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Abstract
Growth hormone secretagogues (GHS) are synthetic, non-natural peptidyl and nonpeptidyl molecules with potent stimulatory effect on somatotrope secretion. They have no structural homology with growth hormone-releasing hormone (GHRH) and act via a specific receptor, which has now been cloned and is present at both the pituitary and hypothalamic level. This evidence strongly suggests the existence of a still unknown natural GHS-like ligand. Several data favour the hypothesis that GHS could counteract somatostatinergic activity at both the pituitary and hypothalamic level and/or, at least partially, via a GHRH-mediated mechanism. However, the possibility that they act via an unknown hypothalamic factor remains open. GH-releasing peptide-6 (GHRP-6) is the first hexapeptide studied extensively in humans. More recently, peptidyl superanalogues GHRP-1, GHRP-2 and hexarelin, and nonpeptidyl mimetics, such as the spiroindoline derivative MK-677, have been synthesized and their effects have been studied in humans. The GH-releasing activity of GHS is marked, dose related and reproducible after intravenous, subcutaneous, intranasal and even oral administration. The effect of GHS is partially desensitized but prolonged, intermittent oral administration increases insulinlike growth factor I (IGF-I) levels. The GH-releasing effect of GHS undergoes age-related variations; it increases from birth to puberty, remains similar in adulthood and decreases with ageing. The effect of GHS on GH release is synergistic with that of GHRH, while it is only partially refractory to inhibitory influences, which nearly abolish the effect of GHRH. GHS maintain their GH-releasing activity in some somatotrope hypersecretory states such as acromegaly, anorexia nervosa, hyperthyroidism and critical illness. The GH response to GHS has been reported clear although reduced in GH deficiency, obesity and hypothyroidism, while it is strongly reduced in patients with pituitary stalk disconnection or Cushing's syndrome. In short children, elderly subjects, critically ill patients and even in adult patients with GH deficiency an increase of IGF-I has been shown after GHS treatment. These data indicate that treatment with orally active GHS in humans enhances the activity of the GH-IGF-I axis and could be clinically useful.
