Successful Treatment of Cushing’s Syndrome with the Glucocorticoid Antagonist RU 486*

Abstract

A patient with Cushing's syndrome due to ectopic ACTH secretion was treated successfully with the new glucocorticoid antagonist RU 486 [17 beta-hydroxy-11 beta-(4-dimethylamino phenyl) 17 alpha-(1-propynyl)estra-4,9-dien-3-one]. This compound is a 19-nor steroid with substitutions at positions C11 and C17 which antagonizes cortisol action competitively at the receptor level. Oral RU 486 was given in increasing doses of 5, 10, 15, and 20 mg/kg . day for a 9-week period. Treatment efficacy was monitored by assessment of clinical status and by measuring several glucocorticoid-sensitive variables, including fasting blood sugar, blood sugar 120 min after oral glucose administration, and plasma concentrations of TSH, corticosteroid-binding globulin, LH, testosterone-estradiol-binding globulin, and total and free testosterone. With therapy, the somatic features of Cushing's syndrome (buffalo hump, central obesity, and moon facies) ameliorated, mean arterial blood pressure normalized, suicidal depression resolved, and libido returned. All biochemical glucocorticoid-sensitive parameters normalized. No side-effects of drug toxicity were observed. We conclude that RU 486 may provide a safe, well tolerated, and effective medical treatment for hypercortisolism.

Emerging drugs for Cushing’s disease

“…In 1985, a patient with Cushing's syndrome secondary to ectopic ACTH secretion was treated with mifepristone [78]. Treatment resulted in resolution of clinical effects of Cushing's syndrome, redistribution of fat and improvement in hyperglycaemia and hypertension.…”

Signal Transduction Pathways in use of Dexamethasone Implant in the Eye

“…It is thought that this effect resulted from the occupied/ bound cytosolic GR; however, the observed effect is sensitive to RU486 (glucocorticoid receptor antagonist [17β3-hydroxy-llβ-(4-dimethylamino phenyl) 17α-(l-propynyl) estra-4,9-dien-3-one]) [32] even without any change on gene transcription, but insensitive to actinomycin (transcription-independent). It can be said that chaperon or co-chaperone multiprotein complexes mediate this effect.…”

Pharmacological management of Cushing's syndrome: an update

“…In man mifepristone blocks glucocorticoid action resulting in negative feedback at the hypothalamic-pituitary level leading to a rise in ACTH, arginine-vasopressin and therefore cortisol (111). Mifepristone, at doses of up to 20 mg/kg, has been successfully used to treat a small number of patients with ectopic ACTH syndrome and there is every reason to believe that it could be successfully used in all patients if it were not for the problem of monitoring therapy (112). As a receptor antagonist it does not lower circulating cortisol levels, which in fact rise, and therefore it is very difficult to dose titrate and judge effectiveness.…”