Prince Henry's Institute of Medical Research, Monash University, Monash Medical Centre, Clayton, Victoria 3168, Australia.
Endocrinology. 2011 Dec;152(12):4948-56. doi: 10.1210/en.2011-1248. Epub 2011 Oct 25.
Embryo implantation requires synchronized dialogue between the receptive endometrium and activated blastocyst via locally produced soluble mediators. During the midsecretory (MS) phase of the menstrual cycle, increased glandular secretion into the uterine lumen contains important mediators that modulate the endometrium and support the conceptus during implantation. This study aimed first to identify the growth factor and cytokine profile of human uterine fluid from fertile women during the midproliferative (MP; nonreceptive) and MS (receptive) phases of the cycle, and from women with unexplained infertility during the MS phase. The second aim was to determine important functions of endometrial secretions for embryo implantation. Analysis of uterine fluid using quantitative Luminex assays revealed the presence of over 30 cytokines and growth factors, of which eight [platelet-derived growth factor-AA, TNF-B, soluble IL-2 receptor-A, Fms-like tyrosine kinase 3 ligand, soluble CD40 ligand, IL-7, interferon-A2, and chemokine (C-X-C motif) ligand 1-3] were previously unknown in human uterine fluid. Comparison of the fertile MP, MS, and infertile MS cohorts revealed vascular endothelial growth factor (VEGF) levels are significantly reduced in uterine fluid during the MS phase in women with unexplained infertility compared with fertile women. Functional studies demonstrated that culturing mouse embryos with either MS-phase uterine fluid from fertile women or recombinant human VEGF significantly enhanced blastocyst outgrowth. Furthermore, treatment of human endometrial epithelial cells with uterine fluid or recombinant human VEGF-A significantly increased endometrial epithelial cell adhesion. Taken together, our data support the concept that endometrial secretions, including VEGF, play important roles during implantation. Identifying the soluble mediators in human uterine fluid and their actions during implantation provides insight into interactions essential for establishing pregnancy, fertility markers, and infertility treatment options.
胚胎着床需要接受性子宫内膜和激活的囊胚通过局部产生的可溶性介质进行同步对话。在月经周期的中期分泌期（MS），增加的腺体分泌到子宫腔中包含重要的介质，调节子宫内膜并支持着床期间的胚胎。本研究首先旨在鉴定来自生育期妇女的人子宫液中的生长因子和细胞因子谱，这些妇女在周期的中增殖期（MP；非接受性）和 MS（接受性）阶段，以及在 MS 阶段的不明原因不孕妇女。第二个目的是确定子宫内膜分泌物对胚胎着床的重要功能。使用定量 Luminex 分析对子宫液进行分析显示，存在超过 30 种细胞因子和生长因子，其中 8 种（血小板衍生生长因子-AA、TNF-B、可溶性 IL-2 受体-A、Fms 样酪氨酸激酶 3 配体、可溶性 CD40 配体、IL-7、干扰素-A2 和趋化因子（C-X-C 基序）配体 1-3）以前在人子宫液中未知。将生育的 MP、MS 和不明原因不孕的 MS 队列进行比较，发现与生育妇女相比，不明原因不孕妇女在 MS 期子宫液中的血管内皮生长因子（VEGF）水平显著降低。功能研究表明，用来自生育妇女的 MS 期子宫液或重组人 VEGF 培养小鼠胚胎显著增强了囊胚的生长。此外，用子宫液或重组人 VEGF-A 处理人子宫内膜上皮细胞显著增加了子宫内膜上皮细胞的粘附。总之，我们的数据支持这样的概念，即子宫内膜分泌物，包括 VEGF，在着床期间发挥重要作用。鉴定人子宫液中的可溶性介质及其在着床过程中的作用，为建立妊娠、生育标志物和不孕治疗选择提供了对重要相互作用的深入了解。
