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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 3 1181-1187
Copyright © 2001 by The Endocrine Society

Original Studies

Characterization of Nocturnal Ultradian Rhythms of Melatonin in Children with Growth Hormone-Dependent and Independent Growth Delay1

A. Muñoz-Hoyos, R. Jaldo, A. Molina-Carballo, G. Escames2, M. Macías3, J. M. Fernández-GarcÍa, R. J. Reiter and D. Acuña-Castroviejo

Departamento de Pediatría (A.M.-H., R.J., A.M.-C., J.M.F.-G.) and Departamento de Fisiología, Instituto de Biotecnología (D.A.-C., G.E., M.M.), E-18012 Granada, Spain; and Department of Cellular and Structural Biology, University of Texas Health Science Center (R.J.R.), San Antonio, Texas

Address all correspondence and requests for reprints to: Dr. D. Acuña-Castroviejo, Departamento de Fisiología, Facultad de Medicina, Avenida de Madrid 11, E-18012 Granada, Spain. E-mail: dacuna{at}goliat.ugr.es


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
To assess the existence of a possible nocturnal ultradian rhythm of melatonin in children, we analyzed 28 pediatric patients (mean age, 9.08 ± 2.2 yr) with GH-dependent and GH-independent growth delay. Plasma melatonin was measured by RIA in children sampled every 30 min between 2100–0900 h. Statistical analysis consisted of cluster analysis to examine the presence of peaks and troughs. The pattern of melatonin levels was related to the cause of growth delay, although the means of the nocturnal concentrations of melatonin were similar in all children. Interestingly, children with a GH deficit showed a nearly normal melatonin profile, whereas children with normal GH values but abnormal growth displayed atypical profiles of melatonin. The results also prove the existence of an ultradian rhythm of melatonin in most of the patients studied. The ultradian rhythm of melatonin in children was characterized by irregular interburst intervals, thus differing from the rhythm previously described in adults that had an almost constant pulse frequency. Moreover, the existence of low and high melatonin producers was revealed in the study, a feature unrelated to the cause of growth delay. The group of children with a GH deficit showed the lowest values of integrated melatonin production and of the area of peaks and troughs. These results prove that children exhibit an ultradian rhythm of melatonin like that in adults. Whereas it is not clear whether the episodic production of melatonin is required for its biological actions, the existence of irregular pulses may reflect endocrine influences at this age and/or the immaturity of the intrinsic pulse generator.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
MELATONIN HAS A diverse range of physiological actions in humans, including effects on the sleep/wake cycle and endocrine modulatory effects (1). This pineal secretory product acts as a chemical messenger of darkness (2), and its production is under photoperiodic control via the suprachiasmatic nucleus. As melatonin is not stored in the pineal gland, circulating levels of the indoleamine faithfully reflect pineal secretory activity. Plasma levels of melatonin increase at night, whereas diurnal levels are low. The circadian rhythm of melatonin parallels the endogenous circadian clock, which provides time information to the organism (3). Humans conserve the photoperiod-responsive mechanism involved in neuroendocrine axis regulation and, thus, changes in the duration of photoperiod affect the onset of nocturnal production of melatonin and GH (4).

There is increasing knowledge regarding the endogenous circadian rhythm of melatonin in adults and its physiological significance (1, 5, 6). Hormonal deficiencies (7) and sleep-wake disorders (8) are related to abnormal circadian melatonin production. However, there is little information concerning the nocturnal melatonin profile in children. Ontogenetic studies have shown that neonates have a circadian rhythm of melatonin that disappears soon after birth, thus reflecting the transfer of maternal melatonin at the end of pregnancy (9). Nevertheless, the pineal gland of neonates responds to physiological stimulus such as darkness (10), although the circadian pattern of melatonin production does not appear until 4–6 months after birth (11).

Melatonin administration reentrains altered circadian rhythms in patients suffering from a chronic disturbance or transitory alterations of these rhythms (12), suggesting that resetting hormonal rhythms may be beneficial in the treatment of some illness (13). In fact, infantile seizures are associated with altered circadian melatonin rhythms (14), and their resynchronization by melatonin administration significantly improved the clinical status of a child with myoclonic epilepsy (15). Furthermore, loss of normal melatonin production is associated with a severe lack of sleep (16), a finding possibly related to the sleep-promoting effect of the indoleamine (17). A relationship between the sleep-wake cycle and GH also exists (18), with GH production increasing during sleep. GH also displays an ultradian rhythm in normal children during development. Except during puberty, when melatonin seems to decrease, pineal activity is maximal during infancy and generally is reduced in advanced age. An impairment of nocturnal melatonin production during aging parallels the decrease in the circadian profiles of GH. Idiopathic GH deficiency has been associated with the absence of the melatonin rhythm (19), although a melatonin-GH relationship is not yet clear.

Melatonin production at night displays ultradian rhythms in normal adults (20), but the existence of an equivalent rhythm in children is unknown. Thus, we considered it worthwhile to test for the presence of an ultradian rhythm of melatonin in the blood of children at night. Therefore, we measured the melatonin levels in 28 children who had growth delay with different etiologies. Plasma levels of melatonin were measured at regular intervals during the 12-h nocturnal period in these patients. Two statistical approaches, cosinor and cluster analyses, were applied to the melatonin values to disclose the characteristics of the rhythms. Thereafter, we looked for any relationship between the nature of the growth delay and the rhythm of melatonin in these children.


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

The study was carried out on 28 pediatric patients (12 males and 16 females) who were admitted to University Hospital (Granada, Spain) for an endocrine evaluation of growth delay. Informed consent was obtained from all parents and from the hospital’s ethical committee, according to the 1983 revised Helsinki Declaration of 1975. The clinical history, somatometric data, height prediction, and analytical results (Table 1Go) suggested GH deficiency in some of the patients. Patients with the following selection criteria, according to Tanner and Whitehouse tables (21), were suitable candidates for the examination of pituitary function: 1) height below the 3rd percentile; 2) growth rates below the 25th [this group included children with near-normal heights, but with their growth rates halted: children with a growth rate below 7 cm/yr before 3 yr of age, below 4–5 cm/yr during the 3 yr before puberty, and below 5.5–6 cm/yr during puberty were considered to have an inadequate growth rate (22)]; and 3) delayed bone maturation (these children had a bone age at least 2 yr below their chronological age). After determination of GH values, children were classified into 3 groups according to diagnosis (Table 1Go): 1) constitutional growth delay (CGD), consisting of 7 patients, aged 7–10 yr (5 males and 2 females); 2) genetic low height (GLH), a group of 16 patients aged 5–12 yr (5 males and 11 females); and 3) partial GH deficit (GHDP), consisting of 5 patients, aged 7–12 yr (2 males and 3 females). Patients included in the CGD and GLH groups had growth delay but normal GH values, whereas patients from the GHPD group had low GH values and GH-dependent growth delay.


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  		Table 1. Characteristics of the children included in the study

 
The children, not given any medication and after an overnight fast except for water, were admitted to the Infantile Endocrine Unit 2 days before the study; the hospital’s regular light-dark cycle was in effect (lights on from 0700–2100 h). An indwelling cannula was placed into the antecubital vein, and blood samples were taken every 30 min between 2100 and 0900 h. Blood was centrifuged at 3000 x g for 10 min, and plasma was separated and frozen at -20 C until the assays were performed.

Melatonin was determined by a commercial RIA (DLD, Hamburg, Germany), and quality control was performed, showing intra- and interassay coefficients of variation of 11.3% and 6.3%, respectively. The recovery of added melatonin was 84.4%, and the sensitivity of the assay was 0.02 nmol/L (23).

Statistics

Data are expressed as the mean ± SE. Cluster analysis was performed to study the presence of peaks (and troughs) of melatonin during the night (24). The program identifies the number of peaks/troughs; the position, duration, amplitude, and concentration at each peak/trough; the mean amplitude and mean duration of the peaks/troughs; the mean interval between peaks; and the maximum peak elevation. One-way ANOVA (ANOVA I) followed by Bonferroni’s test was used to test for the existence of differences and rhythms in the study groups (25). Two-way ANOVA (ANOVA II) was used to study differences between groups of patients (GLH, CGD, and GHPD) and time (hours). Melatonin production during the night was expressed as the mean of the integrated values for melatonin (integrated concentration of melatonin) in each group, determined as the area under the curve from 2100–0900 h by the linear trapezoidal method.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Figure 1Go shows the melatonin secretory pattern of the three groups of patients. Figure 1Go, B–D, shows the patterns of melatonin production for CGD, GLH, and GHPD groups, respectively. Figure 1AGo represents the pattern of melatonin levels for all patients, i.e. it represents the mean of A+B+C. Figure 1AGo shows a clear pattern of increased nocturnal melatonin production, with peak values between 0200 and 0400 h and lowest levels of melatonin at 0900 and 2100 h. For the CGD group (Fig. 1BGo) melatonin levels showed 1) higher values than in the other groups, 2) intermittently highly elevated levels between 0030 and 0430 h, and 3) lowest melatonin levels at 0900 and 2100 h. In GLH group (Fig. 1CGo) the pattern of melatonin levels was significantly different from those in the other groups and was characterized by maximum levels of melatonin between 0430 and 0630 h, suggesting a phase-shift delay of the hormone peak, and minimum levels of melatonin between 2200 and 2400 h. The GHPD group (Fig. 1DGo) was characterized by lower melatonin levels than in the other groups, maximum levels between 0130 and 0330 h, minimum values at 0900 and 2100 h, and secretory peaks after the onset of light in the morning.



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  		Figure 1. Patterns of melatonin levels during the night. A, Mean values of melatonin for the 28 children in this study. B–D, Mean profile of melatonin levels for CGD, GLH, and GHPD groups, respectively. {blacksquare}, Period of darkness.

 
One-way ANOVA applied to the melatonin values of Fig. 1AGo, i.e. the mean melatonin production including the patients in the CGD, GLH, and GHPD groups, yielded Fexp = 3.94 (P < 0.01). After the Bonferroni test we found the following results: 1) an initial phase of low melatonin levels (0.077 ± 0.02 nmol/L) at 2130 h, 2) a second phase corresponding to the middle of the nocturnal period (0230–0430 h) in which the levels of melatonin (0.215 ± 0.03 nmol/L) were the highest, and 3) a latter phase from 0500–0900 h in which melatonin levels decreased (0.065 ± 0.007 nmol/L at 0900 h).

Two-way ANOVA (factor 1 = diagnostic; factor 2 = hour) revealed statistical significance only when the hour was used as the classification factor (F = 2.94; P < 0.0001), but not when the classification factor was the diagnosis (F = 1.73).

Figures 2–4GoGoGo show the nocturnal melatonin rhythms for the patients in the CGD, GLH, and GHPD groups, respectively. Each panel illustrates the individual values for melatonin levels at night for a single individual. Arrows identify the significant peaks and troughs. In the CGD group (Fig. 2Go) we found three patients (individuals 3, 7, and 11) with no significant peaks and troughs; one patient (individual 27) exhibited a low nocturnal melatonin rise with a pulse at 0500 h, whereas individuals 1, 5, and 23 had higher nocturnal melatonin levels, with several significant pulses without a rather uniform interval between them. In the GLH group (Fig. 3Go) we found one patient with very low melatonin levels during the night (individual 15); four children (individuals 9, 13, 17, and 24) also had rather low melatonin profiles, and the remainder of the patients showed a marked increase in nocturnal melatonin levels and the presence of variable secretory pulses in number and intervals between peaks. In the GHPD group (Fig. 4Go), three patients (individuals 14, 18, and 21) showed similar secretory profiles of melatonin with low levels during the night; one patient (individual 4) displayed a secretory pulse at 0130 h, and other patient (individual 8) showed an early initial increase in melatonin that persisted for the first half of the night.



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  		Figure 2. Individual representation of the nocturnal profiles of melatonin for the children included in the CGD group. Arrows identify the significant peaks and/or troughs of melatonin production during the night.

 


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  		Figure 3. Individual representation of the nocturnal profiles of melatonin for the children included in the GLH group. See Fig. 2Go for explanation.

 


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  		Figure 4. Individual representation of the nocturnal profiles of melatonin for the children included in the GHPD group. See Fig. 2Go for explanation.

 
For a given group, the quotient between the number of peaks and troughs and the number of patients yielded the mean number of peaks and troughs for the individuals of the corresponding group. The mean values of peaks and troughs were 3 and 2.4 for the CGD group, 1.8 and 1.1 for the GLH group, and 1 and 0.25 for the GHPD group, respectively. These data suggest that in GHPD group, i.e. children with low GH production, the number of melatonin peaks was less than those in the CGD and GLH groups, both groups of individuals who exhibited normal GH production.

We also compared the melatonin levels in each group to identify differences. The mean nocturnal melatonin levels were similar in CGD, GLH, and GHPD groups (0.15 ± 0.007, 0.14 ± 0.005, and 0.12 ± 0.005 nmol/L, respectively). When the nocturnal levels of melatonin were expressed as the integrated concentration (Fig. 5AGo), the GHPD group showed lower levels than CGD and GLH groups, although these were not significantly different (F = 1.427). The GHPD group also showed the lowest area of peaks and troughs (Fig. 5BGo), although again they were not significantly different from values in the other groups (F = 1.426).



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  		Figure 5. Representation of the integrated production of melatonin (A) and the area of peaks and troughs (B) for the three groups of patients. Although the GHPD group showed the lowest value for each variable, the means did not differ.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The results of this study show for the first time the existence of ultradian rhythms of melatonin during the night in children. The small percentage of children lacking a significant ultradian rhythm of melatonin was independent of the cause of growth delay, as such rhythms were identified in all groups. However, the nocturnal profile of melatonin was different in each group, suggesting a relationship between melatonin levels and growth in these children. The mean melatonin concentration during the night was similar in the three groups. When the data were expressed as time-integrated melatonin levels or as the area of peaks and troughs, the GHPD group showed the lowest values in both cases, indicating that these parameters may reflect the production of melatonin during the night more accurately than the absolute value of melatonin.

The findings also revealed a negative correlation between serum melatonin and body weight in childhood and adolescence, suggesting that an increase in body size may be responsible for the melatonin decrease, rather than an effect of GH and/or other factors involved in growth during this period (26). A larger body size, due to the dilution effect, would be expected to lower mean melatonin levels. The large interindividual differences in melatonin levels found in our study are consistent with previous data (27, 28) and were not related to impaired liver function, age, sex, height, or weight, as no correlations between melatonin and these variables were found.

The mean levels of melatonin were also consistent with those reported previously in children of the same age (29, 30). Interestingly, melatonin profiles showed significant differences depending on the diagnosis. These differences included the presence of large secretory bursts in the CGD group, a delay in both the initial elevation and the maximum of melatonin levels in GLH group, and an almost normal secretory pattern of melatonin in GHPD group, except for the presence of possible peaks of melatonin in the early morning. The results of the cluster analysis showed more abundant peaks and troughs in CGD group, whereas the GHPD group displayed the smallest number of peaks. Our results also discriminated between high and low melatonin producers, a finding unrelated to the diagnosis, as both extremes were present in each of the groups. This feature has also been noted in healthy adults (27, 28), thus suggesting that it is an individual property also expressed in children and is not related to growth delay and/or a GH deficit. The existence of high and low melatonin secretors may reflect a genetic variability in noradrenergic sensitivity at the level of the pineal or variable nocturnal activities of the enzymes involved in melatonin synthesis (28).

There is some disagreement on the existence of ultradian melatonin rhythms. Some reports claim no melatonin pulses (31), whereas other report melatonin pulse frequencies from one pulse per 10 min to two pulses per night (20, 32, 33). Our results support previously published deconvolution studies in adults (34) and show significant interindividual variability in the number, amplitude, and distribution of melatonin pulses during the night (33), without a correlation to tonic melatonin production. The lack of regular interburst intervals in our report compared with those in an adult study suggests that in children the intrinsic pulse generator is immature (20). Other potential causes of the variability, such as the influence of sexual hormones and/or the growth delay effects, might influence the frequency of melatonin pulses. Melatonin may be produced in different tissues, including gut (35) and bone marrow (36), and the possibility that the indoleamine was released from these sources into the blood should be taken into account. The melatonin fluctuations may be an interindividual feature, as in experiments that repeated the measurements of melatonin levels in the same individuals on different nights showed the profiles for each individual to be similar (34). The interindividual differences in melatonin production may be not a specific characteristic of humans, because this phenomena also occurs in lower mammals, such as rats (37). It may be concluded that in children, melatonin production undergoes two distinct secretory modes, in which episodic production is superimposed to tonic production in a subject-dependent variable manner. It seems that the secretory pulse amplitude, frequency, or duration and the secretory rate of melatonin underlying its plasma profile are typical for each individual. The rhythm and pulse stability of melatonin in each individual are probably more important than the absolute values of this pineal product.

Some melatonin actions are linked to the synchronization of endocrine and nonendocrine rhythms, including growth and the sleep-wake cycle (16, 17, 19). The sleep-wake cycle is the primary determinant of the temporal organization of GH release in humans. During childhood, major GH secretory episodes occur shortly after sleep onset caused by a surge of hypothalamic GHRH release (38). Melatonin administration modulates the GH response to GHRH administration in humans (39), whereas GHRH promotes nonrapid eye movement sleep via central mechanisms (38). A relationship among sleep, the melatonin rhythm, and GH production is evident in pathological situations (14, 15, 40). Patients with chronic sleep-wake rhythm disorders show abnormal coupling between the sleep-wake rhythm and circadian pacemaker function (41). Sleep alterations during infancy are related to growth delay (18, 38); however, we did not detect alterations in sleep-wake cycle in our patients, and thus the results do not support a relationship between growth delay and the sleep-wake cycle. Besides, the ultradian secretory pulses, which occurred at random intervals, are seemingly not related to sleep structure (34).

It has been recently reported that the melatonin concentration decays during pubertal development. Melatonin levels during the night showed two ultradian components, compatible with a continuous secretion of the indoleamine (42). Together with our results, these data suggested that from the prepubertal stage, when the pulsatility of melatonin levels is high, the ultradian component of melatonin decreases during puberty. Thus, the decline in melatonin levels occurring coincident with pubertal development may reflect at least in part the reduction in the number of pulses of the indoleamine at this time. This implies that the ultradian component of nocturnal melatonin is a significant aspect of its circadian rhythm (42, 43). Although it was found that the area under the curve of the melatonin concentration was mainly affected by pubertal age, chronological age also influences this value (42). In our study we found that in children with GH deficit, both the area under the curve and total area of peaks and trough was lowest. Thus, chronological age may gain importance in terms of melatonin production when a GH deficit exists.

There are several conditions in human life under which ultradian cycles become a prominent time structure in both physiological and behavioral functions. One of them is infancy. The pattern of events, such as sleep and waking, shows manifestations of endogenous ultradian cycles just before circadian rhythmicity appears, but the ultradian rhythms seem to remain throughout life. This is the Kleitman concept of a basic rest-activity cycle (44). There is reason to believe that different endogenous rhythms in the same organism do not run independently of each other, but form a system of hierarchically organized and interacting oscillators (43). Melatonin may be one of the highest synchronizers of these rhythms. Thus, a longitudinal study of children during maturation of their oscillators, i.e. during development, might be a suitable way in which to analyze these endogenous rhythms and their interactions.

Ultradian secretion appears to be a common characteristic of the endocrine systems. Melatonin may increase the propensity for physiological processes promoting nocturnal sleep or processes that occur during the sleep period (1). Depending on the time of its administration/presence, the indoleamine may antagonize or promote the phase-shifting effects exerted by photoperiod acting directly on the circadian clock (5). Thus, melatonin administration may be useful in the treatment of different desynchronized conditions and may be important in resetting altered biological rhythms to treat illness (5, 12, 13). During infantile epileptic seizures the ultradian system is halted, and the behavior of the handicapped infant seems to be influenced by two distinct ultradian rhythms (43). The observation that melatonin administration overcame epileptic seizures and restored the normal pattern of melatonin in a child at night (15) further supports the synchronizing role of melatonin.

The results demonstrate that children during development display an ultradian rhythm of melatonin. Ultradian rhythms of melatonin may reflect a modulation in the frequency of the photoperiodic information acting on the hypothalamus and/or pituitary to regulate some photoperiodic responses (45). As it is not known whether episodic or ultradian production is essential for the biological actions of melatonin (46) or whether exogenous melatonin administration affects its ultradian rhythm, further studies are necessary to support its use as a medication in children. Studies to date, however, have shown that melatonin treatment in children may be a safe and effective treatment in some sleep disorders (47).


   Footnotes
 
1 This work was supported in part by the Junta de Andalucía (Grupos de Investigación CTS-101 and CTS-190) and the Hospital Universitario of Granada. Back

2 Fellow from the Fondo de Investigación Sanitaria, Ministerio de Sanidad y Consumo, Spain. Back

3 Fellow from the Programa de Formación de Personal Investigador, Ministerio de Educación y Cultura, Spain. Back

Received May 1, 2000.

Revised August 8, 2000.

Revised October 4, 2000.

Accepted November 15, 2000.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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