Sleep-related Growth Hormone Release Research Articles

Interrelations Between Sleep and the Somatotropic Axis

In the human as in other mammals, growth hormone (GH) is secreted as a series of pulses. In normal young adults, a major secretory episode occurs shortly after sleep onset, in temporal association with the first period of slow-wave (SW) sleep. In men, approximately 70% of the daily GH output occurs during early sleep throughout adulthood. In women, the contribution of sleep-dependent GH release to the daily output is lower and more variable. Studies involving shifts of the sleep-wake cycle have consistently shown that sleep-wake homeostasis is the primary determinant of the temporal organization of human GH release. Effects of circadian rhythmicity may occasionally be detected. During nocturnal sleep, the sleep-onset GH pulse is caused by a surge of hypothalamic GHRH release which coincides with a circadian-dependent period of relative somatostatin disinhibition. Extensive evidence indicates the existence of a consistent relationship between SW sleep and increased GH secretion and, conversely, between awakenings and decreased GH release. There is a linear relationship between amounts of SW sleep--whether measured by visual scoring or by delta activity--and amounts of concomitant GH secretion, although dissociations may occur, most likely because of variable levels of somatostatin inhibition. Pharmacological stimulation of SW sleep results in increased GH release, and compounds which increase SW sleep may therefore represent a novel class of GH secretagogues. During aging, SW sleep and GH secretion decrease with the same chronology, raising the possibility that the peripheral effects of the hyposomatotropism of the elderly may partially reflect age-related alterations in sleep-wake homeostasis. While the association between sleep and GH release has been well documented, there is also evidence indicating that components of the somatotropic axis are involved in regulating sleep. The studies are most consistent in indicating a role for GHRH in promoting NREM and/or SW sleep via central, rather than peripheral, mechanisms. A role for GH in sleep regulation is less well-documented but seems to involve REM, rather than NREM, sleep. It has been proposed that the stimulation of GH release and the promotion of NREM sleep by GHRH are two separate processes which involve GHRH neurons located in two distinct areas of the hypothalamus. Somatostatinergic control of GH release appears to be weaker during sleep than during wake, suggesting that somatostatinergic tone is lower in the hypothalamic area(s) involved in sleep regulation and sleep-related GH release than in the area controlling daytime GH secretion. While the concept of a dual control of daytime and sleep-related GH secretion remains to be directly demonstrated, it allows for the reconciliation of a number of experimental observations.

Nocturnal growth hormone surges in type 1 diabetes mellitus are both sleep- and glycemia-dependent: assessment under continuous sleep monitoring

Our work has studied the relationship between nocturnal growth hormone (GH) surges, sleep and glycemia in seven conventionally treated type 1 diabetic patients under continuous sleep monitoring and the results were compared to those found in five age-matched healthy controls. On the experimental day, sleep was monitored from 24.00 to 07.00. Blood glucose levels and GH were assayed in both groups. As a group the diabetics had nocturnal GH responses higher than those in controls. However, the sleep-related GH release is not abnormally high in patients who maintain strict normoglycemia. Early-night hypoglycemia and/or rapidly decreasing blood glucose concentrations enhance sleep-related GH secretion in diabetics, whereas hypoglycemia not associated with slow-wave sleep (SWS) causes a moderate increase in GH. Late-onset nocturnal hypoglycemia is not potent enough to stimulate GH. It is proposed that in diabetics sleep-related GH production is probably not abnormally elevated within a wide range of stable glucose levels, but when these thresholds are crossed or when there is a rapid decrease in blood glucose, then GH secretion is inversely related to the changing blood glucose. Therefore, our study supports the conclusion that sleep-related GH secretion is finely modulated by the actual glycemic fluctuations in diabetic patients.

Evidence for a role of delta sleep-inducing peptide in slow-wave sleep and sleep-related growth hormone release in the rat.

To examine the role of delta sleep-inducing peptide (DSIP) in sleep-related growth hormone (GH) release, male rats were deprived of sleep for 4 hr by placing them on a slowly rotating wheel. Sleep deprivation by this method caused a significant increase in GH release, as indicated by the increase in plasma GH concentrations (P less than 0.01), and also in the amount of slow-wave sleep (SWS) (P less than 0.001) above initial values after removal of the animals from the rotating wheel. These increases were blocked by microinjection into the third cerebral ventricle of highly specific antiserum to DSIP. In control rats receiving an equal volume of normal rabbit serum, the significant increase in plasma GH as well as SWS remained after removal of the rats from the wheel. The increased release of endogenous DSIP in the sleep-deprived animals may have caused an increase in SWS as well as plasma GH. Since DSIP increases plasma GH after its injection into the third cerebral ventricle and since passive immunization against DSIP blocks the increase in SWS and GH release that follows the 4 hr of sleep deprivation, the results suggest that DSIP can be a physiological stimulus for sleep-related GH release as well as for the induction of SWS.

Effects of intravenous corticotropin-releasing hormone upon sleep-related growth hormone surge and sleep EEG in man.

Corticotropin-releasing hormone (CRH) plays a key role in coordinating neuroendocrine, metabolic and behavioral responses in stress and affective disorders. To further investigate the effects of enhanced pituitary-adrenocortical activity upon sleep-related phenomena we administered four intravenous injections of 50 micrograms human (h)-CRH or saline to 11 normal males at 10 p.m., 11 p.m., 12 p.m. and 1 a.m. and measured plasma levels of cortisol and growth hormone (GH) as well as sleep EEG recordings throughout the night. Treatment with h-CRH resulted in a significant increase of mean (+/- SEM) cortisol secretion between 11 p.m. and 3 a.m. (h-CRH: 100.6 +/- 9.5 ng/ml; saline: 39.0 +/- 1.5 ng/ml; p less than 0.01). This initial cortisol increase after repeated h-CRH stimulations was followed by a period of attenuated plasma cortisol between 3 and 7 a.m. (h-CRH: 70.3 +/- 7.0 ng/ml; saline: 115.5 +/- 8.0 ng/ml; p less than 0.01). Cortisol surges after h-CRH were associated with a significant blunting of sleep-related GH release expressed as areas under concentration curves (h-CRH: 1.245 +/- 0.32 ng/ml/min.10(3); saline: 2.462 +/- 0.92 ng/ml/min.10(3), p less than 0.01). In addition to these hormonal effects, h-CRH induced a decrease of REM and slow wave sleep (stages III and IV) while the amount of more shallow sleep (stages I and II) increased. These effects upon sleep structure were more pronounced during the second part of the night.(ABSTRACT TRUNCATED AT 250 WORDS)

Sleep-related growth hormone release in thyrotoxic patients before and during propylthiouracil therapy.

Hyporesponsiveness of GH to insulin-induced hypoglycemia has previously been reported in hyperthyroid patients. In order to clarify the GH secretion in thyrotoxic patients, sleep-related increases in the serum GH concentration were investigated. Eight thyrotoxic females ranging in age from 7 to 15 were treated with PTU. Blood samples for measurement of GH were drawn every 15 minutes during the first few hours of sleep before and during the treatment lasting about three months. The mean maximum serum GH level before the treatment was 10.0 +/- 5.5 ng/ml (mean +/- SD); this rose to 23.2 +/- 14.6 ng/ml (P less than 0.02) during the treatment. The maximum value of more than 10 ng/ml was detected in only 3 out of the 8 patients before treatment. On the other hand, serum GH levels during PTU administration rose to above 10 ng/ml in all patients except one. It was revealed that sleep-related elevations of GH occurred early in sleep and in close association with a slow-wave EEG pattern. The results show that sleep-related GH release is low in the hyperthyroid state, but becomes significantly elevated during PTU administration. However, even in the hyperthyroid state, the sleep-related secretion of GH is closely correlated with the slow-wave sleep stage as in the euthyroid condition.

Methoscopolamine inhibition of sleep-related growth hormone secretion. Evidence for a cholinergic secretory mechanism.

We have examined the effects of cholinergic blockade with 0.5 mg methscopolamine bromide, intramuscularly, on sleep-related and insulin-induced growth hormone (GH) secretion. 17 normal young men were studied; 8 had sleep studies, and 12 (including 3 who also had sleep studies) had insulin tolerance tests (ITT) with 0.1 U/kg of regular insulin. After an adjustment night in the sleep laboratory, saline control night and methscopolamine night studies were done in random sequence; study procedures included electroencephalographic, electromyographic, and electrooculographic recordings, and blood sampling every 20 min for hormone radioimmunoassays. Prolactin levels were also measured during sleep. For methscopolamine night studies, the mean overall control GH level of 2.89+/-0.44 ng/ml and the mean peak control GH level of 11.09+/-3.11 ng/ml were dramatically reduced to 0.75+/-0.01 and 1.04+/-0.25 ng/ml, respectively (P<0.0001 and <0.001). Despite virtual absence of GH secretion during the night in every study subject, no measured sleep characteristic was affected by methscopolamine, including total slow-wave sleep (12.1+/-2.6% control vs. 10.3+/-2.5% drug, P>0.2). Sleep prolactin levels were not changed by methscopolamine. In contrast to the abolition of sleep-related GH secretion, administration of methscopolamine had only a marginal effect on the GH response to insulin hypoglycemia. None of nine time points differed significantly, as was also the case with peak levels, mean increments, and areas under the curves (P>0.2). Analysis of variance did, however, indicate that the lower GH concentrations achieved during ITT after methscopolamine (average 31.7% below control) were significantly different than control concentrations. We conclude that the burst of GH secretion which normally occurs after sleep onset is primed by a cholinergic mechanism which does not influence slow-wave sleep. Cholinergic mechanisms do not appear to play an important role in sleep-related prolactin secretion. The contrast between the complete suppression of sleep-related GH release and the relatively small inhibitory effect on ITT-induced GH secretion suggests that the neurotransmitter mechanisms, and presumably the pathways, which subserve sleep-related GH secretion in man may be different from those which mediate the GH response to pharmacologic stimuli such as insulin.

Effects of Thyrotropin-Releasing Hormone on Sleep and Sleep-Related Growth Hormone Release in Normal Subjects

Effects of TRH on sleep and sleep-related growth hormone (GH) release were examined in four normal volunteers. A bolus of 500 microgram of synthetic TRH was injected iv at the onset of sleep, followed by continuous iv infusion of 1000 microgram of TRH dissolved in saline for 3 h on two nights. Saline alone was infused on two control nights in each of these subjects. Polygraphic sleep records showed that TRH transiently interrupted sleep on both nights in all of the four subjects. The arousal phenomenon was observed from 80 to 151 min after the start of TRH administration until 20 to 212 min after the end of TRH infusion. The mean (+/-SE) percentage of awakening on the nights of TRH administration was significantly larger than on the control nights (36.4 +/- 1.9% vs. 1.3 +/- 0.8%, P less than 0.001). Plasma GH increased in close relationship to the initial appearance of slow wave sleep (SWS) within 40 min after sleep onset on both control nights in all four subjects. On nights of TRH administration, however, plasma GH levels during the initial 80 min of sleep were significantly lower (P less than 0.005) than on control nights, whereas SWS was demonstrated before the interruption of sleep. On nights when sleep was interrupted by forced wakefulness 1 h after sleep onset, plasma GH rose to levels comparable to those on control nights during early sleep periods in all subjects examined. These results suggest that TRH inhibits sleep and sleep-related GH release in normal subjects.

Sleep-related growth hormone release following 2-bromo-alpha-ergocriptine treatment in acromegalic patients.

Plasma growth hormone (GH) concentrations were measured over 24 h in seven acromegalic patients before and during treatment with 2-bromo-alpha-ergocriptine (CB-154). Before treatment basal plasma GH levels were consistently elevated but no significant change was observed between the mean plasma GH levels during sleep and during waking in five of the seven patients examined. The daily administration of CB-154 (5 to 10 mg, orally) for 14 days resulted in a significant fall in the 24 h mean plasma GH levels in six of the seven patients. In all of the six patients who responded to CB-154 treatment, the mean plasma GH concentrations during sleep were significantly greater than during waking. Daytime sleep was associated with a significant rise in plasma GH in both of the two patients examined. It is concluded that CB-154 treatment resulted in a significant decrease in plasma GH levels with sleep-related increase in some acromegalics although the mechanism responsible for this sleep-related GH rise remains to be further investigated.

Suppression by cyproheptadine of human growth hormone and cortisol secretion during sleep.

The effect of cyproheptadine on plasma growth hormone and cortisol levels was studied in seven male volunteers with polygraphic sleep monitoring. Sleep-related growth hormone release was completely inhibited in three of the seven normal subjects by the intravenous infusion of cyproheptadine (5 mg) which was started at the onset of sleep. In the other four, growth hormone release during sleep was significantly decreased or delayed by cyproheptadine when the drug infusion was started at 7:00 p.m., 1-2 h before the onset of sleep. The usual increase in plasma cortisol in the early morning was completely suppressed in all five subjects given cyproheptadine infusions from 4:00 to 7:00 a.m. The intravenous infusion of cyproheptadine increased slow wave sleep, although the time from sleep onset to the first occurrence of slow wave sleep was not affected. In contrast, rapid eye movement sleep was significantly decreased by cyproheptadine. These results suggest that cyproheptadine inhibits growth hormone and ACTH secretion during sleep in man, possibly by antagonizing serotoninergic mechanisms although other actions of the drug are not ruled out.

Inhibition of sleep related growth hormone release by elevated free fatty acids.

ABSTRACT Growth hormone release was measured in four normal young men during normal sleep and during sleep in which free fatty acids (FFA) were elevated by the administration of oral Lipomul® and iv heparin. No correlation was found during normal sleep between plasma glucose and free fatty acid levels and the release of growth hormone coincident with control deep sleep periods. Elevation of FFA levels resulted in a suppression of growth hormone release with deep sleep with a mean peak level of 2.3 ± 0.7 ng/ml as compared to a mean peak of 29.4 ± 1.6 ng/ml obtained during normal sleep nights. Analysis of the data suggests that growth hormone secretion during deep sleep can be influenced by FFA which affect growth hormone secretion in the wake state.