It seems possible that an endogenous GH secretagogue ligand could be synthesized in some discrete population of neurons within the CNS, possibly even synthesized in neuroendocrine cells controlling GH secretion. However, it is equally possible that it is produced peripherally in response to physiological stimuli. Under what physiological circumstances are plasma levels of GH higher than normal, possibly reflecting the release of an endogenous GH secretagogue ligand? Interestingly, the endocrine response to GHRP-6 is in some respects similar to that observed in response to exercise. In humans, infusion of GHRP-6 results in an initial rapid increase in plasma levels of GH, followed by long-lasting elevated fluctuations (25); this profile is in marked contrast to the profile of GH release in response to GHRH infusion, which elicits a rapidly desensitizing response. However, the pituitary response to GHRP-6 desensitizes even more rapidly than that to GHRH, hence the profile of the in vivo actions of GHRP-6 cannot be accounted for from its pituitary actions alone; thus, the long duration of the response in vivo probably reflects the establishment of a new dynamic equilibrium in the hypothalamic output, involving episodic fluctuations in the output of hypothalamic-releasing factors. During prolonged exercise there is similarly a rise in plasma levels of GH that is maintained throughout the exercise period unlike the expected consequences of a sustained exposure to GHRH. Some of the more potent GHRP-6 mimetics have slight effects to increase plasma concentrations of cortisol (resulting from elevated adrenocorticotropin [ACTH] secretion) (26). These secretagogue effects on cortisol are within the normal physiological range and, perhaps significantly, also mimic the cortisol response to exercise. Thus GHRP-6 and related secretagogues may mimic the actions of an endogenous ligand released in response to acute exercise.
Exercise is a potent stimulator of GH secretion in most species, and this has been studied extensively in humans. The magnitude of the GH response depends on several factors, including the intensity and duration of acute exercise, the muscle mass used during exercise, and the degree of training. It appears that a threshold of exercise intensity must be exceeded before any increase in plasma concentration of GH is detected, and this threshold appears to coincide with the threshold for plasma lactate detection (27). Lactate is the end product of anaerobic glucose metabolism; it accumulates in (and is released from) muscles during strenuous exercise. Luger and colleagues (28) demonstrated that, in young men, iv infusion of lactate resulted in a substantial elevation in plasma GH concentration, but since the lactate threshold is higher in trained subjects than in untrained subjects, potentiation of GH secretion in trained subjects cannot be attributed to differences in lactate production alone. Little is known about the central regulation of exercise-induced GH secretion and most studies have been directed toward resolving the question of whether increased plasma concentrations of ^-endorphin (resulting from exercise) mediate the increase in GH secretion. The opiate antagonist naloxone inhibits exercise-induced GH release in highly trained athletes (29), suggesting a stimulatory effect of ^-endorphin on GH responsiveness. Other studies have implicated central cholinergic pathways in exercise-induced GH release since muscarinic antagonists block this GH response (30).
Food deprivation induces a dramatic alteration in GH secretion in all species studied. In rats, food deprivation inhibits pulsatile GH secretion, and refeeding results initially in low-amplitude pulses (at a higher frequency than the endogenous rhythm) giving way to normal 3 h high-amplitude pulses within 6-8 h (31). A variety of nutrients modulate GH secretion including free fatty acids and amino acids (32). The effects of refeeding are mimicked by iv injection of amino acids, but not by iv glucose, whereas iv injection of lipid abolishes pulsatile GH secretion (31). Food deprivation results in a dramatic reduction in GHRH gene transcription in rats, an effect that can be reversed with refeeding of dietary protein (33); in humans, by contrast, fasting stimulates GH secretion. Thus, exercise and diet have a major physiological influence on the hypothalamic regulation of GH secretion, but the pathways involved in these influences are poorly understood.
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