Overview of the ensemble GHIGF1 axis

The GH/IGF1 axis comprises a feedback ensemble controlled jointly by: (i) GH-releasing hormone (GHRH) feedforward; (ii) somatostatin (SS) inhibition; (iii) a GH-releasing oligopeptide (GHRP) signalling pathway; and (iv) GH and IGF1 autonegative feedback (Mueller et al 1999, Argente et al 1991, Baumann & Maheshwari 1997, Baumbach et al 1998, Bowers et al 1990, Bowers 1993, Carlsson et al 1990, Frohman & Jansson 1986, Giustina & Veldhuis 1998, Jaffe et al 1993, Kojima et al 1999, Smith et al 1997, Hofland & Lamberts 1996). This simplified core construct is illustrated in Fig. 3.

GHRH is an established primary agonist driving the biosynthesis and pulsatile secretion of GH in all mammalian species (Giustina & Veldhuis 1998). Conversely, somatostatin (SS) is a dominant inhibitory signal, which antagonizes the exocytotic secretion of GH, but not its biosynthesis or storage (Hofland & Lamberts 1996). GHRPs are potent and selective oligopeptidyl GH secretagogues (Bowers et al 1984), mimicked by certain non-peptidyl agonists and exemplified endogenously by a 3Ser-octanoylated 28-amino acid GHRP-like ligand (Smith et al 1997, Howard et al 1996, Kojima et al 1999, Mueller et al 1999). The foregoing trilogy of neuropeptidyl regulators controls GH secretion via topographically and biochemically distinct receptors and secondary signalling molecules (Barinaga et al 1985, Giustina & Veldhuis 1998, Mayo 1992, Mueller et al 1999). These diverse, but uniquely interactive, features create: (a) cooperative mechanisms of biological control, and (b) multiple vulnerable loci for disrupted neuroregulation in ageing and/or hypogonadism. We believe that such interactive properties further mandate the particularly careful design of

FIG. 3. Working experimental schema of primary tri-peptidyl control of the human GH axis (Giustina & Veldhuis 1998).

experimental interventions, e.g. wherein one 'clamps' two (of the three) input signals in order to assess (sex-steroid induced) changes in the third.

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