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One patient is reported who has the manifestations of Cushing's syndrome in spite of persistent hypocortisolemia. His serum levels of cortisol and free cortisol were below normal, and 24-h urinary excretion of 17-hydroxycorticosteroids and cortisol were decreased. There was a rapid and substantial increase in serum cortisol in response to synthetic ACTH-(1-24). Plasma levels of ACTH were marginally increased by successive administration of CRH and vasopressin, which were followed by substantial increases in serum cortisol. Glucocorticoid activity of the patient's serum, as measured by a RRA was low. There were no responses of urinary 17-hydroxycorticosteroids after metyrapone treatment. These laboratory examinations ruled out any known clinical conditions resulting in hypocortisolemia. The clinical condition could also be explained by cortisol hyperreactivity of the patient's cells. In vitro hyperreactivity to glucocorticoids was demonstrated in cultured skin fibroblasts whose aromatase activity was increased 1.5- to 1.8-fold above that of normal cells, and [3H]thymidine incorporation was inhibited more effectively by the addition of cortisol or dexamethasone. The mechanism by which the patient is hyperreactive to glucocorticoids remains unexplained.

This report describes studies of a man suspected of having primary cortisol resistance. This conclusion is based on his high plasma cortisol levels and high 24-h urinary 17-hydroxycorticosteroid and cortisol excretion, plus the fact that he had no manifestations of Cushing's syndrome. Among family members tested, his mother also had hypercortisolemia. Both mother and son had high levels of unbound plasma cortisol, but their plasma ACTH concentrations were within the normal range. Both were partially resistant to dexamethasone adrenal suppression, and both had mild hypertension without hypokalemia. To study this apparent end-organ resistance to cortisol, we examined the glucocorticoid receptors in peripheral mononuclear cells. Using whole cell assays, glucocorticoid receptors in both patients were found to have reduced total binding capacity. We conclude that these two patients, members of the same family, have primary cortisol resistance accompanied by a reduced number of glucocorticoid receptors.

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