Hypothesis 1 testosterone deprivation accentuates GH autonegative feedback in the ageing male

Autonegative feedback denotes the recognized ability of a GH pulse to inhibit subsequent GH secretion, whether driven spontaneously or by an exogenous GHRH or GHRP stimulus (Carlsson et al 1990, Chihara et al 1981, Clark et al 1988, Rosenthal et al 1986). GH autoinhibition occurs by way of central nervous system (CNS) (rather than pituitary) pathways, which rapidly stimulate SS and repress GHRH secretion (Chihara et al 1981, Pellegrini et al 1996). Autofeedback is non-trivial, since molecular defects of the GH receptor (or IGF1) gene evoke marked secondary GH hypersecretion (Frohman 1996). Conversely, GH secretagogues that putatively oppose SS release, such as L-arginine, overcome GH autofeedback. Thus, GH autonegative feedback influences the activity of each primary neuroregulatory peptide (SS, GHRH and GHRP; Fig. 3).

We have shown that a single i.v. pulse of rhGH reproducibly inhibits subsequent spontaneous (endogenous) GH secretion by 75—80%, as well as that stimulated acutely by bolus GHRH (by 60—75%) and GHRP2 (by 35—50%). GH feeds back less effectively to suppress the GHRP than GHRH stimulus, presumptively because GHRPs partially antagonize SS's actions (Guillaume et al 1994, Bowers 1998). These data suggest the experimental question: does testosterone depletion in older men limit GH and IGF1 output in part by accentuating (hypothalamic SS-mediated) GH autonegative feedback? This issue is additionally noteworthy in view of the recent finding that brain GH receptor density falls in older humans. Since CNS GH receptors mediate GH autofeedback (Giustina & Veldhuis 1998), their attrition in ageing could forecast a countervailing interpretation of waning GH autofeedback. However, oestrogen elevates hypothalamic (and represses liver) GH receptor expression, at least in the rat. Thus, relative oestrogenization in ageing men might actually accentuate GH receptor-dependent autonegative feedback. Given these provocative and divergent regulatory issues, we believe that GH autofeedback studies will be important to pursue in androgen-deficient and androgen-replete older men.

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