The objective of this study was to analyze circadian patterns of urinary 6-sulphatoxymelatonin (aMT6s) excretion in children with primary sleep disorders in comparison with healthy controls. A total of 124 control children and 124 patients (aged 4-14 years) diagnosed with diverse primary sleep disorders were recruited. aMT6s concentrations were measured in diurnal and nocturnal urine, as well as in 24-hour urine. aMT6s levels were significantly higher and showed significantly more evident circadian variations in the control group (P < .001). Four different melatonin (aMT) production and excretion patterns were distinguished in the group with sleep disorders: (1) standard aMT production pattern, (2) low aMT production pattern, (3) aMT production pattern with absence of circadian variation, and (4) aMT hyperproduction pattern. This study highlights the importance of analyzing specific alterations of aMT secretion in each sleep disorder and provides evidences to explain why not all children with sleep disturbances do respond to aMT treatment.
OwensJ. Classification and epidemiology of childhood sleep disorders. Prim Care. 2008;35:533–546.
2.
HeringEEpsteinRElroyS. Sleep patterns in autistic children. J Autism Dev Disord. 1999;29:143.
3.
DewaldJMeijerAOortF. The influence of sleep quality, sleep duration and sleepiness on school performance in children and adolescents: a meta-analytic review. Sleep Med Rev. 2010;14:179–189.
4.
MeijerAHabekothéHVan Den WittenboerG. Time in bed, quality of sleep and school functioning of children. J Sleep Res. 2000;9:145–153.
5.
WiggsLStoresG. Sleep Disturbance in Children and Adolescents with Disorders of Development: Its Significance and Management. London: Mac Keith Press; 2001.
LamPHiscockHWakeM. Outcomes of infant sleep problems: a longitudinal study of sleep, behavior, and maternal well-being. Pediatrics. 2003;111:203–207.
8.
KalesA. Benzodiazepine hypnotics and insomnia. Hosp Pract (Off Ed). 1990;25:7–21.
9.
GreenblattD. Pharmacology of benzodiazepine hypnotics. J Clin Psychiatry. 1992;53(suppl):7–13.
10.
SteinbergRSoykaM. Problems in long-term benzodiazepine treatment [in German]. Schweiz Rundsch Med Prax. 1989;78:784–787.
11.
SingerCWildKSackR. High dose melatonin is well tolerated by the elderly. Sleep Res. 1994;23:86.
12.
Cara-GranadosM. Analysis of biochemical and hematological modifications after prolonged oral intake of N-acetyl-5-methoxytriptamine in healthy volunteers [dissertation]. Granada, Spain: University of Granada; 1998.
13.
LiebermanHWaldhauserFGarfieldG. Effects of melatonin on human mood and performance. Brain Res. 1984;323:201–207.
14.
ZhdanovaIWurtmanRLynchH. Sleep-inducing effects of low doses of melatonin ingested in the evening. Clin Pharmacol Ther. 1995;57:552–558.
15.
McArthurALewyASackR. Non-24-hour sleep-wake syndrome in a sighted man: circadian rhythm studies and efficacy of melatonin treatment. Sleep. 1996;19:544–553.
16.
SahelianR. Melatonin: Nature’s Sleeping Pill. Marina Del Rey, CA: Be Happier Press; 1995.
17.
JanJO’DonnellM. Use of melatonin in the treatment of paediatric sleep disorders. J Pineal Res. 1996;21:193–199.
18.
Muñoz-HoyosAEspín-QuirantesCMolina-CarballoA. Neuroendocrine and circadian aspects (melatonin and beta-endorphin) of atopic dermatitis in the child. Pediatr Allergy Immunol. 2007;18:679–686.
19.
Muñoz-HoyosABonillo-PeralesAÁvila-VillegasR. Melatonin levels during the first week of life and their relation with the antioxidant response in the perinatal period. Neonatology. 2007;92:209–216.
20.
Molina-CarballoAFernández-TardáquilaEUberos-FernándezJ. Longitudinal study of the simultaneous secretion of melatonin and leptin during normal puberty. Horm Res. 2007;68:11–19.
21.
Muñoz-HoyosAHerediaFMorenoF. Evaluation of plasma levels of melatonin after midazolam or sodium thiopental anesthesia in children. J Pineal Res. 2002;32:253–256.
22.
Muñoz-HoyosAJaldoRMolina-CarballoA. Characterization of nocturnal ultradian rhythms of melatonin in children with growth hormone-dependent and independent growth delay. J Clin Endocrinol Metab. 2001;86:1181–1187.
23.
Muñoz-HoyosASánchez-ForteMMolina-CarballoA. Melatonin’s role as an anticonvulsant and neuronal protector: experimental and clinical evidence. J Child Neurol. 1998;13:501–509.
24.
GarcíaJReiterRGuerreroJ. Melatonin prevents changes in microsomal membrane fluidity during induced lipid peroxidation. FEBS Lett. 1997;408:297–300.
25.
ReiterRTangLGarcíaJ. Pharmacological actions of melatonin in oxygen radical pathophysiology. Life Sci. 1997;60:2255–2271.
26.
BlackmerAFeinsteinJ. Management of sleep disorders in children with neurodevelopmental disorders: a review. Pharmacotherapy. 2016;36:84–98.
27.
Sniecinska-CooperAIlesRButlerS. Abnormal secretion of melatonin and cortisol in relation to sleep disturbances in children with Williams syndrome. Sleep Med. 2015;16:94–100.
28.
DamianiJMSweetBVSohoniP. Melatonin: an option for managing sleep disorders in children with autism spectrum disorder. Am J Health Syst Pharm. 2014;71:95–101.
van GeijlswijkIMvan der HeijdenKBEgbertsA. Dose finding of melatonin for chronic idiopathic childhood sleep onset insomnia: an RCT. Psychopharmacology (Berl). 2010;212:379–391.
31.
van GeijlswijkIMKorziliusHPSmitsMG. The use of exogenous melatonin in delayed sleep phase disorder: a meta-analysis. Sleep. 2010;33:1605.
Ferracioli-OdaEQawasmiABlochMH. Meta-analysis: melatonin for the treatment of primary sleep disorders. PLoS One. 2013;8:e63773.
34.
WassmerEQuinnEWhitehouseW. Melatonin as a sleep inductor for electroencephalogram recordings in children. Clin Neurophysiol. 2001;112:683–685.
35.
WassmerEFogartyMPageA. Melatonin as a sedation substitute for diagnostic procedures: MRI and EEG. Dev Med Child Neurol. 2001;43:136.
36.
van MaanenAMeijerAMSmitsMG. Termination of short term melatonin treatment in children with delayed dim light melatonin onset: effects on sleep, health, behavior problems, and parenting stress. Sleep Med. 2011;12:875–879.
37.
ReiterRTanDManchesterL. Biochemical reactivity of melatonin with reactive oxygen and nitrogen species: a review of the evidence. Cell Biochem Biophys. 2001;34:237–256.
38.
Alonso-AlconadaDAlvarezAArteagaO. Neuroprotective effect of melatonin: a novel therapy against perinatal hypoxia-ischemia. Int J Mol Sci. 2013;14:9379–9395.
39.
RobertsonNJFaulknerSFleissB. Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model. Brain. 2013;136:90–105.
40.
CorteseS. Sleep and ADHD: what we know and what we do not know. Sleep Med. 2015;16:5.
41.
BruniOAlonso-AlconadaDBesagF. Current role of melatonin in pediatric neurology: clinical recommendations. Eur J Paediatr Neurol. 2015;19:122–133.
42.
HaimovILaudonMZisapelN. Sleep disorders and melatonin rhythms in elderly people. BMJ. 1994;309:167.
43.
HajakGRodenbeckAAdlerL. Nocturnal melatonin secretion and sleep after doxepin administration in chronic primary insomnia. Pharmacopsychiatry. 1996;29:187–192.
44.
RodenbeckAHuetherGHajakG. Sleep disorders and aging: understanding the causes. In: TouitouY, ed. Biological Clocks, Mechanisms and Application. Amsterdam: Elsevier; 1998:329–332.
45.
LegerDLaudonMZisapelN. Nocturnal 6-sulfatoxymelatonin excretion in insomnia and its relation to the response to melatonin replacement therapy. Am J Med. 2004;116:91–95.
46.
MacFarlaneJCleghornJBrownG. Melatonin and core temperature rhythm in chronic insomnia. Adv Biosci. 1984;53:303–306.
47.
KripkeDElliotJYoungstedtS. Melatonin: marvel or marker?Ann Med. 1998;30:81–87.
48.
BaskettJWoodPBroadJ. Melatonin in older people with age-related sleep maintenance problems: a comparison with age matched normal sleepers. Sleep. 2001;24:418–424.
49.
LushingtonKDawsonDKennawayD. The relationship between 6-sulphatoxymelatonin and polysomnographic sleep in good sleeping controls and wake maintenance insomniacs, aged 55–80 years. J Sleep Res. 1999;8:57–64.
50.
HughesRSackRLewyA. The role of melatonin and circadian phase in age-related sleep-maintenance insomnia: assessment in a clinical trial of melatonin replacement. Sleep. 1998;21:52–68.
51.
TzischinskyOShlitnerALavieP. The association between the nocturnal sleep gate and nocturnal onset of urinary 6-sulphatoxymelatonin. J Biol Rhythms. 1993;8:199–209.
52.
OrenDTurnerEWehrT. Abnormal circadian rhythms of plasma melatonin and body temperature in the delayed sleep phase syndrome. J Neurol Neurosurg Psychiatry. 1995;58:379.
JonesCCampbellSZoneS. Familial advanced sleep-phase syndrome: a short-period circadian rhythm variant in humans. Nat Med. 1999;5:1062–1065.
55.
SatohKMishimaKInoueY. Two pedigrees of familial advanced sleep phase syndrome in Japan. Sleep. 2003;26:416–417.
56.
American Academy of Sleep Medicine. International Classification of Sleep Disorders. 3rd ed. Darien, IL: American Academy of Sleep Medicine; 2014.
57.
World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310:2191–2194.
58.
KennawayD. Melatonin and development: physiology and pharmacology. Semin Perinatol. 2000;24:258–266.
59.
Muñoz-HoyosARodríguez-CabezasTMolina-CarballoA. Melatonin concentration in the umbilical artery and vein in human preterm and term neonates and neonates with acute fetal distress. J Pineal Res. 1992;13:184–191.
60.
Muñoz-HoyosAJaldo-AlbaFMolina-CarballoA. Absence of plasma melatonin circadian rhythm during the first 72 hours of life in human infants. J Clin Endocrinol Metab. 1993;77:699–703.
61.
SmitsMNagtegaalEvan der HeijdenJ. Melatonin for chronic sleep onset insomnia in children: a randomized placebo-controlled trial. J Child Neurol. 2001;16:86–92.
62.
BraamWSmitsMGDiddenR. Exogenous melatonin for sleep problems in individuals with intellectual disability: a meta-analysis. Dev Med Child Neurol. 2009;51:340–349.
63.
OwensJARosenCLMindellJA. Use of pharmacotherapy for insomnia in child psychiatry practice: a national survey. Sleep Med. 2010;11:692–700.
64.
GringrasPGambleCJonesAP. Melatonin for sleep problems in children with neurodevelopmental disorders: randomised double masked placebo controlled trial. BMJ. 2012;345:e6664.
65.
CavalloAGoodWDouglasR. Dose response to melatonin treatment for disordered sleep rhythm in a blind child. Sleep Med. 2002;3:159–161.
66.
RossCMorrisBWhitehouseW. Melatonin treatment of sleep-wake cycle disorders in children and adolescents. Dev Med Child Neurol. 1999;41:850.
67.
FauteckJSchmidtHLerchlA. Melatonin in epilepsy: first results of replacement therapy and first clinical results. Biol Signals Recept. 1999;8:105–110.
68.
JanJFreemanRFastD. Melatonin treatment of sleep-wake cycle disorders in children and adolescents. Dev Med Child Neurol. 1999;41:491–500.
69.
DavittBMorganCCruzO. Sleep disorders in children with congenital anophthalmia and microphthalmia. J AAPOS. 1997;1:151–153.
70.
MartínezG. Circadian regulation of behavior: differences between diurnal and nocturnal species. Biol Reprod. 2009;8:487–496.
71.
DeaconSEnglishJArendtJ. Acute phase-shifting effects of melatonin associated with suppression of core body temperature in humans. Neurosci Lett. 1994;178:32–34.
72.
de LeceaLSutcliffeJ. The hypocretins and sleep. FEBS J. 2005;272:5675–5688.
73.
UberosJAugustin-MoralesMMolina CarballoA. Normalization of the sleep-wake pattern and melatonin and 6-sulphatoxy-melatonin levels after a therapeutic trial with melatonin in children with severe epilepsy. J Pineal Res. 2011;50:192–196.
74.
Yung-SenCMing-HungLJyh-HongL. Melatonin supplementation for children with atopic dermatitis and sleep disturbance: a randomized clinical trial. JAMA Pediatr. 2016;170:35–42.
75.
GuerreroJPozoDDiaz-RodriguezJ. Impairment of the melatonin rhythm in children with Sanfilippo syndrome. J Pineal Res. 2006;40:192–193.
76.
TamarkinLAbastillasPChenH. The daily profile of plasma melatonin in obese and Prader-Willi syndrome children. J Clin Endocrinol Metab. 1982;55:491–495.
77.
UberosJRomeroJMolina-CarballoA. Melatonin and elimination of kynurenines in children with Down’s syndrome. J Pediatr Endocrinol Metab. 2010;23:277–282.
78.
GuénoléFGodboutRNicolasA. Melatonin for disordered sleep in individuals with autism spectrum disorders: systematic review and discussion. Sleep Med Rev. 2011;15:379–387.
79.
GuénoléFBaleyteJ. Effects of melatonin should be studied separately in each neurodevelopmental disorder and with specific sleep diagnoses. Pediatr Neurol. 2012;46:60.
80.
KnookLKavelaarsASinnemaG. High nocturnal melatonin in adolescents with chronic fatigue syndrome. J Clin Endocrinol Metab. 2000;85:3690–3692.
81.
ChamberlainBHermanB. A novel biochemical model linking dysfunctions in brain melatonin, proopiomelanocortin peptides, and serotonin in autism. Biol Psychiatry. 1990;28:773–793.
82.
BraamWKeijzerHStruijker BoudierH. CYP1A2 polymorphisms in slow melatonin metabolisers: a possible relationship with autism spectrum disorder?J Intellect Disabil Res. 2013;57:993–1000.
83.
ClaustratBBrunJChazotG. The basic physiology and pathophysiology of melatonin. Sleep Med Rev. 2005;9:11–24.
84.
DubocovichMMarkowskaM. Functional MT1 and MT2 melatonin receptors in mammals. Endocrine. 2005;27:101–110.
85.
AldhousMFraneyCWrightJ. Plasma concentrations of melatonin in man following oral absorption of different preparations. Br J Clin Pharmacol. 1985;19:517–521.
86.
SmitsMGvan der HeijdenKMeijerAM. Melatonin improves health status and sleep in children with idiopathic chronic sleep-onset insomnia: a randomized placebo-controlled trial. J Am Acad Child Adolesc Psychiatry. 2003;42:1286–1293.
87.
van der HeijdenKBSmitsMGvan SomerenEJ. Prediction of melatonin efficacy by pretreatment dim light melatonin onset in children with idiopathic chronic sleep onset insomnia. J Sleep Res. 2005;14:187–194.
88.
KeijzerHSmitsMGDuffyJF. Why the dim light melatonin onset (DLMO) should be measured before treatment of patients with circadian rhythm sleep disorders. Sleep Med Rev. 2014;18:333–339.
89.
KovácsJBrodnerWKirchlechnerV. Measurement of urinary melatonin: a useful tool for monitoring serum melatonin after its oral administration. J Clin Endocrinol Metab. 2000;85:666–670.
90.
YoungILeoneRFrancisP. Melatonin is metabolized to JV-acetyl serotonin and 6-hydroxymelatonin in man. J Clin Endocrinol Metab. 1985;60:114–119.
91.
GarfinkelDLaudonMNofD. Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet. 1995;346:541–544.
92.
WaldhauserFWaldhauserMLiebermanH. Bioavailability of oral melatonin in humans. Neuroendocrinology. 1984;39:307–313.
93.
CavalloA. The pineal gland in human beings: relevance to pediatrics. J Pediatr. 1993;123:843–851.
94.
Molina-CarballoAMuñoz-HoyosAMartín-GarcíaJ. 5-Methoxytryptophol and melatonin in children: differences due to age and sex. J Pineal Res. 1996;21:73–79.
95.
Molina-CarballoAMuñoz-HoyosAUberos-FernándezJ. Pineal functioning (melatonin levels) in healthy children of different ages. An update and the value of pineal gland study in pediatrics. An Esp Pediatr. 1996;45:33–44.
96.
DiamandisEP. Immunoassay interference: a relatively rare but still important problem. Clin Biochem. 2004;37:331–332.
97.
ColeLAKhanlianSA. Easy fix for clinical laboratories for the false-positive defect with the Abbott AxSym total β-hCG test. Clin Biochem. 2004;37:344–349.
98.
LepageRAlbertC. Fifty years of development in the endocrinology laboratory. Clin Biochem. 2006;39:542–557.
99.
de AlmeidaEDi MascioPHarumiT. Measurement of melatonin in body fluids: standards, protocols and procedures. Childs Nerv Syst. 2011;27:879–891.
