Intranasal administration of neostigmine potentiates both intravenous and intranasal growth hormone (GH)-releasing hormone-induced GH release in short children
E Ghigo, M Procopio, J Bellone, E Mazza, M Mucci, MF Boghen, EE Muller and F Camanni
Administration of cholinergic agonists increases both basal and GH-releasing hormone (GHRH)-induced GH secretion, probably acting via inhibition of endogenous somatostatin release.
The aim of our study was to verify in two groups of children with idiopathic short stature the effect of intranasal administration of neostigmine (inNS; 3 mg), a cholinesterase inhibitor, on basal GH levels as well as on the somatotroph response to GHRH when the peptide was administered either iv (ivGHRH; 1 microgram/kg) or intranasally (inGHRH; 10 micrograms/kg).
In group A (n = 6; age, 10.6-16.0 yr) inNS induced a significant GH increase [inNS vs. saline, area under the curve (AUC; mean +/- SEM), 263.7 +/- 60.2 vs. 73.8 +/- 3.1 micrograms/L.h; P less than 0.03] and potentiated the somatotroph response to ivGHRH (inNS with ivGHRH vs. ivGHRH, 1316 +/- 183.0 vs. 644.9 +/- 154.5 micrograms/L.h; P less than 0.03). In group B (n = 6; age, 11.5-15.9 yr) ivGHRH induced a GH rise clearly higher than that induced by inGHRH (604.2 +/- 154.3 vs. 137.1 +/- 28.2 micrograms/L.h; P less than 0.03). Administration of inNS induced a GH rise similar to that occurring after inGHRH (AUC, 239.2 +/- 69.5 micrograms/L.h) and markedly increased the inGHRH-induced GH response (482.4 +/- 103.6 micrograms/L.h; P less than 0.05 and 0.03 vs. inNS and inGHRH, respectively), so that it overlapped with that induced by ivGHRH alone.
In conclusion, cholinergic agonists such as neostigmine are able to increase both basal and GHRH-induced GH secretion in short children even when given intranasally. Combined intranasal administration of neostigmine and GHRH (10 micrograms/kg) is able to induce a GH rise similar to that induced by ivGHRH alone (1 microgram/kg), suggesting the potential usefulness of this combination cocktail and route of administration for the treatment of short stature.
Exp Gerontol. 2005 Mar;40(3):157-63. Epub 2004 Dec 23
The age-related down-regulation of the growth hormone/insulin-like growth factor-1 axis in the elderly male is reversed considerably by donepezil, a drug for Alzheimer's disease
Obermayr RP, Mayerhofer L, Knechtelsdorfer M, Mersich N, Huber ER, Geyer G, Tragl KH
GH secretion declines by 14%/decade of adult life, leading to the suggestion that people over the age of 60 years are functionally GH deficient. Recently, rivastigmine, a novel cerebral selective cholinesterase-inhibitor (ChEI), was shown to be a powerful drug to enhance GH release to repeated GHRH stimulation in healthy elderly human subjects.
The present study was designed as a randomised controlled trial to evaluate long term effects of donepezil, a cerebral selective ChEI, on basal GH and IGF-1 levels and on GH response to GHRH (1 microg/kg i.v., GHRH test) before and after an 8-week donepezil treatment period.
Donepezil was given orally 5 mg per day for 4 weeks and 10 mg per day for another 4 weeks. Twenty four healthy male volunteers (n=2 x 12, placebo group vs. donepezil group, age: 61-70 years) were studied. Donepezil treatment group: basal GH levels taken at 08:30 a.m. doubled from 0.4+/-0.3 to 0.8+/-0.4 ng/ml (p=0.008). GHRH-test: GH-AUC was 318+/-227 ng/ml/h and increased by 53% to 485+/-242 ng/ml/h (p=0.009). Total serum IGF-1 levels, taken simultaneously with the basal GH levels, showed a considerable increase, too: the baseline IGF-1 levels increased by 31% from 84+/-19 to 110+/-21 ng/ml (p=0.007).
This study demonstrated that the age-related down-regulation of the GH/IGF-1 axis is reversed considerably by donepezil in the elderly male. Future investigation will reveal whether such a new therapeutic intervention can delay the onset or even reverse some manifestations of the somatopause in the long term and evaluate its benefit/risk ratio concerning new treatment implications.
Reply With Quote
Bookmarks