Hypothesis 2 testosterone depletion reduces the potency andor efficacy of GHRHs actions

GHRH stimulates three major responses in somatotropes: (i) exocytotic release of stored GH (immediate effect); (ii) de novo GH gene transcription and GH synthesis (acute and short-term actions); and (iii) somatotrope cellular hypertrophy and proliferation (longer-term response) (Giustina & Veldhuis 1998, Mueller et al 1999). Whereas few if any studies show consistently positive regulation of the GHRHergic pathway by oestrogen (Argente et al 1991), in the male rat (non-aromatizable) androgens up-regulate hypothalamic GHRH gene and peptide expression and enhance pituitary responsiveness to GHRH (Jansson et al 1993, Mueller et al 1999, Argente et al 1991). Likewise, in leuprolide-down-regulated young men, testosterone addback restores the acute stimulatory effect of GHRH (Devesa et al 1991). Notably, several independent clinical studies suggest that endogenous GHRHergic activity is reduced in the ageing male: (1) intermittent i.v. infusion of GHRH (0.33 mg/kg every 90min for 72 h) amplifies pulsatile GH secretion by several fold in older men, albeit not to young-adult levels (Iranmanesh et al 1998); (2) a GHRH-receptor antagonist inhibits GH secretion more effectively in older than young individuals, consistent with reduced hypothalamic GHRH secretion and/or SS excess (Russell-Aulet et al 1999); and (3) post-SS rebound GH secretion is impaired in the elderly, suggesting limited endogenous GHRH drive (degli Uberti et al 1997). However, how testosterone modulates the GHRHergic pathway in ageing humans remains unknown.

Based on the foregoing physiology, and testosterone's ability to rescue hypo-somatotropism in older men (Gentili et al 2000), we postulate that testosterone can (a) enhance endogenous GHRH secretion and/or (b) facilitate somatotrope responsiveness to GHRH. To this end, we are carrying out clinical experiments to drive the GHRHergic signalling pathway in older men while simultaneously fixing inputs by SS and GHRP before and after testosterone supplementation.

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