SOMATOTROPIC DYSREGULATION IN OLD MAMMALS

In old mammals, including humans, the spontaneous growth hormone (GH) secretory pattern is markedly reduced resulting in lower amounts of GH released over 24 h, and the GH response to administration of GH-relea sing hormone (GHRH) is reduced. In agreement with these in vivo findin gs, an impaired responsiveness to GHRH is evident in the pituitary of old male and female rats in vitro, and this is linked with a diminishe d stimulation of adenylate cyclase by GHRH. The poor GH responsiveness to GHRH in old mammals, which in the rat is coupled to a defective nu mber of GHRH receptors in the somatotrophs, is likely due to a primary deficiency of GHRH availability, as implied by the diminished GHRH im munoreactivity and gene expression in and GHRH release from the hypoth alamus of old rats. Attempts have been made to stimulate the sluggish somatotrophic function in elderly humans and dogs using GHRH; in eithe r species positive results were obtained though, overall, it would see m that the GHRH hypofunction does not entirely account for the GH hypo secretory state during ageing. Concerning somatostatin, although the e xpression of this peptide decreases with age in the rat hypothalamus, secretion and activity of this hormone is increased, resulting in an a ltered relationship between GHRH and somatostatin gene expression and secretion. It is likely that defects, especially in catecholaminergic and cholinergic neurons, are instrumental in altering specific peptide rgic neurons. Reportedly, catecholamines induce GH release by stimulat ing GHRH neurons and inhibiting somatostatin-releasing neurons; acetyl choline stimulates GH release via muscarinic receptors, in this way in hibiting the action of somatostatin neurons. In old beagle dogs short- term administration of the az-adrenoceptor clonidine strikingly potent iated GHRH-stimulated GH release, thus implying that clonidine was act ing via inhibition of hypothalamic release of somatostatin, and the co mbination GHRH plus clonidine was highly effective in restoring the pu lsatile release of GH and plasma IGF-1 levels. The possibility is envi saged that GHRH or other GH-releasing peptides, e.g. GH-releasing hexa peptide (GHRP-6) and hexarelin, given in conjunction with compounds al legedly capable of reducing somatostatinergic function (clonidine, arg inine) may be potent pharmacologic tools to reinstate in old humans GK secretion in a physiologic, pulsatile manner.