Melatonin as a Biomarker of Circadian Dysregulation - Cancer ...
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
3306
Review
Melatonin as a Biomarker of Circadian Dysregulation
Dana K. Mirick1 and Scott Davis1,2
1
Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center;
and 2Department of Epidemiology, School of Public Health and Community Medicine,
University of Washington, Seattle, Washington
Abstract
It would be most useful to identify a biomarker of and indirectly through its metabolites in urine, blood,
circadian dysregulation that could be used in epidemi- and saliva. Urinary melatonin has been shown to be
ologic studies of the effects of circadian disruption in stable over time, making it useful in epidemiologic
humans. An indicator of circulating melatonin level studies in which laboratory processing is not immedi-
has been shown to be a good biomarker of circadian ately available, as well as studies of cancer with long
dysregulation and has been associated with nightshift latency periods. Several studies have shown melatonin
work and exposure to light-at-night in both laboratory- to be useful in measuring diurnal type, which is of
based and field studies. Among other circadian increasing interest as it becomes more apparent that
markers (such as core body temperature), it remains successful adaptation to shift work may be dependent
comparatively robust in the presence of various on diurnal preference. (Cancer Epidemiol Biomarkers
external influences. It can be reliably measured directly Prev 2008;17(12):3306 – 13)
Introduction
The production and release of nearly all hormones melatonin production is also unaffected by the factors
exhibits a diurnal timing patterned on approximately described above, it has greater reliability to measure
a 24-h cycle. Lifestyle factors (e.g., nightshift work circadian phase position over other circadian markers
and sleep disruption) or exposures to particular agents (4, 5). This article reviews several key considerations in
[e.g., light-at-night (LAN)] that disrupt circadian rhythm considering circulating melatonin level as a biomarker of
may therefore also alter endocrine function and possibly circadian disruption.
the regulation of reproductive hormones that are
relevant to the etiology of hormone-related diseases,
such as breast or prostate cancer (1). Given the Pineal Gland and Actions of Melatonin: An
importance of normal circadian rhythm in regulating Overview
reproductive hormone levels, a biomarker of circadian
dysregulation that could be used in epidemiologic Melatonin is a primary circadian pacemaker; its purpose
studies of the effects of circadian disruption in humans is to synchronize the internal hormonal environment to
would be most useful and perhaps even used as a tool the light-dark cycle of the external environment. It is
for monitoring the effects of change in lifestyle designed primarily produced and secreted by the pineal gland, a
to reduce the risk of these types of cancer. Circulating neuroendocrine transducer that is stimulated during the
melatonin level is one such biomarker and is preferable dark period of the external environment and sup-
to other circadian markers (e.g., core body temperature) pressed by light as perceived by the retina (6). The
because it is comparatively robust in the presence of retinohypothalamic tract carries information from the
various external influences (2). For example, other retina to the suprachiasmatic nuclei, which generates
circadian markers such as core body temperature and the signal to the pineal gland to regulate melatonin
heart rate can be significantly affected by excessive production accordingly. In effect, melatonin secretion
carbohydrate intake (3); cortisol and thyrotropin-releas- acts as the ‘‘arm’’ of the biological clock: the timing
ing hormone, as well as core body temperature, can be of the melatonin rhythm indicates the status of the
masked by sleep, stress, and activity (4). In contrast, internal clock, with regard to phase position (the
melatonin concentration remains relatively uninfluenced internal clock time versus the external clock time) and
by these factors (3, 4). Furthermore, because the onset of amplitude (2). Further, melatonin acts as a chemical
code for the night: longer nights correlate positively
with longer duration of secretion (7), reaching an upper
Received 7/3/08; revised 9/18/08; accepted 9/26/08.
limit of f12+ h (8). Hence, during the typical sleep-
Requests for reprints: Dana K. Mirick, Program in Epidemiology, Division of Public wake period of the non-nightshift worker, circulating
Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue melatonin concentrations are low during the day and
North, M4-A830, P.O. Box 19024, Seattle, WA 98109-1024. Phone: 206-667-4657; Fax:
206-667-2683. E-mail: dmirick@fhcrc.org higher at night, exhibiting a characteristic rise in
Copyright D 2008 American Association for Cancer Research. concentration after darkness and a peak near the
doi:10.1158/1055-9965.EPI-08-0605 midpoint of the dark interval (9).
Cancer Epidemiol Biomarkers Prev 2008;17(12). December 2008
Downloaded from cebp.aacrjournals.org on March 1, 2020. © 2008 American Association for Cancer
Research.Cancer Epidemiology, Biomarkers & Prevention 3307
Melatonin as a Regulator of Gonadal Function. studies measured urinary melatonin levels in women
Melatonin appears to be involved in the regulation of before their development of breast cancer (58-60). Two of
gonadal function by influencing the hypothalamic- the three reported decreased premenopausal and post-
pituitary-gonadal axis. Animal studies indicate that menopausal breast cancer risk among women with
melatonin can modify the firing frequency of the higher melatonin levels using nocturnal or ‘‘first morn-
hypothalamic gonadotropin-releasing hormone pulse ing void’’ urine samples (58, 59). The third study found
generator, thereby affecting the release of gonadotropins no relationship between melatonin level and breast
(luteinizing hormone and follicle-stimulating hormone) cancer risk (60); however, a primary concern with that
from the pituitary (10-13) and stimulating testicular study was the use of a 24-h urine sample to assess
testosterone or ovarian estrogen production and release melatonin levels, which has several concerns as de-
(14, 15). Animal studies have also shown that melatonin scribed by Hrushesky and Blask (61). There is evidence
can inhibit luteinizing hormone-induced testosterone that melatonin levels are decreased in patients with
production in rats (16-18), inhibits prolactin cell activity breast cancer, although, in each of these studies,
in male and female hamsters (19), and suppresses several melatonin levels were measured after diagnosis; there-
aspects of reproductive physiology in male hamsters fore, it is uncertain whether the disease itself and/or
(20). Human studies indicate that decreased concentra- treatment might have affected melatonin levels among
tions of circulating melatonin (such as those brought the cases (62-67). Nighttime plasma melatonin levels
about by circadian disruption) can result in increased have been reported to be lower in women with estrogen
release of the gonadotropins luteinizing hormone and receptor-positive breast cancer than in estrogen receptor-
follicle-stimulating hormone from the pituitary and negative breast cancer, which in turn are lower than in
estrogen release by the ovaries (21-25). There is also healthy control women, and women with the lowest peak
evidence from clinical studies of a relationship between melatonin concentrations had tumors with the highest
melatonin and male reproductive hormones (26-29). concentrations of estrogen receptors (66). Melatonin
Thus, through its control over gonadal hormone produc- levels have also been found to be lower in cases of
tion, melatonin may have an inhibitory effect on primary breast cancer than in women with benign breast
hormone-dependent tumors. disease (63, 67). Although these findings are consistent
Melatonin as a Direct Oncostatic Agent. Melatonin with the results of laboratory studies and melatonin
may also have a direct effect on the development of cancer. levels are in the direction of what might be predicted, it is
Growth-inhibitory and oncostatic properties of melatonin difficult to assess their biological relevance due to the
have been well described (reviewed in ref. 30). Several in presence of disease and its possible effect on blood
vitro studies have reported a reduction in the growth of melatonin levels.
malignant cells and/or tumors of the breast (31-35)
prostate (36-41), and other tumor sites (42-46) by both Methods of Measuring Circulating Melatonin
pharmacologic and physiologic doses of melatonin. In
rodent models, pinealectomy has been found to enhance Melatonin in Serum and Plasma. Plasma melatonin,
tumor growth (47), and exogenous melatonin administra- which has a very short biological half-life and is rapidly
tion has shown anti-initiating (48) and oncostatic (49-52) metabolized by the liver, reflects the amount of melatonin
activities in various chemically induced cancers as well as circulating during the time of sample collection. Thus,
in virus-transmitted tumors in mice (53). It has recently measurement of melatonin in plasma at regular intervals
been reported that exposure of rats with hematomas or (e.g., hourly) will show a circadian rhythm, enabling
human breast cancer xenografts to light during each 12- identification of the onset of melatonin secretion, the
h dark phase resulted in a dose-dependent suppression of duration of melatonin secretion, peak levels of circulating
nocturnal melatonin blood levels and a stimulation of melatonin and the time at which peak secretion occurred,
tumor growth (54). Sainz et al. (55) have also recently and the total amount of melatonin secreted.
shown that treatment of prostate cancer cells with Initially, assays of plasma melatonin were based on
pharmacologic concentrations of melatonin significantly gas chromatography/mass spectrometry (68). These
reduced the number of prostate cancer cells and stopped were later replaced by more specific and sensitive
cell cycle progression in both androgen-dependent radioimmunoassays (RIA) suitable to the clinical envi-
(LNCaP) and androgen-independent (PC3) epithelial ronment (4). Several techniques have been described for
prostate cancer cells and induced cellular differentiation. measuring melatonin in plasma and serum via RIA.
Several mechanisms have been proposed to explain Graham et al. (69) performed comparative studies of the
such direct anticancer activity: melatonin may have Buhlmann RIA kit (ALPCO), the Rollag and Niswender
antimitotic activity by its direct effect on hormone- assay (70), and the Elias USA assay (71). The three
dependent proliferation through interaction with nuclear techniques were found to be in very high agreement with
receptors; it may affect cell-cycle control; and it may one another, with Pearson’s R correlations equal to 0.98
increase the expression of the tumor suppressor gene and higher over a wide range of concentrations.
p53 (35, 56). Furthermore, some clinical trials suggest Despite the advantages of having such detailed
that melatonin, either alone or in combination with information about the circadian rhythm by direct
standard therapy regimens, exhibits a favorable response measurement of melatonin in blood using the highly
in the treatment of human cancers (57). reliable techniques that are currently available, such
Whether low nocturnal melatonin levels predisposes measurement is possible only in a controlled setting
one to an increased risk of cancer is difficult to (e.g., sleep laboratory), making it impractical in other
determine; several studies of breast cancer in women applications such as an epidemiologic study or other
have been attempted to answer this question. Three widespread population use.
Cancer Epidemiol Biomarkers Prev 2008;17(12). December 2008
Downloaded from cebp.aacrjournals.org on March 1, 2020. © 2008 American Association for Cancer
Research.3308 Melatonin as a Biomarker of Circadian Dysregulation
Melatonin in Saliva. Several techniques have been appropriately executed, measurement of melatonin in the
described to measure melatonin levels in saliva, includ- urine would reflect the cumulative amount of circulating
ing use of an iodinated tracer and solid-phase second melatonin corresponding to the period between the prior
antibody (72), high-performance liquid chromatography- urine void and the collection of the subsequent urine
tandem mass spectrometry using stable isotope dilution sample.
(73), column-switching semi-microcolumn liquid chro- Quantifying melatonin levels in urine is typically
matography/mass spectrometry with online analyte accomplished through measurement of 6-sulfatoxymela-
enrichment (74), and, most recently, automated solid- tonin (aMT6s), the primary metabolite in urine, although
phase extraction, high-performance liquid chromatogra- some studies directly measure urinary melatonin.
phy and fluorescence detection (75). Although exact laboratory methods differ from one
Salivary samples were employed by Nowak et al. (76), study to the next, the basic methods for determination
who compared the melatonin concentrations in blood of urinary aMT6s include assay by either RIA or ELISA;
samples collected from five subjects every 2 to 4 h over a commercial kits are available for both methods. Mea-
26-h period, with the melatonin concentrations in saliva. surement of aMT6s by RIA depends on competition of
They reported a significant correlation between serum and aMT6s in the urine and 125I-labeled aMT6s for a limited
salivary melatonin concentrations (R = 0.81) and conclud- number of high-affinity binding sites on Stockgrand
ed that salivary melatonin concentrations are reliable (Guildford) ultraspecific sheep anti-aMT6s antiserum.
indices of serum melatonin concentrations (76). Leibenluft Determination of aMT6s by ELISA uses a commercially
et al. (77) measured the onset of melatonin production and available kit distributed by ALPCO, using the Buhlmann
proposed this measurement as a practical and reliable aMT6s ELISA, a competitive immunoassay using a
method for assessing circadian phase. In their study, capture second antibody technique. Regardless of the
plasma and salivary measurement of melatonin onset laboratory technique employed, concentrations of aMT6s
were highly correlated (R = 0.93). Voultsios et al. (78) are often adjusted by urinary creatinine concentrations to
described a salivary melatonin assay that had sensitivity account for differing output from one individual to the
and accuracy comparable with gas chromatography/mass next and for separate urine collections within individuals
spectrometry assay of plasma melatonin. These investi- (82). It should be noted, however, that urinary creatinine
gators found the time of salivary melatonin onset was concentration itself can be influenced to some degree
shown to exhibit low intraindividual variability, and the by age (83, 84), body weight and lean muscle mass
time of salivary onset was significantly correlated with (83, 85), sex (83), and race (83, 86), requiring careful
plasma onset. Similarly, the acrophase (the time at which consideration of the effects of these factors on creatinine
the peak of the rhythm occurs) of the saliva and plasma concentrations in interpretation of individual studies of
melatonin rhythms were significantly correlated (78). urinary melatonin that are adjusted for urinary creatinine
However, Laakso et al. (79) compared salivary and serum concentration.
melatonin levels and found that saliva and serum
measurements were not highly correlated in individuals Comparison between Blood and Urinary Melatonin
with low serum melatonin levels and that the proportion Levels. Urinary melatonin concentration shows a circa-
of melatonin found in saliva decreased with increasing dian rhythm, much like melatonin levels in the blood
(87-90). Because melatonin is secreted primarily at night,
serum melatonin levels. They concluded that melatonin
many studies have focused on nocturnal samples when
concentrations measured in saliva do not always consis-
evaluating the correlation between melatonin levels in
tently reflect the absolute concentrations in blood.
blood and urine. Wetterberg (91) first reported a high
Gooneratne et al. (80) reported similar results in that
correlation between plasma melatonin level at 2:00 a.m.
serum and saliva melatonin levels were less correlated in
and morning urine melatonin level and pointed out the
individuals with low serum melatonin levels.
potential clinical significance of urinary melatonin levels.
The development of salivary melatonin assays has
Since then, many other studies have shown a high degree
contributed to the adoption of salivary testing as a useful
of correlation between nocturnal measurements of
method for measuring melatonin, given that it is
urinary aMT6s and plasma and serum melatonin (69,
relatively noninvasive and generally acceptable to study
90, 92-94). In addition to observing the circadian rhythm
participants. Furthermore, with proper training, study
of urinary melatonin, Lang et al. (90) reported a
subjects can collect their own samples at home to be later
correlation of 0.74 between plasma melatonin levels at
delivered to the laboratory for assay. Although one study
midnight and urine collected from 9:00 p.m. to 7:00 a.m.
described above reported a problem with inadequate
the following morning. They also found that correlations
saliva volume for analysis for some individuals (80), the
were somewhat lower when plasma levels were com-
primary drawback to measuring melatonin in saliva is
pared with urine samples from 9:00 p.m. to midnight
that, similar to plasma and serum measurements,
(r = 0.61) and from midnight to 8:00 a.m. (r = 0.51;
salivary melatonin reflects the amount of melatonin
ref. 90), perhaps indicating the importance of collecting
circulating in the body at a given point in time. To
a urine sample over the entire night. Fernandez et al. (93)
capture details of the rhythm of melatonin secretion,
analyzed serum melatonin collected between 8:00 and
such as the time of onset, peak levels, and cumulative
9:00 a.m. with nocturnal urinary aMT6s collected the
secretion, one has to collect saliva samples at regular
preceding night over a 12-h period and found a
intervals throughout the subject’s night.
significant positive correlation in each of the three groups
Melatonin in Urine. Arendt et al. (81) suggested that of women studied (premenopausal, perimenopausal, and
measurement of a major metabolite of melatonin excret- post-menopausal). Graham et al. (69) found a significant
ed in urine would allow noninvasive study of pineal relationship between total nocturnal plasma melatonin
function useful in a broad range of applications. If and both urinary aMT6s corrected for creatinine and
Cancer Epidemiol Biomarkers Prev 2008;17(12). December 2008
Downloaded from cebp.aacrjournals.org on March 1, 2020. © 2008 American Association for Cancer
Research.Cancer Epidemiology, Biomarkers & Prevention 3309
urinary melatonin. Combining the two urinary measures different points over a 5-year period and reported a
of aMT6s and melatonin accounted for 72% of the correlation of 0.56.
variance in total plasma melatonin. Furthermore, peak As part of the Schernhammer et al. study described
nocturnal levels of plasma melatonin were significantly above (100), they also conducted a small pilot study to
related to morning levels of urinary melatonin and evaluate whether delaying urine sample processing by 24
aMT6s (69). Cook et al. (92) assessed the differences in to 48 h affected the results. They found that mean aMT6s
melatonin levels between blood and urine samples levels declined by f20% when processing was delayed.
collected in a laboratory-based setting with nocturnal In contrast, as part of the study conducted by Bojkowski
urine samples collected in a field study and found (a) et al. (97), investigators stored urine samples without
very high correlations (P < 0.001) between first morning preservative either at room temperature for 5 days or
void melatonin and creatinine-corrected aMT6s and both at -20j C for 2 years and found aMT6s to be stable
total nocturnal plasma melatonin output and peak under both conditions.
nocturnal plasma melatonin and (b) that the ranges of
urinary melatonin levels were very similar between the Melatonin as a Biomarker of Circadian Dys-
laboratory and field studies. function
Similarly high correlations have been found in studies
that compared melatonin in plasma and serum with It is well established that ocular light exposure in
urinary melatonin over a 24-h period (76, 81, 94-97). humans can affect hormonal secretion either acutely as
Markey et al. reported a significant correlation (r = 0.76) a direct response to the presence or absence of retinal
between 24-h levels of conjugated 6-hydroxymelatonin light exposure or indirectly as a result of the influence of
and nighttime peak plasma melatonin (95). Nowak et al. light on circadian mechanisms. Indeed, light is the most
collected blood and urine samples every 2 to 4 h over powerful circadian synchronizer in humans (102) and
a 26-h period and found significant correlations between can exert a profound effect on the phase and amplitude
serum melatonin and urinary aMT6s (76). Baskett et al. of the human circadian pacemaker (103). Of particular
reported high agreement between 24-h plasma melatonin interest in the context of melatonin as a biomarker is the
and urinary aMT6s levels in a group of elderly effect of light on pineal function in humans: nocturnal
participants (96). Bojkowski et al. found that total illumination of sufficient intensity completely suppresses
24-h urinary excretion of aMT6s was significantly melatonin production (104, 105); there is considerable
correlated with the area under the curve of the respective individual variability in sensitivity to LAN (106-108);
profiles for plasma melatonin (r = 0.75) and plasma there appears to be a dose-response to LAN in that the
aMT6s (r = 0.70; ref. 97). Although the temporal pattern brighter the light the greater the reduction in nocturnal
of nighttime circulating melatonin levels is lost when a circulating melatonin (109, 110); bright light shifts the
single morning urine sample is used in lieu of repeated phase of melatonin rhythm, with morning hours being
measurement of plasma or serum melatonin throughout associated with phase advance and evening hours with
the night, the studies described above form a convincing phase delays (111); and light quality during the day
argument that circulating levels of melatonin in the blood affects night time melatonin production (106, 112-114) as
can be adequately measured in urine samples of the well as the human circadian pacemaker (115).
appropriate duration, suitable in most epidemiologic Because melatonin is a primary circadian pacemaker
settings. and is quantifiable in the urine, blood, and saliva via
well-proven and reliable techniques applicable to non-
Reproducibility of Urinary Melatonin Measure-
laboratory studies, it has become a powerful tool as a
ments. Several studies have evaluated whether measure-
biomarker of circadian dysregulation.
ment of urinary melatonin within an individual is stable
over time. The stability of such measurements further Laboratory-Based Studies of Melatonin and Expo-
promotes the usefulness of this technique, because long- sure to LAN. Using sleep laboratory-based protocols,
term levels of hormones are often of interest in diseases several studies have used melatonin measurements to
with long latency periods. determine phase advance and delays resulting from
A few studies have investigated whether creatinine- controlled exposure to LAN. Deacon and Arendt (116)
standardized urinary melatonin measurements are simulated circadian rhythm disturbance in a laboratory
stable over time. Davis et al. (98) evaluated nocturnal environment to assess the ability of controlled exposure
aMT6s levels in a group of women ages 20 to 74 years to moderately bright light and subsequent darkness to
over 3 consecutive days and then repeated the measu- delay circadian rhythms. Subjects were exposed to bright
rement protocol 3 to 6 months later. Urinary aMT6s light for a 6-h period for 3 consecutive days, at
concentrations were highly and significantly correlated progressively later times each day, with exposure
on consecutive days (r > 0.85) as well as between beginning at 8:00 p.m. on day 1, 10:00 p.m. on day 2,
measurements sessions (r = 0.75; ref. 98). Levallois et al. and midnight on day 3. Using urinary aMT6s measure-
(99) measured urinary aMT6s concentrations over 2 ments, they detected a delay shift 1 day post-light
consecutive days and a found similarly high correlation treatment and a return to baseline phase position by
(r = 0.92). Schernhammer et al. (100) evaluated the day 4 post-treatment. Furthermore, they reported a high
reproducibility of aMT6s in three urine samples degree of correlation between urine, plasma, and salivary
collected from women over a 3-year period and melatonin in detecting these phase shifts (116). The same
reported a correlation of 0.72 between the measurement investigators later used a similar design, this time with
periods. The longest period of urinary melatonin bright light exposure for a 9-h period for 5 consecutive
reproducibility investigated to date is a study by Travis days, and reported that urinary aMT6s acrophase took at
et al. (101), which evaluated urinary aMT6s at three least 5 days post-treatment to return to normal baseline
Cancer Epidemiol Biomarkers Prev 2008;17(12). December 2008
Downloaded from cebp.aacrjournals.org on March 1, 2020. © 2008 American Association for Cancer
Research.3310 Melatonin as a Biomarker of Circadian Dysregulation
pattern (117). Van Cauter et al. (118) exposed volunteers conducted another study in which urine samples were
to 3 h of bright light (5,000 lux) during constant routine collected every 2 to 3 h throughout the subjective days
conditions following a 7-day entrainment period. Using and an oversleep sample from a group of offshore oil
blood samples collected every 20 min and subsequently workers employed in a 1-week alternating shift schedule
assayed for plasma melatonin, they reported rapid (one week days, one week nights), and reported differing
phase shifts within 24 h of bright light exposure. In a adaptation to the nightshift depending on season of the
study in which 23 volunteers were exposed to 6.5 h of year, using measurement of urinary aMT6s to detect
light of dim to moderate intensity early in the biological phase shift (129). Before this, Midwinter and Arendt
night (119), Zeitzer et al. found that even small changes (130) reported differing shifts in the acrophase of
in ordinary light exposure during the late evening melatonin secretion depending on the season of the year
hours can significantly affect both plasma melatonin using 48-h urine samples collected during a week of
concentrations and the entrained phase of the human nightshift work in a group of workers stationed in the
circadian pacemaker. More recently, Roach et al. (120) Antarctic; they further reported a slower readaptation to
conducted a simulated nightshift work study in which the rhythm following nightshift work during the winter
participants ‘‘worked’’ 7 consecutive 8-h shifts and compared with the summer.
reported a mean phase delay of 5.5 h by night 7 using A recent study conducted by Burch et al. (131)
salivary melatonin measurements to detect the phase compared melatonin levels among workers on perma-
shift. A later study by this same investigative team nent day, swing, and night shifts. Urinary aMT6s was
reported similar results using urinary aMT6s levels to measured in post-work and post-sleep samples, and
assess phase delay (121). disrupted circadian melatonin production was evaluated
Field Studies Assessing the Effects of Shift Work on using the sleep/work aMT6s ratio. They reported that
Melatonin Secretion. Several studies have used meas- night workers had altered melatonin, disrupted sleep,
urements of melatonin in the blood or urine to evaluate and elevated symptom prevalence. Subjects grouped by
and describe the effects of shift work on circadian their sleep/work aMT6s ratio rather than shift had even
rhythm. Touitou et al. (122) found that fast-rotating shift greater symptom prevalence. Risks for two or more
work modifies peak values and rhythm amplitudes of symptoms were 3.5 to 8 times greater among workers
serum melatonin. Using data from the Nurses’ Health with sleep/work ratios of V1 compared with those with
Study II, Schernhammer et al. (100) reported a significant ratios of >1 (131). Thus, they described an objective
inverse association between increasing number of nights means to assess circadian disruption.
worked within the 2 weeks preceding urine collection Melatonin as an Indicator of Diurnal Type. Several
and urinary melatonin levels. Along similar lines, Marie studies have used melatonin measurements to evaluate
et al. (123) reported lower 24-h urinary concentrations of
whether diurnal type (morning versus evening) is
aMT6s in nurses working the nightshift compared with
associated with cumulative nocturnal melatonin secre-
nurses working the dayshift; urinary concentrations of
tion and/or onset of melatonin secretion. A small study
aMT6s were also lower during a day off for nightshift
conducted by Madokoro et al. (132) reported pro-
workers, relative to day-off levels in dayshift workers. In
nounced interindividual differences in plasma mela-
a study conducted by Quera-Salva et al. (124, 125), rapid
change in sleep time and melatonin acrophase was tonin concentration measured before and 1 year after
reported in some nightshift workers but not in others, beginning shift work. They constructed a ratio of
suggesting that some people have a physiologic ability to melatonin concentration measured at 6:00 a.m. to total
readily adapt to rotating shift schedules and reported for melatonin concentration measured during the night
the first time a corresponding rapid shift in melatonin and found that higher morningness-eveningness score
secretion. At the time of publication, this study was (indicating morning type; ref. 133) was correlated with
unique in that it employed melatonin (via urinary this ratio. Gibertini et al. (134) measured nocturnal
aMT6s) to evaluate the variability in individual melatonin levels in blood hourly and assessed the
responses to shift work on circadian rhythm. Since then, circadian type of each participant; they found that
Dumont et al. (126) measured urinary aMT6s every 2 circadian type was strongly related to the melatonin
h during a 24-h period after three consecutive nights of acrophase but not to amplitude of the time of year of
work in another group of nurses. Using a cosinor assessment and that morning types experienced a more
analysis to estimate phase position, they reported rapid decline in melatonin levels after the peak relative
individual variability in adaptation to nightshift work, to evening types. Similarly, Liu et al. (135) reported that
with 5 participants showing a phase delay, 3 a phase morning type was associated with an earlier melatonin
advance, and the remaining 22 showing no phase shift acrophase. More recently, Griefahn et al. (136) found
(the timing of their melatonin secretion was typical of a that the onset of melatonin synthesis was 3 h earlier in
dayshift worker). In a study involving offshore oil morning than in evening types using hourly salivary
workers employed in a weeklong alternating shift melatonin measurements; they also reported melatonin
schedule (one week nights, one week days), Gibbs et al. measurements to be a better indicator of diurnal type
(127) reported adaptation to the nightshift schedule via a than rectal temperature measurements. In a follow-up
delay of aMT6s at the end of the week of nightshifts. study reporting similar results (137), the same inves-
In another study of offshore oil workers employed in a tigators concluded that, because morningness is closely
2-week alternating shift schedule (two weeks of days, related to the ability to cope with shift work, the
two weeks of nights), Barnes et al. (128) reported similar determination of the melatonin profile might be a
results, with the delay of aMT6s occurring during the valuable element of the criteria when assigning a person
first week of the nightshift. This same investigative team to shift work.
Cancer Epidemiol Biomarkers Prev 2008;17(12). December 2008
Downloaded from cebp.aacrjournals.org on March 1, 2020. © 2008 American Association for Cancer
Research.Cancer Epidemiology, Biomarkers & Prevention 3311
Concluding Remarks. Melatonin has been shown to reduction of GnRH-induced increase in cytosolic Ca2+. J Mol
Endocrinol 1999;23:299 – 306.
be a useful biomarker of circadian dysregulation and has 17. Valenti S, Giusti M. Melatonin participates in the control of
been associated with nightshift work and exposure to testosterone secretion from rat testis: an overview of our experience.
LAN in both laboratory-based and field studies. Among Ann N Y Acad Sci 2002;966:284 – 9.
other circadian markers (such as core body temperature), 18. Singh K, Krishna A. Inhibitory effects of melatonin on testosterone
but not on androstenedione production during winter in the
it remains comparatively robust in the presence of vespertilionid bat, Scotophilus heathi . J Pineal Res 1995;19:127 – 32.
various external influences. It can be reliably measured 19. Blask DE. Sexually dimorphic effects of melatonin on prolactin cell
directly and indirectly through its metabolites in urine, function in male and female Syrian hamsters. J Pineal Res 1989;7:
blood, and saliva. Urinary melatonin has been shown to 221 – 30.
20. Reiter RJ, Blask DE, Johnson LY, et al. Melatonin inhibition of
be stable over time, making it useful in epidemiologic reproduction in the male hamster: its dependency on time of day of
studies in which laboratory processing is not immedi- administration and on an intact and sympathetically innervated
ately available; its stability also allows it to be used in pineal gland. Neuroendocrinology 1976;22:107 – 16.
studies of cancer with long latency periods. Several 21. Sandyk R. The pineal gland and the menstrual cycle. Int J Neurosci
1992;63:197 – 204.
studies have shown melatonin to be useful in measuring 22. The pineal gland. Boca Raton: CRC Press; 1981.
diurnal type, which is of increasing interest as it becomes 23. Yie SM, Brown GM, Liu GY, et al. Melatonin and steroids in human
more apparent that successful adaptation to shift work pre-ovulatory follicular fluid: seasonal variations and granulosa cell
may be dependent on diurnal preference. steroid production. Hum Reprod 1995;10:50 – 5.
24. Penny R, Stanczyk F, Goebelsmann U. Melatonin: data consistent
with a role in controlling ovarian function. J Endocrinol Invest 1987;
10:499 – 505.
Disclosure of Potential Conflicts of Interest 25. Voordouw BC, Euser R, Verdonk RE, et al. Melatonin and melatonin-
No potential conflicts of interest were disclosed. progestin combinations alter pituitary-ovarian function in women
and can inhibit ovulation. J Clin Endocrinol Metab 1992;74:108 – 17.
26. Rajmil O, Puig-Domingo M, Tortosa F, et al. Melatonin concentration
Acknowledgments before and during testosterone replacement in primary hypogonadic
The costs of publication of this article were defrayed in part by men. Eur J Endocrinol 1997;137:48 – 52.
27. Luboshitzky R, Lavi S, Thuma I, et al. Testosterone treatment alters
the payment of page charges. This article must therefore be melatonin concentrations in male patients with gonadotropin-
hereby marked advertisement in accordance with 18 U.S.C. releasing hormone deficiency. J Clin Endocrinol Metab 1996;81:
Section 1734 solely to indicate this fact. 770 – 4.
28. Luboshitzky R, Wagner O, Lavi S, et al. Abnormal melatonin
secretion in hypogonadal men: the effect of testosterone treatment.
Clin Endocrinol (Oxf) 1997;47:463 – 9.
References 29. Caglayan S, Ozata M, Ozisik G, et al. Plasma melatonin concentration
1. Czeisler CA, Klerman EB. Circadian and sleep-dependent regula- before and during testosterone replacement in Klinefelter’s syn-
tion of hormone release in humans. Recent Prog Horm Res 1999; drome: relation to hepatic indolamine metabolism and sympathoa-
54:97 – 130. drenal activity. J Clin Endocrinol Metab 2001;86:738 – 43.
2. Pandi-Perumal SR, Smits M, Spence W, et al. Dim light melatonin 30. Blask DE, Dauchy RT, Sauer LA. Putting cancer to sleep at night:
onset (DLMO): a tool for the analysis of circadian phase in human the neuroendocrine/circadian melatonin signal. Endocrine 2005;27:
sleep and chronobiological disorders. Prog Neuropsychopharmacol 179 – 88.
Biol Psychiatry 2007;31:1 – 11. 31. Hill SM, Blask DE. Effects of the pineal hormone melatonin on the
3. Krauchi K, Cajochen C, Werth E, et al. Alteration of internal circadian proliferation and morphological characteristics of human breast
phase relationships after morning versus evening carbohydrate-rich cancer cells (MCF-7) in culture. Cancer Res 1988;48:6121 – 6.
meals in humans. J Biol Rhythms 2002;17:364 – 76. 32. Cos S, Fernandez F, Sanchez-Barcelo EJ. Melatonin inhibits DNA
4. Lewy AJ, Cutler NL, Sack RL. The endogenous melatonin profile as a synthesis in MCF-7 human breast cancer cells in vitro . Life Sci 1996;
marker for circadian phase position. J Biol Rhythms 1999;14:227 – 36. 58:2447 – 53.
5. Lewy AJ. The dim light melatonin onset, melatonin assays and 33. Cos S, Fernandez R, Guezmes A, et al. Influence of melatonin on
biological rhythm research in humans. Biol Signals Recept 1999;8: invasive and metastatic properties of MCF-7 human breast cancer
79 – 83. cells. Cancer Res 1998;58:4383 – 90.
6. Wurtman RJ, Axelrod J. The pineal gland. Sci Am 1965;213:50 – 60. 34. Cos S, Mediavilla MD, Fernandez R, et al. Does melatonin induce
7. Claustrat B, Brun J, Chazot G. The basic physiology and pathophy- apoptosis in MCF-7 human breast cancer cells in vitro ? J Pineal Res
siology of melatonin. Sleep Med Rev 2005;9:11 – 24. 2002;32:90 – 6.
8. Wehr TA. The durations of human melatonin secretion and sleep 35. Mediavilla MD, Cos S, Sanchez-Barcelo EJ. Melatonin increases p53
respond to changes in daylength (photoperiod). J Clin Endocrinol and p21WAF1 expression in MCF-7 human breast cancer cells
Metab 1991;73:1276 – 80. in vitro . Life Sci 1999;65:415 – 20.
9. Czeisler CA, Duffy JF, Shanahan TL, et al. Stability, precision, and 36. Siu SW, Lau KW, Tam PC, et al. Melatonin and prostate cancer cell
near-24-hour period of the human circadian pacemaker. Science proliferation: interplay with castration, epidermal growth factor, and
1999;284:2177 – 81. androgen sensitivity. Prostate 2002;52:106 – 22.
10. Bittman EL, Kaynard AH, Olster DH, et al. Pineal melatonin 37. Rimler A, Lupowitz Z, Zisapel N. Differential regulation by
mediates photoperiodic control of pulsatile luteinizing hormone melatonin of cell growth and androgen receptor binding to the
secretion in the ewe. Neuroendocrinology 1985;40:409 – 18. androgen response element in prostate cancer cells. Neuro Endo-
11. Yellon SM, Foster DL. Melatonin rhythms time photoperiod-induced crinol Lett 2002;23 Suppl 1:45 – 9.
puberty in the female lamb. Endocrinology 1986;119:44 – 9. 38. Marelli MM, Limonta P, Maggi R, et al. Growth-inhibitory activity of
12. Robinson JE, Kaynard AH, Karsch FJ. Does melatonin alter pituitary melatonin on human androgen-independent DU 145 prostate cancer
responsiveness to gonadotropin-releasing hormone in the ewe? cells. Prostate 2000;45:238 – 44.
Neuroendocrinology 1986;43:635 – 40. 39. Xi SC, Tam PC, Brown GM, et al. Potential involvement of mt1
13. Robinson JE. Photoperiodic and steroidal regulation of the luteiniz- receptor and attenuated sex steroid-induced calcium influx in the
ing pulse generator in ewes. In: Crowley WF, Hofler JG, editors. The direct anti-proliferative action of melatonin on androgen-responsive
episodic secretion of hormones. New York: Wiley; 1987. p. 159. LNCaP human prostate cancer cells. J Pineal Res 2000;29:172 – 83.
14. Catt KJ, Dafau ML. Gonadotropic hormones: biosynthesis, secretion, 40. Moretti RM, Marelli MM, Maggi R, et al. Antiproliferative action of
receptors, and actions. In: Yen SSC, Jaffe RB, editors. Reproductive melatonin on human prostate cancer LNCaP cells. Oncol Rep 2000;7:
endocrinology. Philadelphia: W.B. Saunders; 1991. p. 144 – 51. 347 – 51.
15. Adashi EY. The ovarian life cycle. In: Yen SSC, Jaffe RB, editors. 41. Philo R, Berkowitz AS. Inhibition of Dunning tumor growth by
Reproductive endocrinology. Philadelphia: W.B. Saunders; 1991. p. melatonin. J Urol 1988;139:1099 – 102.
202 – 4. 42. Sze SF, Ng TB, Liu WK. Antiproliferative effect of pineal indoles on
16. Valenti S, Thellung S, Florio T, et al. A novel mechanism for the cultured tumor cell lines. J Pineal Res 1993;14:27 – 33.
melatonin inhibition of testosterone secretion by rat Leydig cells: 43. Ying SW, Niles LP, Crocker C. Human malignant melanoma cells
Cancer Epidemiol Biomarkers Prev 2008;17(12). December 2008
Downloaded from cebp.aacrjournals.org on March 1, 2020. © 2008 American Association for Cancer
Research.3312 Melatonin as a Biomarker of Circadian Dysregulation
express high-affinity receptors for melatonin: antiproliferative tions of melatonin in sheep exposed to different lighting regimens.
effects of melatonin and 6-chloromelatonin. Eur J Pharmacol Endocrinology 1976;98:482 – 9.
1993;246:89 – 96. 71. Zimmermann RC, Schroder S, Baars S, et al. Melatonin and the
44. Petranka J, Baldwin W, Biermann J, et al. The oncostatic action of ovulatory luteinizing hormone surge. Fertil Steril 1990;54:612 – 8.
melatonin in an ovarian carcinoma cell line. J Pineal Res 1999;26: 72. English J, Middleton BA, Arendt J, et al. Rapid direct measurement of
129 – 36. melatonin in saliva using an iodinated tracer and solid phase second
45. Shiu SY, Li L, Xu JN, et al. Melatonin-induced inhibition of antibody. Ann Clin Biochem 1993;30:415 – 6.
proliferation and G1/S cell cycle transition delay of human 73. Eriksson K, Ostin A, Levin JO. Quantification of melatonin in human
choriocarcinoma JAr cells: possible involvement of MT2 (MEL1B) saliva by liquid chromatography-tandem mass spectrometry using
receptor. J Pineal Res 1999;27:183 – 92. stable isotope dilution. J Chromatogr B Analyt Technol Biomed Life
46. Kanishi Y, Kobayashi Y, Noda S, et al. Differential growth inhibitory Sci 2003;794:115 – 23.
effect of melatonin on two endometrial cancer cell lines. J Pineal Res 74. Motoyama A, Kanda T, Namba R. Direct determination of
2000;28:227 – 33. endogenous melatonin in human saliva by column-switching semi-
47. Tamarkin L, Cohen M, Roselle D, et al. Melatonin inhibition microcolumn liquid chromatography/mass spectrometry with on-
and pinealectomy enhancement of 7,12-dimethylbenz(a)anthra- line analyte enrichment. Rapid Commun Mass Spectrom 2004;18:
acene-induced mammary tumors in the rat. Cancer Res 1981;41: 1250 – 8.
4432 – 6. 75. Romsing S, Bokman F, Bergqvist Y. Determination of melatonin in
48. Musatov SA, Anisimov VN, Andre V, et al. Effects of melatonin on saliva using automated solid-phase extraction, high-performance
N-nitroso-N-methylurea-induced carcinogenesis in rats and muta- liquid chromatography and fluorescence detection. Scand J Clin Lab
genesis in vitro (Ames test and COMET assay). Cancer Lett 1999;138: Invest 2006;66:181 – 90.
37 – 44. 76. Nowak R, McMillen IC, Redman J, et al. The correlation between
49. Anisimov VN, Popovich IG, Zabezhinski MA. Melatonin and colon serum and salivary melatonin concentrations and urinary 6-hydro-
carcinogenesis. I. Inhibitory effect of melatonin on development of xymelatonin sulphate excretion rates: two non-invasive techniques
intestinal tumors induced by 1,2-dimethylhydrazine in rats. Carci- for monitoring human circadian rhythmicity. Clin Endocrinol (Oxf)
nogenesis 1997;18:1549 – 53. 1987;27:445 – 52.
50. Anisimov VN, Kvetnoy IM, Chumakova NK, et al. Melatonin and 77. Leibenluft E, Feldman-Naim S, Turner EH, et al. Salivary and
colon carcinogenesis. II. Intestinal melatonin-containing cells and plasma measures of dim light melatonin onset (DLMO) in
serum melatonin level in rats with 1,2-dimethylhydrazine-induced patients with rapid cycling bipolar disorder. Biol Psychiatry
colon tumors. Exp Toxicol Pathol 1999;51:47 – 52. 1996;40:731 – 5.
51. Cini G, Coronnello M, Mini E, et al. Melatonin’s growth-inhibitory 78. Voultsios A, Kennaway DJ, Dawson D. Salivary melatonin as a
effect on hepatoma AH 130 in the rat. Cancer Lett 1998;125:51 – 9. circadian phase marker: validation and comparison to plasma
52. Mocchegiani E, Perissin L, Santarelli L, et al. Melatonin admin- melatonin. J Biol Rhythms 1997;12:457 – 66.
istration in tumor-bearing mice (intact and pinealectomized) in 79. Laakso ML, Porkka-Heiskanen T, Alila A, et al. Correlation between
relation to stress, zinc, thymulin and IL-2. Int J Immunopharma- salivary and serum melatonin: dependence on serum melatonin
col 1999;21:27 – 46. levels. J Pineal Res 1990;9:39 – 50.
53. Subramanian A, Kothari L. Melatonin, a suppressor of spontaneous 80. Gooneratne NS, Metlay JP, Guo W, et al. The validity and feasibility
murine mammary tumors. J Pineal Res 1991;10:136 – 40. of saliva melatonin assessment in the elderly. J Pineal Res 2003;34:
54. Blask DE, Brainard GC, Dauchy RT, et al. Melatonin-depleted blood 88 – 94.
from premenopausal women exposed to light at night stimulates 81. Arendt J, Bojkowski C, Franey C, et al. Immunoassay of 6-
growth of human breast cancer xenografts in nude rats. Cancer Res hydroxymelatonin sulfate in human plasma and urine: abolition of
2005;65:11174 – 84. the urinary 24-hour rhythm with atenolol. J Clin Endocrinol Metab
55. Sainz RM, Mayo JC, Tan DX, et al. Melatonin reduces prostate cancer 1985;60:1166 – 73.
cell growth leading to neuroendocrine differentiation via a receptor 82. Klante G, Brinschwitz T, Secci K, et al. Creatinine is an appropriate
and PKA independent mechanism. Prostate 2005;63:29 – 43. reference for urinary sulphatoxymelatonin of laboratory animals and
56. Brzezinski A. Melatonin in humans. N Engl J Med 1997;336:186 – 95. humans. J Pineal Res 1997;23:191 – 7.
57. Vijayalaxmi, Thomas CR, Jr., Reiter RJ, et al. Melatonin: from basic 83. Barr DB, Wilder LC, Caudill SP, et al. Urinary creatinine
research to cancer treatment clinics. J Clin Oncol 2002;20:2575 – 601. concentrations in the U.S. population: implications for urinary
58. Schernhammer ES, Hankinson SE. Urinary melatonin levels and biologic monitoring measurements. Environ Health Perspect 2005;
breast cancer risk. J Natl Cancer Inst 2005;97:1084 – 7. 113:192 – 200.
59. Schernhammer ES, Berrino F, Krogh V, et al. Urinary 6-sulfatox- 84. Moriguchi J, Ezaki T, Tsukahara T, et al. Decreases in urine specific
ymelatonin levels and risk of breast cancer in postmenopausal gravity and urinary creatinine in elderly women. Int Arch Occup
women. J Natl Cancer Inst 2008;100:898 – 905. Environ Health 2005;78:438 – 45.
60. Travis RC, Allen DS, Fentiman IS, et al. Melatonin and breast cancer: 85. Baxmann AC, Ahmed MS, Marques NC, et al. Influence of muscle
a prospective study. J Natl Cancer Inst 2004;96:475 – 82. mass and physical activity on serum and urinary creatinine and
61. Hrushesky WJ, Blask DE. Re: Melatonin and breast cancer: a serum cystatin C. Clin J Am Soc Nephrol 2008;3:348 – 54.
prospective study. J Natl Cancer Inst 2004;96:888 – 9. 86. Martin MD, Woods JS, Leroux BG, et al. Longitudinal urinary
62. Bartsch C, Bartsch H, Jain AK, et al. Urinary melatonin levels in creatinine excretion values among preadolescents and adolescents.
human breast cancer patients. J Neural Transm 1981;52:281 – 94. Transl Res 2008;151:51 – 6.
63. Bartsch C, Bartsch H, Fuchs U, et al. Stage-dependent depression of 87. Lynch HJ, Wurtman RJ, Moskowitz MA, et al. Daily rhythm in
melatonin in patients with primary breast cancer. Correlation with human urinary melatonin. Science 1975;187:169 – 71.
prolactin, thyroid stimulating hormone, and steroid receptors. 88. Akerstedt T, Gillberg M, Wetterberg L. The circadian covariation of
Cancer 1989;64:426 – 33. fatigue and urinary melatonin. Biol Psychiatry 1982;17:547 – 54.
64. Bartsch C, Bartsch H, Bellmann O, et al. Depression of serum 89. Kabuto M. Daytime melatonin in postmenopausal Japanese women.
melatonin in patients with primary breast cancer is not due to an In: Stevens RG, Wilson W, Anderson LE, editors. The melatonin
increased peripheral metabolism. Cancer 1991;67:1681 – 4. hypothesis: breast cancer and the use of electric power. Columbus:
65. Bartsch C, Bartsch H, Karenovics A, et al. Nocturnal urinary 6- Battelle Press; 1997. p. 319 – 34.
sulphatoxymelatonin excretion is decreased in primary breast cancer 90. Lang U, Kornemark M, Aubert ML, et al. Radioimmunological
patients compared to age-matched controls and shows negative determination of urinary melatonin in humans: correlation with
correlation with tumor-size. J Pineal Res 1997;23:53 – 8. plasma levels and typical 24-hour rhythmicity. J Clin Endocrinol
66. Tamarkin L, Danforth D, Lichter A, et al. Decreased nocturnal Metab 1981;53:645 – 50.
plasma melatonin peak in patients with estrogen receptor positive 91. Wetterberg L. Melatonin in humans physiological and clinical
breast cancer. Science 1982;216:1003 – 5. studies. J Neural Transm Suppl 1978;13:289 – 310.
67. Skene DJ, Bojkowski CJ, Currie JE, et al. 6-Sulphatoxymelatonin 92. Cook MR, Graham C, Kavet R, et al. Morning urinary assessment of
production in breast cancer patients. J Pineal Res 1990;8:269 – 76. nocturnal melatonin secretion in older women. J Pineal Res 2000;28:
68. Lewy AJ, Markey SP. Analysis of melatonin in human plasma by gas 41 – 7.
chromatography negative chemical ionization mass spectrometry. 93. Fernandez B, Malde JL, Montero A, et al. Relationship between
Science 1978;201:741 – 3. adenohypophyseal and steroid hormones and variations in serum
69. Graham C, Cook MR, Kavet R, et al. Prediction of nocturnal and urinary melatonin levels during the ovarian cycle, perimeno-
plasma melatonin from morning urinary measures. J Pineal Res pause and menopause in healthy women. J Steroid Biochem 1990;35:
1998;24:230 – 8. 257 – 62.
70. Rollag MD, Niswender GD. Radioimmunoassay of serum concentra- 94. Paakkonen T, Makinen TM, Leppaluoto J, et al. Urinary melatonin: a
Cancer Epidemiol Biomarkers Prev 2008;17(12). December 2008
Downloaded from cebp.aacrjournals.org on March 1, 2020. © 2008 American Association for Cancer
Research.Cancer Epidemiology, Biomarkers & Prevention 3313
noninvasive method to follow human pineal function as studied in nin and alertness rhythms after treatment with moderately bright
three experimental conditions. J Pineal Res 2006;40:110 – 5. light at night. Clin Endocrinol (Oxf) 1994;40:413 – 20.
95. Markey SP, Higa S, Shih M, et al. The correlation between human 117. Deacon S, Arendt J. Adapting to phase shifts. I. An experimental
plasma melatonin levels and urinary 6-hydroxymelatonin excretion. model for jet lag and shift work. Physiol Behav 1996;59:665 – 73.
Clin Chim Acta 1985;150:221 – 5. 118. Van Cauter E, Sturis J, Byrne MM, et al. Demonstration of rapid light-
96. Baskett JJ, Cockrem JF, Antunovich TA. Sulphatoxymelatonin induced advances and delays of the human circadian clock using
excretion in older people: relationship to plasma melatonin and hormonal phase markers. Am J Physiol 1994;266:E953 – 963.
renal function. J Pineal Res 1998;24:58 – 61. 119. Zeitzer JM, Dijk DJ, Kronauer R, et al. Sensitivity of the human
97. Bojkowski CJ, Arendt J, Shih MC, et al. Melatonin secretion in circadian pacemaker to nocturnal light: melatonin phase resetting
humans assessed by measuring its metabolite, 6-sulfatoxymelatonin. and suppression. J Physiol 2000;526 Pt 3:695 – 702.
Clin Chem 1987;33:1343 – 8. 120. Roach G, Burgess H, Lamond N, et al. A week of simulated night
98. Davis S, Kaune WT, Mirick DK, et al. Residential magnetic fields, work delays salivary melatonin onset. J Hum Ergol 2001;30:255 – 60.
light-at-night, and nocturnal urinary 6-sulfatoxymelatonin concen- 121. Roach GD, Lamond N, Dorrian J, et al. Changes in the concentration
tration in women. Am J Epidemiol 2001;154:591 – 600. of urinary 6-sulphatoxymelatonin during a week of simulated night
99. Levallois P, Dumont M, Touitou Y, et al. Effects of electric and work. Ind Health 2005;43:193 – 6.
magnetic fields from high-power lines on female urinary excretion of 122. Touitou Y, Motohashi Y, Reinberg A, et al. Effect of shift work on the
6-sulfatoxymelatonin. Am J Epidemiol 2001;154:601 – 9. night-time secretory patterns of melatonin, prolactin, cortisol and
100. Schernhammer ES, Rosner B, Willett WC, et al. Epidemiology of testosterone. Eur J Appl Physiol Occup Physiol 1990;60:288 – 92.
urinary melatonin in women and its relation to other hormones and 123. Marie HA, Helene GA, Hansen J. Diurnal urinary 6-sulfatoxymela-
night work. Cancer Epidemiol Biomarkers Prev 2004;13:936 – 43. tonin levels among healthy Danish nurses during work and leisure
101. Travis RC, Allen NE, Peeters PH, et al. Reproducibility over 5 years time. Chronobiol Int 2006;23:1203 – 15.
of measurements of 6-sulphatoxymelatonin in urine samples from 124. Quera-Salva MA, Defrance R, Claustrat B, et al. Rapid shift in sleep
postmenopausal women. Cancer Epidemiol Biomarkers Prev 2003; time and acrophase of melatonin secretion in short shift work
12:806 – 8. schedule. Sleep 1996;19:539 – 43.
102. Czeisler CA, Wright KP, Jr. Neurobiology of sleep and circadian 125. Quera-Salva MA, Guilleminault C, Claustrat B, et al. Rapid shift in
rhythms. New York: Marcel Decker; 1999. peak melatonin secretion associated with improved performance in
103. Czeisler CA, Khalsa SBS. Principles and practice of sleep medicine. short shift work schedule. Sleep 1997;20:1145 – 50.
Philadelphia: W.B. Saunders; 1999. 126. Dumont M, haberou-Brun D, Paquet J. Profile of 24-h light exposure
104. Lynch HJ, Deng MH, Wurtman RJ. Light intensities required to and circadian phase of melatonin secretion in night workers. J Biol
suppress nocturnal melatonin secretion in albino and pigmented rats. Rhythms 2001;16:502 – 11.
Life Sci 1984;35:841 – 7. 127. Gibbs M, Hampton S, Morgan L, et al. Adaptation of the circadian
105. Lewy AJ, Wehr TA, Goodwin FK, et al. Light suppresses melatonin rhythm of 6-sulphatoxymelatonin to a shift schedule of seven nights
secretion in humans. Science 1980;210:1267 – 9. followed by seven days in offshore oil installation workers. Neurosci
106. McIntyre IM, Norman TR, Burrows GD, et al. Melatonin super- Lett 2002;325:91 – 4.
sensitivity to dim light in seasonal affective disorder. Lancet 1990; 128. Barnes RG, Deacon SJ, Forbes MJ, et al. Adaptation of the 6-
335:488. sulphatoxymelatonin rhythm in shiftworkers on offshore oil installa-
107. Hebert M, Martin SK, Lee C, et al. The effects of prior light history on tions during a 2-week 12-h night shift. Neurosci Lett 1998;241:9 – 12.
the suppression of melatonin by light in humans. J Pineal Res 2002; 129. Barnes RG, Forbes MJ, Arendt J. Shift type and season affect
33:198 – 203. adaptation of the 6-sulphatoxymelatonin rhythm in offshore oil rig
108. Herljevic M, Middleton B, Thapan K, et al. Light-induced melatonin workers. Neurosci Lett 1998;252:179 – 82.
suppression: age-related reduction in response to short wavelength 130. Midwinter MJ, Arendt J. Adaptation of the melatonin rhythm in
light. Exp Gerontol 2005;40:237 – 42. human subjects following night-shift work in Antarctica. Neurosci
109. McIntyre IM, Norman TR, Burrows GD, et al. Human melatonin Lett 1991;122:195 – 8.
suppression by light is intensity dependent. J Pineal Res 1989;6: 131. Burch JB, Yost MG, Johnson W, et al. Melatonin, sleep, and shift work
149 – 56. adaptation. J Occup Environ Med 2005;47:893 – 901.
110. Nathan PJ, Wyndham EL, Burrows GD, et al. The effect of gender on 132. Madokoro S, Nakagawa H, Misaki K, et al. Nocturnal melatonin
the melatonin suppression by light: a dose response relationship. profiles before and one year after beginning shift-work. Psychiatry
J Neural Transm 2000;107:271 – 9. Clin Neurosci 1997;51:17 – 22.
111. Duffy JF, Wright KP, Jr. Entrainment of the human circadian system 133. Horne JA, Ostberg O. A self-assessment questionnaire to determine
by light. J Biol Rhythms 2005;20:326 – 38. morningness-eveningness in human circadian rhythms. Int J Chrono-
112. Lewy AJ, Sack RL, Miller LS, et al. Antidepressant and circadian biol 1976;4:97 – 110.
phase-shifting effects of light. Science 1987;235:352 – 4. 134. Gibertini M, Graham C, Cook MR. Self-report of circadian type reflects
113. Wehr TA, Giesen HA, Moul DE, et al. Suppression of men’s the phase of the melatonin rhythm. Biol Psychol 1999;50:19 – 33.
responses to seasonal changes in day length by modern artificial 135. Liu X, Uchiyama M, Shibui K, et al. Diurnal preference, sleep habits,
lighting. Am J Physiol 1995;269:R173 – 8. circadian sleep propensity and melatonin rhythm in healthy human
114. Boivin DB, Duffy JF, Kronauer RE, et al. Dose-response relation- subjects. Neurosci Lett 2000;280:199 – 202.
ships for resetting of human circadian clock by light. Nature 136. Griefahn B, Kunemund C, Golka K, et al. Melatonin synthesis: a
1996;379:540 – 2. possible indicator of intolerance to shiftwork. Am J Ind Med 2002;42:
115. Czeisler CA, Allan JS, Strogatz SH, et al. Bright light resets the 427 – 36.
human circadian pacemaker independent of the timing of the sleep- 137. Griefahn B. The validity of the temporal parameters of the daily
wake cycle. Science 1986;233:667 – 71. rhythm of melatonin levels as an indicator of morningness. Chrono-
116. Deacon SJ, Arendt J. Phase-shifts in melatonin, 6-sulphatoxymelato- biol Int 2002;19:561 – 77.
Cancer Epidemiol Biomarkers Prev 2008;17(12). December 2008
Downloaded from cebp.aacrjournals.org on March 1, 2020. © 2008 American Association for Cancer
Research.You can also read
