Protein wasting is a complication of glucocorticoid (GC) therapy. It causes substantial morbidity and there is no treatment. This thesis investigates the metabolic mechanisms underlying GC-induced protein wasting and the potential for anabolic hormones to reverse protein loss. The models of GC excess were Cushing's syndrome and GC therapy. Whole body protein metabolism was assessed using the leucine turnover technique and body composition by dual-energy X-ray absorptiometry to estimate lean body mass (LBM) and fat mass (FM). As previous studies demonstrated that LBM and FM influenced rates of protein metabolism, the magnitude of body compositional abnormality in Cushing's syndrome was determined. After accounting for the greater FM (30%) and lesser LBM (15%), protein metabolism in Cushing's syndrome was characterised by a significant increase in protein oxidation, an abnormality that leads to irreversible protein loss. Successful treatment of Cushing's syndrome normalised protein oxidation. Studies of the acute and chronic effects of therapeutic GCs revealed a time-dependent effect on protein metabolism. GCs acutely increased protein oxidation. However, the rate of protein oxidation during chronic therapy at a similar dose was not significantly different to untreated control subjects. This time-dependent change suggests that GC-induced stimulation of protein oxidation does not persist and could represent a metabolic adaptation to limit protein loss. This finding contrasts with that in Cushing's syndrome, where protein oxidation is persistently elevated. This difference may represent a dose effect. Studies in GH-deficient subjects revealed that GH induced a fall in protein oxidation that was significantly correlated with a subsequent gain in LBM. This suggests that the anabolic potential of a therapeutic substance can be predicted by its ability to suppress protein oxidation acutely. Finally, the potential for GH and androgens to reverse the metabolic effects of GCs was assessed. A preliminary study in GC users revealed that a GH dose of 0.8 mg/d was effective in reducing protein oxidation. In a subsequent study, the GH-induced reduction in protein oxidation in women on GCs was enhanced by combined treatment with dehydroepiandrosterone, an androgen. In summary, GCs induce protein loss by stimulating protein oxidation. GH reverses this effect and this action is enhanced by coadministration of androgens. GH and androgens may be used therapeutically to prevent protein loss induced by GCs.
| Identifer | oai:union.ndltd.org:ADTP/215490 |
| Date | January 2007 |
| Creators | Burt, Morton Garth, St Vincent's Clinical School, UNSW |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | http://unsworks.unsw.edu.au/copyright, http://unsworks.unsw.edu.au/copyright |
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