Effects of direct and indirect acetylcholine receptor agonists on growth hormone secretion in humans

Cholinergic pathways in the central nervous system positively influence growth hormone (GH) secretion. In fact pyridostigmine, a cholinesterase inhibitor, enhances both basal and GH-releasing hormone (GHRH)-induced GH secretion while, conversely, pirenzepine, an antagonist of muscarinic M1 receptors, inhibits the GH response to GHRH and to other physiological and pharmacological stimuli. The effect of the cholinergic system on GH secretion probably takes place via inhibition of the release of endogenous somatostatin. In this study in 36 normal adults (26 males and 10 females, age 22–35 years) we compared the effects of three cholinesterase inhibitors (pyridostigmine, 120 mg p.o., n = 19; neostigmine, 10 μg/kg i.v., n = 6; physostigmine, 12.5 μg/kg i.v., n = 6) and bethanechol, a direct muscarinic receptor agonist that is mainly active on muscarinic M3 receptors (25 μg/kg i.v., n = 5), on both basal and GHRH (1 μg/kg i.v.)-stimulated GH secretion. Pyridostigmine, neostigmine and physostigmine induced a significant GH increase (peak vs. basal levels, mean ± S.E.: 10.4 ± 1.6 vs. 0.6 ± 0.2 μg/l, P = 0.0001; 13.3 ± 1.2 vs. 0.5 ± 1.1 μg/l, P = 0.004; and 14.9 ± 3.1 vs. 2.7 ± 1.1 μg/l, P = 0.025;, respectively). These drugs also induced a similar potentiation of the GH response to GHRH (peak: 48.3 ± 5.6 vs. 16.2 ± 2.2 μg/l, P = 0.0001; 49.2 ± 2.2 vs. 19.9 ± 5.1 μg/l, P = 0.006; and 76.9 ± 12.4 vs. 18.1 ± 5.3 μg/1, P = 0.001, respectively). By contrast, bethanechol neither enhanced basal GH secretion (peak vs. basal level: 3.3 ± 1.2 vs. 2.6 ± 1.2 μg/l) nor potentiated the GH response to GHRH (peak: 16.3 ± 1.3 vs. 15.4 ± 1.6 μg/l). The present findings strongly confirm the stimulatory role of aetylcholine on GH secretion in man, showing that indirect acetylcholine receptor agonists stimulate GH secretion, while the muscarinic M3 agonist bethanechol does not. The results exclude that cholinergic stimulation of GH secretion is mediated by muscarinic M3 receptors, in keeping with the hypothesis that muscarinic M1 receptors play the main role in the neuroregulation of GH secretion.