Mechanisms of implantation: strategies for successful pregnancy

Abstract

Physiological and molecular processes initiated during implantation for pregnancy success are complex but highly organized. This review primarily highlights adverse ripple effects arising from defects during the peri-implantation period that perpetuate throughout pregnancy. These defects are reflected in aberrations in embryo spacing, decidualization, placentation and intrauterine embryonic growth, manifesting in preeclampsia, miscarriages and/or preterm birth. Understanding molecular signaling networks that coordinate strategies for successful implantation and decidualization may lead to approaches to improve the outcome of natural pregnancy and pregnancy conceived from in vitro fertilization.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Signaling network for uterine receptivity and implantation.
Figure 2: Signaling networks in decidualization.
Figure 3: Potential adverse ripple effects during pregnancy arising from stage-specific defects in mice.
Figure 4: Plausible charting of adverse ripple effects in human pregnancy.

Change history

  • 08 January 2013

     In the version of this article initially published, the references included in Figure 3a were incorrect. The error has been corrected in the HTML and PDF versions of the article.

References

  1. 1

    Dey, S.K. et al. Molecular cues to implantation. Endocr. Rev. 25, 341–373 (2004).

  2. 2

    Wang, H. & Dey, S.K. Roadmap to embryo implantation: clues from mouse models. Nat. Rev. Genet. 7, 185–199 (2006).

  3. 3

    Carson, D.D. et al. Embryo implantation. Dev. Biol. 223, 217–237 (2000).

  4. 4

    Norwitz, E.R., Schust, D.J. & Fisher, S.J. Implantation and the survival of early pregnancy. N. Engl. J. Med. 345, 1400–1408 (2001).

  5. 5

    Wilcox, A.J., Baird, D.D. & Weinberg, C.R. Time of implantation of the conceptus and loss of pregnancy. N. Engl. J. Med. 340, 1796–1799 (1999).

  6. 6

    Nagaoka, S.I., Hassold, T.J. & Hunt, P.A. Human aneuploidy: mechanisms and new insights into an age-old problem. Nat. Rev. Genet. 13, 493–504 (2012).

  7. 7

    Psychoyos, A. Endocrine Control of Egg Implantation (American Physiology Society, Washington, D.C., 1973).

  8. 8

    Paria, B.C., Huet-Hudson, Y.M. & Dey, S.K. Blastocyst's state of activity determines the “window” of implantation in the receptive mouse uterus. Proc. Natl. Acad. Sci. USA 90, 10159–10162 (1993).

  9. 9

    Daikoku, T. et al. Conditional deletion of MSX homeobox genes in the uterus inhibits blastocyst implantation by altering uterine receptivity. Dev. Cell 21, 1014–1024 (2011).

  10. 10

    Nikas, G. & Psychoyos, A. Uterine pinopodes in peri-implantation human endometrium. Clinical relevance. Ann. NY Acad. Sci. 816, 129–142 (1997).

  11. 11

    Ma, W.G., Song, H., Das, S.K., Paria, B.C. & Dey, S.K. Estrogen is a critical determinant that specifies the duration of the window of uterine receptivity for implantation. Proc. Natl. Acad. Sci. USA 100, 2963–2968 (2003).

  12. 12

    Giudice, L.C. Potential biochemical markers of uterine receptivity. Hum. Reprod. 14 (suppl. 2), 3–16 (1999).

  13. 13

    Song, H., Lim, H., Das, S.K., Paria, B.C. & Dey, S.K. Dysregulation of EGF family of growth factors and COX-2 in the uterus during the preattachment and attachment reactions of the blastocyst with the luminal epithelium correlates with implantation failure in LIF-deficient mice. Mol. Endocrinol. 14, 1147–1161 (2000).

  14. 14

    Winuthayanon, W., Hewitt, S.C., Orvis, G.D., Behringer, R.R. & Korach, K.S. Uterine epithelial estrogen receptor α is dispensable for proliferation but essential for complete biological and biochemical responses. Proc. Natl. Acad. Sci. USA 107, 19272–19277 (2010).

  15. 15

    Franco, H.L. et al. Epithelial progesterone receptor exhibits pleiotropic roles in uterine development and function. FASEB J. 26, 1218–1227 (2012).

  16. 16

    Simon, L. et al. Stromal progesterone receptors mediate induction of Indian Hedgehog (IHH) in uterine epithelium and its downstream targets in uterine stroma. Endocrinology 150, 3871–3876 (2009).

  17. 17

    Stewart, C.L. et al. Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor. Nature 359, 76–79 (1992).

  18. 18

    Niwa, H., Burdon, T., Chambers, I. & Smith, A. Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes Dev. 12, 2048–2060 (1998).

  19. 19

    Laird, S.M. et al. The production of leukaemia inhibitory factor by human endometrium: presence in uterine flushings and production by cells in culture. Hum. Reprod. 12, 569–574 (1997).

  20. 20

    Piccinni, M.P. et al. Defective production of both leukemia inhibitory factor and type 2 T-helper cytokines by decidual T cells in unexplained recurrent abortions. Nat. Med. 4, 1020–1024 (1998).

  21. 21

    Hambartsoumian, E. Endometrial leukemia inhibitory factor (LIF) as a possible cause of unexplained infertility and multiple failures of implantation. Am. J. Reprod. Immunol. 39, 137–143 (1998).

  22. 22

    Brinsden, P.R., Alam, V., de Moustier, B. & Engrand, P. Recombinant human leukemia inhibitory factor does not improve implantation and pregnancy outcomes after assisted reproductive techniques in women with recurrent unexplained implantation failure. Fertil. Steril. 91, 1445–1447 (2009).

  23. 23

    Hu, W., Feng, Z., Teresky, A.K. & Levine, A.J. p53 regulates maternal reproduction through LIF. Nature 450, 721–724 (2007).

  24. 24

    Hirota, Y. et al. Uterine-specific p53 deficiency confers premature uterine senescence and promotes preterm birth in mice. J. Clin. Invest. 120, 803–815 (2010).

  25. 25

    Kang, H.J. et al. Single-nucleotide polymorphisms in the p53 pathway regulate fertility in humans. Proc. Natl. Acad. Sci. USA 106, 9761–9766 (2009).

  26. 26

    Patounakis, G. et al. The p53 codon 72 single nucleotide polymorphism lacks a significant effect on implantation rate in fresh in vitro fertilization cycles: an analysis of 1,056 patients. Fertil. Steril. 92, 1290–1296 (2009).

  27. 27

    Tranguch, S. et al. Cochaperone immunophilin FKBP52 is critical to uterine receptivity for embryo implantation. Proc. Natl. Acad. Sci. USA 102, 14326–14331 (2005).

  28. 28

    Yang, Z. et al. FK506-binding protein 52 is essential to uterine reproductive physiology controlled by the progesterone receptor A isoform. Mol. Endocrinol. 20, 2682–2694 (2006).

  29. 29

    Tranguch, S. et al. FKBP52 deficiency-conferred uterine progesterone resistance is genetic background and pregnancy stage specific. J. Clin. Invest. 117, 1824–1834 (2007).

  30. 30

    Hirota, Y. et al. Uterine FK506-binding protein 52 (FKBP52)-peroxiredoxin-6 (PRDX6) signaling protects pregnancy from overt oxidative stress. Proc. Natl. Acad. Sci. USA 107, 15577–15582 (2010).

  31. 31

    Hirota, Y. et al. Deficiency of immunophilin FKBP52 promotes endometriosis. Am. J. Pathol. 173, 1747–1757 (2008).

  32. 32

    Yang, H. et al. FKBP52 is regulated by HOXA10 during decidualizaton and in endometriosis. Reproduction 143, 531–538 (2012).

  33. 33

    Xu, J., Wu, R.C. & O'Malley, B.W. Normal and cancer-related functions of the p160 steroid receptor co-activator (SRC) family. Nat. Rev. Cancer 9, 615–630 (2009).

  34. 34

    Mukherjee, A. et al. Steroid receptor coactivator 2 is critical for progesterone-dependent uterine function and mammary morphogenesis in the mouse. Mol. Cell. Biol. 26, 6571–6583 (2006).

  35. 35

    Mukherjee, A., Amato, P., Allred, D.C., DeMayo, F.J. & Lydon, J.P. Steroid receptor coactivator 2 is required for female fertility and mammary morphogenesis: insights from the mouse, relevance to the human. Nucl. Recept. Signal. 5, e011 (2007).

  36. 36

    Matsumoto, H., Zhao, X., Das, S.K., Hogan, B.L. & Dey, S.K. Indian hedgehog as a progesterone-responsive factor mediating epithelial-mesenchymal interactions in the mouse uterus. Dev. Biol. 245, 280–290 (2002).

  37. 37

    Lee, K. et al. Indian hedgehog is a major mediator of progesterone signaling in the mouse uterus. Nat. Genet. 38, 1204–1209 (2006).

  38. 38

    Wei, Q., Levens, E.D., Stefansson, L. & Nieman, L.K. Indian Hedgehog and its targets in human endometrium: menstrual cycle expression and response to CDB-2914. J. Clin. Endocrinol. Metab. 95, 5330–5337 (2010).

  39. 39

    Kurihara, I. et al. COUP-TFII mediates progesterone regulation of uterine implantation by controlling ER activity. PLoS Genet. 3, e102 (2007).

  40. 40

    Petit, F.G. et al. Deletion of the orphan nuclear receptor COUP-TFII in uterus leads to placental deficiency. Proc. Natl. Acad. Sci. USA 104, 6293–6298 (2007).

  41. 41

    Li, Q. et al. The antiproliferative action of progesterone in uterine epithelium is mediated by Hand2. Science 331, 912–916 (2011).

  42. 42

    Huyen, D.V. & Bany, B.M. Evidence for a conserved function of heart and neural crest derivatives expressed transcript 2 in mouse and human decidualization. Reproduction 142, 353–368 (2011).

  43. 43

    Pavlova, A., Boutin, E., Cunha, G. & Sassoon, D. Msx1 (Hox-7.1) in the adult mouse uterus: cellular interactions underlying regulation of expression. Development 120, 335–345 (1994).

  44. 44

    Daikoku, T. et al. Uterine Msx-1 and Wnt4 signaling becomes aberrant in mice with the loss of leukemia inhibitory factor or Hoxa-10: evidence for a novel cytokine-homeobox-Wnt signaling in implantation. Mol. Endocrinol. 18, 1238–1250 (2004).

  45. 45

    Nallasamy, S., Li, Q., Bagchi, M.K. & Bagchi, I.C. Msx homeobox genes critically regulate embryo implantation by controlling paracrine signaling between uterine stroma and epithelium. PLoS Genet. 8, e1002500 (2012).

  46. 46

    Sun, X. et al. Kruppel-like factor 5 (KLF5) is critical for conferring uterine receptivity to implantation. Proc. Natl. Acad. Sci. USA 109, 1145–1150 (2012).

  47. 47

    Liu, R., Zhou, Z., Zhao, D. & Chen, C. The induction of KLF5 transcription factor by progesterone contributes to progesterone-induced breast cancer cell proliferation and dedifferentiation. Mol. Endocrinol. 25, 1137–1144 (2011).

  48. 48

    Ema, M. et al. Kruppel-like factor 5 is essential for blastocyst development and the normal self-renewal of mouse ESCs. Cell Stem Cell 3, 555–567 (2008).

  49. 49

    Lejeune, B., Van Hoeck, J. & Leroy, F. Transmitter role of the luminal uterine epithelium in the induction of decidualization in rats. J. Reprod. Fertil. 61, 235–240 (1981).

  50. 50

    Das, S.K. et al. Heparin-binding EGF-like growth factor gene is induced in the mouse uterus temporally by the blastocyst solely at the site of its apposition: a possible ligand for interaction with blastocyst EGF-receptor in implantation. Development 120, 1071–1083 (1994).

  51. 51

    Paria, B.C., Elenius, K., Klagsbrun, M. & Dey, S.K. Heparin-binding EGF-like growth factor interacts with mouse blastocysts independently of ErbB1: a possible role for heparan sulfate proteoglycans and ErbB4 in blastocyst implantation. Development 126, 1997–2005 (1999).

  52. 52

    Raab, G. et al. Mouse preimplantation blastocysts adhere to cells expressing the transmembrane form of heparin-binding EGF-like growth factor. Development 122, 637–645 (1996).

  53. 53

    Hamatani, T. et al. Global gene expression analysis identifies molecular pathways distinguishing blastocyst dormancy and activation. Proc. Natl. Acad. Sci. USA 101, 10326–10331 (2004).

  54. 54

    Paria, B.C. et al. Cellular and molecular responses of the uterus to embryo implantation can be elicited by locally applied growth factors. Proc. Natl. Acad. Sci. USA 98, 1047–1052 (2001).

  55. 55

    Iwamoto, R. et al. Heparin-binding EGF-like growth factor and ErbB signaling is essential for heart function. Proc. Natl. Acad. Sci. USA 100, 3221–3226 (2003).

  56. 56

    Xie, H. et al. Maternal heparin-binding-EGF deficiency limits pregnancy success in mice. Proc. Natl. Acad. Sci. USA 104, 18315–18320 (2007).

  57. 57

    Stavreus-Evers, A. et al. Co-existence of heparin-binding epidermal growth factor-like growth factor and pinopodes in human endometrium at the time of implantation. Mol. Hum. Reprod. 8, 765–769 (2002).

  58. 58

    Yoo, H.J., Barlow, D.H. & Mardon, H.J. Temporal and spatial regulation of expression of heparin-binding epidermal growth factor-like growth factor in the human endometrium: a possible role in blastocyst implantation. Dev. Genet. 21, 102–108 (1997).

  59. 59

    Chobotova, K. et al. Heparin-binding epidermal growth factor and its receptor ErbB4 mediate implantation of the human blastocyst. Mech. Dev. 119, 137–144 (2002).

  60. 60

    Genbacev, O.D. et al. Trophoblast L-selectin–mediated adhesion at the maternal-fetal interface. Science 299, 405–408 (2003).

  61. 61

    Lessey, B.A. Assessment of endometrial receptivity. Fertil. Steril. 96, 522–529 (2011).

  62. 62

    Prakobphol, A., Genbacev, O., Gormley, M., Kapidzic, M. & Fisher, S.J. A role for the L-selectin adhesion system in mediating cytotrophoblast emigration from the placenta. Dev. Biol. 298, 107–117 (2006).

  63. 63

    Lim, H. et al. Multiple female reproductive failures in cyclooxygenase 2–deficient mice. Cell 91, 197–208 (1997).

  64. 64

    Lee, K.Y. et al. Bmp2 is critical for the murine uterine decidual response. Mol. Cell. Biol. 27, 5468–5478 (2007).

  65. 65

    Benson, G.V. et al. Mechanisms of reduced fertility in Hoxa-10 mutant mice: uterine homeosis and loss of maternal Hoxa-10 expression. Development 122, 2687–2696 (1996).

  66. 66

    Lim, H., Ma, L., Ma, W.G., Maas, R.L. & Dey, S.K. Hoxa-10 regulates uterine stromal cell responsiveness to progesterone during implantation and decidualization in the mouse. Mol. Endocrinol. 13, 1005–1017 (1999).

  67. 67

    Gendron, R.L. et al. Abnormal uterine stromal and glandular function associated with maternal reproductive defects in Hoxa-11 null mice. Biol. Reprod. 56, 1097–1105 (1997).

  68. 68

    Tan, J. et al. Evidence for coordinated interaction of cyclin D3 with p21 and cdk6 in directing the development of uterine stromal cell decidualization and polyploidy during implantation. Mech. Dev. 111, 99–113 (2002).

  69. 69

    Taylor, H.S., Arici, A., Olive, D. & Igarashi, P. HOXA10 is expressed in response to sex steroids at the time of implantation in the human endometrium. J. Clin. Invest. 101, 1379–1384 (1998).

  70. 70

    Taylor, H.S., Igarashi, P., Olive, D.L. & Arici, A. Sex steroids mediate HOXA11 expression in the human peri-implantation endometrium. J. Clin. Endocrinol. Metab. 84, 1129–1135 (1999).

  71. 71

    Popovici, R.M., Kao, L.C. & Giudice, L.C. Discovery of new inducible genes in in vitro decidualized human endometrial stromal cells using microarray technology. Endocrinology 141, 3510–3513 (2000).

  72. 72

    Gellersen, B., Brosens, I.A. & Brosens, J.J. Decidualization of the human endometrium: mechanisms, functions, and clinical perspectives. Semin. Reprod. Med. 25, 445–453 (2007).

  73. 73

    Brar, A.K. et al. Laminin decreases PRL and IGFBP-1 expression during in vitro decidualization of human endometrial stromal cells. J. Cell. Physiol. 163, 30–37 (1995).

  74. 74

    Arias-Stella, J. The Arias-Stella reaction: facts and fancies four decades after. Adv. Anat. Pathol. 9, 12–23 (2002).

  75. 75

    Mori, M. et al. Death effector domain-containing protein (DEDD) is required for uterine decidualization during early pregnancy in mice. J. Clin. Invest. 121, 318–327 (2011).

  76. 76

    Bilinski, P., Roopenian, D. & Gossler, A. Maternal IL-11Rα function is required for normal decidua and fetoplacental development in mice. Genes Dev. 12, 2234–2243 (1998).

  77. 77

    Robb, L. et al. Infertility in female mice lacking the receptor for interleukin 11 is due to a defective uterine response to implantation. Nat. Med. 4, 303–308 (1998).

  78. 78

    Mizugishi, K. et al. Maternal disturbance in activated sphingolipid metabolism causes pregnancy loss in mice. J. Clin. Invest. 117, 2993–3006 (2007).

  79. 79

    Salker, M.S. et al. Deregulation of the serum- and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure. Nat. Med. 17, 1509–1513 (2011).

  80. 80

    Kim, J.J. et al. Expression of cyclooxygenase-1 and -2 in the baboon endometrium during the menstrual cycle and pregnancy. Endocrinology 140, 2672–2678 (1999).

  81. 81

    Critchley, H.O. et al. Role of inflammatory mediators in human endometrium during progesterone withdrawal and early pregnancy. J. Clin. Endocrinol. Metab. 84, 240–248 (1999).

  82. 82

    Marions, L. & Danielsson, K.G. Expression of cyclo-oxygenase in human endometrium during the implantation period. Mol. Hum. Reprod. 5, 961–965 (1999).

  83. 83

    Lim, H. et al. Cyclo-oxygenase-2–derived prostacyclin mediates embryo implantation in the mouse via PPARδ. Genes Dev. 13, 1561–1574 (1999).

  84. 84

    Wang, H. et al. Stage-specific integration of maternal and embryonic peroxisome proliferator-activated receptor δ signaling is critical to pregnancy success. J. Biol. Chem. 282, 37770–37782 (2007).

  85. 85

    Ruan, Y.C. et al. Activation of the epithelial Na+ channel triggers prostaglandin E2 release and production required for embryo implantation. Nat. Med. 18, 1112–1117 (2012).

  86. 86

    Hayashi, K. et al. Wnt genes in the mouse uterus: potential regulation of implantation. Biol. Reprod. 80, 989–1000 (2009).

  87. 87

    Tulac, S. et al. Identification, characterization, and regulation of the canonical Wnt signaling pathway in human endometrium. J. Clin. Endocrinol. Metab. 88, 3860–3866 (2003).

  88. 88

    Mohamed, O.A. et al. Uterine Wnt/β-catenin signaling is required for implantation. Proc. Natl. Acad. Sci. USA 102, 8579–8584 (2005).

  89. 89

    Franco, H.L. et al. WNT4 is a key regulator of normal postnatal uterine development and progesterone signaling during embryo implantation and decidualization in the mouse. FASEB J. 25, 1176–1187 (2011).

  90. 90

    Dunlap, K.A. et al. Postnatal deletion of Wnt7a inhibits uterine gland morphogenesis and compromises adult fertility in mice. Biol. Reprod. 85, 386–396 (2011).

  91. 91

    Parr, B.A. & McMahon, A.P. Sexually dimorphic development of the mammalian reproductive tract requires Wnt-7a. Nature 395, 707–710 (1998).

  92. 92

    Jeong, J.W. et al. Foxa2 is essential for mouse endometrial gland development and fertility. Biol. Reprod. 83, 396–403 (2010).

  93. 93

    Jeong, J.W. et al. β-catenin mediates glandular formation and dysregulation of β-catenin induces hyperplasia formation in the murine uterus. Oncogene 28, 31–40 (2009).

  94. 94

    Song, H. & Lim, H. Evidence for heterodimeric association of leukemia inhibitory factor (LIF) receptor and gp130 in the mouse uterus for LIF signaling during blastocyst implantation. Reproduction 131, 341–349 (2006).

  95. 95

    Song, H. et al. Cytosolic phospholipase A2α is crucial [correction of A2α deficiency is crucial] for 'on-time' embryo implantation that directs subsequent development. Development 129, 2879–2889 (2002).

  96. 96

    Wang, H., Dey, S.K. & Maccarrone, M. Jekyll and Hyde: two faces of cannabinoid signaling in male and female fertility. Endocr. Rev. 27, 427–448 (2006).

  97. 97

    Sun, X. et al. Endocannabinoid signaling directs differentiation of trophoblast cell lineages and placentation. Proc. Natl. Acad. Sci. USA 107, 16887–16892 (2010).

  98. 98

    Wang, H. et al. Aberrant cannabinoid signaling impairs oviductal transport of embryos. Nat. Med. 10, 1074–1080 (2004).

  99. 99

    Horne, A.W. et al. CB1 expression is attenuated in Fallopian tube and decidua of women with ectopic pregnancy. PLoS ONE 3, e3969 (2008).

  100. 100

    Wang, H. et al. Fatty acid amide hydrolase deficiency limits early pregnancy events. J. Clin. Invest. 116, 2122–2131 (2006).

  101. 101

    Trabucco, E. et al. Endocannabinoid system in first trimester placenta: low FAAH and high CB1 expression characterize spontaneous miscarriage. Placenta 30, 516–522 (2009).

  102. 102

    Leach, R.E. et al. Pre-eclampsia and expression of heparin-binding EGF-like growth factor. Lancet 360, 1215–1219 (2002).

  103. 103

    Stavreus-Evers, A., Koraen, L., Scott, J.E., Zhang, P. & Westlund, P. Distribution of cyclooxygenase-1, cyclooxygenase-2, and cytosolic phospholipase A2 in the luteal phase human endometrium and ovary. Fertil. Steril. 83, 156–162 (2005).

  104. 104

    Ye, X. et al. LPA3-mediated lysophosphatidic acid signalling in embryo implantation and spacing. Nature 435, 104–108 (2005).

  105. 105

    Wang, H. et al. Rescue of female infertility from the loss of cyclooxygenase-2 by compensatory up-regulation of cyclooxygenase-1 is a function of genetic makeup. J. Biol. Chem. 279, 10649–10658 (2004).

  106. 106

    Yotsumoto, S. et al. Expression of adrenomedullin, a hypotensive peptide, in the trophoblast giant cells at the embryo implantation site in mouse. Dev. Biol. 203, 264–275 (1998).

  107. 107

    Li, M., Yee, D., Magnuson, T.R., Smithies, O. & Caron, K.M. Reduced maternal expression of adrenomedullin disrupts fertility, placentation, and fetal growth in mice. J. Clin. Invest. 116, 2653–2662 (2006).

  108. 108

    Di Iorio, R., Marinoni, E., Scavo, D., Letizia, C. & Cosmi, E.V. Adrenomedullin in pregnancy. Lancet 349, 328 (1997).

  109. 109

    Li, M., Wu, Y. & Caron, K.M. Haploinsufficiency for adrenomedullin reduces pinopodes and diminishes uterine receptivity in mice. Biol. Reprod. 79, 1169–1175 (2008).

  110. 110

    Maltepe, E., Bakardjiev, A.I. & Fisher, S.J. The placenta: transcriptional, epigenetic, and physiological integration during development. J. Clin. Invest. 120, 1016–1025 (2010).

  111. 111

    Hunkapiller, N.M. et al. A role for Notch signaling in trophoblast endovascular invasion and in the pathogenesis of pre-eclampsia. Development 138, 2987–2998 (2011).

  112. 112

    Cross, J.C. The genetics of pre-eclampsia: a feto-placental or maternal problem? Clin. Genet. 64, 96–103 (2003).

  113. 113

    Cui, Y. et al. Role of corin in trophoblast invasion and uterine spiral artery remodelling in pregnancy. Nature 484, 246–250 (2012).

  114. 114

    Dokras, A. et al. Severe feto-placental abnormalities precede the onset of hypertension and proteinuria in a mouse model of preeclampsia. Biol. Reprod. 75, 899–907 (2006).

  115. 115

    Lam, C., Lim, K.H. & Karumanchi, S.A. Circulating angiogenic factors in the pathogenesis and prediction of preeclampsia. Hypertension 46, 1077–1085 (2005).

  116. 116

    Ormandy, C.J. et al. Null mutation of the prolactin receptor gene produces multiple reproductive defects in the mouse. Genes Dev. 11, 167–178 (1997).

  117. 117

    Harrison, D.E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009).

  118. 118

    Hirota, Y., Cha, J., Yoshie, M., Daikoku, T. & Dey, S.K. Heightened uterine mammalian target of rapamycin complex 1 (mTORC1) signaling provokes preterm birth in mice. Proc. Natl. Acad. Sci. USA 108, 18073–18078 (2011).

  119. 119

    Cnattingius, S., Forman, M.R., Berendes, H.W. & Isotalo, L. Delayed childbearing and risk of adverse perinatal outcome. A population-based study. J. Am. Med. Assoc. 268, 886–890 (1992).

  120. 120

    Krieg, S.A., Henne, M.B. & Westphal, L.M. Obstetric outcomes in donor oocyte pregnancies compared with advanced maternal age in in vitro fertilization pregnancies. Fertil. Steril. 90, 65–70 (2008).

  121. 121

    Nelson, S.M. & Lawlor, D.A. Predicting live birth, preterm delivery, and low birth weight in infants born from in vitro fertilisation: a prospective study of 144,018 treatment cycles. PLoS Med. 8, e1000386 (2011).

  122. 122

    Demidenko, Z.N., Korotchkina, L.G., Gudkov, A.V. & Blagosklonny, M.V. Paradoxical suppression of cellular senescence by p53. Proc. Natl. Acad. Sci. USA 107, 9660–9664 (2010).

  123. 123

    Paria, B.C. & Dey, S.K. Preimplantation embryo development in vitro: cooperative interactions among embryos and role of growth factors. Proc. Natl. Acad. Sci. USA 87, 4756–4760 (1990).

  124. 124

    Melin, J. et al. In vitro embryo culture in defined, sub-microliter volumes. Dev. Dyn. 238, 950–955 (2009).

  125. 125

    Sjöblom, C., Wikland, M. & Robertson, S.A. Granulocyte-macrophage colony–stimulating factor promotes human blastocyst development in vitro. Hum. Reprod. 14, 3069–3076 (1999).

  126. 126

    Martin, K.L., Barlow, D.H. & Sargent, I.L. Heparin-binding epidermal growth factor significantly improves human blastocyst development and hatching in serum-free medium. Hum. Reprod. 13, 1645–1652 (1998).

  127. 127

    Lim, H.J. & Dey, S.K. HB-EGF: a unique mediator of embryo-uterine interactions during implantation. Exp. Cell Res. 315, 619–626 (2009).

  128. 128

    Diaz-Gimeno, P. et al. A genomic diagnostic tool for human endometrial receptivity based on the transcriptomic signature. Fertility and sterility 95 50–60, 60 e51–15 (2011).

  129. 129

    Burnum, K.E. et al. Imaging mass spectrometry reveals unique protein profiles during embryo implantation. Endocrinology 149, 3274–3278 (2008).

  130. 130

    Burnum, K.E. et al. Spatial and temporal alterations of phospholipids determined by mass spectrometry during mouse embryo implantation. J. Lipid Res. 50, 2290–2298 (2009).

  131. 131

    Simón, C. et al. Increasing uterine receptivity by decreasing estradiol levels during the preimplantation period in high responders with the use of a follicle-stimulating hormone step-down regimen. Fertil. Steril. 70, 234–239 (1998).

  132. 132

    Moffett, A. & Loke, C. Immunology of placentation in eutherian mammals. Nat. Rev. Immunol. 6, 584–594 (2006).

  133. 133

    Munoz-Suano, A., Hamilton, A.B. & Betz, A.G. Gimme shelter: the immune system during pregnancy. Immunol. Rev. 241, 20–38 (2011).

  134. 134

    Collins, M.K., Tay, C.S. & Erlebacher, A. Dendritic cell entrapment within the pregnant uterus inhibits immune surveillance of the maternal/fetal interface in mice. J. Clin. Invest. 119, 2062–2073 (2009).

  135. 135

    Samstein, R.M., Josefowicz, S.Z., Arvey, A., Treuting, P.M. & Rudensky, A.Y. Extrathymic generation of regulatory T cells in placental mammals mitigates maternal-fetal conflict. Cell 150, 29–38 (2012).

  136. 136

    Nancy, P. et al. Chemokine gene silencing in decidual stromal cells limits T cell access to the maternal-fetal interface. Science 336, 1317–1321 (2012).

  137. 137

    Gluckman, P.D., Hanson, M.A., Cooper, C. & Thornburg, K.L. Effect of in utero and early-life conditions on adult health and disease. N. Engl. J. Med. 359, 61–73 (2008).

  138. 138

    Ravelli, G.P., Stein, Z.A. & Susser, M.W. Obesity in young men after famine exposure in utero and early infancy. N. Engl. J. Med. 295, 349–353 (1976).

  139. 139

    Carone, B.R. et al. Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 143, 1084–1096 (2010).

  140. 140

    Rosenfeld, C.S. et al. Striking variation in the sex ratio of pups born to mice according to whether maternal diet is high in fat or carbohydrate. Proc. Natl. Acad. Sci. USA 100, 4628–4632 (2003).

  141. 141

    Anway, M.D., Cupp, A.S., Uzumcu, M. & Skinner, M.K. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308, 1466–1469 (2005).

  142. 142

    Chakrabarty, A. et al. MicroRNA regulation of cyclooxygenase-2 during embryo implantation. Proc. Natl. Acad. Sci. USA 104, 15144–15149 (2007).

  143. 143

    Hu, S.J. et al. MicroRNA expression and regulation in mouse uterus during embryo implantation. J. Biol. Chem. 283, 23473–23484 (2008).

  144. 144

    Renthal, N.E. et al. miR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor. Proc. Natl. Acad. Sci. USA 107, 20828–20833 (2010).

  145. 145

    Lynch, V.J., May, G. & Wagner, G.P. Regulatory evolution through divergence of a phosphoswitch in the transcription factor CEBPB. Nature 480, 383–386 (2011).

  146. 146

    Lynch, V.J., Leclerc, R.D., May, G. & Wagner, G.P. Transposon-mediated rewiring of gene regulatory networks contributed to the evolution of pregnancy in mammals. Nat. Genet. 43, 1154–1159 (2011).

  147. 147

    Lubahn, D.B. et al. Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc. Natl. Acad. Sci. USA 90, 11162–11166 (1993).

  148. 148

    Lydon, J.P. et al. Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev. 9, 2266–2278 (1995).

  149. 149

    Mulac-Jericevic, B., Mullinax, R.A., DeMayo, F.J., Lydon, J.P. & Conneely, O.M. Subgroup of reproductive functions of progesterone mediated by progesterone receptor-B isoform. Science 289, 1751–1754 (2000).

  150. 150

    Thomas, K., De Hertogh, R., Pizarro, M., Van Exter, C. & Ferin, J. Plasma LH-HCG, 17 -estradiol, estrone and progesterone monitoring around ovulation and subsequent nidation. Int. J. Fertil. 18, 65–73 (1973).

  151. 151

    Ghosh, D., De, P. & Sengupta, J. Luteal phase ovarian oestrogen is not essential for implantation and maintenance of pregnancy from surrogate embryo transfer in the rhesus monkey. Hum. Reprod. 9, 629–637 (1994).

  152. 152

    Smitz, J. et al. A prospective randomized study on oestradiol valerate supplementation in addition to intravaginal micronized progesterone in buserelin and HMG induced superovulation. Hum. Reprod. 8, 40–45 (1993).

  153. 153

    Rao, A.J. et al. Establishment of the need for oestrogen during implantation in non-human primates. Reprod. Biomed. Online 14, 563–571 (2007).

  154. 154

    McLaren, A. A study of balstocysts during delay and subsequent implantation in lactating mice. J. Endocrinol. 42, 453–463 (1968).

  155. 155

    Yoshinaga, K. & Adams, C.E. Delayed implantation in the spayed, progesterone treated adult mouse. J. Reprod. Fertil. 12, 593–595 (1966).

  156. 156

    Lee, J.E. et al. Autophagy regulates embryonic survival during delayed implantation. Endocrinology 152, 2067–2075 (2011).

  157. 157

    Lopes, F.L., Desmarais, J.A. & Murphy, B.D. Embryonic diapause and its regulation. Reproduction 128, 669–678 (2004).

  158. 158

    Renfree, M.B. & Shaw, G. Diapause. Annu. Rev. Physiol. 62, 353–375 (2000).

  159. 159

    Hess, A.P., Nayak, N.R. & Giudice, L.C. Oviduct and endometrium: cyclic changes in the primate oviduct and endometrium. in. Knobil and Neill's Physiology of Reproduction, Vol. 1 (ed. Neill, J.D.) 337–381 (Elsevier Academic Press, 2006).

  160. 160

    Schlafke, S. & Enders, A.C. Cellular basis of interaction between trophoblast and uterus at implantation. Biol. Reprod. 12, 41–65 (1975).

  161. 161

    World Health Organization. Born Too Soon: The Global Action Report on Preterm Birth. (World Health Organization, Geneva, 2012).

  162. 162

    Roizen, J.D., Asada, M., Tong, M., Tai, H.H. & Muglia, L.J. Preterm birth without progesterone withdrawal in 15-hydroxyprostaglandin dehydrogenase hypomorphic mice. Mol. Endocrinol. 22, 105–112 (2008).

  163. 163

    Park, C.B., DeMayo, F.J., Lydon, J.P. & Dufort, D. NODAL in the uterus is necessary for proper placental development and maintenance of pregnancy. Biol. Reprod. 86, 194 (2012).

  164. 164

    Hamilton, S. et al. Macrophages infiltrate the human and rat decidua during term and preterm labor: evidence that decidual inflammation precedes labor. Biol. Reprod. 86, 39 (2011).

  165. 165

    Wang, H. & Hirsch, E. Bacterially-induced preterm labor and regulation of prostaglandin-metabolizing enzyme expression in mice: the role of Toll-like receptor 4. Biol. Reprod. 69, 1957–1963 (2003).

  166. 166

    Döring, B. et al. Ablation of connexin43 in uterine smooth muscle cells of the mouse causes delayed parturition. J. Cell Sci. 119, 1715–1722 (2006).

  167. 167

    Fonseca, E.B., Celik, E., Parra, M., Singh, M. & Nicolaides, K.H. Progesterone and the risk of preterm birth among women with a short cervix. N. Engl. J. Med. 357, 462–469 (2007).

  168. 168

    Meis, P.J. et al. Prevention of recurrent preterm delivery by 17 α-hydroxyprogesterone caproate. N. Engl. J. Med. 348, 2379–2385 (2003).

  169. 169

    Groom, K.M., Shennan, A.H., Jones, B.A., Seed, P. & Bennett, P.R. TOCOX–a randomised, double-blind, placebo-controlled trial of rofecoxib (a COX-2-specific prostaglandin inhibitor) for the prevention of preterm delivery in women at high risk. BJOG 112, 725–730 (2005).

  170. 170

    Kawagoe, J. et al. Nuclear receptor coactivator-6 attenuates uterine estrogen sensitivity to permit embryo implantation. Dev. Cell 23, 858–865 (2012).

Download references

Acknowledgements

We regret that space limitations precluded us from citing many relevant references. We thank K. Yoshinaga and A. Erlebacher for helpful discussions. Work embodied in this article from S.K.D.'s group was supported in part by US National Institutes of Health (NIH) grants (HD12304, HD068524 and DA06668), the March of Dimes, and the Grand Challenges Explorations Initiative through the Bill & Melinda Gates Foundation. J.C. is supported by an NIH National Research Service Award Fellowship (F30AG040858) and the University of Cincinnati Medical Scientist Training Program (T32 GM063483), and X.S. is supported by a Lalor Foundation Postdoctoral Fellowship.

Author information

Correspondence to Sudhansu K Dey.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Cha, J., Sun, X. & Dey, S. Mechanisms of implantation: strategies for successful pregnancy. Nat Med 18, 1754–1767 (2012). https://doi.org/10.1038/nm.3012

Download citation

Further reading