TY - JOUR
T1 - Novel concepts on pregnancy clocks and alarms
T2 - Redundancy and synergy in human parturition
AU - Menon, Ramkumar
AU - Bonney, Elizabeth A.
AU - Condon, Jennifer
AU - Mesiano, Sam
AU - Taylor, Robert N.
N1 - Publisher Copyright:
© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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.
AB - 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.
KW - Aging
KW - Corticosteroids
KW - Endoplasmic reticulum
KW - Labor and delivery
KW - NK cells
KW - Oxidative stress
KW - Progesterone receptors
KW - Senescence
KW - Unfolded proteins
KW - p38MAPK
UR - http://www.scopus.com/inward/record.url?scp=84995665684&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84995665684&partnerID=8YFLogxK
U2 - 10.1093/humupd/dmw022
DO - 10.1093/humupd/dmw022
M3 - Review article
C2 - 27363410
AN - SCOPUS:84995665684
SN - 1355-4786
VL - 22
SP - 535
EP - 560
JO - Human Reproduction Update
JF - Human Reproduction Update
IS - 5
ER -