Talk:Implantation
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Cite this page: Hill, M.A. (2024, April 25) Embryology Implantation. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Talk:Implantation |
2011
A balancing act: mechanisms by which the fetus avoids rejection by the maternal immune system
Reproduction. 2011 Jun;141(6):715-24. Epub 2011 Mar 9.
Warning JC, McCracken SA, Morris JM. Source Department of Perinatal Research, Kolling Institute of Medical Research, University of Sydney at Royal North Shore Hospital, Sydney, New South Wales 2065, Australia.
Abstract Successful pregnancy requires strict temporal regulation of maternal immune function to accommodate the growing fetus. Early implantation is facilitated by inflammatory processes that ensure adequate vascular remodeling and placental invasion. To prevent rejection of the fetus, this inflammation must be curtailed; reproductive immunologists are discovering that this process is orchestrated by the fetal unit and, in particular, the extravillous trophoblast. Soluble and particulate factors produced by the trophoblast regulate maternal immune cells within the decidua, as well as in the periphery. The aim of this review is to discuss the action of recently discovered immunomodulatory factors and mechanisms, and the potential effects of dysregulation of such mechanisms on the maternal immune response that may result in pregnancy loss or preeclampsia.
PMID 21389077
Hormonal induction of endometrial receptivity
Fertil Steril. 2011 Sep;96(3):530-5.
Paulson RJ. Source Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA. RPaulson@USC.edu
Abstract
OBJECTIVE: To review and synthesize information from the scientific literature pertaining to the hormonal induction of endometrial receptivity before ET. DESIGN: Critical review of selected scientific literature, synthesis and formulation of opinion. SETTING: Not applicable. PATIENT(S): Prospective recipients of oocyte donation or candidates for frozen embryo transfer. INTERVENTION(S): Hormonal treatment for the purpose of induction of endometrial receptivity. MAIN OUTCOME MEASURE(S): Successful induction of endometrial receptivity, as substantiated by live birth rates, pregnancy rates, implantation rates or by measuring putative markers of endometrial receptivity. RESULT(S): The practice of assisted reproductive technology, particularly third-party parenting, in which the source of oocytes is separated from the endometrium, has allowed a separate assessment of embryo and endometrial development. Endometrial receptivity can be induced by exogenously administered E(2) and P in a variety of regimens. The degree of synchrony between embryo and endometrium influences the probability of embryo implantation and may be controlled by initiating P stimulation at different times relative to the stage of embryo development. Many substances have been investigated as adjuncts to E(2) and P in the induction of endometrial receptivity, but at the present time, their value is unproven. CONCLUSION(S): Estrogen and P are the only hormones necessary to prepare the endometrium for implantation. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
PMID 21880274
Human Fallopian tube epithelium constitutively expresses integrin endometrial receptivity markers: no evidence for a tubal implantation window
Mol Hum Reprod. 2011 Oct 16. [Epub ahead of print]
Brown JK, Shaw JL, Critchley HO, Horne AW. Source MRC Centre for Reproductive Health, The University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
Abstract
Understanding of ectopic implantation within Fallopian tube (FT) is limited. In the human uterus, the putative 'window of implantation' in the mid-luteal phase of the menstrual cycle is accompanied by increased endometrial epithelial expression of the integrins α(1)β(1), α(4)β(1), and α(v)β(3) and its ligand osteopontin. Similar cyclical changes in FT integrin expression have been proposed to contribute to ectopic implantation, but supporting data are limited. In the current study, we present quantitative data on human Fallopian tube transcription and translation of the integrin subunits α(1), α(4), α(V), β(1) and β(3) during the follicular and mid-luteal phases of the menstrual cycle, together with a supporting immuocytochemical analysis of their spatial distribution within the Fallopian tube, and that of osteopontin. In contrast to previous studies, our data indicate that all five integrin receptivity markers are constitutively transcribed and translated in the Fallopian tube, with no evidence for changes in their expression or distribution during the window of implantation in the mid-luteal phase of the cycle. Furthermore, we could find no evidence for cyclic redistribution of the integrin α(v)β(3) ligand osteopontin within the Fallopian tube. Although we do not rule out the involvement of integrin endometrial receptivity markers in the establishment of ectopic pregnancy, our findings do not support their differential expression during a tubal implantation window.
PMID 22002573
Prokineticin 1 induces Dickkopf 1 expression and regulates cell proliferation and decidualization in the human endometrium
Mol Hum Reprod. 2011 Oct;17(10):626-36. doi: 10.1093/molehr/gar031. Epub 2011 May 5.
Macdonald LJ, Sales KJ, Grant V, Brown P, Jabbour HN, Catalano RD. Source MRC Human Reproductive Sciences Unit, The Queen's Medical Research Institute, Edinburgh, UK.
Abstract
Prokineticin 1 (PROK1) signalling via prokineticin receptor 1 (PROKR1) regulates the expression of several genes with important roles in endometrial receptivity and implantation. This study investigated PROK1 regulation of Dickkopf 1 (DKK1) expression, a negative regulator of canonical Wnt signalling, and its function in the non-pregnant endometrium and first trimester decidua. DKK1 mRNA expression is elevated during the mid-secretory phase of the menstrual cycle and expression increases further in first trimester decidua. DKK1 protein expression is localized to glandular epithelial and stromal cells during the proliferative, early- and mid-secretory phases, whereas expression is confined to the stroma in the late-secretory phase and first trimester decidua. PROK1 induces the expression of DKK1 in endometrial epithelial cells stably expressing PROKR1 and in first trimester decidua explants, via a Gq-calcium-calcineurin-nuclear factor of activated T-cells-mediated pathway. Endometrial epithelial cell proliferation is negatively regulated by PROK1-PROKR1 signalling. We demonstrate that this effect on cell proliferation occurs via DKK1 expression, as siRNA targeted against DKK1 reduces the PROK1-induced decrease in proliferation. Furthermore, decidualization of primary human endometrial stromal cells with progesterone and cyclic adenosine monophosphate is inhibited by miRNA knock down of PROK1 or DKK1. These data demonstrate important roles for PROK1 and DKK1 during endometrial receptivity and early pregnancy, which include regulation of endometrial cell proliferation and decidualization.
PMID 21546446
2010
Early stages of implantation as revealed by an in vitro model
Reproduction. 2010 May;139(5):905-14. Epub 2010 Feb 23.
Singh H, Nardo L, Kimber SJ, Aplin JD. Source Maternal and Fetal Health Research, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, M13 9WL, UK.
Abstract
Our limited understanding of the processes underlying steroid hormonal control of human endometrial receptivity is largely due to the lack of a relevant model system. To overcome scarcity of material, we have developed a model in which mouse embryos attach to human Ishikawa cells, which express functional steroid hormone receptors. Blastocysts flushed from day 4 pregnant superovulated mice were transferred to confluent Ishikawa cell monolayers. After 48 h of co-culture, 85% of the blastocysts had attached loosely, but only 40% attached stably to the epithelial cell surface. In contrast, 95% of the embryos attached stably to tissue culture plastic. Thus, weak attachment of a majority of the embryos was followed by stronger adhesion of a smaller proportion. Seventeen percent of the transferred blastocysts modified the epithelial cell surface with loss of MUC1 at the attachment site, extending variably to adjacent epithelial cells. Initially, stable attachment occurred without disruption to the integrity of the epithelial monolayer, but at later stages after the embryo had spread laterally, displacement of subjacent cells was observed. A modest increase in stable attachment, but no changes to MUC1 clearance, was observed after assisted hatching. After 24 h priming of Ishikawa cells by 17beta-oestradiol (OE(2)) followed by 72-h incubation with medroxyprogesterone acetate and OE(2), stable attachment increased from 40 to 70%. Initial attachment is efficient either in the presence or in the absence of hormone; steroid treatment increased the incidence of stable attachment. Implantation failure is predicted to occur in this model when embryos fail to progress from initial to stable attachment.
PMID: 20179188 http://www.ncbi.nlm.nih.gov/pubmed/20179188
Local regulation of implantation at the human fetal-maternal interface
Int J Dev Biol. 2010;54(2-3):313-22. Dimitriadis E, Nie G, Hannan NJ, Paiva P, Salamonsen LA.
Prince Henrys Institute of Medical Research, Clayton, Victoria, Australia.
Abstract Embryo implantation and formation of a functional placenta are complex processes that require a plethora of regulatory molecules. In recent years, many of these mediators have been identified, often from studies in experimental animals. Furthermore, their expression patterns at the embryo-maternal interface in women have been characterized and provide clues to their potential actions. What has been missing in most cases is any experimental demonstration of their function. Proteases, cytokines and chemokines are among the molecules identified at the embryo-maternal interface. Functional studies of the protease, proprotein convertase (PC)6, the gp130 cytokines, leukemia inhibitory factor (LIF) and interleukin (IL)11 and the chemokines, CX3CL1 and CCL14 demonstrate potential actions within the uterine cavity. These actions include: enhancing blastocyst development, modifying adhesive properties of the blastocyst and the uterine epithelial surface, and providing chemotactic guidance to the blastocyst. As implantation proceeds, PC6 and IL-11 also act to drive decidualization. The products (proteases, chemokines and cytokines) produced by these decidual cells provide a unique environment. This is important for both directing and restraining trophoblast invasion and for leukocyte trafficking into the decidua until the placenta is fully established.
PMID: 19757390 http://www.ncbi.nlm.nih.gov/pubmed/19757390
Lymphatics in the human endometrium disappear during decidualization
Volchek M, Girling JE, Lash GE, Cann L, Kumar B, Robson SC, Bulmer JN, Rogers PA. Hum Reprod. 2010 Oct;25(10):2455-64. Epub 2010 Aug 21.
BACKGROUND: The mammalian placenta plays a central role in maternal tolerance of the semi-allogeneic fetus and fluid balance between the maternal and fetal compartments. The lymphatics play a role in both these function. The aim of this study was to describe the distribution of lymphatic vessels in human decidua, with particular focus on the lymphatics that surround remodelling spiral arteries during decidualization and trophoblast invasion.
METHODS: Placental bed and non-placental bed (decidua parietalis) biopsies were obtained from 41 women undergoing elective termination of pregnancy at 6-18 weeks gestational age as well as placental bed biopsies from 5 women undergoing elective Caesarean section at term. In addition to routine haematoxylin and eosin staining, double immunohistochemical labelling was performed on serial 3-µm sections to identify lymphatic vessels in conjunction with one of the following: blood vessels, smooth muscle, epithelial and trophoblast cells or proliferating cells. Representative photomicrographs of all sections were obtained from a total of 273 areas (46 samples, average 6 range 3-15 areas per sample). Descriptive findings of the organization of lymphatics in human placental bed and decidua parietalis were made from a total of 1638 images.
RESULTS: Lymphatic vessels positive for podoplanin were abundant in non-decidualized hypersecretory endometrium at all stages of gestation. By contrast, the decidua was nearly always devoid of lymphatics. In some samples, structures that appeared to be regressing lymphatics could be observed at the boundary between non-decidualized hypersecretory and decidualized endometrium. Lymphatic vessels were notably absent from the vicinity of spiral arteries that were surrounded by decidualized stromal cells. Lymphatic vessels in non-decidualized hypersecretory endometrium appeared larger and more elongated as gestation progressed. Proliferating lymphatic vascular endothelial cells were identified in both large vessels, and in streaks of D2-40 positive cells that could have been newly forming lymphatic vessels. Placental bed lymphatics exhibited limited and variable staining with LYVE-1 at all stages of pregnancy apart from term.
CONCLUSIONS: We have made novel observations on lymphatics in the placental bed and their relationship with other structures throughout pregnancy. Endometrial stromal cell decidualization results in a loss of lymphatics, with this phenomenon being particularly apparent around the spiral arteries.
PMID: 20729537
The transcription factor C/EBPbeta is a marker of uterine receptivity and expressed at the implantation site in the primate
Reprod Sci. 2010 May;17(5):434-43. Epub 2010 Mar 11.
Kannan A, Fazleabas AT, Bagchi IC, Bagchi MK.
Department of Vet. Biosciences University of Illinois at Chicago, Chicago, IL, USA. Abstract During early pregnancy, the endometrium undergoes pronounced hormone-dependent functional changes in preparation for embryo implantation. Local autocrine-paracrine signaling at the fetal-maternal interface is crucial for the establishment of pregnancy. We previously reported that the transcription factor C/ EBPbeta, which is expressed at the implantation sites (ISs) in pregnant mice, acts as a key mediator of steroid hormone responsiveness in the endometrium. Mice lacking C/EBPbeta fail to support implantation due to defects in epithelial proliferation and stromal cell differentiation. In the current study, C/EBPbeta expression was dramatically stimulated in the endometrium of baboons (Papio anubis) during the window of uterine receptivity in response to a local infusion of chorionic gonadotropin, an embryonic signal. A robust induction of C/EBPbeta expression was also seen at the IS in the baboon and the human. Collectively, our results indicate that C/EBPbeta is a biomarker of endometrial receptivity and plays a conserved functional role during implantation in the primate.
PMID: 20224108
Immune regulation of conception and embryo implantation-all about quality control?
J Reprod Immunol. 2010 May;85(1):51-7. Epub 2010 Mar 27.
Robertson SA.
Research Centre for Reproductive Health, Discipline of Obstetrics and Gynaecology, University of Adelaide, Adelaide, SA 5005 Australia. sarah.robertson@adelaide.edu.au Abstract Medawar's hypotheses for explaining maternal immune tolerance of the semi-allogeneic fetus are now proven incorrect or insufficient. The mother's immune response is not passive, suppressed, indolent or physically constrained in pregnancy. Instead, her immune system is centrally engaged with all steps of the reproductive process from conception to embryo implantation and placental development. Emerging studies show that immune cells are positioned and equipped to sense antigens and other signals originating in seminal fluid, the embryo and placental trophoblast. The immune response appears competent to utilise this information to discriminate the reproductive fitness and compatibility of the male partner and the integrity and developmental competence of the conceptus tissue. Since the immune response is modulated by the individual's infectious, inflammatory, stress, nutritional and metabolic status, immune influence on progression or disruption of pregnancy may be further influenced by environmental stressors and resource availability. This opinion paper advances the view that the immune system operates in pregnancy to integrate these signals and to exert executive quality control to either accommodate or reject the conceptus. It is argued that 'immune-mediated quality control' would facilitate optimal female reproductive investment and maximise offspring fitness, and thereby explain the evolutionary advantage of maternal immune awareness of the conceptus tissue.
Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved. PMID: 20347158
Regional development of uterine decidualization: molecular signaling by Hoxa-10
Mol Reprod Dev. 2010 May;77(5):387-96.
Das SK.
Reproductive Sciences, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA. sanjoy.das@cchmc.org Abstract Uterine decidualization, a key event in implantation, is critically controlled by stromal cell proliferation and differentiation. Although the molecular mechanism that controls this event is not well understood, the general consensus is that the factors derived locally at the site of implantation influence aspects of decidualization. Hoxa-10, a developmentally regulated homeobox transcription factor, is highly expressed in decidualizing stromal cells, and targeted deletion of Hoxa-10 in mice shows severe decidualization defects, primarily due to the reduced stromal cell responsiveness to progesterone (P(4)). While the increased stromal cell proliferation is considered to be an initiator of decidualization, the establishment of a full-grown functional decidua appears to depend on the aspects of regional proliferation and differentiation. In this regard, this article provides an overview of potential signaling mechanisms mediated by Hoxa-10 that can influence a host of genes and cell functions necessary for propagating regional decidual development.
PMID: 19921737
Natural selection of human embryos: impaired decidualization of endometrium disables embryo-maternal interactions and causes recurrent pregnancy loss
PLoS One. 2010 Apr 21;5(4):e10287.
Salker M, Teklenburg G, Molokhia M, Lavery S, Trew G, Aojanepong T, Mardon HJ, Lokugamage AU, Rai R, Landles C, Roelen BA, Quenby S, Kuijk EW, Kavelaars A, Heijnen CJ, Regan L, Macklon NS, Brosens JJ.
Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital, London, United Kingdom. Abstract BACKGROUND: Recurrent pregnancy loss (RPL), defined as 3 or more consecutive miscarriages, is widely attributed either to repeated chromosomal instability in the conceptus or to uterine factors that are poorly defined. We tested the hypothesis that abnormal cyclic differentiation of endometrial stromal cells (ESCs) into specialized decidual cells predisposes to RPL, based on the observation that this process may not only be indispensable for placenta formation in pregnancy but also for embryo recognition and selection at time of implantation.
METHODOLOGY/PRINCIPAL FINDINGS: Analysis of mid-secretory endometrial biopsies demonstrated that RPL is associated with decreased expression of the decidual marker prolactin (PRL) but increased levels of prokineticin-1 (PROK1), a cytokine that promotes implantation. These in vivo findings were entirely recapitulated when ESCs were purified from patients with and without a history of RPL and decidualized in culture. In addition to attenuated PRL production and prolonged and enhanced PROK1 expression, RPL was further associated with a complete dysregulation of both markers upon treatment of ESC cultures with human chorionic gonadotropin, a glycoprotein hormone abundantly expressed by the implanting embryo. We postulated that impaired embryo recognition and selection would clinically be associated with increased fecundity, defined by short time-to-pregnancy (TTP) intervals. Woman-based analysis of the mean and mode TTP in a cohort of 560 RPL patients showed that 40% can be considered "superfertile", defined by a mean TTP of 3 months or less.
CONCLUSIONS: Impaired cyclic decidualization of the endometrium facilitates implantation yet predisposes to subsequent pregnancy failure by disabling natural embryo selection and by disrupting the maternal responses to embryonic signals. These findings suggest a novel pathological pathway that unifies maternal and embryonic causes of RPL.
PMID: 20422017
Temporal and spatial expression of muc1 during implantation in sows
Int J Mol Sci. 2010 May 27;11(6):2322-35.
Ren Q, Guan S, Fu J, Wang A.
College of Animal Science and Technology, China Agricultural University, Beijing 100193, China; E-Mails: qianer0101@gmail.com (Q.R.); guanshu8@gmail.com (S.G.). Abstract Recent evidence points to an important role for Muc1 in embryo implantation. In this study, Real-time PCR and immunohistochemistry were used to study mRNA and protein levels at, and between, the attachment sites of the endometrium of Day 13, 18 and 24 pregnant sows. The results indicate that Muc1 mRNA expression was higher between attachment sites than at attachment sites during implantation and this effect was significant on Day 13 (P < 0.01) and 24 (P < 0.01). Intense Muc1 immunostaining was observed in luminal epithelium and stroma and the staining between attachment sites was stronger than at attachment sites on Days 13 and 18. Collectively, these results suggest the crucial role of Muc1 in successful implantation and embryo survival.
- Porcine embryos begin to attach to the uterus on Days 13–14 of pregnancy
PMID: 20640155
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904919/?tool=pubmed
Endometrial decidualization: of mice and men
Ramathal CY, Bagchi IC, Taylor RN, Bagchi MK. Semin Reprod Med. 2010 Jan;28(1):17-26. Epub 2010 Jan 26. Review. PMID: 20104425
Endometrial pinopodes indicate a shift in the window of receptivity in IVF cycles
Pinopodes are small, finger-like protrusions from the endometrium.
http://humrep.oxfordjournals.org/content/14/3/787.short
The formation of endometrial pinopodes detected by scanning electron microscopy may be a specific marker for uterine receptivity. Aiming to assess the effects of ovarian stimulation on pinopode formation, we examined sequential endometrial biopsies from 17 oocyte donors. Seven normally menstruating women served as controls. Up to four samples were taken from each woman at 24–72 h intervals between days 14 and 24, giving a total of 69 samples. The day of oocyte retrieval was designated day 14 in ovarian stimulation cycles and the day of luteinizing hormone surge was designated day 13 in natural cycles. Endometrial morphology and pinopode numbers were similar in both groups. Fully developed pinopodes appeared in only one sample per cycle, indicating their short life span. However, the cycle day these structures appeared varied up to 5 days between women and the distribution was as follows: day 18 (n=2), day 19 (n=7), day 20 (n=4), day 21 (n=3), day 22 (n=1) in ovarian stimulation cycles, and day 20 (n=2), day 21 (n=2), day 22 (n=3) in natural cycles. Furthermore, accelerated pinopode formation in ovarian stimulation cycles was positively correlated with day 13 progesterone. Our findings show that ovarian stimulation does not affect endometrial pinopode formation in terms of quantity and life span. The cycle days when pinopodes form are specific to the individual, being on average 1–2 days earlier in ovarian stimulation than in natural cycles. These changes in pinopode expression may reflect shifts in the window of receptivity, resulting in ovo-endometrial asynchrony and limiting implantation success in in-vitro fertilization.
Modulation of the maternal immune system by the pre-implantation embryo
BMC Genomics. 2010 Aug 13;11:474.
Walker CG, Meier S, Littlejohn MD, Lehnert K, Roche JR, Mitchell MD.
DairyNZ Ltd,, Hamilton, New Zealand. Caroline.Walker@dairynz.co.nz Abstract BACKGROUND: A large proportion of pregnancy losses occur during the pre-implantation period, when the developing embryo is elongating rapidly and signalling its presence to the maternal system. The molecular mechanisms that prevent luteolysis and support embryo survival within the maternal environment are not well understood. To gain a more complete picture of these molecular events, genome-wide transcriptional profiles of reproductive day 17 endometrial tissue were determined in pregnant and cyclic Holstein-Friesian dairy cattle.
RESULTS: Microarray analyses revealed 1,839 and 1,189 differentially expressed transcripts between pregnant and cyclic animals (with > or = 1.5 fold change in expression; P-value < 0.05, MTC Benjamini-Hochberg) in caruncular and intercaruncular endometrium respectively. Gene ontology and biological pathway analysis of differentially expressed genes revealed enrichment for genes involved in interferon signalling and modulation of the immune response in pregnant animals.
CONCLUSION: The maternal immune system actively surveys the uterine environment during early pregnancy. The embryo modulates this response inducing the expression of endometrial molecules that suppress the immune response and promote maternal tolerance to the embryo. During this period of local immune suppression, genes of the innate immune response (in particular, antimicrobial genes) may function to protect the uterus against infection.
PMID: 20707927
2009
Secreted phosphoprotein 1 (SPP1, osteopontin) binds to integrin alpha v beta 6 on porcine trophectoderm cells and integrin alpha v beta 3 on uterine luminal epithelial cells, and promotes trophectoderm cell adhesion and migration
Biol Reprod. 2009 Nov;81(5):814-25. Epub 2009 Jul 1.
Erikson DW, Burghardt RC, Bayless KJ, Johnson GA.
Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas 77843, USA. Abstract Conceptus implantation involves pregnancy-specific alterations in extracellular matrix at the conceptus-maternal interface. Secreted phosphoprotein 1 (SPP1, osteopontin) is induced just before implantation and is present at the conceptus-maternal interface in mammals. In the present study, we investigated mechanisms by which SPP1 facilitates porcine conceptus and uterine luminal epithelial cell attachment. Native bovine milk and wild-type rat recombinant SPP1 stimulated trophectoderm cell migration. Bovine milk SPP1, ovine uterine SPP1, and recombinant wild-type, but not mutated, rat SPP1 promoted dose- and cation-dependent attachment of porcine trophectoderm and uterine luminal epithelial cells, which was markedly reduced in the presence of a linear Arg-Gly-Asp integrin-blocking peptide. Affinity chromatography and immunoprecipitation experiments revealed direct binding of alpha v beta 6 trophectoderm and alpha v beta 3 uterine epithelial cell integrins to SPP1. Immunofluorescence microscopy using SPP1-coated microspheres revealed colocalization of the alpha v integrin subunit and talin at focal adhesions as well as at the apical domain of trophectoderm cells. Similarly, immunofluorescence staining of implantation sites in frozen gravid uterine cross sections localized SPP1 and alpha v integrin to the apical surfaces of trophectoderm and luminal epithelium and beta 3 integrin to the apical surface of luminal epithelium. To our knowledge, the present study is the first to demonstrate functionally that SPP1 directly binds specific integrins to promote trophectoderm cell migration and attachment to luminal epithelium that may be critical to conceptus elongation and implantation.
PMID: 19571258
The expression of receptivity markers in the fallopian tube epithelium
Histochem Cell Biol. 2009 Aug;132(2):159-67. Epub 2009 Apr 23.
Makrigiannakis A, Karamouti M, Petsas G, Makris N, Nikas G, Antsaklis A.
In Vitro Fertilization Unit, Department of Obstetrics and Gynaecology, Medical School, University of Crete, Heraklion, 71003, Greece. makrigia@med.uoc.gr
Abstract Pinopodes represent the morphological and integrins, the biomolecular markers of endometrial receptivity. We studied using scanning electron microscopy, the expression of pinopodes on tubal samples and their corresponding endometria, from 21 women of reproductive age (7 from proliferative phase, 7 from day LH +5 and 7 from day LH +7). In addition, we examined the immunohistochemical staining of integrins alpha v beta 3, alpha v beta 5 and their ligands, fibronectin (FN) and osteopontin (OPN) in the same tubal epithelium samples. Pinopodes were detected on the tubal epithelium exclusively during day LH +7, coincident with their formation in the endometrium and synchronous to alpha v beta 3 sharp increase in the oviduct epithelium, suggesting a regulation similar to the endometrium. In contrast, alpha v beta 5, FN and OPN remained unchanged during the cycle. These results show for the first time the formation of pinopodes in the tubal epithelium at the time of endometrial receptivity and correlate it with the upregulation of the intact dimmer alpha v beta 3 in the tubes.
PMID: 19387680
2008
An integrated view of L-selectin and trophinin function in human embryo implantation
J Obstet Gynaecol Res. 2008 Apr;34(2):129-36.
Fukuda MN, Sugihara K. Source Glycobiology Unit, Tumor Microenvironment Program, NCI Cancer Center, Burnham Institute for Medical Research, La Jolla, California 92037, USA. michiko@burnham.org Abstract Determining molecular mechanisms of human embryo implantation is an extremely challenging task due to the limitation of materials and significant differences underlying this process among mammalian species. Recently, L-selectin and its ligand carbohydrate have been proposed as a system that mediates initial adhesion of human blastocysts to the uterine epithelia. We have also identified trophinin as a unique apical cell adhesion molecule potentially involved in the initial adhesion of trophectoderm of the human blastocyst to endometrial surface epithelia. In the mouse, the binding between ErbB4 on the blastocyst and heparin-binding epidermal growth factor-like growth factor on the endometrial surface enables the initial step of the blastocyst implantation. The evidence suggests that L-selectin and trophinin are included in human embryo implantation. This review summarizes findings relevant to the functions of L-selectin and trophinin in human embryo implantation, and proposes a model that reconciles these cell adhesion mechanisms.
PMID: 18412772 http://www.ncbi.nlm.nih.gov/pubmed/18412772
Time of implantation of the conceptus and loss of pregnancy
N Engl J Med. 1999 Jun 10;340(23):1796-9.
Wilcox AJ, Baird DD, Weinberg CR.
Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA. Abstract BACKGROUND: Implantation of the conceptus is a key step in pregnancy, but little is known about the time of implantation or the relation between the time of implantation and the outcome of pregnancy.
METHODS: We collected daily urine samples for up to six months from 221 women attempting to conceive after ceasing to use contraception. Ovulation was identified on the basis of the ratio of urinary estrogen metabolites to progesterone metabolites, which changes rapidly with luteinization of the ovarian follicle. The time of implantation was defined by the appearance of chorionic gonadotropin in maternal urine.
RESULTS: There were 199 conceptions, for 95 percent of which (189) we had sufficient data for analysis. Of these 189 pregnancies, 141 (75 percent) lasted at least six weeks past the last menstrual period, and the remaining 48 pregnancies (25 percent) ended in early loss. Among the pregnancies that lasted six weeks or more, the first appearance of chorionic gonadotropin occurred 6 to 12 days after ovulation; 118 women (84 percent) had implantation on day 8, 9, or 10. The risk of early pregnancy loss increased with later implantation (P<0.001). Among the 102 conceptuses that implanted by the ninth day, 13 percent ended in early loss. This proportion rose to 26 percent with implantation on day 10, to 52 percent on day 11, and to 82 percent after day 11.
CONCLUSIONS: In most successful human pregnancies, the conceptus implants 8 to 10 days after ovulation. The risk of early pregnancy loss increases with later implantation.
PMID: 10362823
http://www.nejm.org/doi/full/10.1056/NEJM199906103402304
In most successful human pregnancies, the conceptus implants 8 to 10 days after ovulation. The risk of early pregnancy loss increases with later implantation.
Myeloid ecotropic viral integration site 1 (MEIS) 1 involvement in embryonic implantation
The HOXA10 homeobox gene controls embryonic uterine development and adult endometrial receptivity. The three-amino-acid loop extension (TALE) family homeobox genes like myeloid ecotropic viral integration site 1 (MEIS) provide enhanced target gene activation and specificity in HOX-regulated cellular processes by acting as HOX cofactors.
http://www.ncbi.nlm.nih.gov/pubmed/18408019
Scanning EM http://humrep.oxfordjournals.org/content/23/6/1394/F6.expansion
Embryo-induced alterations in the molecular phenotype of primate endometrium
J Reprod Immunol. 2009 Dec;83(1-2):65-71. Epub 2009 Oct 31.
Nimbkar-Joshi S, Rosario G, Katkam RR, Manjramkar DD, Metkari SM, Puri CP, Sachdeva G.
Primate Biology Division, National Institute for Research in Reproductive Health, Mumbai, India.
http://www.ncbi.nlm.nih.gov/pubmed/19880195
endometrial expression of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNFalpha), as well as expression of immunosuppressive factors such as transforming growth factor beta-2 (TGFbeta2), interleukin-6 (IL-6) and placental protein-14 (PP-14), even before the embryo starts invading the endometrium.
Pinopodes: a questionable role in endometrial receptivity
Hum Reprod Update. 2009 Mar-Apr;15(2):229-36.
Quinn CE, Casper RF. Source Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Institute of Medical Sciences, University of Toronto, ON, Canada. Abstract BACKGROUND: A better understanding of endometrial receptivity is crucial to the creation and optimization of tests to assess the window of implantation in a clinical setting. Testing endometrial receptivity via scanning electron microscopy of endometrial samples reveals that pinopodes are a very good marker of endometrial receptivity in the rat. There is still disagreement in the literature as to their usefulness as a receptivity marker in both mice and humans.
METHODS: Publications related to the discovery, study and usefulness of pinopodes as a marker of endometrial preparation for implantation in both rodents and humans were identified through MEDLINE and other bibliographic databases.
RESULTS: There is substantial evidence that pinopodes are good markers of endometrial receptivity in the rat. Pinopodes are not useful in the mouse or human as consistent markers of endometrial receptivity for implantation. In the human, pinopodes have a prolonged (>5 days) presence in the luteal phase and fail to delineate the brief (24-48 h) window of receptivity.
CONCLUSIONS: While there are many publications arising from one group supporting the use of pinopodes as a reliable marker of human endometrial receptivity, few independent groups have been able to confirm these results. The clinical usefulness of pinopodes to delineate a period of endometrial receptivity seems unlikely following recent findings that pinopodes are present throughout the luteal phase of the menstrual cycle.
PMID: 18997181
2001
Expression of Wilms' tumor suppressor gene (WT1) in human endometrium: regulation through decidual differentiation
J Clin Endocrinol Metab. 2001 Dec;86(12):5964-72. Makrigiannakis A, Coukos G, Mantani A, Prokopakis P, Trew G, Margara R, Winston R, White J.
Department of Reproductive Science and Medicine, Imperial College School of Medicine, Hammersmith Hospital, W12 ONN OHS, London, United Kingdom. makrigia@med.uoc.gr Abstract The Wilms' tumor suppressor gene (WT1) encodes a zinc-finger containing transcription factor that is selectively expressed in the developing urogenital tract and functions as a tissue-specific developmental regulator. In addition to its gene-regulatory function through DNA binding properties, WT-1 also regulates transcription by formation of protein-protein complexes. These properties place WT-1 as a major regulator of cell growth and differentiation. In view of these observations, we studied WT1 mRNA and protein in human endometrial extracts and in endometrial stromal cells (ESCs) differentiating into decidual cells in vitro, by RT-PCR and Western blotting, respectively. WT1 protein expression was also studied in situ in the proliferative and the secretory phase of the menstrual cycle in the early pregnant state. Analysis by PCR of total RNA prepared from human ESCs demonstrated the presence of WT1 mRNA and four WT1 mRNA splice variants. Western blot analysis of nuclear protein extracts from ESCs yielded one immunoreactive protein of the expected size (approximately 52-54 kDa) recognized by the WT1 antibody. Immunohistochemical staining showed that WT1 protein is localized only to nuclei of human endometrial stromal cells. It remains constant in the proliferative and the secretory phase of the menstrual cycle and is increased remarkably during decidualization in early pregnancy. ESCs decidualized in vitro were investigated for WT-1 expression, which confirmed that decidualizing stimuli (E2, medroxy-progesterone-acetate, and relaxin for 12 d or cAMP and progesterone for 1-4 d) induced WT-1 mRNA (P < 0.05) and increased protein levels (P < 0.05). These data indicate that in humans the WT1 gene is expressed in ESCs and its mRNA and protein levels remain constant in the proliferative and the secretory phase of the menstrual cycle and that WT1 mRNA and protein expression increases significantly in ESCs when these cells differentiate into decidual cells.
PMID: 11739471
Potential roles of decidual prolactin in early pregnancy
Reproduction. 2001 Feb;121(2):197-205.
Jabbour HN, Critchley HO.
MRC Human Reproductive Sciences Unit and Obstetrics and Gynaecology, Department of Reproductive and Development Sciences, Centre for Reproductive Biology, 37 Chalmers Street, Edinburgh EH3 9ET, UK. h.jabbour@hrsu.mrc.ac.uk Abstract Successful establishment of pregnancy is dependent on uterine receptivity at the time of trophoblast invasion and implantation. The endometrium undergoes morphological and functional differentiation during the mid- to late secretory phase of the menstrual cycle in preparation for such an event. These changes are orchestrated by ovarian steroid hormones. However, local autocrine-paracrine signalling at the deciduo-placental interface is crucial for successful establishment of pregnancy. One key cytokine that may regulate many functions in implantation is prolactin. Prolactin is secreted by the decidualized endometrium at the time of predicted conception and, in the event of pregnancy, local expression and secretion of prolactin persists until term. Prolactin mediates its effect on target cells through interaction with single-pass transmembrane receptors. Localization of the sites of expression of the prolactin receptor indicates that the cytokine may regulate an array of functions in the pregnant uterus that are crucial in im-plantation and early pregnancy.
PMID: 11226044
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