Hexarelin-induced growth hormone, cortisol, and prolactin release: a dose-response study.

Dose-response data for GH-releasing peptides are limited. We studied the effects of varying doses (0-1.0 microgram/kg) of hexarelin, a novel GH-releasing peptide, administered iv to healthy adult males on GH, PRL, and cortisol release. In addition, we studied the effect of administration of a single dose of GHRH-(1-29)-NH2 (1.0 microgram/kg), alone or in combination with a low dose of hexarelin (0.125 microgram/kg). Dose-response curves for the maximum GH response and maximum percent change in serum PRL and cortisol concentrations from baseline were constructed. The GH dose-response curve reached a plateau of 140 mU/L, corresponding to a hexarelin dose of 1.0 microgram/kg, with an ED50 of 0.48 +/- 0.02 microgram/kg (mean +/- SEM). The PRL dose-response curve reached a plateau of 180% for the maximum percent rise from baseline, corresponding to a hexarelin dose of 1.0 microgram/kg, with an ED50 of 0.39 +/- 0.02 microgram/kg. The cortisol dose-response curve showed a step increase to approximately 40% at a hexarelin dose of 0.5 microgram/kg. The coadministration of GHRH-(1-29)-NH2 (1.0 microgram/kg) and low dose hexarelin (0.125 microgram/kg) resulted in massive GH release (115 +/- 32.8 mU/L), a moderate rise in serum PRL (84.9 +/- 27.5%), and no rise in serum cortisol. These data show that iv hexarelin was capable of inducing GH, PRL, and cortisol release in a dose-dependent manner. Low dose hexarelin was synergistic with GHRH and potent for GH release with a minimal effect on other hormones.

Cardiomyopathy in propionic acidaemia.

Following the death of a patient with propionic acidaemia with a cardiomyopathy we reviewed 19 patients with the same disorder for evidence of cardiomyopathy. Six patients were found to meet the diagnostic criteria. Three patients died and in the other three the cardiac disease resolved completely. All patients were treated with standard therapy and some received L-carnitine but this did not seem to influence the eventual outcome. Cardiomyopathy is an important complication of propionic acidaemia and may be rapidly fatal.

Interaction of the growth hormone releasing peptide hexarelin with somatostatin.

OBJECTIVE: Growth hormone releasing peptides (GHRPs) are potent growth hormone (GH) secretagogues. Their interaction with growth hormone releasing hormone (GHRH) has been studied extensively. Data on their interaction with somatostatin (SS) are limited. The aim of this study was to determine the effect of changing SS tone and the effects of SS withdrawal on the somatotroph response to hexarelin and GHRH, alone or in combination. In addition, we studied the effect of SS on the prolactin (PRL) and cortisol response to hexarelin. DESIGN: Boluses of saline, hexarelin (1 microgram/kg), GHRH-(1-29)-NH2 (1 microgram/kg) or hexarelin plus GHRH-(1-29)-NH2 were administered intravenously 1 hour after the start of a 3-hour constant intravenous infusion of saline, SS(1-14) (20 micrograms/m2/h) (SS20) or SS(1-14) (50 micrograms/m2/h) (SS50). In a second group of studies, the same boluses as above were administered intravenously at the time of withdrawal of a 3-hour constant intravenous infusion of saline or SS20. In a subset of the second group of studies, saline, hexarelin (0.5 microgram/kg) or GHRH-(1-29)-NH2 (0.5 microgram/kg) was administered intravenously two hours before the withdrawal of the SS(1-14) infusion, which was administered at a higher dose of 50 micrograms/m2/h. Studies were performed in a random order. SUBJECTS: Twelve healthy adult males (20.3-34.6 years) were studied. MEASUREMENTS: Serum GH and PRL concentrations were measured by immunoradiometric assays. Serum cortisol concentrations were measured by radioimmunoassay. RESULTS: Infusion of SS20 resulted in a significant reduction in the peak GH response to hexarelin, GHRH-(1-29)-NH2 or hexarelin plus GHRH-(1-29)-NH2 (P < 0.05). The peak serum GH concentrations following the intravenous administration of the two secretagogues, separately or in combination, were reduced further by the higher dose of SS50, but these were not significantly different from their respective peak serum GH concentrations obtained during the infusion of SS20. The peak serum GH concentration following the intravenous administration of hexarelin plus GHRH-(1-29)-NH2 remained large (52.6 +/- 7.2 mU/l; mean +/- SEM) despite the high dose of SS(1-14) (50 micrograms/m2/h). SS(1-14) did not affect the PRL and cortisol response to hexarelin. Withdrawal of SS20 infusion at the time of intravenous bolus administration of hexarelin, but not GHRH-(1-29)-NH2 or hexarelin plus GHRH-(1-29)-NH2, resulted in a significant increase in peak serum GH concentration (P = 0.03). The intravenous administration of hexarelin (0.5 microgram/kg) or GHRH-(1-29)-NH2 (0.5 microgram/kg) during an intravenous infusion of SS50 resulted in a small GH response (peak concentrations 6.8 +/- 3.6 mU/l and 2.4 +/- 0.5 mU/l, respectively) but the later withdrawal of the infusion was not followed by a rise in serum GH concentrations. CONCLUSIONS: This study shows that SS and hexarelin counteract their respective inhibitory and stimulatory action on GH secretion and provides further evidence for their interaction in vivo. The stimulatory effect of hexarelin on the lactotroph and the hypothalamo-pituitary-adrenal axis is unaltered by SS. Hexarelin plus GHRH are synergistic and have potent GH-releasing activity despite a high dose SS infusion. Withdrawal of SS enhances the GH response to hexarelin, which may reflect simultaneous endogenous GHRH release synergizing with hexarelin. A single cycle of pretreatment with hexarelin during SS infusion is insufficient to allow synthesis and storage of sufficient GH to influence its release following SS withdrawal. These findings add further to the data already gathered about GHRPs and their complex interaction with the main regulators of GH secretions.

Hexarelin induced growth hormone release is influenced by exogenous growth hormone.

OBJECTIVE: Growth hormone releasing peptides (GHRPs) are a group of synthetic compounds capable of releasing GH by an unknown mechanism. The aim of this study was to determine the effect of administering biosynthetic human growth hormone (rhGH) on the GH releasing activity of hexarelin, a new and potent GHRP, and to compare the results with those obtained with growth hormone releasing hormone (GHRH). DESIGN: Boluses of saline or rhGH were administered intravenously, followed 90 minutes later by a second intravenous bolus of saline, hexarelin or GHRH. Studies were performed following an overnight fast. Each subject underwent six studies performed in a random order and separated by at least 2 days. SUBJECTS: Six healthy adult males (23.8-34.3 years) were studied. MEASUREMENTS: Serum GH and IGF-I levels were measured by radioimmunoassay. RESULTS: The peak serum GH response to hexarelin was greater than that to GHRH, irrespective of whether the first bolus was saline (P < 0.05) or rhGH (P < 0.02). Prior administration of rhGH led to a reduction in peak serum GH response to hexarelin or GHRH (P < 0.05); the percentage reduction in response to hexarelin was less than that to GHRH, but this difference was not statistically significant (P = 0.3). There was no change in serum IGF-I concentration before or 90 minutes after the administration of rhGH. CONCLUSIONS: Hexarelin is a potent GH secretagogue subject to partial feedback inhibition by rhGH. This raises issues about its mechanism of action and may have implications for its potential therapeutic use.

Transsphenoidal surgery for pituitary tumours.

OBJECTIVES: Transsphenoidal surgery (TSS) is the preferred method for the excision of pituitary microadenomas in adults. This study was carried out to establish the long term efficacy and safety of TSS in children. STUDY DESIGN: A 14 year retrospective analysis was carried out on 23 children (16 boys and seven girls), all less than 18 years of age, who had undergone TSS at our centre. RESULTS: Twenty nine transsphenoidal surgical procedures were carried out. The most common diagnosis was an adrenocorticotrophic hormone (ACTH) secreting adenoma (14 (61%) patients). The median length of follow up was 8.0 years (range 0.3-14.0 years). Eighteen (78%) patients were cured after the first procedure. No death was related to the operation. The most common postoperative complication was diabetes insipidus, which was transient in most patients. Other complications were headaches in two patients and cerebrospinal fluid leaks in two patients. De novo endocrine deficiencies after TSS in children were as follows: three (14%) patients developed panhypopituitarism, eight (73%) developed growth hormone insufficiency, three (14%) developed secondary hypothyroidism, and four (21%) developed gonadotrophin deficiency. Permanent ACTH deficiency occurred in five (24%) patients, though all patients received postoperative glucocorticoid treatment until dynamic pituitary tests were performed three months after TSS. CONCLUSIONS: TSS in children is a safe and effective treatment for pituitary tumours, provided it is performed by surgeons with considerable experience and expertise. Surgical complications are minimal. Postoperative endocrine deficit is considerable, but is only permanent in a small proportion of patients.

The effect of repeated administration of hexarelin, a growth hormone releasing peptide, and growth hormone releasing hormone on growth hormone responsivity.

OBJECTIVE: Hexarelin is a synthetic six-amino-acid compound capable of releasing GH in animals and in man. Its mechanism of action is not understood and little is known about the GH response after repeated administration. The aim of this study was to determine the GH response to the administration of two intravenous boluses of hexarelin, growth hormone releasing hormone (GHRH) or hexarelin with GHRH. DESIGN: Single boluses of hexarelin (1 microgram/kg), GHRH-(1-29)-NH2 (1 microgram/kg) or hexarelin with GHRH-(1-29)-NH2 were administered intravenously. Each study was performed on two further occasions, with a second bolus being administered 60 or 120 minutes after the first. A control study was performed giving saline intravenously. Studies were performed in a random order. SUBJECTS: Six healthy adult males (25.4-34.1 years) were studied. MEASUREMENTS: Serum GH was measured by radioimmunoassay. GH secretion rates were derived from the measured serum GH concentrations using the technique of deconvolution analysis. RESULTS: The peak GH secretion rate following the first intravenous bolus of hexarelin was greater than that following the first bolus of GHRH-(1-29)-NH2 (P < 0.001), and was greatest following the administration of hexarelin with GHRH-(1-29)-NH2 (P < 0.001). The coadministration of the two secretagogues resulted in peak GH secretion rates significantly greater than the arithmetic sum of those following their isolated administration (P = 0.001), demonstrating synergism. Compared to saline, the administration of a second bolus of hexarelin, GHRH-(1-29)-NH2 or both resulted in significant further GH secretion (P = 0.02, P = 0.002, P = 0.03, respectively). The administration of a second bolus of hexarelin or hexarelin with GHRH-(1-29)-NH2 120 minutes after the first bolus resulted in lower peak GH secretion rates (P = 0.03). The reductions in peak GH secretion rates following the 60-minute boluses were not statistically significant. The peak GH secretion rates following the first GHRH-(1-29)-NH2 boluses were similar to those following the 60 and 120-minute GHRH-(1-29)-NH2 boluses (P = NS). Irrespective of the interval between the boluses of hexarelin with GHRH-(1-29)-NH2, the peak GH secretion rates following the second boluses were not significantly different from the arithmetic sum of those following the administration of the second boluses of hexarelin or GHRH-(1-29)-NH2, indicating loss of synergism on repeated administration. CONCLUSION: This study shows that hexarelin is a potent GH secretagogue active after two successive doses; the magnitude of the GH response to the second dose was influenced by the dosing interval. Hexarelin and GHRH-(1-29)-NH2 are synergistic, a property which is lost after repeated administration. These findings may help our understanding of GHRPs and may have implications for the potential use of hexarelin and other GHRPs as therapeutic agents.

Direct effects of corticotrophin-releasing hormone on stimulated growth hormone secretion.

OBJECTIVE: This study evaluated the effect of corticotrophin-releasing hormone (CRH) on growth hormone releasing hormone (GHRH)-stimulated growth hormone (GH) release in man. DESIGN: Six healthy adult volunteers (age 20-35 years) were studied. On different occasions they each received an intravenous bolus of saline, CRH(1-41) (100 micrograms), adrenocorticotrophic hormone (ACTH) [Synacthen (500 ng/m2)] or hydrocortisone (50 mg), followed 30 minutes later by an intravenous bolus of either GHRH-(1-29)-NH2 (1.0 microgram/kg) or saline. MEASUREMENT: Serum GH concentrations were measured using an immunoradiometric assay, and cortisol concentrations were measured by commercial radioimmunoassay. TSH concentrations were measured using a solid phase immunoradiometric assay kit. RESULTS: Pretreatment with CRH(1-41) attenuated the GH response to GHRH [saline/GHRH-(1-29)-NH2 20.2 +/- 6.2 mU/l; CRH(1-41)/GHRH-(1-29)-NH2 10.9 +/- 2.8 mU/l (P = 0.01)]. This effect was not due to the rise in ACTH or cortisol induced by CRH(1-41), since pretreatment with either ACTH or hydrocortisone significantly augmented the GH response to GHRH-(1-29)-NH2 in the same subjects [ACTH/GHRH-(1-29)-NH2 30.3 +/- 8.8 mU/l (P = 0.01); hydrocortisone/GHRH-(1-29)-NH2 36.4 +/- 11.2 mU/l (P = 0.02)]. CONCLUSION: Our data suggest that the inhibitory effect of CRH(1-41) on GHRH-(1-29)-NH2-induced GH release is not a result of ACTH or cortisol release but reflects a direct action of CRH on GH secretion, possibly via stimulation of somatostatin release. The acute rise in GH following glucocorticoid administration could be explained in part by a rapid suppression of endogenous CRH.

Non-expression of a common mutation in the 21-hydroxylase gene: implications for prenatal diagnosis and carrier testing.

Mutation analysis in the family of a child with 21-hydroxylase deficiency showed that the father and affected child were homozygous for a mutation, A/C655G, believed to activate a cryptic splice site in intron 2 of the 21-hydroxylase gene. The father, who was clinically asymptomatic, showed no biochemical evidence of disease. These results create problems for the management of future pregnancies in such families and for the interpretation of the risk associated with carrier status for this mutation.

Production and disposal of medium-chain fatty acids in children with medium-chain acyl-CoA dehydrogenase deficiency.

The effect of fasting on plasma concentrations of fatty acids has been determined in four children with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. In addition, the in vivo rate of octanoate oxidation was measured, using [1-13C]octanoate. In the three older children (1.5-11.2 years), fasting for up to 18 h stimulated lipolysis, as reflected by the increasing concentration of free fatty acids, but with little rise in concentrations of medium-chain fatty acids, octanoate, decanoate and cis-4-decenoate. In an infant (0.5 year), lipolysis was greater and was accompanied by rising concentrations of medium-chain fatty acids. After 13.5 h there was a rapid increase in the concentration of decanoate and cis-4-decenoate. The calculated in vivo rate of octanoate oxidation was substantial in all patients studied (6.4-13.1 mumol/kg per h) despite very low MCAD activity in vitro. It is concluded that under basal conditions the in vivo oxidation rate of medium-chain fatty acids is near normal in the four children studied with MCAD deficiency.