A B S T R A C T We have studied a man suspected of having primary cortisol resistance on the basis of high 24-h mean plasma cortisol levels (27.4 ug/dl) and no stigmata of Cushing's syndrome. His son had slightly elevated 24-h mean plasma cortisol levels (9.9 sg/dl; normal 7.52 Ag/dl). Both had high plasma protein unbound cortisol and increased urinary free cortisol. Plasma ACTH concentration was high, and both were resistant to adrenal suppression by dexamethasone. The father appeared to have mineralocorticoid excess resulting in hypertension, hypokalemia, and metabolic alkalosis. This was found to be due to markedly elevated plasma levels of deoxycorticosterone and corticosterone. The son, who was normotensive, had mildly increased plasma corticosterone and normal deoxycorticosterone levels. To study the apparent end-organ resistance to cortisol, we examined the glucocorticoid receptor in the white cells and fibroblasts of these patients. In both tissues, using both whole cell and cytosol assays, the glucocorticoid receptor was found to have reduced affinity for dexamethasone. In the cytosol assays, a reduced receptor number was found as well. We conclude that cortisol resistance is a rare familial syndrome owing to an abnormal glucocorticoid receptor with a decreased affinity for cortisol.

A very high cortisol production rate (CPR) with elevated plasma ACTH was found in a hypertensive, hypokalemic, but otherwise healthy male patient. There were no symptoms or signs of Cushing's syndrome. The hypercortisolism appeared to be of the pituitary dependent type. During the follow-up of 36 months, no changes in outward appearance occurred, notwithstanding persistent hypercortisolism. The possibility of either Conn's syndrome or of an enzymatic defect in steroidogenesis could be ruled out. One of the three children (a healthy boy of 20 years) also showed hypertension and hypercortisolism. A possibly genetically determined hyposensitivity to the glucocorticoid action of cortisol is postulated.

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Primary cortisol resistance is an autosomal disease characterized by increased plasma cortisol concentration and high urinary free cortisol, resistance to adrenal suppression by dexamethasone, and the absence of clinical stigmata of Cushing's syndrome. The proband with the severe form had hypertension and hypokalemic alkalosis. In subjects with a less severe resistance to cortisol, there are no clinical abnormalities and the condition is revealed only by detailed examination of several parameters of cortisol secretion.