Sermorelin (GHRH (1-29))

The GH response to low-dose bolus growth hormone-releasing hormone (GHRH(1-29)NH2) is attenuated in patients with longstanding post-irradiation GH insufficiency

Objective: 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. Design: Randomized controlled study. Methods: 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. Results: 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. Conclusion: 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.

Agonist of growth hormone-releasing hormone enhances retinal ganglion cell protection induced by macrophages after optic nerve injury

Optic neuropathies are leading causes of irreversible visual impairment and blindness, currently affecting more than 100 million people worldwide. Glaucoma is a group of optic neuropathies attributed to progressive degeneration of retinal ganglion cells (RGCs). We have previously demonstrated an increase in survival of RGCs by the activation of macrophages, whereas the inhibition of macrophages was involved in the alleviation on endotoxin-induced inflammation by antagonist of growth hormone-releasing hormone (GHRH). Herein, we hypothesized that GHRH receptor (GHRH-R) signaling could be involved in the survival of RGCs mediated by inflammation. We found the expression of GHRH-R in RGCs of adult rat retina. After optic nerve crush, subcutaneous application of GHRH agonist MR-409 or antagonist MIA-602 promoted the survival of RGCs. Both the GHRH agonist and antagonist increased the phosphorylation of Akt in the retina, but only agonist MR-409 promoted microglia activation in the retina. The antagonist MIA-602 reduced significantly the expression of inflammation-related genes Il1b, Il6, and Tnf Moreover, agonist MR-409 further enhanced the promotion of RGC survival by lens injury or zymosan-induced macrophage activation, whereas antagonist MIA-602 attenuated the enhancement in RGC survival. Our findings reveal the protective effect of agonistic analogs of GHRH on RGCs in rats after optic nerve injury and its additive effect to macrophage activation, indicating a therapeutic potential of GHRH agonists for the protection of RGCs against optic neuropathies especially in glaucoma.

Continuous subcutaneous GHRH(1-29)NH2 promotes growth over 1 year in short, slowly growing children

We have treated eight pre-pubertal children with partial GH insufficiency with continuous subcutaneous infusions of GHRH(1-29)NH2 at a dose of 60 ng/kg/min for periods of up to 1 year. In five children treated for 1 year, mean growth velocity increased from 4.6 cm/year (range 4.4-5.2) to 7.0 cm/year (5.7-8.7) (P = 0.04). Three children treated for 3-6 months showed similar height velocity increases. A return to pretreatment growth rates was seen after cessation of treatment in all children. Twenty-four-hour GH profiles performed at intervals of 3 months showed sustained augmentation of pulsatile GH secretion without evidence of desensitization. The presence of pulsatile GH secretion during continuous GHRH administration provides strong evidence in man for the role of somatostatin in determining GH pulse frequency. The ability of the pituitary to respond to a supramaximal bolus of GHRH remained constant during the treatment. Continuous administration of GHRH(1-29)NH2 will become a practicable treatment when formulated into a sustained release or depot preparation. We have shown this to be an effective therapy for some short, slowly growing children. Further studies are required to establish the optimal dosage regimen.

Treatment with GHRH(1-29)NH2 in children with idiopathic short stature induces a sustained increase in growth velocity

Objective: Therapy with GHRH in patients with mild GH insufficiency appears to be more effective than in those with severe insufficiency. We, therefore, studied the clinical response of children with idiopathic short stature to treatment with GHRH(1-29)NH2 (GHRHa) for a period of 12 months.
Design: Eighteen short pre-pubertal children (aged 4.3-11.0 years, 17 male) with idiopathic short stature (height < 3rd centile, peak GH to provocative testing > 20 mU/l) were recruited to receive GHRHa 20 micrograms/kg by twice daily s.c. injection for one year. One patient was non-compliant and was withdrawn prior to 3 months of therapy. Pretreatment height velocity was calculated for 12 months and subjects were measured 3-monthly during therapy. Overnight GH profiles and s.c. GHRH tests (20 micrograms/kg) were performed at 0, 3, 6 and 12 months of therapy. In addition, an i.v. GHRH test (1 microgram/kg) was performed at the start and after 1 month of therapy.
Measurements: Overnight GH profiles were analysed using the Pulsar program.
Results: Mean (SD) height velocity (HV) increased from 4.8(0.9)cm/year pre-treatment to 7.2(1.6)cm/year after 12 months of therapy (P = 0.001). The children growing slowly (HV < 25th centile) before treatment had a greater growth response than those growing normally (HV > or = 25th centile) before treatment. Final height prediction increased by a mean (SD) of 3.4(2.6)cm. Overnight GH levels and GH responses to GHRH testing fell during the 12 months of therapy. Fasting blood glucose and insulin levels increased during therapy, as did IGF-I. Cessation of GHRHa was followed by catch-down growth during the first 3 months off therapy: mean (SD) HV 3.89(1.82)cm/year (P < 0.04), although the HV after 6 months (4.9(1.0))cm/year) and 12 months (4.4(1.0)cm/year) was not different from pretreatment values.
Conclusions: Short-term therapy with twice-daily s.c. injection of GHRHa (20 micrograms/kg) promoted linear growth in short children who were not GH-insufficient. The improved height velocity was sustained throughout the 12 months of treatment, followed by catch-down growth, and returned to pretreatment velocity after cessation of therapy.

Growth response to growth hormone-releasing hormone(1-29)-NH2 compared with growth hormone

To assess the growth-promoting effect of different doses of growth hormone-releasing hormone(1-29)-NH2 (GHRH(1-29)-NH2) in GH deficiency (GHD) of hypothalamic origin, 43 prepubertal children aged between 4.3 and 18.9 years (mean 10.4 +/- 2.9 years) were randomly assigned to three treatment regimens: low-dose GHRH(1-29)-NH2 (LD group; n = 15), high-dose GHRH(1-29)-NH2 (HD group; n = 12) and GH (GH group; n = 16). The LD group received GHRH(1-29)-NH2 at 30 micrograms/kg/day s.c. in three daily doses, the HD group received 60 micrograms/kg/day s.c. in three daily doses and the GH group received GH, 0.1 IU/kg/day s.c. once daily. All children were treated for a period of 6 months. Evaluation included anthropometry, bone age, intravenous and subcutaneous GHRH(1-29)-NH2 tests and determination of insulin-like growth factor I (IGF-I) levels. An increase in height velocity of 2 cm/year or more was observed in all except two children. Height velocity during treatment was lowest in the LD group, but comparable in the HD and GH groups. An increase in height SDS for bone age occurred only in the GH-treated group. GH responses to intravenous GHRH(1-29)-NH2 showed a priming effect of the LD GHRH(1-29)-NH2 treatment, while a decrease in response occurred in the GH-treated group. Following a subcutaneous test dose of one-third of the daily dose of GHRH(1-29)-NH2, GH levels remained unchanged in both the LD and HD groups. There was accumulation of GHRH immunoreactivity over time in the HD group, but there was no correlation between measured GHRH and GH levels.(ABSTRACT TRUNCATED AT 250 WORDS)