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 endogenous 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 idiopathic GH deficiency.(ABSTRACT TRUNCATED AT 400 WORDS)
Müller
E E
EE
Department of Pharmacology, University of Milan, Italy.
Locatelli
V
V
Ghigo
E
E
Cella
S G
SG
Loche
S
S
Pintor
C
C
Camanni
F
F
D000109:Acetylcholine / Q000378:metabolism*; D001923:Brain Chemistry; D002395:Catecholamines / Q000378:metabolism*; D006130:Growth Disorders / Q000188:drug therapy; D013006:Growth Hormone / Q000172:deficiency* / Q000378:metabolism; D013007:Growth Hormone-Releasing Hormone / Q000378:metabolism; D006801:Humans; D007980:Levodopa / Q000627:therapeutic use; D010276:Parasympatholytics / Q000627:therapeutic use; D011729:Pyridostigmine Bromide / Q000627:therapeutic use
D002395:Catecholamines; D010276:Parasympatholytics; D007980:Levodopa; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone; D011729:Pyridostigmine Bromide; D000109:Acetylcholine