Inadequate Implantation Research Articles

Modern concepts about the problem of endometrial infertility against the backdrop of the "thin endometrium" (literature review)

Endometrial infertility is the cause of inadequate implantation and serves as an obstacle to the onset and progression of spontaneous pregnancy and the implementation of assisted reproductive technology (ART) programs. One of the most common mechanisms for the development of infertility is endometrial thinning. Despite the abundance of publications, today there are no generally accepted diagnostic criteria and treatment and rehabilitation approaches for this pathology, which encourages continued scientific research in this direction. Aim was to highlight the problem of decreased fertility caused by “thin endometrium”. To create the review, the bibliographic method was applied and domestic and foreign literary sources from the Pubmed, MedLine, RSCI, e-library and Cyberleninka search engine databases were used. The search depth was 10 years. The following search phrases were used: “uterine factor of infertility”, “endometrial factor of infertility”, “thin endometrium”. Seventy five sources that were included in this review were studied and analyzed. Data presented in the literature indicate that endometrial causes of infertility are associated with incompetence of the uterine cavity mucosa, which may manifest itself as a phenomenon of ”thin endometrium”, the development mechanisms of which have not yet been fully studied. Determining the functional status of the endometrium is very important for predicting the onset of pregnancy in the natural cycle or in ART programs, since even in the presence of a good quality embryo, endometrial deficiency can prevent adequate implantation. Thus, before planning a subsequent pregnancy, it is necessary to diagnose and, if possible, neutralize or correct endometrial causes of infertility. One of the main markers of readiness for implantation at the moment is the thickness of the endometrium.

Immature Platelet Fraction and Thrombin Generation: Preeclampsia Biomarkers.

Preeclampsia, a human pregnancy syndrome, is characterized by elevated blood pressure and proteinuria after the 20th week of gestation. Its etiology remains unknown, and its pathophysiological mechanisms are related to placental hypoperfusion, endothelial dysfunction, inflammation, and coagulation cascade activation. Recently, the role of the complement system has been considered. This syndrome is one of the main causes of maternal and fetal mortality and morbidity. This article discusses the hypothesis of preeclampsia being triggered by the occurrence of inadequate implantation of the syncytiotrophoblast, associated with bleeding during the first stage of pregnancy and with augmented thrombin generation. Thrombin activates platelets, increasing the release of antiangiogenic factors and activating the complement system, inducing the membrane attack complex (C5b9). Immature platelet fraction and thrombin generation may be possible blood biomarkers to help the early diagnosis of preeclampsia.

Female Cat Intravesical Sequestration after Ovariosalpingohisterectomy Using Nylon Clamp

Background: The nylon clamp, marketed as an accessory of electrical devices, has been used as an alternative method for definitive surgical hemostasis by ligature of arteriovenous vessels in ovariosalpingohisterectomy (OSH) in bitches and female cats. However, since May 2015, the Brazilian Veterinary Statutory Body (CFMV - Conselho Federal de Medicina Veterinária) banned its application, once it is a material still not regulated to be used in animals, in addition to the numerous reports of postoperative complications. This paper reports the migration of the clamp used in the OSH to the urinary bladder of the cat and the implications of the presence of the foreign body, in addition to discussing the use of this device in surgeries.Case: A 1-year-old Persian female cat, which, three months after an elective OSH in a private veterinary clinic, presented polyuria and hematuria. The patient presented pain at abdominal palpation; in the WBC were observed leucopenia and eosinophilia, indicating a chronic inflammatory process installed; the urinalysis showed the presence of crystals, increased urinary density, milky aspect indicating presence of pus, proteinuria and hematuria; on ultrasound were observed the presence of two amorphous mobile structures inside the bladder, producing acoustic shadow, measuring approximately 0.4 and 0.6 cm in diameter, suggesting the presence of bladder urolithiasis. Considering the results, the patient was sent for a cystotomy. The association of acepromazine (0.02 mg/kg), midazolam (0.2 mg/kg), morphine (0.2 mg/kg) and ketamine (10 mg/kg) was used intramuscularly as preanesthetic medication. For anesthetic induction, 5 mg/kg of propofol was applied intravenously, in addition to epidural anesthesia with 1 mL/4 kg of lidocaine along 0.1 mg/kg of morphine and, for maintenance, isoflurane in oxygen at 100% was used. Then, a four-centimeter retro-umbilical incision was performed to exhibit the bladder. After the incision on the ventral aspect of the bladder wall, a nylon clamp with approximately 0.8 cm, present in the lumen was found and removed. The seromuscular synthesis of the bladder was with a 3-0 mononylon simple continuous suture, the muscle with a 2-0 mononylon sultan pattern, and in the skin an interrupted simple suture using 2-0 nylon was performed. Postoperative care comprised by amoxicillin with potassium clavulanate (15 mg/kg, orally, 8/8 h, 7 d), meloxican (0.15 mg/kg, orally, 24/24 h, 4 d) and tramadol (12 mg/kg, orally, 12/12 h, 4 d). After ten days, surgical stitches were removed, with good healing and clinical improvement, as well as remission of the symptomatology reported on anamnesis and physical examination.Discussion: The pathophysiology of the nylon clip migration probably occurred in a similar way to the intravesical migration of intrauterine devices (IUDs) to the abdominal cavity, bladder and intestine, in women. According to reports, it is a progressive event, in which several factors may be involved, mainly: inadequate implantation of devices, uterine infections, use of contaminated medical instruments, among others, followed by an inflammatory process, perforation of the uterine wall by the device, adhesions and migration to adjacent structures. In the present report, it is believed that the clamp lock failed in the procedure performed by the veterinarian responsible for OSH, with subsequent loosening and detachment, and migration to the urinary bladder, an organ located ventrally to the uterine body. However, the following hypotheses can also be raised: pregnancy at the moment of castration, followed by uterine stump retraction and release of the clamp; contamination of surgical instruments; postoperative infections and adhesions involving the bladder.

Placental exosomes in maternal-fetal communication and viral resistance

Inadequate implantation and placentation is associated with miscarriage and placental insufficiency. The decidual environment is thought to regulate trophoblast invasion, however this is poorly defined in humans. We aimed to determine the effect of decidualization on trophoblast function.In vitro decidualized primary human endometrial stromal cells (HESC) significantly enhanced first-trimester extravillous trophoblast (EVT) (6–8-weeks gestation) adhesion, outgrowth/invasion. In EVTs from 10 to 12-weeks gestation this effect was absent (adhesion, invasion) or reversed (outgrowth). HESC conditioned media had no effect on trophoblast MMP9 production/activity.Decidualization regulated EVT function in a gestational-dependent manner. This study highlights the importance of trophoblast-decidual synchrony.

Genomic risk for schizophrenia converges into isoform-level coexpression network of the placental transcriptome

Inadequate implantation and placentation is associated with miscarriage and placental insufficiency. The decidual environment is thought to regulate trophoblast invasion, however this is poorly defined in humans. We aimed to determine the effect of decidualization on trophoblast function.In vitro decidualized primary human endometrial stromal cells (HESC) significantly enhanced first-trimester extravillous trophoblast (EVT) (6–8-weeks gestation) adhesion, outgrowth/invasion. In EVTs from 10 to 12-weeks gestation this effect was absent (adhesion, invasion) or reversed (outgrowth). HESC conditioned media had no effect on trophoblast MMP9 production/activity.Decidualization regulated EVT function in a gestational-dependent manner. This study highlights the importance of trophoblast-decidual synchrony.

Trophoblast function is altered by decidual factors in gestational-dependant manner

Inadequate implantation and placentation is associated with miscarriage and placental insufficiency. The decidual environment is thought to regulate trophoblast invasion, however this is poorly defined in humans. We aimed to determine the effect of decidualization on trophoblast function.In vitro decidualized primary human endometrial stromal cells (HESC) significantly enhanced first-trimester extravillous trophoblast (EVT) (6–8-weeks gestation) adhesion, outgrowth/invasion. In EVTs from 10 to 12-weeks gestation this effect was absent (adhesion, invasion) or reversed (outgrowth). HESC conditioned media had no effect on trophoblast MMP9 production/activity.Decidualization regulated EVT function in a gestational-dependent manner. This study highlights the importance of trophoblast-decidual synchrony.

Use of bioresorbable vascular scaffold: a meta-analysis of patients with coronary artery disease.

BackgroundDifferences in outcomes between bioresorbable vascular scaffold (BVS) systems and drug-eluting metal stents (DES) have not been fully evaluated. We aimed to compare clinical and angiographic outcomes in randomised studies of patients with coronary artery disease (CAD), with a secondary analysis performed among registry studies.MethodsA meta-analysis comparing outcomes between BVS and DES in patients with CAD. Overall estimates of treatment effect were calculated with random-effects model and fixed-effects model.ResultsIn 6 randomised trials (3818 patients), BVS increased the risk of subacute stent thrombosis (ST) over and above DES (OR 2.14; CI 1.01 to 4.53; p=0.05), with a trend towards an increase in the risk of myocardial infarction (MI) (125 events in those assigned to BVS and 50 to DES; OR 1.36; CI 0.97 to 1.91; p=0.07). The risk of in-device late lumen loss (LLL) was higher with BVS than DES (mean difference 0.08 mm; CI 0.03 to 0.13; p=0.004). There was no difference in the risk of death or target vessel revascularisation (TVR) between the two devices. In 6 registry studies (1845 patients), there was no difference in the risk of death, MI, TVR or subacute ST between the two stents. Final BVS dilation pressures were higher in registry than in randomised studies (18.7±4.6 vs 15.2±3.3 atm; p<0.001).ConclusionsPatients treated with BVS had an increased risk of subacute ST and slightly higher LLL compared with those with DES, but this might be related to inadequate implantation techniques, in particular device underexpansion.

The Microenvironment of Human Implantation: Determinant of Reproductive Success.

Successful implantation requires synchronous development of embryo and endometrium. Endometrial receptivity results from progesterone-induced differentiation of endometrial cells, generally achieved during the mid-secretory phase of the cycle. Failure to properly develop receptivity results in failed or inadequate implantation and hence no ongoing pregnancy. The blastocyst undergoes final development, apposition, attachment and initiates invasion of the endometrial epithelium within the uterine cavity. Thus, the microenvironment provided by uterine fluid, particularly glandular secretions, is essential for implantation. Analysis of endometrial fluid has identified cytokines, chemokines, proteases, antiproteases and other factors that modulate blastocyst functions relevant to implantation. Exosomes/microvesicular bodies released from the endometrium (and likely also the embryo) are present in uterine fluid. These can transfer miRNA, proteins and lipids between cells, thus providing endometrial-embryo communication in the peri-implantation period. Understanding the uterine microenvironment, and its effects on endometrial-embryo interactions, will provide opportunities to modify current infertility treatments to improve success rates.

Decidualization and syndecan-1 knock down sensitize endometrial stromal cells to apoptosis induced by embryonic stimuli.

Human embryo invasion and implantation into the inner wall of the maternal uterus, the endometrium, is the pivotal process for a successful pregnancy. Whereas disruption of the endometrial epithelial layer was already correlated with the programmed cell death, the role of apoptosis of the subjacent endometrial stromal cells during implantation is indistinct. The aim was to clarify whether apoptosis plays a role in the stromal invasion and to characterize if the apoptotic susceptibility of endometrial stromal cells to embryonic stimuli is influenced by decidualization and Syndecan-1. Therefore, the immortalized human endometrial stromal cell line St-T1 was used to first generate a new cell line with a stable Syndecan-1 knock down (KdS1), and second to further decidualize the cells with progesterone. As a replacement for the ethically inapplicable embryo all cells were treated with the embryonic factors and secretion products interleukin-1β, interferon-γ, tumor necrosis factor-α, transforming growth factor-β1 and anti-Fas antibody to mimic the embryo contact. Detection of apoptosis was verified via Caspase ELISAs, PARP cleavage and Annexin V staining. Apoptosis-related proteins were investigated via antibody arrays and underlying signaling pathways were analyzed by Western blot. Non-decidualized endometrial stromal cells showed a resistance towards apoptosis which was rescinded by decidualization and Syndecan-1 knock down independent of decidualization. This was correlated with an altered expression of several pro- and anti-apoptotic proteins and connected to a higher activation of pro-survival Akt in non-differentiated St-T1 as an upstream mediator of apoptotis-related proteins. This study provides insight into the largely elusive process of implantation, proposing an important role for stromal cell apoptosis to successfully establish a pregnancy. The impact of Syndecan-1 in attenuating the apoptotic signal is particularly interesting in the light of an already described influence on pregnancy disorders and therefore might provide a useful clinical tool in the future to prevent pregnancy complications provoked by inadequate implantation.

Decreased Human Chorionic Gonadotropin and Preterm Delivery in Dichorionic Twin Gestations

INTRODUCTION: Inadequate trophoblast invasion has been postulated as a major contributor to preterm birth. Maternal implantation biomarker, human chorionic gonadotropin (hCG), has been variably predictive of preterm birth. This study allows precise comparison of maximal hCG values exactly at 56 days of gestation in twin gestations conceived with in vitro fertilization. METHODS: Sixty women conceived dichorionic twins with two-blastocyst embryo transfer. Serum hCG was assessed exactly at 56 days and patients were subsequently uniformly managed in a tertiary care obstetrics unit. Delivery was recorded as early preterm (less than 34 weeks of gestation) or late preterm (greater than 34 weeks of gestation). Unpaired t test, receiver operating characteristic curves, and two-by-two tables were used for statistical significance. RESULTS: Fourteen women delivered early preterm (mean 30.4 weeks of gestation) and 46 late preterm (mean 36.3 weeks of gestation, P<.05). Day 56 hCG was significantly lower in early compared with late preterm birth (91,105 compared with 165,200, P<.001). The receiver operating characteristic curve was very significant with area under the curve=88%. A cut point of hCG 130,000 identified a positive predictive value of early preterm birth of 69% and a negative predictive value of early preterm birth of 92%. CONCLUSIONS: Maternal biomarkers (hCG) of trophoblast growth compared at their precise biologic maximums are significantly decreased in twins with subsequent early preterm birth. Lower hCG values may represent inadequate implantation and subsequent placental dysfunction and direct clinical strategies to patients at higher risk of early preterm birth.

Human Implantation: A Tale of Mutual Maternal and Fetal Attraction1

Implantation in humans has been conceptualized largely on the basis of mouse models [1]. It is viewed as a stepwise process involving apposition and adherence of a blastocyst to the endometrium, followed by breaching of the luminal epithelium and, finally, invasion of maternal tissues. This process seems analogous to an invading cancer, with the embryo driving the destruction of endometrial epithelial cells, the enzymatic digestion of stromal matrix, and finally, the invasion of the maternal decidua and inner myometrium (Fig. 1a). Within this context, the role of the maternal decidua is to both tolerate and control the invading semiallogeneic fetal trophoblast. Excessive trophoblast invasion of the uterus presents clinically as placenta accreta or choriocarcinoma, conditions associated with considerable maternal morbidity and, occasionally, death. Conversely, inadequate or deregulated invasion of trophoblast compromises the survival of the fetus and causes a spectrum of pregnancy complications, including miscarriage, intrauterine growth restriction, preeclampsia, and stillbirth. Hence, both excessive and inadequate implantation can have disastrous consequences.

Corin, an enzyme with a putative role in spiral artery remodeling, is up-regulated in late secretory endometrium and first trimester decidua

What is the nature of cellular Corin expression in human gestational tissues? CORIN is expressed in non-pregnant late secretory phase endometrium, first trimester human implantation sites and is up-regulated with decidualization ex vivo. Adequate trophoblast invasion and spiral artery remodeling/transformation is critical for successful implantation. CORIN, best known for its role in activating atrial natruietic peptide (ANP) to regulate blood pressure, has recently been proposed to be centrally involved in trophoblast invasion and spiral artery remodeling. It is postulated that ANP, activated by CORIN, promotes trophoblast invasion and that a deficiency causes pre-eclampsia. Mice deficient in either Corin or ANP displayed poor trophoblast invasion, impaired spiral artery remodeling and phenocopied human pre-eclampsia. However, the precise cellular localization of CORIN within human gestational tissues has not been well characterized. We measured CORIN protein localization in a number of human gestational tissues relevant to early embryo/placental implantation: non-pregnant (NP) endometrial biopsies (n = 5 per phase of the menstrual cycle), first trimester placental bed biopsies (n = 12) and pre-term control (n = 10) and severe early onset preeclamptic placentas (n = 15). Endometrial stromal cells were isolated from human endometrial biopsies (n = 5) and induced to decidualize ex vivo. Finally, CORIN concentrations were measured in serum obtained from pregnant women during the first trimester of whom, 56 subsequently ended up with a healthy term delivery (controls), 18 developed fetal growth restriction (FGR) and 21 had a miscarriage. We performed immunohistochemistry to assess CORIN localization. Changes in Corin mRNA expression in human endometrial stromal cells decidualized ex vivo were measured by quantitative RT-PCR, and levels of CORIN within human sera were measured by ELISA. CORIN was expressed in both NP late secretory phase endometrium and first trimester decidua within placental bed biopsies. Importantly, decidualization of primary human endometrial cells ex vivo significantly increased Corin expression (P < 0.05). CORIN was also detected within the villous cytotrophoblast, but there was no change in mRNA levels in placentas complicated by severe preterm pre-eclampsia when compared with pre-term controls. Although CORIN was detected in first trimester serum, levels did not change across gestation, nor could they predict miscarriage or FGR (other disorders of impaired placental invasion). Owing to the fact that we utilized early pregnancy human specimens, this is mainly a descriptive study with a limited amount of functional experiments. This is the first study to thoroughly characterize Corin mRNA and protein expression in human gestational tissue. Our findings support recent data from murine studies collectively suggesting that CORIN plays a critical role in trophoblast migration and spiral artery remodeling during early pregnancy in humans. Therefore, further studies of CORIN biology in early pregnancy may identify new therapeutic targets to improve implantation quality in early pregnancy and potentially reduce the rates of pregnancy complications caused by inadequate implantation (pre-eclampsia, FGR and miscarriage). This study was supported by The National Health and Medical Research Council of Australia (Salary support #490970, #490995). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors declare that no competing interests exist.

Medical management of connector pin thrombosis with the Amplatzer cardiac plug left atrial closure device

Transcatheter closure of the left atrial appendage with the Amplatzer™ cardiac plug device and double antiplatelet treatment for 3 mo has become an alternative treatment for patients with atrial fibrillation at high embolism risk and contraindications for chronic oral anticoagulation. The inadequate implantation of the left atrial appendage closure device and the discontinuation of double antiplatelet therapy are well-known as factors related to device thrombosis. Nevertheless, device thrombosis after adequate implantation requiring surgical treatment or restarting chronic oral anticoagulation has been reported and can reach 15% of patients. The connector pin thrombosis of the Amplatzer™ cardiac plug, despite a good adherence to antiplatelet treatment, has been recently described as a potential mechanism for device thrombosis. Our clinical case reports the management of this condition for the first time, showing that the early detection of thrombotic complications by transesophageal echocardiography permits solving this serious complication with medical treatment only.

Islet Transplantation &amp;β-Cell Replacement Therapies for Diabetes

Restoration of physiologic metabolic control is the ultimate therapeutic goal for patients with diabetes but is difficult to achieve by means of medical therapy. Transplantation of islets of Langerhans represents a viable therapeutic option for patients with insulin-dependent diabetes. It is currently offered to patients with a brittle form of diabetes and hypoglycemia unawareness. Current limitations of islet transplantation include scarcity of deceased donor pancreata, partially effective islet isolation and purification protocols, need for life-long systemic immunosuppression, inadequate implantation sites, lack of predictive tests, and noninvasive graft monitoring protocols. Great progress has been recorded in different research areas aimed at overcoming current limitations of islet cell transplantation. These areas include stem cells technology, xenotransplantation, development of novel immunosuppressive regimens, immune tolerance, immunoisolation protocols, alternative sites for islet implantation, immune monitoring, and noninvasive imaging techniques. This special issue was open to the scientific community working on the development of beta-cell replacement. Of the several papers received, ten received favorable peer reviews and were selected for publication in this issue to cover specific topics of general interest in this field. The paper by C. Jahansouz et al. provides a comprehensive and historical overview of beta-cell replacement therapies. The paper by P. Chhabra and K. L. Brayman reviews emerging clinical and preclinical approaches toward enhancing the clinical outcome of islet cell transplantation and includes aspects related to cytoprotection and immune interventions. The paper by H. Wang et al. is focused on important cytoprotective pathways such as carbon monoxide and heme oxygenase-1 and their ability to enhance islet cell viability and engraftment. The paper by X. Wang et al. offers a perspective on the B7-H4 co-stimulation pathway and its potential toward enhancing immune regulation and prolonging islet graft survival. Recognizing the current limitations of human pancreas donation after brain death, alternative cellular-based approaches are actively being explored to widen the clinical application of beta-cell replacement therapies. The paper by M. R. Hammerman provides interesting new experimental data on porcine islet cell engraftment in xenogeneic recipients without immunosuppression. In his paper H. Noguchi shares an overview of his experience with novel protocols aimed at ameliorating pancreas preservation injury and improving the yield and quality of islets obtained for transplantation. I. Meivar-Levy et al. explore the use of hepatic cells expressing albumin and mesenchymal properties that have been engineered to produce insulin as an alternative and potentially unlimited source of transplantable insulin-producing cells. F. Carlotti et al. assess the important issue of the pros and cons related to the translatability of results obtained in rodent studies to humans when studying beta-cell regeneration. There are increasing efforts aimed at developing novel implantation sites for islet cells. The paper by D. Espes et al. describes the promising properties of intramuscular site which makes of it a viable option for islet cell implantation. P. Wang et al. review the important and rapidly evolving field in vivo islet imaging. The use of molecular imaging techniques may be of invaluable assistance toward monitoring islet grafts as well as a tool to better understand the physiopathological changes that occur after transplantation. Thierry Berney Olle Korsgren Andrew Posselt Antonello Pileggi

Endoscopic Abdominoplasty

We describe a technique for endoscopic abdominoplasty in which we used 3 incisions, following the triangulation principles. To maintain the subcutaneous cavity, CO2 was insufflated at 8 mm Hg, and Esmarch bandages were placed at the submammary fold in a circumferential way to prevent subcutaneous emphysema. The aponeurosis plication was done with interrupted "8" figure sutures, with extracorporeal knots tied up in a double fisherman knot. The rest of the technique is similar to those previously described. Seven patients were treated, with an average age of 35.7 years (range, 25-60), and the mean length of surgery was of 197.11 minutes (range, 129-240). After surgery, 2 patients had mild pulmonary hypoventilation treated only with oxygen through a nasal mask for 24 hours. There were other complications such as seromas, inadequate implantation of the navel, and superficial periumbilical necrosis. According to the patients' opinion, the esthetic results have been satisfactory so far.

Síndrome de ovario poliquístico, endometrio y riesgo de aborto

El síndrome de ovario poliquístico (SOP) es la endocrinopatía más frecuente en mujeres en edad reproductiva, se observa en el 5-7% de ellas. El diagnóstico se hace ante la presencia de por lo menos dos componentes de la triada: oligoovulación, hiperandrogenismo y ovarios poliquísticos. Estas mujeres tienen niveles elevados de lutropina (LH), hiperinsulinemia e hiperandrogenismo y se ha reportado un aumento en la incidencia de aborto en este grupo de pacientes. Este hecho podría estar relacionado con los cambios endometriales observados en estas mujeres y que se asocian a niveles elevados de andrógenos e insulina, provocando así, inadecuada implantación y probablemente mayor pérdida del embarazo en el primer trimestre. Medidas terapéuticas, como el uso de sensibilizantes a la acción de la insulina, que contribuyen a disminuir los niveles de insulina y por lo tanto de andrógenos, podrían tener un efecto favorable al disminuir la incidencia de aborto en pacientes con SOP.

Hypertension in pregnancy

Selected articles on hypertensive diseases in pregnancy from the past year are highlighted. The concept that endothelial cell dysfunction plays an important role in the pathogenesis of preeclampsia has been strengthened. The initial inciting event is still unclear, but inadequate implantation and decreased antioxidant activity may play a role. Magnesium sulfate is still the anticonvulsant of choice for seizure prophylaxis, but the exact mechanism of its action remains controversial. The ideal screening test to identify those patients likely to develop preeclampsia is still lacking, and the side effects and risks of aspirin prophylaxis are not yet known. The results from the National Institutes of Health-sponsored multicenter trial on this subject should be forthcoming.