The hypothalamic release andor actions of SS in ageing men

Beyondits primary repressive role (above), SS paradoxically maintains somatotrope responsiveness to recurrent stimulation by secretagogues (Baumbach et al 1998,

Kraicer et al 1986, Sugihara et al 1989). Specifically, intermittent SS exposure obviates the biochemical down-regulation of GH secretion induced by repeated GHRH and GHRP stimuli (Smith et al 1997). Thus, a critical mechanistic question is whether testosterone depletion limits GH secretion in part by augmenting sustained rather than intermittent SSergic activity (Fryburg et al 1997, Giustina et al 1997, Giustina & Veldhuis 1998, Veldhuis et al 1997).

Clinical studies are particularly pertinent here, in view of possible species differences in SS and androgen physiology (Argente et al 1990, Painson et al 2000, Pincus et al 1997). For example, in the rat, non-aromatizable androgens (but not oestrogen) stimulate GH secretion and up-regulate hypothalamic SSergic activity. In contrast, in the human, non-aromatizable androgens (stanozolol, fluoxymesterone, oxandrolone and 5a-DHT) do not stimulate GH secretion consistently (Devesa et al 1991, Fryburg et al 1997, Giustina & Veldhuis 1998, Keenan et al 1993, Veldhuis et al 1997). Thus, aromatizable and nonaromatizable androgen actions are readily distinguishable in the two species, whereas testosterone's impact on SSergic signalling may not be distinctive.

Clinical studies of this issue are further relevant in older humans, in whom accentuated SS inhibition is widely inferred, but its susceptibility to relief by sex-steroid hormone repletion is unknown (Chihara et al 1981). Our pilot data document that short-term testosterone administration in older men exerts qualitatively identical actions to those reported in hypogonadal boys and young men (Fryburg et al 1997, Gentili et al 2000, Giustina et al 1997, Veldhuis et al 1997); specifically: (i) augmentation of GH secretory burst mass and basal GH release; (ii) amplification of the 24 h rhythmicity of GH secretion; (iii) heightening of the irregularity (approximate entropy) of GH release; and (iv) elevation of plasma IGF1 concentrations (Fig. 6). All four responses are strongly controlled by SS under various pathophysiological conditions (Giustina & Veldhuis 1998, Mueller et al 1999, Mulligan et al 1999b). For example, we have shown that SS or octreotide infusions selectively suppress GH secretory burst mass and basal GH release in young and older men (Mulligan et al 1999b). Likewise, SSergic inputs likely influence the 24 h rhythmicity of GH secretion, since the latter persists during an unvarying exogenous GHRH or GHRP2 infusion (Evans et al 2000, Iranmanesh et al 1998, Shah et al 1999a, 2000). In corollary, SS signalling governs the quantifiable irregularity (entropy) of GH secretory patterns (Gevers et al 1998, Pincus et al 1996, Straume et al 1995). Lastly, longer-term inhibition of GH output by SS clearly lowers IGF1 production. Testosterone strongly impacts each of these four categories of GH/IGF1 responsiveness in older men (Gentili et al 2000), thus pointing to (but not proving) its ability to control SSergic signalling the elderly male.

Available clinical data do not exclude an opposing hypothesis that an aromatizable androgen actually elevates SSergic input, as reported for both

FIG. 6. Fourfold stimulation by short-term (3 week) parenteral testosterone supplementation of: (i) GH secretory burst mass; (ii) 24 h rhythmic GH release; (iii) GH ApEn (irregularity measure); and (iv) serum IGF1 concentrations in older men

aromatizable and non-aromatizable androgens in the rodent (Giustina & Veldhuis 1998, Mueller et al 1999, Chihara et al 1981, Frohman 1996). Indeed, diethylstilbestrol administration to young men and the normal preovulatory milieu in young women enhance GH release stimulated by secretagogues that putatively withdraw SSergic restraint (Frantz & Rabkin 1965). Given such divergent clinical data, it will be crucial to clarify how testosterone deficiency modulates SSergic signalling in the human.

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