Involvement of Brain Catecholamines and Acetylcholine in Growth Hormone Deficiency States : Pathophysiological, diagnostic and therapeutic implications

A cohort of brain neurotransmitters, especially catecholamines and acetylcholine, play a crucial role in the control of neurosecretory growth hormone-releasing hormone (GH-RH)- and somatostatin (SS)-producing neurons, and hence growth hormone (GH) secretion. Stimulation of alpha-2-adrenoceptors or of muscarinic cholinergic receptors in the hypothalamus stimulates GH release, probably via stimulation of GH-RH and inhibition of somatostatin release, respectively. Additionally, stimulation of dopamine receptors is stimulatory to GH release, while activation of beta-receptors inhibits GH release via stimulation of hypothalamic somatostatin function. As a corollary, in GH deficiency states drugs affecting catecholaminergic and cholinergic functions may be exploited for diagnostic and/or therapeutic purposes, and may be useful for a better understanding of the underlying pathophysiology. Levodopa (L-dopa) [125 to 500mg orally], the physiological precursor of the catecholamines, administered either alone or in combination with carbidopa (50mg orally), to prevent its peripheral decarboxylation to dopamine, and/or the beta-adrenoceptor antagonist propranolol (0.75 mg/kg orally), and the alpha-2-adrenoceptor agonist clonidine (0.15 mg/m2 orally), are a fairly reliable stimulus of GH release. In normal subjects, however, false-negative GH responses and wide inter-individual variability may occur with these drugs. Additionally, the GH secretory response to these provocation tests is a poor predictor of endogeneous 24-hour GH secretion, since levodopa or clonidine may elicit a response within normal limits in children of short stature with reduced 24-hour GH secretion and good responsiveness to GH therapy. The availability of GH-RH, a direct probe of pituitary somatotrophs, held out promise of unravelling the hypothalamic or pituitary origin of GH secretory disturbance. It soon became apparent, however, that this was not the case, because of the wide inter- and intraindividual variation in the GH response. However, the coadministration of GH-RH and muscarinic cholinergic agonists, for example pyridostigmine (which deprive the pituitary of hypothalamic SS inhibitory influences), is a useful diagnostic probe. In a large group of normal children and adolescents who received an intravenous injection of GH-RH, preceded by oral administration of pyridostigmine (60mg orally), none gave a false-negative response; this was also true for a group of short children with different forms of GH disturbances, in whom 8-hour nocturnal GH secretion was within normal limits. However, some false-negative responses occurred in children following testing with GH-RH, clonidine or pyridostigmine alone. Interestingly, the cut-off point for normality following pyridostigmine + GH-RH was as high as 20 ng/ml, while for the other provocation tests it is only 5 to 10 ng/ml. Responses lower than 20 ng/ml were present in all children with organic and most of the children with idopathic GH deficiency. The fact that in most subjects with GH deficiency and/or short stature GH-RH evokes variable but unequivocal rises in plasma GH levels points to a dysfunction of hypothalamic regulation; the dysfunction would primarily affect neurotransmitter and not hypophysiotropic neurosecretory neurons. In children with isolated GH deficiency (IGHD), 6 months of oral administration of levodopa (60 mg/kg) or bromocriptine (2.5mg) increased growth velocity, basal GH levels and in some of the children serum somatomedin-C levels. Similarly, clonidine (0.1 mg/m2 orally) given for 3 months to 1 year to children with isolated GH deficiency or constitutional delay of growth (CGD) induced in some of them a clearcut stimulation of linear growth. After 2 months of treatment in a group of children with constitutional delay of growth, clonidine increased the 24-hour GH concentration and the mean GH pulse amplitude. In contrast, pyridostigmine (60 to 180mg orally) does not have growth-promoting therapeutic potential, probably because it fails to potentiate the GH-RH-induced rise in GH at night. A GH hyposecretory dysfunction is also present in obese children and adults. In these patients acute pretreatment with pyridostigmine significantly increased baseline GH levels and the GH response to GH-RH, these indices becoming similar to those of lean control subjects receiving GH-RH alone. However, combined administration of pyridostigmine and GH-RH elicited a higher GH response in lean control subjects than in obese subjects. Decreases in GH pulse amplitude and frequency and marked blunting of the GH response to various secretagogues occurs in both animals and humans during aging. The mechanism of these changes in unclear but studies in aged animals have shown that passive immunisation with antisomatostatin serum or treatment with pilocarpine or clonidine stimulates GH release.