melatonin: characteristics, concerns, and prospects

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2005 20: 291J Biol RhythmsJosephine Arendt

Melatonin: Characteristics, Concerns, and Prospects

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10.1177/0748730405277492JOURNALOF BIOLOGICALRHYTHMS / August 2005Arendt / MELATONIN

MELATONIN

Melatonin: Characteristics,Concerns, and Prospects

Josephine Arendt1

Centre for Chronobiology, School of Biomedical and Molecular Sciences,University of Surrey, Guildford, Surrey, United Kingdom

Abstract Melatonin is of great importance to the investigation of human biologi-cal rhythms. Its rhythm in plasma or saliva provides the best available measureof the timing of the internal circadian clock. Its major metabolite 6-sulphatoxymelatonin is robust and easily measured in urine. It thus enableslong-term monitoring of human rhythms in real-life situations where rhythmsmay be disturbed, and in clinical situations where invasive procedures are diffi-cult. Melatonin is not only a “hand of the clock”; endogenous melatonin acts toreinforce the functioning of the human circadian system, probably in manyways. Most is known about its relationship to sleep and the decline in core bodytemperature and alertness at night. Current perspectives also include a possibleinfluence on major disease risk, arising from circadian rhythm disruption.Melatonin clearly has the ability to induce sleepiness and lower core body tem-perature during “biological day” and to change the timing of human rhythmswhen treatment is appropriately timed. It can entrain free-running rhythms andmaintain entrainment in most blind and some sighted people. Used therapeuti-cally it has proved a successful treatment for circadian rhythm disorder, particu-larly the non-24-h sleep wake disorder of the blind. Numerous other clinicalapplications are under investigation. There are, however, areas of controversy,large gaps in knowledge, and insufficient standardization of experimental con-ditions and analysis for general conclusions to be drawn with regard to most sit-uations. The future holds much promise for melatonin as a therapeutictreatment. Most interesting, however, will be the dissection of its effects onhuman genes.

Key words melatonin, light, rhythms, human

The importance of melatonin in human circadianbiology means that most other sections of this editionwill consider it in relation to the specific area underscrutiny. This review will discuss its use as a markerrhythm for the timing of the internal clock and itseffects on the human circadian system.

Melatonin is a tiny molecule, but it has had a hugeimpact on the field of biological rhythms. In fact, ifWeb citations are a guide (1.9 × 106 citations), it isalmost as famous as serotonin (2.3 × 106) but not quiteas well known as DNA (42.5 × 106). It arouses interestin fields as disparate as evolutionary biology and tran-

291

1. To whom all correspondence should be addressed: Josephine Arendt, Centre for Chronobiology, School of Biomedical andMolecular Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UK; e-mail: [email protected].

JOURNAL OF BIOLOGICAL RHYTHMS, Vol. 20 No. 4, August 2005 291-303DOI: 10.1177/0748730405277492© 2005 Sage Publications

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scendental meditation. Why should this be? Its pro-duction by the pineal gland, Descartes’s “Seat of theSoul,” and its colloquial sobriquet “hormone of dark-ness” no doubt explain some of the more irrationalinterest. But the fact that it appears to be the only sol-idly established humoral method of signaling time ofday and time of year to other physiological systemsunderpins its all pervasive presence in themultidisciplinary field of chronobiology. Melatoninsuppression by bright light at night, and itstransduction of photoperiodic information in animals,initiated the first light treatments of SAD (seasonalaffective disorder). Possible suppression of melatoninduring night shift work has been hypothesized toincrease the risk of major disease (Stevens and Davis,1996). One of the first (and some subsequent) demon-strations that light pulses could shift the human circa-dian clock used melatonin as the marker rhythm. Theuse of 6-sulphatoxymelatonin (aMT6s) as anoninvasive marker of circadian timing has enabledbetter definitions and new insights into human clocktiming in field studies (for a review, see Rajaratnamand Arendt, 2001).

The suppression and phase-shifting of melatoninby light has provided endpoints for the recent identifi-cation of a novel circadian photoreceptor system (seethis issue) maximally responsive to short wavelengthlight.

The chronobiotic and sleep-inducing properties ofmelatonin have led to its use to treat circadian rhythmdisorders such as the non-24-h sleep disorder of theblind, delayed sleep phase syndrome, shift work, andjet lag (see this issue). These properties have inspirednew pharmacological approaches to the treatment ofhealth problems. However, lack of consistency in fieldtrials of shift work and jet lag suggests that furtherinvestigation is needed (see this issue).

IN THE BEGINNING

In the beginning, it would have been hard to predictthese developments. Aaron Lerner, who first identi-fied and characterized melatonin (Lerner et al., 1958),was looking for the most potent (amphibian) skin-lightening factor known to be present in the pinealgland. We now know that the primary and essentialphysiological function of the changing melatonin pro-file in mammals is to convey information concerningdaylength to body physiology for the organization of

daylength-dependent (photoperiodic) seasonal func-tions (Arendt, 1995). In mammals, melatonin appearsto have a more modest role in the organization of adultcircadian physiology, mostly being associated withsleep and the core temperature rhythm. It may bemore important in the perinatal period (Davis, 1997).There is nevertheless evidence for an influence on sys-tems such as glucose homeostasis (la Fleur et al., 2001),the immune system (Maestroni, 1998), and cardiovas-cular function (Scheer et al., 2004). It is made at nightin all species investigated to date, thus any response tothe melatonin signal must differ in nocturnal anddiurnal animals, including humans, as it does in short-and long-day breeders (Arendt, 1995).

A HAND OF THE CLOCK

The secretion of melatonin from the pineal is proba-bly the most direct peripheral link to the central circa-dian clock. This may be too simplistic, since evidenceexists for differential changes in melatonin and othervariables driven by the SCN (De Leersnyder et al.,2001; Perreau-Lenz et al., 2004; Weibel et al., 1997).Moreover, there is some evidence that shifting sleeptime can change melatonin phase without affectingthe core body temperature rhythm (Gordijn et al.,1999). Investigation of pineal function in humans, anda more precise and less “masked” representation ofthe human clock than core body temperature, awaiteddevelopment of suitable measurement methods formelatonin and subsequently its primary metaboliteaMT6s (for references to early assays, see Arendt,1995).

To assess the basic characteristics of the human cir-cadian system requires highly controlled conditions(variants of constant routine methodology) and pre-cise definitions of the rhythm characteristics (Duffyand Dijk, 2002). At present, in controlled conditions,melatonin is considered to be the best index of circa-dian timing in humans (Klerman et al., 2002). For clini-cal assessments of possible circadian abnormality, theuse of melatonin “onset”—the start of the eveningrise—in plasma or saliva has been extensively used asa phase marker of the internal clock, as it avoids over-night sampling (Lewy and Sack, 1989). There are dis-advantages to this approach, as it provides no infor-mation on the duration of secretion, peak levels, andtotal production. There is some evidence that 2 oscilla-tors usually known as M (morning) and E (evening)

292 JOURNAL OF BIOLOGICAL RHYTHMS / August 2005



are concerned with the generation of the melatoninrhythm. The rise is theoretically associated with E, andthe fall with M (Illnerova and Vanecek, 1988). Differ-ential effects on the rise and fall, and even on thedetails of the overnight profile, may well be clinicallyimportant. There is extensive evidence for good corre-lations in both timing and amplitude between therhythms of plasma and saliva melatonin and the uri-nary metabolite aMT6s (Bojkowski et al., 1987; Elliottet al., 2002; Nowak et al., 1987; Ross et al., 1995;Voultsios et al., 1997). However, all have their disad-vantages. Plasma sampling is invasive and is subjectto restrictions due to preservation of blood volume—but it can be accomplished during sleep, whereas 24-hsampling of saliva implies disruption of sleep. Urinecollection for aMT6s production over 1-h intervalsprovides data comparable to sampling for 4-h inter-vals with an 8-h oversleep collection (Naidoo, 1999)but inevitably with less resolution than can beobtained with blood or saliva. A prior knowledge ofcircadian phase would certainly enhance the consis-tency of results obtained for treatment of conditionssuch as jet lag and shift work with melatonin. To thisend, the development of a technique for rapid, simplemelatonin measurement (a biosensor, for example)would find extensive use.

CHARACTERISTICS OF MELATONINSECRETION AND PRODUCTION

Profile Characteristics

Figure 1 illustrates the rhythm characteristics thatcan be derived from profiles of plasma and salivamelatonin (1 hourly sample or less) together with uri-nary aMT6s (3 to 4 hourly sampling or less, with a lon-ger oversleep collection). No worthwhile data can bederived from single time-point sampling. Very fre-quent sampling (<30 min) may lead to apparent epi-sodic secretion (Geoffriau et al., 1999). This may be, atleast in part, an artifact of assay noise (Bojkowski et al.,1987). The presence of 2 peaks of secretion has alsobeen noted at times (Arendt, 1985; Wehr et al., 1995)and related to possible dual oscillator control ofmelatonin synthesis. In healthy individuals, the tim-ing, amplitude, and even the details of the profile canbe highly reproducible from day to day and week toweek rather like a hormonal fingerprint (Arendt, 1988;Klerman et al., 2002), even without strictly controlled

sampling conditions. The very large interindividualvariations have been ascribed to the size of the pinealgland rather than to variations in enzymic activity, atleast in sheep (Gomez Brunet et al., 2002). Diurnalpreference (morningness) and short free-running cir-cadian period are associated with earlier melatoninphase (Duffy et al., 1999; Gibertini et al., 1999). No con-sistent gender differences have been found (notably ifbody weight is taken into account). A small number ofapparently normal individuals have no detectablemelatonin in plasma at all times of day.

Seasonal and Lifetime Variations

There are seasonal variations in human melatonin(and aMT6s), with an earlier phase in summer(Bojkowski and Arendt, 1988; Broadway et al., 1987),and, according to some reports, increased levels andduration of secretion in winter in high latitudes(Kauppila et al., 1987). Plasma melatonin declinesduring development: this is likely to be due to con-stant production with increasing body weight(Cavallo and Dolan, 1996). aMT6s excretion declinesin adults with age in most reports (Bojkowski andArendt, 1990; Kennaway et al., 1999), as does the

Arendt / MELATONIN 293

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Figure 1. The markers used to characterize melatonin and aMT6s(6-sulphatoxymelatonin) rhythms are illustrated diagrammati-cally. Area under the curve or total 24-h excretion (aMT6s) is usedto assess total secretion. At present, there is no standard definitionof onset-offset (and hence duration). More sophisticated curve-fit-ting techniques have been employed and appear to give reliabledata (Brown et al., 1997; Gamst et al., 2004; Revell et al., 2005).



amplitude of the plasma melatonin rhythm (withsome exceptions). The subject of aging and themelatonin rhythm is covered elsewhere in this issue.aMT6s appears to have a progressively earlieracrophase with aging (B. Middleton and J. Arendt,unpublished data).

Abnormal Rhythms

The above comments apply strictly to healthyunmedicated adults in a normal entrained environ-ment. The “normal” melatonin profile provides thebasis from which the extent of any circadian rhythmdisruption can be assessed (for example, in blindness,shift work, jet lag, and delayed and advanced sleepphase). At present, different laboratories define theirown normal values. A variety of observations in dis-ease states indicate that the amplitude and sometimesthe timing of the rhythm may be modified. It is hard todraw any general conclusions, and it is rare for suchstudies to control for all known masking factors. Abo-lition of the rhythm by destruction of pinealinnervation, pinealectomy (Zeitzer et al., 2000a; seeArendt, 1995, for earlier references), and situationsaffecting stimulation/inhibition of synthesis/metab-olism have predictable effects on measured levels (seeTable 1).

Light Exposure

Recently, interest has been aroused in the possiblehealth hazards of light at night (LAN), one hypothesisbeing that melatonin suppression is the culprit(Stevens and Davis, 1996). Bright (>2500 lux, white)light can suppress melatonin completely (Lewy et al.,1980), but domestic-intensity light such as might beencountered at night on the night shift, causes signifi-cant suppression (Bojkowski et al., 1987; Zeitzer et al.,2000b). Moreover, previous light exposure can influ-ence the amount of suppression (Hebert et al., 2002;Owen and Arendt, 1992). There are inconsistentreports of either increase, decrease, or no change inmelatonin amplitude in night shift workers. It will beimportant to resolve this problem in large populationswith simultaneous measurements of light exposure.The LAN hypothesis has been extended to suggestthat a lower incidence of cancer in blind people may bedue to greater melatonin production (Erren andStevens, 2002). Blind subjects with no conscious orunconscious light perception may (and usually do)show free-running rhythms or synchronized rhythmswith abnormal phase (see Skene, this issue). In limiteddata so far available, they do not have either a higheramplitude or a longer duration than sighted subjects(Klerman et al., 2001; Lockley et al., 1997).


Table 1. Some Miscellaneous Factors Influencing Human Melatonin Secretion

Factor Effect(s) on Melatonin Comment Reference(s)

Posture ↑ Standing (night) Controversial *Nathan et al., 1998; Voultsios et al., 1997Exercise ↑ Phase shifts Hard exercise Buxton et al., 2003ß-adrenoceptor-A ↓ Synthesis Antihypertensives *5HT UI ↑ Fluvoxamine Metabolic effect *Hartter et al., 2001NE UI ↑ Change in timing Antidepressants *MAOA I ↑ May change phase Antidepressants *α-adrenoceptor-A ↓ alpha-1, ↑ alpha-2 *Benzodiazepines Variable ↓ Diazepam, GABA mechanisms Mann et al., 1996; Monteleone et al., 1989; Monteleone

alprazolam et al., 1997; Niles, 1991Testosterone ↓ ? Treatment *Luboshitzky et al., 1997OC ↑ Kostoglou-Athanassiou et al., 1998; Wright and Badia, 1999Estradiol ↓ ? Not clear *Okatani et al., 2000Menstrual cycle Inconsistent ↑ Amenorrhea *Laughlin et al., 1991Smoking Possible changes ↑↓ ? Tarquini et al., 1994Alcohol ↓ Dose dependent Ekman et al., 1993Caffeine ↑ Delays clearance Hartter et al., 2003; Shilo et al., 2002; Wright et al., 1997

(exogenous)Aspirin, Ibuprofen ↓ Murphy et al., 1996Chlorpromazine ↑ Metabolic effect *Benserazide Possible phase change, Aromatic amino-acid

Parkinson patients decarboxylase-I *

*Most references prior to 1995 can be found in Arendt (1995). A recent revue addresses mostly animal in vivo and in vitro effects (Simonneauxand Ribelayga, 2003). A = antagonist; U = uptake; I = inhibitor; MAO = monoamine oxidase; OC = oral contraceptives; 5HT = 5-hydroxytryptamine; ↑ = increase; ↓ = decrease.



Electromagnetic Field Exposure

A related melatonin suppression hypothesis hasbeen applied to possible effects of EMF on melatonin.Primarily cross-sectional studies investigating aMT6sin urine have been used to investigate melatonin pro-duction in populations at risk. Very few of these stud-ies have carried out complete 24- to 48-h sampling todefine amplitude and timing of the rhythm, and theresults are weak and inconsistent (Brainard et al.,1999). In view of the very large interindividual varia-tion, it is necessary to use subjects as their own con-trols in small studies. Recent laboratory investigationsof this kind on the acute effects of EMF on 24-h profilesof plasma melatonin show no effects (Griefahn et al.,2001; Warman G R et al., 2003).

Essentials

The timing and duration of melatonin secretion areits critical features with regard to physiological func-tions. The relevance of small changes in melatoninamplitude remains obscure, particularly in view of theenormous individual variation between normalhealthy subjects.

EFFECTS OF MELATONIN ONHUMAN RHYTHMS

Preface

Endogenous melatonin is concerned with biologi-cal timing. There is a vast literature concerned witheffects of exogenous melatonin that do not (at least forthe moment) appear to be directed primarily at timingmechanisms. Such effects will not be considered here.(For reviews, see, for example, Bartsch and Bartsch,1997; Maestroni, 1998; Mahle et al., 1997; Reiter, 2003.)

Acute Effects

Aaron Lerner was the first person to show, 40 yearsago, that melatonin had sleep-inducing effects (citedin Lerner and Nordlund, 1978). He had the courageand scientific curiosity to take 100 mg and reportedsleepiness after the dose. Now it is clear that low (0.3–10 mg) doses of melatonin during the “biological day,”that is, when endogenous melatonin levels are low,can induce transient sleepiness or sleep, and lowercore body temperature, in suitably controlled circum-

stances (posture is important; the greatest effects areseen with recumbent subjects in very dim light)(Cajochen et al., 1997; Deacon and Arendt, 1995).These effects are opposite to the acute effects of brightlight given at night. A substantial body of literaturehas described effects on sleep and sleep structure com-parable to but not identical with benzodiazepines(Stone et al., 2000). There is little evidence to suggestthat it has important effects in normal sleepers if givenat habitual bedtime. The effects of melatonin on sleephave been extensively reviewed recently (Brzezinskiet al., 2005; and see this issue).

Phase-Shifting Effects

Early work suggested that 2 mg melatonin taken inthe late afternoon could advance the timing of theendogenous melatonin rhythm, as well as inducingearly sleepiness or “fatigue” (Arendt et al., 1985). Inthe same dose range (0.5–10 mg), it is able to shift cir-cadian timing to both later and earlier times whenadministration is appropriately timed (Lewy et al.,1992). There is, however, some controversy regardingthe ability of melatonin to phase-delay the circadiansystem using a single morning dose (Wirz-Justice et al.,2002). Phase advances (and possibly phase delays) aredose-dependent using a single dose in the range 0.05 to 5mg (Deacon and Arendt, 1995). As for light, appropri-ate timing of treatment to delay or advance can inprinciple be predicted from a phase-response curve insubjects whose body clock phase is known (Lewy etal., 1998). The reported PRCs to melatonin are essen-tially the reverse of that to light.

On reflection, it is perhaps surprising that thereported PRC does not show evidence ofmultioscillator control of melatonin secretion. Theacute response of the onset and offset of both synthesis(AANAT activity) and melatonin secretion differ withrespect to phase shifts by light (Illnerova and Vanecek,1988; Warman V L et al., 2003). Early work alsoshowed possible differential effects of melatonin itselfon the onset and offset of endogenous melatoninsecretion (Arendt et al., 1985). If melatonin exerts itseffects via a putative morning and evening oscillator, amore complex form of PRC might be expected. Thescatter of current PRC data may simply be obscuringmore interesting phenomena.

Arecent controlled study showed that daily admin-istration for 8 days of a “surge sustained” releasepreparation (1.5 mg) of melatonin at 1600 h followedby recumbency and very dim light for 16 h led to sub-




stantial phase advances of a number of circadian“marker” rhythms and an advanced timing and redis-tribution of sleep during the dark phase. No increasein total sleep time was seen, reinforcing the view thatmelatonin acts on the timing mechanisms of sleeprather than being a conventional hypnotic. The experi-mental design was such that both acute sleep-induc-ing and phase-shifting effects could be differentiated(Fig. 2) (Rajaratnam et al., 2003; Rajaratnam et al.,2004).

Entrainment

A single melatonin treatment (5 mg fast release) atthe right time in controlled experiments can advancethe timing of the internal clock by up to ~1.5 h (Deacon

and Arendt, 1995). The inherent period of the humancircadian clock is, on average, about 24.18 h in forceddesynchrony experiments (Czeisler et al., 1999) and24.33 h in constant very dim light with knowledge ofclock time (Middleton et al., 1997, 1996). Free-runningblind people may have a slightly longer averageperiod (~24.5 h) (Hack et al., 2003). Entrainment there-fore requires on average a daily advance shift of ~0.2to 0.5 h. Thus, melatonin should be eminently capableof entraining free-running rhythms in both sightedand blind people. However, unpredictable effectssuch as conflicting light exposure and residual highmelatonin levels in a phase-delay region of the PRCmay compromise the desired result.

If there is no good reason to remain entrained tonormal clock time, one would predict (with hindsight)that entrainment might be less efficient (with any


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Figure 2. Separation of direct and circadian effects of melatonin. Mean sleep efficiency levels (polysomnography, % per hour +SEM, topleft and top right, n = 8) and mean plasma melatonin levels (bottom left and bottom right, n = 8) on the last day (D10 closed circles) and thewashout day (D11, open circles) of an 8-day melatonin treatment (1.5 mg surge-sustained release at 16 h, followed by 16 h recumbent in verydim light). The direct, sleep-facilitating effect of melatonin (top left) is illustrated by comparing profiles on D10 and D11. The circadianeffect of melatonin (top right) is illustrated by comparing profiles on D11 after melatonin (mel) (closed circles) or placebo (plac) (open cir-cles). Bottom left shows mean plasma melatonin profiles during treatment (closed circles) compared to after treatment had stopped (opencircles). Bottom right shows plasma melatonin levels during a constant routine (after the treatment period) with an advance in timing of theendogenous melatonin profile (closed circles) compared to placebo (open circles) (reproduced with permission from Rajaratnam et al.,2003).



zeitgeber). This was probably the case with sightedsubjects kept in a dim light environment conducive tofree-running but with knowledge of clock time.Melatonin (5 mg daily, 2000 h) was able to maintainentrainment to 24 h in these circumstances when treat-ment was started at the beginning of free-running con-ditions, albeit with fragmentation of sleep in 4 of 16subjects (Middleton et al., 1997). However, when treat-ment was started at different circadian times after aperiod of free run, advances, 1 delay, shortening ofperiod, and in some cases a period indistinguishablefrom 24 h were shown by different individuals. Thesleep fragmentation patterns suggested thatmelatonin may have split 2 coupled oscillatorsinfluencing sleep timing.

There is no doubt that timed melatonin administra-tion (0.5–5 mg at 24-h intervals, usually at desired bed-time) can fully entrain (or synchronize) the free-run-ning circadian rhythms of most blind subjects, with aconsequent improvement in sleep and daytime alert-ness (even without entrainment, sleep is improved)(Arendt et al., 1997; and see Skene, this issue). Evi-dently these subjects are motivated to remain in syn-chrony with clock time and it is likely that otherzeitgebers reinforce the effects of melatonin. Interest-ingly, if entrainment does not occur, shortening of

period is also seen in the blind. It is possible that oneaction of melatonin is to shorten period, to the extentthat entrainment is possible by other time cues ifpresent.

Problems Using Melatonin as a Chronobiotic

Various factors may influence the ability ofmelatonin to entrain both blind and sighted humansincluding dose, formulation, individualpharmacokinetics, free-running period, receptor sen-sitivity, and behavior. In sighted subjects, unknowncircadian phase, unpredictable light exposure, andself-selected sleep times are probably the reason forsome inconsistency in the clinical trials of melatonin inshift work and jet lag. Figure 3 illustrates the diversityof response to phase shift in untreated healthy adults.Unless circadian phase is known, correct timing toinduce a shift in the desired direction is almost impos-sible to predict. There is, however, some scant evi-dence that appropriate melatonin treatment prior tophase shift can dictate the direction in which the inter-nal clock adapts (Arendt, 1995). Pre-phase-shift treat-ment has rarely been employed. Rigorous recent inde-pendent assessments of its usefulness do not agree. ACochrane review (Herxheimer and Petrie, 2002) con-


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Figure 3. Large individual variations in the rate and direction of adaptation of the 6-sulphatoxymelatonin (aMT6s) rhythm after abruptforced phase shifts of 9 h (laboratory study) and 12 h (real shift work). Left panel: 7 subjects underwent a synchronized 9-h phase delay,imposed by shifting exposure to bright light, darkness, and scheduled sleep by 3 h per day for 3 days and maintaining the 9-h shift in light-dark exposure and sleep time for a further 2 days. An abrupt 9-h phase advance (return of sleep-wake schedule to local clock time) wasimposed on day 5. Right panel: 11 subjects working on offshore oil installations underwent an abrupt shift in work time from 1800–0600h to0600–1800 h on day 7. The individual daily calculated peak time (acrophase) for aMT6s is shown in each case. This variability indicates thattiming of melatonin treatment to adapt to phase shift needs to be as a function of individual circadian phase. Adapted from Deacon andArendt (1996) (left panel) and Gibbs et al. (2002) (right panel) by permission.



cluded that there was good evidence for beneficialeffects in jetlag. However, a recent analysis by theAgency for Healthcare Research and Quality (http://www.ahrq.gov/news/press/pr2004/melatnpr.htm)of the effects of melatonin “supplements” on sleep inshift work, jet lag, and delayed sleep phase syndrome(DSPS) concluded that there was only good evidencefor an effect in DSPS.

Oncostatic Effects of Melatonin,Light at Night, and Clock Genes

There is now quite substantial evidence thatmelatonin has some oncostatic activity in vitro (Blasket al., 2002). Various mechanisms have been proposedincluding inhibition of estrogen transduction path-ways (in mammary cancer) (Hill et al., 2000) and inhi-bition of tumor fatty acid uptake (Sauer et al., 2001).Melatonin receptors, particularly MT1, are impli-cated. However, there are frequent differences inresponse even within the same cell line (e.g., thehuman breast cancer cell line MCF 7). There is somepreliminary evidence for beneficial effects of com-bined chemotherapy or immunotherapy andmelatonin (Lissoni et al., 2000; Lissoni et al., 2003).This subject is included here since there is evidencethat pinealectomy, photoperiod per se (for references,see Arendt, 1995), and forced phase shifts of the light-dark cycle (Filipski et al., 2004) can influence growthof tumors. In vivo, it has also been reported thatmelatonin may increase or decrease tumor growth,depending on photoperiod, in hamsters (Stanberry et al.,1983).

It has been proposed that light at night during nightshift work suppresses melatonin and that this loss ofmelatonin “activity” is responsible for the increasedcancer risk (e.g., Schernhammer and Schulmeister,2004; Stevens and Davis, 1996). However, to attributeany detrimental effects directly to loss of melatonin isoverspeculative. Light at night has numerous othereffects. The mere fact of frequent disruption of all cir-cadian rhythms, not just melatonin, is effectively aphysiological insult.

Most important perhaps, light directly influencesthe expression of the clock gene feedback loops driv-ing circadian rhythms (Reppert, 2000). Disruption ofclock gene function is associated with increased risk ofcancer in recent animal studies (Fu and Lee, 2003).Numerous potential mechanisms may be invoked inview of the ubiquitous nature of circadian rhythms. A

particular length polymorphism in hper3 (the “lark”variant; Archer et al., 2003) has been associated withincreased breast cancer risk in premenopausal women(Zhu et al., 2005). This preliminary study will requireconfirmation in larger numbers. Thus, a more plausi-ble hypothesis regarding the risk of breast cancer insubjects exposed to light at night would involve thewhole circadian axis. Perhaps here may lie one aspectof the oncostatic activity of melatonin. By acting as acircadian coupling agent countering desynchronyamong central and peripheral clocks, and optimizingphase with respect to external time cues, cellular andsystem processes may be optimized and defense sys-tems augmented. These considerations may alsoapply to risk of other major diseases associated withshift work (for example, heart disease, metabolicsyndrome, possible decreased fertility).

MECHANISM OF ACTION

The locations and pharmacology of melatoninreceptors have recently been extensively reviewed.Two cloned receptors, MT1 and MT2 (Masana andDubocovich, 2001; Reppert et al., 1995), are of particu-lar importance with regard to rhythm physiology andpharmacology. Using gene knockout technology inmice and pharmacological manipulations, the resultsto date suggest that the phase-shifting melatoninreceptor in the SCN is MT2, while MT1 is associatedwith acute suppression of SCN electrical activity (Liuet al., 1997). MT1 has important actions within the parstuberalis (PT) controlling seasonal prolactin varia-tions in ruminants (de Reviers et al., 1989; Lincoln andClarke, 1994; Williams and Morgan, 1988). Geneticpolymorphism has been identified within melatoninmembrane receptors, and further investigation ofthese polymorphisms in relation to photoperioidism,human disease, sensitivity to melatonin, and so on, isongoing (Ebisawa et al., 2000; Migaud et al., 2002).

Probably the most interesting development in theeffects of melatonin concerns its influence on periph-eral gene expression in the pars tuberalis (Messageret al., 1999). Lincoln et al. (2003) suggested that thephotoperiodic melatonin signal is decoded via dif-ferential phasing of per and cry expression in the PT.In rodent pars tuberalis cells, rhythmic expression ofthe clock gene per1 appears to be dependent on sensiti-zation of adenosine A2b receptors, which in turndepend on melatonin activation of MT1 receptors(von Gall et al., 2002). Clearly it is possible that the




melatonin signal is a widespread humoral mechanismrelated to biological timing, acting through modifica-tion of peripheral clock gene expression. However, itappears not to affect SCN clock gene expressionacutely (Poirel et al., 2003). The effects of melatonin onperipheral, as well as central, clock gene expressionare likely to be a rich field of enquiry.

PHYSIOLOGICAL ROLE OFMELATONIN IN HUMANS

The melatonin rhythm is not essential to humanlife, or indeed human sleep and circadian rhythms. Itmay even be disadvantageous in some circumstances(working out of phase) in the 24/7/365 society. Thebest evidence for a physiological role in human circa-dian rhythms concerns the timing and reinforcementof “night time physiology,” for example, the nadir ofcore temperature, alertness and performance, and thetiming of sleep. Any system with a circadian compo-nent may be susceptible to the influence of endoge-nous melatonin. It appears to modulate response tochanging time cues as an adjunct to light and, possibly,in some circumstances, in conflict with light.

Important aspects of human seasonality includechanges in mood, sleep timing, immune system, con-ception rate (even the success of in vitro fertilization—better in long days; Rojansky et al., 2000). Roennebergand Aschoff (1990) found clear evidence of humanseasonality when analyzing a large number ofmonthly birth rates worldwide—with an increase inconception rate in spring. There is evidence thatmelatonin signals daylength to human physiology, asit does in other species (Arendt, 1999). There is evensome preliminary evidence that human pinealectomy(which abolishes the melatonin rhythm) decreaseshuman seasonality (Macchi et al., 2002). Melatoninclearly reinforced the effects of a shortenedphotoperiod in recent human experiments(Rajaratnam et al., 2003). It is not inconceivable thatmelatonin/photoperiod may have a therapeutic func-tion with regard to human fertility. Since melatoninhas powerful physiological effects in photoperiodicspecies, it behooves us to be certain of its uses and lim-itations, and long-term safety needs to be assessed.There is very little evidence in the short term for toxic-ity or undesirable effects in humans. The extraordi-nary “hype” of the miraculous powers of melatonin inthe recent past did a disservice to acceptance of itsgenuine benefits.

ACKNOWLEDGMENTS

I would like to thank all the very numerous col-leagues with whom I have collaborated over the years.This review was written during the tenure of grantsfrom the UK Health and Safety Executive, The EnergyInstitute, The Antarctic Funding Initiative, and withsupport from Stockgrand Ltd, University of Surrey.

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melatonin: characteristics, concerns, and prospects

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