The clinical significance of small endometrial polyps.

OBJECTIVE: Small endometrial polyps are relatively common in asymptomatic women and may regress spontaneously. In symptomatic women, the finding of a small polyp (<1cm diameter) raises the question of the clinical pertinence and necessity of excision. Sparse data are available on the effectiveness of hysteroscopic excision of small polyps to manage abnormal uterine bleeding. The aim of this study was to assess outcome after hysteroscopic excision of small endometrial polyps in symptomatic patients. STUDY DESIGN: This was an observational cohort study enrolling 255 premenopausal women presenting with abnormal uterine bleeding and a small endometrial polyp on office hysteroscopy, undertaken between January 2004 and February 2007. The study group was referred for polypectomy by operative hysteroscopy. The outcome of the procedure was reviewed 6-12 months later by a telephone interview to assess the pattern of uterine bleeding after the procedure and overall satisfaction. RESULTS: Significant improvement in the magnitude of bleeding was experienced by 70% of participants, but only 30% of them reported return to regular menses. Satisfaction with the procedure was reported by 80%. Younger patients reported a less favorable bleeding pattern and were found to be less satisfied with the outcome of the procedure. CONCLUSIONS: Symptomatic women with small endometrial polyps can be treated safely and efficiently with hysteroscopic excision. In the younger age group of patients, however, the outcome of the procedure may be less favorable and may necessitate the addition of endometrial ablation to improve outcome and increase patient satisfaction.

MiRNA-mediated control of HLA-G expression and function.

HLA-G is a non-classical HLA class-Ib molecule expressed mainly by the extravillous cytotrophoblasts (EVT) of the placenta. The expression of HLA-G on these fetal cells protects the EVT cells from immune rejection and is therefore important for a healthy pregnancy. The mechanisms controlling HLA-G expression are largely unknown. Here we demonstrate that miR-148a and miR-152 down-regulate HLA-G expression by binding its 3'UTR and that this down-regulation of HLA-G affects LILRB1 recognition and consequently, abolishes the LILRB1-mediated inhibition of NK cell killing. We further demonstrate that the C/G polymorphism at position +3142 of HLA-G 3'UTR has no effect on the miRNA targeting of HLA-G. We show that in the placenta both miR-148a and miR-152 miRNAs are expressed at relatively low levels, compared to other healthy tissues, and that the mRNA levels of HLA-G are particularly high and we therefore suggest that this might enable the tissue specific expression of HLA-G.

Intrauterine balloon tamponade as a treatment for immune thrombocytopenic purpura-induced severe uterine bleeding.

OBJECTIVE: To report our experience of applying balloon tamponade in the treatment of intrauterine bleeding in two patients with immune thrombocytopenic purpura (ITP). Immune thrombocytopenic purpura is a well-known hematologic autoimmune disease. The uterus may be a major site of bleeding in patients with ITP. Halting bleeding is imperative to reduce blood loss and platelet consumption and to allow medical treatment to increase platelet count. Balloon tamponade has been described as an effective method to control bleeding in a variety of clinical situations; it is an effective and accessible modality, requiring no analgesia or anesthesia, and helps facilitate continuous monitoring of uterine bleeding. DESIGN: Report of two cases. SETTING: Obstetrics and gynecology department in a tertiary care center in Jerusalem, Israel. PATIENT(S): Two patients with ITP with severe uterine bleeding refractory to treatment with estrogen and IV IgG. INTERVENTION(S): Intrauterine balloon tamponade. MAIN OUTCOME MEASURE(S): Cessation of uterine bleeding, appearance of complications. RESULT(S): Insertion of balloon tamponade successfully controlled bleeding in both cases. The patient in case 1 subsequently had persistent hypomenorrhea. The patient in case 2 had abdominal pain and suspected pelvic inflammation. CONCLUSION(S): Our presented cases demonstrate that uterine bleeding can be controlled successfully in patients with ITP with an intrauterine balloon. This novel application raises many technical issues, such as the appropriate filling pressures and duration of treatment. Possible risks, such as endometrial injury, still remain to be resolved and mandate future clinical research.

Inhibitory NK receptor recognition of HLA-G: regulation by contact residues and by cell specific expression at the fetal-maternal interface.

The non-classical HLA-G protein is distinguished from the classical MHC class I molecules by its expression pattern, low polymorphism and its ability to form complexes on the cell surface. The special role of HLA-G in the maternal-fetal interface has been attributed to its ability to interact with specific receptors found on maternal immune cells. However this interaction is restricted to a limited number of receptors. In this study we elucidate the reason for this phenomenon by comparing the specific contact residues responsible for MHC-KIR interactions. This alignment revealed a marked difference between the HLA-G molecule and other MHC class I molecules. By mutating these residues to the equivalent classical MHC residues, the HLA-G molecule regained an ability of interacting with KIR inhibitory receptors found on NK cells derived either from peripheral blood or from the decidua. Functional NK killing assays further substantiated the binding results. Furthermore, double immunofluorescent staining of placental sections revealed that while the conformed form of HLA-G was expressed in all extravillous trophoblasts, the free heavy chain form of HLA-G was expressed in more distal cells of the column, the invasion front. Overall we suggest that HLA-G protein evolved to interact with only some of the NK inhibitory receptors thus allowing a control of inhibition, while permitting appropriate NK cell cytokine and growth factor production necessary for a viable maternal fetal interface.

The incidence and haemodynamic significance of gas emboli during operative hysteroscopy: a prospective echocardiographic study.

AIMS: Operative hysteroscopy is associated with complications including the development of gas embolism. The aim of this study was to utilize continuous echocardiographic imaging during operative hysteroscopy to assess the extent and the haemodynamic effects of gas embolism in these patients. METHODS AND RESULTS: Women undergoing operative hysteroscopy under general anaesthesia without a history of cardiac disease were eligible. Transthoracic echocardiography (TTE) was performed continuously in all study participants with assessment of the extent and frequency of gas embolism, right ventricular function and pulmonary hypertension. Twenty-three women (mean age: 48.0 +/- 9.4 years) participated in the study. All subjects had evidence of bubble embolism in the right atrium (RA) and 20 of 23 (85%) had evidence of continuous flow of bubbles. In the 17 patients with adequate assessment, estimated pulmonary artery systolic pressure was 19.1 +/- 3.7 mmHg prior to the procedure and 23.3 +/- 3.4 following the procedure, a statistically significant difference (P < 0.05). There were no significant changes between the two groups in right ventricular end-diastolic area, end-systolic area, or fractional area change. CONCLUSION: Our study demonstrates a high frequency of continuous gas embolism during hysteroscopy, which is associated with a small but statistically significant increase in pulmonary artery systolic pressure without affecting right ventricular function.

Mifepristone followed by high-dose oxytocin drip for second-trimester abortion: a randomized, double-blind, placebo-controlled, pilot study.

OBJECTIVE: To study the effect of mifepristone for priming and induction of second-trimester abortion in conjunction with a high-concentration oxytocin drip. STUDY DESIGN: Prospective, randomized, placebo-controlled, pilot study. Thirty patients with 14-25 weeks' gestational age abortion received either 600 mg of mifepristone or placebo in 3 identical capsules followed, 48 hours later, by a high-concentration oxytocin drip (HCOD). RESULTS: The mifepristone group showed significantly higher success rates as compared to the placebo group (92.3% vs. 52.9%, p<0.05). The time interval to abortion (from beginning of HCOD) was also significantly shorter in the mifepristone group as compared to the placebo group (11.3 +/- 6.0 hours vs. 17.6 +/- 6.5 hours, p <0.05). Probability of success as calculated by the Kaplan-Meier method was found to be highly significant (log rank test p = 0.001). CONCLUSION: Our results suggest that mifepristone is very effective for priming and induction of second-trimester abortion and shortens significantly the time interval to evacuation following HCOD.

Uterine perfusion following laparoscopic clipping of uterine arteries at myomectomy.

Laparoscopic clipping of uterine arteries facilitates laparoscopic myomectomy with minimal blood loss. This paper shows the return to normal myometrial perfusion following this procedure with literary evidence of the safety and efficacy of this technique.

The natural course of endometrial polyps: could they vanish when left untreated?

OBJECTIVE: To report the occurrence of spontaneous regression of three endometrial polyps detected by hysteroscopy. DESIGN: Case series. SETTING: A uterine imaging unit in an academic medical center. PATIENT(S): Three patients diagnosed as having an endometrial polyp of 5-8 mm on hysteroscopy. INTERVENTION(S): Patient deferral of the surgical procedure for several months. MAIN OUTCOME MEASURE(S): Presence of a uterine polyp in the next hysteroscopy. RESULT(S): The polyps disappeared spontaneously. CONCLUSION(S): Deferral of hysteroscopic polypectomy for a few months in asymptomatic women in the hope of spontaneous regression of the polyps may be justified.

FGF 10 and Sprouty 2 modulate trophoblast invasion and branching morphogenesis.

Branching morphogenesis (BM) of the chorionic villous tree is a crucial component of early placental formation. Fibroblast growth factors (FGFs), their receptor tyrosine kinase (RTK) and negative regulators like Sprouty (Spry) proteins are pivotal factors in the development of diverse branching organ systems. The aim of this study was to examine the effect of FGF10 and Sprouty 2 on BM of the chorionic villi in vitro. Villous explants of first trimester placentas were cultured and their outgrowths were monitored. The effect of FGF10 was tested on matrigel migration/invasion assay, collagenolytic activity of single cell trophoblasts and on villous explants outgrowths. siRNA of Spry2 was used to reduce its expression and to investigate the role of Sprouty 2 in villous explants outgrowths. Quantitative RT-PCR and immunohistochemistry were performed to determine Sprouty 2 and HLA-G (a marker of invasion) expression. FGF 10 stimulated by 8-fold the migration/invasion of single cell trophoblast enhanced their collagenolytic activity. Reduction of Spry2 expression in villous explants showed a marked increase in villous outgrowths. This was accompanied by enhanced staining for HLA-G and by the reduction of Spry2 expression that was confirmed by immunohistochemistry and by quantitative RT-PCR. We conclude that trophoblast outgrowth and invasion (part of placental villi sprouting) at the fetal maternal interface is in part under delicate control of FGF 10 and Sprouty 2. FGF 10 promotes invasion and outgrowth of trophoblasts. In addition, it increases Spry2 expression, which attenuates trophoblast sprouting.

Decidual NK cells regulate key developmental processes at the human fetal-maternal interface.

Human CD56(bright) NK cells accumulate in the maternal decidua during pregnancy and are found in direct contact with fetal trophoblasts. Several mechanisms have been proposed to explain the inability of NK cells to kill the semiallogeneic fetal cells. However, the actual functions of decidual NK (dNK) cells during pregnancy are mostly unknown. Here we show that dNK cells, but not peripheral blood-derived NK subsets, regulate trophoblast invasion both in vitro and in vivo by production of the interleukin-8 and interferon-inducible protein-10 chemokines. Furthermore, dNK cells are potent secretors of an array of angiogenic factors and induce vascular growth in the decidua. Notably, such functions are regulated by specific interactions between dNK-activating and dNK-inhibitory receptors and their ligands, uniquely expressed at the fetal-maternal interface. The overall results support a 'peaceful' model for reproductive immunology, in which elements of innate immunity have been incorporated in a constructive manner to support reproductive tissue development.

Modified vulvar vestibulectomy: simple and effective surgery for the treatment of vulvar vestibulitis.

OBJECTIVE: To evaluate the success of a simple modified vestibulectomy in treating vulvar vestibulitis. STUDY DESIGN: Fifty-nine patients with vulvar vestibulitis refractory to nonsurgical treatment underwent modified vestibulectomy. Response was defined as return to normal coitus and was graded as complete, partial or non-responsive. RESULTS: The postoperative follow-up period was 6 months-10 years. Thirty-nine (73.6%) patients reported complete response, 7 (13.2%) had partial response, and 7 (13.2%) were non-responsive to surgery. CONCLUSION: Surgery is an effective treatment for vulvar vestibulitis refractory to conservative treatment. Simple modified vestibulectomy is considerably less invasive, technically simpler and probably less time consuming. Postoperative results employing this surgical procedure are found to be in line with postoperative results reported by others who employ surgical methods that are more extensive.

Fibroblast growth factor-10 and fibroblast growth factor receptors 1-4: expression and peptide localization in human decidua and placenta.

The development of the chorionic villous tree into a complex and organized ramified tubular network can be termed branching morphogenesis. Studying the molecular mechanisms involved in this process may contribute to the understanding of pregnancy complications such as preeclampsia. We hypothesized that fibroblast growth factor-10 (FGF-10) and fibroblast growth factor receptors 1-4 (FGFR 1-4) are expressed in human decidual and placental tissues. We analyzed the expression of FGF-10 and FGFRs 1-4 in 1st, 2nd and 3rd trimester placentas, as well as in decidua. RT-PCR and immunohistochemistry were employed to study mRNA and protein expression. FGF-10 was expressed by decidual cells and by cytotrophoblasts of the cytotrophoblast columns during all three trimesters. FGFR 1-4 were expressed in the placenta but not in the decidua. Placental expression of FGFRs was temporally regulated: In 1st trimester placentas, FGFR 1-4 were expressed by Hofbauer cells, FGFR-1 and FGFR-4 were expressed in cytotrophoblast columns, and the latter was also expressed by syncytiotrophoblasts. Similar expression was seen in 2nd trimester placentas with additional expression of FGFR-1 in blood vessel walls. The expression of FGFR-1 and FGFR-4 in the 3rd trimester was comparable to that seen in the 2nd trimester. The expression of FGF-10, FGFR-1 and FGFR-4 in the maternal-fetal interphase suggests their role in decidual-trophoblast interaction. The abundance of FGFR expression in Hofbauer cells implies that mesenchymal-trophoblast interaction is important for regulation of villous development.

The significance of intrauterine lesions detected by ultrasound in asymptomatic postmenopausal patients.

A retrospective study on 82 women with an incidental sonographic finding suspected to be intrauterine polyps was undertaken to assess the histopathologic characteristics of such polyps utilising operative hysteroscopy. Endometrial polyps were found in 68 patients, submucousal myomas in 7, atrophic endometrium in 6 and thickened proliferative endometrium was found in 1 patient. Simple hyperplasia was found in one polyp but neither endometrial carcinoma nor complex hyperplasia was found. The total complication rate was 3.6%. It appears that the risk of endometrial carcinoma in postmenopausal women with asymptomatic endometrial polyps is low, although a larger series is required to confirm this finding.

Growth factor receptor-protein bound 2 (GRB2) upregulation in the placenta in preeclampsia implies a possible role for ras signalling.

OBJECTIVES: To screen for genes with altered expression in placentas from pregnancies complicated by preeclampsia. STUDY DESIGN: To corroborate gene expression profile of preeclamptic and normal placentas (ATLAS Clontech), by dot blot, Northern blot analysis and RT-PCR for growth factor receptor bound-protein 2 (GRB2), using immunohistochemistry to localize its expression in the placenta. RESULTS: Increased expression of GRB2 upregulated in the microarrays was found in preeclampsia by Dot blot and Northern blot analysis. RT-PCR performed with primers specific for GRB2 and its alternatively spliced isoform GRB3-3 showed that most of the cDNA represented in the array was GRB2. The protein was localized to the smooth muscle wall of stem vessels by immunohistochemistry. CONCLUSION: The ras signalling activated by placental receptor tyrosine kinases may play a role in the segmental thickening of the stem vascular wall in preeclamptic placentas, resulting in reduced blood flow to the developing fetus.

Placental pathology in fetal thrombophilia.

The aim of this study was to test the hypothesis that placental vascular lesions of the fetal circulation are caused by fetal thrombophilic mutations. The study included 64 newborns of women with one or more of the following pregnancy complications: preeclampsia, placental abruption, and intrauterine growth restriction. The most prevalent inherited thrombophilias--factor V Leiden, factor II (prothrombin) G20210A, and homozygosity for methyltetrahydrofolate reductase C677T--were examined in maternal blood and fetal umbilical cord blood. One pathologist reviewed all of the slides for fetal vascular lesions. Associations between fetal thrombotic vasculopathy and fetal thrombophilia were tested for using Fisher's exact test; Z scores and gestational age were compared using the Student t-test. Fetal thrombophilic mutations were diagnosed in 19 of 64 newborns, 15 of whom had coexistent maternal thrombophilia. There was no statistical difference in the prevalence of thrombotic lesions of the fetal circulation between newborns with and without thrombophilia. The combination of maternal and fetal thrombophilia was also not associated with increased fetal vascular lesions. The results indicate that fetal thrombophilia alone, even in the context of maternal underperfusion, is not associated with fetal vascular lesions of the placenta, although it may represent an underlying risk factor for lesions triggered by other process(es).

Fetal inherited thrombophilias influence the severity of preeclampsia, IUGR and placental abruption.

OBJECTIVE: To determine whether common inherited thrombophilias in the fetus influence the severity of severe preeclampsia, IUGR and placental abruption. DESIGN: A case-control study among patients with complicated pregnancies. Cases were defined as fetuses with thrombophilia. SETTING: A university hospital with 3700 deliveries per year. POPULATION: Seventy cases with severe preeclampsia, IUGR or placental abruption. METHODS: Mothers and neonates were tested for mutation of factor V Leiden, prothrombin gene and methylenetetrahydrofolate reductase. MAIN OUTCOME MEASURES: Gestational age at delivery, birth weight and early neonatal complications. RESULTS: Gestational age at delivery and birth weight were significantly lower in fetuses with factor V Leiden or prothrombin gene mutation compared to control fetuses. CONCLUSIONS: Fetal factor V Leiden mutation and prothrombin gene mutation may influence the course of severe preeclampsia, IUGR and placental abruption. These thrombophilic changes may cause an earlier appearance or lead to a late pregnancy complication of a greater severity.

[Prenatal diagnosis of developmental congenital malformations--the limitations of ultrasound scanning].

Prenatal diagnosis of congenital malformations is a major goal of obstetric sonography. Although significant progress has been made in the ability to detect fetal anomalies by ultrasound, some fetal anomalies cannot be detected during second trimester routine ultrasound scanning. Among the "undiagnosed anomalies" are many fetal anomalies that follow a developmental course in-utero and have a late-onset sonographic appearance, and hence cannot be diagnosed early in pregnancy or during the traditional mid-second trimester scan. Several mechanisms cause in-utero development of fetal malformations, and the developmental course of each fetal anomaly depends on the cause, mechanism, extent and timing of the insult. In some cases the destructive or disruptive event might occur at a relatively advanced gestational age and thus go undiagnosed. Some malformations are the result of an early insult but are manifested and detected late, while others have a "late onset". This concept of the developmental natural course of fetal anomalies in-utero, must be recognized and lead to a new nomenclature for fetal malformations. In this review we describe some developmental fetal malformations and discuss the clinical, diagnostic and medicolegal implications.

[Fallopian tube prolapse after hysterectomy].

Fallopian tube prolapse is a rare complication of hysterectomy, characterized by vaginal discharge, abdominal pain, pelvic inflammatory disease and vaginal bleeding. The diagnosis is often delayed, and is usually done after an histopathological examination identifies fallopian tube on biopsy. The advised treatment is surgical resection, which can be done through vaginal incision, abdominally or by laparoscopy. We report a case of fallopian tube prolapse after vaginal hysterectomy in 47-year-old patient in whom the prolapsed-tube was successfully resected vaginally, and review the presentation and surgical methods to correct this rare complication.