At present, the mechanism(s) underlying the reduced spontaneous and stimulated GH secretion in aging is still unclear. To obtain new information on this mechanism(s), the GH responses to both single and combined administration of GH-releasing hormone (GHRH; 1 microgram/kg iv) and arginine (ARG; 30 g infused over 30 min), a well known GH secretagogue probably acting via inhibition of hypothalamic somatostatin release, were studied in seven elderly normal subjects and seven young healthy subjects. Basal GH levels were similar in both groups, while insulin-like growth factor-I levels were lower in elderly subjects (76.7 +/- 9.2 vs. 258.3 +/- 29.2 micrograms/L; P = 0.01). In aged subjects GHRH induced a GH increase (area under the curve, 314.9 +/- 91.9 micrograms/L.h) which was lower (P = 0.01) than that in young subjects (709.1 +/- 114.4 micrograms/L.h). On the other hand, the ARG-induced GH increase in the elderly was not significantly different from that in young subjects (372.8 +/- 81.8 vs. 470.6 +/- 126.5 micrograms/L.h). ARG potentiated GH responsiveness to GHRH in both elderly (1787.1 +/- 226.0 micrograms/L.h; P = 0.0001 vs. GHRH alone) and young subjects (2113.0 +/- 444.3 micrograms/L.h; P = 0.001 vs. GHRH alone). The potentiating effect of ARG on the GHRH-induced GH response was greater in elderly than in young subjects (1013.0 +/- 553.5% vs. 237.9 +/- 79.1%; P = 0.0001); thus, the GH increase induced by combined administration of ARG and GHRH overlapped in two groups. In conclusion, these results show that, differently from the GHRH-induced GH increase, the somatotroph response to combined administration of ARG and GHRH does not vary with age. Our finding suggests that an increased somatostatinergic activity may underlie the reduced GH secretion in normal aging.

In five healthy young men, pretreatment with the cholinergic muscarinic antagonist pirenzepine (0.6 mg/kg iv) almost completely abolished the rise in plasma growth hormone (GH) elicited by an iv bolus injection of 1 microgram/kg human pancreatic GH-releasing factor 1-40 (hp-GRF-40). These data demonstrate that cholinergic receptor sites involved in GH-releasing mechanisms do not interact with GRF-secreting structures in the central nervous system. A mechanism mediated via hypothalamic release of somatostatin or, alternatively, a direct pituitary site of action, can be postulated for the blocking effect of pirenzepine.

In 11 elderly normal subjects and in 17 young healthy subjects we studied the response of plasma growth hormone to GH-releasing hormone (GHRH(29), 1 \g=m\g/kgiv) alone and preceded by pyridostigmine ( 120 mg orally 60 min before GHRH), a cholinesterase inhibitor likely able to suppress somatostatin release. The GH response to pyridostigmine alone was also examined. Basal plasma GH levels were similar in elderly and young subjects. In the elderly, GHRH induced a GH rise (AUC, median and range: 207.5,.0 \g=m\g \ m=. \1\m=-\1\ m=. \ h\ m=-\ 1) which was lower (p = 0.006) than that observed in young subjects (548.0, 112.5-2313.5 \ g=m\ g \ m=. \ 1\ m=-\ 1 \ m=. \ h\ m=-\ 1). The pyridostigmine-induced GH rise in the elderly was similar to that in young subjects (300.5, 163.0-470.0 vs 265.0, 33.0-514.5 \g=m\g \m=.\ 1\ m=-\ 1 \m=.\ h\ m=-\ 1). Pyridostigmine potentiated the GH responsiveness to GHRH in both elderly (437.5, 152.0-1815.5 \ g=m\ g \m=.\1\m=-\1\m=.\h\m=-\1; p = 0.01 vs GHRH alone) and young subjects (2140.0, 681.5-4429.5 \ g=m\ g \ m=. \ 1\ m=-\ 1\ m=. \ h\ m=-\ 1; p = 0.0001 vs GHRH alone). However, the GH response to pyridostigmine + GHRH was significantly lower (p = 0.0001) in elderly than in young subjects. In conclusion, the cholinergic enhancement by pyridostigmine is able to potentiate the blunted GH response to GHRH in elderly subjects, inducing a GH increase similar to that observed after GHRH alone in young adults. This finding suggests that an alteration of somatostatinergic tone could be involved in the reduced GH secretion in normal aging. However, a decreased GH response to combined administration of pyridostigmine and GHRH in elderly subjects suggests that other abnormalities may coexist, leading to the secretory hypoactivity of somatotropes.There is evidence for an age-related decrease of GH secretion both in animal and in man. Baseline GH levels were reported decreased (1,2) or unchanged (3,4), whereas it has been widely shown that spontaneous GH peak amplitude, mainly during sleep, is reduced in normal aging (4-7). In agreement with these findings, IGF-I levels were found decreased and exogenous GH restored them to values similar to those recorded in young sub¬ jects (1).At present the mechanism(s) underlying the re¬ duced GH secretion in aging is still unclear. In an¬ imals, evidence of an hypothalamic pathogenesis of this GH hyposecretory state has been presented (8)(9)(10)(11)(12)(13)(14)(15). In man, a low somatotrope responsiveness to some stimuli (16,17) and even to has been reported. However, the GH response to GHRH has been shown fully (20) or at least partly (21) restored by repetitive GHRH administration, suggesting an altered GHRH control of somatotropes in aging.We showed that in man the enhancement of the cholinergic activity by pyridostigmine, a cholinesterase inhibitor (22), induces an increase in basal GH levels and clearly potentiates the GHRH-induced somatotrope responsiveness even unmasking a marked GH response in subjects who did non re¬ spond to the neurohormone a...

No abstract

Abstract. In normal adults, repeated GHRH administration leads to progressively decreasing somatotrope responses. To verify whether this GH secretory pattern also connotes normal growing children, we have studied the effects of two consecutive (every 120 min) 1 μg/kg iv GHRH boluses on GH release in normal adults (N = 7, age 23.2–30.6 years) children (N = 6, age 10.4–13.2 years). In the adults, the GH response to the second GHRH bolus (peak, mean ± sem: 2.9 ± 0.8 μg/l) was lower (P< 0.02) than that to the first bolus (15.9 ± 2.4 μg/l). Conversely, in children the GH response to the second GHRH bolus (25.6 ± 6.3 μg/l) overrode the first one (13.6 ± 6.5 μg/l), but this difference did not attain statistical significance. In adults cholinergic enhancement by pyridostigmine, a cholinesterase inhibitor, was previously shown to re-instate, even to potentiate somatotrope responsiveness to consecutive GHRH boluses. Thus, in 5 children GH response to repeated GHRH boluses was retested administering pyridostigmine (60 mg orally) 30 min before the second GHRH bolus. In these subjects, pyridostigmine failed significantly to potentiate the GH responsiveness to the second GHRH bolus (30.3 ± 4.6 vs 25.0 ± 7.6 μg/l). These data indicate that differently from in adults, in children repeated GHRH administration does not reduce somatotrope responsiveness and that cholinergic enhancement fails to potentiate GH responsiveness to the second GHRH bolus.