Van Den Berghe and collaborators have pioneered studies on the effects of hypothalamic releasing hormones in patients with severe NTIS. The logic supporting this approach is that it corrects a major cause of the low hormonal state, and may allow normal feed-back control and peripheral regulation of hormones, thus being more physiological than replacing the peripheral hormone deficit directly. Extensive studies document restoration of T4 and T3 levels following administration of TRH and GH secretagaugue (153). In a rabbit model of NTIS treatment with GHRP-2 and TRH reactivated the GH and TSH axes and altered liver deiodinase activity, driving T4 to T3 conversion. In NTIS there are suppressed pulsatile GH, TSH, LH secretion in the face of low serum concentrations of IGF-I, IGFBP-3 and the acid-labile subunit (ALS), thyroid hormones, and total and estimated free testosterone levels, whereas free estradiol (E2) estimates are normal. Ureagenesis and breakdown of bone tissue are increased. Baseline serum TNF-alpha, IL-6 and C-reactive protein level and white blood cell (WBC) count are elevated; serum lactate is normal. 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 (154. Contrary to expectation, intensive insulin therapy suppressed serum IGF-I, IGFBP-3, and acid-labile subunit concentrations. This effect was independent of survival of the critically ill patient. Concomitantly, serum GH levels were increased by intensive insulin therapy. The data suggest that intensive insulin therapy surprisingly suppressed the somatotropic axis despite its beneficial effects on patient outcome. GH resistance accompanied this suppression of the IGF-I axis. To what extent and through which mechanisms the changes in the GH-IGF-IGFBP axis contributed to the survival benefit under intensive insulin therapy remain elusive (155). While outcome studies using this approach are not available, it is quite possible that treatment of NTIS by use of hypothalamic releasing hormones may be a preferred approach.