THE ENHANCING EFFECT OF PYRIDOSTIGMINE ON THE GH RESPONSE TO GHRH UNDERGOES AN ACCELERATED AGE-RELATED REDUCTION IN DOWN-SYNDROME

Cholinergic agonists are known to potentiate GHRH-induced GH secretion , probably acting via inhibition of hypothalamic somatostatin release. Their effect is reduced in aging and in patients with Alzheimer's dis ease. This may be the consequence of age-related cholinergic impairmen t, which, in turn, could cause somatostatinergic hyperactivity leading to GH hyposecretion. As in Down syndrome (DS) neural alterations have been reported similar to those in aging, including cholinergic impair ment, we verified the GH response to GHRH (1 mu g/kg i.v. at 0 min) al one or combined with pyridostigmine (PD), a cholinesterase inhibitor ( 60 and 120 mg, respectively, in children and adults, orally at -60 min ) in 15 DS children (13.5 +/- 0.6 years) and in II DS young adults (24 .0 +/- 1.2 years). Fifteen normal children(11.9 +/- 0.5 years), 15 nor mal adults (27.3 +/- 0.9 years) and 16 normal elderly(76.3 +/- 1.5 yea rs) were studied as controls. IGF-I levels showed an age-related reduc tion both in DS (children vs. adults, mean +/- SEM: 354.8 +/- 44.9 vs. 204.4 +/- 29.4 mu g/l, p < 0.02) and in controls (normal children vs. normal adults vs. normal elderly: 281.4 +/- 36.3 vs. 175.4 +/- 11.2 v s. 72.5 +/- 6.6 mu g/l, p < 0.001). The GH response to GHRH in DS chil dren was higher than in DS adults (areas under curve: 1,197.6 +/- 241. 5 vs. 434.4 +/- 83.3 mu g/l/h, p < 0.01). On the other hand, in normal subjects the GHRH-induced GH rise was similar in children and adults (1,056.2 +/- 128.4 vs. 800.8 +/- 124.5 mu g/l/h) and both were higher than that in elderly subjects(296.0 +/- 61.0 mu g/l/h, p < 0.001). PD enhanced the GH response to GHRH both in DS and in normal subjects (p < 0.005). The GH response to PD+GHRH was lower in DS adults than in DS children(1,068.1 +/- 145.7 vs. 1,897.4 +/- 198.8 mu g/l/h, p < 0.001) as well as in normal elderly subjects with respect to that in normal children and normal adults (832.3 +/- 144.7 vs. 2,172.1 +/- 156.1 and 2,347.6 +/- 322.4 mu g/l/h, respectively, p < 0.001). The GH response to GHRH alone or combined with PD in DS adults was lower (p < 0.01) th an that in normal adults and similar to that in normal elderly subject s. In conclusion, the present data demonstrate that the stimulated CH secretion in DS undergoes an accelerated age-related reduction. They a lso suggest the existence of a precocious impairment of central cholin ergic activity in DS, which, in turn, could cause somatostatinergic hy peractivity and reduced GH secretion.