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

Objective. The therapeutic success of low doses of glucocorticoids is media ted entirely by classical genomic effects, whereas that of high doses is al so mediated to an as yet unknown extent by nongenomic effects. We assessed the relative therapeutic importance of these nongenomic effects in pulse th erapy. Methods. A [H-3]dexamethasone radioligand binding assay was used to measure the number of glucocorticoid receptor sites (R, given as number of sites p er cell) and glucocorticoid receptor binding affinity (K-d, 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), less th an or equal to 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 K-d were found. Ar 5407 +/- 1968, the number of receptor sites in p atients not receiving glucocorticoid therapy (Group A) was significantly hi gher than that of controls (p < 0.01). In patients receiving glucocorticoid therapy this value was reduced at 3855 +/- 866 (Group B), 3358 +/- 963 (Gr oup C), and 2685 +/- 962 (Group D). The values in Groups C and D were signi ficantly 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 r eceptor downregulation occurs. Therefore, we assume an increase in the rela tive contribution of the nongenomic effects of glucocorticoids to the thera peutic success under these conditions.