Menon Ramkumar, Bonney Elizabeth A, Condon Jennifer, Mesiano Sam, Taylor Robert N
Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine and Perinatal Research, The University of Texas Medical Branch at Galveston, 301 University Blvd., MRB, Room 11.138, Galveston, TX 77555-1062, USA
Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Vermont College of Medicine, 792 College Parkway, Fanny Allen Campus, Suite 101, Colchester, Burlington, VT 05446, USA.
Hum Reprod Update. 2016 Sep;22(5):535-60. doi: 10.1093/humupd/dmw022. Epub 2016 Jun 30.
The signals and mechanisms that synchronize the timing of human parturition remain a mystery and a better understanding of these processes is essential to avert adverse pregnancy outcomes. Although our insights into human labor initiation have been informed by studies in animal models, the timing of parturition relative to fetal maturation varies among viviparous species, indicative of phylogenetically different clocks and alarms; but what is clear is that important common pathways must converge to control the birth process. For example, in all species, parturition involves the transition of the myometrium from a relaxed to a highly excitable state, where the muscle rhythmically and forcefully contracts, softening the cervical extracellular matrix to allow distensibility and dilatation and thus a shearing of the fetal membranes to facilitate their rupture. We review a number of theories promulgated to explain how a variety of different timing mechanisms, including fetal membrane cell senescence, circadian endocrine clocks, and inflammatory and mechanical factors, are coordinated as initiators and effectors of parturition. Many of these factors have been independently described with a focus on specific tissue compartments.In this review, we put forth the core hypothesis that fetal membrane (amnion and chorion) senescence is the initiator of a coordinated, redundant signal cascade leading to parturition. Whether modified by oxidative stress or other factors, this process constitutes a counting device, i.e. a clock, that measures maturation of the fetal organ systems and the production of hormones and other soluble mediators (including alarmins) and that promotes inflammation and orchestrates an immune cascade to propagate signals across different uterine compartments. This mechanism in turn sensitizes decidual responsiveness and eventually promotes functional progesterone withdrawal in the myometrium, leading to increased myometrial cell contraction and the triggering of parturition. Linkage of these processes allows convergence and integration of the gestational clocks and alarms, prompting a timely and safe birth. In summary, we provide a comprehensive synthesis of the mediators that contribute to the timing of human labor. Integrating these concepts will provide a better understanding of human parturition and ultimately improve pregnancy outcomes.
协调人类分娩时间的信号和机制仍是一个谜，更好地理解这些过程对于避免不良妊娠结局至关重要。尽管我们对人类分娩启动的认识得益于动物模型研究，但相对于胎儿成熟度而言，分娩时间在不同胎生物种中存在差异，这表明存在系统发育上不同的时钟和警报机制；但清楚的是，重要的共同途径必定会汇聚以控制分娩过程。例如，在所有物种中，分娩都涉及子宫肌层从松弛状态转变为高度兴奋状态，在此状态下肌肉有节奏且有力地收缩，软化宫颈细胞外基质以允许扩张和伸展，从而使胎膜发生剪切以促进其破裂。我们回顾了一些为解释多种不同时间机制如何协调作为分娩的启动因素和效应因素而提出的理论，这些机制包括胎膜细胞衰老、昼夜内分泌时钟以及炎症和机械因素。许多这些因素已被分别描述，重点在于特定的组织区域。在本综述中，我们提出核心假设，即胎膜（羊膜和绒毛膜）衰老作为协调的、冗余信号级联反应的启动因素导致分娩。无论受氧化应激或其他因素影响，这个过程构成一种计数装置，即一个时钟，它测量胎儿器官系统的成熟度以及激素和其他可溶性介质（包括警报素）的产生，并促进炎症反应并协调免疫级联反应以在不同子宫区域传播信号。这种机制进而使蜕膜反应性敏感化，并最终促进子宫肌层功能性孕酮撤退，导致子宫肌层细胞收缩增加并引发分娩。这些过程的联系使得妊娠时钟和警报能够汇聚和整合，促使适时且安全的分娩。总之，我们全面综合了促成人类分娩时间的介质。整合这些概念将能更好地理解人类分娩并最终改善妊娠结局。
