Glucocorticoid dose dependent downregulation of glucocorticoid receptors in patients with rheumatic diseases.

OBJECTIVE: The therapeutic success of low doses of glucocorticoids is mediated entirely by classical genomic effects, whereas that of high doses is also mediated to an as yet unknown extent by nongenomic effects. We assessed the relative therapeutic importance of these nongenomic effects in pulse therapy.
METHODS: A [3H]dexamethasone radioligand binding assay was used to measure the number of glucocorticoid receptor sites (R, given as number of sites per cell) and glucocorticoid receptor binding affinity (Kd, given in nM) in peripheral blood mononuclear cells isolated from 26 healthy control blood donors and 27 patients with rheumatic diseases. Patients were divided into 4 groups on the basis of their glucocorticoid dose: 0 mg (Group A), < or = 0.25 mg (Group B), 0.25 to 1 mg (Group C), and > 1 mg (Group D) of prednisolone equivalent per kg per day.
RESULTS: Sex independent normal values of 3605 +/- 1136 for R and 5.39 +/- 3.4 for Kd were found. At 5407 +/- 1968, the number of receptor sites in patients not receiving glucocorticoid therapy (Group A) was significantly higher than that of controls (p < 0.01). In patients receiving glucocorticoid therapy this value was reduced at 3855 +/- 866 (Group B), 3358 +/- 963 (Group C), and 2685 +/- 962 (Group D). The values in Groups C and D were significantly lower than those in untreated patients (p < 0.02).
CONCLUSION: In pulse therapy doses of glucocorticoids that exceed receptor saturation are administered for several days, but in addition significant receptor downregulation occurs. Therefore, we assume an increase in the relative contribution of the nongenomic effects of glucocorticoids to the therapeutic success under these conditions.