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

Abstract

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.

Non‐competitive steroid inhibition of oestrogen receptor functions

“…Trilostane has been used successfully in conditions associated with overproduction of adrenal steroids, such as Cushing's and Conn's syndromes. 12,13 In breast cancer, several trials showed that trilostane at doses up to 960 mg/day (with hydrocortisone or other glucocorticoid supplement to compensate for adrenal inhibition) was indeed effective as a therapy for the control of post-menopausal breast cancer. 14 -20 However, when all the trials, totalling nearly 800 patients, are taken into account, there appear to be anomalies not accounted for by the postulated mode of action.…”

Cushing's syndrome and hypertension.

“…63 The initial results were enthusiastic, 64 but more recently trilostane has been found to be relatively ineffective in Cushing's syndrome. 65 Ketoconazole, an imidazole derivative with antifungal properties, has been shown to block adrenocorticosteroid synthesis and blunt ACTH-induced cortisol release.…”

Long-term Efficacy of Trilostane for Cushing's Syndrome due to Adrenocorticotropin-Independent Bilateral Macronodular Adrenocortical Hyperplasia

“…Here we report a patient with Cushing's syndrome due to AIMAH who was treated for 7 years with trilostane, which inhibits the synthesis of cortisol by competitive and reversible blocking of 3β-hydroxysteroid dehydrogenase (3β-HSD) (5). This case may suggest a possible new approach to the management of Cushing's syndrome due to AIMAH.…”