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Reactivation of Pituitary Hormone Release and Metabolic Improvement by Infusion of Growth Hormone-Releasing Peptide and Thyrotropin-Releasing Hormone in Patients with Protracted Critical Illness¹

Department of Intensive Care Medicine (G.V.d.B., P.W., F.W.) and Laboratory for Experimental Medicine and Endocrinology (R.B.), University Hospital Gasthuisberg, University of Leuven, B-3000 Leuven, Belgium; Loma Linda University, Jerry L. Pettis Veterans Administration Medical Center (S.M.), Loma Linda, California 92357; Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney University (R.C.B.), St. Leonards, New South Wales 2065, Australia; the Department of Medicine, Division of Endocrinology, University of Virginia Health Sciences Center (J.D.V.), Charlottesville, Virginia 29908; and the Department of Medicine, Division of Endocrinology, Tulane University Medical Center (C.Y.B.), New Orleans, Louisiana 70112-2699

Address all correspondence and requests for reprints to: Greet Van den Berghe, M.D., Ph.D., Department of Intensive Care Medicine, University Hospital Gasthuisberg, University of Leuven, B-3000 Leuven, Belgium. E-mail: greta.vandenberghe{at}uz.kuleuven.ac.be

Protracted critical illness is marked by protein wasting resistant to feeding, by accumulation of fat stores, and by suppressed pulsatile release of GH 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 combined GHRP-2 and TRH infusion for 5 days, which allowed a limited evaluation of 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 subjects at baseline and subsequently received 5 days of placebo and 5 days of GHRP-2 plus TRH (1+1 µg/kg·h) infusion in random order.

At baseline, impaired anabolism, as indicated by biochemical markers (osteocalcin and leptin), was linked to hyposomatotropism [reduced pulsatile GH secretion, as determined by deconvolution analysis, and low GH-dependent insulin-like growth factor and binding protein (IGFBP) levels]. Biochemical markers of accelerated catabolism (increased protein degradation and bone resorption) were related to tertiary hypothyroidism and the serum concentration of IGFBP-1, but not to hyposomatotropism. Metabolic markers were independent of elevated serum cortisol.

After 5 days of GHRP-2 plus TRH infusion, osteocalcin concentrations increased 19% vs. -6% with placebo, and leptin had rose 32% vs. -15% with placebo. These anabolic effects were linked to increased IGF-I and GH-dependent IGFBP, which reached near-normal levels from day 2 onward. In addition, protein degradation was reduced, as indicated by a drop in the urea/creatinine ratio, an effect that was related to the correction of tertiary hypothyroidism, 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 detectably altered.

In conclusion, 5-day infusion of GHRP-2 plus TRH in protracted critical illness reactivates blunted GH and TSH secretion, with preserved pulsatility, peripheral responsiveness, and feedback inhibition and without affecting serum cortisol, and induces a shift toward anabolic metabolism. This provides the first evidence of the metabolic effectiveness of short term GHRP-2 plus TRH agonism in this particular wasting condition.

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