Growth Hormone Secretion in Alzheimer's Disease: Studies with Growth Hormone-Releasing Hormone Alone and Combined with Pyridostigmine or Arginine

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.

Human Ageing and the Growth Hormone/Insulin-Like Growth Factor-I (GH/IGF-I) Axis - The Impact of Growth Factors on Dementia

“…Indeed, cholinergic agonists are able to increase both spontaneous and GHRH-induced GH secretion in AD patients [142,[152][153][154]156] without any difference with normal elderly [142,153], although both responses are reduced compared with normal young subjects [142]. These findings, therefore, confirmed the presence of neuroendocrine cholinergic derangement in the ageing brain but demonstrated that, at least at hypothalamic level, cholinergic pathways are not more impaired in AD than in normal elderly.…”

“…On the other hand, other studies focusing on the effects of other neuroactive drugs able to stimulate GH secretion, such as clonidine, pyridostigmine and apomorphine, generally confirmed that AD shows a GH response similar to that in normal elderly subjects [141,142,[152][153][154][155][156].…”

“…The GH response to GHRH has been reported similar, increased or reduced in AD in comparison with age-matched controls [141][142][143][149][150][151][152][153][154][155], and a delayed GH response to GHRH was observed by some [150] but not by other authors [142,152]. On the other hand, other studies focusing on the effects of other neuroactive drugs able to stimulate GH secretion, such as clonidine, pyridostigmine and apomorphine, generally confirmed that AD shows a GH response similar to that in normal elderly subjects [141,142,[152][153][154][155][156].…”

“…However, the GH-inhibitory effect of cholinergic antagonists is preserved in both AD and normal aged people, indicating that the activity of tuberoinfundibular SS neurons within the hypothalamus is indistinguishable in normal and pathological ageing [153]. On the other hand, the GH responsiveness to GHRH combined to arginine is normal in AD [142], indicating that the hyperactivity of hypothalamic SS neurons probably reflects peculiar impairment of the cholinergic control of hypothalamic SS release. Actually, this hypothesis disagrees with the evidence that both SS immunoreactivity and receptors are reduced in many brain areas of AD patients [157][158][159].…”

“…Like normal ageing, AD is connoted by a GH hyposecretory state [141][142][143][144]. However, studies comparing GH and IGF-I secretion in AD with that in normal elderly subjects provided conflicting results [141][142][143][144][145][146][147] Increased or unchanged GH levels were reported in AD patients compared to age-matched controls [141][142][143][144], while the majority of studies reported IGF-I increased in the early stages of AD and reduced at later stages [141][142][143][144][145][146][147], although others showed IGF-I levels in AD lower than in age-matched controls independently from the stage of the disease [148]. Slight age and/or nutritional differences as well as a more pronounced impairment of insulin sensitivity and/or glucose metabolism between AD and normal elderly subjects have been hypothesized to account for these controversial data [137,144].…”