Reactivation of pituitary hormone release and metabolic improvement by infusion of growth hormone-releasing peptide and thyrotropin-releasing hormonein patients with protracted critical illness

Protracted critical illness is marked by protein wasting resistant to feedi ng, by accumulation of fat stores, and by suppressed pulsatile release of G H and TSH. We previously showed that the latter can be reactivated by brief infusion of GH-releasing peptide (GHRP-2) and TRH. Here, we studied combin ed GHRP-2 and TRH infusion for 5 days, which allowed a limited evaluation o f the metabolic effectiveness of this novel trophic endocrine strategy. Fourteen patients (mean +/- SD age, 68 +/- 11 yr), critically ill for 40 +/ - 28 days, were compared to a matched group of community-living control sub jects at baseline and subsequently received 5 days of placebo and 5 days of GHRP-2 plus TRH (1+1 mu g/kg . h) infusion in random order. At baseline, impaired anabolism, as indicated by biochemical markers (osteo calcin and leptin), was linked to hyposomatotropism [reduced pulsatile GH s ecretion, as determined by deconvolution analysis, and low GH-dependent ins ulin-like growth factor and binding protein (IGFBP) levels]. Biochemical ma rkers of accelerated catabolism (increased protein degradation and bone res orption) were related to tertiary hypothyroidism and the serum concentratio n of IGFBP-1, but not to hyposomatotropism. Metabolic markers were independ ent of elevated serum cortisol. After 5 days of GHRP-2 plus TRH infusion, osteocalcin concentrations increa sed 19% vs. -6% with placebo, and leptin had rose 32% us. -15% with placebo . These anabolic effects were Linked to increased IGF-I and GH-dependent IG FBP, which reached near-normal levels from day 2 onward. In addition, prote in degradation was reduced, as indicated by a drop in the urea/creatinine r atio, an effect that was related to the correction of tertiary hypothyroidi sm, with near-normal thyroid hormone levels reached and maintained from day 2 onward. Concomitantly, a spontaneous tendency of IGFBP-1 to rise and of insulin to decrease was reversed. Cortisol concentrations were not detectab ly altered. In conclusion, 5-day infusion of GHRP-2 plus TRH in protracted critical ill ness reactivates blunted GH and TSH secretion, with preserved pulsatility, peripheral responsiveness, and feedback inhibition and without affecting se rum cortisol, and induces a shift toward anabolic metabolism. This provides the first evidence of the metabolic effectiveness of short term GHRP-2 plu s TRH agonism in this particular wasting condition.