Excessive ovarian stimulation up-regulates the Wnt-signaling molecule DKK1 in human endometrium and may affect implantation: an in vitro co-culture study

被引:77
作者
Liu, Yunao [1 ]
Kodithuwakku, Suranga P. [1 ,2 ]
Ng, Pak-Yiu [1 ]
Chai, Joyce [1 ]
Ng, Ernest H. Y. [1 ,3 ]
Yeung, William S. B. [1 ,3 ]
Ho, Pak-Chung [1 ,3 ]
Lee, Kai-Fai [1 ,3 ]
机构
[1] Univ Hong Kong, Dept Obstet & Gynaecol, Li Ka Shing Fac Med, Pokfulam, Hong Kong, Peoples R China
[2] Univ Peradeniya, Dept Anim Sci, Peradeniya 20400, Sri Lanka
[3] Univ Hong Kong, Ctr Reprod Dev & Growth, Li Ka Shing Fac Med, Pokfulam, Hong Kong, Peoples R China
关键词
ovarian stimulation; endometrium; Wnt-signaling; implantation; spheroids; SERUM ESTRADIOL CONCENTRATIONS; GENE-EXPRESSION PROFILES; CELL-LINE ISHIKAWA; MOUSE BLASTOCYST; PERIIMPLANTATION ENDOMETRIUM; PREIMPLANTATION PERIOD; SECRETED ANTAGONISTS; UTERINE RECEPTIVITY; GNRH ANTAGONIST; HIGH RESPONDERS;
D O I
10.1093/humrep/dep429
中图分类号
R71 [妇产科学];
学科分类号
100211 ;
摘要
High serum estradiol (E-2) levels following ovarian stimulation lead to reduced implantation and pregnancy rates, yet the underlying mechanisms remain unknown. We investigated if aberrant expression of genes in the Wnt-signaling pathway may be involved. Microarray and real-time PCR analysis were performed to analyze gene expression profiles of endometrial samples taken at day hCG + 7 in stimulated cycles, and days LH + 7 and LH + 10 in natural cycles. Expression of several Wnt-signaling transcripts, including Dickkopf homolog 1 (DKK1), DKK2 and secreted frizzled-related protein 4 (sFRP4), was analyzed throughout the menstrual cycle. JAr spheroid/Ishikawa endometrial cell co-culture experiments were established to study effects of DKK1 on spheroid attachment in vitro. We identified 351 differentially expressed genes. Endometrial samples taken at hCG + 7 had similar expression profiles to those at LH + 10. DKK1 transcripts were up-regulated and DKK2 and sFRP4 were down-regulated in the stimulated compared with LH + 7 group (all P < 0.05). DKK1 transcripts were low in proliferative phase (PS) and increased in late-secretory phase (LS, P < 0.05), although DKK2 peaked in mid-secretory phase (P < 0.05). sFRP4 transcripts were high in PS. Treatment of spheroid with recombinant human DKK-1 protein dose-dependently suppressed (P < 0.05 versus control) spheroids attachment onto endometrial cells (associated with decreased beta-catenin protein): this suppression was nullified by anti-DKK1 antibody. Gene expression patterns in stimulated cycles resembled those of LS in natural cycles, when the implantation window is about to close, suggesting high serum E-2 and/or progesterone concentrations may advance endometrial development, altering the implantation window and possibly decreasing pregnancy rate. Aberrant expression of DKK1 might impair embryo attachment and implantation in vivo.
引用
收藏
页码:479 / 490
页数:12
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