hexarelin and beta-Thalassemia

Thalassemic patients today undergo intensive transfusion and chelation regimes that offer them prolonged survival and improved quality of life. Nevertheless, they face the consequences of chronic illness and therapies which affect multiple bodily functions. Endocrine derangements involve, among others, the GH-IGF-I axis with consequent impairment of growth. In such cases, GH release, as assessed with stimulation tests, may be normal whereas ultradian GH secretion seems to be subnormal. New GH secretagogues (GHRs) are agents that stimulate pituitary GH release by acting upon different receptors than the endogenous hypothalamic secretagogue, growth hormone-releasing hormone (GHRH). Examples are the growth hormone releasing peptides (GHRPs) GHRP-6, GHRP-1, GHRP-2, Hexarelin and the nonpeptidyl MK-0677. These can be administered by multiple routes, even per os or intranasally, thus obviating the need for injections. Their GH releasing capacity is more pronounced and prolonged than that of GHRH and their use is devoid of serious side effects. The most recently developed GHRs seem to be capable of producing sustained GH release in many cases and can thus be viewed as therapeutic candidates in cases of reduced GH secretion with intact pituitary, as seems to be the case in a group of thalassemic patients.

Topics: beta-Thalassemia; Growth Disorders; Growth Hormone-Releasing Hormone; Hormones; Human Growth Hormone; Humans; Indoles; Oligopeptides; Spiro Compounds

A significant percentage of children with beta-thalassemia major shows retardation in longitudinal growth as they progress towards puberty due to skeletal dysplasia, endocrine gland hypofunction or trace element deficiencies. The aim of this study was to evaluate GH/IGF-I secretion and action in prepubertal patients with beta-thalas-semia major. Eight prepubertal patients with short stature (group A) and seven prepubertal patients with normal stature (group B) were studied. Basal and stimulated (after administration of the hexapeptide Hexarelin) GH levels were measured with IRMA (Nichols); IGF-I and IGFBP-3 levels were measured with RIA (Nichols). IGF-I binding proteins (IGFBPs) were analyzed qualitatively with Western ligand blot. IGF-I binding to B-lymphocytes of the patients was also measured with competitive binding studies using human recombinant IGF-I and 125I-IGF-I (Amersham). Basal GH levels did not differ statistically between the groups. Peak GH levels after Hexarelin stimulation test were higher in group A (A: 27.9 +/- 15.6 ng/ml vs B: 9.1 +/- 4.7 ng/ml) (Wilcoxon test, p < 0.05). IGF-I levels in the two groups were low-normal and comparable (A: 168.0 +/- 81.6 ng/ml vs B: 126.6 +/- 25.5 ng/ml). IGFBP-3 levels were low in both groups (A: 1.21 +/- 0.27 microg/ml vs B: 1.08 +/- 0.20 microg/ml). Western ligand blot did not reveal any discernible difference in IGFBPs. However, IGF-I binding on B-lymphocytes was at least 20% lower in group A compared to group B (t-test, p < 0.01). IGF-I binding inversely correlated with peak GH levels (r = -0.54, p < 0.05). Patients in group A were older and chronological age correlated with IGF-I levels (r = 0.53, p < 0.05) whereas it inversely correlated with IGF-I binding (r = -0.63, p < 0.05). Moreover, patients in group A had higher ferritin levels. No correlation was found between ferritin levels, desferrioxamine dose/compliance or liver enzyme levels and the parameters of the GH axis studied. However, desferrioxamine dose x years correlated with IGFBP-3 (r = 0.56, p < 0.05) and correlated inversely with IGF-I binding (r = -0.74, p < 0.01). In conclusion, we have shown adequate GH secretion, higher secretive capacity after the administration of Hexarelin and lower IGF-I binding in prepubertal beta-thalassemic patients with short stature. Whatever the cause, reduced IGF-I action has to be considered when treating beta-thalassemic patients with short stature.

Topics: B-Lymphocytes; beta-Thalassemia; Body Height; Child; Female; Human Growth Hormone; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Male; Oligopeptides