Reproduction in humans is unique in two major aspects. First, the incidence of chromosomally abnormal and developmentally compromised human preimplantation embryos is exceptionally high, and second, the uterus decidualizes spontaneously each cycle, a process also responsible for the menstrual shedding of the endometrium in the absence of pregnancy. Emerging evidence suggests that these distinctive reproductive traits are functionally linked. Thus, the decidual process enables the mother to limit investment in compromised pregnancies, while menstruation imposes a need for constant recruitment of mesenchymal stem cells to regenerate and renew the endometrium each cycle. Endometrial stem cells are immune-privileged compared with other types of adult stem cells, suggesting a role for these cells in accommodating deeply invading semi-allogenic fetal trophoblast. Thus, by coupling reproductive competence to a process of constant tissue renewal, decidualization enables the human uterus to adapt to pregnancy failure and a changing ecology.
By imposing the need for cyclic renewal of the endometrium, spontaneous decidualization followed by menstruation bestows unique functions on the human endometrium that are essential for reproductive success.
Introduction
Being a predominantly monotocous species with deeply invasive embryos that display intrinsic chromosomal instability, reproductive success is far from guaranteed in human beings. Recent studies have highlighted just how abnormal ‘normal’ human embryos are (Mertzanidou et al., 2013, Vanneste et al., 2009). Mertzanidou and colleagues used array comparative genomic hybridization to analyse all the blastomeres of normally developing cleavage-stage embryos that were part of a cohort of embryos that resulted in healthy births. In line with other studies, chromosomal errors were detected in 70% of these top-quality embryos (Mertzanidou et al., 2013). The mitotic error rate in cleavage stage embryos is higher than the meiotic aneuploidy rate. Consequently, the genome of an individual blastomere is not representative of the genome of other cells in the embryo. While these observations explain the unequivocal failure of preimplantation genetic screening to improve the efficacy of IVF treatment to date (Harper and Sengupta, 2012), they also raise important and as-yet unresolved questions regarding the origins and significance of embryonic mosaicism during early stages of development. Time-lapse image analysis suggested that exchange of chromosome-containing fragments between blastomeres may contribute to the generation of human embryonic aneuploidies (Chavez et al., 2012). Whatever the underlying mechanisms, it is clear that human beings generate extraordinarily diverse preimplantation embryos, which are occasionally entirely diploid, mostly mosaic and not uncommonly completely chromosomally chaotic. Culture as part of assisted reproduction treatment may also result in subtle epigenetic changes that compromise the long-term developmental potential of embryos (reviewed in Lucas, 2013, Mann and Denomme, in press, this issue). This situation presents the mother with an important dilemma: how to maximize the likelihood of reproductive success when faced with such an extraordinary prevalence of highly invasive but chromosomally abnormal embryos?
Conflicts between parent and offspring are thought to drive reproductive evolution and innovation (Haig, 1993). Because of these innate differences in evolutionary interests, it has been postulated that the embryonic genome evolves to extract as much as possible from the mother to ensure its own propagation, whereas maternal genes evolve to safeguard success not only of current but also future offspring. This hypothesis predicts that reproductive success depends on a constant homeostatic rebalancing of embryonic and maternal traits. An evolutionary change in one of the parties must be met by adaptation in the other (Chuong et al., 2013, Crespi and Semeniuk, 2004, Emera et al., 2012b). In view of the intrinsic genomic instability that characterizes human preimplantation embryonic development, the maternal–fetal conflict hypothesis predicts that a strategy must have emerged to safeguard the mother against prolonged investment in invasive but developmentally abnormal embryos. It also predicts that the diversity inherent in human embryos must be met by an intrinsic ability to adapt the maternal response to an individual conceptus.
This review describes the specialist functions of the endometrium that enables it to meet the challenges imposed by human embryos. For didactic purposes, we have divided these functions into a five-step programme for reproductive fitness (Figure 1).
Section snippets
Step 1: Be prepared
The most salient feature of the human reproductive cycle is ‘spontaneous’ decidualization, which refers to the fact that the endometrium mounts a pregnancy response in each menstrual cycle (Brosens et al., 2002, Gellersen et al., 2007). Decidualization is defined by the mesenchymal to epithelial transformation of endometrial fibroblasts into secretory decidual cells. In most mammalian species, decidualization is triggered by embryonic signals, but in humans and a handful of other species, it is
Step 2: Attack is the best form of defence
Implantation is commonly depicted as a step-wise process involving apposition and adhesion of a blastocyst to the endometrium, followed by breaching of the luminal epithelium and then active invasion of embryonic trophectoderm into the uterine stroma (Dey et al., 2004, Fazleabas and Kim, 2003, Genbacev et al., 2003). For obvious reasons, this concept is based on animal models, especially murine studies. Whether or not this model is truly applicable to implantation in humans is anyone’s guess.
Step 3: Quality control and personalized implantation
Encapsulation by decidual cells may serve to protect the early conceptus from maternal perturbations related to metabolism, stress, infections, oxygen tension or endocrine disruptors. A prominent feature of decidual cells is indeed their ability to resist environmental stressors, including oxidative stress (Kajihara et al., 2006, Leitao et al., 2010, Leitao et al., 2011). This extraordinary resistance is based not only on the induction of various free radical scavengers but also on the
Step 4: Default rejection
Menstruation is rarely mentioned in the context of the implantation process, undoubtedly because this extraordinary biological phenomenon is almost absent in non-primate animal models such as mice. Yet an inducible disposal mechanism for unwanted concepti seems a logical requirement if the endometrium engages – as asserted – in embryo recognition and natural selection at implantation. Menstruation, defined as the cyclic bleeding caused by shedding of the superficial endometrium, is confined to
Step 5: Regenerate and adapt
Most cycles during the reproductive years are non-conception cycles. Consequently, menstruation is viewed as a non-adaptive consequence of uterine evolution, i.e. it is an unfortunate by-product of spontaneous decidualization that serves no purpose other than to reinitiate the endometrial cycle to allow a future pregnancy (Emera et al., 2012a, Finn, 1998). However, it is striking that a number of other reproductive traits have evolved in parallel, all of which promote menstruation over
Conclusions and perspective
Based on the prevalence of whole chromosomal aneuploidies and complex imbalances in human preimplantation embryos, pregnancy failure should be the norm in healthy couples, perhaps occasionally punctuated by the birth of a healthy baby. The fact that most couples are reproductively successful attests, at least in part, to the extraordinary plasticity embedded in the human uterus. The primary driver is spontaneous decidualization and cyclic menstruation, which also bestow on the human endometrium
Acknowledgements
This work was supported the Biomedical Research Unit in Reproductive Health, a joint initiative between the University Hospitals Coventry and Warwickshire National Health Service Trust and Warwick Medical School.
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Professor Jan Brosens graduated from the Catholic University Leuven, Belgium in 1990 and pursued postgraduate training in obstetrics and gynaecology in the UK. He became a member of the Royal College of Obstetricians and Gynaecologists in 1995 and a Fellow of the College in 2008. He obtained a PhD from the University of London in 1999, working on the mechanisms underpinning decidualization. He was awarded a Wellcome Trust Clinical Scientist Fellowship in 1998. He joined Imperial College London, first as Chair of Reproductive Sciences (2004) and then Chair of Reproductive Medicine (2008). In May 2011, he was appointed as Chair of Obstetrics and Gynaecology and leader of the newly established Division of Reproductive Health at the University of Warwick.
