Talk:Implantation

2010

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. PMID: 20729537

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.

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.

2009

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

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.

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

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