NEUROTRANSMITTER CONTROL OF GROWTH-HORMONE SECRETION IN CHILDREN AFTER CRANIAL RADIATION-THERAPY

Cranial radiation for childhood cancer can cause growth hormone defici ency (GHD), usually due to hypothalamic rather than pituitary dysfunct ion. To investigate whether this hypothalamic dysfunction is secondary to altered neurotransmitter input from other brain centers, we used n eurotransmitter-excitatory substances to study the GH secretory respon se in 17 children who had received 12 to 60 Grey (Gy) to the cranium a nd 40 short children with normal endocrine function. As expected, the irradiated children had decreased mean GH secretion in response to ins ulin-induced hypoglycemia and arginine infusion, and decreased mean 24 hour GH concentrations, compared to the control group. In contrast, t he two groups had similar GH secretory responses to GHRH stimulation a nd somatostatin suppression. Assessment of neurotransmitter pathways i n the irradiated children revealed significantly lower mean peak GH co ncentrations in response to 5 of the 6 substances tested compared to c ontrol children: alpha-adrenergic stimulation (clonidine), beta-adrene rgic blockade (propranolol), cholinergic stimulation, dopaminergic sti mulation (L-dopa), and GABA-ergic stimulation (valproic acid). Results of serotonergic stimulation (L-tryptophan) were not statistically sig nificant. Eleven patients who had abnormal GH secretion underwent 4 or more tests with neurotransmitter-stimulatory agents; 3 patients had p eak GH concentrations of < 2.5 mug/l to all tests, whereas 4 patients had a peak GH concentration of greater-than-or-equal-to 7 mug/l to one or more tests but < 5 mug/l to one or more other tests. These observa tions suggest that radiation damage may sometimes spare growth hormone -releasing hormone (GHRH) and somatostatin secretion while affecting n eurotransmitter pathways. We postulate that the hierarchy of sensitivi ty to radiation damage may be hypothalamic and extra-hypothalamic neur otransmitters > hypothalamic GHRH and/or somatostatin secretion > pitu itary GH secretion.