Growth Hormone & IGF Research 2000, Supplement B, $57-$62

Review article

Interrelationships between growth

hormone and sleep
E. Van Cauter ~,~and G. CopinschP
1Department of Medicine, University of Chicago, Chicago, Illinois, USA, and 2Laboratoryof Experimental Medicine and Centre d'Etudes des Rythmes
Biologiques (CERB), Universit~ Libre de Bruxelles, Brussels, Belgium

Summary In healthy young adults, the 24-hour profile of plasma growth hormone (GH) levels consists of stable low
levels abruptly interrupted by bursts of secretion. In normal women, daytime GH secretory pulses are frequent.
However, in normal men, a sleep-onset-associated pulse is generally the major or even the only daily episode of active
secretion. Extensive evidence indicates the existence of a consistent relationship between slow-wave (SW) sleep and
increased GH secretion. There is a linear relationship between the amount of SW sleep (measured by either visual
scoring or spectral analysis of the EEG) and the amount of concomitant GH secretion. During ageing, SW sleep and
GH secretion decrease exponentially and with the same chronology. Pharmacological stimulation of SW sleep results
in increased GH release, and compounds that increase SW sleep may therefore represent a novel class of GH
secretagogues. @2000 Harcourt PublishersLtd

Key words: Ageing, growth hormone, growth hormone-releasing hormone, rapid-eye-movement sleep, slow-wave
sleep, somatostatin.

R E L A T I O N S H I P B E T W E E N SLEEP A N D G R O W T H phase delays, interruptions followed by re-initiations of

HORMONE SECRETION
The observation that growth hormone (GH) secretion is
markedly stimulated during sleep in normal adults was
made more than 30 years ago (reviewed in ref. 1). In
healthy young adults, the 24-h profile of plasma GH
levels consists of stable low levels abruptly interrupted
by bursts of secretion, and the most reproducible pulse
occurs shortly after sleep onset. In normal men, the
sleep-onset GH pulse is often the only daily episode of
active secretion detectable in mid-life and older adult-
hood. In normally cycling women, daytime GH pulses are
more frequent, and the sleep-onset-associated pulse,
while present in most cases, does not generally account
for the majority of 24-h GH release.
Sleep onset has been shown to elicit a GH secretory
pulse in individuals submitted to a variety of manipula-
tions of the sleep-wake cycle, including phase advances,
Correspondence to: E. Van Cauter, Department of Medicine, MC 1027,
University of Chicago, 5841 South Maryland Avenue, Chicago, iL 60637,
USA. Tel: +1 773 702 0169; Fax: +1 773 702 9194;
E-mail: evcauter@medicine.bsd.uchicago.edu
sleep, 3-h sleep-wake cycles, etct The mean GH profile
resulting from a 12-h shift of the sleep period is illus-
trated in Fig. 1.
Nocturnal GH secretion is frequently decreased in clin-
ical conditions involving sleep disorders, for instance, in
individuals with obstructive sleep apnoea 2-4. Successful
treatment of the sleep disorder with continuous positive
airway pressure increases the amount of GH secreted
during the first hours of sleep 3,4.In children, surgical cor-
rection of obstructive sleep apnoea may restore normal
GH secretion and normal growth rate%
Slow-wave sleep
As early as the late 1960s, well-documented studies
showed a consistent relationship between the appear-
once of slow-wave (SW) sleep stages (III and IV) in the
EEG and GH levels during early sleep, as well as during
the later part of the night I. Nocturnal GH levels were
found to be partially suppressed by selective SW sleep
deprivation. Moreover, it was shown that daytime naps
were more consistently associated with a GH secretory

1096-6374/00/030057+06 $35.00/0 © 2000 Harcourt PublishersLtd

58 E. Van Cauter and G. Copinschi
30
20
c~
Y,
10
I
Nocturnal sleep
18:00 22:00 02:00 06:00 10:00 14:00 18:00 22:00 02:00 06:00 10:00 14:00 18:00 22:00
Time
Fig. 1 Profiles of plasma GH levels in 18 normal young men studied during a 52-h period, including 8 h of nocturnal sleep, 28 h of sleep
deprivation and 8 h of daytime sleep (author's unpublished data). Values are expressed as means +- SEM. Reproduced with permission
from Van Cauter et al. 1 and the American Academy of Sleep Medicine.
pulse in the afternoon, when the propensity for SW sleep
is higher than in the morning, when rapid-eye-move-
ment (REM) sleep is predominant. These findings
strongly suggested that nocturnal GH secretion is critic-
ally dependent on the occurrence of SW sleep.
More recently, the relationship between sleep stages
and GH release was re-examined using a deconvolution
procedure to estimate GH secretory rates, which were
mathematically derived from plasma GH concentrations
by eliminating the effects of hormonal distribution and
clearance 5. Thus, this deconvolution procedure provides
an accurate estimation of the amount of GH released
during each secretory pulse and allows the temporal
limits of each pulse to be delineated more precisely. In
one study of normal young men, blood samples for
plasma GH determinations were obtained at 30-s inter-
vals. Maximal GH release was found to occur within min-
utes following the onset of SW sleep 6. In another study,
also performed in normal young men, approximately
70% of GH pulses during sleep were observed during SW
sleep, and the amount of GH secreted during these
pulses quantitatively correlated with the duration of the
SW episodeL Furthermore, the longer the SW episode,
the more likely it was to be associated with a GH pulse. A
'r ' 'l 'k\\\\\\'4a
Nocturnal sleep deprivation Daytime sleep
similar correlation was found between GH secretion and
concomitant values of delta activity (i.e. the spectral
power of the EEG in the frequency range 0.5-3.5 Hz) 7.
Thus, extensive evidence demonstrates a robust rela-
tionship between SW sleep and pituitary GH secretion.
However, nocturnal GH secretion can also occur in the
absence of SW sleep, and approximately one-third of SW
periods are not associated with detectable GH secretion,
indicating that this relationship is not obligatory5.
Because GH secretion is under dual stimulatory and
inhibitory control, involving GH-releasing hormone
(GHRH) and somatostatin, respectively, the variability
of somatostatinergic tone may underlie dissociations
between SW sleep and nocturnal GH release. The short-
term negative feedback exerted by GH on its own secre-
tion is likely responsible for observations of an absent
GH pulse during the first SW period when a secretory
pulse occurs before sleep onset.
Awakenings interrupting sleep
The abrupt suppression of ongoing GH secretion during
early sleep occurs whenever sleep is interrupted by spon-
taneous or forced awakenings+,L It has been suggested

(A)
288
~> 160
128
80
0~
40
8
10
I
28
I
38 48
' 58
'
I
6' 0
±
?'o 8'0 8'0
Age (years)
Fig. 2 Patterns of the (A) duration of SW sleep and (B) amount of nocturnal GH secretion throughout adult life, obtained from 102 healthy
non-obese men, 18-83 years of age. The individuals were grouped according to age. For each age group, values are expressed as means
+- SEM. Reproduced with permission from Van Cauter et al. 1and the American Academy of Sleep Medicine.
that this inhibitory effect of nocturnal awakenings on
GH secretion could be mediated by an increase in
somatostatin release 9, possibly related to an increase in
corticotropic activity. Indeed, awakenings during sleep
are also consistently associated with a pulse of cortisol
secretion, and the administration of corticotropin-releas-
ing hormone may inhibit the GH response to GHRH
stimulation ~°. These findings indicate that sleep fragmen-
tation will generally decrease nocturnal GH secretion.
I M P A C T OF H O R M O N E S OF T H E
S O M A T O T R O P I C A X I S ON SLEEP
There is substantial evidence indicating that components
of the somatotropic axis are involved in the regulation of
sleep quality. In normal human individuals, injections of
exogenous GH may stimulate REM sleep and decrease SW
sleep 11. In animals, acute suppression of circulating GH
concentrations by antiserum to GH is associated with mod-
est but significant suppression of both REM and non-REM
sleep ~2.A limited number of clinical studies, all originating
from the same group, have examined sleep quality in con-
ditions of deficient or excessive GH secretion. Although
the findings have been somewhat inconsistent, they tend
to indicate that pathological increases and decreases in
somatotropic function are associated with significant alter-
ations in sleep (reviewed in ref. 13). In GH-deficient indi-
viduals, prolonged treatment with biosynthetic GH at a
Close of 2 IU/kg/day (0.66mg/kg/day), equivalent to 2
IU/m2/day, resulted in a marked increase in REM sleep and
a trend toward increased duration of SW sleep ~4.
A large number of studies have consistently demon-
strated significant effects of GHRH on sleep quality. In
rodents, intracerebral as well as systemic injections of
GHRH stimulate non-REM sleep, even in hypoph-
ysectomized animals ~5-~8. Systemic injections of
GHRH also stimulate REM sleep in intact, but not in
Interrelationships between GH and sleep 59
(B)
~~1800
800
600
480
Z
288
0
10 2'8 30
'
I I
40 58 68
I
t !
1o 8'0 8'0
Age (years)
hypophysectomized, rodents lz,~s. Conversely, the inhibi-
tion of endogenous GHRH, by the administration of
GHRH antagonists or antibodies to GHRH, decreases
both GH secretion and non-REM sleep 19,2°. In humans,
injections of GHRH during sleep have similarly been
shown to increase delta activity and the amount of visu-
ally scored SW sleep 2~-24. The sleep-promoting effects of
this peptide may depend on the timing of administra-
tion 23,2s. The persistence of the stimulatory effects of
GHRH on non-REM sleep in hypophysectomized rodents
indicates that these effects are not mediated by GH lz,~8.
Recent studies suggest that GH secretion is addition-
ally under the control of an as yet unidentified stimula-
tory pathway, which may be activated by synthetic
compounds such as the GH-releasing peptides (GHRPs)
and their non-peptide analogues (also known as GH
secretagogues)2¢2L Single injections of a GHRP had no
stimulatory effects on SW sleep, even when given late at
night (i.e. at a time when SW sleep is not predominant) 2s.
In contrast, a 7-day oral treatment with MK-677 (a GH
secretagogue acting via the GHRP receptor) 29 increased
both stage IV and REM sleep, and decreased the
frequency of deviations from normal sleep in normal
young men 3°,3~, even though plasma GH levels were no
longer elevated at the time of the sleep study. However,
plasma insulin-like growth factor I (IGF-I) levels were
increased. Thus, these effects of MK-677 on sleep could
be mediated by increased IGF-I levels. Indeed, higher
plasma levels of IGF-I have been found to be associated
with increased delta sleep in healthy older men 32.
PUTATIVE MECHANISMS UNDERLYING THE
R E L A T I O N S H I P B E T W E E N SW SLEEP A N D
GH RELEASE
The mechanisms relating SW sleep and GH secretion are
still a matter of speculation. Sleep-onset-associated GH
60 E. Van Cauter and G. Copinschi
secretion appears to be regulated by GHRH stimulation
occurring during a period of relative somatostafin with-
drawal. Indeed, the late evening and nocturnal hours
coincide in humans with a trough in the diurnal varia-
tion in hypothalamic somatostatin tone 33, and GH secre-
tion during early sleep is almost totally suppressed by the
administration of a specific GHRH antagonist. These
findings demonstrate an important role for GHRH in the
control of sleep-related GH release 34. Based on rodent
data, it has been suggested that the stimulation of GH
secretion and the promotion of SW sleep are two separate
processes that involve GHRH neurons situated in two
distinct areas of the hypothalamus35-3L The association
between SW sleep and GH release would reflect synchro-
nous activity of GHRH neurons in these distinct regions.
However, the existence of a quantitative relationship
between various measures of SW activity and the
amount of GH secreted suggests that the GHRH neurons
implicated in promoting SW sleep could also participate
in the control of nocturnal pituitary GH secretion.
There is also evidence that, under physiological condi-
tions, nocturnal GH secretion may be less sensitive to
somatostatin inhibition than daytime GH secretion 38-42.
For instance, sleep-associated GH secretion cannot be
suppressed by acute hyperglycaemia43, a potent inhibitor
of daytime GH release that is mediated, in part, by
increased hypothalamic somatostatin tone. These data
suggest that distinct mechanisms underlie GH secretion
during wakefulness and during sleep, and could be inter-
preted as evidence of weaker somatostatinergic control
in the area(s) involved in sleep regulation.
P O T E N T I A L FOR N O V E L T H E R A P E U T I C
APPROACHES
The remarkable relationship between SW sleep and GH
secretion suggests that pharmacological approaches that
stimulate SW sleep may also increase nocturnal GH
release. Commercially available hypnotics tend to inhibit,
rather than increase, SW sleep and, as expected, do not
stimulate GH secretion 44,45.In contrast, the reliable stimu-
lation of SW sleep in normal individuals is observed
following oral administration of ritanserin, which is a
selective 5HT 2 receptor antagonist, or 7-hydroxybutyrate
(GHB), which is used as an investigational drug for the
treatment of narcolepsy4~. We recently found that bed-
time administration of GHB to normal young men, even
at a very low dose, produced a two-fold rise in the
amount of GH secreted during sleep, and this rise quanti-
tatively correlated with the increase in the amount of
stage 1V sleep seen during early sleep4L This effect
resulted from an increase in the duration and amplitude
of the normal GH secretory pulse associated with sleep
onset, rather than from the induction of additional pulses.
Similarly, the administration of ritanserin produced paral-
lel and highly correlated increases of SW sleep and noc-
turnal GH releaseL Thus, compounds that enhance SW
sleep could represent a novel class of GH secretagogues.
Ageing is associated with exponential decreases in SW
sleep and circulating levels of GH 4a. In normal men,
25-35 years and 60-70 years of age, daily GH secretion is
about 50% and 30%, respectively, of the secretion in men
aged 1 6 - 2 5 years 48. Ageing affects SW sleep and GH
release (during both sleep and wakefulness) with a similar
chronology, as illustrated in Fig. 2, suggesting the involve-
ment of common but as yet unknown mechanisms.
Ongoing trials are examining whether or not SW sleep
can be pharmacologically restored in older adults and
whether the restoration of SW sleep is associated with a
concomitant marked increase in the amount of GH
secretion. If SW sleep and nocturnal GH secretion can be
pharmacologically stimulated in the elderly, novel
therapeutic strategies for the simultaneous treatment of
age-related sleep alterations and relative GH deficiency
may become available.
CONCLUSIONS
Extensive evidence substantiates the existence of a
robust relationship between SW sleep and GH release in
humans, consistent with the hypothesis that activation
of hypothalamic GHRH activity is involved in the control
of both nocturnal GH release and SW sleep.
Simultaneous increases in SW sleep and GH release
observed in studies using SW-enhancing drugs suggest
pharmacological agents that reliably stimulate SW sleep
may represent a new class of GH secretagogues that
would be particularly well suited to treating the relative
hyposomatotropism of the elderly.
ACKNOWLEDGEMENTS
This work was supported in part by grants from the US
National Institutes of Health (NIDDK DK-41814 and
NIA AG-11412), the Belgian Fonds de la Recherche
Scientifique M4dicale (FRSM) and the Universit6 Libre de
Bruxelles.
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