Pharmacology Mechanism of Action

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Physiologic secretion of GH is normally pulsatile, with the majority of secretion during the first few hours of sleep (13). Maintenance of this pattern is dependent upon the balance between stimulation by GHRH and inhibition by somatostatin, both secreted by the hypothalamus. However, the factor or factors responsible for regulating secretion of these hormones are unknown. The mechanism of GH release by the growth hormone secretagogues is complex and not completely understood. Both animal and human data demonstrate that the secretagogues bind to pituitary somatotrophs and cause direct stimulation of GH secretion (3,12,14-23). The secretagogues also bind to cells within the hypothalamus (24) where the growth hormone secretagogue receptor has been identified (12). Most studies suggest that the physiologic action of the secretagogues occurs both at the pituitary and at the level of the hypothalamus, and therefore an intact hypothalamic-pituitary axis is required for a vigorous GH response (Fig. 1). Consistent with this, animal studies have shown stimulation of hypothalamic GHRH secretion in response to hexarelin, but no change in hypophysial portal somatostatin levels (25). Clinical data are also supportive of hypothalamic and pituitary sites of action. Pombo et al. (26) studied patients with neonatal pituitary stalk transection and found the GH response to GHRH (1 ^g/kg iv), GHRP-6 (1 ^g/kg iv) and the combination of GHRH and GHRP-6 was dramatically reduced compared to controls with normal hypothalamo-pituitary anatomy (Fig. 2). In the control subjects studied by this group, the mean peak GH response to the combination treatment was nearly 70 ng/mL, compared to a GH mean peak in the subjects with stalk transection of <5 ng/mL. However, the response to GHRH was also suppressed in these patients. Thus it is likely that the limited GH secretion was owing to an unresponsive pituitary rather than to lack of hypothalamic-pituitary communication. Additional con-

Fig. 1. Schematic representation of sites of action of growth hormone secretagogues. The primary sites of action in vivo are thought to be at the level of the hypothalamus as well as at the pituitary.
Fig. 2. Controls (n = 7) or subjects with perinatal pituitary stalk transection (n = 7) were treated on separate occasions with GHRH (1 Mg/kg, iv), GHRP-6 (1 Mg/kg, iv), and GHRH + GHRP-6. Samples were collected for serum GH analysis for 90 min post-dosing. Adapted from Pombo et al. (26).

vincing data have been reported by Loche et al. (27). This group found that among growth hormone deficient patients with anatomical pituitary abnormalities on magnetic resonance imaging, 10 of 11 subjects demonstrated a blunted GH response to a single dose of hexarelin. In contrast, patients with idiopathic GH deficiency had a significantly higher peak GH response to hexarelin equal to that of short normal children. Similar findings were reported by Popovic et al. (28) in a group of 12 patients with hypothalamo-pituitary disconnection who received a single dose of GHRH, GHRP-6, or the combination. Compared to age and sex-matched normal controls, these patients had a similar GH response to GHRH, implying normal pituitary function. However, the GH response to GHRP-6 and the combination of GHRP-6 and GHRH was much lower in the patient group, consistent with GHRH deficiency at the pituitary level (hypothalamo-pituitary disconnection) and suggestive of a primarily hypothalamic site of action for GHRP-6.

Several lines of evidence indirectly support an interaction of growth hormone secre-tagogues and somatostatin. Stimulation of GH by the secretagogues is synergistic with GHRH (29-32). Coadministration of atropine with GHRP-6 completely inhibits the stimulation of GH secretion, whereas coadministration with pyridostigmine increases GH secretion, as does insulin-induced hypoglycemia (33). To explain these data, these authors propose that somatostatin tone was increased by atropine, a cholinergic receptor antagonist, and decreased by pyridostigmine and hypoglycemia. They conclude that GHRP-6 induced GH secretion is dependent upon somatostatin tone, but does not act through mediating somatostatin release. In explaining the results of GHRP-6 infusion in healthy male volunteers, Huhn et al. (34) have suggested that growth hormone secretagogues act as functional somatostatin antagonists. Several other investigators have provided indirect data to support this hypothesis. Maccario et al. (35) studied the interaction of hexarelin with glucose and free fatty acids (FFA) in six healthy men. Glucose is thought to inhibit GH secretion by stimulation of somatostatin secretion and FFA may act directly at the pituitary. Both oral glucose and FFA dramatically decreased the GH secretory response to GHRH, but only blunted the response to hexarelin. These data support a mechanism of action for the GHRPs of antagonizing the action of somatostatin at the pituitary. Jaffe et al. (36) reached a similar conclusion in a study in which a 34-h iv infusion of GHRP-6 or saline was administered to nine healthy young men. During the GHRP infusion there was a significant increase in GH secretion, especially during non-sleep hours, when somatostatin tone is highest. Similarly, once daily dosing with MK-0677, a long-acting growth hormone secretagogue, resulted in a greater increase in GH and IGF-1 when dosed in the morning than in the evening (37). Taken together, data in humans are consistent with animal data, suggesting that the primary mechanism of action of the growth hormone secretagogues in vivo is within the central nervous system at the level of the hypothalamus or higher, with effects including both an increase in GHRH secretion and functional somatostatin antagonism.

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