美中桥:辅助生殖治疗使用GnRH拮抗剂,GnRH拮抗剂的好处是什么?

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  Author:Efstratios M.Kolibianakis and Georg Griesinger

  作者:Efstratios M.Kolibianakis and Georg Griesinger

  Book:Human Assisted Reproductive Technology

  书籍:人类辅助生殖技术(2011年第一版)

  Editors:David K.Gardner,Botros RMB Rizk and Tommaso Falcone

  主编:David K.Gardner,Botros RMB Rizk和Tommaso Falcone

  前述

  Introduction

  Gonadotropin releasing hormone(GnRH)analogs have been used since 1984 for the purpose to inhibit premature luteinizing hormone(LH)surge in ovarian stimulation.In contrast to GnRH antagonists,GnRH agonists are characterized by a lack of immediate suppression of endogenous gonadotropins,requiring a long pretreatment period prior to initiation of gonadotropn stimulation.Despite this significant disadvantage,they were used exclusively to control endogenous LH secretion until the end of the 1990s,since they were the only clinically available analog.

  促性腺激素释放激素(GnRH)类似物从1984年起开始用于试管促排周期,以达到抑制过早出现LH高峰的目的。与GnRH拮抗剂相比,GnRH激动剂的一个劣势在于不能及时抑制内源性促性腺激素的释放,因此需要在开始使用促性腺激素一段时间前先做预控制。虽然GnRH激动剂存在明显的弱点,但是直到1990年代末,我们还是只能用激动剂来控制内源性LH的分泌,因为当时临床上可以使用的类似物只有激动剂。

  The availability of GnRH antagonists did not only offer clinicians an alternative to GnRH agonists but,more importantly,has led to the development of new concepts aiming to increase safety and simplicity in ovarian stimulation.These include the modified natural cycle,mild IVF,the use of GnRH agonist for triggering of final oocyte maturation,the administration of antagonists during the luteal phase for management of severe OHSS,as well as control of endogenous LH with GnRH antagonists in intrauterine insemination cycles.

  RnRH拮抗剂的发明不仅给临床医生提供了GnRH激动剂的替代品,而且更重要的是,这一发明促使他们在提高卵巢促排安全性和简便性方面进行了创新,包括改良了自然周期方案,发明了微促方案,用激动剂诱导卵泡最后成熟过程,在黄体期补充拮抗剂预防卵巢过度刺激综合征,以及在宫腔内受精周期中应用拮抗剂方案控制内源性LH峰值等。

  GnRH拮抗剂方案

  Scheme of GnRH antagonist administration

  Administration of GnRH antagonists can be performed by either a single dose or by using a daily scheme.Administration of a single-dose antagonist is effective in suppressing endogenous LH for 4 days.If the criteria to trigger final oocyte maturation have not been met by the end of this time period(which was the case for about 10%of patients in a large phase III trial),daily antagonist dose can be administered accordingly.

  GnRH拮抗剂的给药可以分为单剂量方案和多剂量方案。在单剂量方案中,一次性注射的拮抗剂对于抑制内源性LH的有效时间为4天。如果在这4天内卵泡还未能达到能诱导成熟的阶段(在一项大型三期测验中,大约有10%的患者出现这种情况),可以再相应增加拮抗剂给药。

  Apparently,the single-dose administration is patient friendlier compared to the daily dose,since it is associated with a decreased number of antagonist injections.However,theoretically it might result in unnecessary antagonist administration.In this respect,although daily antagonist necessitates multiple injections,it allows using the minimally necessary dose of antagonist in a given treatment cycle.

  显然,单剂量方案比多剂量方案对患者更加友好,需要注射拮抗剂的次数不多。但理论上单剂量方案可能会导致增加不必要的给药。因此,尽管多剂量方案需要多次注射,但是能尽量减少促排周期中的拮抗剂使用剂量。

  △CEF医院图

  Until today only two comparative RCTs between the two schemes of antagonist administration have been published,including 215 patients.Stratified analysis of these two trials shows no difference in the probability of clinical pregnancy.However,since they are based on a small number of patients,the results are not conclusive.Nevertheless,the majority of published antagonist studies have been performed with the daily dose protocol.

  到目前为止有两项研究用随机对照试验比较了拮抗剂的两种给药方案的结果,研究对象总共有215个患者。这两个研究采用了分层分析,结果显示两种给药方案的患者在临床妊娠率方面没有差异。不过因为研究对象人数比较少,研究结果并不是结论性的。但目前大多数发表的针对拮抗剂方案的研究都是采用多剂量方案。

  GnRH拮抗剂最佳药量

  Optimal dose of GnRH antagonist

  Three RCTs were performed by the ganirelix dose-finding study group to establish the dose under which GnRH antagonists should be used in IVF.Results reported in 1998 showed that the optimal dose was 0.25mg for the daily dose scheme and 3mg for the single dose scheme.

  加尼瑞克剂量研究小组做了三组随机对照试验,研究试管周期中拮抗剂的使用剂量,并于1998年发表了研究结果:建议多剂量方案每日最佳剂量是0.25mg,单剂量方案最佳剂量是3mg。

  Higher antagonist doses for daily administration have been associated with very low LH levels and a lower probability of pregnancy.Moreover,they lead to detectable antagonist in circulation by the day of embryo transfer,which has been suggested to be detrimental for embryo implantation.

  每日剂量超过0.25mg后,再增加给药量,会导致LH水平大幅下降,降低妊娠率,甚至在胚胎移植当天还能在体内检测到拮抗剂成分,这可能会对胚胎着床产生不利影响。

  GnRH拮抗剂给药时间

  Timing of GnRH antagonist administration

  Antagonist administration was performed in the initial comparative trials between GnRH agonists and GnRH antagonists with a fixed scheme,starting on day 6 of stimulation.Optimization of this fixed antagonist protocol,based on data regarding endogenous LH control,has recently moved antagonist initiation to an earlier time point,e.g.to day 5 of stimulation.

  在早期GnRH激动剂和拮抗剂的对比试验中,通常固定方案会选择在促排第6天开始使用拮抗药。根据后期研究数据,为了更好控制内源性LH峰值,优化后的方案会提前开始给药,例如在促排第5天开始。

  △CEF医院图

  In the flexible antagonist scheme,antagonist is started when an LH surge is likely to occur.Since there is significant heterogeneity between individual treatment cycles,different criteria have been used to guide antagonist initiation,which are based on either ultrasound and/or hormonal criteria.

  在灵活方案中,会在LH峰值预计要出现时就开始使用拮抗剂。由于个体周期存在显著差异,通常会采用不同标准来决定拮抗剂给药开始时间,例如超声波和/或激素检测结果。

  Fixed compared to flexible antagonist initiation is a simpler protocol that requires less monitoring.On the other hand,it might lead to unnecessary antagonist administration,since in a proportion of patients an LH surge is unlikely to occur on day 5 of stimulation due to absence of follicular development.

  固定方案比灵活方案更容易安排开始给药时间,能减少检测次数,但是也有可能会导致不必要的给药,因为一部分患者在促排用药下卵泡未发育,促排第5天很可能不会出现LH峰值。

  Both the fixed(day 6 of stimulation)and the flexible protocol(using different criteria for antagonist initiation)have been compared in four RCTs,the results of which have been summarized in a meta-analysis that did not show a significant difference in clinical pregnancy rates between the two protocols.However,all studies showed the same direction of effect,which was not in favor of the flexible protocol.

  根据一项对四次随机对照试验的meta分析结果,采用固定方案(促排第6天给药)和灵活方案(基于不同标准决定开始给药时间)的临床妊娠率没有显著差异。然而,所有的研究都是类似的结果,从结果看,灵活方案并不优于固定方案。

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