 3 and 4. Sleep onset latency was defined by the onset of the first epoch of stage 1 sleep followed by stage 2 sleep, with reference to the time when lights were turned off (2300 h). Latency of stage 2, SWS, and REM sleep was calculated with reference to sleep onset. Time spent in the different sleep stages and awake as well as plasma concentrations of melatonin, ACTH, cortisol, and GH were determined for the entire sleep period, and also for the first and second half of the subject’s sleep period. In addition, maximum concentrations of melatonin, cortisol, and GH as well as minimum levels in cortisol (cortisol nadir) were determined and their latencies were calculated with respect to sleep onset. Plasma levels of melatonin and GH were measured by RIA [melatonin (Bühlmann AG, Allschwil, Switzerland), sensitivity 1.29 pmol/liter; GH (DPC Biermann, Bad Nauheim, Germany), sensitivity 0.9 µg/liter]. Plasma concentrations of ACTH were determined by immunoluminometric assay (Brahms Diagnostica GmbH, Henningsdorf, Germany; sensitivity 0.22 pmol/liter) and that of cortisol by enzyme immunoassay (DSL, Sinsheim, Germany, sensitivity 2.76 nmol/liter, intraassay and interassay coefficients of variations were generally <7.5% and <12%, respectively). In the adjective list, subjects had to rate prior sleep using the items "continuous," "good," "relaxed," and "sufficient," and current mood using the items "balanced," "energetic," "vivid," "fresh," "well-rested," and "relaxed" (translated from German). The answer to each item required a rating on a five-point scale where 1 = agree and 5 = disagree.

Polysomnographic and hormonal parameters characterizing the entire night were statistically compared between the melatonin and placebo condition using two-sided paired t tests. Repeated measures ANOVA was used to analyze differences between the first and second half of the sleep periods between both treatment conditions. Results of the adjective list were analyzed by Wilcoxon’s tests. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Polysomnographic data are shown in Table 1Go. Sleep in the blind subjects on the placebo condition was characterized by a large proportion of wake time, a moderate duration of total sleep time and poor sleep efficiency. Compared with the effects of placebo, melatonin increased total sleep time and sleep efficiency, and reduced waking after sleep onset (P < 0.05, respectively). The increment in total sleep time was primarily due to an increase in stage 2 sleep (P < 0.01), but also REM sleep tended to increase after melatonin (P < 0.06). Independent of the treatment condition, SWS dominated during early sleep and REM sleep prevailed during the second half of sleep [F(1,11) = 13.52; P < 0.01 and F(1,11) = 5.19; P < 0.05, for respective ANOVA main effects first/second half of sleep]. In separate comparisons of the sleep halves, melatonin was found to increase REM sleep particularly during late sleep (P < 0.05). None of the other sleep parameters, including sleep onset latency and latencies of the different sleep stages, indicated any significant influence of melatonin, which in part appeared to be due to the considerable variance of these parameters under the placebo condition.


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  		TABLE 1. Mean (±SEM) total sleep time, sleep efficiency (total sleep time divided by total time in bed), latencies (in minutes) of sleep onset (with reference to 2300 h), stage 2 sleep, SWS and REM sleep (with reference to sleep onset), number of awakenings and time (in minutes) spent awake, in stage 1 sleep, stage 2 sleep, SWS and REM sleep

 
As expected, administration of melatonin distinctly increased plasma melatonin concentrations, averaging 246.61 ± 132.04 pmol/liter on the placebo nights and 5940.60 ± 1300.74 pmol/liter on the melatonin nights (P < 0.01). As depicted in Fig. 1Go the endogenous melatonin rhythms revealed on the placebo nights in all of the 12 subjects showed a random pattern across the night, with no evidence for a sychronized occurrence of peaks or troughs. Administration of melatonin induced a high peak in plasma melatonin concentrations within about 1 h in each subject, and baseline melatonin concentrations were recovered toward the end of the night.



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  		FIG. 1. Individual nocturnal melatonin profiles of 12 totally blind men after administration of placebo and melatonin. Top panel, Severely disturbed plasma melatonin profiles in the blind subjects as revealed on the placebo nights. Bottom panel, Melatonin profiles after administration of melatonin (note extended scaling of y-axis).

 
Average plasma ACTH and cortisol levels during the entire night did not differ between the placebo and melatonin conditions. In addition, on the placebo nights the blind subjects did not show the normal modulation of ACTH or cortisol levels across sleep, so that respective average concentrations were comparable for the first and second half of sleep (P > 0.58 and P > 0.67, for ACTH and cortisol, respectively; Fig. 2Go; and Table 2Go). In contrast, on the melatonin nights ACTH and cortisol concentrations developed the typical temporal dynamic, reaching a trough during the first half and distinctly increasing during the second half of sleep [F(1,11) = 8.22; P < 0.01 and F(1,11) = 7.40; P < 0.02, for treatment x first/second half interactions, respectively for ACTH and cortisol; Figs. 2Go and 3Go]. Figure 2Go also shows ACTH and cortisol profiles from our blind individuals in comparison to profiles from 12 age-matched sighted subjects drawn from previous studies (shaded areas). Separate comparisons of the effects of melatonin and placebo for the first and second sleep half indicated that ACTH concentrations during late sleep were higher on melatonin than placebo nights (P < 0.05). In addition, melatonin decreased plasma cortisol levels during the first half of sleep (P < 0.05) and tended to increase them over respective levels on the placebo nights during the second half (P < 0.08). Cortisol nadir concentrations were consistently lowered after melatonin, as compared with placebo (P < 0.05). GH average and peak concentrations as well as GH peak latency during sleep were not affected by melatonin (Table 2Go). With respect to subjective sleep quality, subjects rated the amount of sleep as "more sufficient" after melatonin than placebo administration (P < 0.05). In addition, subjects felt more "balanced," "vivid," "well-rested" and "relaxed" after sleep in the melatonin condition as compared with the placebo condition (P < 0.05, for all comparisons).



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  		FIG. 2. Nocturnal profiles of ACTH and cortisol plasma concentrations after placebo and melatonin. Indicated are means (±SEM) of plasma ACTH (top panel) and cortisol (bottom panel) concentrations after administration of placebo (black circles) and melatonin (open circles) in blind individuals. Shaded areas represent ACTH and cortisol profiles from a sample of 12 sighted healthy control subjects within the same age range as our blind individuals (selected from previous studies).

 

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  		TABLE 2. Plasma ACTH (pmol/liter), cortisol (nmol/liter) and GH (µg/liter) after administration of placebo and melatonin

 


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  		FIG. 3. Average plasma ACTH and cortisol concentrations during early and late sleep after administration of placebo and melatonin. Concentrations of plasma ACTH (top panel) and cortisol (bottom panel) during the first (black bars) and second half of the night. *, P < 0.05; **, P < 0.01, for pairwise comparisons.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
A single dose of 5 mg melatonin acutely improved sleep in totally blind subjects by increasing sleep time and sleep efficiency, and reducing wake time after sleep onset. The improvement in sleep time was primarily due to an increase in stage 2 sleep. Consistent with earlier studies using a 5-mg dose of melatonin, we also found a slight increase in time spent in REM sleep (31, 36), particularly in the second half of the sleep period where this sleep stage is typically prevalent. SWS was not affected by melatonin in the present study. Diverging from earlier findings (4, 6), we also failed to find a reduction in sleep onset latency after melatonin administration. One explanation for this finding is that, with the exception of one subject who showed a large decrease in sleep onset latency (from 156 after placebo to 23 min after melatonin), sleep onset latencies were not abnormally delayed in our subjects (i.e. <39 min). This might have prevented the emergence of an accelerating effect of melatonin on sleep onset. Subjectively, sleep quality was also improved by melatonin. On the morning after melatonin administration, subjects reported a more positive mood and felt more well rested. Thus the existence of hangover effects from melatonin seems unlikely.

The blind subjects displayed distinct disturbances in sleep-related neuroendocrine activity, which appeared to be even more prominent than those of sleep. The endogenous melatonin profiles in most subjects did not show the regular nocturnal increase around sleep onset, and there was also no discernible fall around the time of morning awakening on the placebo nights (Fig. 1Go). These disturbances agree with previous observations of distinct abnormalities in the circadian rhythm of melatonin secretion in totally blind subjects (16, 17) and probably reflect the lack of entraining light-dark cues and a tendency of blind individuals to develop under these conditions a circadian epoch with a period length lasting slightly longer than 24 h (16, 17, 31). However, although lacking light-dark cues, it should be noted that our blind subjects due to other environmental stimuli were not completely unentrained. Regardless of this question (which is beyond the scope of the present study), it is notable that the disturbed temporal profiles of nocturnal melatonin in our blind subjects was paralleled by pronounced alterations in pituitary-adrenal activity. Patterns of pituitary-adrenal activity in the blind subjects lacked both the characteristic sleep-associated minimum in ACTH and cortisol concentrations during the first half of sleep along with a strong rise in concentrations during the second half of sleep (Fig. 2Go). It has been proposed that the two rhythms of melatonin and pituitary-adrenal secretory activity are phase-locked due to a common oscillator located in the SCN (17) whose coupling strength is reduced in the absence of light-dark cues.

In addition to controlling circadian secretory activity, the SCN is densely packed with high affinity melatonin receptors (37), which are not only effective in mediating the effects of endogenous melatonin but are probably also major targets of exogenously administered melatonin. Accordingly, it has been found that in blind individuals with free-running endogenous melatonin rhythms, the daily administration of melatonin before bedtime over several weeks, successfully entrained the circadian melatonin rhythm to a 24-h period (38). Resetting the clock of the circadian rhythm might therefore be the mechanism that mediated the acutely improving effect of melatonin administration also on sleep and neuroendocrine patterns in the present study.

A central finding of the present study is the prompt normalization of patterns of pituitary-adrenal activity seen after melatonin administration in the blind subjects. It could be argued that this entrainment of pituitary-adrenal activity to sleep reflects an effect of melatonin that is mediated mainly by its improving influence on central nervous sleep. Sleep exerts a distinct control over pituitary-adrenal regulation, separate from that of circadian oscillators (18). Specifically, early sleep and in particular SWS have been found to inhibit spontaneous pituitary-adrenal activity (19) as well as responsiveness of this system to administration of vasopressin and CRH (20, 39). However, here melatonin affected neither SWS nor the release of GH known to be closely linked to the expression of SWS. This observation argues against sleep as mediator of the changes in pituitary-adrenal activity after melatonin. Rather, melatonin seems to affect in parallel central nervous sleep and pituitary-adrenal activity probably via an influence on supraordinate circadian oscillators.

The neurophysiological mechanisms underlying the influence of melatonin on sleep and pituitary-adrenal regulation are not yet known. Recently, a neuronal circuit connecting the SCN and the locus coeruleus via the dorsomedial hypothalamus has been identified, providing a possible substrate for the circadian pacemaker to modify monoaminergic brain levels, thereby influencing the regulation of sleep and wakefulness (40). However, whether melatonin is able to suppress pituitary-adrenal activity in a similarly direct manner, i.e. independent from sleep, is presently unclear as are the pineal-hypothalamic links that, perhaps via an action on releasing factors such as CRH and vasopressin, mediate such inhibition (32, 41, 42). Also, we emphasize here that a pharmacological dose of melatonin was used; this dose induced clearly supraphysiological blood concentrations and, thus, precludes any speculations concerning the physiological role of endogenous melatonin for pituitary-adrenal function and sleep.

Synchronizing temporal patterns of pituitary-adrenal activity to sleep is critical for its adaptive function. A growing body of evidence supports that sleep serves to maintain metabolic homeostasis and consolidate memories (22, 43, 44). Specifically, it has been shown that enhanced cortisol levels in the early night result in decreased glucose tolerance and in increased sympathetic output. Moreover, an effective inhibition of cortisol during SWS-rich early sleep has been identified as a necessary prerequisite for the formation of so-called declarative memories during sleep known to rely basically on hippocampal functions (24, 25). Hence, chronically impaired suppression of pituitary-adrenal activity during early sleep is not only expected to facilitate development of obesity, diabetes, and hypertension but also to result in memory dysfunction (27, 43). Apparently, sleep embraces its physiological functions only in a synchrony of central nervous and endocrine patterns of activity, among which pituitary-adrenal secretion is of particular relevance. Totally blind individuals lack this synchrony, which may predispose them to develop metabolic diseases and memory deficits. The present data indicate that this synchrony can be achieved by a single administration of a pharmacological dose of melatonin.


   Footnotes
 
This study was funded by Grant no. 475 from the Deutsche Forschungsgemeinschaft (to J.B.).

Abbreviations: REM, Rapid eye movement; SCN, suprachiasmatic nucleus; SWS, slow wave sleep.

Received March 27, 2003.

Accepted August 13, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals