Sleep, 19(10):S218-S220
© 1996 American Sleep Disorders Association and Sleep Research Society
Neuroendocrine Function In Sleep Apnea
Metabolic Aspects of Sleep Apnea
Ronald R. Grunstein
Sleep Disorders Centre, Royal Prince Alfred Hospital, Camperdown, Sydney, Australia
Summary: Sleep apnea is associated with abnormalities in metabolic function. First. there is a strong epidemiological link between central obesity and sleep apnea. Some evidence suggests that sleep apnea may promote weight
gain or prevent weight loss by several mechanisms: reduction in anabolic (growth hormone and testosterone)
hormone secretion, influences on energy balance and insulin sensitivity, and altered central serotonergic tone. Key
Words: Sleep apnea-Obesity-Energy expenditure-Growth hormone-Insulin-Serotonin.
Sleep apnea has a number of characteristic clinical
features that indicate a strong association with metabolic and/or endocrine dysfunction. Metabolic/endocrine disorders, such as acromegaly and hypothyroidism, are all closely associated with sleep apnea (1). In
this paper, we review the effects of recurrent upper
airway obstruction, hypoxemia, and sleep fragmentation on body metabolism.
MATERIALS AND METHODS
Detailed methodology of these studies have been
reported in several papers (2-10).
creased in OSA. Central obesity is associated with
neck, thoracic, abdominal, and, presumably, extraluminal UA fat deposition, leading to upper airway loading.
Central obesity is a predictor of cardiovascular and
psycho-social morbidity in both genders (4,8-9). Importantly, the health-risk profile of central obesity and
OSA are closely interrelated (4,8-9) and, therefore, are
potential confounders of each other in cross-sectional
and prospective epidemiological studies.
Sleep apnea and anabolic hormones
Certain hormones influence the metabolic balance
between anabolism and catabolism. Anabolic hormones include growth hormone, testosterone, and, to
some extent, insulin.
RESULTS AND DISCUSSION
Sleep apnea, gender, and obesity
Obstructive sleep apnea (OSA) is more prevalent in
males, suggesting that certain factors associated with
male or female gender increase or decrease the risk of
developing sleep-disordered breathing. These include
both differences in upper airway (UA) anatomy and
respiratory control. Alternatively, distribution of body
fat differs in men and, in particular, premenopausal
women, with men having a more central body-fat distribution. We have observed that this central form of
fat distribution is strongly associated with sleep apnea
(4) with both waist and neck circumferences being inAccepted for publication September 1996.
Address correspondence and reprint request to Ronald R. Grunstein, Sleep Disorders Centre, Royal Prince Alfred Hospital, Camperdown, Sydney 2050, Australia.
Growth hormone
Obstructive sleep apnea leads to marked fragmentation or absolute reduction in slow-wave sleep. As
growth hormone secretion is closely linked to the first
slow-wave sleep period, we investigated whether OSA
may lead to abnormalities in the somatotrophic axis.
Insulin-like growth factor I (IGF-l), a biological
marker of growth-hormone secretion was reduced in
severe sleep apnea (2). Treatment of sleep apnea by
nasal continuous positive airway pressure (nCPAP)
leads to an increase in IGF-l to control levels (2).
Nocturnal growth-hormone levels, as measured by frequent blood sampling, are reduced in OSA and increased with nCPAP treatment. This increase in
S2l8
t'
'J
METABOLIC ASPECTS OF SLEEP APNEA
*
0.6
~Stg1·2
.Stg3-4
GH
Insulin
o Wake
0.5
(uglL)
S219
0.4
• REM
0.3
0.2
0.1
o
PRE·CPAP
POST·CPAP
FIG. 1. Plasma growth-honnone (GH) levels in different sleep
stages in eight patients with severe sleep apnea before and after
CPAP. Note that the relationship between slow-wave sleep and GH
concentrations becomes significant on CPAP treatment.
growth hormone is associated with restoration of normal slow-wave sleep architecture suggesting that the
disrupted sleep patterns that exist in sleep apnea are
responsible for the observed deficits in somatotrophic
function (5) (Fig. 1). This is consistent with recent
evidence that arousals following growth-hormone
(GH) releasing-hormone (GHRH) infusion interrupt
the normal GH response to GHRH. The response is
restored following resumption of sleep (11). As the
pulsatile secretion of GH results from the interaction
of GHRH and somatostatin at the level of the somatotrope, it is certainly possible that repetitive arousal
in sleep apnea may impair the GH response to endogenous bursts of GHRH into the pituitary portal circulation.
Some of our patients with severe sleep apnea have
similar levels of IGF-I to adult patients with GH deficiency (2). Deficiency of GH in adulthood (12) has
potential clinical sequelae in four main areas: poorer
quality of life, body composition (increased fat and
decreased muscle mass), bone, and mineral metabolism. In addition, a number of studies have strongly
suggested that GH deficiency is associated with accelerated aging, premature atherosclerosis, and increased
cardiovascular mortality (12).
Testosterone
Severe OSA is associated with low-testosterone levels that are increased by nCPAP (2). Paradoxically,
low-testosterone levels may be protective in sleep apnea (6). We have observed a young man develop sleep
apnea and a more collapsible UA following testosterone therapy for stature control, and other study groups
have data in groups of hypogonadal men. However,
blockade of testosterone action by flutamide, a nonsteroidal competitive inhibitor of androgen binding,
led to no improvement in sleep apnea despite hormonal evidence of androgen blockade (3).
Insulin levels are increased in patients with sleep
apnea. Although this is largely explained by co-existing central obesity, sleep apnea appears to have an
independent effect. Moreover, we have recently shown
that sleep apnea is associated with CPAP-reversible
insulin resistance (7). Thus, both central obesity and
sleep apnea appear to have independent effects on reducing insulin sensitivity. This, in turn, will have potential effects on increasing cardiovascular risk, promoting the development of diabetes and influencing
weight control.
Sleep apnea and energy balance
The high prevalence of obesity in OSA suggests that
sleep apnea may even have a potential weight-promoting effect by maintaining net-energy accumulation.
There are several reasons why 24 hour energy expenditure (EE) may be altered in sleep apnea and potentially influence weight regulation. During sleep, EE
typically falls, relative to the awake basal state (13).
However, in healthy subjects, natural- and artificiallyinduced repetitive arousals often produce sustained periods of increased EE (13). Sleep deprivation itself
causes increased EE. Recovery from sleep deprivation
with ad lib sleep is associated with complete reversal
of this increased EE. Second, the increasing breathing
efforts against the occluded UA in sleep apnea may
lead to increased EE in sleep. Therefore, frequent
arousals and the chronic sleep disruption experienced
by patients with sleep apnea may lead to increased EE
in sleep that would favor weight loss. However, this
may be countered by mechanisms favouring weight
gain. Patients with sleep apnea are characterized by
daytime sleepiness that may reduce spontaneous physical activity (SPA) (fidgeting and routine physical activities).
In order to investigate EE in patients with sleep apnea, 24 hour EE (measured in a small hotel-room-sized
metabolic chamber) was measured in patients with severe sleep apnea and in a control group. Subsequently,
patients with severe sleep apnea were treated with
nCPAP and the 24 EE was remeasured. Data from this
study revealed that severe sleep apnea is associated
with an increased level of EE during sleep, and this
level falls on nCPAP treatment (10). Spontaneous
physical activity is difficult to assess in a restricted
environment like the chamber but the increased sleep
EE in OSA pre-CPAP must be balanced by reduced
day-EE or increased food intake; otherwise, patients
with OSA would lose weight and cure themselves!
Sleep, Vol. 19, No. 10, 1996
R. R. GRUNSTEIN
S220
CENTRAL
OBESITY
SLEEP
APNEA
?
•
NET
EFFECTS
ON
INSULIN
SENSITIVITY
ANABOLIC
HORMONE
SECRETION
ENERGY
ALTERED CENTRAL
SEROTENERGIC TONE
EXPENDITURE
FIG. 2. A diagram of potential interrelationships between sleep
apnea and central obesity that may favor the development or maintenance of the obese state in sleep apnea.
CONCLUSION
There is a close link between central obesity and
sleep apnea. Sleep apnea may promote weight gain or
prevent weight loss by several mechanisms-reduction
in anabolic-hormone secretion as well as influences on
energy balance and insulin sensitivity. Recent data
suggesting altered serotonergic tone in untreated sleep
apnea (14) would support a propensity for weight gain
(Fig. 2). Further research into metabolic changes after
CPAP treatment, using sophisticated imaging and muscle-analysis techniques, may provide more data in the
future.
Acknowledgements: Research for the above studies has
been funded by the NHMRC of Australia, National Heart
Foundation of Australia, and the MRC of Sweden. The support of collaborators listed in the various referenced papers
was pivotal to this work.
Sleep, Vol. 19, No. 10, 1996
REFERENCES
1. Grunstein RR. Endocrine and metabolic disturbances in obstructive sleep apnea. In: Saunders NA, Sullivan CE, eds. Sleep and
breathing, 2nd edition. New York: Marcel Dekker, 1993.
2. Grunstein RR, Handelsman OJ, Lawrence S, Blackwell C, Caterson 10, Sullivan CEo Neuroendocrine dysfunction in sleep
apnea: reversal by nasal continuous positive airway pressure. J
Clin Endocrinol Metab 1989;68:352-8.
3. Stewart 0, Grunstein RR, Berthon-Jones M, Handelsman OJ,
Sullivan CEo Androgen blockade does not affect sleep disordered breathing or chemosensitivity in men with obstructive
sleep apnea. Am Rev Respir Dis 1992;146:1389-93.
4. Grunstein RR, Wilcox I, Yang TS, Hedner J. Snoring and sleep
apnea in men-association with central obesity and hypertension. Int J Obesity 1993;17:533-40.
5. Grunstein RR, Handelsman OJ, Stewart OA, Sullivan CEo
Growth hormone secretion is increased by nasal CPAP treatment
of sleep apnea. Am Rev Respir Dis 1993; 147:A686.
6. Cistulli P, Grunstein RR, Sullivan CEo Effect of testosterone on
upper airway collapsibility during sleep. Am J Respir Crit Care
Med 1994;149:530-2.
7. Brooks B, Cistulli PA, Borkman M, et al. Effect of nasal continuous positive airway pressure treatment on insulin sensitivity
in patients with Type II diabetes and obstructive sleep apnea. J
Clin Endocrinol Metab 1994;79:1681-5.
8. Grunstein RR, StenlOf K, Hedner J, Sjostrom L. Impact of obstructive sleep apnea and sleepiness on metabolic and cardiovascular risk factors in the Swedish Obese Subjects (SOS)
Study. Int J Obesity 1995;19:410-8.
9. Grunstein RR, StenlOf K, Hedner J, Sjostrom L. Impact of self
reported sleep apnea symptoms on psycho-social performance
in the Swedish Obese Subjects (SOS) Study. Sleep 1995;18:
635-43.
10. Stenlbf K, Grunstein RR, Henning B, Hedner J, Sjostrom L.
Energy expenditure in sleep apnea. Am J Physiol (in press).
11. Van Cauter E, Caufriez A, Kerkofs M, van Onderbergen A,
Thorner MO, Copinschi G. Sleep, awakenings, and insulin-like
growth factor 1 modulate the growth hormone (GH) secretory
response to GH-releasing hormone. J Clin Endocrinol Metab
1992;74:1451-9.
12. Bengtsson B-A, Eden S, Lonn Let al. Treatment of adults with
growth hormone (GH) deficiency with recombinant human GH.
J Clin Endocrinol Metab 1993;76:309-17.
13. Bonnet MH, Berry RB, Arand OL. Metabolism during normal,
fragmented and recovery sleep. J Appl PhysioI1991;71:1112-8.
14. Hudgel OW, Gordon EA, Meltzer HY. Abnormal serotenergic
stimulation of cortisol production in obstructive sleep apnea. Am
J Respir Crit Care Med 1995;152:186-92.