The combined administration of GH-releasing peptide-2 (GHRP-2), TRH and GnRH to men with prolonged critical illness evokes superior endocrine and metabolic effects compared to treatment with GHRP-2 alone

Abstract

Central hyposomatotrophism, hypothyroidism and hypogonadism are present concomitantly in men with prolonged critical illness. This study evaluated the impact of combined treatment with GH-releasing peptide-2 (GHRP-2), TRH and GnRH for 5 days compared with GHRP-2 + TRH and with GHRP-2 alone. Thirty-three men with prolonged critical illness participated at baseline compared to 50 age- and body mass index (BMI)-matched controls. Patients were randomly assigned to 5 days of placebo (n = 7), GHRP-2 (1 microg/kg/h; n = 9), GHRP-2 + TRH infusion (1 + 1 microg/kg/h; n = 9) or pulsatile GnRH (0.1 microg/kg every 90 min) together with GHRP-2 + TRH infusion (n = 8). GH, TSH and LH secretion were quantified by deconvolution analysis of serum concentration time series obtained by sampling every 20 min from 2100 to 0600 h at baseline and on nights 1 and 5 of treatment. Serum concentrations of IGF-I, IGFBPs, thyroid hormones, gonadal and adrenal steroids, proinflammatory cytokines and selected metabolic and inflammation markers were measured daily. Patients revealed suppressed pulsatile GH, TSH and LH secretion in the face of low serum concentrations of IGF-I, IGFBP-3 and the acid-labile subunit (ALS) (P < 0.0001 each), thyroid hormones (P < 0.0001) and total and estimated free testosterone (P < 0.0001) levels, whereas free oestradiol (E2) estimates were normal. Serum dehydroepiandrosterone sulphate (DHEAS) levels were also suppressed whereas morning cortisol was normal. Serum levels of type I procollagen (PICP) and bone alkaline phosphatase (sALP) were elevated whereas osteocalcin (OC) was low (P = 0.03). Ureagenesis (P < 0.0001) and breakdown of bone tissue (P < 0.0001) were increased. Baseline serum TNF-alpha, IL-6 and C-reactive protein level and white blood cell (WBC) count were elevated; serum lactate was normal. Only low T4 and high IGFBP-1 levels independently predicted mortality. GHRP-2 infusion reactivated GH secretion and normalized serum IGF-I, IGFBP-3 and ALS. GHRP-2 + TRH infusion reactivated both the GH axis and the thyroid axis, with normal levels of T4 and T3 reached within 1 day. Only GHRP-2 + TRH infusion combined with GnRH pulses reactivated the GH and TSH axis and at the same time increased pulsatile LH secretion compared to placebo. Only GnRH pulses together with GHRP-2 + TRH infusion increased testosterone significantly from day 2 (peak increase of + 312%) through day 5 and serum E2 with > 80% from day 1 through day 3 (all P = 0.05). Ureagenesis was reduced by GHRP-2 + TRH + GnRH (P = 0.01) and by GHRP-2 + TRH (P = 0.009) but not by GHRP-2 alone. Serum OC levels were increased only by GHRP-2 + TRH + GnRH (P = 0.03), with a trend for GHRP-2 + TRH (P = 0.09), but not by GHRP-2 alone. On day 5, serum lactate levels and WBC count were increased by GHRP-2 infused alone and in combination with TRH but not by GHRP-2 + TRH + GnRH. Coadministration of GHRP-2, TRH and GnRH reactivated the GH, TSH and LH axes in prolonged critically ill men and evoked beneficial metabolic effects which were absent with GHRP-2 infusion alone and only partially present with GHRP-2 + TRH. These data underline the importance of correcting the multiple hormonal deficits in patients with prolonged critical illness to counteract the hypercatabolic state.