Selective Lack of Growth Hormone (GH) Response to the GH-Releasing Peptide Hexarelin in Patients with GH-Releasing Hormone Receptor Deficiency¹

Abstract

The mechanism of the synergistic relationship between GH-releasing peptide (GHRP) and GHRH with respect to GH secretion is poorly understood. We report the response to hexarelin, a potent GHRP, in patients affected with a homozygous mutation in the GHRH receptor gene, with consequent GHRH resistance and GH-deficient dwarfism. This newly described syndrome is the human homolog of the little (lit/lit) mouse. Intravenous administration of hexarelin (2 g/kg) to four male adult patients (dwarfs of Sindh) resulted in a complete lack of elevation in plasma GH levels (Ͻ1 ng/mL), an at least 50-to 100-fold deviation from the normal response. In contrast, plasma PRL, ACTH, and cortisol levels rose in a normal manner in response to hexarelin. We conclude that an intact GHRH signaling system is critical for GHRPs to exert their effect on GH release, but that the GHRH system is not necessary for the effect of GHRP on PRL and ACTH secretion. Hexarelin (and probably other GHRPs) are not effective agents for the treatment of patients with GHRH resistance due to GHRH receptor deficiency. (J Clin Endocrinol Metab 84: 956 -959, 1999) T HE GH-RELEASING peptides (GHRP) are a class of small peptides that stimulate GH and, to a lesser degree, PRL and ACTH secretion from the pituitary gland (1-3). They interact with a recently cloned specific receptor that is expressed in the hypothalamus and pituitary (4). Orally active nonpeptide GHRP mimetics that bind to the same receptor and act as GH/PRL/ACTH secretagogues have been developed (3). The GHRPs are believed to represent analogs of a still unknown endogenous ligand for the GHRP receptor. This putative ligand is thought to participate in the regulation of GH secretion, in conjunction with GHRH and somatostatin. GHRPs synergize with GHRH in releasing GH by an unknown, primarily hypothalamic mechanism; coadministration of GHRP with GHRH in vivo results in a large potentiation of the GHRH effect (5, 6). The effect of GHRP on GHRH action at the pituitary level is smaller and additive rather than synergistic (7,8). Despite efforts at elucidating the GHRH-GHRP relationship, the nature of their interaction remains poorly understood, partly because of the difficulty in isolating the effects of GHRH, somatostatin, and GHRP in vivo.To shed further light on the cross-talk between GHRH and GHRP, we studied individuals with a unique new syndrome of genetic GHRH receptor (GHRH-R) deficiency (dwarfism of Sindh) (9, 10) to determine the efficacy of GHRP in elaborating GH, PRL, and ACTH release in the absence of GHRH signaling. Patients affected by this mutation in the GHRH-R are profoundly GH deficient because of GHRH resistance at the pituitary level (9 -12). A practical aim of the study was to determine whether GHRP or its oral analogs may represent a therapeutic modality for the affected patients who live in a rural area of Pakistan where medical services are limited. Hexarelin, the GHRP used in this study, is a potent GHRP whose effects in normal human subjects are well characterized (1...

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