sermorelin and Brain-Neoplasms

Previous studies have suggested that post-irradiation GH insufficiency results from a loss of GHRH secretion, since many patients were able to release GH following exogenous GHRH stimulation. However, supramaximal doses of GHRH were used and the response may decline with time after radiotherapy. We re-evaluated the GHRH dose-response curve in patients post cranial irradiation and in controls.. Randomized controlled study.. Five adult male long-term survivors of childhood brain tumours (median age 21.8 years (18.4-26.7); 13.7 years (11.4-15.7) post-radiotherapy, >30Gy) and five matched controls were studied. An intravenous bolus of GHRH(1-29)NH(2) was administered in doses at the lower (0.05 microg/kg) and upper (0.15 microg/kg) range of the dose-response curves for young males, as well as the standard supramaximal dose (1. 0 microg/kg). GH was measured before stimulation, every 2min for the first hour and every 5min for the second hour. All studies were conducted in a random fashion.. Significantly lower peak and area under the curve (AUC) GH concentrations occurred in the irradiated group using 0.15 microg/kg (median peak Irradiated, 4. 5mU/l vs median Controls, 37.4mU/l; P<0.01) and 1.0 microg/kg (median peak Irradiated, 4.8mU/l vs median Controls, 15.2mU/l; P<0. 05) GHRH(1-29)NH(2). In irradiated subjects there was an incremental rise in GH output with increasing doses of GHRH(1-29)NH(2 )(median AUC: 122mU/l.min vs 179mU/l.min vs 268mU/l.min; P=0.007) reflecting altered pituitary sensitivity and reduced responsiveness.. The GH response to bolus GHRH(1-29)NH(2) is attenuated in adult long-term survivors of childhood brain tumours. This may reflect direct pituitary damage and/or the loss of the tropic effects of chronic GHRH deficiency.

Topics: Adolescent; Adult; Brain Neoplasms; Human Growth Hormone; Humans; Male; Radiation Injuries; Reference Values; Sermorelin; Time Factors

Pulsatile GH release in humans is thought to involve the coordinated interaction of growth hormone-releasing hormone (GHRH) and somatostatin (SS). Disordered GH secretion is seen in most patients following high dose (> 30 Gy) cranial irradiation in childhood and could result from dysregulation of these hypothalamic hormones or reflect direct pituitary damage. We have used a peptide 'clamp' to assess the relative roles of continuous GHRH and intermittent SS in GH pulse generation in healthy volunteers and short-and long-term survivors of childhood brain tumours.. Randomized controlled study.. 12 adult male long-term survivors of childhood brain tumours (median age 17.0 years (15.2-19. 7); 12.2 years (5.8-14.0) postradiotherapy, > 30Gy whole brain irradiation) with 9 matched control volunteers and 6 short-term survivors of childhood brain tumours (median age 6.4 years (5.9-7. 7); 2.5 years (1.7-3.6) post radiotherapy, > 30Gy whole brain irradiation) with 6 matched controls (studies of spontaneous GH release alone).. Serum GH concentrations in 24 h spontaneous GH profiles and during three 'clamp' studies: continuous GHRH(1-29)NH2 (60 ng/kg/minutes, subcutaneous infusion, 24 h); intermittent SS(1-14) withdrawal (20microg/m2/hour, intravenous infusion, 3 h on/1 h off, 2-3 cycles over 8-12 h); intermittent SS and continuous GHRH combined (2-3 cycles over 8-12 h). Data were analysed by spectral analysis, 'peak' and 'trough' determination and serial array averaging.. In normal adults, discrete pulsatility was seen in all profiles of spontaneous GH secretion. Continuous GHRH amplified peak GH concentrations (median basal peak 21.1 mU/l vs. GHRH 62.0 mU/l, P = 0.008) whilst pulse timing remained unaffected. Rebound GH release following SS withdrawal alone was variable. Combining continuous GHRH with intermittent SS produced regular GH responses upon SS withdrawal (20.3 mU/l; range 2. 3-105.4). Heterogeneous patterns of spontaneous GH release were seen in the irradiated subjects. Spontaneous peak GH release was reduced in the children following irradiation (Irradiation 14.9 mU/l vs. Control 25.1 mU/l, P = 0.007). Peak GH concentrations were significantly amplified by GHRH in half of them. Adult long-term survivors had lower spontaneous GH concentrations and continuous GHRH amplified GH release in most subjects (Spontaneous 4.2 mU/l vs. GHRH 6.5 mU/l, P = 0.008) but peak concentrations remained far less than those of controls. Combining intermittent SS with continuous GHRH regularized GH release in many patients but the GH responses remained attenuated (4.6 mU/l; 2.5-17.5).. GH pulsatility can be generated in normal volunteers by the combination of continuous GHRH and intermittent SS and provides indirect evidence for a role for GHRH in GH synthesis and replenishment of stored GH pools at times of high SS tone. Patterns of GH release in short-and long-term survivors of childhood brain tumours are heterogeneous suggesting that combined hypothalamic deficiencies of GHRH and SS occur following high dose radiotherapy. The attenuated GH release seen in long-term survivors compared to controls suggests that GH secretory dysfunction does not simply reflect reduced GHRH and SS secretion, and that trophic effects or pituitary damage may be important with time.

Topics: Adolescent; Adult; Brain Neoplasms; Case-Control Studies; Cranial Irradiation; Humans; Male; Secretory Rate; Sermorelin; Somatostatin; Statistics, Nonparametric; Time Factors

The effects of new growth hormone-releasing hormone (GHRH) antagonists JMR-132 and MIA-602 and their mechanism of action were investigated on 2 human glioblastoma cell lines, DBTRG-05 and U-87MG, in vitro and in vivo. GHRH receptors and their main splice variant, SV1 were found on both cell lines. After treatment with JMR-132 or MIA-602, the cell viability decreased significantly. A major decrease in the levels of phospho-Akt, phospho-GSK3β and phosho-ERK 1/2 was detected at 5 and 10 min following treatment with the GHRH antagonists, whereas elevated levels of phospho-p38 were observed at 24 hr. The expression of caspase-3 and poly(ADP-ribose) (PARP), as the downstream executioners of apoptosis were found to be significantly elevated after treatment. Following treatment of the glioblastoma cells with GHRH antagonists, nuclear translocation of apoptosis inducing factor (AIF) and Endonuclease G (Endo G) and the mitochondrial release of cytochrome c (cyt c) were detected, indicating that the cells were undergoing apoptosis. In cells treated with GHRH antagonists, the collapse of the mitochondrial membrane potential was shown with fluorescence microscopy and JC-1 membrane potential sensitive dye. There were no significant differences between results obtained in DBTRG-05 or U-87MG cell lines. After treatment with MIA-602 and JMR-132, the reduction rate in the growth of DBTRG-05 glioblastoma, xenografted into nude mice, was significant and tumor doubling time was also significantly extended when compared with controls. Our study demonstrates that GHRH antagonists induce apoptosis through key proapoptotic pathways and shows the efficacy of MIA-602 for experimental treatment of glioblastoma.

Topics: Animals; Apoptosis; Brain Neoplasms; Cell Growth Processes; Cell Line, Tumor; Cell Survival; Glioblastoma; Growth Hormone-Releasing Hormone; Humans; Male; Membrane Potential, Mitochondrial; Mice; Mice, Nude; NIH 3T3 Cells; Protein Isoforms; Receptors, Neuropeptide; Receptors, Pituitary Hormone-Regulating Hormone; Sermorelin; Signal Transduction; Xenograft Model Antitumor Assays

A synthetic 29-amino acid analogue of human pancreatic GH-releasing hormone (GHRH(1-29)NH2) has recently been shown to stimulate the release of GH in normal subjects. We have studied the GH response to GHRH(1-29)NH2 in nine children irradiated for brain and nasopharyngeal tumours, who were not growing and were deficient in GH as assessed by insulin-induced hypoglycaemia. Serum GH rose in response to GHRH(1-29)NH2 in all the children, and in five the peak serum GH response was greater than 20 mu./l. The data suggest that when hypothalamo-pituitary irradiation results in GH deficiency, this is due to a failure of the synthesis or delivery of endogenous GHRH from the hypothalamus to the pituitary cells. It also suggests that it may be possible to treat such children using synthetic GHRH in place of exogenous GH.

Topics: Body Height; Brain Neoplasms; Child; Child, Preschool; Female; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Hypothalamus; Male; Nasopharyngeal Neoplasms; Peptide Fragments; Pituitary Gland; Sermorelin

We have assessed the role of growth hormone-releasing hormone (GHRH) as a diagnostic test in 40 children and young adults with growth hormone deficiency (GHD), principally using the GHRH(1-29)NH2 analogue. Following 200 micrograms GHRH as an acute intravenous bolus, serum GH rose to normal or just subnormal levels in 13 out of 17 children with structural lesions, and in 8 of 14 patients with idiopathic GHD or panhypopituitarism. Of 9 children (mean age 12 years) with GHD following treatment with cranial irradiation for nonendocrine tumours, all responded acutely to GHRH. 12- and 24-hour infusions with GHRH(1-29)NH2, and 1- and 2-week treatments with twice-daily subcutaneous GHRH(1-29)NH2, showed persistent stimulation of GH release. It is concluded that many children with GHD of diverse aetiology will respond both acutely and chronically to treatment with GHRH.

Topics: Adolescent; Adult; Body Height; Brain Neoplasms; Child; Child, Preschool; Growth Disorders; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Hypopituitarism; Insulin-Like Growth Factor I; Peptide Fragments; Sermorelin; Somatomedins