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The Journal of Clinical Endocrinology & Metabolism 90(5):3106 –3114
Copyright © 2005 by The Endocrine Society
doi: 10.1210/jc.2004-1056
REVIEW: On the Interactions of the HypothalamicPituitary-Adrenal (HPA) Axis and Sleep: Normal HPA
Axis Activity and Circadian Rhythm, Exemplary
Sleep Disorders
Theresa M. Buckley and Alan F. Schatzberg
Stanford Sleep Disorders Clinic and Research Center (T.M.B.) and Department of Psychiatry, Stanford University (A.F.S.,
T.M.B.), Stanford, California 94305
The hypothalamic-pituitary-adrenal (HPA) axis plays important roles in maintaining alertness and modulating sleep. Dysfunction of this axis at any level (CRH receptor, glucocorticoid
receptor, or mineralocorticoid receptor) can disrupt sleep.
Herein, we review normal sleep, normal HPA axis physiology
and circadian rhythm, the effects of the HPA axis on sleep, as
well as the effects of sleep on the HPA axis. We also discuss the
potential role of CRH in circadian-dependent alerting, aside
from its role in the stress response. Two clinically relevant
sleep disorders with likely HPA axis dysfunction, insomnia
T
HE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA)
axis and sleep interact in multiple ways. In the first part
of this paper, we review the effects of the HPA axis on sleep
and, conversely, the effect of sleep on the HPA axis. Normal
sleep is first described, followed by HPA axis organization
and control and modulation of the cortisol circadian rhythm.
We focus on a dose-response relationship of the effects of
cortisol activity on sleep, emphasizing relative activation of
specific glucocorticoid receptors (GRs) with the resultant
effects on CRH and subsequently on ACTH and cortisol. A
potential relationship between CRH and circadian-dependent alerting is explored. In the second part of the paper, we
review two sleep disorders [insomnia and obstructive sleep
apnea (OSA)] that are associated with HPA axis dysfunction
and hypothesize how specific HPA axis abnormalities may
play a role in the pathophysiology and/or clinical complications of these disorders.
Normal Physiology
Normal sleep
Each stage of sleep has a characteristic associated electroencephalogram (EEG) frequency and waveform. Generally,
First Published Online February 22, 2005
Abbreviations: AVP, Arginine vasopressin; CPAP, continuous positive airway pressure; CSF, cerebrospinal fluid; EEG, electroencephalogram; EMG, eye movement and chin electromyography; GR, glucocorticoid receptor; HPA, hypothalamic-pituitary-adrenal; LC, locus
coeruleus; MR, mineralocorticoid receptor; NE, norepinephrine; OSA,
obstructive sleep apnea; PVN, paraventricular nucleus; REM, rapid eye
movement; SCN, suprachiasmatic nucleus; SWS, slow wave sleep.
JCEM is published monthly by The Endocrine Society (http://www.
endo-society.org), the foremost professional society serving the endocrine community.
and obstructive sleep apnea, are discussed. In insomnia, we
discuss how HPA axis hyperactivity may be partially causal to
the clinical syndrome. In obstructive sleep apnea, we discuss
how HPA axis hyperactivity may be a consequence of the
disorder and contribute to secondary pathology such as insulin resistance, hypertension, depression, and insomnia.
Mechanisms by which cortisol can affect slow wave sleep are
discussed, as is the role the HPA axis plays in secondary effects of primary sleep disorders. (J Clin Endocrinol Metab 90:
3106 –3114, 2005)
increased EEG frequency is associated with wakefulness, and
decreased EEG frequency is associated with increased depth
of sleep. EEG frequencies are characterized as beta (⬎13
cycles/sec), alpha (eight to 13 cycles/sec), theta (four to
seven cycles/sec), and delta (less than four cycles/sec) (1).
EEG waveform in combination with two additional variables
[eye movement and chin electromyography (EMG)] determines sleep stage.
Stage 1 sleep is characterized by mixed frequency theta,
slow rolling eye movements, and slightly reduced EMG.
Stage 2 sleep is characterized by mixed frequency EEG in
combination with sleep spindles and K complexes that are
brief stereotyped superimposed waveforms. Stage 3 sleep is
characterized by 20 –50% delta EEG, whereas stage 4 sleep is
characterized by greater than 50% delta EEG. The rapid eye
movement (REM) stage is characterized by mixed frequency
EEG with theta or sawtooth waves in combination with rapid
eye movements and nearly absent chin EMG (1).
Normal sleep architecture is characterized by cycles of
light sleep (stages 1 and 2), deeper slow-wave sleep (stages
3 and 4), and REM sleep throughout the night (2). Stage wake
is a fifth state. REM cycles occur approximately every 90 –110
min (2). There is a predominance of percentage of time spent
in slow-wave sleep (SWS) in the first half of the night and a
predominance of time spent in REM sleep in the second half
(2). Alternatively, the sleep infrastructure can be alternatively defined as having only three stages of sleep: REM,
non-REM (i.e. stages 1– 4), and stage wake.
Normal HPA axis
CRH is found in both hypothalamic [paraventricular nucleus (PVN)] and extrahypothalamic sites (for example, the
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Buckley and Schatzberg • HPA Axis Rhythm and Sleep
limbic system, sympathetic brainstem and spinal cord, and
interneurons of cortex) (3). Important limbic system sites that
additionally influence the HPA axis include the amygdala
and bed nucleus of the stria terminalis (4). Two CRH receptor
subtypes have been identified: CRH1 and CRH2. CHR1 receptors are heavily located in the anterior pituitary and are
also found widely throughout the brain (3). CRH2 receptors
predominate in the periphery but can be found in some brain
regions as well (3). Other neuropeptides of potential importance include arginine vasopressin (AVP) and urocortin.
AVP acts synergistically with CRH, particularly in the pituitary (3). Urocortin, a recently identified neuropeptide, also
activates CRH receptors. Urocortin and CRH are agonists for
CRH1 receptors, and urocortin, urocortin II, and urocortin III
are agonists for CRH2 receptors (5).
The PVN secretes CRH, which in turn acts on CRH receptors in the anterior pituitary to cause the release of ACTH
into the bloodstream (6). ACTH acts on the adrenal cortex to
cause the production and release of cortisol. Cortisol has
numerous actions, including feedback inhibition at the level
of the PVN and the anterior pituitary, to control CRH or
ACTH synthesis and release. In addition, the HPA axis receives important feedback from other areas of the brain, such
as the hippocampus, amygdala, and bed nucleus of the stria
terminalis (6).
Normal HPA circadian rhythm
The circadian rhythm of cortisol secretion derives from
connections between the PVN and the primary endogenous
pacemaker, the suprachiasmatic nucleus (SCN). Lesions of
the SCN in rats result in the loss of corticosteroid periodicity
(7). The human endogenous, SCN-controlled cortisol circadian rhythm is characterized as follows. The nadir for cortisol
occurs at about midnight. Cortisol levels begin to rise about
2–3 h after sleep onset (8, 9) and continue to rise into the early
waking hours. The peak, or acrophase, in cortisol occurs at
about 0900 h. As the day continues, there is a gradual decline
in cortisol levels. As sleep ensues, there is a continued decrease to the nadir. The leveling off is described as the quiescent period. Within this cycle are about 15–18 pulses of
FIG. 1. Schematic of cortisol waveform parameters.
J Clin Endocrinol Metab, May 2005, 90(5):3106 –3114
3107
corticotropin of various amplitudes. A graphical representation of the serum cortisol waveform is given in Fig. 1.
CRH is released in a circadian-dependent, pulsatile fashion from the parvocellular cells of the PVN (6). Connections
from the SCN to the PVN are direct and indirect, the latter
via intermediate structures such as the dorsomedial hypothalamus, for example (10). CRH and AVP receptors on the
anterior pituitary control the subsequent release of ACTH
into the bloodstream (6). Cerebrospinal fluid (CSF) CRH and
cortisol rhythms are dissociated in time (11), and the mechanism is controversial (i.e. whether this is simply a servoloop) (12). One possibility is that CRH measured in CSF may
lag after production in the brain (12). Alternatively, CRH
measured in CSF may represent extrahypothalamic sources
(12), distinct from CRH secreted into the hypophyseal-portal
system from the PVN. Finally, direct connections from the
SCN to the adrenal cortex, which bypass the PVN, have been
reported and may help explain the apparent temporal dissociation between CRH and cortisol rhythms (13).
In contrast to CSF CRH, CRH transcription levels in the
PVN may better reflect the source and timing of circadiandriven hypothalamic CRH. In rats, CRH gene transcription
levels in the PVN rise linearly throughout the nocturnal
active period, drop sharply in the morning, then decrease
linearly throughout the daytime inactive period (12). The
timing of the nocturnal active period in rats is analogous to
the timing of the onset of the daytime active period in humans. If a similar pattern of CRH transcription in the PVN
is evident in humans, this would suggest that CRH gene
transcription levels in the PVN may rise linearly throughout
the day and decrease linearly throughout the night. Again,
the reason for dissociation between the timing of serum
cortisol and CRH rhythms would remain to be explained.
HPA feedback regulation
In brain, cortisol binds to high-affinity mineralocorticoid
receptors (MRs; type I) in the hippocampus that modulate the
underlying circadian rhythm as well as to low-affinity GRs
(type II) in the hypothalamus, pituitary, cortex, and elsewhere. Cortisol preferentially binds to high-affinity receptors
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before filling low-affinity receptors (14). The effect of MR
predominates in the early nocturnal period and is most
prominent at the time of the nocturnal nadir (15). In contrast,
the effect of GR dominates in the morning, when cortisol
levels are highest.
Whether feedback onto the PVN is excitatory or inhibitory
depends on the location and type of the receptor. For example, GR activation at the level of the PVN and pituitary exerts
direct negative feedback on subsequent CRH and ACTH. MR
activation at the hippocampus and amygdala exerts negative
feedback inhibition on CRH through the bed nucleus of the
stria terminalis (4 – 6). In contrast, GR activation in the amygdala results in an increase in CRH in response to stress (16).
The key HPA axis and feedback relationships are summarized in Fig. 2.
HPA locus coeruleus (LC)/norepinephrine (NE)
system interactions
In addition to the known association between CRH and its
effect on sleep EEG, the HPA axis has important excitatory
reciprocal interactions with the brainstem sympathetic
LC-NE system (3, 4). CRH activates the LC; in turn, NE
activates both hypothalamic CRH and the amygdala (3, 4).
Circadian variations in CSF NE are highly positively correlated with variations in serum cortisol (17), and NE is a
known wake-promoting neurotransmitter.
Effects of Glucocorticoids and CRH on Sleep
Light sleep and SWS
As described in this report, EEG frequency tends to increase with wakefulness, whereas EEG frequency tends to
decrease with increasing depth of sleep. In this respect, factors that increase EEG frequency will tend to negatively
impact sleep, causing lighter sleep and wakefulness. CRH
appears to be one putative factor to increase sleep EEG and
thereby increase wakefulness. Exogenous CRH increases
EEG frequency in rats (18). Similarly, in healthy males, exogenous CRH is known to decrease SWS and increase light
sleep and awakenings (19). Sleep disruption with CRH is
more pronounced in middle-aged men than in young men
(20).
Early studies exploring the effects of the HPA axis on sleep
FIG. 2. HPA axis and MR/GR feedback relationships.
Buckley and Schatzberg • HPA Axis Rhythm and Sleep
focused on the direct effects of glucocorticoids on sleep,
rather than the effects of CRH. The results of these early
studies, which at times were contradictory, can be reconciled
in light of the currently known effects of CRH on sleep EEG
and the indirect effects that glucocorticoids have on CRH
regulation.
For example, early studies reported that glucocorticoids
decreased REM sleep and increased time spent awake (21).
A later study reported that cortisol activated MR and increased SWS; in contrast, dexamethasone activated GR and
increased awakening (22, 23). At that time, administration of
dexamethasone was thought to be equivalent to the administration of high dose cortisol. The mechanism for the effect
on sleep EEG was attributed to direct GR activation. More
recently, low doses of dexamethasone have been viewed as
suppressing cortisol release peripherally while not penetrating the brain. Thus, low-dose dexamethasone may actually
create a state of low brain cortisol with a compensatory
increase in central CRH (24). This would, in turn, decrease
SWS. In contrast, very high doses of dexamethasone activate
GRs (24).
Additional studies also suggest that relative MR vs. GR
activation influences sleep EEG differently and suggest that
glucocorticoids inhibit or enhance SWS depending on the
dose of exogenous corticosterone used (23, 25, 26). Although
high-affinity mineralocorticoid receptors are predominately
occupied at lower doses of the steroid, greater occupancy of
the low affinity GR is seen at higher doses of corticosterone
(14). Consistent with this dose-related effect, the administration of hydrocortisone to healthy males can at times increase SWS and at other times increase wakefulness and
stage 1 sleep, the latter occurring at higher doses (23). Studies
using exogenous corticosterone in adrenalectomized rats (26)
and intact rats (25) similarly show opposite effects on EEG
depending on the dose. Low doses of hydrocortisone decrease wakefulness and increase SWS, and high doses increase wakefulness and decrease SWS (25, 26). Regarding GR
activation in humans, SWS was shifted from the first to the
second sleep cycle after 10 d of administration of methylprednisolone (presumably at a dose that occupied a high
proportion of GRs) to multiple sclerosis patients (27). The
results were attributed to down-regulation of GR with time
(27).
More recent studies suggest that the effect of corticosterone on sleep EEG depends on GR-mediated feedback on
CRH, with elevated cortisol leading to suppression of CRH,
resulting in an increase in SWS (28 –30). The effect of exogenous cortisol decreasing SWS at high doses (as described in
the above dose-related studies), however, has not been
explained.
We propose that the effects of both exogenous and endogenous cortisol on SWS depend on optimal cortisol levels
to effect maximal nocturnal CRH suppression. Additionally,
both the type of receptor activated by cortisol (MR or GR) and
the location of receptor activated influence CRH and, ultimately, the EEG response. CRH suppression is enhanced by
MR-mediated PVN inhibition, particularly via the hippocampus. In contrast, higher levels of cortisol would additionally occupy GR, which could exert either inhibitory (for
example, via the PVN) or excitatory feedback (for example,
Buckley and Schatzberg • HPA Axis Rhythm and Sleep
via the amygdala) on CRH, depending on the location of the
receptors activated.
Previous studies reporting decreased SWS at higher levels
of cortisol, where GR is fully occupied (22, 25, 26), may reflect
an overriding effect of excess GR activation at the level of the
amygdala. GR activation in the amygdala (opposite to its
inhibitory action at the PVN and anterior pituitary) occurs at
very high doses of cortisol and at times of stress and may
exert a positive feedback effect on PVN CRH. It might also
reflect a direct inhibitory effect of excess GR on colocalized
MR (as can occur in the hippocampus), thereby limiting
MR-mediated inhibition of PVN CRH.
REM sleep
The effects of cortisol and CRH on REM sleep are unclear
and at times contradictory in the literature. Activation of GRs
may decrease REM sleep in healthy controls (22), but acute
corticosterone replacement given before bedtime to Addison’s patients (to create a state of elevated cortisol and decreased ACTH and decreased CRH) reduced REM latency
and increased total time spent in REM sleep (31). High dose
methylprednisolone (presumably at a dose sufficient to
cause significant GR activation) reduced REM latency in
multiple sclerosis patients after 10 d, but not after 2 d, of
treatment (27) CRH may have a direct effect as well. In one
study, exogenous CRH decreased the amount of REM sleep
(19). In another study, a CRH antagonist decreased REM
latency after short-term, but not long-term, administration
(32).
Ultradian pattern of sleep
The ultradian pattern of sleep is characterized by the alternating and repeating cycles of REM and non-REM sleep
that occur throughout the night. Cycles of REM sleep tend to
begin as cortisol levels fall, and cycles of SWS tend to begin
with rising levels of cortisol (33, 34). An increase in cortisol
with REM during the last sleep cycle (especially the fifth, if
present) has been reported (35).
Waking
CRH can be produced in response to SCN-mediated circadian input (nonstressed) as well as in response to stress.
Hence, CRH can contribute to both stressed and nonstressed
waking. This waking effect is consistent with an increase in
high frequency (32– 64 Hz) EEG in rats administered CRH
(18) and an increase in light sleep in human subjects given
exogenous CRH (19). More importantly, CRH has an arousing and waking effect even in the absence of stress (36, 37).
J Clin Endocrinol Metab, May 2005, 90(5):3106 –3114
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amygdala GRs may be preferentially activated, increasing
CRH. Elevated CRH increases sleep EEG frequency, thereby
decreasing SWS and increasing light sleep and wakefulness.
In addition to the effects of CRH on sleep EEG frequency,
CRH reciprocally activates the LC/NE system, thereby increasing wakefulness through the ascending reticular activating system (38). The LC ascending reticular activating
system projects to each of the three structures: the basal
forebrain and cortex, the hypothalamus, and the thalamus
(38).
Effect of Sleep on HPA Axis and Cortisol Rhythm
Sleep initiation
Sleep initiation (and SWS in particular) occurs concurrent
with low HPA axis activation (39, 40). Early studies pointed
to sleep deprivation increasing HPA activity and suggest that
an unknown factor, possibly secreted during SWS, inhibits
the HPA axis (41). GHRH has been proposed as a putative
inhibitor of the HPA axis during early sleep (42, 43), and
GHRH drives GH secretion. A large pulse of GH occurs
shortly after sleep onset, and its timing corresponds to SWS
in the first part of the night (44). Steiger et al. (45, 46) and
Schier et al. (45,46) proposed that the effects of GHRH on SWS
dominate in the first half of the night, and the effects of CRH
dominate in the second half.
Awakening responses
Nocturnal awakenings are associated with pulsatile releases of cortisol, as previously reported (34, 47, 48). These
arousals are followed by temporary inhibition of cortisol
secretion. Wakefulness may help increase the negative feedback sensitivity of the HPA system. In contrast sleep may
inhibit the negative feedback inhibition of the HPA axis (47).
Distinct from nocturnal awakenings, the marked and
rapid rise in cortisol and ACTH that occurs after final morning awakening and continues for about a 60-min period is
termed the awakening response. It is predictable and is independent of the mode of awakening (naturally or with an
alarm) (49). It does not appear to be simply a continuation of
the morning rise in cortisol or due to a wake-up stimulus.
Spontaneous final awakening time is not linked to either a
sleep stage or a specific cortisol level (50). Anticipation of
awakening at a certain time can augment the early morning
rise of cortisol that occurs before awakening (51). This effect
is distinct from and has no impact on the subsequent cortisol
awakening response (51).
Summary
Summary
In summary, the predominant circadian rhythm of cortisol
secretion appears to be driven by the SCN. A peak in cortisol
secretion occurs in the early morning, and the nadir occurs
at about midnight. This curve is influenced by several modulators, including feedback from MRs and GRs. Low levels
of cortisol seen in the evening and nighttime are associated
with MR binding; at higher cortisol levels, GRs are activated.
These receptors feed back to control CRH. In times of stress,
In summary, concurrent with early nocturnal SWS, the
HPA axis is suppressed. Conversely, sleep deprivation is
associated with HPA axis activation. Sleep fragmentation or
nocturnal awakenings have been shown to cause additional
pulsatile cortisol release. The cortisol rhythm is additionally
influenced by the time of final awakening. There is a predictable cortisol rise that occurs after awakening, termed the
awakening response, and an anticipatory rise that occurs if
awakening is expected at a certain hour.
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Circadian-Dependent Alerting
As described herein, CRH production in the PVN appears
to be driven by the SCN as well as by the stress response. It
is also modulated by feedback from GRs and MRs. The
opponent process model of sleep regulation in humans proposes that the SCN-driven circadian alerting signal begins in
the morning and rises in a linear fashion throughout the day
(52). We hypothesize that SCN-driven CRH activity (nonstressed) may be an important circadian alerting signal, as
suggested by the following. First, CRH increases wakefulness on sleep EEG. PVN CRH projects heavily to the locus
coeruleus (53–56). In turn, the LC-NE system promotes
wakefulness via ascending projections to the basal forebrain
and cortex, hypothalamus, and thalamus (38). Secondly,
CRH gene transcription in the nocturnal active period in the
rat begins at the start of the nocturnal active period and rises
throughout (12). A corresponding daytime active alerting
signal in humans would coincide with the timing of the
circadian alerting signal proposed by the opponent process
model of sleep regulation. Thirdly, human data on CSF CRH
exist (17), and visual inspection of these data show a general
rise in CSF CRH during the day (including an afternoon dip)
and a fall during the nocturnal sleep period. Ideally, the
timing of CRH activity in the PVN (as opposed to its timing
in the CSF) may be the best marker for the timing of the direct
effects of CRH on circadian alerting.
Obviously, the hypothesis for CRH as a key circadian
alerting signal would need careful testing, and determining
the cause of the expected dissociation in time between PVN
CRH and cortisol rhythms [as occurs between CSF CRH and
cortisol (11)] requires additional study. Furthermore, hypocretin has alternatively been proposed as an alerting signal
(57–59), and the relationship between CRH and hypocretin
in circadian-dependent alerting would need additional elucidation. We believe that both CRH and hypocretin are important circadian signals. However, the hypocretin system
may be most important as an upstream stabilizer or sleep
switch (60) (between the ventrolateral preoptic nucleus and
tuberomamillary nucleus) for the thalamic and hypothalamic
portions of the circadian-driven SCN-CRH-LC-NE alerting
pathways of the ascending reticular activating system (38).
Assuming that the timing of CRH in the PVN is the ultimate circadian alerting marker, a test protocol might consist
of a forced desynchrony protocol in either primates or rats.
In primates, measures of cisternal CSF CRH, with time, may
be helpful to more closely approximate PVN CRH. In rats,
measures of PVN CRH mRNA levels with time in killed rats
would more closely track the temporal changes and help test
this hypothesis.
Exemplary Sleep Disorders with HPA
Axis Dysfunction
Dysfunction of the HPA axis may play a causative role in
some clinical sleep disorders, such as insomnia. In other
cases, HPA axis dysfunction may be secondary to a clinical
sleep disorder, such as OSA, and may lead to secondary
complications. Below we describe such HPA axis-sleep relationships in two conditions.
Buckley and Schatzberg • HPA Axis Rhythm and Sleep
Insomnia
Depression is often associated with sleep disturbances and
hypercortisolemia (4). Stress tends to worsen sleep acutely,
and cortisol is a key hormone secreted during the stress
response. Recent work by both Vgontzas et al. and Rodenbeck et al. confirmed that chronic insomnia, without depression, is associated with elevated cortisol levels (61– 64). In
insomnia, cortisol is increased, particularly in the evening
and the first part of the nocturnal sleep period (61– 64).
Although much of the previous literature has emphasized
cortisol in sleep, an inspection of cortisol and CRH rhythms
suggest that increased cortisol may not be the primary cause
of the sleep disturbance, but, rather, may be a marker for
increased nocturnal CRH activity. Additionally, given the
known relationship between CRH and the LC/NE stress axis
(3, 4), elevated cortisol may also be a marker for increased
central NE activity. NE increases sleep EEG frequency (via
the LC ascending reticular activating system), and CRH reciprocally stimulates the LC/NE system. An early study by
Vgontzas et al. (61) showed activation of both limbs of the
stress response (HPA axis and sympathetic system) in insomnia. A recent study of neuroendocrine measures in subjects with melancholic depression and healthy controls reported a significant positive correlation between plasma
cortisol and CSF NE levels (17).
Additionally, preceding evening cortisol levels while
awake correlate with the number of subsequent nocturnal
awakenings that night in both subjects with and without
insomnia (63, 64). Increased HPA activity promotes sleep
fragmentation, yet this same sleep fragmentation increases
cortisol levels [the latter demonstrated by Spath-Schwalbe et
al. (47)]. These two facts suggest a model for initiation and
perpetuation of a vicious cycle of severe chronic insomnia
(63, 64).
Fatigue in insomnia may be explained by an abnormal
rhythm of IL-6 and TNF, both fatigue-producing cytokines
(65). Although total 24-h levels are not elevated in insomnia
patients, levels are shifted from nighttime to evening for IL-6
and conversely for TNF. This shift has been proposed to
contribute to daytime fatigue (65).
Pharmacological intervention to normalize HPA axis abnormalities may be beneficial for treating the underlying
physiological disturbance. Based on our hypothesis, the goal
would be to decrease nocturnal CRH hyperactivity (of which
nocturnal cortisol may be a marker). As suggested in Fig. 2,
a GR antagonist may suppress amygdala-driven CRH activation during administration (92). Alternatively, it may reset
the HPA axis after its discontinuation, as suggested in psychiatric patients (66). In contrast, an MR agonist may help
augment nocturnal hippocampal suppression of CRH. Finally, a CRH antagonist would have a direct effect, and a
CRH1 antagonist would be of particular interest.
OSA
The sequence of events in an episode of apnea consists of
upper airway constriction, progressive hypoxemia secondary to asphyxia, autonomic and EEG arousal sufficient to
prompt one to open and clear the airway to reverse the
asphyxia, followed by successive relaxation of the airway,
Buckley and Schatzberg • HPA Axis Rhythm and Sleep
upper airway constriction, etc. As the cycle repeats itself
throughout the night, the patient’s sleep is fragmented. Daytime sleepiness results, along with a host of untoward medical side effects and long-term consequences. The most efficacious treatment for sleep apnea is continuous positive
airway pressure (CPAP). CPAP is worn on a nightly basis
and acts like a constant pressure air splint to prevent collapse
of the upper airway during sleep.
We believe that there may be a significant interplay between HPA axis hyperactivity and untreated OSA as well as
upper airway resistance syndrome. Nocturnal awakenings
are associated with pulsatile cortisol release (47) and autonomic activation. Autonomic activation is associated with
increased catecholamine release as well as CRH and cortisol
release. Hence, we hypothesize that OSA will cause activation of the HPA axis through this same mechanism of autonomic activation, awakening, and arousal.
Activation of the HPA axis may be a risk factor in the
development of the metabolic syndrome in untreated OSA.
Cortisol decreases insulin sensitivity, contributing to glucose
intolerance over time. Sleep deprivation itself is associated
with HPA axis hyperactivity and has been shown to negatively affect glucose tolerance (67). Taken together, other
recent reviews point to a role of the HPA axis in the metabolic
syndrome in OSA as well. A recent review of the metabolic
syndrome in OSA hypothesized that visceral obesity and
insulin resistance predict the metabolic syndrome and that
subsequent sleep apnea with elevated nocturnal cortisol and
insulin levels may exacerbate the metabolic syndrome (68).
Similarly, another recent review proposed that OSA leads to
diabetes via increased sympathetic activity with secondary
release of catecholamines and subsequent glucose intolerance (69). Although obesity is an independent risk factor for
OSA, the presence of OSA may exacerbate the metabolic
syndrome. Clearly, HPA axis hyperactivity would be only
one among a host of other contributing factors to the metabolic syndrome in OSA. The reader is referred to other
recent reviews for discussion of such factors (70, 71).
In addition, the increases in leptin observed in OSA may
be secondarily related to changes in the HPA axis. Although
there is an inverse circadian relationship between leptin and
cortisol (72, 73) that appears to be centrally driven, a secondary direct interaction between cortisol and leptin occurs
as well. In response to stress, both the sympathetic and HPA
axes are activated. Although sympathetic activation suppresses leptin, HPA activation stimulates leptin secretion
(74). The prevailing response of leptin to stress thus depends
on which system dominates (74). Examples where high cortisol and high leptin levels coexist include sepsis and Cushing’s disease (75, 76), suggesting that the HPA axis effect
dominates in these disorders. In contrast, a recent study of
forced sleep deprivation reported decreased leptin levels and
attributed the results to sympathetic activation (77, 78).
The literature varies regarding the effects of OSA on the
HPA system itself. These studies have primarily focused on
the effects of CPAP on cortisol. Several studies have reported
that CPAP does not reduce cortisol levels (79) or that acute
withdrawal of CPAP therapy does not result in an increase
in cortisol levels (80). In contrast, other studies have reported
that CPAP does reverse hypercortisolemia (81), particularly
J Clin Endocrinol Metab, May 2005, 90(5):3106 –3114
3111
with prolonged use (82). Several of these studies were limited, in that cortisol was measured at a single time point, and
consequently do not measure potential clinically important
HPA axis and rhythm changes.
We propose that HPA hyperactivity may also play a role
as one mechanism in the pathophysiology of OSA in hypertension. A very recent study demonstrated that elevated
aldosterone is a cause of hypertension in obstructive sleep
apnea, but the cause of hyperaldosteronism was unknown
(83). Because ACTH stimulates both aldosterone and cortisol
synthesis and secretion, we hypothesize that HPA axis hyperactivity from OSA may increase aldosterone and thereby
contribute to hypertension. This same mechanism has been
proposed for explaining hypertension in depression (84).
Returning to our original assumption that autonomic activation and arousal cause HPA axis activation in OSA, treatment and elimination of the arousal with long-term CPAP,
for example, should reverse the hypercortisolemic state. In
fact, a recent study showed that 8 wk of treatment with CPAP
caused significant reductions in serum leptin (85). The underlying mechanism may be a normalization of HPA axis
hyperactivity with CPAP therapy.
If left untreated, this HPA axis hyperactivity in OSA may
be a risk factor not only for the metabolic syndrome, but also
for insomnia and depression as well, because both are associated with hypercortisolemic states. Similar sleep EEG
changes were found in depression and Cushing’s disease,
and a role for obstructive sleep apnea has been suggested
(86). Cases of paranoid psychosis (87–90) have been reported
from untreated sleep apnea and may be related to psychotic
major depression that is also associated with marked HPA
axis hyperactivity (91).
In summary, OSA is characterized by repeated episodes of
upper airway obstruction during sleep. Secondary arousal
may cause activation of the HPA axis. CPAP is an established, highly effective therapy for treating the underlying
cause of the obstructive sleep apnea syndrome, upper airway
obstruction. Long-term use of CPAP may be important to
reverse the underlying HPA axis abnormalities, which may
partially contribute to 1) the metabolic syndrome, particularly diabetes and hypertension; 2) depression; and 3) insomnia. In addition to CPAP, we propose that a course of
pharmacological intervention may help normalize the secondary HPA axis abnormalities and their consequences. This
would follow a similar approach to that described for
insomnia.
Summary and Conclusions
The common denominator for the effect of the HPA axis
on sleep EEG depends on CRH, with CRH decreasing SWS
and increasing wakefulness. Furthermore, we propose that
MRs and GRs can be activated or suppressed to modify CRH
levels via their feedback relationships on CRH. CRH suppression is enhanced by MR-mediated PVN inhibition, particularly via the hippocampus. This would augment CRH
suppression in the early sleep period and at the time of the
nocturnal nadir, when SWS is expected to occur. In contrast,
excess GR activation at the level of the amygdala (as opposed
to at the PVN) may activate CRH (16) and decrease SWS.
3112 J Clin Endocrinol Metab, May 2005, 90(5):3106 –3114
MR and GR can be activated by cortisol as well as by other
agents. At low endogenous or exogenous cortisol levels at
which only MRs are activated, SWS is enhanced. At medium
cortisol levels at which MRs and PVN GRs are activated, SWS
is enhanced. At very high cortisol levels or in times of stress,
where possibly amygdala GRs are significantly occupied
relative to PVN GRs, SWS is decreased.
We hypothesize that SCN-driven CRH (nonstressed) may
be an important circadian alerting signal. Given the known
effect of CRH on wakefulness and the parallel timing of
production of PVN CRH mRNA in the nocturnal active period of rats with the timing of the hypothesized circadian
alerting signal, this hypothesis warrants additional testing.
Studies to explain the temporal dissociation between the
circadian phase of CRH and cortisol would be required as
well.
As evidenced throughout, HPA axis hyperactivity can
have many negative effects on sleep. It can lead to sleep
fragmentation, decreased SWS, and shortened sleep time.
Likewise, sleep disturbances can exacerbate HPA axis dysfunction, worsening the cycle. Sleep disorders associated
with HPA dysfunction, discussed herein, include insomnia
and OSA. In insomnia, HPA dysfunction may contribute to
the clinical sleep disorder. In OSA, HPA dysfunction may be
a consequence of the clinical sleep disorder.
In insomnia, HPA axis hyperactivity inhibits sleep and
increases awakenings. We believe that this effect is mediated
by increased nocturnal CRH and NE, and that the increased
nocturnal cortisol reported in insomnia (62– 64) is a marker
for elevated nocturnal CRH (and possibly elevated central
NE). Likewise, fragmented sleep increases HPA axis activity,
creating a vicious cycle. Furthermore, alterations in fatigueproducing cytokines may explain the daytime complaints of
tiredness and fatigue. Correction of HPA axis abnormalities
with GR and CRH antagonists, and possibly MR agonists,
may offer a potential means to decrease nocturnal CRH and
help restore normal sleep.
In OSA, findings are mixed about whether HPA axis hyperactivity is uniformly present. We hypothesize that OSA
can lead to HPA axis activation due to the repeated arousals
and subsequent cortisol release. Moreover, secondary HPA
axis hyperactivity may contribute to the metabolic syndrome
through its effects on glucose metabolism and leptin. HPA
axis hyperactivity may also be one factor contributing to
hypertension via the stimulatory effects of ACTH on aldosterone secretion. It is understood that many other factors
may contribute to the metabolic syndrome, as reviewed in
some of the recent literature (70, 71).
In addition to metabolic and cardiovascular consequences,
prolonged untreated OSA may be a risk factor for insomnia
itself and some forms of depression with hypercortisolemia,
again through HPA axis activation. Pulsatile cortisol secretion during apneic events may change HPA axis dynamics
and be the underlying mechanism that creates a state of
hypercortisolemia. We propose that this mechanism may
help explain the reversal of depression in some treated patients and offer a means of preventive intervention in others.
CPAP is an established, highly effective therapy for treating the underlying cause of this clinical syndrome, upper
airway obstruction, and may be important to reverse the
Buckley and Schatzberg • HPA Axis Rhythm and Sleep
secondary HPA axis abnormalities. In addition to CPAP,
pharmacological measures to reverse secondary HPA axis
abnormalities might be beneficial. These would follow a similar approach as that described for insomnia.
Obviously, insomnia and OSA syndrome are distinct syndromes with different clinical manifestations. Not everyone
with HPA axis hyperactivity develops the metabolic syndrome or hypertension. Again, HPA axis hyperactivity may
contribute to the expression of some of the clinical manifestations of OSA (such as the metabolic syndrome, insomnia,
and depression), but a host of other factors play significant
roles as well. Additional studies to explore the role of the
HPA axis in the etiology or clinical manifestations in these
sleep disorders as well as others are warranted. These may
lead to new forms of prevention as well as treatment.
Acknowledgments
The authors appreciate Dr. Ruth Benca’s review of the manuscript
and helpful suggestions.
Received June 7, 2004. Accepted February 10, 2005.
Address all correspondence and requests for reprints to: Dr. Theresa
Buckley, Stanford Sleep Disorders Clinic and Research Center and Department of Psychiatry, 401 Quarry Road, Suite 3301, Stanford, California 94305. E-mail: [email protected].
Work on this manuscript is supported in part by grants from the
National Institutes of Mental Health 5T32MH19938; R0-1MH50604; National Center for Research Resources, National Institutes of Health Grant
5 M01 RR000070, and the Pritzker Foundation.
A.F.S. is a co-founder of Corcept Therapeutics, a biopharmaceutical
company with an interest in GR antagonists.
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