Use of GHRH in Therapy

Even when the acute GH response to GHRH is reduced, repeated doses of GHRH can produce increases in GH and IGF-1 levels in normal older subjects, and thus GHRH could potentially be used to stimulate GH secretion chronically as an alternative to GH treatment. The overall utility of this type of treatment is subject to many of the same unresolved questions as concern GH administration, but there are several physiologic and practical considerations that may eventually favor the use of secretagogues over GH in those settings (if any) in which GH enhancement ultimately proves useful. The GH response to GHRH is modulated by negative feedback inhibition by IGF-1 and somatostatin, and these physiologic modulators may partially buffer against overtreatment. In some settings, the biologic response to GH is modulated by its pattern of administration (pulsatile vs continuous) as well as by the total quantity administered (45). In this context the pulsatile pattern of GH evoked even by continuous infusions of GHRH may prove advantageous. Although the GH response to GHRH treatment in aging may be blunted by increased somatostatin tone, a variety of enhancing adjuvants, including ^-adrenergic antagonists, arginine, and the combination of GHRH with GHRP's, can boost those responses. As noted, in the context of pediatric GH deficiency chronic suppression of somatostatin can also augment the therapeutic response (37), but it is not known whether this is also true in aging.

Fig. 10. GH plasma levels (± SD) measured over 24 h in young (A) and older men (B) at baseline, and in older men during treatment with GHRH(1-29)NH2, 0.5 mg (C) or 1 mg (D) sc twice daily. Arrowheads show the times of the GHRH injections. From ref. 47.

To date, most studies of GHRH treatment in aging have been of short duration (six weeks or less), long enough to assess endocrine-metabolic responses but not changes in body composition or function. Corpas et al. showed that either continuous infusions (46) or twice-daily subcutaneous injections (47) of 0.5 or 1 mg GHRH(1-29)NH2 could stimulate GH secretion (Fig. 10) and elevate plasma levels of IGF-1 in healthy older men, reaching normal young adult IGF-1 values with the higher dose. Vittone et al. recently described the effects of six weeks of open-label treatment in 11 healthy older men with the same total daily dose of GHRH (2 mg sc) as in the earlier high-dose study, but given as a single bedtime injection (48). Two measures of muscle strength improved; but in this study plasma IGF-1 and IGFBP-3 levels did not rise. The authors concluded that divided doses of GHRH may be more effective than a single higher dose.

The only published study of longer duration to date is the report of Khorram et al., in which single nightly injections of a GHRH analog were given for 16 wk (49). Lean body mass increased in men but not in women in this study group. Two longer-term studies using single nightly injections of 1 mg GHRH(1-29)NH2 are in progress at the University of Washington. The first examines the combined effects of six months' treatment with GHRH or placebo, together with strength or endurance conditioning exercise, upon metabolism, body composition, and physical functional performance (50). The second focuses upon effects upon pulsatile GH secretion, sleep, and cognition.

Preliminary results from this latter study are encouraging, but also highlight the practical limitations of the current formulation of GHRH. Once-nightly GHRH stimulates an increase in 24-h GH secretion in both men and estrogen-replaced women. In men there is an approx 40% increase in circulating IGF-1, with a lesser effect in the women; and there is an approx 5% decrease in body fat in both sexes (55). These preliminary findings are consistent with the gender difference in responses reported by Khorram and colleagues (49), and with reports of a lesser response in women to treatment with GH (56). The stimulation of GH secretion, however, is restricted to the acute response in the 2-3 h immediately following the GHRH injections. There is no enhancement of spontaneous GH secretion later in the night, and the rise in IGF-1 may even inhibit late-night GH pulses. Thus, a longer-acting GHRH preparation will be needed to stimulate all-night episodic GH secretion.

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