Pituitary-adrenal response to RU 486 in man.
New therapeutic indications of the antiprogesterone RU 486 are emerging which require long-term administration and raise the question of its safety because of the associated antiglucocorticoid action of the drug. A trial was designed to assess the antiglucocorticoid effect of RU 486, possible manifestations of peripheral cortisol deprivation, and the adrenocortical and corticotrophin reserves. Ten normal males were given RU 486 per os (200 mg/day) or placebo between 0800-0900 h for eight days in a randomized, double-blind, crossover design, with a 1-month interval between the two periods. RU 486 induced the overactivation of the pituitary-adrenal axis. 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 micrograms; and 0800 h plasma ACTH, 29.2 +/- 3.7 and 60.2 +/- 8.4 pg/ml. All of these variations were different from those during placebo treatment (0.0001 < p < .03) and disappeared four days after the end of treatment. 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 exaggerated 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/ml. Direct pituitary stimulation (100 micrograms ovine corticotrophin release hormone (CRH), followed by 1 IU LVP) also induced exaggerated corticotroph and adrenocortical responses (p < .005). Peak values before and at the end of treatment were, respectively: plasma ACTH, 147.7 +/- 24.6 and 254.0 +/- 41.3 pg/ml: 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 clinical symptoms. This state results in a reversible cortisol overproduction and a preservation of adrenocortical and pituitary reserves.
Bertagna
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Groupe d'Etude en Physiopathologie Endocrinienne, INSERM CIF 9208, Institut Cochin de Génétique Moléculaire, Faculté Cochin, Paris, France.
D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006339:Heart Rate / Q000187:drug effects; D006727:Hormone Antagonists / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D008297:Male; D015735:Mifepristone / Q000009:adverse effects / Q000494:pharmacology*; D010913:Pituitary-Adrenal System / Q000187:drug effects*
D006727:Hormone Antagonists; D015735:Mifepristone; D006854:Hydrocortisone