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

OBJECTIVES Pulsatile GH release in humans is thought to involve the coordin ated interaction of growth hormone-releasing hormone (GHRH) and somatostati n (SS). Disordered GH secretion is seen in most patients following high dos e (>30 Gy) cranial irradiation in childhood and could result from dysregula tion 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 (medi an age 17.0 years (15.2-19.7); 12.2 years (5.8-14.0) postradiotherapy, >30G y whole brain irradiation) with 9 matched control volunteers and 6 short-te rm 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 24h spontaneous GH profiles and dur ing three 'clamp' studies: continuous GHRH(1-29)NH2 (60 ng/kg/minutes, subc utaneous infusion, 24h); intermittent SS(1-14) withdrawal (20 mu g/m(2)/hou r, intravenous infusion, 3h on/1h off, 2-3 cycles over 8-12h); intermittent SS and continuous GHRH combined (2-3 cycles over 8-12 h). Data were analys ed 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 timi ng remained unaffected. Rebound GH release following SS withdrawal alone wa s variable. Combining continuous GHRH with intermittent SS produced regular GH responses upon SS withdrawal (20.3 mU/l; range 2.3-105.4). Heterogeneou s patterns of spontaneous GH release were seen in the irradiated subjects. Spontaneous peak GH release was reduced in the children following irradiati on (Irradiation 14.9 mU/l vs. Control 25.1 mU/l, P=0.007). Peak GH concentr ations were significantly amplified by GHRH in half of them. Adult long-ter m survivors had lower spontaneous GH concentrations and continuous GHRH amp lified 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 m any 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 comb ination of continuous GHRH and intermittent SS and provides indirect eviden ce 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 su rvivors of childhood brain tumours are heterogeneous suggesting that combin ed hypothalamic deficiencies of GHRH and SS occur following high dose radio therapy. The attenuated GH release seen in longterm survivors compared to c ontrols suggests that GH secretory dysfunction does not simply reflect redu ced GHRH and SS secretion, and that trophic effects or pituitary damage may be important with time.