© Freund Publishing House Ltd., London Journal of Pediatric Endocrinology & Metabolism, 13, 1493-1502 (2000) Hypothalamic Growth Hormone-Insulin-like Growth Factor-I Axis across the Human Life Span Ezio Ghigo, Emanuela Arvat, Laura Gianotti, Fabio Lanfranco, Fabio Broglio, Gianluca Aimaretti, Mauro Maccario and Franco Camanni Department of Internal Medicine, Division of Endocrinology, University of Turin, Turin, Italy ABSTRACT The activity of the growth hormone (GH)- insulin-like growth factor-I (IGF-I) axis under- goes 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 respon- siveness of somatotrophs to various stimuli, including GHRH, is not as marked as the spontaneous secretion of GH at puberty. How- ever, 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 ago- nists, 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 potenti- ates both spontaneous and GHRH-induced GH secretion to the same extent in normally growing children, adults and elderly individuals, indi- cating that the releasable pool of GH is generally preserved across the human life span. Thus, the reduction in spontaneous and GHRH-induced Reprint address: E. Ghigo Division of Endocrinology Ospedale Molinette C.so Dogliotti 14 10126 Torino, Italy e-mail: ezio.ghigo@unito.it 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 indivi- duals, as well as in individuals with premature brain aging. However, there is evidence indi- cating 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. KEY WORDS growth hormone, human life span, insulin-like growth factor-I, neurotransmitters INTRODUCTION The activity of the growth hormone (GH)- insulin-like growth factor-I (IGF-I) axis undergoes marked variations across the human life span. GH secretion is transiently elevated at birth, markedly increases at puberty, then progressively decreases to very low levels in senescence 1 ' 9 . IGF-I secretion generally reflects the GH status, except in new- borns, who secrete high levels of GH but low levels of IGF-I 8 ' 10 . It is well known that the increased activity of the GH-IGF-I axis at puberty is coupled with gonadal development and is devoted to sustaining the pubertal growth spurt 1 ' 11,12 . However, it is now common opinion that a component of the senescence-related changes in body composition, the functions of various systems (e.g. the cardio- vascular system) and metabolism could reflect the VOLUME 13, SUPPLEMENT 6, 2000 1493 Brought to you by | Kungliga Tekniska Högskolan Authenticated Download Date | 3/7/15 12:45 PM