The relative roles of continuous growth hormone-releasing hormone (GHRH(1-29)NH2) and intermittent somatostatin(1-14)(SS) in growth hormone (GH) pulse generation: studies in normal and post cranial irradiated individuals.
Achermann JC., Hindmarsh PC., Robinson IC., Matthews DR., Brook CG.
OBJECTIVES: 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. DESIGN: Randomized controlled study. PATIENTS: 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). MEASUREMENTS: 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. RESULTS: 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). CONCLUSION: 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.