Treatment of Cushing's Syndrome with Trilostane (WIN 24,540), an Inhibitor of Adrenal Steroid Biosynthesis*

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Abstract
Seven patients with Cushing's syndrome were treated with trilostane (WIN 24,540) (4α,5-epoxy-17β-hydroxy-3-oxo-5α-androstane-2α-carbonitrile), an inhibitor of adrenal steroid biosynthesis. Trilostane treatment reduced steroid biosynthesis and it also improved biochemical manifestations of the disease in all of the patients treated. The average cortisol secretory rate decreased significantly with treatment, from 47.1 to 23.4 mg/24 h (P < 0.005), and urinary 17-hydroxycorticosteroids decreased from 15.7 to 8.7 mg/24 h (PP < 0.01), and 0800 h plasma cortisol levels declined from 25.0 to 12.0 μg/dl (P < 0.05). Conversely, dehydroepiandrosterone sulfate excretion in urine increased from 1.3 to 5.8 mg/24 h (P < 0.025) and in plasma increased from 162 to 458 μg/dl (P < 0.05). Plasma and urinary free dehydroepiandrosterone increased 2-fold. Urinary 17-ketosteroid excretion increased from 18 to 43 mg/24 h (P < 0.001). A significant reduction in urinary excretion of tetrahydroaldosterone, tetrahydrodeoxycorticosterone, and 18-hydroxytetrahydrodeoxycorticosterone was observed with treatment. Inhibition of steroid biosynthesis was accompanied by a 2-fold increase in PRA and no change in serum cholesterol levels. Mean arterial blood pressure decreased with treatment from 109 to 97 mm Hg (P < 0.005), and fasting blood sugar decreased from 117 to 98 mg/dl (P < 0.005), accompanied by rise in plasma potassium levels from 3.8 to 4.3 milliequivalents/liter (P < 0.025). Two patients on long term therapy also showed an improvement in clinical features of their disease. There were no significant treatment-related side effects. A patient with metastatic adrenocortical carcinoma, simultaneously producing both an excessive amount of cortisol and ACTH, is described. It is concluded that trilostane is an effective inhibitor of 3β-hydroxysteroid dehydrogenase enzyme system in human adrenal gland; it inhibits biosynthesis of cortisol and it is useful in the treatment of Cushing's syndrome.