Biologic Activities of Growth Hormone Secretagogues in Humans

Abstract

Growth hormone secretagogues (GHSs) are synthetic peptidyl and nonpeptidyl molecules with strong, dose-dependent, and reproducible growth hormone (GH)-releasing activity even after oral administration. GHSs release GH via actions on specific receptors (GHS-R) at the pituitary and, mainly, at the hypothalamic levels. GHSs likely act as functional somatostatin antagonists and meantime enhance the activity of GH-releasing hormone (GHRH)-secreting neurons. The GH-releasing effect of GHSs is independent of gender but undergoes marked age-related variations. Estrogens play a major role in enhancing the GH response to GHSs at puberty, which GHRH hypoactivity, somatostatinergic hyperactivity and impaired activity of the putative GHS-like ligand and receptors probably explain the reduced GH-releasing effect of GHSs in aging. The activity of GHSs is not fully specific for GH. Their slight prolactin-releasing activity probably comes from direct pituitary action. In physiological conditions, the ACTH-releasing activity of GHSs is dependent on central actions; a direct action on GHS-R in pituitary ACTH-secreting tumors likely explains the peculiar ACTH and cortisol hyperresponsiveness to GHSs in Cushing disease. GHSs have specific receptor subtypes in other central and peripheral endocrine and nonendocrine tissues mediating GH-independent biologic activities. GHSs influence sleep pattern, stimulate food intake, and have cardiovascular activities. GHs have specific binding in normal and neoplastic follicular derived human thyroid tissue and inhibit the proliferation of follicular-derived neoplastic cell lines. The discovery of ghrelin, a 28 amino acid peptide synthesized in the stomach but also in other tissues, has opened new fascinating perspectives of research in this field.

Ghrelin administration affects circulating pituitary and gastro-entero-pancreatic hormones in acromegaly

“…Its PRL-releasing activity seems to be due to a direct effect on mammosomatotroph cells (6), whereas the release of ACTH appears to be mediated by ghrelin at the hypothalamic level (6). Moreover, in the rat, ghrelin modulates gastric motility and acid secretion (7,8), inhibits gastric emptying (7) and increases insulin and gastrin secretion (9).…”

Recombinant adenovirus-mediated expression of GHS-R1a in HEK 293 cells

“…There are 2 variants of GHS-R1: GHS-R1a and GHS-R1b, resulting from the alternative processing of pre-mRNA of the same gene [11] . GHSR1a acts as the receptor for ghrelin, and mediates a wide spectrum of ghrelin actions [12,13] . Therefore, exploring the mechanisms underlying the regulation of GHS-R1a would contribute to a better understanding of the physiological role of ghrelin [14] .…”

Ghrelin-stimulation test in the diagnosis of canine pituitary dwarfism

“…In healthy humans, intravenous administration of GHRP-6 or ghrelin also increases circulating concentrations of PRL, ACTH, and cortisol (Massoud et al, 1996;Casanueva and Dieguez, 1999;Takaya et al, 2000;Arvat et al, 2001;Ghigo et al, 2001). In rats, GHRP-6 activates the hypothalamic-pituitary-adrenal axis (Thomas et al, 1997).…”

“…However, the action of ghrelin and the synthetic GHSs is not exclusively confined to GH release. For example, in humans these substances also stimulate the secretion of prolactin (PRL), adrenocorticotrophic hormone (ACTH), and cortisol (Massoud et al, 1996;Takaya et al, 2000;Arvat et al, 2001;Ghigo et al, 2001). In rats, GHRP-6 activates the hypothalamic-pituitary-adrenal axis (Thomas et al, 1997).…”