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Abstract：
Polycystic ovary syndrome (PCOS) is a complex common endocrine disorder affecting women of reproductive age. Ovulatory dysfunction is recognized as a primary infertile factor, however, even when ovulation is medically induced and restored, PCOS patients continue to experience reduced cumulative pregnancy rates and a higher spontaneous miscarriage rate. Hyperandrogenism, a hallmark feature of PCOS, affects ovarian folliculogenesis, endometrial receptivity, and the establishment and maintenance of pregnancy. Decidualization denotes the transformation that the stromal compart of the endometrium must undergo to accommodate pregnancy, driven by the rising progesterone levels and local cAMP production. However, studies on the impact of hyperandrogenism on decidualization are limited. In this study, we observed that primary endometrial stromal cells from women with PCOS exhibit abnormal responses to progesterone during in vitro decidualization. A high concentration of testosterone inhibits human endometrial stromal cells (HESCs) decidualization. RNA-Seq analysis demonstrated that pyruvate dehydrogenase kinase 4 (PDK4) expression was significantly lower in the endometrium of PCOS patients with hyperandrogenism compared to those without hyperandrogenism. We also characterized that the expression of PDK4 is elevated in the endometrium stroma at the mid-secretory phase. Artificial decidualization could enhance PDK4 expression, while downregulation of PDK4 leads to abnormal decidualization both in vivo and in vitro. Mechanistically, testosterone excess inhibits IGFBP1 and PRL expression, followed by phosphorylating of AMPK that stimulates PDK4 expression. Based on co-immunoprecipitation analysis, we observed an interaction between SIRT1 and PDK4, promoting glycolysis to facilitate decidualization. Restrain of AR activation resumes the AMPK/SIRT1/PDK4 pathway suppressed by testosterone excess, indicating that testosterone primarily acts on decidualization through AR stimulation. Androgen excess in the endometrium inhibits decidualization by disrupting the AMPK/SIRT1/PDK4 signaling pathway. These data demonstrate the critical roles of endometrial PDK4 in regulating decidualization and provide valuable information for understanding the underlying mechanism during decidualization.
摘要：
多囊卵巢综合征（PCOS）是一种复杂的常见内分泌疾病，影响育龄妇女。排卵功能障碍被认为是主要的不育因素，然而,即使是药物诱导和恢复排卵，PCOS患者继续经历降低的累积妊娠率和更高的自发流产率。雄激素过多症,PCOS的标志性特征,影响卵巢卵泡发育，子宫内膜容受性，以及怀孕的建立和维持。蜕膜化是指子宫内膜基质部分必须经历的转化，以适应妊娠，受孕酮水平上升和当地cAMP产量的驱动。然而,关于高雄激素血症对蜕膜化影响的研究有限。在这项研究中,我们观察到,PCOS女性患者的原代子宫内膜基质细胞在体外蜕膜化过程中表现出对孕酮的异常反应.高浓度的睾酮抑制人子宫内膜基质细胞(HESC)蜕膜化。RNA-Seq分析表明，与没有高雄激素血症的PCOS患者相比，丙酮酸脱氢酶激酶4（PDK4）在高雄激素血症患者子宫内膜中的表达显着降低。我们还表征了在分泌中期子宫内膜基质中PDK4的表达升高。人工蜕膜化能增强PDK4的表达，而PDK4的下调导致体内和体外的异常蜕膜化。机械上,睾酮过量抑制IGFBP1和PRL表达，然后磷酸化刺激PDK4表达的AMPK。基于免疫共沉淀分析，我们观察到SIRT1和PDK4之间的相互作用,促进糖酵解以促进蜕膜化.AR激活的抑制恢复了睾酮过量抑制的AMPK/SIRT1/PDK4途径，表明睾酮主要通过AR刺激作用于蜕膜化。子宫内膜雄激素过量通过破坏AMPK/SIRT1/PDK4信号通路抑制蜕膜化这些数据证明了子宫内膜PDK4在调节蜕膜化中的关键作用，并为了解蜕膜化过程中的潜在机制提供了有价值的信息。
