Division of Obstetrics and Gynecology, Department of Women's and Children's Health, Karolinska Institutet, and Karolinska University Hospital, S-171 76 Stockholm, Sweden.
Department of Endometrial Receptivity Analysis, Igenomix S.L., Valencia, Spain.
Hum Reprod. 2018 Oct 1;33(10):1889-1897. doi: 10.1093/humrep/dey272.
How does a single dose of mifepristone on Day 2 after the LH peak (LH + 2) affect the endometrial receptivity transcriptome as assessed by the receptive signature established by the endometrial receptivity analysis (ERA)?
A single dose of mifepristone on day LH + 2 renders the endometrium non-receptive by altering the transcriptome associated with endometrial receptivity.
Mifepristone is a progesterone receptor modulator that has been shown to alter endometrial receptivity. The ERA is a computational predictor that utilizes gene expression data of 248 genes from next generation sequencing to identify endometrial receptivity status.
STUDY DESIGN, SIZE, DURATION: Endometrial biopsies were collected on day LH + 7 from controls (n = 11) and from women treated with mifepristone (n = 7). For further comparative analysis, samples were also obtained from women in the proliferative phase (n = 7).
PARTICIPANTS/MATERIALS, SETTING, METHODS: Mifepristone treatment consisted of 200 mg administered on day LH + 2. Endometrial biopsies were treated for RNA isolation and cDNA conversion and sequencing. Endometrial receptivity status was assessed by the ERA computational predictor. Differential gene expression between groups was also assessed. Ingenuity Pathway Analysis was used for network analysis. Validation of gene expression results was done by qPCR.
Control samples were all staged around 'receptive' as would be clinically expected for LH + 7. Treatment samples were all staged as non-receptive (all but one was classified as 'proliferative' and the last as 'pre-receptive'). Differential gene expression analysis yielded 60 differentially expressed genes between the control and treatment groups. Bioinformatic pathway analysis for differential expression showed inactivation of the progesterone and glucocorticoid receptors, consistent with mifepristone action.
LIMITATIONS, REASONS FOR CAUTION: The primary limitations are the relative small number of subjects and the use of a limited gene panel.
This study sheds further light on the endometrial receptivity altering effects of mifepristone and on progesterone action. It further shows the capacity of the ERA to identify pharmacologically induced non-receptive endometrium, which expands its possible use clinically and in research.
STUDY FUNDING/COMPETING INTEREST(S): C.v.G. and N.R.B. have no conflicts of interest. P.G.L. reports honorarium from University of HK/Shenzhen, other from NIF, India, outside the submitted work. K.G.D. reports consultancy for Bayer AG, Exelgyn, HRA-Pharma, Gedeon Richter, MSD, Mithra, Exeltis and Natural cycles, payment for lectures from Bayer AG, NSD, Ferring, HRA-Pharma, Exelgyn and Exeltis and clinical trials for Bayer AG, MSD, Exeltis, Mithra, HRA-Pharma and Sun Pharma. C.S. has a patent gene expression profile (ERA) issued to Igenomix and is scientific director of Igenomix S.L. M.R., R.N. and J.M.V. are employees of Igenomix S.L.
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在 LH 峰后第 2 天（LH+2）给予单次剂量米非司酮如何通过改变与子宫内膜容受性相关的转录组来影响子宫内膜容受性？
在 LH+2 时给予单次剂量的米非司酮通过改变与子宫内膜容受性相关的转录组使子宫内膜失去容受性。
米非司酮是一种孕激素受体调节剂，已证明其可改变子宫内膜容受性。ERA 是一种计算预测器，它利用下一代测序的 248 个基因的基因表达数据来识别子宫内膜容受性状态。
研究设计、大小和持续时间：在 LH+7 天从对照组（n=11）和接受米非司酮治疗的女性（n=7）中采集子宫内膜活检。为了进一步进行比较分析，还从增殖期的女性（n=7）中获得了样本。
参与者/材料、设置、方法：米非司酮治疗包括在 LH+2 时给予 200mg。对子宫内膜活检进行 RNA 分离和 cDNA 转化和测序处理。子宫内膜容受性状态通过 ERA 计算预测器进行评估。还评估了组间的差异基因表达。使用途径分析进行网络分析。通过 qPCR 验证基因表达结果。
对照组的所有样本都处于“接受”阶段，这是 LH+7 时临床上预期的。治疗组的所有样本都被归类为非接受性（除一个样本被归类为“增殖性”外，最后一个样本被归类为“预接受性”）。差异基因表达分析显示，对照组和治疗组之间有 60 个差异表达基因。差异表达的生物信息学途径分析显示孕激素和糖皮质激素受体失活，与米非司酮的作用一致。
局限性、谨慎的原因：主要限制是受试者数量相对较少和使用有限的基因面板。
这项研究进一步阐明了米非司酮对子宫内膜容受性的改变作用以及孕激素的作用。它进一步显示 ERA 有能力识别药理学诱导的非接受性子宫内膜，这扩大了其在临床和研究中的可能用途。
研究资金/竞争利益：C.v.G.和 N.R.B.没有利益冲突。P.G.L.报告了香港大学/深圳大学、印度 NIF 的酬金，以及拜耳 AG、Exelgyn、HRA-Pharma、Gedeon Richter、MSD、Mithra、Exeltis 和自然周期的其他酬金，拜耳 AG、NSD、Ferring、HRA-Pharma、Exelgyn 和 Exeltis 的演讲报酬以及拜耳 AG、MSD、Exeltis、Mithra、HRA-Pharma 和 Sun Pharma 的临床试验。C.S.拥有一项已颁发给 Igenomix 的基因表达谱（ERA）专利，是 Igenomix S.L.的科学总监。M.R.、R.N.和 J.M.V.是 Igenomix S.L.的员工。
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