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).

　　克羅米芬檸檬酸(CC)是一種非甾體三苯基乙烯衍生物，具有雌激素激動(dòng)劑和拮抗劑的特性，即選擇性雌激素受體調(diào)節(jié)劑。雌激素激動(dòng)劑僅在內(nèi)源性雌激素水平很 低時(shí)才會(huì)表現(xiàn)。在其他情況下，克羅米芬檸檬酸鹽主要充當(dāng)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).克羅米酚檸檬酸是順式克羅米芬和反式克羅米芬兩種不同立體異構(gòu)體的外消旋混合物，具有不同的特性。順式克羅米芬是一種更有效的抗雌激素異構(gòu)體，并且是克羅米芬檸檬酸起到促排卵作用的主要成分(1)。順式克羅米芬的半衰期是幾天，而反式克羅米的代謝速度要慢得多，服藥后一年多還會(huì)在體內(nèi)循環(huán)，并且可能在連續(xù)的治療周期中積累下來(lái)(2)?？肆_米芬檸檬酸鹽可通過(guò)肝臟代謝并從糞便中排出。大約85%的藥物會(huì)在6天后被代謝出去，雖然它的代謝痕跡可能會(huì)在體內(nèi)循環(huán)中保留更長(zhǎng)時(shí)間(3)。

　　Clomiphene citrate’s structural similarity to estrogen allows it to bind to estrogen receptors (ER) throughout the bo. 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).

　　克羅米芬檸檬酸鹽與雌激素的結(jié)構(gòu)相似，所以它能與體內(nèi)的雌激素受體結(jié)合且持續(xù)很長(zhǎng)時(shí)間。天然雌激素與受體結(jié)合是數(shù)小時(shí)，而克羅米芬能結(jié)合長(zhǎng)達(dá)數(shù)周時(shí)間。結(jié)合時(shí)長(zhǎng)的延長(zhǎng)較終會(huì)通過(guò)干擾受體補(bǔ)充的正常過(guò)程來(lái)消耗受體濃度(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 iolved since CC treatment increased pulse amplitude, but not frequency in anovulatory women with polycystic ovarian syndrome, in whom the GnRH pulse frequency is alrea abnormally high (6).

　　一般認(rèn)為下丘腦是主要作用部分，因?yàn)樵谂怕颜５呐灾?，使用克羅米芬治療會(huì)增加促性腺激素釋放激素的脈沖頻率(5)。然而，這也可能與垂體水平有關(guān)，因?yàn)榭肆_米芬增加了脈沖幅度，但不會(huì)增加多囊卵巢綜合征的不排卵女性的脈沖頻率，這些患者的促性腺激素釋放激素的脈沖頻率已經(jīng)異常高(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 domit 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 bo and an intact hypothalamic/pituitary axis capable of producing endogenous gonadotropins.

　　克羅米芬對(duì)下丘腦和可能對(duì)垂體的抗雌激素作用被認(rèn)為是卵巢促排卵的主要作用機(jī)制。下丘腦的雌激素受體的消耗會(huì)阻止機(jī)體對(duì)體內(nèi)循環(huán)雌激素水平的正確理解，即雌激素濃度被錯(cuò)誤地認(rèn)為處在低水平，從而導(dǎo)致對(duì)下丘腦和垂體促腺激素產(chǎn)生的促性腺激素釋放激素和促性腺激素的雌激素負(fù)反饋減少。在克羅米芬治療期間，促黃體生成素和促卵泡素水平會(huì)上升，然后在常用的5天療程結(jié)束后再次下降。在成功的治療周期中，有一個(gè)或多個(gè)優(yōu)勢(shì)卵泡出現(xiàn)并發(fā)育成熟，使雌激素水平上漲，較終觸發(fā)中期黃體峰值和排卵。克羅米芬促排卵成功的兩個(gè)主要先決條件很重要：體內(nèi)雌激素水平正常，以及能夠產(chǎn)生內(nèi)源性促性腺激素的完整下丘腦/垂體軸。

　　References

　　參考文獻(xiàn)

　　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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