Decidualization resistance in the origin of preeclampsia.

Preeclampsia is a major obstetrical complication with short- and long-term life-threatening consequences for both mother and child. Shallow cytotrophoblast invasion through the uterine decidua into the spiral arteries is implicated in the pathogenesis of preeclampsia, although the cause of deficient arterial invasion remains unknown. Research that is focused on the "soil"-the maternal decidua-highlights the importance of this poorly understood but influential uterine layer. Decidualization of endometrial cells regulates embryo invasion, which is essential for spiral artery remodeling and establishing the maternal-fetal interface. Exploration of the association between impaired decidualization and preeclampsia revealed suboptimal endometrial maturation and uterine natural killer cells present in the decidua before preeclampsia development. Furthermore, decidualization defects in the endometrium of women with severe preeclampsia, characterized by impaired cytotrophoblast invasion, were detected at the time of delivery and persisted 5 years after the affected pregnancy. Recently, a maternal deficiency of annexin A2 expression was found to influence aberrant decidualization and shallow cytotrophoblast invasion, suggesting that decidualization resistance, which is a defective endometrial cell differentiation during the menstrual cycle, could underlie shallow trophoblast invasion and the poor establishment of the maternal-fetal interface. Based on these findings, the transcriptional signature in the endometrium that promotes decidualization deficiency could be detected before (or after) conception. This would serve to identify women at risk of developing severe preeclampsia and aid the development of therapies focused on improving decidualization, perhaps also preventing severe preeclampsia. Here, we discuss decidualization deficiency as a contributor to the pathogenesis of pregnancy disorders with particular attention to severe preeclampsia. We also review current diagnostic strategies and discuss future directions in diagnostic methods based on decidualization.

Assessment of Anti-Mullerian Hormone and Anti-Mullerian Hormone Type II Receptor Variants in Women with Repeated Implantation Failures.

Repeated implantation failure (RIF) is a common endocrine disease that causes female infertility and the etiology is unknown. The abnormal expression of key proteins and hormones at the maternal-fetal interface affected the maternal-fetal communication and leads to adverse pregnancy outcomes. The expression of anti-Mullerian hormone (AMH) and AMH receptor II (AMHRII) was observed in the endometrium. This study aimed to investigate the expression of AMH and AMHRII at the human endometrium, decidual tissue, and blastocyst. Furthermore, the expression of AMH and AMHRII were examined in the RIF patients using immunohistochemistry and quantitative real-time PCR to test the AMHRII expression. The results demonstrated that AMH and AMHRII were present in healthy endometrium and AMHRII was highly expressed in mid-luteal phase. In addition, AMHRII expression was detected throughout the pregnancy and AMHRII's highest expression was in the second trimester. AMHRII was expressed in the blastocysts; however, AMH was not observed. The positive expression rate for AMHRII was significantly higher in the endometrium from RIF. Estrogen receptor (ER), insulin-like growth factor binding protein 1(IGFBP1), and prolactin (PRL) were significantly less expressed in RIF with high expression of AMHRII. The apoptosis was significantly higher in patients with high expression of AMHRII than in patients with normal expression of AMHRII. Our data suggests that AMHRII had an effect on RIF via the AMH and AMHRII signaling pathway. It participated in the development of RIF by interfering with endometrial decidualization and apoptosis.

Tracking placental development in health and disease.

Pre-eclampsia and fetal growth restriction arise from disorders of placental development and have some shared mechanistic features. Initiation is often rooted in the maldevelopment of a maternal-placental blood supply capable of providing for the growth requirements of the fetus in later pregnancy, without exerting undue stress on maternal body systems. Here, we review normal development of a placental bed with a safe and adequate blood supply and a villous placenta-blood interface from which nutrients and oxygen can be extracted for the growing fetus. We consider disease mechanisms that are intrinsic to the maternal environment, the placenta or the interaction between the two. Systemic signalling from the endocrine placenta targets the maternal endothelium and multiple organs to adjust metabolism for an optimal pregnancy and later lactation. This signalling capacity is skewed when placental damage occurs and can deliver a dangerous pathogenic stimulus. We discuss the placental secretome including glycoproteins, microRNAs and extracellular vesicles as potential biomarkers of disease. Angiomodulatory mediators, currently the only effective biomarkers, are discussed alongside non-invasive imaging approaches to the prediction of disease risk. Identifying the signs of impending pathology early enough to intervene and ameliorate disease in later pregnancy remains a complex and challenging objective.

Role of connexins in female reproductive system and endometriosis.

Gap junction form channels between the cells and facilitate the function of cellular cross talk. Connexins, the gap junction proteins play an essential role in female reproductive health and its expression anomalies are correlated with female reproductive disorders like polycystic ovarian syndrome, recurrent miscarriage, pre-term birth and endometriosis. Endometriosis is a chronic gynecologic disorder caused by ectopic endometrial lesions growing outside the uterine cavity. Embryonic implantation is adversely affected in case of endometriosis leading to infertility. Endometriosis also interferes with ovulatory functions, reduces fertilization and impaires blastocyst implantation. There lies a lacunae in understanding of the role of gap junctions protein connexins in endometriosis. Therefore, this study discusses the role of connexins in improving female fertility by taming the processes of oogenesis, germ line development, uterine receptivity, placental growth, implantation, decidualization and concludes by focusing the role of connexins in endometriosis.

Preeclampsia: a defect in decidualization is associated with deficiency of Annexin A2.

BACKGROUND: Decidualization defects in the endometrium have been demonstrated at the time of delivery in women with severe preeclampsia and to linger for years, which suggests a maternal contribution to the pathogenesis of this condition. Global transcriptional profiling reveals alterations in gene expression, which includes down-regulation of Annexin A2 in severe preeclampsia patients with decidualization resistance. OBJECTIVE: We investigated the functional role of Annexin A2 deficiency during endometrial decidualization and its potential contribution to shallow trophoblast invasion during implantation and subsequent placentation using in vitro and in vivo modeling. STUDY DESIGN: Annexin A2 gene and protein levels were assessed during in vitro decidualization of human endometrial stromal cells isolated from biopsy specimens that were collected from women with previous severe preeclampsia (n=5) or normal obstetric outcomes (n=5). Next, Annexin A2 was inhibited with small interference RNA in control human endometrial stromal cells that were isolated from endometrial biopsy specimens (n=15) as an in vitro model to analyze decidualization defects at the morphologic level and the secretion of prolactin and insulin-like growth binding protein-1. Annexin A2-inhibited cells were used to evaluate motility and promotion of embryo invasion. Decidualization and placentation defects of Annexin A2 deficiency were confirmed with the use of an Annexin A2-null mouse model. RESULTS: Annexin A2 gene and protein levels were down-regulated during in vitro decidualization of human endometrial stromal cells from women with previous severe preeclampsia compared with control individuals. To assess its role in the endometrial stroma, we inhibited Annexin A2 expression and detected decidualization failure as evidenced by impaired morphologic transformation, which was associated with altered actin polymerization and low prolactin and insulin-like growth binding protein-1 secretions. Functionally, in vitro models demonstrated that Annexin A2 inhibition failed to support embryo invasion. This finding was corroborated by reduced trophoblast spreading through human endometrial stromal cells, lack of motility of these cells, and reduced trophoblast invasion in the presence of conditioned media from Annexin A2-inhibited cells. Extending our discovery to an animal model, we detected that Annexin A2-null mice have a functional deficiency in decidualization and placentation that impairs fetal growth as a feature that is associated with severe preeclampsia. CONCLUSION: Together, in vitro and in vivo results suggest that endometrial defects in Annexin A2 expression impair decidualization of endometrial stromal cells as well as the uterine microenvironment that promotes embryo implantation and placentation. Our findings highlight the maternal contribution to the pathogenesis of severe preeclampsia and suggest that evaluation of Annexin A2 may provide a novel strategy to assess a woman's risk of experiencing this disease and perhaps discover therapeutic interventions to improve decidualization.

Endometrial Immune Dysfunction in Recurrent Pregnancy Loss.

Recurrent pregnancy loss (RPL) represents an unresolved problem for contemporary gynecology and obstetrics. In fact, it is not only a relevant complication of pregnancy, but is also a significant reproductive disorder affecting around 5% of couples desiring a child. The current knowledge on RPL is largely incomplete, since nearly 50% of RPL cases are still classified as unexplained. Emerging evidence indicates that the endometrium is a key tissue involved in the correct immunologic dialogue between the mother and the conceptus, which is a condition essential for the proper establishment and maintenance of a successful pregnancy. The immunologic events occurring at the maternal-fetal interface within the endometrium in early pregnancy are extremely complex and involve a large array of immune cells and molecules with immunoregulatory properties. A growing body of experimental studies suggests that endometrial immune dysregulation could be responsible for several, if not many, cases of RPL of unknown origin. The present article reviews the major immunologic pathways, cells, and molecular determinants involved in the endometrial dysfunction observed with specific application to RPL.

Elevated insulin levels compromise endometrial decidualization in mice with decrease in uterine apoptosis in early-stage pregnancy.

Women with hyperinsulinism and insulin resistance have reduced fertility, but the underlying mechanism is still poorly understood. Aberrant endometrial decidualization in early pregnancy was linked to pregnancy complications. In this study, we aimed to test whether elevated insulin levels compromise decidualization in early-stage pregnancy. C57BL/6J mice in high insulin-exposed group were given a subcutaneous injection of recombinant insulin at a concentration of 0.05 IU daily. During decidualization in early pregnancy, serum levels of insulin, E2, P4, LH, FSH and blood glucose were significantly altered in mice treated with high insulin levels. The number of embryo implantation sites and endometrial decidual markers BMP2, ER, PR was significantly decreased by high insulin levels in vivo. Artificial decidual induction in primary mouse endometrial stromal cells and immortal human endometrial stromal cells line were all compromised after treated with 100 nmol/L insulin levels. All these results on flow cytometry, transmission electron microscopy and western blotting of Bax, Bcl2, cleaved Caspase3, cleaved PARP proteins level showed that decidual cells apoptosis was significantly decreased. Mitochondrial transmembrane potential also significantly increased by the influence of high insulin levels. PI3K and p-Akt were much higher after insulin exposure and the compromised decidualization by high insulin treatment was rescued by PI3K/Akt inhibitor LY294002 both in vitro and in vivo. In conclusion, we demonstrated that elevated insulin levels could compromise mice decidualization in early-stage pregnancy and PI3K/p-Akt-regulated apoptosis was essential for this role. It provides a clue for future investigation on compromised reproduction in women with hyperinsulinemia.

A functional role for AMPK in female fertility and endometrial regeneration.

Adenosine monophosphate-activated protein kinase (AMPK) is a highly conserved heterotrimeric complex that acts as an intracellular energy sensor. Based on recent observations of AMPK expression in all structures of the female reproductive system, we hypothesized that AMPK is functionally required for maintaining fertility in the female. This hypothesis was tested by conditionally ablating the two catalytic alpha subunits of AMPK, Prkaa1 and Prkaa2, using Pgr-cre mice. After confirming the presence of PRKAA1, PRKAA2 and the active phospho-PRKAA1/2 in the gravid uterus by immunohistochemistry, control (Prkaa1/2 fl/fl ) and double conditional knockout mice (Prkaa1/2 d/d ) were placed into a six-month breeding trial. While the first litter size was comparable between Prkaa1/2 fl/fl and Prkaa1/2 d/d female mice (P = 0.8619), the size of all subsequent litters was dramatically reduced in Prkaa1/2 d/d female mice (P = 0.0015). All Prkaa1/2 d/d female mice experienced premature reproductive senescence or dystocia by the fourth parity. This phenotype manifested despite no difference in estrous cycle length, ovarian histology in young and old nulliparous or multiparous animals, mid-gestation serum progesterone levels or uterine expression of Esr1 or Pgr between Prkaa1/2 fl/fl and Prkaa1/2 d/d female mice suggesting that the hypothalamic-pituitary-ovary axis remained unaffected by PRKAA1/2 deficiency. However, an evaluation of uterine histology from multiparous animals identified extensive endometrial fibrosis and disorganized stromal-glandular architecture indicative of endometritis, a condition that causes subfertility or infertility in most mammals. Interestingly, Prkaa1/2 d/d female mice failed to undergo artificial decidualization. Collectively, these findings suggest that AMPK plays an essential role in endometrial regeneration following parturition and tissue remodeling that accompanies decidualization.

Environmentally relevant levels of bisphenol A affect uterine decidualization and embryo implantation through the estrogen receptor/serum and glucocorticoid-regulated kinase 1/epithelial sodium ion channel α-subunit pathway in a mouse model.

OBJECTIVE: To investigate whether bisphenol A (BPA) exposure is associated with uterine decidualization and embryo implantation failure in mice. DESIGN: Experimental animal study and in vitro study. SETTING: University-based infertility center. ANIMAL(S): ICR mice. INTERVENTION(S): Mice treated with different doses of BPA; Ishikawa cells cultured in medium of different concentrations of BPA. MAIN OUTCOME MEASURE(S): Embryo implantation sites, uterine weight, quantitative real-time reverse transcriptase-polymerase chain reaction, Western blot analysis, hematoxylin and eosin staining, and immunohistochemical, cell proliferation, and statistical analyses. RESULT(S): In the experiment of mouse model, administration of 1-100 µg/kg/day of BPA by gavage led to reduction of the number of embryo implantation sites in a dose-dependent manner; 100 µg/kg/day of BPA statistically significantly reduced the number of implantation sites compared with the control group. The uterine weight change (the wet weight of the decidualized uterine horn divided by the wet weight of the undecidualized uterine horn of the mouse) in groups exposed to BPA (100-10,000 µg/kg/day) were statistically significantly lower compared with the control group. Immunohistochemical analysis demonstrated that administration of 100, 1,000, or 10,000 µg/kg/day of BPA by gavage statistically significantly down-regulated the expression of epithelial Na+ channel α-subunit (ENaCα) in the luminal epithelial cells and desmin in decidual cells of the oil-induced decidualized uterine horns. Administration of 100 µg/kg/day BPA on embryo days 0.5-3.5 by gavage statistically significantly decreased the level of uterine serum and glucocorticoid-regulated kinase 1 (SGK1) protein expression on embryo days 4 and 6. After treatment with 0.001, 0.01, 0.1, or 1.0 µg/mL of BPA for 48 hours, the SGK1, ENaCα, and phospho-SGK1 protein expression of Ishikawa cells was down-regulated, and the effect of BPA on SGK1 could be abrogated by fulvestrant. CONCLUSION(S): Our study provides the first indication that BPA exposure at levels as low as 100 µg/kg/day can impair embryo implantation in mice and BPA can affect decidualization of the uterus in mouse model. Our results suggest that BPA can down-regulate SGK1 and ENaCα protein expression through estrogen receptors in Ishikawa cells.

Physiological and pathological implications of retinoid action in the endometrium.

Retinol (vitamin A) and its derivatives, collectively known as retinoids, are required for maintaining vision, immunity, barrier function, reproduction, embryogenesis and cell proliferation and differentiation. Despite the fact that most events in the endometrium are predominantly regulated by steroid hormones (estrogens and progesterone), accumulating evidence shows that retinoid signaling is also involved in the development and maintenance of the endometrium, stromal decidualization and blastocyst implantation. Moreover, aberrant retinoid metabolism seems to be a critical factor in the development of endometriosis, a common gynecological disease, which affects up to 10% of reproductive age women and is characterized by the ectopic localization of endometrial-like tissue in the pelvic cavity. This review summarizes recent advances in research on the mechanisms and molecular actions of retinoids in normal endometrial development and physiological function. The potential roles of abnormal retinoid signaling in endometriosis are also discussed. The objectives are to identify limitations in current knowledge regarding the molecular actions of retinoids in endometrial biology and to stimulate new investigations toward the development potential therapeutics to ameliorate or prevent endometriosis symptoms.

Literature Review on the Role of Uterine Fibroids in Endometrial Function.

Uterine fibroids are benign uterine smooth muscle tumors that are present in up to 8 out of 10 women by the age of 50. Many of these women experience symptoms such as heavy and irregular menstrual bleeding, early pregnancy loss, and infertility. Traditionally believed to be inert masses, fibroids are now known to influence endometrial function at the molecular level. We present a comprehensive review of published studies on the effect of uterine fibroids on endometrial function. Our goal was to explore the current knowledge about how uterine fibroids interact with the endometrium and how these interactions influence clinical symptoms. Our review shows that submucosal fibroids produce a blunted decidualization response with decreased release of cytokines critical for implantation such as leukocyte inhibitory factor and cell adhesion molecules. Furthermore, fibroids alter the expression of genes relevant for implantation, such as bone morphogenetic protein receptor type II, glycodelin, among others. With regard to heavy menstrual bleeding, fibroids significantly alter the production of vasoconstrictors in the endometrium, leading to increased menstrual blood loss. Fibroids also increase the production of angiogenic factors such as basic fibroblast growth factor and reduce the production of coagulation factors resulting in heavy menses. Understanding the crosstalk between uterine fibroids and the endometrium will provide key insights into implantation and menstrual biology and drive the development of new and innovative therapeutic options for the management of symptoms in women with uterine fibroids.

Dysfunction of WNT4/WNT5A in deciduas: possible relevance to the pathogenesis of preeclampsia.

OBJECTIVES: Preeclampsia affects 5-7% of all human pregnancies worldwide. It is characterized primarily by hypertension and proteinuria. Although the pathogenesis of preeclampsia is still not fully understood, the deficiency in decidualization is considered to have a role in this disease. WNT4 and WNT5A are highly expressed in the deciduas of mice and human beings; their deficiency causes the abnormality of mouse decidualization, and consequently affects the development of the placenta and the fetus. We aimed to define the roles of WNT4 and WNT5A in human decidulization and their relationship with preeclampsia. METHODS: In this study, we investigated the expression of WNT4 and WNT5A in human deciduas and their functions during decidualization, as well as their relationship with preeclampsia. We obtained deciduas from 20 women whose pregnancies were complicated by severe preeclampsia and from 20 women with uncomplicated pregnancies, as well as human endometrial stromal cells (hESCs). The levels of WNT4 and WNT5A were examined by real-time PCR, immunohistochemistry, and western blotting in deciduas. The expression of WNT4 and WNT5A in cultured hESCs was determined during decidualization. Furthermore, the roles of WNT4, WNT5A, and BMP2 on decidualization as well as their interactions were studied in cultured hESCs by interference of their expression with specific small interfering RNA, respectively. RESULTS: WNT4 and WNT5A were present in the decidual tissues of women with preeclampsia and women with uncomplicated pregnancies. Their expression levels of mRNA and protein in women with severe preeclampsia were significantly lower compared with women with uncomplicated pregnancies (P < 0.05). WNT4 and WNT5A were upregulated in decidualized hESCs. Knocking down of BMP2 or WNT4 in hESCs resulted in a significant increase of WNT5A mRNA and a significant reduction in the transcription of decidualization markers, insulin-like growth factor binding protein1 and prolactin (P < 0.05). In addition, silencing of WNT5A resulted in a reduction of the transcription of insulin-like growth factor binding protein1 and prolactin mRNA (P < 0.05). CONCLUSION: Our data suggest that WNT4 and WNT5 are relevant to normal decidualization, and thus trophoblast invasion and implantation. Their deficiency is likely involved in the development of preeclampsia.

microRNAs and Endometrial Pathophysiology.

Embryo implantation requires a reciprocal interaction between the blastocyst and endometrium and is associated with complex regulatory mechanisms. Since their discovery, microRNAs became prominent candidates providing missing links for many biological pathways. In recent years, microRNAs were implicated as one of the important players in regulation of various biological and physiological endometrial related processes. This chapter aims to present recent knowledge pertaining to the diverse aspects of microRNAs in the embryo-endometrial relationship. We will focus on the role of microRNAs in decidualization and their part in natural and stimulated cycles. Next, we will present recent studies deliberating the role of microRNAs in recurrent pregnancy loss and in the important phenomenon of recurrent implantation failure. Lastly, demonstrating an important aspect of embryo implantation and invasion, we will outline few microRNA related shared pathways of implantation and carcinogenesis.

Folate deficiency decreases apoptosis of endometrium decidual cells in pregnant mice via the mitochondrial pathway.

It is well known that maternal folate deficiency results in adverse pregnancy outcomes. In addition to aspects in embryonic development, maternal uterine receptivity and the decidualization of stromal cells is also very important for a successful pregnancy. In this study, we focused on endometrium decidualization and investigated whether apoptosis, which is essential for decidualization, was impaired. Flow cytometry and TUNEL detection revealed that apoptosis of mouse endometrium decidual cells was suppressed in the dietary folate-deficient group on Days 7 and 8 of pregnancy (Day 1 = vaginal plug) when decidua regression is initiated. The endometrium decidual tissue of the folate deficiency group expressed less Bax compared to the normal diet group while they had nearly equal expression of Bcl2 protein. Further examination revealed that the mitochondrial transmembrane potential (ΔΨm) decreased, and the fluorescence of diffuse cytoplasmic cytochrome c protein was detected using laser confocal microscopy in normal decidual cells. However, no corresponding changes were observed in the folate-deficient group. Western blotting analyses confirmed that more cytochrome c was released from mitochondria in normal decidual cells. Taken together, these results demonstrated that folate deficiency could inhibit apoptosis of decidual cells via the mitochondrial apoptosis pathway, thereby restraining decidualization of the endometrium and further impairing pregnancy.

Fetal programming theory: implication for the understanding of endometriosis.

Comparison of the transcriptomes and proteomes of the decidualization-specific genes that express high vs low levels of the eutopic and ectopic endometrium of women with endometriosis compared with controls, could be useful in understanding the pathogenesis of endometriosis. Genome-wide comparison between decidual tissue and non-decidual tissue identified many genes significantly modulated in the process of decidualization. Comparison of eutopic endometrium and endometriotic sites also revealed up- and down-regulated genes. A combined analysis of the experimental data showed specific genes up-regulated both at the endometriotic site and in the decidualization process, representing a broad diversity of molecular functions, including cell cycle regulation, angiogenesis and adhesion molecules. In contrast, down-regulated genes identified in endometriosis among genes overexpressed in decidualization encode Müllerian embryogenesis, which includes transcription factors, hormonal regulation and cytokine expression. The mechanism responsible for insufficient decidualization in endometriosis may be mediated through down-regulation of the Müllerian embryogenesis-related genes. In conclusion, a range of decidualization resistance has been associated with endometriosis. Future study will identify the putative mechanisms relating epigenetic changes of decidualization susceptibility genes in early life to the risk of developing endometriosis in adulthood.

Cardiovascular and thrombogenic risk of decidual vasculopathy in preeclampsia.

OBJECTIVE: Women with a history of preeclampsia (PE) have an increased prevalence of cardiometabolic, cardiovascular, and prothrombotic risk factors. Remotely, these women are at increased risk of developing cardiovascular and thrombotic disease. Decidual vasculopathy (DV) describes vascular lesions in the maternal spiral arteries of the uterus, which are found in approximately 40-60% of women with PE. DV is thought to be related to atherosclerosis because of their morphological similarity. The aim of this study was to investigate the association of cardiovascular and thrombogenic risk factors with DV in women with a history of PE. STUDY DESIGN: We retrospectively analyzed the cardiovascular and thrombogenic risk of women with a history of PE, comparing cases with DV (n = 95) with cases without the lesions (n = 81) 7 months after the index pregnancy. Data from a cohort of patients with a history of PE were matched with records from our pathology database. RESULTS: The DV group showed higher diastolic blood pressure (73 vs 70 mm Hg, P = .031), lower left ventricular stroke volume (71 vs 76 mL, P = .032), higher total peripheral vascular resistance (1546 vs 1385, P = .009), and a higher percentage of low plasma volume (34% vs 19%, P = .030). DV did not relate to other cardiovascular parameters, urinary protein, body mass index, lipid or glucose metabolism parameters, or thrombophilia. CONCLUSION: In this study, in women with a history of PE, cases with DV had increased cardiovascular risk, exhibiting circulatory alterations, suggesting reduced venous reserves and elevated arterial tone, without metabolic or thrombophilic disturbances.

Ovarian stimulation leads to a severe implantation defect in mice.

The aim of the present study was to evaluate whether ovarian stimulation could induce embryo implantation dysfunction in mice and to explore the possible mechanisms involved. Ovarian stimulation was performed with intraperitoneal injections of 0, 2.5, 5.0, 7.5 and 10.0 IU pregnant mare serum gonadotrophin followed by the same dose of human chorionic gonadotrophin 48h later. A dose-dependent implantation defect in stimulated mice was demonstrated, which can be mainly explained by premature luteolysis and secondary endometrial changes induced by an imbalance in oestradiol and progesterone.

Sonographic study of the decidua basalis in early pregnancy loss.

OBJECTIVES: To describe the sonographic findings in the decidua basalis layer in spontaneous early pregnancy loss and to compare them with those in normal pregnancy. METHODS: We reviewed 119 scans at 4-10 weeks' gestation from 110 patients who miscarried clinically at less than 13 weeks' gestation and 132 scans also at 4-10 weeks from 98 patients who had normal uncomplicated term pregnancies. The thickness and echogenicity of the decidua basalis layer were compared between pregnancies which suffered early loss and normal controls. RESULTS: Relative thinning of the decidua basalis was observed in cases of early pregnancy loss from 5-6 weeks onwards when compared with normal pregnancies. In embryonic pregnancies that subsequently miscarried, the decidua basalis did not show the rising trend in thickness that was observed in normal pregnancies. Shortly before and after embryonic demise, the decidua appeared relatively more echogenic compared with that in normal pregnancy and the placenta showed areas of hypoechogenicity. Embryonic demise was followed by disorganization of the decidual layer, which became difficult to recognize. Pregnancy with an empty sac showed a more gradual trend in the thinning of the decidua basalis, but the uniformity and echogenicity of the layer appeared to be relatively better preserved with time. CONCLUSION: The decidua basalis layer in pregnancies that are destined to miscarry in the first trimester differs sonographically from that in normal pregnancies. The sonographic differences are suggestive of a defective decidual-placental complex resulting from deficient trophoblastic invasion.

Decidualized human endometrial stromal cells mediate hemostasis, angiogenesis, and abnormal uterine bleeding.

Factor VII binds trans-membrane tissue factor to initiate hemostasis by forming thrombin. Tissue factor expression is enhanced in decidualized human endometrial stromal cells during the luteal phase. Long-term progestin only contraceptives elicit: 1) abnormal uterine bleeding from fragile vessels at focal bleeding sites, 2) paradoxically high tissue factor expression at bleeding sites; 3) reduced endometrial blood flow promoting local hypoxia and enhancing reactive oxygen species levels; and 4) aberrant angiogenesis reflecting increased stromal cell-expressed vascular endothelial growth factor, decreased Angiopoietin-1 and increased endothelial cell-expressed Angiopoietin-2. Aberrantly high local vascular permeability enhances circulating factor VII to decidualized stromal cell-expressed tissue factor to generate excess thrombin. Hypoxia-thrombin interactions augment expression of vascular endothelial growth factor and interleukin-8 by stromal cells. Thrombin, vascular endothelial growth factor and interleukin-8 synergistically augment angiogenesis in a milieu of reactive oxygen species-induced endothelial cell activation. The resulting enhanced vessel fragility promotes abnormal uterine bleeding.

The evaluation of selected indices of apoptosis in placentas from pregnancies complicated by fetal growth restriction.

BACKGROUND: Fetal growth restriction is related to a high rate of prematurity and mortality. In cases of unknown origin utero-placental circulation changes are the main factor which is due to the changes in blood vessels. The understanding of the mechanism may help in further prevention of FGR. MATERIAL AND METHODS: The expression of bcl-2 and bax in normal pregnancies and complicated by FGR were compared. The study was conducted in 2005-2006 at The Medical University of Lodz--HRP Unit and The Kopernik Hospital--Lodz. Bcl-2 and bax were estimated using an immunohistochemical method. Bcl-2 was estimated in trophoblast, bax in decidua and trophoblast. RESULTS: In a study group the mean value of bcl-2 in trophoblast was 37.04 +/- 10.51, in a control group the mean value was 65.74 +/- 6.97. The estimation of bax was done in trophoblast and decidua separately. In the group of FGR mean value of bax expression in trophoblast was 45.35 +/- 10.5. In decidua the mean bax expression value was 24.11 +/- 7.3. In controls in trophoblast the mean value was 12.53 +/- 7.54, in decidua the mean expression of bax was 6.63 +/- 2.24. CONCLUSION: 1. Apoptosis in trophoblast is lower in normal pregnancy than in FGR. 2. Increased expression of pro-apoptotic proteins in placenta might be one of the reason for FGR development.