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This version published online on October 9, 2003
Endocrinology, doi:10.1210/en.2003-1005
A more recent version of this article appeared on January 1, 2004
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Submitted on August 5, 2003
Accepted on September 30, 2003

Endocrine and metabolic effects of growth hormone (GH) compared with GH-releasing peptide, thyrotropin-releasing hormone and insulin infusion in a rabbit model of prolonged critical illness

Frank Weekers1*, Marina Michalaki1, Willy Coopmans1, Eric Van Herck1, Johannes D. Veldhuis1, Veerle M. Darras1, and Greet Van den Berghe1

1 Department of Intensive Care Medicine, Burn Unit and Center for Experimental Surgery & Anesthesiology (FW, MM and GVdB), Laboratory for Experimental Medicine and Endocrinology (EVH, WC), Laboratory for Comparative Endocrinology (VMD), Catholic University of Leuven, Leuven, Belgium and Department of Medicine, Mayo Graduate and Medical Schools, Mayo Clinic, Rochester MN 55905 (JDV).

* To whom correspondence should be addressed. E-mail: Frank.Weekers{at}uz.kuleuven.ac.be.

Treatment with rhGH increases mortality of critical illness. We postulated that combined GHRP-2, TRH and insulin infusion is a less toxic anabolic strategy through a putative inability to overstimulate the GH axis and a capacity to normalize thyroid hormone concentrations while foregoing excessive hyperglycemia. Burn-injured, parenterally fed New Zealand White rabbits were randomized to receive 4 days saline (n = 8), 60 µg/kg/h GHRP-2 + 60 µg/kg/h TRH intravenously (n = 9) or 3.5 mg/kg rhGH subcutaneously (n = 7). In the GHRP-2+TRH group, insulin was adjusted to maintain blood glucose <180 mg/dl. Endocrine function and biochemical organ-system function markers were studied. Animals were killed for assay of deiodinase activity in snap-frozen liver. Mortality, organ-system function, hyperglycemia and insulin requirement were equal in the 3 groups. GHRP-2+TRH increased pulsatile rabbit GH (rGH) and TSH release on day 1. After 4 days, rGH secretion, T4 and T3 concentrations were elevated, with a significant increase in hepatic activity of type 1 deiodinase (D1) and decrease in type 3 deiodinase (D3). Exogenous rhGH suppressed endogenous rGH secretion and increased IGF-I more than GHRP-2+TRH, without altering thyroid hormones. Unlike GHRP-2+TRH, rhGH downregulated liver D3 and did not affect D1. We conclude that in experimentally induced critical illness, GHRP-2+TRH reactivated the GH and TSH axes and altered liver deiodinase activity, driving T4 to T3 conversion. In contrast to the human, high dose rhGH was not rapidly lethal in this rabbit model. Whether this is explained by lack of rhGH-induced insulin resistance and hyperglycemia remains unclear.
Key words: stress • growth hormone • GHRP-2 • IGF-I • thyrotropin • thyroid hormone • catabolic state • rabbit




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