Radiation and neuroregulatory control of growth hormone secretion.
OBJECTIVE
Cranial irradiation frequently results in growth hormone (GH) deficiency. Patients with radiation-induced GH deficiency usually remain responsive to exogenous growth hormone releasing hormone, implying radiation damages the hypothalamus rather than the pituitary. Little is known about the effect of cranial irradiation on the neuroendocrine control of GH secretion. This study was to determine the effect of cranial irradiation on somatostatin tone.


METHODS
Somatostatin tone was examined by manipulating cholinergic tone in young adults with radiation-induced GH deficiency and a control population. Each individual underwent three separate studies: the GH response to 100 micrograms GHRH-(1-29)-NH2 was assessed alone, and 60 minutes after pyridostigmine or pirenzepine.


METHODS
Eight young male adults with radiation induced GH deficiency following treatment in childhood for a brain tumour or acute lymphoblastic leukaemia, and ten healthy adult men were studied.


METHODS
Serum growth hormone was measured at 15-minute intervals throughout each of the three study periods.


RESULTS
One of 10 controls and four of eight irradiated subjects had a peak GH level to GHRH analogue of less than 20 mU/l. After pretreatment with pyridostigmine, all subjects except one irradiated subject had a peak GH level of greater than 20 mU/l. Pretreatment with pyridostigmine and pirenzepine significantly modified the GH response to GHRH analogue within both groups (P < 0.0005). Pretreatment with pyridostigmine significantly enhanced the GH response to GHRH analogue (median (range) area under the curve, 9029 (1956-20940) mU/l/min in controls vs 1970 (628-3608) mU/l/min in the irradiated group) compared with GHRH analogue alone (1953 (512-16140) mU/l/min in control group vs 997 (266-3488) mU/l/min in the irradiated group). Pretreatment with pirenzepine significantly attenuated the GH response to GHRH analogue (552 (64-1274) mU/l/min in controls vs 305 (134-2726) mU/l/min in irradiated group). Between the groups there was no significant difference in GH area under the curve (AUC) after GHRH analogue alone. There was a significantly (P = 0.0014) greater increment of GH secretion after pyridostigmine and GHRH analogue compared with GHRH analogue alone (difference in AUC of pyridostigmine+GHRH analogue and GHRH analogue alone 6348 (696-12856) mU/l controls vs 542 (120-1340) mU/l in the irradiated group) and significantly (P = 0.033) greater suppression of GH secretion after pirenzepine and GHRH analogue compared with GHRH analogue alone (difference in AUC of GHRH analogue alone and pirenzepine+GHRH analogue 1644 (222-15205) mU/l in controls vs 479 (469-1623) mU/l in the irradiated group) in the control population compared with those who had received cranial irradiation in childhood.


CONCLUSIONS
These data suggest that cranial irradiation reduces but does not abolish somatostatin (SRIH) tone and also reduces endogenous GHRH secretion. Although SRIH tone is reduced, it can be increased by cholinergic manipulation and is therefore not irreversibly fixed. This has possible implications if GHRH analogues were used to treat children with radiation induced GH deficiency.
Ogilvy-Stuart
A L
AL
Department of Endocrinology, Christie Hospital, Manchester, UK.
Wallace
W H
WH
Shalet
S M
SM
D000328:Adult; D001932:Brain Neoplasms / Q000532:radiotherapy; D016371:Cranial Irradiation / Q000009:adverse effects*; D013006:Growth Hormone / Q000097:blood / Q000172:deficiency* / Q000378:metabolism; D013007:Growth Hormone-Releasing Hormone / Q000494:pharmacology; D006801:Humans; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D010890:Pirenzepine / Q000494:pharmacology; D011729:Pyridostigmine Bromide / Q000494:pharmacology; D013004:Somatostatin / Q000097:blood / Q000378:metabolism*
D010446:Peptide Fragments; D010890:Pirenzepine; D013004:Somatostatin; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone; C059148:somatotropin releasing hormone (1-29); D011729:Pyridostigmine Bromide