Semin Reprod Med 2007; 25(6): 445-453
DOI: 10.1055/s-2007-991042
© Thieme Medical Publishers

Decidualization of the Human Endometrium: Mechanisms, Functions, and Clinical Perspectives

Birgit Gellersen1 , Ivo A. Brosens2 , Jan J. Brosens3
  • 1Endokrinologikum Hamburg, Hamburg, Germany
  • 2Leuven Institute for Fertility and Embryology, Leuven, Belgium
  • 3Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital, London, United Kingdom
Further Information

Publication History

Publication Date:
25 October 2007 (online)

ABSTRACT

The fetomaternal interface, consisting of the maternal decidua and the invading fetal trophoblast, critically regulates placental function and the growth and development of the conceptus. In its broadest sense, decidualization could be viewed as the postovulatory process of endometrial remodeling in preparation for pregnancy, which includes secretory transformation of the uterine glands, influx of specialized uterine natural killer cells, and vascular remodeling. A more restricted definition of the decidual process denotes the morphological and biochemical reprogramming of the endometrial stromal compartment. This differentiation process is dependent entirely on the convergence of the cyclic adenosine monophosphate and progesterone signaling pathways that drives integrated changes at both the transcriptome and the proteome level. As a consequence, decidualizing stromal cells acquire the unique ability to regulate trophoblast invasion, to resist inflammatory and oxidative insults, and to dampen local maternal immune responses. In humans, decidualization of the stromal compartment occurs in the mid-luteal phase of the menstrual cycle, independently of pregnancy. This raises the possibility that biochemical analysis of timed endometrial biopsy samples taken in a nonconception cycle could be informative of subsequent pregnancy outcome.

REFERENCES

  • 1 Brosens J J, Pijnenborg R, Brosens I A. The myometrial junctional zone spiral arteries in normal and abnormal pregnancies: a review of the literature.  Am J Obstet Gynecol. 2002;  187 1416-1423
  • 2 Ramsey E M, Houston M L, Harris J W. Interactions of the trophoblast and maternal tissues in three closely related primate species.  Am J Obstet Gynecol. 1976;  124 647-652
  • 3 Brosens I, Robertson W B, Dixon H G. The physiological response of the vessels of the placental bed to normal pregnancy.  J Pathol Bacteriol. 1967;  93 569-579
  • 4 Croy B A, van den Heuvel M J, Borzychowski A M, Tayade C. Uterine natural killer cells: a specialized differentiation regulated by ovarian hormones.  Immunol Rev. 2006;  214 161-185
  • 5 Hanna J, Goldman-Wohl D, Hamani Y et al.. Decidual NK cells regulate key developmental processes at the human fetal-maternal interface.  Nat Med. 2006;  12 1065-1074
  • 6 Brosens J J, de Souza N M, Barker F G. Uterine junctional zone: function and disease.  Lancet. 1995;  346 558-560
  • 7 Brosens J J, Gellersen B. Death or survival-progesterone-dependent cell fate decisions in the human endometrial stroma.  J Mol Endocrinol. 2006;  36 389-398
  • 8 Gellersen B, Brosens J. Cyclic AMP and progesterone receptor cross-talk in human endometrium: a decidualizing affair.  J Endocrinol. 2003;  178 357-372
  • 9 Aplin J D, Charlton A K, Ayad S. An immunohistochemical study of human endometrial extracellular matrix during the menstrual cycle and first trimester of pregnancy.  Cell Tissue Res. 1988;  253 231-240
  • 10 Wynn R M. Ultrastructural development of the human decidua.  Am J Obstet Gynecol. 1974;  118 652-670
  • 11 Tanaka K, Minoura H, Isobe T et al.. Ghrelin is involved in the decidualization of human endometrial stromal cells.  J Clin Endocrinol Metab. 2003;  88 2335-2340
  • 12 Giudice L C. Microarray expression profiling reveals candidate genes for human uterine receptivity.  Am J Pharmacogenomics. 2004;  4 299-312
  • 13 Dimitriadis E, White C A, Jones R L, Salamonsen L A. Cytokines, chemokines and growth factors in endometrium related to implantation.  Hum Reprod Update. 2005;  11 613-630
  • 14 Kajihara T, Jones M, Fusi L et al.. Differential expression of FOXO1 and FOXO3a confers resistance to oxidative cell death upon endometrial decidualization.  Mol Endocrinol. 2006;  20 2444-2455
  • 15 Labied S, Kajihara T, Madureira P A et al.. Progestins regulate the expression and activity of the Forkhead transcription factor FOXO1 in differentiating human endometrium.  Mol Endocrinol. 2006;  20 35-44
  • 16 Christian M, Zhang X, Schneider-Merck T et al.. Cyclic AMP-induced forkhead transcription factor, FKHR, cooperates with CCAAT/enhancer-binding protein β in differentiating human endometrial stromal cells.  J Biol Chem. 2002;  277 20825-20832
  • 17 Christian M, Pohnke Y, Kempf R, Gellersen B, Brosens J J. Functional association of PR and CCAAT/enhancer-binding protein β isoforms: promoter-dependent cooperation between PR-B and liver-enriched inhibitory protein, or liver-enriched activatory protein and PR-A in human endometrial stromal cells.  Mol Endocrinol. 2002;  16 141-154
  • 18 Horcajadas J A, Riesewijk A, Dominguez F, Cervero A, Pellicer A, Simon C. Determinants of endometrial receptivity.  Ann N Y Acad Sci. 2004;  1034 166-175
  • 19 de Ziegler D, Fanchin R, de Moustier B, Bulletti C. The hormonal control of endometrial receptivity: estrogen (E2) and progesterone.  J Reprod Immunol. 1998;  39 149-166
  • 20 Brar A K, Frank G R, Kessler C A, Cedars M I, Handwerger S. Progesterone-dependent decidualization of the human endometrium is mediated by cAMP.  Endocrine. 1997;  6 301-307
  • 21 Brosens J J, Hayashi N, White J O. Progesterone receptor regulates decidual prolactin expression in differentiating human endometrial stromal cells.  Endocrinology. 1999;  140 4809-4820
  • 22 Telgmann R, Maronde E, Taskén K, Gellersen B. Activated protein kinase A is required for differentiation-dependent transcription of the decidual prolactin gene in human endometrial stromal cells.  Endocrinology. 1997;  138 929-937
  • 23 Dessauer C W, Posner B A, Gilman A G. Visualizing signal transduction: receptors, G-proteins, and adenylate cyclase.  Clin Sci. 1996;  91 527-537
  • 24 Bergamini C M, Pansini F, Bettocchi Jr S et al.. Hormonal sensitivity of adenylate cyclase from human endometrium: modulation by estradiol.  J Steroid Biochem. 1985;  22 299-303
  • 25 Tanaka N, Miyazaki K, Tashiro H, Mizutani H, Okamura H. Changes in adenylyl cyclase activity in human endometrium during the menstrual cycle and in human decidua during pregnancy.  J Reprod Fertil. 1993;  98 33-39
  • 26 Tang B, Gurpide E. Direct effect of gonadotropins on decidualization of human endometrial stromal cells.  J Steroid Biochem Mol Biol. 1993;  47 115-121
  • 27 Li X, O'Malley B W. Unfolding the action of progesterone receptor.  J Biol Chem. 2003;  278 39261-39264
  • 28 Mote P A, Balleine R L, McGowan E M, Clarke C L. Colocalization of progesterone receptors A and B by dual immunofluorescent histochemistry in human endometrium during the menstrual cycle.  J Clin Endocrinol Metab. 1999;  84 2963-2971
  • 29 Mulac-Jericevic B, Conneely O M. Reproductive tissue selective actions of progesterone receptors.  Reproduction. 2004;  128 139-146
  • 30 Smith C L, O'Malley B W. Coregulator function: a key to understanding tissue specificity of selective receptor modulators.  Endocr Rev. 2004;  25 45-71
  • 31 Wagner B L, Norris J D, Knotts T A, Weigel N L, McDonnell D P. The nuclear corepressors NCoR and SMRT are key regulators of both ligand- and 8-bromo-cyclic AMP-dependent transcriptional activity of the human progesterone receptor.  Mol Cell Biol. 1998;  18 1369-1378
  • 32 Mak I YH, Brosens J J, Christian M et al.. Regulated expression of signal transducer and activator of transcription, Stat5, and its enhancement of PRL expression in human endometrial stromal cells in vitro .  J Clin Endocrinol Metab. 2002;  87 2581-2588
  • 33 Krikun G, Schatz F, Mackman N, Guller S, Demopoulos R, Lockwood C J. Regulation of tissue factor gene expression in human endometrium by transcription factors Sp1 and Sp3.  Mol Endocrinol. 2000;  14 393-400
  • 34 Owen G I, Richer J K, Tung L, Takimoto G, Horwitz K B. Progesterone regulates transcription of the p21 WAF1 cyclin- dependent kinase inhibitor gene through Sp1 and CBP/p300.  J Biol Chem. 1998;  273 10696-10701
  • 35 Liu T, Ogle T F. Signal transducer and activator of transcription 3 is expressed in the decidualized mesometrium of pregnancy and associates with the progesterone receptor through protein-protein interactions.  Biol Reprod. 2002;  67 114-118
  • 36 Johnson E S. Protein modification by SUMO.  Annu Rev Biochem. 2004;  73 355-382
  • 37 Bossis G, Melchior F. SUMO: regulating the regulator.  Cell Div. 2006;  1 13
  • 38 Abdel-Hafiz H, Takimoto G S, Tung L, Horwitz K B. The inhibitory function in human progesterone receptor N termini binds SUMO-1 protein to regulate autoinhibition and transrepression.  J Biol Chem. 2002;  277 33950-33956
  • 39 Jones M C, Fusi L, Higham J H et al.. Regulation of the SUMO pathway sensitizes differentiating human endometrial stromal cells to progesterone.  Proc Natl Acad Sci USA. 2006;  103 16272-16277
  • 40 Kliman H J. Uteroplacental blood flow. The story of decidualization, menstruation, and trophoblast invasion.  Am J Pathol. 2000;  157 1759-1768
  • 41 Fazleabas A T, Kim J J, Strakova Z. Implantation: embryonic signals and the modulation of the uterine environment-a review.  Placenta. 2004;  25(suppl A)18 S26-S31
  • 42 Red-Horse K, Zhou Y, Genbacev O et al.. Trophoblast differentiation during embryo implantation and formation of the maternal-fetal interface.  J Clin Invest. 2004;  114 744-754
  • 43 Murphy V E, Smith R, Giles W B, Clifton V L. Endocrine regulation of human fetal growth: the role of the mother, placenta, and fetus.  Endocr Rev. 2006;  27 141-169
  • 44 Shih I eM, Kurman R J. Molecular basis of gestational trophoblastic diseases.  Curr Mol Med. 2002;  2 1-12
  • 45 Burton G J, Jauniaux E. Placental oxidative stress: from miscarriage to preeclampsia.  J Soc Gynecol Investig. 2004;  11 342-352
  • 46 Ferretti C, Bruni L, Dangles-Marie V, Pecking A P, Bellet D. Molecular circuits shared by placental and cancer cells, and their implications in the proliferative, invasive and migratory capacities of trophoblasts.  Hum Reprod Update. 2007;  13 121-141
  • 47 Cohen M, Meisser A, Bischof P. Metalloproteinases and human placental invasiveness.  Placenta. 2006;  27 783-793
  • 48 Frank H G, Kaufmann P. Nonvillous parts and trophoblast invasion. In: Bernischke K, Kaufmann P Pathology of the Human Placenta. New York; Springer Verlag 2000: 171-272
  • 49 Salamonsen L A. Role of proteases in implantation.  Rev Reprod. 1999;  4 11-22
  • 50 Popovici R M, Betzler N K, Krause M S et al.. Gene expression profiling of human endometrial-trophoblast interaction in a coculture model.  Endocrinology. 2006;  147 5662-5675
  • 51 Minas V, Loutradis D, Makrigiannakis A. Factors controlling blastocyst implantation.  Reprod Biomed Online. 2005;  10 205-216
  • 52 Xu G, Guimond M J, Chakraborty C, Lala P K. Control of proliferation, migration, and invasiveness of human extravillous trophoblast by decorin, a decidual product.  Biol Reprod. 2002;  67 681-689
  • 53 Reed C C, Waterhouse A, Kirby S et al.. Decorin prevents metastatic spreading of breast cancer.  Oncogene. 2005;  24 1104-1110
  • 54 Seidler D G, Goldoni S, Agnew C et al.. Decorin protein core inhibits in vivo cancer growth and metabolism by hindering EGF receptor function and triggering apoptosis via caspase-3 activation.  J Biol Chem. 2006;  281 26408-26418
  • 55 Zhu J X, Goldoni S, Bix G et al.. Decorin evokes protracted internalization and degradation of the epidermal growth factor receptor via caveolar endocytosis.  J Biol Chem. 2005;  280 32468-32479
  • 56 Leach R E, Kilburn B, Wang J, Liu Z, Romero R, Armant D R. Heparin-binding EGF-like growth factor regulates human extravillous cytotrophoblast development during conversion to the invasive phenotype.  Dev Biol. 2004;  266 223-237
  • 57 Burrows T D, King A, Loke Y W. Trophoblast migration during human placental implantation.  Hum Reprod Update. 1996;  2 307-321
  • 58 Floridon C, Nielsen O, Hølund B et al.. Localization and significance of urokinase plasminogen activator and its receptor in placental tissue from intrauterine, ectopic and molar pregnancies.  Placenta. 1999;  20 711-721
  • 59 Gellersen B, Briese J, Oberndörfer M et al.. Expression of the metastasis suppressor KAI1 in decidual cells at the human maternal-fetal interface: Regulation and functional implications.  Am J Pathol. 2007;  170 126-139
  • 60 Odintsova E, Sugiura T, Berditchevski F. Attenuation of EGF receptor signaling by a metastasis suppressor, the tetraspanin CD82/KAI-1.  Curr Biol. 2000;  10 1009-1012
  • 61 Odintsova E, Voortman J, Gilbert E, Berditchevski F. Tetraspanin CD82 regulates compartmentalisation and ligand-induced dimerization of EGFR.  J Cell Sci. 2003;  116 4557-4566
  • 62 Kauffman E C, Robinson V L, Stadler W M, Sokoloff M H, Rinker-Schaeffer C W. Metastasis suppression: the evolving role of metastasis suppressor genes for regulating cancer cell growth at the secondary site.  J Urol. 2003;  169 1122-1133
  • 63 Burton G J, Jauniaux E, Watson A L. Maternal arterial connections to the placental intervillous space during the first trimester of human pregnancy: the Boyd collection revisited.  Am J Obstet Gynecol. 1999;  181 718-724
  • 64 Jauniaux E, Poston L, Burton G J. Placental-related diseases of pregnancy: Involvement of oxidative stress and implications in human evolution.  Hum Reprod Update. 2006;  12 747-755
  • 65 Jauniaux E, Watson A L, Hempstock J, Bao Y P, Skepper J N, Burton G J. Onset of maternal arterial blood flow and placental oxidative stress. A possible factor in human early pregnancy failure.  Am J Pathol. 2000;  157 2111-2122
  • 66 Storz G, Imlay J A. Oxidative stress.  Curr Opin Microbiol. 1999;  2 188-194
  • 67 Thannickal V J, Fanburg B L. Reactive oxygen species in cell signaling.  Am J Physiol Lung Cell Mol Physiol. 2000;  279 L1005-L1028
  • 68 Barnouin K, Dubuisson M L, Child E S et al.. H2O2 induces a transient multi-phase cell cycle arrest in mouse fibroblasts through modulating cyclin D and p21 Cip1 expression.  J Biol Chem. 2002;  277 13761-13770
  • 69 Tran H, Brunet A, Grenier J M et al.. DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein.  Science. 2002;  296 530-534
  • 70 Myatt L, Cui X. Oxidative stress in the placenta.  Histochem Cell Biol. 2004;  122 369-382
  • 71 Maruyama T, Kitaoka Y, Sachi Y et al.. Thioredoxin expression in the human endometrium during the menstrual cycle.  Mol Hum Reprod. 1997;  3 989-993
  • 72 Maruyama T, Sachi Y, Furuke K et al.. Induction of thioredoxin, a redox-active protein, by ovarian steroid hormones during growth and differentiation of endometrial stromal cells in vitro.  Endocrinology. 1999;  140 365-372
  • 73 Talbi S, Hamilton A E, Vo K C et al.. Molecular phenotyping of human endometrium distinguishes menstrual cycle phases and underlying biological processes in normo-ovulatory women.  Endocrinology. 2006;  147 1097-1121
  • 74 Borthwick J M, Charnock-Jones D S, Tom B D et al.. Determination of the transcript profile of human endometrium.  Mol Hum Reprod. 2003;  9 19-33
  • 75 Riesewijk A, Martin J, van Os R et al.. Gene expression profiling of human endometrial receptivity on days LH + 2 versus LH + 7 by microarray technology.  Mol Hum Reprod. 2003;  9 253-264
  • 76 Thyss R, Virolle V, Imbert V, Peyron J F, Aberdam D, Virolle T. NF-κB/Egr-1/Gadd45 are sequentially activated upon UVB irradiation to mediate epidermal cell death.  EMBO J. 2005;  24 128-137
  • 77 Zerbini L F, Libermann T A. Life and death in cancer. GADD45α and γ are critical regulators of NF-κB mediated escape from programmed cell death.  Cell Cycle. 2005;  4 18-20
  • 78 Koopman L A, Kopcow H D, Rybalov B et al.. Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential.  J Exp Med. 2003;  198 1201-1212
  • 79 Kudo Y, Boyd C A, Spyropoulou I et al.. Indoleamine 2,3-dioxygenase: distribution and function in the developing human placenta.  J Reprod Immunol. 2004;  61 87-98
  • 80 Kudo Y, Hara T, Katsuki T et al.. Mechanisms regulating the expression of indoleamine 2,3-dioxygenase during decidualization of human endometrium.  Hum Reprod. 2004;  19 1222-1230
  • 81 Lee G K, Park H J, Macleod M, Chandler P, Munn D H, Mellor A L. Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division.  Immunology. 2002;  107 452-460
  • 82 Mellor A L, Chandler P, Lee G K et al.. Indoleamine 2,3-dioxygenase, immunosuppression and pregnancy.  J Reprod Immunol. 2002;  57 143-150
  • 83 Munn D H, Shafizadeh E, Attwood J T, Bondarev I, Pashine A, Mellor A L. Inhibition of T cell proliferation by macrophage tryptophan catabolism.  J Exp Med. 1999;  189 1363-1372
  • 84 Munn D H, Zhou M, Attwood J T et al.. Prevention of allogeneic fetal rejection by tryptophan catabolism.  Science. 1998;  281 1191-1193
  • 85 Lamkanfi M, Festjens N, Declercq W, Vanden Berghe T, Vandenabeele P. Caspases in cell survival, proliferation and differentiation.  Cell Death Differ. 2007;  14 44-55
  • 86 Hess A P, Hamilton A E, Talbi S et al.. Decidual stromal cell response to paracrine signals from the trophoblast: amplification of immune and angiogenic modulators.  Biol Reprod. 2007;  76 102-117
  • 87 Brosens J J, Fusi L, Pijnenborg R, Brosens I A. Reproductive disorders and pregnancy outcome. In: Critchley H, Cameron I, Smith S Implantation and Early Development. London; RCOG Press 2005: 240-251
  • 88 Francis J, Rai R, Sebire N J et al.. Impaired expression of endometrial differentiation markers and complement regulatory proteins in patients with recurrent pregnancy loss associated with antiphospholipid syndrome.  Mol Hum Reprod. 2006;  12 435-442
  • 89 Girardi G, Berman J, Redecha P et al.. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome.  J Clin Invest. 2003;  112 1644-1654
  • 90 Girardi G, Bulla R, Salmon J E, Tedesco F. The complement system in the pathophysiology of pregnancy.  Mol Immunol. 2006;  43 68-77
  • 91 Brosens I A, De Sutter P, Hamerlynck T et al.. Endometriosis is associated with a decreased risk of pre-eclampsia.  Hum Reprod. 2007;  22 1725-1729
  • 92 Kim J J, Taylor H S, Lu Z et al.. Altered expression of HOXA10 in endometriosis: potential role in decidualization.  Mol Hum Reprod. 2007;  13 323-332
  • 93 Li X F, Charnock-Jones D S, Zhang E et al.. Angiogenic growth factor messenger ribonucleic acids in uterine natural killer cells.  J Clin Endocrinol Metab. 2001;  86 1823-1834
  • 94 Taylor R N, Lebovic D I, Mueller M D. Angiogenic factors in endometriosis.  Ann N Y Acad Sci. 2002;  955 89-100 (discussion 118, 396-406)

Jan BrosensM.D. Ph.D. 

Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital

London W12 ONN, United Kingdom

Email: j.brosens@ic.ac.uk

    >