PITUITARY-RESPONSIVENESS TO GH-RELEASING HORMONE, GH-RELEASING PEPTIDE-2 AND THYROTROPIN-RELEASING-HORMONE IN CRITICAL ILLNESS

OBJECTIVE Protein hypercatabolism and preservation of fat depots are h allmarks of critical illness, which is associated with blunted pulsati le GH secretion and low circulating IGF-I, TSH, T4 and T3, Repetitive TRH administration is known to reactivate the pituitary-thyroid axis a nd to evoke paradoxical GH release in critical illness. We further exp lored the hypothalamic-pituitary function in critical illness by exami ning the effects of GH-releasing hormone (GHRH) and/or GH-releasing pe ptide-2 (GHRP-2) and TRH administration. PATIENTS AND DESIGN Criticall y ill adults (n = 40; mean age 55 years) received two i.v. boluses wit h a 6-hour interval (0900 and 1500 h) within a cross-over design, Pati ents were randomized to receive consecutively placebo acid GHRP-2 (n = 10), GHRH and GHRP-2 (n = 10), GHRP-2 and GHRH + GHRP-2 (n = 10), GHR H + GHRP-2 and GHRH + GHRP-2 + TRH (n = 10). The GHRH and GHRP-2 doses were 1 mu g/kg and the TRH dose was 200 mu g. Blood samples were obta ined before and 20, 40, 60 and 120 minutes after each injection. MEASU REMENTS Serum concentrations of GH, T4, 73, rT3, thyroid hormone bindi ng globulin (TBG),IGF-I, insulin and cortisol were measured by RIA; PR L and TSH concentrations were determined by IRMA, RESULTS Critically i ll patients presented a striking GH response to GHRP-2 (mean +/- SEM p eak GH 51 +/- 9 mu g/l in older patients and 102 +/- 26 mu g/l in youn ger patients; P = 0.005 vs placebo), The mean GH response to GHRP-2 wa s more than fourfold higher than to GHRH (P = 0.007). In turn, the mea n GH response to GHRH + GHRP-5 was 2.5-fold higher than to GHRP-5 alon e (P = 0.07), indicating synergism, Adding TRH to the GHRH + GHRP-2 co mbination slightly blunted this mean response by 18% (P = 0.01). GHRP- 2 had no effect on serum TSH concentrations whereas both GHRH and GHRH + GHRH-2 evoked an increase in peak TSH levels of 53 and 32% respecti vely. The addition of TRH further increased this TSH response > ninefo ld (P = 0.005), elicited a 60% rise in serum T3 (P = 0.01) and an 18% increase in T4 (P = 0.005) levels, without altering rT3 or TBG levels. GHRH and/or GHRP-2 induced a small increase in serum PRL levels. The addition of TRH magnified the PRL response 2.4-fold (P = 0.007). GHRP- 2 increased basal serum cortisol levels (531 +/- 29 nmol/l) by 35% (P = 0.02); GHRH provoked no additional response, but adding TRH further increased the cortisol response by 20% (P = 0.05). CONCLUSIONS The spe cific character of hypothalamic-pituitary function in critical illness is herewith extended to the responsiveness to GHRH and/or GHRP-5 and TRH. The observation of striking bursts of GH secretion elicited by GH RP-2 and particularly by GHRH + GHRP-2 in patients with low spontaneou s GH peaks opens the possibility of therapeutic perspectives for GH se cretagogues in critical care medicine.