Growth hormone axis

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In the acute phase circulating levels of growth hormone (GH) are elevated. The peak GH levels as well as interpulse concentrations are high (Ross et al 1991, Voerman et al 1992) and the GH pulse frequency is increased. Serum insulin-like growth factor (IGF)1 concentrations are low, (Ross et al 1991). The combination of high GH levels and low IGF1 levels has been interpreted as resistance to GH, which may be related to decreased GH receptor expression (Hermansson et al 1997). The other GH-dependent peptides IGF binding protein (IGFBP)3 and acid labile subunit (ALS) are also decreased in the circulation (Baxter 1997, Timmins et al 1996), preceded by a drop in the GH binding protein (GHBP). Circulating levels of the small IGFBPs such as IGFBP1, IGFBP2 and IGFBP6 are elevated (Baxter et al 1998, Rodrigues-Arnao et al 1996). It has been suggested that these changes are brought about by the effects of cytokines such as tumour necrosis factor (TNF)a, interleukin (IL)1 and IL6. The hypothesis is that reduced GH receptor expression and thus low IGF1 levels are the primary events (cytokine-induced) which, in turn, through reduced negative feedback inhibition, induce the abundant release of GH during acute stress, exerting direct lipolytic, insulin-antagonizing and immune-stimulating actions, while the indirect IGF1-mediated effects of GH are attenuated. This explanation is plausible in that such changes would prioritize essential substrates such as glucose, FFAs and amino acids (glutamine) towards survival rather than anabolism. Increased IGFBP3 protease activity in plasma has also been reported, however, and is thought to result in increased dissociation of IGF1 from the ternary complex, thereby shortening the IGF1 half-life in the circulation (Baxter 1997, Gibson & Hinds 1997).

In prolonged critical illness (PCI) the pattern ofGH secretion is very chaotic and the quantity of GH released in pulses is much reduced compared with the acute phase (Van den Berghe et al 1997a, 1998, 1999). Furthermore, although the non-pulsatile fraction is still elevated and the number of pulses is still frequent, mean nocturnal GH concentrations are scarcely elevated compared with the healthy non-stressed condition. The mean nocturnal GH level is about 1 mg/l, though levels are easily detectable and peak GH levels hardly ever exceed 2 mg/l; these results are surprisingly, independent of age, gender, body composition and type of underlying disease (Fig. 1).

The pulsatile component of GH secretion, which is substantially reduced, correlates positively with circulating levels of IGF1, IGFBP3 and ALS, all of which are low (Van den Berghe et al 1997a, 1998, 1999). Thus the more pulsatile GH secretion is suppressed, the lower circulating levels of the GH-dependent IGF1 and ternary complex binding proteins become. This clearly no longer represents a state of GH resistance! The elevated serum levels of GHBP, assumed

FIG. 1. Nocturnal serum concentration profiles of GH, TSH and PRL illustrating the differences between the initial phase (interrupted line) and the chronic phase (dotted line) of critical illness within an intensive care setting. The continuous lines illustrate normal patterns.

to reflect GH receptor expression in peripheral tissues, in PCI patients are in line with recovery of GH-responsiveness with time during severe illness. The low levels of IGF1, IGFBP3, ALS and IGFBP5 are tightly related to biochemical markers of impaired anabolism such as low serum osteocalcin and leptin (Van den Berghe et al 1999). These findings suggest that relative GH deficiency, epitomised by reduced pulsatile GH secretion participates in the pathogenesis of the 'wasting syndrome' especially in the chronic phase of critical illness. Furthermore there is a gender dissociation in that men show a greater loss of pulsatility and regularity within the GH secretory pattern than women (despite indistinguishable total GH output) and concomitantly lower IGF1 and ALS levels (Van den Berghe et al 2000). It remains unknown whether the sexual dimorphism within the GH—IGF1 axis and the fact that males seem to be at higher risk for an adverse outcome from PCI than females is a casual or causal association.

The pathogenesis of the secretory pattern of GH in PCI is probably complex. One of the possibilities is a deficiency of the endogenous GH releasing peptide (GHRP)-like ligand together with reduced somatostatin tone and maintenance of some GH releasing hormone (GHRH) effect. In reality the GH responses to a bolus injection of GHRP are exuberant in long-stay intensive care patients and several-fold higher than the response to GHRH, the latter being normal or often subnormal. GHRH and GHRP evoke a clear synergistic response under these circumstances (Van den Berghe et al 1996), revealing the highest GH response ever reported in a human study (Fig. 2). The pronounced GH responses to secretagogues exclude the possibility that the blunted GH secretion during the chronic phase of critical illness is due either to a lack of pituitary capacity to synthesise GH or to exaggerated somatostatin-induced suppression of GH

FIG. 2. (Upper part) Nocturnal serum GH profiles in the prolonged phase of illness illustrating the effects of continuous infusion of placebo, GHRH (1 mg/kg per h), GHRP2 (1 mg/kg per h) or GHRH plus GHRP2 (1+1 mg/kg per h). The age range of the patients was 62—85 yrs; the duration of illness was between 13—48 days: infusions were started 12 h before the onset of the respective profile. (Lower part) Exponential regression lines have been reported between pulsatile GH secretion and the changes in circulating IGF1, ALS and IGFBP3 obtained with a 45 h infusion of either placebo, GHRP2 or GHRH plus GHRP2. They indicate that the parameters of GH responsiveness increase in proportion to GH secretion up to a point beyond which a further increase in GH secretion has apparently little or no additional effect. In the chronic non-thriving phase of critical illness, GH sensitivity is clearly present in contrast to the acute phase of illness, which is thought to be primarily a condition of GH resistance (Van den Berghe et al 1998).

FIG. 2. (Upper part) Nocturnal serum GH profiles in the prolonged phase of illness illustrating the effects of continuous infusion of placebo, GHRH (1 mg/kg per h), GHRP2 (1 mg/kg per h) or GHRH plus GHRP2 (1+1 mg/kg per h). The age range of the patients was 62—85 yrs; the duration of illness was between 13—48 days: infusions were started 12 h before the onset of the respective profile. (Lower part) Exponential regression lines have been reported between pulsatile GH secretion and the changes in circulating IGF1, ALS and IGFBP3 obtained with a 45 h infusion of either placebo, GHRP2 or GHRH plus GHRP2. They indicate that the parameters of GH responsiveness increase in proportion to GH secretion up to a point beyond which a further increase in GH secretion has apparently little or no additional effect. In the chronic non-thriving phase of critical illness, GH sensitivity is clearly present in contrast to the acute phase of illness, which is thought to be primarily a condition of GH resistance (Van den Berghe et al 1998).

release. The combination of reduced somatostatin tone and deficiency of an endogenous GHRP-like ligand would explain the reduced GH burst amplitude, the increased frequency of spontaneous GH secretory bursts, and the elevated interpulse levels as well as the striking responsiveness to GHRP alone or in combination with GHRH. Females with PCI have a markedly greater GH response to a bolus of GHRP compared with males, a difference which is eliminated when GHRH is injected together with GHRP. Lower endogenous GHRH action in men with PCI possibly due to the concomitant profound testosterone deficiency (Van den Berghe et al 2000) accompanying loss of action of an endogenous GHRP-like ligand with prolonged stress in both genders, may explain this finding.

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