PITUITARY-ADRENAL RESPONSE TO RU-486 IN MAN

New therapeutic indications of the antiprogesterone RU 486 are emergin g which require long-term administration and raise the question of its safety because of the associated antiglucocorticoid action of the dru g. A trial was designed to assess the antiglucocorticoid effect of RU 486, possible manifestations of peripheral cortisol deprivation, and t he adrenocortical and corticotrophin reserves. Ten normal males were g iven RU 486 per as (200 mg/day) or placebo between 0800-0900h for eigh t days in a randomized, double-blind, crossover design, with a 1-month interval between the two periods. RU 486 induced the overactivation o f the pituitary-adrenal axis. Baseline values (mean +/-SEM) before and at end of treatment were, respectively: 0800h plasma cortisol, 147.3/-15.5 and 257.6+/-8.8 ng/ml; 0800h salivary cortisol, 5.8+/-1.2 and 1 5.2+/-0.8 ng/ml; nocturnal (2200-0800h) urinary cortisol, 8.4+/-1.5 an d 33.7+/-11.1 mu g; and 0800h plasma ACTH, 29.2+/-3.7 and 60.2+/-8.4 p g/ml. All of these variations were different from those during placebo treatment (0.0001<p<.03) and disappeared four days after the end of t reatment. A daily record of subjective clinical symptoms, body weight and temperature, blood pressure, and heart rate showed no side effects , and no 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 vs. 4.7+/-0.1 mmol/L; p<.04) . The adrenocortical response to Cortrosyn (0.25 mg IM) was exaggerate d during RU 486 treatment (p<.006). peak values before and at the end of treatment were, respectively: plasma cortisol, 272.5+/-15.2 and 347 .1+/-20.6 ng/ml; and salivary cortisol, 17.0+/-2.2 and 31.1+/-3.1 ng/m l. Direct pituitary stimulation (100 mu g ovine corticotrophin release hormone (CRH), followed by 1 IU LVP) also induced exaggerated cortico troph and adrenocortical responses (p<.005). Peak values before and at the end of treatment were, respectively: plasma ACTH, 147.7+/-24.6 an d 254.0+/-41.3 pg/mI; and plasma cortisol, 231.6+/-7.3 and 319.2+/-12. 3 ng/ml. These data show that 8-day treatment with 200 mg RU 486 daily induces a hormonally detectable antiglucocorticoid effect without cli nical symptoms. This state results in a reversible cortisol overproduc tion and a preservation of adrenocortical and pituitary reserves. (C) 1997 Elsevier Science Ltd.