Decidua Joanne Muter, University of Warwick, Coventry, United Kingdom Jan J Brosens, University of Warwick, Coventry, United Kingdom; and University Hospitals Coventry and Warwickshire, Coventry, United Kingdom © 2018 Elsevier Inc. All rights reserved.
Introduction Decidualization denotes the transformation of the endometrial stroma into the decidual matrix that supports embryo implantation and subsequent placenta formation. This process is foremost characterized by the differentiation of endometrial stromal cells (EnSCs) into secretory decidual cells (Gellersen and Brosens, 2014). Decidualization only occurs in species where the trophoblast breaches the luminal endometrial epithelium and invades maternal tissues. The depth of decidual transformation is determined by the degree of placental trophoblast invasion (Ramsey et al., 1976). In most mammals, decidualization is initiated upon embryo implantation. However, in a handful of species, including humans, Old World monkeys, some bats, elephant shrew, and spiny mouse, decidualization is “spontaneous,” meaning that it is initiated independently of an implanting embryo during the midluteal phase of each cycle (Emera et al., 2012). Once triggered, the decidual phenotype is strictly dependent on sustained progesterone signaling. In the absence of pregnancy, falling ovarian progesterone production triggers a cascade of inﬂammatory events in the decidualizing endometrium, which upon recruitment and activation of leucocytes becomes irrevocable and leads to partial tissue destruction, bleeding and menstrual shedding. Hence, spontaneous decidualization is inextricably linked to cyclic menstruation; and the term “decidua,” derived from the Latin verb “decidere” (meaning to fall off, to detach, or to die), aptly captures the nature of the process. Although decidual transformation of EnSCs starts during the midluteal phase of the cycle, characteristic morphological changes are apparent only at the onset of the late-luteal phase, that is approximately 9–10 days after the postovulatory rise in circulating progesterone levels (Fig. 1). Decidualizing cells lose their ﬁbroblastic appearance and become enlarged. They are further characterized by rounding of the nucleus, enlargement of the rough endoplasmic reticulum and Golgi apparatus, and accumulation of glycogen and lipid droplets (Gellersen and Brosens, 2014). Because of this expansion of the cellular secretory machinery, many genes that are constitutively expressed in epithelial cells are induced in EnSCs upon decidualization. The lag-period between ovulation and the onset of decidual process reﬂects the fact that transcriptional activation of decidual genes is strictly dependent on a sharp rise in intracellular production of the second messenger cyclic adenosine monophosphate (cyclic AMP) during the luteal phase. Cyclic AMP activates protein kinase A and induces the expression of decidua-speciﬁc transcription factors, such as the Forkhead box protein O1 (FOXO1), HOXA10 (Homeobox A10) and HOXA11, CCAAT-enhancer-binding proteins (C/EBPs). Once the decidual process is initiated, the liganded progesterone receptor (PGR) physically binds these core decidua-speciﬁc transcription factors, thus maintaining and amplifying the expression of differentiation genes, including PRL (coding prolactin) and IGFBP1 (insulin-like growth factor-binding protein 1) (Gellersen and Brosens, 2014). Typically, decidual transformation starts with EnSCs around the spiral arteries and underlying the luminal epithelium. Shortand long-range cytokines and morphogens then control the spatiotemporally progression of the decidual process, which in pregnancy encompasses the entire endometrium. It is important to note that decidualization of the stroma occurs in concert with profound changes in glandular gene expression and inﬂux of immune cells, especially uterine natural killer (uNK) cells and, to
Fig. 1 Immunohistochemistry for CD56 (brown) and hematoxylin in human endometrium from the midluteal phase. Note decidual transformation of EnSCs around the spiral arties (arrows). Scale bar ¼ 100 mm.
Encyclopedia of Reproduction, 2nd edition, Volume 2
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a lesser extent, macrophages. For an in-depth description of the molecular drivers of decidualization, we refer the reader to a recent review (Gellersen and Brosens, 2014). Here we focus on the emerging functions of the decidual process that enables the endometrium to transit from a cycling to a gestational tissue.
Ontogeny of Spontaneous Decidualization Decidualization evolved in the stem lineage of Eutherian (placental) mammals. It bestows essential traits onto the uterus that enables controlled trophoblast invasion and confers maternal immune tolerance of the antigenically distinct fetus. These functions in turn underpin the formation of a hemochorial placenta and ensure effective maternal–fetal communication. Evolutionary, EnSCs acquired the ability to accommodate an invading conceptus upon genomic integration of transposable elements (TEs) enriched in cis’regulatory elements that co-opted speciﬁc transcription factors to drive decidual gene expression (Lynch et al., 2011). As aforementioned, decidualization is triggered by the implanting embryo in all but menstruating mammals. However, the ability of human EnSCs to decidualize in response to maternal cues is not innate but acquired (Brosens et al., 2017). For example, the fetal human endometrium is exposed during gestation to progressively rising plasma concentrations of unbound estrogens and progesterone, which at birth are several-fold higher when compared to the maternal circulation. Circulating progesterone levels drop very rapidly in the newborn yet overt vaginal bleeding is uncommon, affecting approximately 5% of neonates. Further, an autopsy study on 169 newborn girls demonstrated inactive or weakly proliferative endometrium in 68% of term babies and secretory glandular changes in 27% of newborns. Evidence of decidualization of the stroma or menstrual changes was observed in only 5% of cases. The lack of neonatal menstruation in most newborns suggests that endometrium only acquires the ability to decidualize around the menarche. The process that renders the endometrium permissive to decidualization is as yet unclear, although there are a number of pointers. In nonmenstruating mammals, decidualization is readily triggered in hormonally primed animals by exogenous stress signals, including endometrial scratching or exposure of the uterine cavity to oil. An emerging line of thought is that rapid estrogen-dependent growth during the follicular phase causes replicative exhaustion of a subpopulation of endometrial cells, which then produce an endogenous stress signal in response to acute senescence during the midluteal phase (Brosens et al., 2017). Cellular senescence is characterized by permanent cell cycle exit and secretion of a host of inﬂammatory mediators, commonly referred to as senescence-associated secretory phenotype. Several lines of circumstantial evidence support this hypothesis including the fact that the menarche is preceded by a prolonged rise in estrogen levels and sustained uterine growth. Further, telomere lengths of endometrial cells are shortest during the midluteal phase in the cycle, indicative of replication stress. Furthermore, permanent cell cycle exit at G0/G1 during the midluteal phase is a prerequisite not only for cellular senescence but also for terminal differentiation of EnSCs into decidual cells. Clinically, it is well established clinically that rapid estrogen-dependent endometrial growth during the proliferative phase is necessary for successful embryo implantation (Brosens et al., 2017).
Decidualization: A Multistep Process Decidualization is not an all or nothing process as is often assumed. Instead, differentiating EnSCs transit through distinct phases (Fig. 2) each of which bestows unique functions onto the endometrium that are essential for successful implantation (Gellersen and Brosens, 2014). Analysis of EnSCs in culture demonstrated that the decidual pathway starts with a burst of reactive oxygen species (ROS) and secretion of a host of chemokines and other inﬂammatory mediators (Al-Sabbagh et al., 2011; Lucas et al., 2016; Salker et al., 2012), many of which are involved in recruitment and activation of innate immune cells. Feedback pathways ensure that the inﬂammatory decidual response is self-limiting, lasting between 2 and 4 days. The second decidual phase is characterized by simultaneous downregulation of various chemokines and inﬂammatory mediators (Al-Sabbagh et al., 2011; Lucas et al., 2016). During this antiinﬂammatory phase, decidual cells are increasingly connected and form a matrix through gap and tight junctions. In concert, decidual cells express high levels of 11b-hydroxysteroid dehydrogenase type 1, an enzyme that converts inert cortisone to active cortisol (Kuroda et al., 2013). This cortisol gradient in the decidua likely contributes to the protection of the invading allogeneic fetal trophoblast against a maternal immune response. Further, by silencing chemokine expression, decidual cells actively prevent effector T cells from entering the feto-maternal interface (Erlebacher, 2013). The third and ﬁnal phase involves the resolution of the decidual phenotype, triggered in a nonconception cycle by falling progesterone levels. In pregnancy, senescence is thought to drive decidual inﬂammation. During this phase, secretion of inﬂammatory factors and matrix metalloproteinases sets in motion a cascade of events that either results in menstruation or contributes to the onset of parturition (Gellersen and Brosens, 2014). In recent years, new insights into the functional importance of this triphasic decidual pathway have emerged.
The Window of Implantation A limited implantation window is critical as it synchronizes two parallel but initially independent processes: embryo development and endometrial maturation. In mice, a single endocrine signal not only functionally switches a progesterone-primed, prereceptive endometrium to a receptive state but also activates the “dormant” preimplantation embryo. This obligatory maternal implantation
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Endometrial stromal cell (ESC)
The window of implantation Proinflammatory
Endometrial epithelial cell (EEC)
Embryo biosensoring and selection Antiinflammatory
Proinflammatory ESC Decidual ESC Uterine NK cell
+cAMP/P4 Release of proinflammatory cytokines Rounding of the nucleus ER and Golgi expansion
Release of antiinflammatory cytokines Uterine NK cell influx Production of a cortisol gradient
Fig. 2 Schematic diagram of the distinct phases upon spontaneous decidualization, rendering the endometrium ﬁrst receptive to embryo implantation and selective for embryos of different developmental potential. For full details, see text.
signal consists of a transient rise in postovulatory estradiol production. By contrast, there is no evidence that the midluteal implantation window in human endometrium is controlled by a nidatory estradiol surge, perhaps reﬂecting that synchronized implantation of multiple human embryos is neither required nor desirable. Instead, compelling experimental evidence suggests that the initial autoinﬂammatory decidual response renders the endometrium receptivity for embryo implantation. For example, exposure of the mouse uterus to proinﬂammatory secretome of decidualizing human EnSCs induces the expression of evolutionarily conserved implantation genes, including Wnt4, leukemia inhibitory factor (Lif), and bone morphogenetic protein 2 (Bmp2), and enables efﬁcient implantation of in vitro cultured mouse blastocysts (Salker et al., 2012). Furthermore, human blastocysts degrade when cultured in medium conditioned by undifferentiated EnSCs but not decidual cells, suggesting that the endometrium is actively embryotoxic prior to decidualization (Peter Durairaj et al., 2017).
Embryo Biosensoring and Selection Human embryos are characterized by intrinsic genomic instability (McCoy et al., 2015). Meiotic chromosomal aneuploidies correlate strongly with maternal age and disproportionally affect smaller maternal chromosomes. By contrast, chaotic cell divisions caused by spindle abnormalities in early cleavage stage embryos result in complex mitotic aneuploidies that are independent of maternal age, frequently involve larger chromosomes, and are not biased towards either maternal or paternal homologs. As a consequence of mitotic disjunction during the cleavage stages, mostdif not alldhuman preimplantation embryos harbor aneuploid blastomeres. While some chromosomal errors may lead to early embryonic arrest, complex mosaic aneuploidies remain prevalent at the blastocyst stage. The human endometrium is adapted to deal with this diversity in embryo quality. In fact, the coupling of spontaneous decidualization to menstrual shedding could be viewed as an ingenious solution to deal with chaotic and potentially highly invasive blastocysts. First, with menstruation being the default position, an effective and safe “disposal system” for aberrant embryos is built into the cycle. Second, a signiﬁcant lag-period exists between implantation and sufﬁcient progesterone production by the emerging placenta. This lag-period makes it incumbent on the implanting embryo to produce sufﬁcient “ﬁtness” signals, such as human chorionic gonadotropin (hCG), to avoid corpus luteum failure and inevitable rejection. Furthermore, decidual cells have emerged as exquisite biosensors of embryo quality and mount a tailored response to an implanting blastocyst that either supports further development or results in a stress response that facilitates early disposal (Brosens et al., 2014). Different experimental models have highlighted the particular aptness of decidualizing cells in sensing poor quality human embryos. In coculture, decidualizing EnSCs respond to a developmentally compromised blastocyst by silencing the secretion of
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multiple implantation factors, including interleukin-1beta and Heparin-binding EGF-like growth factor (HB-EGF). By contrast, undifferentiated EnSCs appear impervious to embryonic signals, irrespective of developmental potential. Furthermore, genomewide expression proﬁling revealed a dramatic up-regulation of implantation and metabolic genes in mouse uteri transiently exposed to spent medium of human IVF embryos that resulted in ongoing pregnancies following transfer. By contrast, culture medium conditioned by low-quality human embryos triggered a stress response in the mouse uterus akin to the response observed in primary decidualizing EnSCs (Brosens et al., 2014). When extrapolated to the in vivo situation, these observations strongly suggest that human embryos are subjected to both positive and negative selection pressures at implantation. Efﬁcient biosensoring and negative selection of poor quality embryos at implantation results in preclinical attrition. However, lack of negative selection increases the risk of implantation of developmentally compromised embryos and early pregnancy loss. Similarly, failure of positive selection results in high-quality embryos developing in an unsupportive or hostile maternal environment, which arguably predisposes for fetal miscarriage. The clinical hallmark of persistent lack of embryo selection at implantation is superfertility, deﬁned by a mean time to pregnancy of three cycles or less. The estimated incidence of superfertility in the general population is 3%. By contrast, 40% of patients suffering recurrent pregnancy loss (RPL), deﬁned here as three consecutive miscarriages, are reportedly superfertile. The incidence is even higher in women who experienced ﬁve or more miscarriages (Salker et al., 2010). The mechanism that imparts responsiveness of decidual cells to soluble signals from developmentally competent and incompetent embryos is poorly understood. Nevertheless, HSPA8 has been identiﬁed as the most downregulated decidual gene in differentiating EnSC cultures exposed to the secretome of developmentally impaired human embryos (Brosens et al., 2014). HSPA8 encodes heat shock 70 kDa protein 8 (HSC70), a key regulator of cellular protein homeostasis. HSC70 levels increase upon decidualization in parallel with expansion of the endoplasmic reticulum that drives the secretory phenotype of differentiating EnSCs. Hence, the importance of this molecular chaperone increases as decidual cells expand their secretory machinery, which may explain why undifferentiated endometrial ﬁbroblasts are not bequeathed with a biosensor function.
Decidual Resolution and Menstruation Falling progesterone levels in a nonconception cycle reactivates the inﬂammatory decidual phenotype, harbingering menstrual shedding of the superﬁcial endometrial layer. Women now experience in excess of 400 cycles of menstrual shedding and scar-free regeneration during the reproductive years. However, there are two consequences of cycling endometrium shedding and regeneration that tend to be overlooked. First, cell turnover in cycling endometrium is very high. Not surprisingly, the human endometrium is rich in glandular progenitor cells and mesenchymal stem-like cells (MSC), which reside not only in the basal endometrium but also in a perivascular niche around the spiral arteries. Endometrial MSC are identiﬁed by speciﬁc cell surface markers, such as Sushi Domain containing 2 (SUSD2) or coexpression of CD146 and platelet-derived growth factor receptor beta (PDGFRb) (Gellersen and Brosens, 2014). Apart from MSC, the endometrial stromal compartment consists of other distinct subpopulations that are deﬁned either by the stage of lineage commitment (e.g., transit amplifying cells, mature progeny, and presenescent cells) or topology (e.g., perivascular EnSCs). Growing evidence indicates that response to deciduogenic signals differs profoundly between subpopulations of EnSCs. For example, perivascular EnSCs are relatively quiescent in an undifferentiated state but become a dominant source of chemokines and cytokines upon decidualization (Murakami et al., 2014). Thus, the spatiotemporal control of decidual response is governed by distinct responses in various EnSC subpopulations. A second important consequence of menstruation is that spontaneous decidualization is an iterative process. As the abundance of different EnSC subpopulations likely ﬂuctuates from cycle to cycle, the quality of the decidual response may equally vary in different cycles. Consequently, cyclic menstruation and renewal renders the endometrium intrinsically dynamic and arguably capable of adapting in response to reproductive failure.
Decidual Cells: Instructors of Local Immune Cells As aforementioned, spontaneous decidualization of EnSCs during the luteal phase of the cycle occurs in parallel with recruitment of innate immune cells, predominantly CD56bright/CD16 uNK cells. During the late-luteal phase, as many as 30%–50% of cells in the endometrial stroma are uNK cells. Compared to their circulating (CD56dim/CD16þ) counterparts, uNK are less cytotoxic but more proangiogenic; and exert an evolutionarily conserved role in orchestrating vascular adaptation and trophoblast invasion during pregnancy. Decidual cells play a pivotal role in instructing uNK cells; meaning that they provide the necessary cues that enable these cells to carry out their specialist functions in pregnancy. For example, conditioned medium from decidual cells supplemented with interleukin-15 and stem cell factor convert peripheral NK cells into uNK-like cells. Coculture with decidual stromal cells also convert CD34þ hematopoietic precursors into phenotypic uNK cells. Further, when injected into immunocompromised pregnant mice, induced uNK-like cells migrate to the uterus and improve placental perfusion. Thus, decidual cells not only protect the semiallogenic conceptus against a maternal immune response though local cortisol production and by actively excluding T-cells, they are also instrumental in adapting innate immune cells for pregnancy (Brosens et al., 2017).
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Decidual Autonomy in Early Pregnancy In early pregnancy, the conceptus is embedded in a matrix of decidual cells. As the process of interstitial and endovascular trophoblast invasion commences, the embryo–maternal interface is increasing subjected to intense tissue remodeling and exposed to profound changes ﬂuctuations in oxygen tension associated with vascular remodeling. Decidual cells are programmed to resist a range of environmental stress signals, thus ensuring survival of the conceptus. Several molecular mechanisms underpin this quasiautonomous state of decidua prior to the onset of placental perfusion around 10 weeks of pregnancy (Fig. 3).
Cessation of Circadian Rhythms An early event that signals autonomy of decidualizing EnSCs is cessation of circadian gene expression. Circadian oscillations are predicated on transcriptional–translational feedback loops that balance the activities of the transcriptional activators CLOCK and BMAL1 and repressors encoded by PER and CRY genes. An early event in the decidual pathway is loss of the clock protein Period 2 (PER2), which in turn silences circadian gene expression in differentiating EnSCs (Muter et al., 2015). As the implanting conceptus is also aperiodic, cessation of circadian oscillations in surrounding decidual cells is arguably essential for optimal embryo–maternal interactions. However, PER2 differs from other core clock proteins in that it exhibits several structural features of steroid receptor coregulators. Further, PER2 knockdown arrests EnSCs at G2/M and results in a grossly disorganized decidual response. Thus, regulation of PER2 expression across the cycle synchronizes endometrial proliferation with initiation of aperiodic decidual gene expression. The importance of transition is underscored by the observation that endometrial PER2 transcript levels in the midluteal phase of the cycle correlate inversely with the number of previous miscarriages in RPL patients (Muter et al., 2015).
Oxidative Stress Resistance ROS, including superoxide anion radical, hydrogen peroxide, and the hydroxyl radical, are highly reactive, diffusible, and ubiquitous molecules that are generated as inevitable byproducts of aerobic respiration and metabolism. Mammalian cells possess multiple mechanisms to remove ROS, including endogenous enzymatic and dietary nonenzymatic antioxidants. Detoxiﬁcation of superoxide by superoxide dismutase enzymes converts it to hydrogen peroxide. Catalase and glutathione peroxidase further degrade hydrogen peroxidase to produce water as the end product. Physiological levels of ROS are required to ensure proper functioning of different biological pathways and to maintain tissue homeostasis. However, excessive levels of ROS cause irreversible damage to DNA, proteins, and lipids, ultimately resulting in cell death. Decidual cells are remarkably resistant to oxidative cell death compared to their undifferentiated progenitor cells (Gellersen and Brosens, 2014). This resistance is partly accounted for by the induction of various free radical scavengers, most notably superoxide dismutase 2, monoamine oxidases A and B, thioredoxin, glutaredoxin, and peroxiredoxin. Several genes coding free radical
Fig. 3 Illustration of molecular mechanisms of decidual autonomy in early pregnancy. For full details, see text. (1) Cessation of circadian rhythms, (2) oxidative stress resistance, (3) uncoupling of stress signaling and SUMOylation, and (4) silencing of phospholipase C signaling. MnSOD, manganese superoxide dismutase; MEKK1, MAPK kinase kinase 1; PIAS1, protein inhibitor of activation STAT-1; PIP2, phosphatidylinositol 4,5bisphosphate; DAG, diacylglycerol.
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scavengers are transcriptionally controlled by FOXO1, a core decidual transcription factor. However, a second mechanism contributes to the exceptional ROS resistance in decidual cells. Exposure of undifferentiated EnSCs to exogenous free radicals rapidly activates the c-Jun NH-terminal kinase (JNK) stress signaling pathway and upregulates another forkhead protein, FOXO3a, which in turn triggers cell death. However, decidual cells strongly upregulate mitogen-activated protein (MAP) kinase phosphatase-1 (MKP-1), which not only silences the JNK pathway but also inhibits FOXO3a expression. Hence, while undifferentiated HESCs are programmed to self-destruct in response to oxidative stress signals, this mechanism is ﬁrmly disabled upon differentiation into decidual cells (Gellersen and Brosens, 2014).
Uncoupling of Stress Signaling and SUMOylation A striking adaptation in decidual cells involves the small ubiquitin related modiﬁer (SUMO) conjugation/deconjugation pathway. SUMOylation, an important posttranslational protein modiﬁcation that affects a large number of substrates, is catalyzed through a sequence of enzymatic reactions. This reversible posttranslational protein modiﬁcation regulates numerous cellular processes, including cell signaling, nuclear transport, transcription, and DNA replication and repair. Nuclear receptors, including PGR, are important SUMO targets. The transcriptional activity of PGR in response to progesterone binding is strongly repressed upon SUMOylation. Interestingly, decidualization is associated with global cellular hypoSUMOylation, effected by altered expression of SUMO-speciﬁc ligases and proteases. Various stress signals convert on the SUMO pathway, including ROS, hypoxia, heat shock, and genotoxic stress. However, induction of MKP1 and silencing of the JNK pathway ensure that decidual cells do not exhibit a hyperSUMOylation response when exposed to exogenous stress signals (Gellersen and Brosens, 2014). Importantly, this means that progesterone signaling is unimpeded in the decidua under the oxidative stress conditions imposed by pregnancy.
Silencing of Phospholipase C Signaling Further decidual autonomy is achieved via induction of phospholipase C (PLC)-related catalytically inactive protein 1 (PRIP-1). PRIP-1 is a progesterone-inducible scaffold protein that uncouples PLC activation downstream of Gq-protein-coupled receptors from intracellular Ca2 þ release by attenuating inositol trisphosphate (IP3) signaling (Muter et al., 2016). As many external signals are transduced by Gq-protein-coupled receptors, strong induction PRIP-1 is a remarkably simple solution to ensure decidual autonomy. Furthermore, by chelating IP3, PRIP-1 also limits Ca2 þ release from the expanding endoplasmic reticulum, thereby safeguarding decidual cells against excessive Ca2 þ accumulation in the mitochondrial matrix, permeabilization of the mitochondrial outer membrane, and cell death caused by leakage of apoptosis factors from the intermembrane space.
Clinical Perspective Failure of the endometrium to mount a decidual response inevitably leads to implantation failure whereas a prolonged and disordered autoinﬂammatory decidual response is linked to out-of-phase implantation, impaired embryo biosensoring, and RPL. Clinically, implantation failure is the rate-limiting step in assisted reproductive technologies whereas miscarriage is the most common complication of pregnancy. The incidence of clinical miscarriage after 6 weeks of pregnancy is approximately 15%. When preclinical losses are taken in account, the incidence of early pregnancy attrition is estimated to be between 30% and 50%. Numerous gene ablation studies in mice have identiﬁed key signals, pathways, and downstream transcription factors that are indispensable for decidualization (Gellersen and Brosens, 2014). However, clinical translation of this information into either new treatment or endometrial biomarkers predictive of reproductive failure has so far be elusive. So, what are the roadblocks? An obvious hurdle is that human blastocysts, unlike their murine counterparts, are chromosomally diverse. Because of intrinsic mosaicism, it remains difﬁcult, if not impossible, to predict accurately the developmental potential of an individual embryo, even following preimplantation genetic screening. Consequently, it is often not possible to ascertain retrospectively if implantation failure or early pregnancy loss was caused by an embryonic, a maternal factor, or a combination. In general, the likelihood of an underlying endometrial defect compromising nidation or development of a competent embryo increases with each additional failure. Another hurdle, perhaps less appreciated, is that spontaneous decidualization and cyclic menstruation renders the endometrium intrinsically dynamic (Lucas et al., 2016). In other words, analysis of the endometrium in a given cycle may not necessarily be predictive of implantation competence in a subsequent cycle. Yet, these perceived hurdlesdembryo diversity and endometrial plasticitydalso belie the clinical observation that the cumulative live birth rate for most women is high, even after multiple implantation failures or miscarriages. For example, several randomized double-blind placebo control studies reported live births rates of 65% or more in patients with three consecutive miscarriages who were assigned to the placebo group. Even after ﬁve consecutive miscarriages, the likelihood of a live birth in a subsequent pregnancy remains in excess of 50%. Similar high cumulative live birth rates have been reported following implantation failure in IVF. Hence, it is as paramount to understand the mechanisms that enable a successful pregnancy to occur after multiple failures as it is to deﬁne the primary cause of reproductive failure. The discovery of speciﬁc endometrial defects associated with RPL, such as stem cell deﬁciency (Lucas et al., 2016), is opening up the possibility of prepregnancy screening of women at risk of reproductive failure. Effective interventions, however, will require a more in-depth understanding of the mechanisms that control endometrial homeostasis, and by extension the decidual pathway, from cycle to cycle.
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