hexarelin and Growth-Disorders

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

Hexarelin (HEX), a synthetic hexapeptide with a strong GH-stimulating activity, has been suggested as a stimulus for evaluating GH secretion. However, in childhood it has never been compared with other stimuli capable to reduce the effect of the somatostatinergic tone and of the low production of gonadal steroids.. We evaluated GH response (expressed as the maximum value after stimulus [Cmax] and as area under the curve [AUC], mean +/- SD) to HEX at a dose of 2 micrograms/kg i.v., in comparison with those obtained after GHRH (1 microgram/kg i.v.) + pyridostigmine (PD, 60 mg p.o.) and arginine + ethynylestradiol (E2, 1 mg/day p.o. for 3 days before the test), in 5 subjects with familial short stature (FSS), 11 with constitutional growth delay (CGD), prepubertal (Tanner's stage I) and early pubertal (stage II), and in 8 healthy children age-matched as controls.. HEX induced a Cmax of 31.9 +/- 18.4 micrograms/l and an AUC of 1511 +/- 923 micrograms/min x l in stage I, of 36.7 +/- 12.3 micrograms/l and 1938 +/- 903 micrograms/min x l in stage II (ns). GHRH + PD induced a Cmax of 33.8 +/- 14.6 micrograms/l and an AUC of 2072 +/- 1233 micrograms/min x l in stage I, of 29.6 +/- 15.6 micrograms/l and 1901 +/- 1252 micrograms/min x l in stage II (ns). ARG + E2 induced a Cmax of 17.8 +/- 7 micrograms/l and an AUC of 1157 +/- 505 micrograms/min x l in stage I, of 15.6 +/- 11.6 micrograms/l and 649 +/- 452 micrograms/min x l in stage II (ns). The Cmax of HEX was higher than that of ARG + E2 in both stages I and II (p < 0.05); AUC of HEX, was higher than that of ARG + E2 only in stage II (p < 0.01); the Cmax and the AUC of GHRH + PD were higher than those of ARG + E2 both in stage I (p < 0.01 and p < 0.05, respectively) and in stage II (p < 0.05). No difference, neither in the extent of GH response to HEX and GHRH + PD nor in that to stimuli between subjects and controls, was found. HEX has given 32% false positives in stage I and 17% in stage II, GHRH + PD 12% and 15%, while ARG + E2 provided 20% in stage I and 32% in stage II. On the whole, specificity was 76% for HEX and ARG + E2 and 89% for GHRH + PD.. HEX induced greater GH response than that of ARG + E2 but similar to that of GHRH + PD and its specificity was not different to that of ARG + E2 and lower than that of GHRH + PD: then its use does not show a diagnostic advantage in respect to the other two stimuli in peripubertal age.

Topics: Adolescent; Area Under Curve; Arginine; Child; Drug Interactions; Estrogens; Female; Growth Disorders; Growth Hormone-Releasing Hormone; Growth Substances; Human Growth Hormone; Humans; Male; Oligopeptides; Puberty; Pyridostigmine Bromide

A clinical, prospective experiment was carried out to determine whether long-term intranasal administration of the growth hormone-releasing peptide hexarelin (His-D-2-methyl-Trp-Ala-Trp-D-Phe -Lys-NH2) affects pituitary growth hormone secretion. Hexarelin (60 micrograms/kg t.i.d.) was administered to seven prepubertal constitutionally short children (mean age +/- SD = 7.6 +/- 2.4 years). Serum human growth hormone (hGH) response to an intranasal (20 micrograms/kg) and i.v. (1 mircogram/kg) bolus of hexarelin before, during and after 6-10 months of treatment was measured. The mean ( +/- SD) peak rise of hGH to the intranasal bolus before treatment was 70.6 +/- 28.2 mU/l. After 7 days of hexarelin treatment, mean peak values dropped to 34.1 +/- 15.7 mU/l (p < 0.002) and thereafter remained constant for 6 months of treatment at 37.5 +/- 10.3 mU/l (p < 0.03). The pretreatment peak to th i.v. hexarelin bolus was 84.8 +/- 52.5 mU/l, and at the end of the treatment period it was 19.8 +/- 10.9 mU/l (p < 0.05). Three months after stopping treatment the mean ( +/- SD) hGH response rose to 42.1 +/- 4.7 mU/l (p < 0.005). Growth velocity increased from 5.3 +/- 0.9 cm/year (before treatment) to 7.4 +/- 1.6 cm/year at 6-10 months of treatment (p < 0.005). In conclusion, teh partial suppression of pituitary hGH responsiveness to long-term intranasal hexarelin treatment, probably due to desensitization, does not affect the observed increase in growth velocity.

Topics: Administration, Intranasal; Body Height; Child; Child, Preschool; Drug Tolerance; Female; Growth Disorders; Growth Hormone; Growth Substances; Humans; Injections, Intravenous; Male; Oligopeptides; Time Factors

Hexarelin is a recently synthesized small growth hormone releasing peptide (GHRP) (His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys- NH2). It is active by intravenous, oral and intranasal administration in animals and man. The aim of this study was to find out whether long-term administration of this peptide would promote growth in short children.. Intranasal hexarelin was administered in a dose of 60 micrograms/kg thrice daily to 8 prepubertal short children aged 4-11.6 years for periods of up to 8 months.. Hexarelin treatment stimulated insulin-like growth factor-I (IGF-I) secretion raising the level from 10.4 +/- 3.9 (SD) to 14.1 +/- 4.6 nmol/l (P < 0.004). The rise in IGF-I led to a significant increase in the mean (+/- SD) linear growth velocity from 5.3 +/- 0.8 to 8.3 +/- 1.7 cm/year (P < 0.0001). There was also a significant decrease in skinfold thickness despite increase in body weight and an increase in head circumference. Additional findings were a rise in serum phosphate from 1.5 +/- 0.1 to 1.8 +/- 0.1 mmol/l (P < 0.004) and of alkaline phosphatase from 219 +/- 74 to 261 +/- 75 U/l (P < 0.05).. The long-term GH/IGF-I stimulating, anabolic and growth promoting effects achieved by intranasal administration of this hexapeptide, seemingly without undesirable side-effects, suggests clinical potential for this new class of drugs.

Topics: Administration, Intranasal; Alkaline Phosphatase; Body Weight; Cephalometry; Child; Child, Preschool; Drug Administration Schedule; Female; Growth Disorders; Growth Substances; Hormones; Humans; Insulin-Like Growth Factor I; Male; Oligopeptides; Phosphates; Skinfold Thickness; Stimulation, Chemical

Elevated serum lipoprotein(a) (Lp(a)) is a strong risk factor for coronary artery disease (CAD). Genetic factors appear to account for the major variance in Lp(a) levels but the contribution hormones make in modulating Lp(a) levels is not yet clear. In the present investigation we determined the effects of human growth hormone (hGH) and insulin-like growth factor-I (IGF-I) on circulating Lp(a).. Four groups of patients were studied. Group a: adults with GH deficiency (n = 7) treated with hGH (0.05 U/kg/day, s.c.); group b: girls with Turner syndrome (n = 7) treated with hGH (0.1 U/kg/day, s.c.); group c: prepubertal boys with idiopathic short stature (n = 6) treated with the GH secretagogue (GHRP) hexarelin (60 micrograms t.i.d. intranasally); group d: Laron syndrome patients (n = 10) treated with IGF-I (100-200 micrograms/kg/day, s.c.). Following overnight fasting, serum was sampled before the initiation of treatment and during 6-9 months treatment.. Serum IGF-I rose significantly in all the subjects in all four groups. In the first three groups in which IGF-I was elevated by exogenous or endogenous GH stimulation, serum Lp(a) increased significantly (119 +/- 35%, P < 0.01; 126 +/- 44%, P < 0.05; 102 +/- 29%, P < 0.01 for groups a, b, and c respectively). By contrast, serum Lp(a) levels decreased in group d to whom exogenous IGF-I was administered (-66 +/- 5%, P < 0.001). The differential effect of endogenous vs exogenous IGF-I on serum Lp(a) paralleled the behaviour of serum insulin. Insulin was significantly increased in all the subjects receiving hGH or GHRP (65.2 +/- 31%, P = 0.109; 93.7 +/- 53%, P = 0.062; 353.8 +/- 52.7%, P < 0.01 for groups a, b, and c respectively) whereas insulin levels were reduced following exogenous administration of IGF-I (-34.1 +/- 9.1%, P < 0.01).. We conclude that long-term GH treatment increases and IGF-I decreases circulating levels of Lp(a). These findings may have clinical relevance in view of the increasing use of hGH in children and adults and the role of Lp(a) as a CAD risk factor.

Topics: Adult; Aging; Child; Coronary Disease; Female; Growth Disorders; Growth Hormone; Growth Hormone-Releasing Hormone; Growth Substances; Humans; Incidence; Insulin; Insulin-Like Growth Factor I; Lipoprotein(a); Male; Oligopeptides; Recombinant Proteins; Risk Factors

Hexarelin is a new synthetic growth hormone releasing peptide. We have tested the efficacy of intranasal (i.n.) administration of hexarelin to stimulate plasma GH and have compared this to the intravenous (i.v.) administration of the peptide.. Ten children with familial short stature (FSS) aged 5.5-15.5 years and two known GH deficient patients aged 24 and 28 years without GH treatment.. All 12 subjects were submitted to i.v. (1 microgram/kg) and i.n. (20 micrograms/kg) hexarelin tests with a one-week interval between tests. Blood samples for GH, TSH, fT4 and T3 were obtained at 0, 15, 30, 60, 90 and 120 minutes. The hormone determinations were made by standard radio-immunoassays (RIA).. Both the i.n. and i.v. administration of hexarelin induced a large GH response, the mean (+/- SD) being 72.2 +/- 35.5 mU/l for the i.n. test and 79.6 +/- 53.0 mU/l for the i.v. test. The peak GH in the i.v. test occurred at 15-30 minutes and in the i.n. test between 30 and 60 minutes. The GH deficient patients showed no GH response in either test. Plasma TSH decreased in the FSS children from a mean (+/- SD) of 1.0 +/- 0.26 to 0.64 +/- 0.2 mU/l (P < 0.005) during the i.n. test and from 1.0 +/- 0.3 to 0.7 +/- 0.3 mU/l (P < 0.05) during the i.v. test. In the isolated GH deficient patient, plasma TSH decreased from 1.06 +/- 0.38 mU/l to 0.86 +/- 0.17 during the i.v. test and from 1.60 +/- 0.01 to 1.11 +/- 0.06 mU/l during the i.n. test. There were no significant changes in plasma fT4 or T3 in any of the tests.. The synthetic hexapeptide hexarelin is a potent pituitary GH stimulator when administered intranasally. The GH response was similar to that observed after intravenous hexarelin. Simultaneously, there was a significant decrease in plasma TSH but the concentrations remained in the normal range. These findings appear to be of theoretical and practical relevance to the investigation and management of short children.

Topics: Administration, Intranasal; Adolescent; Child; Child, Preschool; Female; Growth Disorders; Growth Hormone; Growth Substances; Hormones; Humans; Injections, Intravenous; Male; Oligopeptides; Thyrotropin