Decreased plasma cholesterol esterification and cholesteryl ester transfer in hypopituitary patients on glucocorticoid replacement therapy

Abstract

Cardiovascular risk is increased in hypopituitary patients. No data are available with respect to the effect of glucocorticoid replacement therapy on high density lipoproteins (HDL) metabolism in such patients. Plasma lecithin:cholesterol acyl transferase (LCAT), cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP) are important determinants of HDL remodelling. The possible influence of conventional glucocorticoid replacement on plasma lipids, plasma LCAT, CETP and PLTP activity levels, as well as on plasma cholesterol esterification (EST) and cholesteryl ester transfer (CET) was evaluated in 24 consecutive hypopituitary patients (12 men and 12 women) with untreated growth hormone deficiency of whom 17 had adrenal insufficiency and were treated with cortisone acetate, 25 to 37.5 mg daily. Twenty-three patients were on stable levothyroxin therapy and 22 patients used sex steroids. Urinary excretion of cortisol and cortisone metabolites was higher (p<0.001) in glucocorticoid-treated patients. Body mass index (p<0.08) and fat mass (p<0.12) were not significantly different in patients receiving and not receiving glucocorticoids. Fasting blood glucose, plasma insulin and insulin resistance were similar in the groups. Plasma total (p<0.05) and very low+low density lipoprotein cholesterol (p<0.01) were lower in patients receiving glucocorticoids, whereas HDL cholesterol and plasma triglycerides were not different between patients treated and not treated with glucocorticoids. Plasma LCAT activity was 45% lower (p<0.02) and CETP activity was 34% lower (p<0.05) in patients on glucocorticoid treatment. Multiple regression analysis showed that these effects were independent of gender and fat mass. In glucocorticoid-receiving patients, plasma EST and CET were decreased by 80% (p<0.01) and by 58% (p<0.05), respectively. These changes were at least partly attributable to lower LCAT and CETP activity levels. In contrast, plasma PLTP activity was not different between patients with and without glucocorticoid treatment, suggesting that exogenous glucocorticoids exert a different regulatory effect on plasma CETP compared to PLTP. In conclusion, this preliminary study suggests that conventional glucocorticoid replacement in hypopituitary patients is associated with a decrease in plasma cholesterol esterification and cholesteryl ester transfer, indicating that these steps in HDL metabolism are impaired. Such abnormalities in HDL metabolism could be involved in increased cardiovascular risk in glucocorticoid-treated hypopituitary patients, despite a lack of deterioration in plasma lipids.

Common Variation in the CETP Gene and the Implications for Cardiovascular Disease and its Treatment: An Updated Analysis

“…Furthermore, we have documented that the association of HDL cholesterol with the -629 C→A CETP polymorphism is blunted in growth hormone-replaced hypopituitary patients treated with glucocorticoids for adrenal insufficiency, a patient category in which plasma triglycerides are also high [64]. Since glucocorticoids have been found to lower plasma CETP activity and cholesteryl ester transfer [65], it is possible that in case of glucocorticoid supplementation, the HDL effect of CETP gene variation is diminished as a result of lower plasma cholesteryl ester transfer despite higher triglycerides. Finally, the effect of CETP variation on HDL cholesterol has also been evaluated in patients with Type 1 and Type 2 diabetes mellitus.…”

Extensive Regulation of Diurnal Transcription and Metabolism by Glucocorticoids

“…This may be linked to an inadequate replication of the natural circadian GC rhythm [7]. Only limited information is available on the metabolic changes present in patients with AI [8,9], particularly with respect to their temporal dynamics. Animal models, preferentially with a diurnal lifestyle, could contribute to improve therapy by providing a mechanistic understanding of metabolic dysregulation in AI.…”

Investigation of glucocorticoid receptor polymorphisms in relation to metabolic parameters in Addison's disease

“…Beentjes et al showed that hypopituitary patients who were not supplemented with GH, and were evaluated before and after receiving hydrocortisone replacement, had decreased plasma cholesterol esterification when given hydrocortisone, and thus, HDL production may be impaired in AD in the same way. Hydrocortisone decreases LCAT activity, explaining this phenomenon (36).…”