Familial cortisol resistance: differential diagnostic and therapeutic aspects

A 26-yr-old woman presented with hirsutism, male pattern scalp baldness ("geheimratsecken"), and menstrual irregularities. She had no hypertension or other signs and symptoms of Cushing's syndrome. Plasma cortisol levels were greatly elevated and did not suppress normally in response to dexamethasone. Cortisol binding to transcortin was normal. Plasma androstenedione and testosterone levels were also increased, but 17-hydroxyprogesterone and aldosterone levels were normal. Further studies revealed an increased cortisol production rate, increased 24-h urinary cortisol excretion, increased plasma ACTH levels, a normal diurnal rhythm of cortisol at an elevated level, and normal increments of plasma ACTH, cortisol, GH, and PRL in response to insulin-induced hypoglycemia. The father and two brothers also had increased plasma cortisol levels, which did not suppress normally in response to dexamethasone. Chronic therapy with dexamethasone (at first 1 and later 0.5 mg, three times daily) for more than 30 weeks resulted in decreased hirsutism, normalization of scalp hair and menstrual cyclicity, and normal plasma testosterone and androstenedione levels. No signs or symptoms of Cushing's syndrome developed, and the central regulation of secretion of ACTH, cortisol, GH, and PRL (insulin test, diurnal rhythm) remained qualitatively normal at a lower set-point. We conclude that this patient had autosomal dominantly inherited hereditary (partial) cortisol insensitivity, which had resulted in increased adrenocortical cortisol and androgen secretion. The latter had not resulted in clinical symptoms in the three afflicted male members of the family, but had in the propositus. The results also indicate the potential usefulness of the insulin test in distinguishing this disorder from Cushing's disease.