Familial Cortisol Resistance: Differential Diagnostic and Therapeutic Aspects

Abstract

A 26-yr-old woman presented with hirsutism,male pattern scalp baldness (“geheimratsecken”), and menstrualirregularities. She had no hypertension or other signs and symptomsof Cushings syndrome. Plasma cortisol levels were greatlyelevated and did not suppress normally in response to dexamethasone.Cortisol binding to transcortin was normal. Plasmaandrostenedione and testosterone levels were also increased, but17-hyroxyprogesterone and aldosterone levels were normal. Furtherstudies revealed an increased cortisol production rate, increased24-h urinary cortisol excretion, increased plasma ACTHlevels, a normal diurnal rhythm of cortisol at an elevated level,and normal increments of plasma ACTH, cortisol, GH, and PRLin response to insulin-induced hypoglycemia. The father andtwo brothers also had increased plasma cortisol levels, which didnot suppress normally in response to dexamethasone. Chronic therapy with dexamethasone (at first 1 and later 0.5mg, three times daily) for more than 30 weeks resulted indecreased hirsutism, normalization of scalp hair and menstrualcyclicity, and normal plasma testosterone and androstenedionelevels. 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 dominantlyinherited hereditary (partial) cortisol insensitivity, which hadresulted in increased adrenocortical cortisol and androgen secretion.The latter had not resulted in clinical symptoms in thethree afflicted male members of the family, but had in thepropositus. The results also indicate the potential usefulness ofthe insulin test in distinguishing this disorder from Cushing’s disease.