help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Salti, R.
Right arrow Articles by Cornélissen, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Salti, R.
Right arrow Articles by Cornélissen, G.
The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 6 2137-2144
Copyright © 2000 by The Endocrine Society

Special Articles

Nocturnal Melatonin Patterns in Children

R. Salti, F. Galluzzi, G. Bindi, F. Perfetto, R. Tarquini, F. Halberg and G. Cornélissen

University of Florence (R.S., G.B., F.P., R.T.), Florence, 50139 Italy; and University of Minnesota (F.H., G.C.), Minneapolis, Minnesota 55455

Address all correspondence and requests for reprints to: Franz Halberg, M.D., Director, Halberg Chronobiology Center, University of Minnesota, Department of Laboratory Medicine, Room 715 Mayo, 420 Delaware Street SE (P.O. Box 609 Mayo), Minneapolis, Minnesota 55455. E-mail: halbe001{at}tc.umn.edu


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Time patterns in nocturnal concentrations of circulating melatonin of children are quantified in 8 girls and 8 boys, 8.7–16.8 yr of age, classified by Tanner pubertal stage. Between 1900 and 0700 h, each provided blood samples at 30-min intervals for melatonin RIA. Associations with gender, body mass index, and chronological and pubertal age determined by multiple linear regression and ANOVA reveal that the area under the curve of 12-h melatonin concentrations was affected by pubertal rather than chronological age, an effect to which data collected during darkness contributed the most. Each data series was also analyzed by a least squares spectrum at frequencies of 1–20 cycles/day. Ultradian changes with periods of 3.4 and 1.5 h, putatively associated with rapid eye movement sleep cycles, characterize nocturnal melatonin in boys and girls.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
MELATONIN IS an indolamine isolated by Lerner et al. (1), found in the pineal gland, among other sites (2). Its conventionally stated inhibitory effect on numerous endocrine functions (3) may be time dependent, including pro- and antigonadotropic actions (4). In a circadian rhythmic action, aqueous pineal homogenate or melatonin can lead to time-varying opposite effects, stimulating corticosterone production in vitro by the rodent adrenal, leaving it unaffected or inhibiting it (5, 6). Melatonin is present in several body fluids (urine, blood, saliva, and cerebrospinal fluid). As originally demonstrated by Wurtman’s group, melatonin secretion in humans is circadian periodic, with low concentrations during the day and high concentrations at night (7), as in all laboratory animals studied to date (8, 9), without the difference in timing between nocturnally and diurnally active species previously reported, e.g. for circulating corticosterone, eosinophil counts, core temperature, and mitotic counts (10).

Involvement of melatonin and other pineal compounds, such as 5-methoxytryptophol, in the maturation process of humans has been suggested (11). This pineal indole has also been proposed as a marker of the different chronobiology in the pubertal development of boys and girls (11). The purpose of the present study is to compare effects of pubertal stage vs. chronological age and body mass index on circulating melatonin, determined in blood sampled at 30-min intervals from 1900–0700 h in children of both genders, classified by pubertal (Tanner) stage. This investigation also seeks any patterns in nocturnal melatonin of children.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Between September 1992 and December 1995, eight girls and eight boys entered the study. Five children were at pubertal (Tanner) stage I, five were in stage II, four were in stage III, and two were in stage IV. Their chronological age and gender were recorded together with height and weight. Body mass index was computed as weight/height2 (where weight is expressed in kilograms and height in meters). The children’s characteristics are summarized in Table 1Go. The study was approved by the ethics committee of Meyer Children’s Hospital and the institutional review boards of the University of Florence (Florence, Italy). Informed written consent was obtained from the parents after a detailed explanation of the study had been provided to the children and parents.


View this table:
[in this window]
[in a new window]
  		Table 1. Characteristics of the children investigated

 
Both height and bone age corresponded with chronological age. Height was measured using a Harpenden stadiometer, bone age was assessed by the Greulich and Pyle method (12), and pubertal staging was performed using the criteria of Tanner and Whitehouse (13). All children were hospitalized because of minor illness or for diagnostic investigations. None of the children had evidence of neurological, endocrine, or psychiatric disorders known to affect the time course of circulating melatonin (Table 1Go). Children with acute illness, such as pneumonia, gastroenteritis, and lower urinary tract infection, were sampled after the acute span following their recovery. None was febrile during blood collection. Children who underwent herniotomy were studied before surgery.

The specimens were collected during the months of September to March (autumn/winter). Participants were admitted to the research ward between 1400 and 1500 h. One parent was allowed to stay with the child at all times. After placement of an indwelling iv catheter, the children were given a mixed meal (1800–1830 h) and were then allowed to play or to ambulate freely on the unit from 1830–1900 h. Blood sampling (2 mL) started at 1900 h and continued at 30-min intervals until 0700 h. After each blood withdrawal, children were perfused with 2 cc 0.9% saline infusion. All children were supine (in bed) from the start (1900 h) to the completion (0700 h) of the study. From 1900–2300 h, they were allowed to watch television, listen to music, and/or read; they could have snacks, but were allowed to get up for no more than a few minutes to go to the bathroom. From 2300–0700 h, all children were asleep and did not get up. On the day of the study, children were synchronized to the hospital routine. The usual bedtime and time of awakening of school children in Italy are between 2200 and 2300 h and between 0700 and 0730 h, respectively.

Artificial white light (500–800 lux), typical of the illumination of hospital rooms and similar to domestic lighting in Italy, was used from the onset of the study (1900 h) until 2300 h. A dim light was used for the collection of samples during the dark span (2300–0700 h). Particular attention was paid to allowing the children to remain asleep.

Melatonin concentrations were measured by RIA (Nichols Institute Diagnostics, San Juan Capistrano, CA) using [125I]melatonin as tracer and a solid phase antirabbit (donkey) coated cellulose suspension (14). After collection, blood samples were immediately spun at 1500 x g for 12 min, and plasma was separated, transferred to plastic tubes, frozen, and stored at -20 C until assay. Before determination of melatonin, samples were extracted with 100% diethyl ether (3 mL diethyl ether shaken for 2 min with 0.5 mL sample plasma); the mixture was frozen at -20 C, the ether extract was decanted, and the aqueous phase was discarded. The supernatants were evaporated to dryness in a 37 C water bath under a stream of 100% nitrogen gas. The dried extracts were reconstituted in RIA buffer (0.5 mL phosphate buffer, pH 7.4, containing concentrated BSA). The buffer extracts or buffer samples containing graded concentrations of melatonin were then mixed with 0.1 mL antimelatonin antiserum and, after 6 h of incubation at 4 C, with 0.1 mL [125I]melatonin. The mixture was incubated for 18 h at 4 C, and then 0.1 mL antirabbit precipitant was added. After a 30-min incubation at room temperature, the antibody-bound [125I]melatonin precipitate was collected by centrifugation (15 min at 1500 x g at 4 C). Radioactivity was measured in a liquid scintillation counter. The average percent recovery calculated for this extraction procedure is above 90%. The sensitivity of the assay, measured as the smallest single value that can be distinguished from zero at the 99% confidence limit, was 3 pg/mL. The precision (intraassay variance) of the method was 13.5% at 19.4 pg/mL and 8.0% at 59.0 pg/mL. The reproducibility (interassay variance) was 16.6% at 18.4 pg/mL and 5.9% at 54.8 pg/mL. The cross-reactivity of the primary antibody with the most important indoleamines is the following: less than 0.1% for 6-sulfatoxymelatonin, N-acetyltryptophan, 5-methoxytryptophan, tryptamine, L-tryptophan, serotonin, and serotonin creatine sulfate; 0.02% for N-acetylserotonin; 0.05% for 5-methoxytryptamine, and 1% for 6-hydroxymelatonin. All serum concentrations for each patient were determined in duplicate in single-run assays, to minimize interassay variability.

The area under the curve (AUC) was calculated from each nightly melatonin profile by numerical integration and expressed as picograms per mL/h. For the investigation of temporal changes in circulating melatonin, the data were log10-transformed to normalize their distribution and to render the variance more homogeneous. Each data series was analyzed by chronobiometry (15, 16, 17). In view of the large prominence of the circadian rhythm in circulating melatonin, even though the data were collected only between 1900 and 0700 h, a least squares spectrum assessed components in the range of 1–20 cycles/day (with trial periods of 1.2–24 h). The computation was carried out with the understanding that the estimation of the circadian component may not be reliable, placing the emphasis on the ultradian variations. The results were further summarized by the population-mean cosinor at each trial period. Rhythmometric end points, together with the AUC, were then analyzed by multiple ANOVA and by multiple regression to investigate any effect of gender, chronological age, or pubertal stage (18). Results were considered statistically significant if P < 0.05 in testing the null hypothesis.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Plots of original data are shown in Fig. 1AGo. Time point means and SEs for children in each pubertal stage are illustrated in Fig. 1BGo. Even though the data were collected only for 12 h, albeit at 30-min intervals, the circadian component could be demonstrated with statistical significance by population-mean cosinor, with an acrophase by night, as anticipated around 0230 h. The statistically significant first few harmonics most likely account for the nonsinusoidal waveform of the circadian rhythm of circulating melatonin. Two additional ultradian components, with periods of 3.4 and 1.5 h, were statistically significant, whether the data analyzed were expressed in original units or after they had been log10-transformed (Table 2Go). They were both characterized by an amplitude larger than 3 pg/mL, the sensitivity of the RIA assay used for melatonin determination.



View larger version (29K):
[in this window]
[in a new window]
  		Figure 1. Time course of circulating melatonin in individual children (A) and as means and SEs by pubertal stage (B). The light span was from 1900–2300 h; the dark span was from 2300–0700 h.

 

View this table:
[in this window]
[in a new window]
  		Table 2. Least squares spectrum of circulating melatonin

 
These two ultradian components are biologically meaningful because they are probably related to the rapid eye movement (REM) cycle. Their waveforms are visualized in Fig. 2Go, obtained by stacking the data of all children over an idealized cycle. In Fig. 2Go, the original data from each child are expressed as a percentage of the corresponding time series mean value to eliminate interindividual differences in nocturnal melatonin concentration, so that the pattern could be viewed more easily. These summaries are complemented by one-way ANOVA testing for the equality of all class means. Even though this approach is less powerful than the cosinor (19, 20, 21), the 3.4-h component is validated with statistical significance (F = 2.480; P = 0.031) and the 1.5-h component is validated with borderline statistical significance (F = 2.587; P = 0.077).



View larger version (58K):
[in this window]
[in a new window]
  		Figure 2. Pattern of ultradian components with periods of 3.43 h (left) and 1.5 h (right), characterizing nocturnal circulating melatonin in children of both genders and different pubertal stages. To reduce the interindividual variation in mean values, the individual data series have been expressed as a percentage of their mean value (100%).

 
As the light intensity changed around 2300 h and around 0700 h, a light-exposed mean (between 1900 and 2230 h) and a dark-exposed mean (between 2330 and 0630 h) were calculated for each child along with the difference between these two means. On the average, the light-dark difference was statistically significantly different from zero (paired t = 4.172; P = 0.001), the dark-exposed values were invariably higher than the light-exposed values [except for two of the children who had a slightly earlier circadian acrophase (by about 2–3 h) compared to the other children].

The AUC during the entire 12 h and during the spans from 1900–2230 h and from 2330–0630 h, the light-exposed and dark-exposed means and their difference, as well as the 12-h mean value were first compared between boys and girls. In the absence of a statistically significant difference between boys and girls for these end points, the data from both genders were pooled for comparison among the four pubertal stages (none of the children investigated was in stage 5). As in other published studies, the AUC differed with statistical significance among the pubertal stages (F = 23.881; P < 0.001; Fig. 3AGo). This difference in AUC was mostly accounted for by a difference in AUC during the dark-exposed span (F = 9.018; P = 0.002; Fig. 3BGo); the AUC during the light-exposed span differed with only borderline statistical significance (F = 3.039; P = 0.071; Fig. 3CGo). Similar findings apply to the mean values of circulating melatonin concentrations. No difference was found for the light-dark difference.



View larger version (25K):
[in this window]
[in a new window]
  		Figure 3. Changes in 12-h AUC (A), dark-exposed 2330–0630 h AUC (B), and light-exposed 1900–2230 h AUC (C) of circulating melatonin in children grouped by pubertal stage. The decrease in AUC as a function of pubertal stage is primarily contributed by the dark-exposed AUC. The largest decrease occurs between pubertal stage 2 and pubertal stages 3 and 4.

 
Linear regression analyses confirmed a large decrease in AUC as a function of pubertal stage (r = -0.816; P < 0.001; Fig. 4AGo), accounted for primarily by a decrease in AUC between 2330 and 0630 h (r = -0.761; P = 0.001). The decrease in AUC between 1900 and 2230 h was less pronounced (r = -0.539; P = 0.031). Similar changes as a function of chronological age were observed (Fig. 4BGo), but to a lesser degree (12-h AUC: r = -0.562; P = 0.023; AUC between 2330 and 0630 h: r = -0.505; P = 0.046; AUC between 1900 and 2230 h: r = -0.368; P = 0.161). No statistically significant change in 12-h AUC was found as a function of body mass index (r = -0.397; P = 0.127). Multiple linear regression analyses corroborated the primary effect of pubertal stage on dark-exposed melatonin concentrations, gauged by the AUC. After accounting for the decrease in AUC as a function of chronological age, an effect of pubertal stage on the 12-h AUC remained demonstrable (F = 4.337; P = 0.036).



View larger version (11K):
[in this window]
[in a new window]
  		Figure 4. Stronger association of 12-h AUC of circulating melatonin as a function of pubertal stage (A) than as a function of chronological age (B).

 
Despite the very small sample size available for study (there was only one stage 2 boy, one stage 3 girl, and one child of each gender in stage 4), a small difference as a function of pubertal stage was found to be of borderline statistical significance for the 3.4-h amplitude (F = 2.678; P = 0.094), and the 3.4-h amplitude was higher in boys than in girls (t = 2.389; P = 0.032; P values for ordering only because they were not corrected for multiple testing). Tentatively, a two-way ANOVA, using gender and pubertal stage as main factors, found the 12-h AUC to differ primarily as a function of pubertal stage (F = 27.379; P < 0.001); the gender effect was of borderline statistical significance (F = 4.789; P = 0.060), with no major interaction (F = 2.116; P = 0.176). Similar results in terms of pubertal stage, but not gender, were obtained for the AUC computed between 2330 and 0630 h (pubertal stage: F = 6.629; P = 0.015; gender: F = 1.850; P = 0.211; interaction: F = 0.422; P = 0.742); the results were not statistically significant for the AUC computed between 1900 and 2230 h. Although a larger sample size would be needed to check on the reliability of these results and to carry such multiple factorial analyses further, the trends suggested in the present study are consistent with an effect of pubertal stage on circulating melatonin concentrations observed primarily during the dark span.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
During childhood, serum melatonin concentrations have been reported to drop by approximately 80% (22). Arrest of pineal growth after the end of infancy has been proposed as one possible mechanism underlying this observation; based on magnetic resonance imaging brain studies, Schmidt et al. showed that the average size of the pineal gland did not differ with age (between 1 day and 15 yr), whereas the average pituitary size increased by about 100%, being slightly larger in girls than in boys.

Important somatic changes occur during adolescence, which lead to sexual maturation, pubertal growth, and active functions of reproduction. Mean ages of onset of puberty are estimated to be 10.9 and 11.2 yr in girls and boys, respectively (23). Menarche is estimated to occur around 13.4 yr and may be related to a critical weight (23). At the onset of puberty, the hypothalamus, after being quiescent, resumes a marked pulsatile secretion of GnRH, leading to an increased secretion of pituitary gonadotropins which, in turn, stimulates the gonadal functions, that is the secretion of testosterone or estradiol and the maturation of spermatogenesis or the ovarian follicle (24). Cerebral adrenergic and/or dopamine neurotransmitters, endogenous opioids, and melatonin from the pineal gland are some of the neuroendocrine factors thought to be involved in the onset of puberty (23).

Reports on a coincidence of pineal tumors and precocious puberty in man initiated a host of animal experiments. These revealed a modulating effect on sexual maturation and gonadal activity in several species, brought about by melatonin and its circadian secretion pattern (25). The mean nighttime serum melatonin concentration in humans was low during the first 6 months of life (mean ± SE, 27.3 ± 5.4 pg/mL), increased to a peak value at 1–3 yr of age (329.5 ± 42.0 pg/mL), and declined thereafter, averaging 62.5 ± 9.0 pg/mL in individuals aged 15–20 yr and 29.2 ± 6.1 pg/mL in old age (70–90 yr) (26). The age dependence was modulated by two exponential functions with different slopes for ages 1–20 and 20–90 yr (26). The decrease in nocturnal serum melatonin in children and adolescents correlated with body weight and body surface area, whereas no such correlation was found at a later age (26, 27).

In children, a progressive decrease in nocturnal serum melatonin has been reported with advancing age, suggesting a reduction in the circadian amplitude with maturation (24). Nocturnal plasma melatonin concentrations determined hourly between 1800 and 0800 h in 62 healthy children, 5–17 yr of age, indicated a statistically significant linear decreasing trend in peak melatonin with pubertal stage (28) (Tanner criteria; from 153.6 ± 72.6 pg/mL for stage 1 and 141.0 ± 26.2 pg/mL for stage 2 to 116.6 ± 43.6 pg/mL for stages 3–5). Results from our study indicate peak melatonin concentrations (mean ± SE) of 130.7 ± 12.2 pg/mL for stage 1, 113.6 ± 9.1 pg/mL for stage 2, and 67.1 ± 13.4 pg/mL for stages 3 and 4. Although these values are slightly lower than those reported by Cavallo (28), they also show a slight decline in melatonin peak as well as in 12-h AUC from prepubertal stage 1 to pubertal stage 2 and a greater decline from stage 2 to the more advanced stages of puberty, 3 and 4. Similar results were reported for a population of 113 children (29) as well as for the relationship of the urinary excretion rate of 6-hydroxymelatonin sulfate, the main metabolite of melatonin, to pubertal development (30). In overnight urine collections, 6-hydroxymelatonin sulfate was statistically significantly higher in 99 prepubertal children (35.5 ± 2.3 ng/h·kg BW) than in 86 pubertal children (18.1 ± 1.1 ng/h·kg BW) or in 29 adults (15.0 ± 1.5 ng/h·kg BW); no difference was found among pubertal stages 2–5 (30).

Compared to regularly cycling women, female patients with anorexia nervosa were reported to have lowered concentrations of circulating gonadotropins and several steroids and elevated peak concentrations of melatonin and serotonin (31). Continuous physical training, in turn, has been reported to produce alterations in antireproductive hormone secretion such as melatonin, which can play an inhibitory role on the menstrual cycle hormone patterns in physically active pubertal girls (32).

The usual trend in melatonin observed as a function of pubertal stage is altered in the presence of pubertal disorders (29). Based on serum samples collected at 15-min intervals from 1900–0700 h in a controlled light-dark environment, complete bed rest, and fasting with simultaneous sleep recordings, dark-time melatonin concentrations were reportedly elevated in male patients with hypogonadotropic hypogonadism (286 ± 26 pmol/L) or delayed puberty (205 ± 44 pmol/L) compared with those in healthy controls (178 ± 64 pmol/L) (33). By contrast, the plasma melatonin concentrations of a girl with central precocious puberty were reportedly low for chronological age, but appropriate for pubertal status (34). Moreover, nocturnal serum melatonin (between 2300 and 0100 h) was statistically significantly lower in 1- to 5-yr-old patients with central precocious puberty compared to healthy controls, whereas pubertal patients aged 5–9 yr had circulating melatonin concentrations in the same range as healthy subjects approaching pubertal age (24). In contrast to endocrinologically unremarked children, there was no age-dependent decrease in nocturnal melatonin in untreated precocious puberty; rather, it appeared that serum melatonin had already declined in association with the onset of sexual maturation (24).

Pituitary-gonadal suppression induced by long-term GnRH analog treatment did not result in a return to prepubertal melatonin values, and nocturnal serum melatonin concentrations actually decreased during therapy (24). This result was interpreted as indicating that the reduction of nocturnal melatonin with unremarked puberty is probably not dependent on pubertal gonadotropin or a sex steroid milieu (24). To determine whether the pharmacokinetics of melatonin change during puberty, melatonin in serum and saliva and 6-hydroxymelatonin sulfate in urine were determined after an iv infusion of melatonin in prepubertal, pubertal, and adult subjects (35). Results suggested that prepubertal children metabolize melatonin faster than adults (35). In light of its physiological role in animals, among potential deleterious effects of long-term use of melatonin treatment, the inhibition of reproductive function and the delayed timing of puberty have been put forward (36).

It has rightly been pointed out that many studies of melatonin in human subjects are difficult to interpret because of methodological considerations (37). Among limitations listed by Cavallo (37) are the use of single blood samples collected during the day or the night, failure to include temporal characteristics of melatonin secretion, lack of control of the actual duration and intensity of light exposure, and use of broad clinical features without hormonal markers to define puberty.

The present investigation, although restricted to nocturnal blood sampling, suggests a relation of melatonin with pubertal stage rather than with chronological age. One weakness of the study was a slight difference in age between boys and girls (t = 2.425; P = 0.029); the boys were slightly older (158.5 ± 11.4 months) than the girls (127.9 ± 5.4 months). Nonetheless, the negative relationship of 12-h AUC is seen more prominently vs. pubertal stage than vs. chronological age, even when the data are analyzed separately for boys and girls; whereas a regression vs. pubertal stage yields statistically significant results for both genders (boys: r = -0.835; P = 0.010; girls: r = -0.847; P = 0.008), a regression vs. chronological age shows a weaker association that is statistically significant only for boys and not for girls (boys: r = -0.744; P = 0.034; girls: r = -0.365; P = 0.374). In each case, the major contribution of an effect of pubertal stage on AUC is from the dark-exposed determinations of melatonin (boys: r = -0.741; P = 0.035; girls: r = -0.844; P = 0.008). It is hence unlikely that the difference in chronological age between boys and girls biased the results. Regardless of pubertal and chronological age, the study also detected ultradian components whose role in human development awaits further investigation, which would benefit from concomitant polygraphic recordings to allow examination of any role played by REM sleep in the synchronization of these ultradian components.

Even though a literature review failed to locate prior studies reporting on ultradian components in circulating melatonin in children, the approximately 1.5-h component described herein is in keeping with an earlier report on the episodic secretion of melatonin in pre- and postpubertal girls and boys (38). In the latter study, Penny (38) determined the concentration of melatonin in serum samples obtained at 15-min intervals during a 4-h span (0800–1300 h) from 11 girls, 9.5–16.5 yr of age, and from 8 boys, 9.0–16.8 yr of age. In 1985, when Penny’s results were published, methods sensitive enough to reliably measure daytime melatonin may not yet have been available. The author reports, however, a lower limit of 2.5 pg for the sensitivity of the melatonin assay used (38). The increment in secretory episodes of melatonin (found in all subjects) in his study averaged 50 ± 5 pg/mL, well above the limit of sensitivity of the assay used. The 3.1 ± 0.4 and 3.4 ± 0.5 episodes reported over 4 h for girls and boys, respectively, correspond approximately to an average 1.5-h cycle and may thus be trustworthy. The extent to which this component of variation relates to the REM cycle also awaits further studies, notably because one of the major short-term side effects following oral ingestion of synthetic melatonin is the increased tendency toward sleepiness (7, 36).

Another investigation of six young men studied twice at 1-week intervals, each time for 12 h (from 2000–0800 h) with blood sampling at 20-min intervals, revealed an episodic secretion of melatonin (39). The mean frequency of 4.0 to 4.5 peaks/night and 3.5 to 4.0 troughs/night reported in that study corresponds approximately to the 3.4-h component observed herein. It should be pointed out, however, that attempts to assess the short-term secretion pattern of melatonin have provided inconsistent results; Trinchard-Lugan and Waldhauser (40) could not detect clear pulses, but, rather, found a continuous release of the hormone in their studies based on very densely sampled blood at 3- to 10-min intervals. Some of the discrepancy among these different studies may stem from the specific methodology used and the precise hypothesis tested by the different investigators. Focus on any pulsatile secretion of melatonin is usually investigated by computer programs searching specifically for pulses, that is sharp (abrupt) changes in the circulating concentration of the hormone. The methods used herein, in turn, do not make such an assumption, and the approximately 3.4- and 1.5-h ultradian components detected in the present study are compatible with a continuous secretion of melatonin. The concentrations are smoothly modulated by the two ultradian components superposed upon the more prominent circadian rhythm.

Any relation with sleep patterns that exhibit similar ultradian variations awaits the concomitant assessment of circulating melatonin, preferably at intervals much shorter than 30 min, and of electroencephalographic and electrooculographic data. Once such data become available, more powerful techniques could be used, including superposed epochs and the computation of cross-spectral coherence. Polysomnographic studies have already shown the possibility to treat REM sleep behavior disorder (REM sleep without muscle atonia) with melatonin (41). Moreover, melatonin administration in doses of 5 mg or more before nocturnal sleep was reportedly associated with an increase in REM sleep (42). When administered at 1000 h in doses of 1, 10, and 40 mg, however, melatonin did not affect REM sleep (43). A chronobiological approach that takes into consideration both the time structure (chronome) of circulating melatonin and the schedule of administration of melatonin may help avoid controversy (42, 43) while also shedding new light concerning the etiology of pathology. A case in point may be sudden infant death syndrome, which tends to occur in the cold winter months and in the early morning hours, when darkness is prolonged, and which is reportedly associated with an increase in REM sleep from 0200–0500 h (44) as well as with lowered concentrations of melatonin in ventricular cerebrospinal fluid obtained at autopsy (45). It is also fitting that melatonin has been described as a sleep-promoting hormone (46); its participation in sleep was already postulated in 1986 (47). In summary, the results presented herein confirm known changes in nocturnal melatonin concentrations in relation to pubertal stage while revealing ultradian components that may serve as added tools in a variety of physiological and medical applications along with other components of the chronome of circulating melatonin.

Received June 4, 1999.

Revised January 8, 2000.

Accepted March 11, 2000.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Lerner AB, Case JD, Heinzelman RV. 1959 Structure of melatonin [Letter to the Editor]. J Am Chem Soc. 81:6084–6085.
  2. Wetterberg L, Sanchez de la Peña S, Halberg F. 1990 Circadian rhythm of melatonin release from pineal, hypothalamus and pituitary in hypertensive rats. Prog Clin Biol Res. 341B:145–153.
  3. Fèvre-Montange M. 1985 La mélatonine. Presse Med. 14:1659–1663.
  4. Turek FW, Desjardins C, Menaker M. 1975 Melatonin: antigonadal and progonadal effects in male golden hamsters. Science. 190:280–282.[Abstract/Free Full Text]
  5. Halberg F. 1983 Quo vadis basic and clinical chronobiology: promise for health maintenance. Am J Anat. 168:543–594.[CrossRef][Medline]
  6. Sanchez de la Peña S, Halberg F, Ungar F, Lakatua D. 1988 Ex vivo hierarchy of circadian-infradian rhythmic pineal-pituitary-adrenal intermodulations in rodents. In: Pancheri P, Zichella L, eds. Biorhythms and stress in the physiopathology of reproduction. New York: Hemisphere; 177–214.
  7. Dollins AB, Zhdanova IV, Wurtman RJ, Lynch HJ, Deng MH. 1994 Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance. Proc Natl Acad Sci USA. 91:1824–1828.[Abstract/Free Full Text]
  8. Quay WB. 1964 General biochemistry of the pineal gland of mammals. In: Reiter RJ, ed. The pineal gland. Boca Raton: CRC Press; 173–198.
  9. Lynch HJ, Wurtman R, Moskowitz MA, Archer MC, Ho MH. 1975 Daily rhythm in human urinary melatonin. Science187 :169–171.
  10. Halberg F, Halberg E, Barnum CP, Bittner JJ. 1959 Physiologic 24-hour periodicity in human beings and mice, the lighting regimen and daily routine. In: Withrow RB, ed. Photoperiodism and related phenomena in plants and animals. Washington DC: American Association for Advances in Science; Publication 55:803–878.
  11. Molina-Carballo A, Munoz-Hoyos A, Martin-Garcia JA, Uberos-Fernandez J, Rodriguez-Cabezas T, Acuno-Castroviejo D. 1996 5-methoxytryptophol and melatonin in children: differences due to age and sex. J Pineal Res. 21:73–79.[Medline]
  12. Greulich WW, Pyle SI. 1959 Radiographic atlas of skeletal development of hand and wrist, 2nd Ed. Stanford: Stanford University Press.
  13. Tanner JM, Whitehouse RH. 1976 Clinical longitudinal standards for height, weight, height velocity, weight velocity and stages of puberty. Arch Dis Child. 51:170–179.[Abstract]
  14. Plebani M, Masiero M, Burlina AP, Chiozza ML, Scanarini M, Burlina A. 1990 Measurement of melatonin in blood by radioimmunoassay. Analytical considerations and clinical usefulness. Child Nervous System. 6:220–221.[CrossRef]
  15. Halberg F. 1969 Chronobiology. Annu Rev Physiol. 31:675–725.[CrossRef][Medline]
  16. Halberg F. 1980 Chronobiology: methodological problems. Acta Med Rom. 18:399–440.
  17. Cornélissen G, Halberg F. 1998 Chronomedicine. In: Armitage P, Colton T, eds. Encyclopedia of biostatistics, volume 1. Chichester: Wiley & Sons; 642–649.
  18. Sokal RR, Rohlf FJ. 1981 Biometry: the principles and practice of statistics in biological research, 2nd Ed. San Francisco: Freeman.
  19. Bingham C, Cornélissen G, Halberg F. 1993 Power of "phase 0" chronobiologic trials at different signal-to-noise ratios and sample sizes. Chronobiologia. 20:179–190.[Medline]
  20. Halberg F, Bingham C, Cornélissen G. 1993 Clinical trials: the larger the better? Chronobiologia. 20:193–212.[Medline]
  21. Cornélissen G, Halberg F. 1994 Introduction to chronobiology. Medtronic chronobiology seminar 7. URL http://revilla.mac.cie.uva.es/chrono.
  22. Schmidt F, Penka B, Trauner M, et al. 1995 Lack of pineal growth during childhood. J Clin Endocrinol Metab. 80:1221–1225.[Abstract]
  23. Sizonenko PC. 1989 Physiology of puberty. J Endocrinol Invest. 12(Suppl):59–63.
  24. Waldhauser F, Boepple PA, Schemper M, Mansfield MJ, Crowley Jr WF. 1991 Serum melatonin in central precocious puberty is lower than in age-matched prepubertal children. J Clin Endocrinol Metab. 73:793–796.[Abstract]
  25. Waldhauser F, Steger H. 1986 Changes in melatonin secretion with age and pubescence. J Neural Trans. 21(Suppl):183–197.
  26. Waldhauser F., Weiszenbacher G., Tatzer E., et al. 1988 Alterations in nocturnal serum melatonin levels in humans with growth and aging. J Clin Endocrinol Metab. 66:648–652.[Abstract]
  27. Young IM, Francis PL, Leone AM, Stovell P, Silman RE. 1988 Constant pineal output and increasing body mass account for declining melatonin levels during human growth and sexual maturation. J Pineal Res. 5:71–85.[Medline]
  28. Cavallo A. 1992a Plasma melatonin rhythm in normal puberty: interactions of age and pubertal stages. Neuroendocrinology. 55:372–379.
  29. Cavallo A. 1992b Melatonin secretion during adrenarche in normal human puberty and in pubertal disorders. J Pineal Res. 12:71–78.
  30. Cavallo A, Dolan LM. 1996 6-Hydroxymelatonin sulfate excretion in human puberty. J Pineal Res. 21:225–230.[Medline]
  31. Hoffmann G, Pollow K, Nowara D, Pollow B, Schaffrath M. 1996 Zirkadiane Serotonin- und Melatonin-Serumspiegel bei Anorexia-nervosa-Patientinnen im Vergleich zu normal-menstruierenden Frauen. Geburtshilfe Frauenheilkd. 56:485–490.[Medline]
  32. Diaz B, Garcia R, Colmenero MD, Terrados N, Fernandez B, Marin B. 1993 Melatonin and gonadotropin hormones in pubertal sportsgirls. Rev Esp Fisiol. 49:17–22.[Medline]
  33. Luboshitzky R, Lavi S, Thuma I, Herer P, Lavie P. 1996 Nocturnal secretory patterns of melatonin, luteinizing hormone, prolactin and cortisol in male patients with gonadotropin-releasing hormone deficiency. J Pineal Res. 21:49–54.[Medline]
  34. Commentz JC, Helmke K. 1995 Precocious puberty and decreased melatonin excretion due to a hypothalamic hamartoma. Horm Res. 44:271–275.[Medline]
  35. Cavallo A, Ritschel WA. 1996 Pharmacokinetics of melatonin in human sexual maturation. J Clin Endocrinol Metab. 81:1882–1886.[Abstract]
  36. Arendt J. 1997 Safety of melatonin in long-term use [Review]. J Biol Rhythms. 12:673–681.
  37. Cavallo A. 1993 Melatonin and human puberty: current perspectives. J Pineal Res. 15:115–121.[Medline]
  38. Penny R. 1985 Episodic secretion of melatonin in pre- and postpubertal girls and boys. J Clin Endocrinol Metab. 60:751–756.[Abstract]
  39. Claustrat B, Brun J, Garry P, Roussel B, Sassolas G. 1986 A once-repeated study of nocturnal plasma melatonin patterns and sleep recordings in six normal young men. J Pineal Res. 3:301–310.[Medline]
  40. Trinchard-Lugan I, Waldhauser F. 1989 The short-term secretion pattern of human serum melatonin indicates apulsatile hormone release. J Clin Endocrinol Metab. 69:663–669.[Abstract]
  41. Kunz D, Bes F. 1999 Melatonin as a therapy in REM sleep behavior disorder patients: an open-labeled pilot study on the possible influence of melatonin on REM-sleep regulation. Movement Disord. 14:507–511.
  42. Dijk DJ, Cajochen C. 1997 Melatonin and the circadian regulation of sleep initiation, consolidation, structure, and the sleep EEG. J Biol Rhythms. 12:627–635.
  43. Hughes RJ, Badia P. 1997 Sleep-promoting and hypothermic aspects of daytime melatonin administration in humans. Sleep 20:124–131.
  44. Cornwell AC, Feigenbaum P, Kim A. 1998 SIDS, abnormal nighttime REM sleep and CNS immaturity. Neuropediatrics29 :72–79.
  45. Sturner WQ, Lynch HJ, Deng MH, Gleason RE, Wurtman RJ. 1990 Melatonin concentrations in the sudden infant death syndrome. Forensic Sci Int. 45:171–180.[CrossRef][Medline]
  46. Zhdanova IV, Lynch HJ, Wurtman RJ. 1997 Melatonin: a sleep-promoting hormone. Sleep 20:899–907.
  47. Wurtman RJ. 1986 Melatonin in humans. J Neur Trans. 21(Suppl):1–8.



This article has been cited by other articles:


Home page
 Endocr. Rev.Home page
A.-S. Parent, G. Teilmann, A. Juul, N. E. Skakkebaek, J. Toppari, and J.-P. Bourguignon
The Timing of Normal Puberty and the Age Limits of Sexual Precocity: Variations around the World, Secular Trends, and Changes after Migration
Endocr. Rev., October 1, 2003; 24(5): 668 - 693.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
A. Muñoz-Hoyos, R. Jaldo, A. Molina-Carballo, G. Escames, M. Macías, J. M. Fernández-GarcÍa, R. J. Reiter, and D. Acuña-Castroviejo
Characterization of Nocturnal Ultradian Rhythms of Melatonin in Children with Growth Hormone-Dependent and Independent Growth Delay
J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1181 - 1187.
[Abstract] [Full Text]

Home page
 J. Clin. Endocrinol. Metab.Home page
R. J. Wurtman
Editorial: Age-Related Decreases in Melatonin Secretion--Clinical Consequences
J. Clin. Endocrinol. Metab., June 1, 2000; 85(6): 2135 - 2136.
[Full Text]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Salti, R.
Right arrow Articles by Cornélissen, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Salti, R.
Right arrow Articles by Cornélissen, G.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals