Effects of intranasal glucocorticoids on endogenous glucocorticoid peripheral and central function

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Background: In a previous study, we reported a 4-fold increase in serum leptin following total parenteral nutrition given after surgery. We hypothesised that the perioperative fasting and stress contributed to this, possibly mediated by increased serum insulin and cortisol. Objective: To test the hypothesis that fasting, in combination with glucocorticoids, sensitises the leptin response to subsequent energy intake. Design: Healthy volunteers were randomised into two groups, one group received dexamethasone (DEX), 0.1 mg twice daily for 3 days, while the other group served as a control. Each group was then subdivided into two feeding protocols. Protocol 1, where a standard meal was given at 0, 24, 36 and 48 h and protocol 2 where the same meal was given at 0 and 48 h. Blood samples were drawn before, as well as every other hour during the study period for determination of serum leptin, insulin, glucose and cortisol concentrations. Results: In all groups serum leptin increased significantly following each meal ðP , 0:01Þ: The rise in serum leptin in response to the standard meal was higher when the meal was taken in the evening ðP , 0:001Þ or following longer duration of fasting ðP , 0:02Þ: In those fasting for 48 h, leptin decreased by 60% and showed no diurnal variation. DEX intake increased leptin concentrations in those fasting for short periods ðP , 0:02Þ but not for 48 h. Conclusions: Long durations of fasting sensitise the response of leptin to subsequent energy intake and abolish the DEX-induced upregulation of leptin. Meal timing is an important factor determining the leptin diurnal rhythm, but other factors must contribute since the leptin response to a standard meal taken in the evening was greater than to the same meal taken in the morning.

Section: A Elimam and C Marcusmentioning

confidence: 98%

Meal timing, fasting and glucocorticoids interplay in serum leptin concentrations and diurnal profile

Elimam

Marcus²

2002

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“…Table 2 Correlations between serum cortisol concentrations and cortisol receptor characteristics in patients with Cushing's syndrome (n = 13) and in control subjects (n = 14). (7,8). The possible mechanism of this receptor downregulation is poorly understood.…”

Section: European Journal Of Endocrinology (2000) 142mentioning

confidence: 99%

“…It is now well established that the ability of GCs to exert their biological effects requires the presence of a sufficient amount of intact receptor molecules (4,6). There is evidence that GRs undergo down-regulation after exposure to ligand in vitro, in animals and men (7,8). This receptor down-regulation is supposed to be an additional form of negative feedback regulation of GC action, apart from the regulation of GC serum levels by the HPA-axis (6).…”

Section: Introductionmentioning

confidence: 99%

Decreased ligand affinity rather than glucocorticoid receptor down-regulation in patients with endogenous Cushing's syndrome

Huizenga¹,

Herder²,

Koper³

et al. 2000

Objective: Glucocorticoids (GCs) serve a variety of important functions throughout the body. The synthesis and secretion of GCs are under the strict influence of the hypothalamo-pituitary-adrenal axis. The mechanisms of action of GCs are mediated by the intracellular glucocorticoid receptor (GR). Over the years, many studies have been performed concerning the regulation of GR expression by GC concentrations. Methods: In the present study, we determined the characteristics of the GR in peripheral mononuclear blood leukocytes (PBML) from thirteen patients with endogenous Cushing's syndrome and fifteen control subjects, using a whole cell dexamethasone binding assay. Furthermore, cortisol concentrations were determined in order to investigate a possible relationship between serum cortisol levels and receptor characteristics. Results: There were no differences in mean receptor number between patients and controls. On the other hand, a significantly lower ligand affinity was identified in cells from patients with Cushing's syndrome compared with controls. A complete normalisation of the ligand affinity was observed after treatment in the only patient tested in this respect, whereas the receptor number was not affected. In patients, there was a statistically significant negative correlation between cortisol concentrations and ligand affinity, which was not found in controls. Conclusion: Receptor down-regulation does not occur in PBML from patients with endogenous Cushing's syndrome. On the other hand, there seems to be a diminished ligand affinity which possibly reflects receptor modification in response to exposure to the continuously high cortisol levels in patients with Cushing's syndrome. This assumption is substantiated by the fact that in one patient a normalisation of the ligand affinity after complete remission of the disease was seen.

“…This was done to exclude stress as the cause of the difference in cortisol levels the first time the experiment was performed. A long period was left between the measurements because of our previous finding that the hypothalamic-pituitary-adrenal axis is affected for a long time after exposure to low doses of glucocorticoids (28).…”

Section: Subjects and Experimental Protocolmentioning

confidence: 99%

Variations in glucocorticoid levels within the physiological range affect plasma leptin levels

Elimam¹,

Knutsson²,

Brönnegård³

et al. 1998

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Objective: Leptin, the obese gene product, is thought to regulate body fat through its action on hypothalamic receptors that influence satiety. The hormonal regulation of leptin is important, since it might affect adiposity. Leptin regulation in man is poorly understood. We studied the relation between endogenous cortisol and leptin levels as well as the acute and chronic effects of a low dose of dexamethasone (DEX) on plasma leptin levels in healthy male volunteers. Subjects and experimental protocol:The correlation between basal plasma levels of leptin and cortisol and the chronic effect of DEX treatment were studied in 12 subjects. Plasma leptin and cortisol levels were determined every other hour for 24 h, before and after 2 weeks of oral administration of 0.1 mg DEX twice daily. The acute effect was studied in 20 subjects, who received 1 mg DEX at 2300 h. Fasting blood samples were taken at 0800 h on the same day (i.e. before DEX) and on the day after. Results: Under basal conditions, we found a correlation between mean plasma levels of leptin and cortisol (r ¼ 0.7, P < 0.02). Mean plasma leptin levels had increased by 50% after 2 weeks of DEX treatment (P < 0.05). The circadian rhythm of leptin was preserved, but the night peak occurred 2.5 h earlier (P < 0.05). Fasting plasma leptin levels were 20% higher 9 h after 1 mg DEX orally than at the same time on the day before (P < 0.002). Conclusion: Physiological variations in cortisol are involved in the regulation of leptin. European Journal of Endocrinology 139 615-620