Hypothalamic Growth Hormone-Insulin-like Growth Factor-I Axis across the Human Life Span

Abstract

ABSTRACT The activity of the growth hormone (GH)- insulin-like growth factor-I (IGF-I) axis undergoes marked variations across the human life span, mainly reflecting age-related changes in the neural control of somatotroph function. IGF-I secretion generally reflects GH status, except in newborns, who secrete high levels of GH but low levels of IGF-I. Changes in the gonadal steroid milieu, particularly estradiol, play a major role in the enhanced activity of the GH-IGF-I axis at puberty and probably reflect further changes in the neuroendocrine control of somatotroph secretion. The change in responsiveness of somatotrophs to various stimuli, including GHRH, is not as marked as the spontaneous secretion of GH at puberty. However, in childhood, somatotrophs are unusually refractory to the somatostatin-mediated negative GH autofeedback mechanism. Normal children show normal responsiveness to the stimulatory influence of α-adrenergic and cholinergic agonists, galanin and arginine, but the activating effect of these stimuli on somatotroph secretion is reduced in elderly individuals, with the notable exception of arginine. Arginine potentiates both spontaneous and GHRH-induced GH secretion to the same extent in normally growing children, adults and elderly individuals, indicating that the releasable pool of GH is generally preserved across the human life span. Thus, the reduction in spontaneous and GHRH-induced GH secretion in the elderly probably reflects age-related changes in neurotransmitter control, leading to GHRH hypoactivity and absolute or relative somatostatin hyperactivity in the aged hypothalamus. Cholinergic impairment in the aging brain probably involves hypothalamic pathways and leads to decreased activity of the GH-IGF-I axis in normal and elderly individuals, as well as in individuals with premature brain aging. However, there is evidence indicating that age-related variations in the activity of the natural GH-secretagogue ligand(s) at the hypothalamic level could also play a role in the age-dependent changes in the GH-IGF-I axis.