摘要
研究目的
辅助生育技术发展至今应用于人类已有近30年的历史,由于促排卵药物的应用和单精子卵胞浆注射等实验室技术改进,取得了突破性进展。但是,从90年代后期至今,胚胎种植率一直徘徊在20%左右,临床妊娠率也在40%左右浮动。正常子宫内膜仅在一个极短的关键时期允许胚胎着床,在这一时期子宫内膜对胚胎的接受性达到最高,被称为“种植窗”(window of implantation,WOI)。种植窗期在卵巢激素调节下,子宫内膜形态组织结构和分泌蛋白都发生一序列变化,使子宫内膜的容受性达到最大,以利于胚胎着床。形态学检查已经发现促排卵周期的子宫内膜种植窗口期与自然周期有1～2天的差别,也发现了一些与胚胎种植相关的基因,但还没有一个基因可以独立决定子宫内膜容受性的好坏。胚胎着床窗口的出现和消失依赖于子宫内膜一套特定基因时空特异性表达,目前我们对此所知甚少。我们拟通过全基因组表达谱分析,比较自然周期和促排卵周期种植窗口期子宫内膜的基因表达差异,以期发现有价值的子宫内膜容受性相关基因。
研究方法
吸取输卵管性不孕和男性不孕拟行IVF-ET患者的内膜20人份。5份行HU133 plus2.0芯片扫描,其中自然周期LH峰后4天(LH+4)2份,LH峰后7天(LH+7)1份,促排卵周期注射HCG后7天(HCG+7)2份。另外LH+7标本7份和HCG+7标本8份行实时定量PCR(QPCR)验证。所有标本经病理组织学认定与所属期别相符。在芯片扫描及Q-PCR验证结果进行分析的基础上,本研究选取其中一个新的可能与着床相关的差异表达基因S100P行进一步研究。
结果
LH+7与LH+4的表达差异在3倍以上的基因581个,其中在LH+7表达上调基因395个、下调基因186个。HCG+7与LH+7的表达差异在3倍以上的基因320个,其中在HCG+7表达下调基因145个、上调基因175个。在QPCR验证中,我们发现LH+7日PAEP、S100P、SOD、GDF15等上调基因,在HCG+7日均出现表达不良。本研究芯片扫描的对照组为LH+4日子宫内膜,与以往文献报道LH+2日子宫内膜进行比较,结果提示LH+4日与LH+2日绝大多数基因表达相似。在S100P的进一步研究中,免疫荧光技术对S100P的定位显示S100P蛋白在人子宫内膜腺上皮细胞表达,RT-PCR与Western-blot技术检测到S100P在人种植窗子宫内膜特异性高表达,而S100其他家族成员S100A4、S100A13和S100A6的表达变化不明显。
结论
基因芯片扫描提供了不同时期人子宫内膜的全基因表达谱。通过本研究的芯片扫描及随后的Q-PCR验证,我们发现了一批可能与子宫内膜容受性相关的基因,如PAEP、S100P、SOD和GDF15等,这些基因在促排卵后出现表达不良:由于LH+4日与LH+2日绝大多数基因表达相似,推测种植窗的基因表达变化可能是在1～2天内快速同步进行的,种植窗的开放可能存在“扳机”效应;S100P在核酸与蛋白水平均呈现种植窗的高表达,S100P可能成为新发现的子宫内膜容受性相关基因。
Objective
In vitro fertilization-embryo transfer(IVF-ET)has been employed in treating infertility for about 30 years.Despite the more stable techniques in lab and the increased number of high-quality embryos,implantation rate is still around 20%.The receptivity of endometrium may be the main hinder.Appearance and disappearance of implantation window depend on expression of a specific set of genes in endometrium. Morphological finding showed 1-2 days difference of the implantation window in the controlled ovarian hyperstimulation(COH)cycle comparing to the natural cycle,and that some genes have been detected relating to embryo adhesion and invasion. However,there is no gene which can decide the endometrial receptivity all by itself. In this study scanning the complete genome array of endometrium at the luteal phase of COH cycle and the natural cycle was conducted to find the gene expression of implantation window with the aim to know more about genes associated with endometrial receptivity.
Methods
Five endometrial samples from days of LH+4、LH+7 and HCG+7 were taken into HU133 plus2.0 microarray scanning.These 5 samples and the other 7 samples from day of LH+7 and 8 samples from HCG+7 received Real-time PCR quantitation(QPCR)test.All samples were certainly matched with their stages of pathohistology.Based on the results of microarray scanning,we selected S100P which was suspected to be a new implantation associated gene for further research by immunofluorence,RT-PCR and western-blot analysis.
Results
Comparing the complete genome expression spectra of LH+7 to that of LH+4,581 genes have expression differences,among which 395 were up-regulation genes and 186 were down-regulation genes.When it went to HCG+7 and LH+7,320 genes have expression differences,among which 145 genes were down-regulated,and 175 genes were up-regulated.In the QPCR test,some up-regulation gene's expression was much lower on the day HCG+7 than LH+7,such as PAEP、S100P、SOD and GDF15.The results demonstrated that S100P which was low in proliferative phase and early secrectory phase,elevated significantly in implantantion window(LH+7). The other three S100 family members S100A4,S100A13 and S100A6,was not comparable with S100P expression during the menstrual cycle.
Conclusions
Microarray scanning provides a global gene expression spectrum of different phase of human endometrium.A set of genes,such as PAEP,S100P,SOD and GDF15, express high at the implantation window phase of the endometrium,but not show adequate expression after controlled ovarian hyperstimulation;From the hierarchical clustering the characters of endometrium at LH+4 are in great resemblance with the characters of endometrium at LH+2.This may hint that gene expression changes at implantation window proceed quickly within 1 or 2 days,and that there may exist a "trigger effect" for the opening of implantation window.The S100P gene which has not been described before expressed especially high in implantation window. Therefore S100P may be a new gene associated with endometrial receptivity.
引文
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1.Norbert Gleicher,Andrea Weghofer,David Barad.Update on the comparison of assisted reproduction outcomes between Europe and the USA:the 2 002 data,Fertility and Sterility.2007,87:1301-1305
2.罗国群,等。控制性超促排卵对子宫内膜种植窗的影响。国外医学计划生育/生殖健康分册。2006,25(2):74-76
3.Nikas G,Develioglu OH,Toner JP,et al.Endometrial pinopodes indicate a shift in the window of receptivity in IVF cycles.Hum Reprod.1999,14:787-792
4.Damario MA,Lesneck TG,Lessey BA,et al.Endometrial markers of uterine,receptivity utilizing the donor oocyte model.Hum Reprod.2001,16:1893-1897
5.Anne Riesewijk,Julio Martin,Roselinde van Os,et al.Gene expression profiling of human endometrial receptivity on days LH+2 versus LH+7 by microarray technology.Mol Hum Reprod.9:253-264.
6.Riesewijk A,Martin J,Horcajadas JA,et al.Gene expression profiling of human endometrial receptivity on days LH+2 versus LH+7 by microarray technology.Mol Hum Reprod.2003,9:253-264
7. Mirkin S, Arslan M, Churikov D,et al. In search of candidate genes critically expressed in the human endometrium during the window of implantation. Hum Reprod . 2005, 20:2104-2117
8. Kao LC, Tulac S, Lobo S, et al. Global gene profiling in human endometrium during the window implantation. Endocrinology.2002,143:2119-2138.
9. Carson D, Lagow E, Thathiah A, et al. Changes in gene expression during the early to mid-luteal (receptive phase) transition in human endometrium detected by high-density microarray screening. Mol Hum Reprod 8,971-979.
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