The Fertility Clinic, Department D, Odense University Hospital, OHU, Entrance 55, Odense C 5000, Denmark.
Hum Reprod. 2012 Nov;27(11):3259-72. doi: 10.1093/humrep/des279. Epub 2012 Aug 28.
Do differences in endometrial gene expression exist after ovarian stimulation with four different regimens of triggering final oocyte maturation and luteal phase support in the same patient?
Significant differences in the expression of genes involved in receptivity and early implantation were seen between the four protocols.
GnRH agonist triggering is an alternative to hCG triggering in GnRH antagonist co-treated cycles, resulting in an elimination of early ovarian hyperstimulation syndrome. Whereas previous studies have revealed a low ongoing clinical pregnancy rate after GnRH agonist trigger due to a high early pregnancy loss rate, despite supplementation with the standard luteal phase support, more recent studies, employing a 'modified' luteal phase support including a bolus of 1500 IU hCG on the day of oocyte aspiration, have reported ongoing pregnancy rates similar to those seen after hCG triggering.
STUDY DESIGN, SIZE DURATION: A prospective randomized study was performed in four oocyte donors recruited from an oocyte donation program during the period 2010-2011.
PARTICIPANTS, MATERIALS, SETTING, METHODS: Four oocyte donors in a university IVF center each prospectively underwent four consecutive stimulation protocols, with different modes of triggering final oocyte maturation and a different luteal phase support, followed by endometrial biopsy on Day 5 after oocyte retrieval. The following protocols were used: (A) 10 000 IU hCG and standard luteal phase support, (B) GnRH agonist (triptorelin 0.2 mg), followed by 1500 IU hCG 35 h after triggering final oocyte maturation, and standard luteal phase support, (C) GnRH agonist (triptorelin 0.2 mg) and standard luteal phase support and (D) GnRH agonist (triptorelin 0.2 mg) without luteal phase support. Microarray data analysis was performed with GeneSpring GX 11.5 (RMA algorithm). Pathway and network analysis was performed with the gene ontology software Ingenuity Pathways Analysis (Ingenuity® Systems, www.ingenuity.com, Redwood City, CA, USA). Samples were grouped and background intensity values were removed (cutoff at the lowest 20th percentile). A one-way ANOVA test (P< 0.05) was performed with Benjamini-Hochberg multiple testing correction.
Significant differences were seen in endometrial gene expression, related to the type of ovulation trigger and luteal phase support. However, the endometrial gene expression after the GnRH agonist trigger and a modified luteal phase support (B) was similar to the pattern seen after the hCG trigger (A).
LIMITATIONS, REASONS FOR CAUTION: The study was performed in four oocyte donors only; however, it is a strength of the study that the same donor underwent four consecutive stimulation protocols within 1 year to avoid inter-individual variations.
These endometrial gene-expression findings support the clinical reports of a non-significant difference in live birth rates between the GnRH agonist trigger and the hCG trigger, when the GnRH agonist trigger is followed by a bolus of 1500 IU hCG at 35 h post trigger in addition to the standard luteal phase support.
STUDY FUNDING/ COMPETING INTERESTS: This study was supported by an un-restricted research grant by MSD Belgium.
EudraCT number 2009-009429-26, protocol number 997 (P06034).
在同一位患者中，使用四种不同的方案触发卵母细胞成熟和黄体期支持，是否存在子宫内膜基因表达的差异？
在四种方案中，观察到参与接受性和早期着床的基因表达存在显著差异。
促性腺激素释放激素激动剂（GnRH agonist）触发是 GnRH 拮抗剂治疗周期中 hCG 触发的替代方案，可消除早期卵巢过度刺激综合征。尽管黄体期支持中补充了标准黄体期支持，但先前的研究显示 GnRH 激动剂触发后的持续临床妊娠率较低，因为早期妊娠丢失率较高，尽管采用了包括卵母细胞抽吸当天给予 1500IU hCG 冲击的“改良”黄体期支持，但最近的研究报告称，持续妊娠率与 hCG 触发后相似。
研究设计、大小和持续时间：在 2010-2011 年期间，从卵子捐赠计划中招募了四位卵子供体进行了一项前瞻性随机研究。
参与者、材料、设置、方法：四位卵子供体在一所大学的 IVF 中心，每位参与者均前瞻性地接受了四种连续的刺激方案，采用不同的触发卵母细胞成熟的方式和不同的黄体期支持，随后在卵母细胞回收后第 5 天进行子宫内膜活检。使用以下方案：（A）10000IU hCG 和标准黄体期支持，（B）GnRH 激动剂（triptorelin 0.2mg），然后在触发卵母细胞成熟后 35 小时给予 1500IU hCG，并给予标准黄体期支持，（C）GnRH 激动剂（triptorelin 0.2mg）和标准黄体期支持，（D）GnRH 激动剂（triptorelin 0.2mg）而不给予黄体期支持。使用 GeneSpring GX 11.5（RMA 算法）进行微阵列数据分析。使用基因本体软件 Ingenuity Pathways Analysis（Ingenuity® Systems，www.ingenuity.com，Redwood City，CA，USA）进行途径和网络分析。对样品进行分组并去除背景强度值（截止值为最低的 20%）。使用单向方差分析（ANOVA）检验（P<0.05），并进行 Benjamini-Hochberg 多重检验校正。
在排卵触发和黄体期支持的类型相关的子宫内膜基因表达方面，观察到显著差异。然而，GnRH 激动剂触发和改良黄体期支持（B）后的子宫内膜基因表达模式与 hCG 触发（A）相似。
局限性、谨慎的原因：该研究仅在四位卵子供体中进行；然而，该研究的一个优势是，同一位供体在 1 年内接受了四种连续的刺激方案，以避免个体间的差异。
这些子宫内膜基因表达发现支持了临床报告，即 GnRH 激动剂触发后加用 1500IU hCG 冲击，并补充标准黄体期支持，与 hCG 触发相比，活产率无显著差异。
研究资助/利益冲突：本研究由 MSD 比利时提供的一项不受限制的研究资助。
EudraCT 编号 2009-009429-26，方案编号 997（P06034）。
