Clomiphene Citrate 克罗米芬柠檬酸盐

分类:医学文献 23 0

Clomiphene citrate (CC) is a nonsteriodal triphenylethylene derivative that exhibits both estrogen agonist and antagonist properties, i.e. selective estrogen receptor modulator. Estrogen agonist properties are manifest only when endogenous estrogen levels are extremely low. Otherwise, CC acts mainly as an antiestrogen (1).

克罗米芬柠檬酸(CC)是一种非甾体三苯基乙烯衍生物,具有雌激素激动剂和拮抗剂的特性,即选择性雌激素受体调节剂。雌激素激动剂仅在内源性雌激素水平极低时才会表现。在其他情况下,克罗米芬柠檬酸盐主要充当抗雌激素(1)。

Clomiphene citrate is a racemic mixture of two distinct steroisomers, enclomiphene and zuclomiphene, having different properties. Enclomiphene is the more potent antiestrogenic isomer and the one primarily responsible for the ovulation-stimulation actions of CC (1). Enclomiphene has a half-life of few days while the other isomer, zuclomiphene, is cleared far more slowly with levels detectable in the circulation for more than one year after treatment and may actually accumulate over consecutive treatment cycles (2). Clomiphene citrate is cleared through the liver and excreted in the stool. About 85 percent of an administered dose is eliminated after approximately 6 days, although traces may remain the circulation for much longer (3).克罗米酚柠檬酸是顺式克罗米芬和反式克罗米芬两种不同立体异构体的外消旋混合物,具有不同的特性。顺式克罗米芬是一种更有效的抗雌激素异构体,并且是克罗米芬柠檬酸起到促排卵作用的主要成分(1)。顺式克罗米芬的半衰期是几天,而反式克罗米的代谢速度要慢得多,服药后一年多还会在体内循环,并且可能在连续的治疗周期中积累下来(2)。克罗米芬柠檬酸盐可通过肝脏代谢并从粪便中排出。大约85%的药物会在6天后被代谢出去,虽然它的代谢痕迹可能会在体内循环中保留更长时间(3)。

Clomiphene citrate’s structural similarity to estrogen allows it to bind to estrogen receptors (ER) throughout the body. Such binding lasts for an extended period of time, up to weeks rather than hours as is the case with natural estrogen. Such extended binding ultimately depletes ER concentrations by interfering with the normal process of ER replendishment (4).

克罗米芬柠檬酸盐与雌激素的结构相似,所以它能与体内的雌激素受体结合且持续很长时间。天然雌激素与受体结合是数小时,而克罗米芬能结合长达数周时间。结合时长的延长最终会通过干扰受体补充的正常过程来消耗受体浓度(4)。

It is believed that the hypothalamus is the main site of action because in normally ovulatory women, CC treatment was found to increase gonadotropin-releasing hormone (GnRH) pulse frequency (5). However, actions at the pituitary level may also be involved since CC treatment increased pulse amplitude, but not frequency in anovulatory women with polycystic ovarian syndrome, in whom the GnRH pulse frequency is already abnormally high (6).

一般认为下丘脑是主要作用部分,因为在排卵正常的女性中,使用克罗米芬治疗会增加促性腺激素释放激素的脉冲频率(5)。然而,这也可能与垂体水平有关,因为克罗米芬增加了脉冲幅度,但不会增加多囊卵巢综合征的不排卵女性的脉冲频率,这些患者的促性腺激素释放激素的脉冲频率已经异常高(6)。

The antiestrogenic effect on the hypothalamus, and possibly the pituitary, is believed to be the main mechanism of action for ovarian stimulation. Depletion of hypothalamic ER prevents correct interpretation of circulating estrogen levels, i.e. estrogen concentrations are falsely perceived as low leading to reduced estrogen negative feedback on GnRH production by the hypothalamus and gonadotropins by the pituitary. During CC treatment, levels of both LH and FSH rise, then fall again after the typical 5-day course of therapy is completed. In successful treatment cycles, one or more dominant follicles emerge and mature, generating a rising tide of estrogen that ultimately triggers the mid-cycle LH surge and ovulation. It is important to stress the two main prerequisites for the success of CC ovarian stimulation: presence of reasonable estrogen levels in the body and an intact hypothalamic/pituitary axis capable of producing endogenous gonadotropins.

克罗米芬对下丘脑和可能对垂体的抗雌激素作用被认为是卵巢促排卵的主要作用机制。下丘脑的雌激素受体的消耗会阻止机体对体内循环雌激素水平的正确理解,即雌激素浓度被错误地认为处在低水平,从而导致对下丘脑和垂体促腺激素产生的促性腺激素释放激素和促性腺激素的雌激素负反馈减少。在克罗米芬治疗期间,促黄体生成素和促卵泡素水平会上升,然后在常用的5天疗程结束后再次下降。在成功的治疗周期中,有一个或多个优势卵泡出现并发育成熟,使雌激素水平上涨,最终触发中期黄体峰值和排卵。克罗米芬促排卵成功的两个主要先决条件很重要:体内雌激素水平正常,以及能够产生内源性促性腺激素的完整下丘脑/垂体轴。

References

参考文献

1. Practice Committee of the American Society for Reproductive Medicine. American Society for Reproductive Medicine, Birmingham, Alabama, USA. Use of clomiphene citrate in women. Fertil Steril 2004;82 Suppl 1: S90-96.

2. Young SL, Opsahl MS, Fritz MA. Serum concentrations of enclomiphene and zuclomiphene across consecutive cycles of clomiphene citrate therapy in anovulatory infertile women. Fertil Steril 1999;71:639-644.

3. Mikkelson TJ, Kroboth PD, Cameron WJ, et al. Single-dose pharmacokinetics of clomiphene citrate in normal volunteers. Fertil Steril 1986;46:392-396.

4. Greenblatt RB, Barfield WE, Jungck EC, Ray AW. Induction of ovulation with MRL/41. Preliminary report. JAMA 1961;178:101-104.

5. Kerin JF, Liu JH. Phillipou G, Yen SS. Evidence for a hypothalamic-pituitary-ovarian response to clomiphene citrate in women. J Clin Endocrinol Metab 1985;61:265-268.

6. Kettel LM, Roseff SJ, Berga SL, Mortola JF, Yen SS. Hypothalamic-pituitary-ovarian response to clomiphene citrate in women with polycystic ovary syndrome. Fertil Steril 1993;59:532-538.

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