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.

It is well known that in normal adults the growth hormone (GH) response to GH-releasing hormone (GHRH) is inhibited by previous administration of the neurohormone. In 7 healthy volunteers (age 20–34 years) we studied the GH responses to two consecutive GHRH boluses (1 µg/kg i.v. every 120 min) alone or coadministered with arginine (30 g i.v. over 30 min). The GH response to the first GHRH bolus (area under the curve, mean ± SEM: 506.3 ± 35.1 µg/l/h) was higher (p = 0.0001) than that to the second one (87.1 ± 14.6 µg/l/h). The latter response was clearly increased (p = 0.0001) by coadministering arginine (980.5 ± 257.5 µg/l/h). When every GHRH bolus was combined with arginine a marked potentiation of GH response to both boluses was found. However, the second combined administration of arginine and GHRH induced a GH increase which was lower compared to the first one (p = 0.016). In conclusion, our results show that arginine potentiates the GHRH-induced GH secretion preventing the lessening of somatotrope responsiveness to the neurohormone alone. As there is evidence that this phenomenon is due to an enhanced somatostatin release, these findings give further evidence of a somatostatin-suppressing effect of arginine.

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

There is evidence that GH secretion is reduced in normal elderly subjects as well as in patients with Alzheimer''s disease (AD). To clarify the mechanisms underlying this GH hyposecretory state in 14 elderly subjects (age 65–75 years) and 15 AD patients (age 61–78 years), we studied the effects of both pyridostigmine (PD, 120 mg orally), a cholinesterase inhibitor, and arginine (ARG, 0.5 g/kg i.v.), two substances likely acting via inhibition of hypothalamic somatostatin, on GH response to GHRH (1 (µg/kg i.v.). The GH response to PD alone was also studied. Twenty-two young healthy volunteers were studied as control group. Basal GH levels were similar in young, elderly and AD subjects (0.7 ± 0.2, 0.8 ± 0.2 and 0.9 ± 0.2 µg/1). IGF-I levels were lower (p < 0.005) in elderly (73.9 ± 8.2 µg/1) and in AD subjects (108.0 ± 5.9 µg/l) than in young subjects (288.7 ± 22.1 µg/l); however, they were higher (p < 0.01) in AD patients than in the elderly subjects. The PD-induced GH release did not significantly differ in young, elderly and AD subjects while the GH responses to GHRH in the elderly (AUC: 297.9 ± 49.2 µg/l/h) and in AD subjects (437.6 ± 93.5 µg/l/h) were lower (p < 0.01) than in young subjects (658.6 ± 100.1 µg/l/h). PD potentiated the GH response to GHRH both in elderly and in AD subjects (901.7 ± 222.4 and 1,070.3 ± 207.2 µg/l/h, p < 0.005) but these responses were lower (p < 0.0001) than those recorded in young subjects (2,041.1 ± 245.6 µg/l/h). ARG potentiated the GHRH-induced GH rise both in elderly and in AD subjects (1,545.2 ± 246.0 and 1,659.3 ± 196.8 µg/l/h,p < 0.001) but in this case, the GH response to GHRH + ARG overlapped with that in young subjects (2,140.2 ± 229.5 µg/l/h). In contrast to young subjects, in elderly and in AD subjects, the potentiating effect of ARG on GHRH-induced GH rise was higher (p < 0.01) than that of PD. These results show that testing neural controls of GH secretion with different neuroactive substances does not allow to differentiate normal aging from AD. In both groups, somatotroph responsiveness to GHRH is potentiated by the enhancement of the cholinergic activity but much more by ARG, which is compatible with the presence of a cholinergic impairments.