Seven patients with
Cushing's syndrome were treated with
trilostane (
WIN 24,540) 4 alpha,5-epoxy-17 beta-hydroxy-3-oxo-5 alpha-androstane-2 alpha-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 less than 0.005), and urinary
17-hydroxycorticosteroids decreased from 15.7 to 8.7 mg/24 h (P less than 0.01). Urinary free
cortisol excretion decreased from 277 to 88 microgram/24 h (P less than 0.01), and 0800 h plasma
cortisol levels declined from 25.0 to 12.0 microgram/dl (P less than 0.05). Conversely,
dehydroepiandrosterone sulfate excretion in urine increased from 1.3 to 5.8 mg/24 h (P less than 0.0025) and in plasma increased from 162 mg/24 h (P less than 0.025). Plasma and urinary free
dehydroepiandrosterone increased 2-fold. Urinary 17-ketosteroid excretion increased from 18 to 43 mg/24 h (P less than 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 less than 0.005), and fasting
blood sugar decreased from 117 to 98 mg/dl (P less than 0.005), accompanied by rise in plasma
potassium levels from 3.8 to 4.3 milliequivalents/liter (P less than 0.025). Two patients on long term
therapy also showed an improvement in clinical features of their disease. There were no significant treatment-related
carcinoma, simultaneously producing both an excessive amount of
cortisol and
ACTH, is described. It is concluded that
trilostane is an effective inhibitor of
3 beta-hydroxysteroid dehydrogenase enzyme system in human adrenal gland; it inhibits biosynthesis of
cortisol and it is useful in the treatment of
Cushing's syndrome.