Control

Infusion Day 1

Males

Infusion Day 30

FIG. 4. (Left) Testosterone-dependent decline in 24 h GH secretion driven by pulsatile i.v. infusion of GHRH (0.33 /ig/kg/pulse) every 90 min for 3 days in 19 men (Iranmanesh et al 1998). (Right) Partial reconstitution of daily GH and IGF1 production by continuous s.c. GHRP2 infusion for 30 days in 12 healthy older men.

Thus, we propose that multifold neuroregulatory failure underlies impoverished GH secretion in ageing, namely, combined GHRH and/or GHRP deficiency and SS excess. Several plausible mechanistic considerations render this thesis more compelling.

GHRP and GHRH

GHRPs act at both hypothalamic and pituitary loci (Smith et al 1997). At CNS sites, these agonists stimulate electrical firing and c-fos gene expression in rodent NPY and GHRH neurons, elicit GHRH secretion acutely into sheep portal blood, and induce somnolence or alter appetite (Arvat et al 1998, Dickson et al 1995, Giustina & Veldhuis 1998, Guillaume et al 1994, Iranmanesh et al 2000, Locke et al 1995). At the pituitary level, GHRPs stimulate GH secretion directly (albeit less powerfully) in vitro, and putatively act at joint hypothalamo—pituitary loci to enhance somatotrope GH gene expression in the infant rat in vivo (Bowers et al 1984). Central (hypothalamic) actions of GHRPs are critical clinically, since hypothalamo—pituitary interruption virtually abolishes GHRP-stimulated GH secretion, even when somatotrope responsiveness to GHRH is preserved (Giustina & Veldhuis 1998, Mueller et al 1999). Maximal effects of GHRPs also require a functional GHRH receptor, as inferred from genetic studies in mice (lit/ lit mutation) and humans (dwarfs of Sindh) (Baumann & Maheshwari 1997, Frohman 1996), and based on the ability of a selective GHRH-receptor antagonist to suppress GHRP-stimulated GH secretion in young men.

Most studies document prominent in vivo synergy between the secretagogue effects of GHRP and GHRH in the human, pig and rodent (Bowers 1998, Giustina & Veldhuis 1998, Mueller et al 1999, Bowers et al 1990; Fig. 5). How testosterone modulates the foregoing GHRH—GHRP synergy at any age remains unknown.

Somatostatin and GHRPs

GHRPs act as so-called 'functional SS antagonists' by increasing the ID50 of SSs inhibition of spontaneous and GHRH-stimulated GH secretion by two—threefold in vitro and by 8—10-fold in vivo (Bowers 1998, Smith et al 1997). GHRPs partially oppose central SSergic activity, but do not directly block SS binding to pituitary cells or SS secretion into portal blood (Bowers 1998, Guillaume et al 1994).

Somatostatin, GHRH and GHRP triology

Tri-peptidyl interactions operate in the rat and human, since experimentally reducing SSergic input will markedly amplify invivo dual-agonist (GHRH/GHRP)

FIG. 5. Synergistic stimulation of GH secretion by bolus injection of GHRH (1 mg/kg) and GHRP2 (1 mg/kg) in middle-aged men, which can be enhanced further by post-SS (octreotide) rebound. See text for details.

synergy (Arvat et al 1998, Bowers 1998, Smith et al 1997). Indeed, co-infusion ofL-arginine (to withdraw SS) and GHRH or GHRP, or all three stimuli combined, will evoke supra-additive GH secretion in older humans, which is equivalent to that achieved in young adults (Arvat et al 1998, Bowers 1998). These data are consistent with excessive SSergic restraint and combined GHRH/GHRP deficiency in ageing (Bowers 1998, Giustina & Veldhuis 1998). In contrast, the magnitude of bihormonal GHRH/GHRP synergy (without L-arginine) wanes substantially in older humans. Accordingly, we propose to examine the endogenous control of all three (SS, GHRH, and GRHP) signalling pathways to better explicate the mechanisms ofhyposomatotropism in the older male.

GH autonegative feedback

An abrupt increase in the GH concentration feeds back physiologically to limit further secretion (Berman et al 1994, Chapman et al 1997, Clark et al 1988, Giustina & Veldhuis 1998, Harel & Tannenbaum 1992, Rosenthal et al 1986). This time-lagged and reversible autoregulatory action probably sustains normal GH pulsatility (Frohman 1996). Autonegative feedback is mediated via GH's stimulation of hypothalamic SS release and reciprocal inhibition of GHRH secretion, without any direct action on somatotropes (Frohman 1996, Smith et al 1997). The ability of testosterone to stimulate GH and IGF1 production simultaneously would suggest that testosterone may act to override such autoinhibition by GH (Gentili et al 2000, Giustina et al 1997, Giustina & Veldhuis 1998, Veldhuis et al 1997).

Integrative issues

The foregoing interactive features of GH neuroregulation highlight the crucial need to explore interactive mechanisms subserving impoverishment of GH/ IGF1 output in the ageing and relatively hypogonadal male. Below we evaluate several such presumptive neuroregulatory mechanisms, which could plausibly mediate testosterone's failing drive of the GH/IGF1 axis in older men.

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