Abnormal Induction of Aromatase Activity by Dexamethasone in Fibroblasts from a Patient with Cortisol Resistance*

Abstract

Cortisol resistance is a rare condition due to abnormal glucocorticoid receptor function. Stimulation of aromatase activity by dexamethasone (DEX) in cultured human skin fibroblasts provides a model for studying the biological activity of glucocorticoid receptors in cells. Skin fibroblasts derived from an affected father and his less severely affected son with cortisol resistance were used for this study. Saturation analysis of DEX receptor binding was performed after incubation of cells with various DEX concentrations (1-50 nmol/L). In normal cells, the mean maximal binding capacity (Bmax) and dissociation constant (Kd) were 24 +/- 3 pmol/mg DNA and 14 +/- 3 nmol/L, respectively. Although the Bmax in cells of the father (33 +/- 2 pmol/mg DNA) was normal, the Kd (31 +/- 7 nmol/L) was abnormally elevated. By contrast, both the Bmax and Kd in cells of the son were normal. The dose response of aromatase activity to DEX stimulation was determined by assay of aromatase activity after incubation of cells in the absence or presence of DEX (0.25-500 nmol/L) for 14 h. In three strains of normal fibroblasts, the mean concentration of DEX that produced a half-maximal response was 6 +/- 1 nmol/L). In cells from the father, the mean concentration of DEX that produced half-maximal stimulation of aromatase (27 +/- 4 nmol/L) was abnormally elevated. By contrast, the concentration of DEX that half-maximally stimulated aromatase activity (6.0 and 5.9 nmol/L) was normal in cells from the son. These data provide additional evidence of abnormal glucocorticoid action in the father, but not in his son, and demonstrate the potential usefulness of determining aromatase induction by DEX as a means of assessing the biological activity of the glucocorticoid receptor.