Based on the review of studies using various pharmacological agents, it may be concluded that sleep-onset GH secretion is regulated by GHRH stimulation occurring during a period of relative somatostatin withdrawal. Indeed, in humans, GH secretion during early sleep may be nearly totally suppressed by the administration of a specific GHRH antagonist, thus demonstrating an important role for GHRH in the control of sleep-related GH release (123). On the other hand, the late evening and nocturnal hours appear to coincide with the trough of a diurnal variation in hypothalamic somatostatin tone (29). Cholinergic muscarinic blockade by a variety of drugs, including methscopolamine, scopolamine, atropine, and pirenzepine suppresses sleep-related GH secretion (124-127). Conversely, piperidine, a nicotinic cholinergic receptor stimulator, enhances GH secretion during early sleep (128). Thus, cholinergic mechanisms must be partially involved in the control of sleep-related GH secretion. A large body of evidence has suggested this cholinergic control is effected via the regulation of hypothalamic somatostatin.
There is evidence that, under physiological conditions, sleep-related GH secretion may be less sensitive to somatostatin inhibition than spontaneous daytime GH secretion or daytime GH secretion in response to a variety of stimuli. Indeed, during sleep, GH secretion is not suppressible by acute hyperglycemia (129), a potent mechanism of inhibition of daytime GH release mediated in part by increased hypothalamic somatostatin activity. Similarly, aging, which is thought to be associated with a progressive increase in somatostatinergic tone (130), seems to affect GH secretion less during sleep than during wake, as the secretory output associated with the sleep-onset GH pulse remains relatively preserved (77). Reductions in somatostatinergic tone achieved by pharmacological treatment will generally enhance sleep-related GH secretion in adults (128,131) but in children, such treatments affect daytime, but not nocturnal, GH release because hypothalamic somatostatin activity is thought to be already minimal at night in this population (132-134). Differences in sensitivity of sleep-related vs daytime GH release to variations in hypothalamic somatostatin activity suggest that distinct mechanisms underly GH secretion during wake and during sleep.
Indeed, based on rodent data, it has been proposed that the stimulation of GH release and the promotion of non-REM sleep by GHRH are two separate processes that involve GHRH neurons in two distinct areas of the hypothalamus (135-137). The control of pituitary GH release would primarily involve GHRH neurons in the arcuate nucleus (138). The promotion of non-REM sleep by GHRH would implicate another area of the mediobasal hypothalamus where GHRH neurons are concentrated, within and around the ventromedial nucleus (138). The majority of GHRH neurons in this latter region project to various parts of the basal forebrain which are involved in sleep regulation and may therefore be part of the mechanism linking somatotropic activity and sleep (135-137). The association between GH release and SW sleep could represent synchronous activity in these two regions. However, the findings in several studies of a quantitative relationship between amount of GH secreted and various measures of SW activity suggest that the GHRH neurons which are implicated in the promotion of non-REM sleep also participate to some extend in the control of pituitary GH release (14,40,59). The data suggestive of a lesser somatostatinergic control of GH release during sleep than during wake would be interpreted as evidence for weaker somatostatinergic control in the areas involved in sleep regulation and sleep-related GH secretion than in the area controlling daytime GH release. Although 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, including occasional dissociations between nocturnal GH secretion and SW sleep.
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