Author:Efstratios M.Kolibianakis and Georg Griesinger
作者：Efstratios M.Kolibianakis and Georg Griesinger
Book:Human Assisted Reproductive Technology
書籍：人類輔助生殖技術(shù)(2011年第一版)
Editorsavid K.Gardner,Botros RMB Rizk and Tommaso Falcone
主編：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.
促性腺激素釋放激素(GnRH)類似物從1984年起開始用于試管促排周期，以達(dá)到抑制過早出現(xiàn)LH高峰的目的。與GnRH拮抗劑相比，GnRH激動(dòng)劑的一個(gè)劣勢在于不能及時(shí)抑制內(nèi)源性促性腺激素的釋放，因此需要在開始使用促性腺激素一段時(shí)間前先做預(yù)控制。雖然GnRH激動(dòng)劑存在明顯的弱點(diǎn)，但是直到1990年*末，我們還是只能用激動(dòng)劑來控制內(nèi)源性LH的分泌，因?yàn)楫?dāng)時(shí)臨床上可以使用的類似物只有激動(dòng)劑。
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拮抗劑的發(fā)明不僅給臨床醫(yī)生提供了GnRH激動(dòng)劑的替*品，而且更重要的是，這一發(fā)明促使他們在提高*巢促排安全性和簡便性方面進(jìn)行了創(chuàng)新，包括改良了自然周期方案，發(fā)明了微促方案，用激動(dòng)劑誘導(dǎo)*泡最后成熟過程，在黃體期補(bǔ)充拮抗劑預(yù)防*巢過度刺激綜合征，以及在宮腔內(nèi)受精周期中應(yīng)用拮抗劑方案控制內(nèi)源性LH峰值等。
GnRH拮抗劑方案
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拮抗劑的給藥可以分為單劑量方案和多劑量方案。在單劑量方案中，一次性注射的拮抗劑對于抑制內(nèi)源性LH的有效時(shí)間為4天。如果在這4天內(nèi)*泡還未能達(dá)到能誘導(dǎo)成熟的階段(在一項(xiàng)大型三期測驗(yàn)中，大約有10%的患者出現(xiàn)這種情況)，可以再相應(yīng)增加拮抗劑給藥。
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.
顯然，單劑量方案比多劑量方案對患者更加友好，需要注射拮抗劑的次數(shù)不多。但理論上單劑量方案可能會(huì)導(dǎo)致增加不必要的給藥。因此，盡管多劑量方案需要多次注射，但是能盡量減少促排周期中的拮抗劑使用劑量。
△CEF醫(yī)院圖
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.
到目前為止有兩項(xiàng)研究用隨機(jī)對照試驗(yàn)比較了拮抗劑的兩種給藥方案的結(jié)果，研究對象總共有215個(gè)患者。這兩個(gè)研究采用了分層分析，結(jié)果顯示兩種給藥方案的患者在臨床妊娠率方面沒有差異。不過因?yàn)檠芯繉ο笕藬?shù)比較少，研究結(jié)果并不是結(jié)論性的。但目前大多數(shù)發(fā)表的針對拮抗劑方案的研究都是采用多劑量方案。
GnRH拮抗劑最佳藥量
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.
加尼瑞克劑量研究小組做了三組隨機(jī)對照試驗(yàn)，研究試管周期中拮抗劑的使用劑量，并于1998年發(fā)表了研究結(jié)果：建議多劑量方案每日最佳劑量是0.25mg,單劑量方案最佳劑量是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.
每日劑量超過0.25mg后，再增加給藥量，會(huì)導(dǎo)致LH水平大幅下降，降低妊娠率，甚至在胚胎移植當(dāng)天還能在體內(nèi)檢測到拮抗劑成分，這可能會(huì)對胚胎著床產(chǎn)生不利影響。
GnRH拮抗劑給藥時(shí)間
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激動(dòng)劑和拮抗劑的對比試驗(yàn)中，通常固定方案會(huì)選擇在促排第6天開始使用拮抗藥。根據(jù)后期研究數(shù)據(jù)，為了更好控制內(nèi)源性LH峰值，優(yōu)化后的方案會(huì)提前開始給藥，例如在促排第5天開始。
△CEF醫(yī)院圖
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.
在靈活方案中，會(huì)在LH峰值預(yù)計(jì)要出現(xiàn)時(shí)就開始使用拮抗劑。由于個(gè)體周期存在顯著差異，通常會(huì)采用不同標(biāo)準(zhǔn)來決定拮抗劑給藥開始時(shí)間，例如超聲波和/或激素檢測結(jié)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.
固定方案比靈活方案更容易安排開始給藥時(shí)間，能減少檢測次數(shù)，但是也有可能會(huì)導(dǎo)致不必要的給藥，因?yàn)橐徊糠只颊咴诖倥庞盟幭?泡未發(fā)育，促排第5天很可能不會(huì)出現(xiàn)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.
根據(jù)一項(xiàng)對四次隨機(jī)對照試驗(yàn)的meta分析結(jié)果，采用固定方案(促排第6天給藥)和靈活方案(基于不同標(biāo)準(zhǔn)決定開始給藥時(shí)間)的臨床妊娠率沒有顯著差異。然而，所有的研究都是類似的結(jié)果，從結(jié)果看，靈活方案并不優(yōu)于固定方案。
溫馨提示：我們是USIB美中橋，如需要了解更多試管嬰兒資訊，請掃一掃下方二維碼關(guān)注“USIBIVF”,以及關(guān)注美中橋“USIBIVF”公眾號(hào)，即時(shí)獲取更多的試管嬰兒資訊。
發(fā)表于2021-06-29 16:15:34
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最新討論
作者：Efstratios M.Kolibianakis and Georg Griesinger
Book:Human Assisted Reproductive Technology
書籍：人類輔助生殖技術(shù)(2011年第一版)
Editors
主編：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.
促性腺激素釋放激素(GnRH)類似物從1984年起開始用于試管促排周期，以達(dá)到抑制過早出現(xiàn)LH高峰的目的。與GnRH拮抗劑相比，GnRH激動(dòng)劑的一個(gè)劣勢在于不能及時(shí)抑制內(nèi)源性促性腺激素的釋放，因此需要在開始使用促性腺激素一段時(shí)間前先做預(yù)控制。雖然GnRH激動(dòng)劑存在明顯的弱點(diǎn)，但是直到1990年*末，我們還是只能用激動(dòng)劑來控制內(nèi)源性LH的分泌，因?yàn)楫?dāng)時(shí)臨床上可以使用的類似物只有激動(dòng)劑。
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拮抗劑的發(fā)明不僅給臨床醫(yī)生提供了GnRH激動(dòng)劑的替*品，而且更重要的是，這一發(fā)明促使他們在提高*巢促排安全性和簡便性方面進(jìn)行了創(chuàng)新，包括改良了自然周期方案，發(fā)明了微促方案，用激動(dòng)劑誘導(dǎo)*泡最后成熟過程，在黃體期補(bǔ)充拮抗劑預(yù)防*巢過度刺激綜合征，以及在宮腔內(nèi)受精周期中應(yīng)用拮抗劑方案控制內(nèi)源性LH峰值等。
GnRH拮抗劑方案
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拮抗劑的給藥可以分為單劑量方案和多劑量方案。在單劑量方案中，一次性注射的拮抗劑對于抑制內(nèi)源性LH的有效時(shí)間為4天。如果在這4天內(nèi)*泡還未能達(dá)到能誘導(dǎo)成熟的階段(在一項(xiàng)大型三期測驗(yàn)中，大約有10%的患者出現(xiàn)這種情況)，可以再相應(yīng)增加拮抗劑給藥。
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.
顯然，單劑量方案比多劑量方案對患者更加友好，需要注射拮抗劑的次數(shù)不多。但理論上單劑量方案可能會(huì)導(dǎo)致增加不必要的給藥。因此，盡管多劑量方案需要多次注射，但是能盡量減少促排周期中的拮抗劑使用劑量。
△CEF醫(yī)院圖
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.
到目前為止有兩項(xiàng)研究用隨機(jī)對照試驗(yàn)比較了拮抗劑的兩種給藥方案的結(jié)果，研究對象總共有215個(gè)患者。這兩個(gè)研究采用了分層分析，結(jié)果顯示兩種給藥方案的患者在臨床妊娠率方面沒有差異。不過因?yàn)檠芯繉ο笕藬?shù)比較少，研究結(jié)果并不是結(jié)論性的。但目前大多數(shù)發(fā)表的針對拮抗劑方案的研究都是采用多劑量方案。
GnRH拮抗劑最佳藥量
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.
加尼瑞克劑量研究小組做了三組隨機(jī)對照試驗(yàn)，研究試管周期中拮抗劑的使用劑量，并于1998年發(fā)表了研究結(jié)果：建議多劑量方案每日最佳劑量是0.25mg,單劑量方案最佳劑量是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.
每日劑量超過0.25mg后，再增加給藥量，會(huì)導(dǎo)致LH水平大幅下降，降低妊娠率，甚至在胚胎移植當(dāng)天還能在體內(nèi)檢測到拮抗劑成分，這可能會(huì)對胚胎著床產(chǎn)生不利影響。
GnRH拮抗劑給藥時(shí)間
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激動(dòng)劑和拮抗劑的對比試驗(yàn)中，通常固定方案會(huì)選擇在促排第6天開始使用拮抗藥。根據(jù)后期研究數(shù)據(jù)，為了更好控制內(nèi)源性LH峰值，優(yōu)化后的方案會(huì)提前開始給藥，例如在促排第5天開始。
△CEF醫(yī)院圖
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.
在靈活方案中，會(huì)在LH峰值預(yù)計(jì)要出現(xiàn)時(shí)就開始使用拮抗劑。由于個(gè)體周期存在顯著差異，通常會(huì)采用不同標(biāo)準(zhǔn)來決定拮抗劑給藥開始時(shí)間，例如超聲波和/或激素檢測結(jié)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.
固定方案比靈活方案更容易安排開始給藥時(shí)間，能減少檢測次數(shù)，但是也有可能會(huì)導(dǎo)致不必要的給藥，因?yàn)橐徊糠只颊咴诖倥庞盟幭?泡未發(fā)育，促排第5天很可能不會(huì)出現(xiàn)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.
根據(jù)一項(xiàng)對四次隨機(jī)對照試驗(yàn)的meta分析結(jié)果，采用固定方案(促排第6天給藥)和靈活方案(基于不同標(biāo)準(zhǔn)決定開始給藥時(shí)間)的臨床妊娠率沒有顯著差異。然而，所有的研究都是類似的結(jié)果，從結(jié)果看，靈活方案并不優(yōu)于固定方案。
溫馨提示：我們是USIB美中橋，如需要了解更多試管嬰兒資訊，請掃一掃下方二維碼關(guān)注“USIBIVF”,以及關(guān)注美中橋“USIBIVF”公眾號(hào)，即時(shí)獲取更多的試管嬰兒資訊。