Bertagna X, Escourolle H, Pinquier J L, Coste J, Raux-Demay M C, Perles P, Silvestre L, Luton J P, Strauch G
Clinique des Maladies Endocriniennes et Métaboliques, ECLIMED Institut de Recherche Thérapeutique, Centre Hospitalier Universitaire Cochin, France.
J Clin Endocrinol Metab. 1994 Feb;78(2):375-80. doi: 10.1210/jcem.78.2.8106625.
New therapeutic indications based on the antiprogesterone action of RU 486 (Mifepristone) are emerging which require long term administration and raise the question of its safety because of the 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 corticotroph reserves. Ten normal male volunteers (aged 21-29 yr) were given RU 486 (200 mg/day) or placebo between 0800-0900 h for 8 consecutive days in a randomized, double blind, cross-over design, with a 1-month interval between the two periods. RU 486 induced 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 significantly different from those during placebo treatment (0.0001 < P < 0.03) and disappeared within 4 days after the end of treatment. A daily record of subjective clinical symptoms, body weight and temperature, blood pressure, and heart rate showed 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 vs. 4.7 +/- 0.1 mmol/L; P = 0.04). The adrenocortical response to Cortrosyn (0.25 mg, im) was exaggerated during RU 486 treatment (P < 0.006): 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 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, 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 from reversible cortisol overproduction with preservation of adrenocortical and pituitary reserves.
基于RU 486（米非司酮）抗孕酮作用的新治疗适应症不断涌现，这些适应症需要长期用药，且由于该药物的抗糖皮质激素作用，引发了其安全性问题。本试验旨在评估RU 486的抗糖皮质激素作用、外周皮质醇缺乏的可能表现以及肾上腺皮质和促肾上腺皮质激素储备情况。10名正常男性志愿者（年龄21 - 29岁），采用随机、双盲、交叉设计，于08:00 - 09:00时连续8天服用RU 486（200 mg/天）或安慰剂，两个周期之间间隔1个月。RU 486导致垂体 - 肾上腺轴过度激活；治疗前及治疗结束时的基线值（均值±标准误）分别为：08:00时血浆皮质醇，147.3±15.5和257.6±8.8 ng/mL；08:00时唾液皮质醇，5.8±1.2和15.2±0.8 ng/mL；夜间（22:00 - 08:00时）尿皮质醇，8.4±1.5和33.7±11.1μg；08:00时血浆促肾上腺皮质激素，29.2±3.7和60.2±8.4 pg/mL。所有这些变化与安慰剂治疗期间的变化均有显著差异（0.0001＜P＜0.03），且在治疗结束后4天内消失。对主观临床症状、体重和体温、血压及心率的每日记录显示，治疗期间既无副作用，也无任何显著变化。血液电解质和嗜酸性粒细胞计数未改变；治疗结束时空腹血糖略高（5.0±0.2对4.7±0.1 mmol/L；P = 0.04）。在RU 486治疗期间，对可的松（0.25 mg，肌肉注射）的肾上腺皮质反应增强（P＜0.006）：治疗前及治疗结束时的峰值分别为：血浆皮质醇，272.5±15.2和347.1±20.6 ng/mL；唾液皮质醇，17.0±2.2和31.1±3.1 ng/mL。直接垂体刺激（100μg羊促肾上腺皮质激素释放激素，随后在15分钟内注射1 IU赖氨酸加压素）也诱导了促肾上腺皮质激素和肾上腺皮质反应增强（P＜0.005）；治疗前及治疗结束时的峰值分别为：血浆促肾上腺皮质激素，147.7±24.6和254.0±41.3 pg/mL；血浆皮质醇，231.6±7.3和
