ADMINISTRATION OF RU-486 FOR 8 DAYS IN NORMAL VOLUNTEERS - ANTIGLUCOCORTICOID EFFECT WITH NO EVIDENCE OF PERIPHERAL CORTISOL DEPRIVATION

New therapeutic indications based on the antiprogesterone action of RU 486 (Mifepristone) are emerging which require long term administratio n and raise the question of its safety because of the antiglucocortico id action of the drug. A trial was designed to assess the antiglucocor ticoid effect of RU 486, possible manifestations of peripheral cortiso l deprivation, and the adrenocortical and corticotroph reserves. Ten n ormal male volunteers (aged 21-29 yr) were given RU 486 (200 mg/day) o r placebo between 0800-0900 h for 8 consecutive days in a randomized, double blind, cross-over design, with a 1-month interval between the t wo periods. RU 486 induced overactivation of the pituitary-adrenal axi s; baseline values (mean +/- SEM) before and at end of treatment were, respectively: 0800 h plasma cortisol, 147.3 +/- 15.5 and 257.6 +/- 8. 8 ng/mL; 0800 h salivary cortisol, 5.8 +/- 1.2 and 15.2 +/- 0.8 ng/mL; nocturnal (2200-0800 h) urinary cortisol, 8.4 +/- 1.5 and 33.7 +/- 11 .1 mu g; and 0800 h plasma ACTH, 29.2 +/- 3.7 and 60.2 +/- 8.4 pg/mL. All of these variations were significantly different from those during placebo treatment (0.0001 < P < 0.03) and disappeared within 4 days a fter the end of treatment. A daily record of subjective clinical sympt oms, body weight and temperature, blood pressure, and heart rate showe d neither side-effects nor any significant variation during treatment. Blood electrolyte and eosinophil counts were unchanged; fasting blood glucose was slightly higher at the end of treatment (5.0 +/- 0.2 us. 4.7 +/- 0.1 mmol/L; P = 0.04). The adrenocortical response to Cortrosy n (0.25 mg, im) was exaggerated during RU 486 treatment (P < 0.006): p eak values before and at the end of treatment were, respectively: plas ma cortisol, 272.5 +/- 15.2 and 347.1 +/- 20.6 ng/mL; and salivary cor tisol, 17.0 +/- 2.2 and 31.1 +/- 3.1 ng/mL. Direct pituitary stimulati on (LOG pg ovine CRH, followed by 1 IU lysine vasopressin over 15 min) also induced exaggerated corticotroph and adrenocortical responses (P < 0.005); peak values before and at the end of treatment were, respec tively: plasma ACTH, 147.7 +/- 24.6 and 254.0 +/- 41.3 pg/mL; and plas ma cortisol, 231.6 +/- 7.3 and 319.2 +/- 12.3 ng/mL. These data show t hat 8-day treatment with 200 mg RU 486 daily induces a hormonally dete ctable antiglucocorticoid effect without clinical symptoms. This state results from reversible cortisol overproduction with preservation of adrenocortical and pituitary reserves.