Physiological synergy between the actions of GH and testosterone

GH and testosterone stimulate skeletal and muscular growth synergistically in late puberty (Giustina & Veldhuis 1998, Keenan et al 1993, Klindt et al 1990, Zachmann 1992). Recent studies also document target-tissue synergy between GH and androgen in healthy older men. Thus, restoring both GH and testosterone output in the older male by nearly physiological means would be important. However, the precise mechanistic basis for joint failure of GH and testosterone secretion in ageing is not known. To this end, a better comprehension of their interactive neuroendocrine control will be required.

Basic linkages between the somatotropic and gonadal axes

Extensive clinical data affirm that testosterone bioavailability and GH secretion rise in parallel in puberty and fall concurrently in ageing (Fig. 1; Copinschi & Van Cauter 1994, Dudl et al 1973, Giustina & Veldhuis 1998, Corpas et al 1992, Fryburg et al 1997, Hartman et al 1991, Iranmanesh et al 1991, 1994, Martha et al

1992, Mulligan et al 1999a, Veldhuis et al 1991,1995). Causality is inferable since, at least in androgen-deficient individuals, administration of testosterone effectually drives the secretion of both GH and IGF1, and augments local tissue-specific IGF1 activity (Fryburg et al 1997, Gentili et al 2000, Snyder et al 1999, Urban et al 1995, Wennink et al 1990). Conversely, GH and IGF1 amplify the biosynthesis and tissue actions of androgens (Balducci et al 1993, Carani et al 1999, Giustina & Veldhuis 1998, Kulin et al 1981, Lin et al 1986). Thus, testosterone positively modulates the secretion and activity of the GH/IGF1 system (Fryburg et al 1997, Gentili et al 2000, Veldhuis et al 1997), whereas GH and IGF1 impact the production and effects of testosterone. Deficits in one or more of the foregoing interactions may contribute to the pathophysiology of combined GH and androgen deficiency in ageing, systemic illness and debilitated states.

Our recent clinical studies document that testosterone retains full efficacy in driving threefold amplification of pulsatile, 24 h rhythmic and entropic GH secretion in older men, as otherwise observed in boys and young men (Fryburg et al 1997, Gentili et al 2000, Shah et al 1999a, Veldhuis et al 1997, 2000a). However, the exact neuroendocrine mechanisms that mediate these stimulatory actions of testosterone are not established at any age. The following observations underscore possible clues to and the implications of elucidating such basic mechanistic pathways.

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