Diagnostic studies with intravenous and intranasal growth hormone-releasing peptide-2 in children of short stature.

Abstract

GH secretion is primarily regulated by the hypothalamic-releasing hormones GHRH and somatostatin. Additionally, several neurotransmitters act at the hypothalamus and pituitary to modulate GH release. The agents commonly used in clinical practice to diagnose GH deficiency, such as arginine, insulin and L-dopa, act through the neural GH network. Many children with a poor GH response to conventional agents have a significant serum GH response to iv GHRH. GH-releasing peptides (GHRPs) are synthetic peptides that like GHRH act directly on pituitary somatotrophs to stimulate GH release. GHRP-2, an investigational drug, is one of the most potent members of the GHRP family. It has been shown to be effective in adults via the oral and intranasal as well as the iv route of administration. In this study, GH responses to GHRP-2 were compared with GH responses to other provocative agents in children of short stature. GHRP-2 was administered iv or intranasally to children with short stature. In the same subjects, GHRP-2 was administered iv in combination with GHRH. Twenty-four children undergoing evaluation for GH deficiency received at least one conventional agent (arginine, L-dopa/exercise, insulin) in addition to iv GHRH and GHRP-2. The GH responses to GHRH or GHRP-2 were similar in each child, and both were equally reliable predictors of pituitary reserve. The conventional agents used in GH testing were less likely to predict the capacity of the pituitary to release GH than were either GHRH or GHRP-2. There was no correlation between maximal GH response to standard tests with GH responses to GHRH or GHRP-2. A subset of the group of 21 children who had a robust response to iv GHRP-2 were later administered GHRH+GHRP-2 simultaneously. The GH response to GHRH+GHRP-2 was synergistic in this group of 12 children, similar to previously reported observations in adults of normal stature. Fifteen of the 21 children who had a robust response to the iv GH-releasing factors also received intranasal GHRP-2. All 15 of these children had a significant GH response to intranasal GHRP-2 over a dose range of 5-20 micrograms/kg per dose. The mean peak GH response to 15 micrograms/kg was 31.3 micrograms/L. The intranasal preparation was well tolerated.(ABSTRACT TRUNCATED AT 400 WORDS)

Growth Hormone‐Releasing Peptides

“…The synergistic release of GH induced when GHRP and GHRH are administered together intravenously is a consistent and sometimes dramatic finding in animals and in humans (14,19,28,29,102). This synergism cannot be reproduced in vitro.…”

“…Glucose and free fatty acids only partially inhibit the GH response to hexarelin (87). Also, GHRPs have been used to diagnose GH deficiency in children (93,102,127 (94); GHRP-2, 0.3-3 Ilg/ kg subcutaneously once daily, 6 months]. In each study, height velocity was increased about 2.5-3.0 crn!…”

Growth Hormone Secretagogues

“…GHRP-2 has been shown to be effective in stimulating GH secretion in adults and children via the oral, intranasal as well as the iv route of administration [13]. It was well tolerated, able to stimulate GH secretion and enhanced growth velocity without side effects or toxicities in an eight months trial of prepubertal children with growth failure [14].…”

Synthesis and Pharmacological Profile of an Orally-Active Growth Hormone Secretagogue, SM-130686

“…Since GH-replacement therapy for GH-deficient patients has been successful in the clinical application of rhGH, several groups have examined the clinical efficacy of GHS in this disease. Pihoker's group administered peptidyl GHS, GHRP-2 or GHRH to 24 children of short stature [41] and found that 21 children responded to GHRP-2 and to GHRH, and showed enhanced GH release, although these children seemed to be a heterogeneous group of patients. The Merck group has investigated GH responses to orally administered MK-677 in GH-deficient adults who had been treated with rhGH during their childhood and did not have a pituitary or hypothalamic tumor, and had not undergone surgery or radiotherapy.…”