A Refill for the Brain Mineralocorticoid Receptor: The Benefit of Cortisol Add-On to Dexamethasone Therapy

Some serious medical conditions require life-saving treatment with high doses of synthetic glucocorticoids such as dexamethasone. A substantial number of patients subjected to this treatment develops psychosis, mood disturbances, or sleep problems. A recent clinical trial demonstrated that dexamethasone therapy for young patients with acute lymphoblastic leukemia caused severe adverse psychological effects and sleep disturbances in about 30% of these patients. These side effects were ameliorated by coadministration of a low dose of the naturally occurring glucocorticoid hormone cortisol. This paradoxical finding was predicted by the idea that the synthetic glucocorticoid targets the glucocorticoid receptor, causing suppression of cortisol secretion and, thus, depletion of the brain mineralocorticoid receptor (MR) of its endogenous ligand. The refill of the unoccupied brain MR with physiological amounts of cortisol ameliorates the dexamethasone-induced psychological side effects. In the present report, we discuss the mechanistic underpinning of the MR refill concept in glucocorticoid therapy.