S P E C I A L
F E A T U R E
R e v i e w
An Endocrinologist’s Guide to the Clock
Madhu J. Prasai, Ida Pernicova, Peter J. Grant, and Eleanor M. Scott
Division of Cardiovascular and Diabetes Research, LIGHT Laboratories, University of Leeds, Leeds LS2 9JT,
United Kingdom
Context: It has long been recognized that a “biological clock” residing in the suprachiasmatic
nucleus controls circadian or daily variations in physiological processes. Old observations are now
being revisited after the discovery of the cellular mechanism of timekeeping, the molecular clock,
an autoregulatory feedback loop of transcription factors that cycles over a period of approximately
24 h. Its functioning or breakdown impinges upon the physiology and pathophysiology of numerous systems, including the endocrine system and metabolism. Here we provide an introduction
to those aspects of the clock most relevant to the endocrinologist.
Evidence Acquisition: Articles were identified by searching PubMed using the search terms
“circadian” and “clock” and refining results to include articles relating to endocrinology and
metabolism.
Evidence Synthesis: We discuss current understanding of the mechanisms through which hormonal and metabolic axes fall under the influence of the circadian clock. Of particular interest is
the complex interaction of genetic and environmental factors in determining health or disease
states.
Conclusions: Research into the molecular clock provides a novel window onto endocrine and
metabolic disease. These advances present new avenues for diagnostic and therapeutic
strategies. (J Clin Endocrinol Metab 96: 913–922, 2011)
I
t has long been known that organisms exhibit a multiplicity of physiological and behavioral rhythms that
recur every 24 h. This in turn gave rise to speculation over
the existence of a biological clock able to “tell the time”
from the ambient day/night cycle. In the 1950s, the term
“circadian” was coined to denote these daily cycles, and
clock theory was consolidated (1). Experimental data and
mathematical modeling proposed that an oscillator generates a characteristic sine-wave output with a regular
cycle length, or period, responsible for repeating 24-h
rhythms. Crucially, the clock is endogenous, not reactive.
It does not merely passively respond to environmental
changes but sustains free-running cycles that persist even
when organisms are housed in constant darkness in deprivation of external time cues. Such time cues are called
Zeitgebers, and by a process of phase-shifting they may
reset or entrain the clock to a new environmental rhythm.
The master Zeitgeber is light. The output of the clock had
thus been described in sophisticated terms before its
source was discovered. In 1972, it was shown that a central master clock resides in the suprachiasmatic nucleus
(SCN) of the hypothalamus and receives photic inputs via
the retinohypothalamic tract that enable it to synchronize
to light (2, 3). The molecular mechanism underlying clock
function was seen in Drosophila in the early 1970s (4), but
mammalian homologs proved elusive until the generation
in 1994 of the Clock⌬19 mouse, an animal with a dominant negative mutation of a core clock gene (5).
The cogs of the molecular clock (Fig. 1) are now known
to consist of a negative feedback system of transcription
factors whose transcription and translation oscillates
slowly over the magic number of 24 h to create a regular,
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2011 by The Endocrine Society
doi: 10.1210/jc.2010-2449 Received October 15, 2010. Accepted December 29, 2010.
First Published Online February 2, 2011
Abbreviations: AMPK, AMP-activated protein kinase; DIO, deiodinase; FEO, food-entrainable oscillator; SCN, suprachiasmatic nucleus; SIRT, sirtuin.
J Clin Endocrinol Metab, April 2011, 96(4):913–922
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FIG. 1. The molecular clock. Positive limb: BMAL1 and CLOCK are transcribed and form complexes that act upon E-box elements to promote the
transcription of PER and CRY genes. Negative limb: PER and CRY form complexes that feed back to inhibit the transcription of BMAL1 and CLOCK.
Clock proteins induce cyclical transcription of clock-controlled genes, propagating circadian rhythms in cellular physiology. Posttranslational protein
modifications regulate clock protein function including phosphorylation (P), acetylation (A), ubiquitination (U), and sumoylation (S).
repetitive, self-sustaining cycle. The core system has a positive limb, dimers of BMAL1 with either CLOCK or
NPAS2, which act on E-box elements to promote transcription of PER and CRY (period and cryptochrome)
genes, which in turn form the negative limb of the cycle by
feeding back to inhibit CLOCK and BMAL1 transcription (6). It is increasingly clear that this is an oversimplification: the system is complicated by a secondary tier of
accessory genetic feedback loops, posttranslational protein modifications governing stability and subcellular
localization, and interactions of accessory regulatory proteins (7). The output of the system is composed of clockcontrolled genes, whose transcription is regulated by the
core clock genes and which can be identified on microarray studies by their robust circadian cycling. The effect of
a malfunction in the core clock machinery with respect to
these clock-controlled genes is more than just a flattening
of daily fluctuations; gene transcription tends to be suppressed to the daily minimum level with a consequent severe loss of function of the resultant protein.
Elucidation of the molecular clock led to the important
discovery that the clock mechanism is not confined to the
SCN, but that functional, cycling clocks exist in virtually
all peripheral tissues (8). The challenge of understanding
the circadian system now resides in piecing together the
jigsaw of independent yet interdependent timekeepers
held under the leadership of the SCN. The robust circadian
variation displayed by endocrine axes and their circulation in plasma implicates them as potential mediators of
time between SCN and periphery (Fig. 2). Hierarchical
systems offer numerous opportunities for control— but
also for dysfunction. The system may break down at the
molecular level in the cell, through desynchronization of
periphery from center, or through abnormalities of central
pacing. Another layer of complexity arises from the interplay of genetic and environmental factors in circadian
function, harking back to the interest of early studies in the
clock as a putative evolutionary agent. Powerful studies
now make a link from sleep disruption (9, 10) and shift
work (11)— environmental causes of circadian disruption—to diseases of Western lifestyle such as obesity and
type 2 diabetes. Transgenic mice and human population
genetic studies open up to scrutiny the genetic aspects of
circadian hormonal and metabolic regulation.
J Clin Endocrinol Metab, April 2011, 96(4):913–922
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vailing environmental cycle (14). In cultured rat adipocytes, addition of melatonin to the culture medium in a
circadian pattern entrains clock gene
expression and lipid synthetic pathways (15).
How important is melatonin in setting time? Mouse experiments suggest
that although under stable conditions
circadian rhythms are normal when
melatonin signaling is disrupted, entrainment to new light schedules may be
impaired (13). Human studies provide
further detail (for reviews, see Refs. 16
and 17). In shift workers and the blind,
excess or absent light respectively disturbs melatonin rhythms (18, 19) with
variable desynchronization of the rest/
activity pattern from the cycles of melatonin and other circadian markers,
such as core body temperature and corFIG. 2. Endocrine organs subject to circadian variation. The SCN forms the central master
tisol. Symptomatically, this manifests
pacemaker that exerts hierarchical control over downstream endocrine organs.
in disordered sleep, which points to one
of the few existing therapeutic applicaOur interrogation of the circadian clock system in en- tions of circadian studies. Taken orally in the late afterdocrine health and disease may therefore be divided into noon/early evening, 0.5–10 mg melatonin induces sleep
two themes. First, how might the endocrine system help and phase-advances the clock (16), useful both for chronic
the SCN to disseminate the clock signal and coordinate entrainment and for acute phase-shifts to counteract jet
body time? Second, how are individual endocrine axes lag. Thus, although not essential for generation of circaaffected by disruption of their endogenous clockwork or dian rhythm at the cellular level, melatonin is a useful tool
by disconnection from whole body time?
for coordination of physiological rhythms at the wholebody level. Further roles in setting seasonal rhythms and
in diabetes are discussed in Insulin and melatonin and The
Hormones as Circadian Agents
Calendar.
Melatonin
Melatonin was discovered in the 1950s, and its ability
to entrain circadian rhythms has been known since the
1980s (12). In circadian studies, it is one of the most reliable markers of entrainment, and as hormone of the dark
it is an evident link between external light and internal
physiological cycles. Even in nocturnal animals, whose
hormonal rhythms are largely inverted, melatonin peaks
at night. The SCN controls its synthesis through tonic
inhibition of noradrenergic stimulation of the pineal
gland. When SCN firing diminishes in darkness, sympathetic activity is unleashed, and melatonin synthesis is facilitated; conversely, a light pulse during the dark period
snaps off melatonin production within 5 min (13). Melatonin receptors are found widely in peripheral tissues and
the SCN, enabling melatonin both to pass on information
downstream from the master clock and, by inhibiting SCN
firing, to adjust central clock time in reflection of the pre-
Glucocorticoids
A second link between the SCN and the periphery is
glucocorticoids. Their robust circadian variation denotes
the influence of the clock system, whereas their pervasive
role in metabolic processes extends this influence over numerous peripheral tissues. Indeed, glucocorticoids are
postulated to modify expression of 20% of the genome
(20). How the circadian clock determines glucocorticoid
rhythms is discussed under The hypothalamic-pituitaryadrenal axis; how do glucocorticoids discharge their function as messengers of the clock? In vitro they can synchronize clock gene cycling in cultured rat fibroblasts (21), and
in vivo they can entrain liver, kidney, and heart (22). A
transcriptome study found that 100 of 169 cycling genes
in the liver lost rhythmicity after adrenalectomy (23), indicating a profound influence on certain tissues. The
mechanism of entrainment is via a glucocorticoid respon-
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Endocrinologist’s Guide to the Clock
sive element in the promoter sequence of Per genes (24),
which allows glucocorticoids to shift clock gene rhythms
in target organs to align with the SCN rhythm. Reciprocally, CLOCK negatively modulates glucocorticoid function through acetylation of the glucocorticoid receptor
(20). Glucocorticoids are not required for clock gene cycling (23), and because the SCN lacks the glucocorticoid
receptor (22), they cannot directly modulate central
rhythms. A recent study found that in mice exposed to new
light schedules, glucocorticoid disruption increased the
rate of behavioral entrainment and realignment of peripheral clock gene cycling (25). The authors postulate that
glucocorticoids indirectly feed back to the SCN to damp
entrainment, thus preventing inappropriate shifts to
“noise.” This is, however, maladaptive in conditions such
as jet lag that require reentrainment.
The Calendar
Although the most evident biological rhythms occur over
24 h, there are superimposed cycles with lengths either
shorter (“ultradian”) or longer than the circadian period.
Thus, a circannual calendar maintains free-running rhythms
of seasonal physiology such as pellage and moult, fertility,
and body weight (26). There appear to be several overlapping
calendars, the best known being the prolactin and thyroid
systems. Although the clock requires the presence or absence
of light for timekeeping, the calendar more subtly uses the
ratio of light to dark during each 24 h (the photoperiod),
which waxes in summer as days lengthen and wanes in winter as days become short.
Sheep experiments elegantly demonstrate in the prolactin axis how melatonin and the molecular clockwork
encode photoperiod. MT1 receptor-expressing cells in the
pars tuberalis of the pituitary act on lactotrophs to produce a prolactin signal that varies according to season. The
melatonin signal is transduced into an interval, ␺, between
the peak of Per gene expression in the early light phase and
the Cry peak at the start of the dark period. ␺ is compressed in winter when days are short but nights are long,
but it is extended in summer (27).
In a second axis, TSH released from the pituitary acts
on ependymal cells in the hypothalamus expressing the
TSH receptor, causing increased expression of type II deiodinase (DIO2), which converts T4 to metabolically active T3, and decreased type III deiodinase (DIO3), which
catabolizes T3 (28). Melatonin and the molecular clock
induce cyclic expression of the TSH ␤-subunit and also
control DIO2 and DIO3 expression (29). High levels of T3
are found in long summer days, and T3 implants in
hamster hypothalamus cause the animals to become re-
J Clin Endocrinol Metab, April 2011, 96(4):913–922
sistant to the change in phenotype induced by short
winter days (30).
The calendar remains incompletely understood because experiments are long in duration and resource-hungry. It is not known how prolactin and T3 induce complex
seasonal physiological changes in downstream target tissues. The relevance of information from strongly seasonal
animals such as sheep and hamsters to humans is also
unclear. Although there is some evidence for human seasonality, its extent is controversial and is most likely
masked by lifestyle and environment (31, 32).
Endocrine and Metabolic Dysfunction
Caused by Disruption of the Clock
Glucose and clock genes
There is a circadian pattern of circulating glucose. A
“dawn phenomenon” rise coincides with anticipated demand at the start of the animal’s active period and is due
to increased hepatic glucose production driven by the SCN
and autonomic system (33). Besides a basal rhythm in
plasma glucose, there is also a diurnal variation in responsiveness to glucose challenge that may be blunted in diabetes (34). Clock-mutated mice have impaired glucose
handling, both in C57BL6 (35) and other strains (36).
Two studies have used tissue-specific clock disruption to
explore these abnormalities via the clock’s control of hepatic
gluconeogenesis and pancreatic insulin secretion. Liver-specific Bmal1 deletion produces fasting hypoglycemia and improved glucose clearance despite normal insulin production,
with disruption of Pepck, the rate-limiting enzyme in gluconeogenesis, and Glut2, the rate-limiting transporter of glucose from the hepatocyte (37). When the pancreatic clock is
disrupted, mice become hyperglycemic with impaired glucose tolerance and hypoinsulinemic due to impairment of
␤-cell insulin exocytosis (38). Both groups found that pathology was exacerbated by aging.
Insulin and melatonin
For some time, there has been reason to suspect a link
between melatonin and insulin. A circadian rhythm of insulin secretion independent of glucose levels or feeding has
been demonstrated in rats and humans (39), with the lowest secretion occurring at night when melatonin levels are
maximal. This implies that melatonin inhibits insulin secretion— but confusingly, pinealectomy leads to a decrease in insulin secretion and a rise in plasma glucose,
whereas melatonin supplementation has the opposite effect (40). Melatonin experimentally has been shown to
influence both the pancreas (41) and peripheral insulinsensitive tissues, where it ameliorates the diabetogenic ef-
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fects of a high-fat diet in mice in liver (42) and skeletal
muscle (43). A caveat of these studies is that only pharmacological and not physiological doses of melatonin
have yielded results; the in vivo relevance is not clear.
Interest has been rekindled by a recent surge of human
studies demonstrating a convincing link between the
MNTR1B receptor and type 2 diabetes (44 – 47). MNTR1B
gene polymorphisms are linked to raised fasting plasma glucose, reduced ␤-cell insulin secretion, and risk of type 2 diabetes, a cross-population finding in Europeans, Han Chinese, and Indian Asians. MNTR1B receptors (MT2 in
rodents) inhibit glucose-mediated insulin release in rat pancreas and cultured human islet cells (44). Subjects carrying a
risk allele of MTNR1B have up-regulation of the pancreatic
receptor (44), whereas in vitro studies have shown some reduced signaling through variant receptors (47). Furthermore, type 2 diabetic humans and rat models (Goto Kakizaki) have reduced melatonin levels due to impaired pineal
synthesis (48). For reviews of animal studies, see Ref. 49, and
for human studies, see Ref. 50.
Obesity and cellular metabolism
A connection between the molecular clock and obesity
was first revealed by the Clock⌬19 mouse, which unexpectedly was found to be obese with elevated plasma cholesterol, triglycerides, and glucose and fatty liver (51).
Studies of the same mutation in non-C57BL6 strains, however, contradict; they show no obesity, no hyperlipidemia,
and reduced liver triglyceride (52). This seems to suggest
that disruption of Clock may potentiate the onset of obesity in individuals, like the C57BL6, with an underlying
susceptibility. Bmal1 knockout mice, in contrast, have
low body weight and deficient adipogenesis (53). Polygenic (54) and high-fat diet-induced models of obesity (55)
have demonstrated disruption of rhythms in peripheral
clocks, clock-dependent genes, and metabolic parameters,
suggesting a complex interaction between genetics and
environment.
The mechanisms whereby clock and obesity interact
may be predicted through an examination of clock-controlled genes. A second negative-feedback loop in the core
clock mechanism consists of ROR␣ and REV-ERB␣,
which respectively activate and repress BMAL1 transcription (56). ROR␣ is induced during adipogenesis, whereas
REV-ERB␣ participates in lipid metabolism (57). A large
number of nuclear receptors involved in cell metabolism
show strong circadian rhythmicity (58), including PPAR␥
and PPAR␣, which regulate adipocyte lipogenesis and hepatic fatty acid oxidation and ketogenesis, respectively
(59). Further down the hierarchy are more rhythmic clock
output genes encoding essential components of lipid and
cholesterol metabolism such as lipoprotein lipase, the low-
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density lipoprotein receptor and sterol regulatory element
binding protein 1 (60). Notably, anabolic and catabolic
enzymes cycle out of phase, allowing temporal segregation
of opposing processes in the cell. Adipokines such as leptin
and adiponectin are secreted rhythmically by the adipocyte. Thorough reviews of fat and the clock are available (61, 62).
Two further intermediaries are worthy of mention:
SIRT1 (sirtuin) and AMPK (AMP-activated protein kinase). Both are activated mutually and by a drop in intracellular nutrient availability: AMPK through a rise in
AMP levels (indicative of a fall in the AMP:ATP ratio), and
SIRT1 through a drop in its essential cofactor NAD⫹ (indicative of a fall in the NAD⫹:NADH ratio). Both interact
directly with and enzymatically alter the stability of the
core clock machinery, thereby firmly tying molecular
timekeeping to cellular metabolic status (63, 64). They
stimulate fatty acid oxidation in skeletal muscle, inhibit
gluconeogenesis and promote cholesterol scavenging in
liver, inhibit lipogenesis in adipose tissue, and enhance
insulin secretion from pancreatic ␤-cells (65, 66). Both are
especially relevant to type 2 diabetes and obesity: AMPK
activity is reduced in diet-induced obese mice (67),
whereas overexpression of SIRT protects against hepatic
steatosis and glucose intolerance in obesity (68). Mainstays of therapeutics such as metformin and thiazolidinediones, plus resveratrol, a polyphenol found in red wine,
activate AMPK and SIRT (69). An interesting question is
whether such drugs might improve circadian profiles in
metabolic disease as well as clinical outcomes.
Human data to complement animal work are nascent.
A genome association study in 2002 postulated a link between the CLOCK gene locus and obesity (70). We and
others have reported associations between common haplotypes of CLOCK and components of the metabolic syndrome (71, 72), which may be due to an association between CLOCK variants and caloric intake (73). BMAL1
has been linked to hypertension and type 2 diabetes (74)
and PER2 to raised fasting glucose (75). Levels of clock
gene mRNA expression in human adipose explants correlate with features of the metabolic syndrome (76).
The next point to be addressed is that of the relation
between sleep disruption and obesity. The Clock⌬19
mouse has abnormal sleep architecture and became obese
partly because of greater food intake during the daytime
inactive phase when wild-type mice were asleep (51). A
recent study has demonstrated elegantly that mice fed only
by day have greater weight gain than those fed by night,
despite equivalent caloric intake (77). Night eating syndrome in humans is a rare condition in which substantial
nocturnal eating causes obesity with altered hormonal
profiles suggestive of circadian misalignment (78). Exper-
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Endocrinologist’s Guide to the Clock
imentally induced circadian desynchrony caused abnormalities of leptin, glucose, and cortisol profiles (79). Sleep
deprivation leads to up-regulation of orexigenic neuropeptides, stimulation of appetite, and impairment of glucose tolerance and insulin sensitivity (for reviews, see Refs.
9 and 80). The evidence emphasizes the importance of
lifestyle coordination for shift workers to minimize the
adverse consequences of physiological and behavioral
misalignment.
Food and time setting
It has been recognized since 1922 that restricted feeding—the limitation of food availability to a defined period
of the day—potently synchronizes not only behavioral
rhythms such as running wheel activity but also physiological rhythms such as core temperature and glucocorticoid peak to the time of the previous day’s meal (81). It is
an evident survival requirement that an organism must
process its meal efficiently. This might mean appropriate
temporal expression of digestive proteins or waking to eat
if food availability is restricted to the opposite phase of the
normal rest-activity cycle. The molecular clock was directly linked to food entrainment when restricted feeding
was shown to shift the expression of clock genes in the liver
to align with time of food presentation (82– 84). Two important concepts are food anticipatory activity, the spike in
activity preceding food presentation that is the primary measure of entrainment to food, and the food-entrainable oscillator (FEO), the putative site that mediates entrainment.
Questions arise. Where is the FEO? The dorsomedial
hypothalamus (85), dopaminergic reward pathways (86),
and ghrelin-secreting gastric cells (87) are possibilities, although most likely the FEO does not reside in a discrete
anatomical structure, but rather represents a diffuse cooperating network of neural areas (88). What is the food
signal that communicates to the FEO? Could it be a food
metabolite or a gastrointestinal hormone released upon
food ingestion? Glucocorticoids (89) and individual metabolites such as glucose (90) have been suggested, but it
is difficult intellectually to credit any single agent as being
responsible for the full complexity of food-entrained
rhythms. How does food-entrainment override the circadian system? Food anticipatory activity persists despite
SCN ablation (91), so it is independent of the central clock.
Even a peripheral clock does not seem to be required—
numerous studies have comprehensively disrupted the
spectrum of clock genes and broadly agree that food entrainment is unimpaired (92, 93). This is circadian heresy:
how does food set time so potently without either the
central or the peripheral clock? A recent study showed
impaired food entrainment in mice lacking Parp1 [poly(APD-ribose) polymerase], which like AMPK and SIRT is
J Clin Endocrinol Metab, April 2011, 96(4):913–922
activated by changes in nutrient status in the cell and interacts with clock machinery (94). The full answer remains
to be elucidated.
The hypothalamic-pituitary-adrenal axis
The hypothalamic-pituitary-adrenal axis displays
robust circadian variation throughout its hierarchical
levels, from ACTH to glucocorticoid (for review, see
Ref. 95). The role of glucocorticoids as SCN messengers
has already been examined, but how does the SCN generate their rhythmic secretion? Three components are
involved: ACTH release, intrinsic molecular clockwork
within the adrenal gland, and autonomic innervation of
the adrenal via the splanchnic nerve. ACTH, despite its
own rhythmic secretion, is not essential for rhythmic
glucocorticoid production because its suppression by
dexamethasone does not abolish glucocorticoid circadian variation (96), although overall levels drop to 10%
of normal. There appears to be a temporal window of
sensitivity to ACTH that is maintained by the adrenal
peripheral clock (97). StAR (steroidogenic acute regulatory protein) and 3-␤-HSD (␤-hydroxysteroid dehydrogenase) are two rate-limiting enzymes in glucocorticoid
synthesis that are clock-controlled (98). Transplantation
of adrenals from animals with deleted Per2/Cry1 into
wild-type animals and vice versa suggests that whereas a
functional central clock is able to override a defective
peripheral clock, normal peripheral organs may only
compensate for a defective central clock under optimal
light/dark environmental conditions (97). Splanchnic
nerve inputs allow direct neural communication between SCN and adrenal, and light pulses induce Per1
expression and glucocorticoid release (99). Of note,
stress-induced acute rises in glucocorticoid output appear to be independent of the circadian system (100)—a
redundancy that indicates the necessity of glucocorticoids to life.
Growth hormone
GH is released largely at night in complex ultradian
pulses that do not readily fit a classic circadian pattern
(101). Indirectly, the clock system directs secretion
through slow-wave sleep, which is strongly associated
with GH release (102), although the precise mechanism of
circadian influence is not understood. There is sexual dimorphism of plasma GH with distinct male and female
patterns of growth, which may be clock-determined. Male
Cry⫺/⫺ double knockout mice revert to female GH secretion profiles and female pattern growth. GH supplementation mimicking the male temporal pattern restores male gene expression pattern in liver (103).
Supporting evidence is offered by a human study of Chi-
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nese subjects, which found that PER3 VNTR (variable number tandem repeats) was associated with higher circulating
IGF-I levels (104).
The thyroid axis
In humans, there is a well-known circadian rhythm in
TSH secretion, with a peak at 02.30. Rhythmicity of T3
levels is less well established, but there appears to be low
amplitude cycling that follows the TSH rhythm (105). The
action of thyroid hormones in setting seasonal rhythms
has already been discussed. A further role has been postulated in facilitating clock gene expression in the limbic
system (106). However, gaps remain in our understanding
of the role of thyroid hormones in the circadian system.
The reproductive axis
The reproductive axis shows a rhythmic and hierarchical organization consistent with influence of the clock system. Profiles of hormones such as LH, FSH, and testosterone show robust diurnal variation. Reproductive
hormones also demonstrate the ability to synchronize
downstream tissues: LH and FSH cause large phase-shifts
in clock gene expression in rat ovary (107), and estrogen
synchronizes the uterus (108). The testis, however, is a rare
tissue where there is no detectable clock gene cycling and
thus merits special mention. Immunohistochemistry suggests that expression of individual clock genes appears to
be induced by specific stages of spermatogenesis (109,
110).
Centrally in the axis, the impact of the clock system is
best seen in the regulation of the preovulatory GnRH
surge. The importance of precise timing and SCN inputs is
long established (111). Current thinking identifies two
critical factors that are linked by the neurotransmitter
kisspeptin: a background of time-gated priming by rising
estradiol concentrations, plus a neural signal via the SCN.
Kiss gene expression and Kiss neuron activation are rhythmic (112) and are expressed in brain areas that mediate
between the SCN and GnRH neurons. Kiss neurons express estrogen receptors, and Kiss expression is induced by
estradiol (113).
Peripherally, studies of transgenic mice further elucidate the role of the clock in reproduction. Homozygous,
but not heterozygous, Bmal1 knockout mice are infertile
with morphologically small gonads (114) and reduced steroid hormone production and abnormal estrogen receptor
␤ expression. The LH surge and ovulation appear to be
normal, but there is failure of embryos to implant and
develop (115). Reproductive abnormalities in Clock⌬19
animals, however, are probably slight (116 –118).
Human studies are few. A genetic study in Chinese men
suggested a link between clock gene polymorphisms and
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variations in levels of testosterone hormone and binding
proteins (104). Polymorphisms of BMAL1 and NPAS2
have been linked to miscarriage, whereas female shift
workers may be prone to menstrual disturbances, subfertility, and miscarriage (119).
Conclusion
Although evidence mounts for the circadian clock’s coordination of hormonal and metabolic rhythms, much research remains at the laboratory stage with limited translation into clinical practice. Three broad areas, however,
do currently exist. Genetic studies may constitute the first
step in therapeutics, enabling risk stratification and the
modification of other risk factors that are amenable to
treatment. Examples include the associations between
CLOCK polymorphisms and obesity and between melatonin and diabetes. Secondly, pharmacological therapy
may take advantage of agents such as melatonin with the
ability to synchronize clocks or more physiological dosing
schedules that better mimic circadian patterns (120).
Thirdly, environmental causes of circadian disruption
such as sleep deprivation and shift work may be addressed.
Although disturbances of the circadian clock may exacerbate
endocrine disease in susceptible individuals, health may be
salvageable under optimal environmental conditions.
Acknowledgments
Address all correspondence and requests for reprints to: Dr.
E. M. Scott, Division of Cardiovascular and Diabetes Research,
LIGHT Laboratories, University of Leeds, Clarendon Way,
Leeds LS2 9JT, United Kingdom.
M.J.P. is supported by the British Heart Foundation Clinical
Research Training Fellowship FS/08/076/26287.
Disclosure Summary: There are no competing interests.
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