Mechanisms of implantation: strategies for successful pregnancy.

Whereas the previous section recounts examples of deferred implantation leading to poor pregnancy outcome, aberrant decidualization can also give rise to adverse pregnancy phenotypes including defects in placentation, intrauterine fetal growth restriction and parturition ( Fig. 3 ). For example, models that show shallow spiral artery invasion precludes normal placentation, a signature of preeclampsia 110 – 112 , although poor trophoblast invasion into decidua is one of several potential causes for preeclampsia 97 , 113 , 114 . Trophoblast migration and remodeling of decidual arterioles are also associated with human preeclampsia 115 . Preeclampsia is considered to be more prevalent in first pregnancies than in subsequent pregnancies. Whether reproductive hormones and other pregnancy factors during the first pregnancy prime the system for subsequent pregnancies requires further investigation. This is reminiscent of a study showing poor mammary gland development during the first, but not subsequent, pregnancies in prolactin receptor–deficient mice 116 . One example of an adverse consequence of defective decidualization is preterm birth 24 . Mice with uterine deletion of Trp53 ( Trp53 d/d ) show normal implantation, but 50–60% of Trp53 d/d mice have preterm birth with dystocia and fetal death 24 . These mice have compromised decidualization with more terminally differentiated decidual cells with polyploidy, increased expression of pAkt, p21 and Cox2 and senescence-associated growth restriction. Interestingly, preterm birth in Trp53 d/d mice is rescued by the selective Cox2 inhibitor celecoxib 24 . Many risk factors, such as gene mutation, infection and inflammation and stress, that lead to preterm birth also trigger cellular senescence via mammalian target of rapamycin complex 1 (mTORC1) signaling. Rapamycin (mTORC1 inhibitor) attenuates senescence and increases life span in mice 117 . Indeed, Trp53 d/d decidua have increased mTORC1 activity, which is inhibited by rapamycin with attenuation of premature decidual senescence and rescue of preterm birth 118 . This is noteworthy, considering women with advanced age have a higher incidence of preterm birth 119 – 121 . Although p53 activation induces senescence to attenuate cancer, its loss can also activate senescence in certain cells and can be reversed by rapamycin 122 . It seems that p53’s role in the uterus during pregnancy is different from its role in tumorigenesis. Although there have been attempts to better understand the underlying mechanism to develop measures to prevent preterm birth, progress has been limited because of the complex nature of this pathophysiologic state that integrates both genetic predisposition and environmental factors ( Box 3 ).

Many crucial genes show overlapping uterine expression at more than one stage, and their stage-specific roles are difficult to ascertain. Hand2 , Klf5 , Bmp2 and Ptgs2 are such genes and are expressed at blastocyst attachment with continued expression during decidualization 41 , 46 , 63 , 64 . Implantation is considered a proinflammatory reaction, and one early discernible mark is an increased endometrial vascular permeability at the attachment site. Cyclooxygenase (Cox)-derived prostaglandins were shown to mediate these effects 63 and exist in two isoforms, Cox1 ( Ptgs1 ) and Cox2. They have differential spatiotemporal expression during pregnancy. In mice, Ptgs1 is expressed in the epithelium early on day 4 ( ref. 63 ), suggesting its role in generalized uterine edema that may participate in luminal closure for blastocyst apposition. Ptgs1 deletion shows no apparent implantation defects due to compensation by Ptgs2 ( ref. 1 ). Ptgs2 is induced in the luminal epithelium and underlying stroma at the attachment site 63 , signifying its roles in attachment and localized endometrial vascular permeability. Cox2 is also expressed in the uterus and/or blastocyst during implantation in several species including primates and humans, which indicates a conserved role of Cox2 in implantation 80 – 82 . Ptgs2 −/− mice show implantation failure 63 , although genetic background–dependent compensation by Ptgs1 can partially rescue implantation 2 . Cox2-derived prostacyclin was shown to participate in implantation by activating uterine peroxisome proliferator–activated receptor-δ (PPAR-δ) and retinoid X receptor 83 . Whereas maternal PPAR-δ is crucial for implantation and decidualization, embryonic PPAR-δ is required for placentation 84 . Upon attachment, Ptgs2 is localized at the antimesometrial site but moves to the opposite side (mesometrial), the presumptive site of placentation, by day 6 of pregnancy 63 , 83 . Ptgs2 −/− females also show defective ovulation, fertilization, decidualization and placentation 63 , asserting roles of Cox2-derived prostaglandin signaling at several stages of pregnancy. A recent report shows that activation of epithelial sodium channels induces Cox2 and is necessary for implantation 85 . Bmp2 also shows overlapping expression during pregnancy in mice. It is expressed in the subepithelial stroma coincident with the attachment reaction followed by heightened expression in decidua 54 . Its antagonist Noggin is expressed during receptivity but disappears with stromal Bmp2 expression upon attachment and thereafter 54 . Uterine deletion of Bmp2 showed decidualization failure with apparently normal attachment reaction, leading to infertility 64 . Interestingly, beads carrying BMP2 did not elicit implantation-like responses but affected spacing of embryos when co-transferred with the beads 54 . Although Bmp7 is expressed during early decidualization, its function is yet to be determined 54 . Cell-specific expression of Wnt ligands, receptors and inhibitors in mouse and human endometria during the reproductive cycle and pregnancy suggests roles for Wnt signaling in implantation and decidualization 44 , 86 , 87 . Wnt signaling is executed by canonical or noncanonical pathways depending on the subcellular localization of β-catenin, transcriptional modulation of targets and co-receptor identity. Studies in TOPGAL reporter mice found canonical Wnt signaling in the luminal epithelium and myometrium at the implantation site, suggesting a role in implantation 88 . Wnt4 is expressed in the subepithelial stroma at the time of implantation and becomes more robust during decidualization 89 . Wnt4 expression is aberrant in Lif −/− and Hoxa-10 −/− mice 44 ; its uterine deletion confers infertility with defective adenogenesis 89 , 90 . In contrast, Wnt7a is expressed in the epithelium, and its deletion incurs subfertility with defective implantation and aberrant development of oviduct, uterus, cervix and vagina along the anteroposterior axis 91 . Mice with Wnt7a deletion also show defective gland formation 90 . Similarly, uterine deletion of Foxa2 , encoding a forkhead homeobox-containing transcription factor necessary for uterine gland formation, leads to infertility 92 . Conversely, β-catenin overexpression shows glandular hyperplasia, suggesting a role of canonical signaling in gland formation 93 . Collectively, subfertility and implantation failure seen with uterine deletion of Wnt4 and Wnt7a , respectively, are perhaps the consequence of structural aberrations and sparse gland formation. Lif is expressed in a biphasic manner, first in glandular epithelia on day 4 morning and later in the subepithelial stroma at the blastocyst attachment site on day 4 night 94 . Pla2g4a −/− mice with defective implantation show glandular Lif expression but loss of stromal expression 95 . The relative contributions of glandular and stromal LIF to implantation would require cell-type–specific deletion. Marijuana and its major psychoactive component Δ 9 -tetrahydrocannabinoid have been known for decades to affect reproduction in animals and humans. Identification of the endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG) and their G protein–coupled receptors CB1 ( Cnr1 ) and CB2 ( Cnr2 ) in the uterus and embryo helped in the exploration of implications of endocannabinoid signaling in female fertility 96 . Indeed, this signaling has profound effects on embryo development, oviductal embryo transport, uterine receptivity, placentation and parturition in mice, suggesting that the endocannabinoid system is operative at key stages of pregnancy. There is evidence that high peripheral anandamide levels correlate with recurrent pregnancy losses in women 96 . AEA and 2-AG are present in the mouse uterus, the former being tightly regulated 97 ; AEA levels are lower in receptive uteri but higher in nonreceptive uteri. Furthermore, CB1 in the blastocyst is downregulated with activation before implantation in delayed implanting mice ( Box 1 ) 96 . Cnr1 −/− females are subfertile with oviductal retention of blastocysts 98 . Whereas embryonic CB1 contributes to synchronous preimplantation embryo development, oviductal CB1 in collaboration with adrenergic receptors directs timely passage of embryos through the oviduct 98 . Fallopian tubes in women with ectopic pregnancy also show downregulation of CNR1 ( ref. 99 ). Interestingly, persistently high AEA levels resulting from deletion of the gene encoding fatty acid amide hydrolase ( Faah ), which degrades AEA, also lead to defective implantation 100 . Appropriate differentiation of trophoblast stem cells requires regulated endocannabinoid signaling; its aberrant signaling results in compromised placentation and trophoblast invasion 97 . Whether this model is relevant to the human preeclampsia phenotype would require further investigation. The endocannabinoid system is present in human placentas, suggesting its importance in placental function 101 . Therefore, tightly regulated endocannabinoid signaling is crucial for pregnancy success.

Despite advances in the understanding of fertility and the overcoming of many deficiencies in human fertility by assisted reproductive technology, the implantation rate and number of ‘take-home’ babies still remain low. Limiting factors for low pregnancy success in IVF programs (~30%) include poor embryo quality and transfer of embryos into uteri of unknown state of receptivity. Another global problem is the high incidence of preterm birth and its adverse consequences on life-long health of the offspring. The fact that disturbances in early pregnancy can give rise to these enduring problems lends credence to the importance of identifying pregnancy-stage specific mediators, the aberration of which compromises pregnancy outcome ( Fig. 4 ). As progress continues toward constructing a blueprint for normal implantation and pregnancy events, the challenges to be addressed are described below. In IVF programs, the major barriers are poor rate of embryo development to blastocysts in culture, high aneuploidy rates and the lack of reliable markers of uterine receptivity for embryo transfer 2 , 6 . Mouse embryos cultured in very small volumes of medium show superior development to blastocysts 123 , 124 , and pregnancy outcome in IVF programs is superior when blastocysts are transferred rather than preblastocyst embryos. Therefore, IVF clinics may benefit from adopting and refining these approaches to reduce aneuploidy and enhance embryo development to improve implantation rates. Increasing pregnancy success by blastocyst transfer would also limit the number of embryos transferred, precluding the risk of multiple pregnancies. A clinical trial suggests that addition of granulocyte-macrophage colony–stimulating factor to culture medium improves implantation rate 125 (Origio A/S). Likewise, addition of HB-EGF to culture medium is known to show beneficial effects on embryo development and attachment in vitro 126 , 127 . A clinical trial assessing HB-EGF’s effects on pregnancy improvement could be worthwhile. Identification of embryonic signals that promote implantation also remains elusive. With advances in high-efficiency mass spectrometry (MALDI-MS) technology, it may be possible to identify new low-abundance proteins and/or lipid mediators secreted by embryos in culture that promote their own growth or signal the endometrium for implantation. This can be attempted by analyzing media in which IVF-derived human embryos were cultured. Another pressing need is to identify reliable biomarkers to ascertain the uterine receptive state. Although DNA microarrays have identified potential biomarkers for human endometrial receptivity 128 , the use of MALDI-MS could also be a powerful approach to map uterine proteomics and lipidomics profiles at defined physiological states to identify biomarkers of receptivity and better understand human implantation to improve fertility. Recent application of in situ mass spectrometry in periimplantation mouse uteri also provides opportunities to generate spatiotemporal maps of proteins and lipids and their modifications on human endometrium 129 , 130 . Numerous mediators are crucial for conferring uterine receptivity and implantation ( Fig. 2 ). However, the exact molecular cross-talk between these pathways is far from clear. In particular, the molecular mechanism behind spontaneous transition of the receptive uterus to the refractory phase remains unknown, and much work is needed to understand and manipulate this transition. Coordinated interactions between estrogen and P 4 are crucial for conferring uterine receptivity and for moving the uterus to the nonreceptive phase in mice 11 , 131 . As high estrogen levels provoke uterine nonreceptivity, one cause of the high implantation failure rate of IVF may be high estrogen levels arising from ovarian hyperstimulation by gonadotropins to retrieve multiple oocytes 131 . By manipulating estrogen levels, it may be possible to prolong the receptive window to improve IVF-conceived pregnancy rates 11 . More knowledge regarding the signaling network will help in manipulating the receptive window. In this respect, Msx1 is an attractive candidate for extending the receptive phase. Given that Msx genes are also expressed in human endometria, similarly to the situation in mice, identifying small-molecule targets that influence Msx signaling is an approach worth exploring. Cell-specific expression of Msx genes should also be evaluated throughout the menstrual cycle to better understand their roles and regulation. One aspect of pregnancy success is maternal immunological adaptation to the fetus, which is considered an allograft 132 . Multiple mechanisms have been proposed to explain the fetus’s competency to escape rejection by the maternal immune system 133 . In mice, these include entrapment of dendritic cells within decidua, preventing immunogenic exposure of maternal T cells to fetal or placental antigens in uterine draining lymph nodes and systemic immunosuppression by regulatory T cells (T reg cells) 134 . A recent work on T reg cells during pregnancy describes enhancer elements that drive the T reg -specific transcription factor FOXP3 ( ref. 135 ). The enhancer element CNS1 differentially induces Foxp3 expression in peripheral T reg cells (pT reg cells) upon exposure to antigens and thymic T reg cells. When pT reg -specific CNS1 was deleted, females lost their pT reg cell population and showed somewhat higher embryo resorption rates when mated with allogeneic males. However, the rate remained unaltered when CNS1-deficient females were mated to syngenic males, implicating pT reg cells in maintaining maternal immunological restraint to fetal and placental alloantigens. Intriguingly, CNS1 exists only in eutherian mammalian genomes, linking the evolution of pT reg cells with placentation. Another recent study in mice shows that decidua has an important role in preventing T cell–mediated immunological assault on the fetus and placenta 136 . An epigenetic program in decidua silences the expression of many inflammatory chemokine genes that recruit activated T helper type 1 CD4 + T cells and CD8 + cytotoxic T lymphocytes to inflammation sites, thus restricting chemokine expression in decidual cells, even under inflammation, and preventing activated T cell recruitment with fetal and placental specificity. In sum, the decidua provides immunological protection to the fetus and placenta. This evolving area of research warrants further investigation. The genome-epigenome relationship and transmission of epigenomic information across generations are areas of intense research. Exposure to environmental endocrine disrupters in utero or varying the composition of maternal or paternal diets during pregnancy have profound effects on adult-onset diseases (Barker’s hypothesis) 137 , 138 and impart transgenerational consequences on the offspring’s health, ranging from metabolism to sex determination 139 – 141 . It would be interesting to know whether epigenetic changes affecting the mother’s fertility can alter the offspring’s fertility. Advances in research on noncoding RNAs including long noncoding RNAs, PIWI-interacting RNAs, miRNAs and siRNAs with parallel leaps in sequencing technology could be exploited to study gene regulation during pregnancy 142 – 144 . Until more information is gathered to identify targets and the underlying regulatory mechanisms, the functions of noncoding RNAs in pregnancy will remain limited. Furthermore, predictive gene regulation by cis -regulatory elements and transposons and their evolutionary adaptations in eutherian pregnancies have come to light 145 , 146 . It remains to be seen whether these elements can be validated in a physiological setting. Nonetheless, this area of research may have bearing on the different implantation strategies adapted by various species. In this Review, we discuss adverse pregnancy outcomes stemming from aberrant implantation and defective decidualization. Sensitive noninvasive methods to identify the more precise timing of implantation in humans will help to identify whether adverse pregnancy effects arise from defective implantation and decidualization.

Although many genes necessary for uterine receptivity and implantation are induced and regulated by estrogen, P 4 or both, transcription factors have recently been identified whose expressions are not greatly altered by these hormones but that profoundly influence receptivity and implantation in mice. One such gene is Msx1 , encoding an ancient evolutionarily conserved homeobox transcription factor 9 . Msx1 was shown to be absent in the pregnant mouse uterus 43 , but later studies found its distinct, transient expression in the epithelium around the time of receptivity, with peak expression on day 4 morning 44 . The expression declined approaching the time of blastocyst attachment and remained undetected thereafter. These observations suggested Msx1’s role in uterine receptivity 9 . Expression of Msx2 , another member in the family, is low to undetectable in the uterus during this time. However, Msx2 is upregulated in a similar fashion as Msx1 in Msx1 -depleted uteri, suggesting its compensatory role. Uterine deletion of Msx genes showed graded levels of compromised fertility depending on single or double deletion 9 ; mice deleted of uterine Msx1 ( Msx1 d/d ) produced small litters or no litters, whereas deletion of both Msx1 and Msx2 ( Msx1 d/d ; Msx2 d/d ) resulted in complete infertility due to failed or defective implantation with loss of stromal bone morphogenetic protein 2 ( Bmp2 ) expression and cyclooxygenase-2 ( Ptgs2 ) expression restricted to the epithelium. Interestingly, mice with uterine deletion of Msx2 have normal fertility 9 . The infertility phenotype in Msx1 d/d ; Msx2 d/d mice as reported earlier was later confirmed by another group 45 . The role of Msx1 and Msx2 is implicated in human implantation since they are downregulated in the endometrium during the window of receptivity, similar to the situation in mice 2 , 9 . With approaching blastocyst attachment, the luminal epithelium transits from a higher to lower state of polarity 9 . This transition was not evident in Msx1 d/d ; Msx2 d/d uteri at the anticipated time of implantation. Wnt5a, a traditionally noncanonical Wnt and mediator of cell polarity, was upregulated in the epithelium and stroma in Msx1 d/d and Msx1 d/d ; Msx2 d/d mice. Wnt5a–β-catenin/E-cadherin signaling was identified as a potential downstream target of Msx to influence implantation by altering cell polarity 9 . Msx1 expression persists in P 4 -primed delayed implanting uteri with blastocyst dormancy but is rapidly downregulated with initiation of implantation by estrogen or LIF ( Box 2 ), which suggests an indirect effect of estrogen via LIF induction. Implantation largely fails in P 4 -primed delayed implanting Msx -deleted uteri after estrogen treatment, which suggests that Msx is required to maintain uterine readiness to implantation. Moreover, uterine Lif expression is downregulated in these mice, but LIF administration fails to rescue implantation, which suggests complex and nonlinear relationship between LIF and Msx. How Msx expression is so tightly regulated in the receptive uterus is yet to be explored. Another gene necessary for implantation is that encoding Kruppel-like factor 5 ( Klf5 ), a zinc finger–containing transcription factor. Uterine Klf5 is also unresponsive to alteration by ovarian hormones 46 , although it is influenced by estrogen and P 4 in human breast cancer cells 47 . In mouse uteri, KLF5 is present in luminal and glandular epithelia until decidualization is initiated on day 5. At this time, KLF5 is expressed in proliferating stromal cells around the implantation chamber with downregulation in the epithelium. With differentiation, decidual cell expression decreases, suggesting KLF5’s participation in cell-specific proliferation and differentiation during pregnancy. Systemic deletion of Klf5 confers embryonic arrest at the blastocyst stage 48 . In contrast, mice with uterine deletion of Klf5 ( Klf5 d/d ) are essentially infertile as a result of defective implantation 46 . Blastocysts remain entrapped within the uterine lumen beyond the anticipated time of implantation, as is evident from intact luminal epithelium. Decidualization was still initiated, albeit at a reduced extent, with Hoxa10 and Bmp2 expression being crucial for decidualization. The partial decidual response was not sustained and embryos disintegrated 46 . These findings corroborate with an earlier study that a functional luminal epithelium is necessary for decidual response 49 . Collectively, the results suggest that signals originating from a blastocyst and transmitted through the epithelium can initiate decidualization without direct contact of the blastocyst with the stroma. Nonetheless, a functional circuitry involving the blastocyst, luminal epithelium and stroma is essential for normal implantation and decidualization. Identification of such genes that regulate receptivity but are relatively unaffected by ovarian hormones may help improve in vitro fertilization (IVF)-conceived pregnancy rates or alternatively help develop nonsteroidal contraceptives.

A two-way communication between the blastocyst and receptive uterus leads to attachment reaction and implantation. Preparation of the uterus to realize receptivity and blastocyst attachment to the luminal epithelium are endowed with distinct and overlapping gene expression. Therefore, it is difficult to appreciate the molecular dialog between these two entities during this progression. Heparin-binding epidermal growth factor–like growth factor (HB-EGF) stands out to be an important molecular link in mediating embryo-uterine interactions with impending attachment reaction in mice. It is expressed in the luminal epithelium surrounding each blastocyst several hours before the attachment reaction 50 . HB-EGF is produced in soluble and transmembrane forms, and both forms influence blastocyst function in a paracrine and juxtacrine manner via the EGF family of receptors expressed on the blastocyst cell surface 51 , 52 , placing HB-EGF as a unique molecule for blastocystluminal epithelium adhesion ( Fig. 1 ). Implantation-competent blastocysts also express HB-EGF, which can induce its own gene ( Hegf1 ) in the uterus in a paracrine manner 53 , 54 . This auto-induction loop is the first known molecular link between the blastocyst and uterus that leads to attachment reaction. Although systemic deletion of Hegf1 causes perinatal lethality 55 , its uterine deletion defers implantation beyond the normal window, producing reduced litter size; partial fertility restoration is apparently due to compensation by amphiregulin, another HB-EGF–like growth factor 56 . Studies in humans later found that HB-EGF expression is maximal in the receptive epithelium and is concurrent with pinopodes 57 , and cells expressing the transmembrane form of HB-EGF can adhere to blastocysts expressing cell surface ErbB4 ( refs. 58 , 59 ). Adhesion molecules such as integrins, L-selectin ligands and selectin oligosaccharides are also implicated in blastocyst attachment and placentation in humans 60 – 62 . One approach to study certain aspects of blastocyst attachment is to transfer inert blastocyst-size beads preloaded with factors as shown previously for HB-EGF and L-selectins 54 , 60 . As Ptgs2 and Bmp2 are expressed in both the epithelium and/or underlying stroma at the site of attachment, they are also considered essential for implantation and decidualization; deletion of either gene confers infertility 63 , 64 . Owing to their overlapping expression beyond implantation, their roles in decidualization are detailed below.

Normally, the blastocyst is the stimulus for decidualization in mice. Stromal cells surrounding the implanting blastocyst undergo extensive proliferation and differentiation into specialized cell types called decidual cells (decidualization). In humans, the initiation of this process (predecidualization) does not require the presence of a blastocyst but becomes more robust with implantation. The importance of pre-decidualization is perhaps to prepare the endometrium for implantation and seems analogous to extensive stromal cell proliferation with expression of decidual marker genes before implantation in mice. Decidualization is a complex interplay of transcription factors, morphogens, cytokines, cell cycle regulators and signaling pathways. In mice, the abdominalB-like Hox genes Hoxa10 and Hoxa11 are expressed in the stroma at receptivity and become more intense upon decidualization 65 – 67 . They are essential for decidualization, and its failure in Hoxa10 −/− mice is due to reduced stromal cell proliferation to P 4 , although attachment reaction often occurs 65 , 66 . Hoxa11 −/− mice have a similar but more robust infertility phenotype 67 . Defective decidualization in Hoxa10 −/− mice is coincident with downregulation of a cell cycle regulatory axis involving cyclinD3, cdk4/6 and p21 ( refs. 66 , 68 ). In women, both Hoxa10 and Hoxa11 are upregulated in the receptive endometrium, suggesting their roles in decidualization 69 , 70 . In addition, decidualization induced by P 4 , estrogen and dibutyryl cAMP in human cell culture systems is associated with expression of prolactin and insulin-like growth factor-binding protein 1 as decidual markers 71 – 73 . It would be interesting to see whether signaling molecules necessary for decidualization in mice are also necessary for human decidualization in culture. Many decidual cells undergo endoreduplication (polyploidy), a process by which cells undergo rounds of DNA replication without cytokinesis. Endoreduplication may serve to support embryonic growth by increasing protein synthesis through enhanced gene transcription. Although decidual polyploidy is well established in rodents, early literature provides evidence for this phenotype in humans but requires validation with reliable markers 74 . Whether decidual polyploidy is necessary for pregnancy success was examined in mice carrying deletion of the death effector domain–containing protein (DEDD) 75 . Dedd deficiency resulted in defective decidualization with reduced polyploidy, which led to infertility; the attachment reaction was normal. DEDD executed its function by forming a complex with cyclin D3, cdk4/6 and AKT. Deletion of the cytokine receptor Il11ra1 gene or sphingosine kinases Sphk1 and Sphk2 in a gene dosage– dependent manner also cause defective decidualization 76 – 78 . Serum- and glucocorticoid-inducible kinase (SGK1), involved in epithelial ion transport and cell survival, was reported to be essential for implantation and preserving decidual-placental integrity 79 . In mice, intraluminal delivery of an Sgk1 -overexpressing vector interfered with implantation. In contrast, Sgk1 deletion had no apparent effect on implantation but led to abnormal development of the decidual-placental interface, restricted fetal growth and death. This study is clinically relevant because SGK1 was differentially expressed in different pregnancy pathologies in women. In a human in vitro system, SGK1 silencing impaired decidualization by invoking oxidative stress. These findings are intriguing, but it would be interesting to know whether the effects are specific to decidualization or are consequences of defective uterine receptivity or implantation in a mouse model. Nevertheless, the results show that some genes are differentially regulated during early pregnancy.