Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital, London, United Kingdom.
PLoS One. 2010 Apr 21;5(4):e10287. doi: 10.1371/journal.pone.0010287.
Recurrent pregnancy loss (RPL), defined as 3 or more consecutive miscarriages, is widely attributed either to repeated chromosomal instability in the conceptus or to uterine factors that are poorly defined. We tested the hypothesis that abnormal cyclic differentiation of endometrial stromal cells (ESCs) into specialized decidual cells predisposes to RPL, based on the observation that this process may not only be indispensable for placenta formation in pregnancy but also for embryo recognition and selection at time of implantation.
METHODOLOGY/PRINCIPAL FINDINGS: Analysis of mid-secretory endometrial biopsies demonstrated that RPL is associated with decreased expression of the decidual marker prolactin (PRL) but increased levels of prokineticin-1 (PROK1), a cytokine that promotes implantation. These in vivo findings were entirely recapitulated when ESCs were purified from patients with and without a history of RPL and decidualized in culture. In addition to attenuated PRL production and prolonged and enhanced PROK1 expression, RPL was further associated with a complete dysregulation of both markers upon treatment of ESC cultures with human chorionic gonadotropin, a glycoprotein hormone abundantly expressed by the implanting embryo. We postulated that impaired embryo recognition and selection would clinically be associated with increased fecundity, defined by short time-to-pregnancy (TTP) intervals. Woman-based analysis of the mean and mode TTP in a cohort of 560 RPL patients showed that 40% can be considered "superfertile", defined by a mean TTP of 3 months or less.
Impaired cyclic decidualization of the endometrium facilitates implantation yet predisposes to subsequent pregnancy failure by disabling natural embryo selection and by disrupting the maternal responses to embryonic signals. These findings suggest a novel pathological pathway that unifies maternal and embryonic causes of RPL.
复发性流产（RPL）定义为连续 3 次或更多次自然流产，其病因广泛归因于胚胎中反复的染色体不稳定或尚未明确的子宫因素。我们基于这样一种观察结果提出假设，即在妊娠中，除了胎盘形成外，这一过程可能对于胚胎着床时的胚胎识别和选择也不可或缺，即异常的子宫内膜基质细胞（ESCs）周期性分化为特化的蜕膜细胞会导致 RPL。
方法/主要发现：对中分泌期子宫内膜活检的分析表明，RPL 与蜕膜标志物催乳素（PRL）的表达降低有关，但与促动力素-1（PROK1）水平升高有关，PROK1 是一种促进着床的细胞因子。这些体内发现与从有和无 RPL 病史的患者中纯化的 ESCs 并在培养中蜕膜化时完全一致。除了 PRL 产生减弱、PROK1 表达延长和增强外，RPL 还与 ESC 培养物用人绒毛膜促性腺激素处理时两种标志物的完全失调有关，人绒毛膜促性腺激素是一种由着床胚胎大量表达的糖蛋白激素。我们推测，胚胎识别和选择受损在临床上与受孕时间（TTP）间隔较短的高生育力相关。对 560 名 RPL 患者队列中的平均和模式 TTP 进行的基于女性的分析表明，40%的患者可被认为是“超生育力”，定义为平均 TTP 为 3 个月或更短。
子宫内膜周期性蜕膜化受损有利于着床，但通过使自然胚胎选择失效并破坏母体对胚胎信号的反应，导致随后的妊娠失败。这些发现表明了一种新的病理途径，将母体和胚胎原因导致的 RPL 统一起来。
