Primary adrenocortical micronodular adenomatosis causing Cushing's syndrome. Effects of ketoconazole on steroid production and in vitro performance of adrenal cells

Abstract

Abstract. Mild Cushing's syndrome was diagnosed in a 35 year old woman. Elevated plasma and urinary cortisol levels were unsuppressible with up to 32 mg dexamethasone per day. Aldosterone, 18-OH-corticosterone and testosterone in plasma were normal and dehydroepiandrosterone-sulphate was low. No adrenal tumour was found by CT or adrenal venography, and bilateral cortisol secretion was demonstrated by steroid measurements in adrenal venous blood. A circadian rhythm of plasma cortisol was absent. Plasma ACTH was suppressed, even after injection of CRH, during insulininduced hypoglycaemia and after metyrapone administration, which led to a large fall in plasma cortisol but to a subnormal rise of plasma 11-deoxy-cortisol. The clinical diagnosis of primary micronodular adenomatosis of the adrenal gland was histologically confirmed, when the patient finally underwent bilateral adrenalectomy. In vitro, the adrenal cells did not produce more cortisol and aldosterone than adrenal cells from cadaver kidney donors. In vivo and in vitro, cortisol was slightly less than normally responsive to ACTH. Intermittent treatment of the patient with 800 mg/day of ketoconazole led to a rapid fall of cortisol secretion and clinical signs of adrenocortical insufficiency. Treatment for 7 weeks with 200–400 mg ketoconazole per day reduced plasma and urinary cortisol less dramatically into the normal range. This case unequivocally documents autonomous dysfunction of the adrenal cortex in this rare form of Cushing's syndrome and the efficacy of ketoconazole in the treatment of ACTH-independent hypercortisolism.

Use of ketoconazole in the treatment of a virilizing adrenocortical carcinoma

“…Pronounced lowering effects of ketoconazole on cortisol levels were also reported in a patient with an adrenal adenoma (22) and a patient with adrenocortical micronodular adenomatosis ( 19). This could be ex¬ plained by insufficient compensatory ACTH elev¬ ation (6)(7)(8) or inability of tumour cells to respond (22). We think that in our patient three additional reasons could account for this effect: the use of a high dose of ketoconazole which could severely af¬ fect 11-ß-hydroxylase (3), a pre-existing partial 11-ß-hydroxylase block in the tumour, and insuffi¬ ciency of the contralateral adrenal gland.…”

“…Pronounced lowering effects of ketoconazole on cortisol levels were also reported in a patient with an adrenal adenoma (22) and a patient with adrenocortical micronodular adenomatosis ( 19). This could be ex¬ plained by insufficient compensatory ACTH elev¬ ation (6)(7)(8) or inability of tumour cells to respond (22).…”

Pharmacological management of Cushing's syndrome: an update

“…Ketoconazole is an imidazole derivative developed as an oral antifungal agent that inhibits cholesterol, sex steroid and cortisol synthesis by acting on the 11β-hydroxylase and C17-20 lyase enzymes (8)(9)(10)(11). It is the most frequently used agent in the treatment of Cushing's syndrome with the starting dose being 200 mg twice daily increasing as necessary to 1200 mg/day in four divided doses (12,13).…”

PRKAR1A mutations in primary pigmented nodular adrenocortical disease

“…In some rare cases unilateral adrenalectomy was done, but even in the rare patients in whom the clinical Cushing's syndrome was controlled by unilateral adrenalectomy, alterations of the dynamic of cortisol secretion are still present, in favor of a bilateral disease [29]. Few patients have been treated by OP'DDD or ketoconazole [30,31].…”