Heikinheimo O, Gordon K, Williams R F, Hodgen G D
Jones Institute for Reproductive Medicine, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk 23507, USA.
Contraception. 1996 Jan;53(1):55-64. doi: 10.1016/0010-7824(95)00255-3.
Continuous administration of the antiprogesterone RU486 inhibits ovulation in women and in monkeys; in this regard RU486 may act as a progestin agonist rather than as an antagonist. We compared the site(s) and mechanism(s) of RU486-induced ovulation inhibition with those of levonorgestrel (LNG). Six regularly menstruating cynomolgus monkeys each received placebo, RU486 (1 mg/kg/d) or LNG (2 g/kg/d) i.m. between days (cd) 2-22 of three separate menstrual cycles. Serum levels of estradiol (E2), progesterone (P4), androstenedione, LH and FSH were analyzed by RIAs in daily blood samples. Basal and GnRH-stimulated (1 and 50 g of GnRH i.v. 2 h apart) secretion of LH and FSH was assessed using serial blood samples collected for 12 h on cd 10. Mean cycle length was prolonged by RU486 and LNG treatments from 32 d to 70 d and 52 d, respectively (p < 0.02). Ovulation was inhibited in five of the six primates during RU486, and in all six during LNG treatment. During RU486 treatment, serum E2 levels were similar to those of the control cycle; despite peaks of E2 secretion, no LH peaks were seen. In contrast, E2 concentrations were profoundly suppressed during LNG treatment (p < 0.005). The reduction in serum E2 was accompanied by lower levels of androstenedione, and suppressed ratio of E2/androstenedione (p < 0.02) suggesting both reduced synthesis and aromatization of androgen precursors during administration of LNG. Consequently, LNG treatment was associated with higher levels of serum FSH and LH (p < 0.001; 1-way ANOVA). Similarly, as during the luteal phase of the menstrual cycle, the amplitude of basal LH-pulses was increased during LNG treatment (p < 0.05), whereas RU486 treatment did not affect basal LH secretion. The GnRH-stimulated release of LH was similar during the placebo, RU486 and LNG cycles; enhanced release of FSH was seen during administration of LNG. Thus, in the present model system, RU486 seems to inhibit ovulation mainly at the level of hypothalamus, possibly by interfering with the steroidal positive feedback signals from the ovary. However, LNG inhibits ovulation differently, most likely via direct progesterone-like effects on folliculogenesis and the hypothalamus. The pituitary does not appear to be the major site of action(s) of RU486 or LNG. Thus, the differential mechanisms of ovulation inhibition by RU486 and LNG seem to result from lesser intraovarian impact of RU486 as well as dissimilar influences on tonic gonadotropin secretory levels. We conclude that when inhibiting ovulation, RU486 does not act as a progestin agonist, but rather, functions through a hypothalamic mechanism(s), which might be unique to RU486 as a progesterone antagonist.
持续给予抗孕激素RU486可抑制女性和猴子的排卵；就此而言，RU486可能作为孕激素激动剂而非拮抗剂起作用。我们比较了RU486诱导排卵抑制的部位和机制与左炔诺孕酮（LNG）的相关情况。六只月经周期规律的食蟹猴在三个不同月经周期的第2至22天，每只分别接受安慰剂、RU486（1毫克/千克/天）或LNG（2微克/千克/天）的肌肉注射。通过放射免疫分析法（RIAs）分析每日血样中的雌二醇（E2）、孕酮（P4）、雄烯二酮、促黄体生成素（LH）和促卵泡生成素（FSH）的血清水平。在月经周期第10天，通过采集连续12小时的血样来评估基础状态以及促性腺激素释放激素（GnRH）刺激（静脉注射1微克和50微克GnRH，间隔2小时）后的LH和FSH分泌情况。RU486和LNG治疗分别使平均周期长度从32天延长至70天和52天（p < 0.02）。在接受RU486治疗的六只灵长类动物中有五只排卵受到抑制，而在接受LNG治疗的所有六只动物中排卵均受到抑制。在RU486治疗期间，血清E2水平与对照周期相似；尽管有E2分泌高峰，但未观察到LH高峰。相比之下，在LNG治疗期间E2浓度被显著抑制（p < 0.005）。血清E2的降低伴随着雄烯二酮水平的降低以及E2/雄烯二酮比值的抑制（p < 0.02），这表明在LNG给药期间雄激素前体的合成和芳香化均减少。因此，LNG治疗与血清FSH和LH水平升高相关（p < 0.001；单因素方差分析）。同样，如同在月经周期的黄体期一样，在LNG治疗期间基础LH脉冲的幅度增加（p < 0.05），而RU486治疗不影响基础LH分泌。在安慰剂、RU486和LNG周期中，GnRH刺激后的LH释放情况相似；在LNG给药期间观察到FSH释放增强。因此，在当前模型系统中，RU486似乎主要在下丘脑水平抑制排卵，可能是通过干扰来自卵巢的甾体正反馈信号。然而，LNG以不同方式抑制排卵，最有可能是通过对卵泡生成和下丘脑的直接孕激素样作用。垂体似乎不是RU486或LNG的主要作用部位。因此，RU486和LNG抑制排卵的不同机制似乎是由于RU486对卵巢内的影响较小以及对促性腺激素基础分泌水平的不同影响所致。我们得出结论，在抑制排卵时，RU486并非作为孕激素激动剂起作用，而是通过一种下丘脑机制起作用，这可能是RU486作为孕激素拮抗剂所特有的。
