Heikinheimo O, Gordon K, Lähteenmäki P, Williams R F, Hodgen G D
Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk 23507, USA.
J Clin Endocrinol Metab. 1995 Jun;80(6):1859-68. doi: 10.1210/jcem.80.6.7775633.
Continuous administration of RU 486 impairs follicular development and inhibits ovulation in women. Yet, the mechanism of ovulation inhibition remains unknown. To characterize the mechanism(s) of ovulation inhibition, we studied six regularly menstruating cynomolgus monkeys for three consecutive (control-rest-treatment) cycles. Monkeys received 1 mg/kg.day RU 486 in between cycle days 2-22. Basal and GnRH-stimulated (1 and 50 micrograms GnRH, iv, 2 h apart) secretion of LH and FSH was assessed using serial blood samples (every 15 min for 12 h) collected on cycle day 10. Serum levels of estradiol (E2), progesterone (P4), RU 486, cortisol, LH, FSH, and PRL were analyzed by RIAs, the bioactivity of LH was assessed using a mouse Leydig cell assay. The mean cycle length was prolonged by RU 486 treatment from 31.8 to 69.8 days (P = 0.008). During RU 486 treatment, patterns of E2 secretion varied considerably; the mean +/- SD E2 level was 204 +/- 139 pmol/L. LH peaks and P4 profiles compatible with luteal function were seen only before resumption of menstruation. However, one monkey had an increase in P4 after the GnRH challenge-induced LH secretion. Basal levels of LH varied between suppressed and apparently normal values, whereas basal FSH seemed little affected by RU 486 treatment. In two monkeys with E2 secretion indicative of normal follicular development, minor peaks of LH, but no rises in serum P4, were seen. The ratio of bioactive/immunoactive LH was reduced in these monkeys during RU 486 treatment compared to that during the washout period of the treatment cycle. Surprisingly, the pituitary responsiveness to acute GnRH challenge was not affected by RU 486 administration. The individual levels of RU 486 were similar during the treatment period (mean, 40 nmol/L). A resumption of ovulatory cycles occurred when RU 486 concentrations were below 2.5 nmol/L. We conclude that in cynomolgus monkeys, inhibition of ovulation by RU 486 occurs mainly at the level of the hypothalamus, with possible additional effects on the granulosa cell function and alterations of LH bioactivity.
连续给予RU 486会损害女性的卵泡发育并抑制排卵。然而，排卵抑制的机制仍不清楚。为了阐明排卵抑制的机制，我们对6只月经周期规律的食蟹猴进行了连续三个（对照-休息-治疗）周期的研究。在周期的第2至22天之间，猴子每天接受1 mg/kg的RU 486。在周期第10天，通过连续采集血样（每15分钟采集一次，共12小时）来评估基础状态以及GnRH刺激（静脉注射1和50微克GnRH，间隔2小时）后的LH和FSH分泌。通过放射免疫分析法测定血清雌二醇（E2）、孕酮（P4）、RU 486、皮质醇、LH、FSH和PRL的水平，使用小鼠睾丸间质细胞试验评估LH的生物活性。RU 486治疗使平均周期长度从31.8天延长至69.8天（P = 0.008）。在RU 486治疗期间，E2分泌模式差异很大；平均±标准差E2水平为204±139 pmol/L。仅在月经恢复前观察到与黄体功能相符的LH峰值和P4曲线。然而，一只猴子在GnRH激发诱导LH分泌后P4有所升高。基础LH水平在被抑制和看似正常的值之间变化，而基础FSH似乎几乎不受RU 486治疗的影响。在两只E2分泌表明卵泡发育正常的猴子中，观察到LH有小峰值，但血清P4没有升高。与治疗周期的洗脱期相比，在RU 486治疗期间这些猴子的生物活性LH/免疫活性LH比值降低。令人惊讶的是，垂体对急性GnRH激发的反应性不受RU 486给药的影响。治疗期间RU 486的个体水平相似（平均值为40 nmol/L）。当RU 486浓度低于2.5 nmol/L时，排卵周期恢复。我们得出结论，在食蟹猴中，RU 486对排卵的抑制主要发生在下丘脑水平，可能对颗粒细胞功能有额外影响，并改变LH的生物活性。
