The Endogenous Melatonin Profile as a Marker for Circadian Phase Position

Several circadian rhythms have been used to assess the phase of the endogenous circadian pacemaker (ECP). However, when more than one marker rhythm is measured, results do not always agree. Questions then inevitably arise. Are there multiple oscillators? Are some markers more reliable than others? Masking is a problem for all marker rhythms. Masking of melatonin is minimized by sampling under dim light. The dim-light melatonin onset (DLMO) is particularly convenient since it can usually be obtained before sleep. However, assessing the DLMO in low melatonin producers may be problematic, particularly with the commonly used operationally defined threshold of 10 pg/ml. This study evaluates various circadian phase markers provided by the plasma melatonin profile in 14 individuals, several of whom are low melatonin producers. The amount (amplitude) of melatonin production appears to influence the phase of many points on the melatonin profile. Accordingly, when low producers are in a data set, we now prefer a lower DLMO threshold than the one previously recommended (10 pg/ml). Indeed, there are some low producers who never exceed this threshold at any time. Radioimmunoassays are now available that have the requisite sensitivity and specificity to support the use of a lower threshold. Nevertheless, the dim-light melatonin offset (DLMOff), even when operationally defined at thresholds less than 10 pg/ml, appears to be confounded by amplitude in this study; in such cases, it may be preferable to use the melatonin synthesis offset (SynOff) because it is not confounded by amplitude and because, theoretically, it is temporally closer to the endogenous mechanism signaling the offset of production. The question of whether the termination mechanism of melatonin synthesis is related to an interval timer or to a second oscillator loosely coupled to the onset oscillator is probably best answered using the SynOff rather than the DLMOff. It is hoped that these findings will make a useful contribution to the debate on the best ways to use points on the melatonin profile to assess circadian phase position in humans.

[1]  G. Barbato,et al.  Conservation of photoperiod-responsive mechanisms in humans. , 1993, The American journal of physiology.

[2]  C. Czeisler,et al.  A mathematical model of diurnal variations in human plasma melatonin levels. , 1997, The American journal of physiology.

[3]  J. Redman,et al.  THE CORRELATION BETWEEN SERUM AND SALIVARY MELATONIN CONCENTRATIONS AND URINARY 6‐HYDROXYMELATONIN SULPHATE EXCRETION RATES: TWO NON‐INVASIVE TECHNIQUES FOR MONITORING HUMAN CIRCADIAN RHYTHMICITY , 1987, Clinical endocrinology.

[4]  A. Lewy,et al.  Morning vs evening light treatment of patients with winter depression. , 1998, Archives of general psychiatry.

[5]  J. Arendt,et al.  Immunoassay of 6-hydroxymelatonin sulfate in human plasma and urine: abolition of the urinary 24-hour rhythm with atenolol. , 1985, The Journal of clinical endocrinology and metabolism.

[6]  S. Markey,et al.  Analysis of melatonin in human plasma by gas chromatography negative chemical ionization mass spectrometry. , 1978, Science.

[7]  C. Lynch,et al.  Role of the matrixin MMP-2 in multicellular organization of adipocytes cultured in basement membrane components. , 1997, The American journal of physiology.

[8]  A. Lewy,et al.  Exogenous Melatonin's Phase-Shifting Effects on the Endogenous Melatonin Profile in Sighted Humans: A Brief Review and Critique of the Literature , 1997, Journal of biological rhythms.

[9]  D. Mebs.  ReviewCatecholamines: Basic and clinical frontiers: Usdin, E., Kopin, I. J. and Barchas, J. (Eds.) (1979) 2 volumes, 1953 pp. Oxford: Pergamon Press , 1981 .

[10]  D. Kripke,et al.  Altered waveform of plasma nocturnal melatonin secretion in premenstrual depression. , 1990, Archives of general psychiatry.

[11]  A. Lewy,et al.  Assessment and treatment of chronobiologic disorders using plasma melatonin levels and bright light exposure: the clock-gate model and the phase response curve. , 1984, Psychopharmacology bulletin.

[12]  J. Waterhouse,et al.  The effect of sleep upon human circadian rhythms. , 1978, Chronobiologia.

[13]  C A Czeisler,et al.  Light exposure induces equivalent phase shifts of the endogenous circadian rhythms of circulating plasma melatonin and core body temperature in men. , 1991, The Journal of clinical endocrinology and metabolism.

[14]  T. Wehr.  Melatonin and Seasonal Rhythms , 1997, Journal of biological rhythms.

[15]  C. M. Singer,et al.  The human phase response curve (PRC) to melatonin is about 12 hours out of phase with the PRC to light. , 1998, Chronobiology international.

[16]  C. M. Singer,et al.  Melatonin, light and chronobiological disorders. , 1985, Ciba Foundation symposium.

[17]  A. Lewy,et al.  Antidepressant and circadian phase-shifting effects of light. , 1987, Science.

[18]  D A Newsome,et al.  Light suppresses melatonin secretion in humans. , 1980, Science.

[19]  A. Lewy,et al.  The role of melatonin and circadian phase in age-related sleep-maintenance insomnia: assessment in a clinical trial of melatonin replacement. , 1998, Sleep.

[20]  D. M. White,et al.  Morning vs evening light treatment for winter depression. Evidence that the therapeutic effects of light are mediated by circadian phase shifts. , 1990, Archives of general psychiatry.

[21]  C. Matthews,et al.  Human plasma melatonin and urinary 6‐sulphatoxy melatonin:studies in natural annual photoperiod and in extended darkness , 1991, Clinical endocrinology.

[22]  J. Vanecek,et al.  Pineal rhythm in N-acetyltransferase activity in rats under different artificial photoperiods and in natural daylight in the course of a year. , 1980, Neuroendocrinology.

[23]  A. Lewy,et al.  Melatonin as a Chronobiotic: Treatment of Circadian Desynchrony in Night Workers and the Blind , 1997, Journal of biological rhythms.

[24]  C. M. Singer,et al.  Immediate and Delayed Effects of Bright Light on Human Melatonin Production: Shifting “Dawn” and “Dusk” Shifts the Dim Light Melatonin Onset (DLMO) a , 1985, Annals of the New York Academy of Sciences.

[25]  F. Goodwin,et al.  PLASMA MELATONIN IN MANIC-DEPRESSIVE ILLNESS , 1979 .

[26]  A. Lewy.  The Dim Light Melatonin Onset, Melatonin Assays and Biological Rhythm Research in Humans , 1999, Neurosignals.

[27]  A. Lewy,et al.  Melatonin shifts human circadian rhythms according to a phase-response curve. , 1992, Chronobiology international.

[28]  B. Goldman,et al.  The pineal gland and mammalian photoperiodism. , 1983, Neuroendocrinology.

[29]  J. Axelrod.  The pineal gland. , 1965, Canadian Medical Association journal.

[30]  C. Eastman,et al.  Medium-intensity light produces circadian rhythm adaptation to simulated night-shift work. , 1998, Sleep.

[31]  R. Leproult,et al.  Rapid phase advance of the 24-h melatonin profile in response to afternoon dark exposure. , 1998, American journal of physiology. Endocrinology and metabolism.

[32]  E N Brown,et al.  The Statistical Analysis of Circadian Phase and Amplitude in Constant-Routine Core-Temperature Data , 1992, Journal of biological rhythms.

[33]  A. Lewy,et al.  The dim light melatonin onset as a marker for circadian phase position. , 1989, Chronobiology international.

[34]  Claude Gronfier,et al.  Effect of the shift of the sleep-wake cycle on three robust endocrine markers of the circadian clock. , 1998, American journal of physiology. Endocrinology and metabolism.

[35]  D. Dawson,et al.  Salivary Melatonin as a Circadian Phase Marker: Validation and Comparison to Plasma Melatonin , 1997, Journal of Biological Rhythms.