Endometriosis and breast cancer: A survey of the epidemiological studies.

Endometriosis is a chronic gynecological disease with a wide spectrum of clinical manifestations that affects approximately 10% of women of reproductive age. Recent reviews have demonstrated the connection between endometriosis and breast cancer, which represents the most frequently diagnosed female cancer and the most common cause of cancer-related mortality among women worldwide. The aim of this study was to conduct a survey of available published epidemiological studies indicating the association between endometriosis and breast cancer, and simultaneously to categorize the results based on the strength of the association, with the intention of the critical evaluation of the existing data. We performed a rigorous search of the PubMed/Medline database, using the key words 'endometriosis' and 'breast cancer' for all studies published in the English language until September 2015. We found 4 retrospective cohort studies, 4 case-control studies and 3 case-cohort studies that demonstrated a notable risk for developing breast cancer among women with endometriosis. By contrast, we also found 5 case-control studies, 1 prospective cohort study, 1 case-cohort study and 1 cross-sectional study that demonstrated a negative association between endometriosis and breast cancer. In conclusion, as regards the clarification of a 'robust' or 'weak' association between endometriosis and breast cancer, no definite conclusions could be drawn, due to the limited number of studies and the limitations of each of these studies. New well-designed, prospective cohort or randomized control trials with long-term follow-up are warranted in order to provide evidence-based clinical recommendations for proper counseling, screening and treatment strategies for patients with endometriosis, and hence to improve public health.

Role of the angiopoietin/Tie system in pregnancy (Review).

Angiopoietin-1 and -2 are endogenous ligands for the vascular endothelium-specific receptor tyrosine kinase Tie-2. The angiopoietin/Tie system plays a critical role in the regulation of endothelial cell survival and vascular maturation and stability. Apart from its well-established role in vascular morphogenesis, emerging data support the involvement of angiopoietins in inflammation and various malignancies. Previous studies have underlined the significance of several angiogenic factors in normal placental development. In addition, angiogenic imbalance is observed in pregnancy complications related to impaired placentation, such as preeclampsia (PE) and intrauterine growth restriction (IUGR). However, there is only limited information available on the role of the angiopoietin/Tie system in the establishment of a competent feto-maternal vascular system. In this review, we present the current knowledge regarding the role of angiopoietins in normal pregnancy and pregnancy complications.

Placental mRNA expression of angiopoietins (Ang)-1, Ang-2 and their receptor Tie-2 is altered in pregnancies complicated by preeclampsia.

OBJECTIVE: To investigate the placental expression of angiopoietin (Ang)-1, Ang-2 and their receptor, Tie-2, in preeclampsia (PE) with or without intrauterine growth restriction (IUGR). METHODS: Case-control study including placentas from 28 PE pregnancies, 30 PE-IUGR pregnancies and 40 controls. The expression status of the genes was evaluated by quantitative real-time PCR. RESULTS: In both PE and PE-IUGR groups, compared to the control group, there was significantly higher expression of Ang-2 (p < 0.001) and Tie-2 (p = 0.008) and lower expression of Ang-1 (p = 0.001). The magnitude of the difference was similar for Ang-1 for both groups, whereas the magnitude of the differences was higher for Ang-2 and Tie-2 in PE-IUGR group compared to controls. Ang-2 and Tie-2 were correlated in both PE (r = 0.8602, p < 0.001) and PE-IUGR (r = 0.6342, p < 0.001) groups. In PE-IUGR group, Ang-1 was associated to Ang-2 (r = 0.3458, p = 0.0452) and Tie-2 (r = 0.4448, p = 0.0084). Log10Ang-1 but not Ang-2 was gestational age dependent (R2 = 0.40, p < 0.001). After conversion in Multiples of the Median (MoM) log10 MoM Ang-1 was reduced in the PE group (mean = -0.8181, p < 0.001) and the PE-IUGR group (mean = -1.2583, p < 0.001) compared to control group (mean = -0.0924). DISCUSSION: We have demonstrated increased placental expression of Ang-2 and Tie-2 along with lower expression levels of Ang-1 in pregnancies with PE and PE-IUGR. CONCLUSION: The angiopoietin axis seems to be disrupted in PE pregnancies. Whether the results of this study represent the angiogenic imbalance observed in PE pregnancies or they are part of the pathophysiology of this condition has to be further investigated.

Dialkyl phosphates in amniotic fluid as a biomarker of fetal exposure to organophosphates in Crete, Greece; association with fetal growth.

The aim of this study was to evaluate fetal exposure to organophosphate pesticides (OPs) by measuring their non-specific dialkyl-phosphate metabolites (DAPs) in amniotic fluid (AF), and to examine the potential association between prenatal exposure and fetal growth. AF samples were collected from 415 women during the second gestational trimester. The determined OPs metabolites were DMP, DMTP, DEP, DETP, and DEDTP. DAPs were extracted by liquid-solid extraction, derivatized and analyzed by gas chromatography-mass spectrometry. 97.8% of AF samples were positive for at least one DAP. DAPs levels did not differ between urban and rural areas. Macrosomic neonates have significantly higher sum levels of DMPs (p=0.043), which exerted a linear positive association with birth-weight centile (b=4.43, p=0.016). Conclusively, as DAPs are detectable in AF they may be used as a potential biomarker of fetal exposure to OPs. Sum levels of DMPs appear to be associated with birth weight independently of other covariates.

Partial trisomy 2p and partial monosomy 2q arising from a paternal intrachromosomal 2q-into-2p between-arm insertion and paracentric inversion: molecular cytogenetic characterization of a four-break rearrangement.

We report on a 26-month-old boy with an interstitial duplication of 2p22.3p22.2 and an interstitial deletion of 2q14.1q21.2. The abnormality was derived from his father having a balanced paracentric inversion and pericentric insertion. The deletion in the child was identified by cytogenetic analysis and characterized in more detail by molecular cytogenetics and array comparative genomic hybridization. The latter revealed a 20-Mb deletion in the long arm and a 5.6-Mb duplication in the short arm of chromosome 2. Fluorescence in situ hybridization in paternal chromosomes characterized an intrachromosomal insertion of 2q14.1q21.2 into 2p23; additionally a paracentric inversion of 2p13p23 was observed. The boy with the unbalanced karyotype suffered from severe psychomotor retardation, thrombophilia due to protein C deficiency, and hypertrophic cardiomyopathy and also had phenotypic abnormalities. Most of these features have previously been described in individuals with interstitial deletion of 2q14.1.

Corticotropin-releasing hormone and progesterone plasma levels association with the onset and progression of labor.

UNLABELLED: PURPOSE OF LNVESTIGATION: To examine the relationship between maternal plasma progesterone along with corticotropin- releasing hormone (CRH) plasma levels and the progression of labor. MATERIALS AND METHODS: Maternal serum CRH and progesterone were measured during the latent phase of labor, active labor, and 24 hours postpartum in women who went into spontaneous labor and delivered vaginally at term. Progesterone (P) levels in women delivered by an elective cesarean section at term were also measured as baseline. RESULTS: Mean maternal plasma P was 18% higher in the active phase than in the latent phase of labor (p < 0.01), and declined significantly by 24 hours postpartum (p < 0.001). Mean level of serum CRH was 24% higher in the active phase than in the latent phase of labor (p < 0.01), and subsequently declined significantly by 24 hours postpartum (p < 0.001). CONCLUSIONS: As labor progresses, P and CRH increase and subsequently decrease precipitously in the immediate postpartal period. P levels tend to drop in women who are in early labor compared with non-laboring full-term women.

Mediators of chronic inflammation in polycystic ovarian syndrome.

Polycystic ovarian syndrome (PCOS) is an endocrine disorder affecting 5-10% of reproductive-age women. Hyperandrogenemia, which characterizes the syndrome, stimulates the maturation of adipocytes and favors central obesity. The linking hub between obesity and other metabolic manifestations of the syndrome seems to be chronic low-grade inflammation. We discuss the most reliable current data regarding the role of inflammatory mediators in PCOS, with particular focus on the genetic mechanisms implicated. C-reactive protein levels are 96% higher in PCOS patients than in healthy controls. Patients with the -308A polymorphism of the tumor necrosis factor-α gene have elevated androgens in comparison with carriers of the -308G. Interleukin 18 (IL-18) is elevated in lean patients, with a further rise in the presence of obesity and insulin resistance. Polymorphisms of the IL-1a, IL-1b and IL-6 genes have also been associated with PCOS. Plasminogen activator inhibitor-1 levels are positively associated with the syndrome, and carriers of the 4G allele of the 4G/5G polymorphism are at risk of developing PCOS. Other mediators discussed include adhesion molecules, osteoprotegerin, asymmetric dimethylarginine, homocysteine and advanced glycation end-products. The elucidation of the pathogenetic mechanisms implicated in PCOS and their connection with low-grade inflammation may in the future offer the opportunity for the formulation of novel therapeutic strategies and individualized therapy for these patients.

Three-dimensional ultrasound and three-dimensional power Doppler improve the preoperative evaluation of complex benign ovarian lesions.

PURPOSE OF INVESTIGATION: To evaluate the diagnostic accuracy of three-dimensional ultrasound (3D-US) and three-dimensional power-Doppler (3DPD-US) as adjuncts to conventional B-mode-US in evaluation of complex benign ovarian lesions. METHODS: Transvaginal B-mode-US, 3D-US and 3DPD-US were performed in 29 patients with unilateral ovarian lesion. Patients were classified as low or high risk for malignancy according to a standardized scoring system composed of ten morphological and vascular parameters. Preoperative scores were matched to the histological results and the diagnostic performance of the scoring system was calculated. RESULTS: Seven out of the 16 cases of endometriomas (44%) were graded as low risk masses according to B-mode-US, while the addition of 3D-US and 3DPD-US increased the accuracy to 56% and 94%, respectively. All dermoid cysts were classified as high risk cases by B-mode-US, but 3D-US and 3DPD-US correctly classified 14% and 57% of cases, respectively. The use of B-mode-US, 3D-US and 3DPD-US correctly classified all four cystadenomas. Only the use of 3DPD-US correctly classified one out of two hemorrhagic corpus luteum cases, whereas the other imaging modalities characterized these lesions as high risk. The overall diagnostic accuracy increased from 38%, 48%, ana 83% with the application of B-mode-US alone, or combined with 3D-US and 3DPD-US, respectively. CONCLUSION: Conventional ultrasound supplemented with 3D-US and 3DPD-US and the evaluation of findings according to a specific scoring system can facilitate the preoperative classification of complex benign ovarian lesions.

Maternal serum insulin-like growth factor-binding protein-3 (IGFBP-3) at 11-13 weeks in preeclampsia.

The objective of this study was to determine if the maternal serum concentration of insulin-like growth factor-binding protein-3 (IGFBP-3) at 11-13 week's gestation is altered in pregnancies that subsequently develop preeclampsia (PE). Maternal serum concentration of IGFBP-3, pregnancy-associated plasma protein-A (PAPP-A) and uterine artery pulsatility index (PI) were measured in 60 cases that developed PE, including 20 that developed early-PE requiring delivery before 34 weeks, and compared with 120 unaffected controls. In the unaffected pregnancies, the median multiple of the normal median (MoM) values of serum IGFBP-3, PAPP-A and uterine artery PI were 1.0 MoM. In late-PE, but not in early-PE, serum IGFBP-3 was significantly increased (1.16 and 1.06 MoM, respectively), whereas in early-PE, but not in late-PE, uterine artery PI was increased (1.41 and 1.11 MoM, respectively) and serum PAPP-A was decreased (0.53 and 0.87 MoM, respectively). In the PE group, there was no significant association between IGFBP-3 and either uterine artery PI (P=0.775) or maternal serum PAPP-A (P=0.275). First-trimester serum IGFBP-3 is increased in pregnancies that subsequently develop late-PE in a mechanism that is unrelated to impaired placentation, as reflected in uterine artery PI and serum PAPP-A.

Hypomethylation along with increased H19 expression in placentas from pregnancies complicated with fetal growth restriction.

The expression of imprinted genes is regulated by epigenetic modifications, such as DNA methylation. Many imprinted genes are expressed in the placenta and affect nutrient transfer capacity of the placental exchange barrier. The H19 gene is abundantly expressed by the human placenta and is implicated in the pathogenesis of congenital growth disorders such as Beckwith-Wiedemann (BWS) and Silver-Russell (SRS) syndromes. The aim of this study was to investigate the role of DNA methylation on H19 transcription and imprinting, in the pathophysiology of fetal growth restriction (FGR). Thirty one and 17 placentas from FGR-complicated and normal pregnancies were collected, respectively. We studied gene transcription, genotyping and methylation analysis of the AluI H19 on exon 5 polymorphism. Placental expression levels of H19 were significantly increased in the FGR group. The H19 mRNA levels were similar between normal placental samples that demonstrated loss and maintenance of imprinting. Placentas from growth-restricted pregnancies had lower methylation levels compared to normals, in the H19 promoter region. We have demonstrated an increased H19 transcription in the FGR group of placentas. The hypomethylation of the H19 promoters is compatible with the aberrant expression. The association of these two findings is reported for the first time in placental tissues, however, its significance remains unknown. Whether the results of this study represent an adaptation of the placenta to hypoperfusion, or they are part of FGR pathophysiology has to be further investigated.

Reduced placental prolyl hydroxylase 3 mRNA expression in pregnancies affected by fetal growth restriction.

OBJECTIVE: To investigate the role of the hypoxia-inducible factor (HIF) pathway in fetal growth restriction (FGR). DESIGN: A case-control study. SETTING: Research laboratory and gynaecology clinic. SAMPLE: Twenty placentas from normal pregnancies and 20 from FGR pregnancies. METHODS: RNA extraction, cDNA synthesis, quantitative real-time polymerase chain reaction (qRT-PCR) assay, statistical analysis. MAIN OUTCOME MEASURES: mRNA expression of HIF-1α, HIF-2α and HIF-ß (ARNT), along with prolyl hydroxylase domain 3 (PHD3), which leads to proteasomal degradation of HIF-α subunits. RESULTS: No statistically significant differences in the transcription levels of ARNT and HIF-2α were found between FGR and normal placentas. By contrast, PHD3 and HIF-1α mRNA were downregulated in FGR placentas. PHD3 mRNA expression was associated with gestational age at delivery (P = 0.008), birthweight centile (P = 0.029) and abnormal umbilical artery (UA) Doppler measurements (P = 0.034). CONCLUSIONS: As PHD3 regulates the HIF-mediated hypoxic response in FGR, we deduce that fetal adaptation to hypoxia ranges from impaired to adequate, as observed by the gradient of PHD3 downregulation in relation to the severity of FGR.

Intrauterine inflammation and preterm delivery.

Spontaneous preterm delivery, prematurity, and low birth weight due to prematurity account for a great part of neonatal morbidity and mortality. Specifically, chronic amniotic fluid inflammation may cause preterm labor, with the involvement of different mediators that produce diverse aspects of the inflammatory response. Although bacteria are considered to be the main trigger for intrauterine infection/inflammation, viral infections also appear to be involved. Recently, molecular genetic techniques have helped us better understand the underlying pathophysiologic processes. This is especially important because epidemiological and experimental studies indicate that intrauterine infection and inflammation constitute a risk factor for adverse neurological outcome in preterm infants. Chronic subclinical chorioamnionitis associated with preterm birth can also modify lung development. Although no current clinical strategy is aimed at adapting the maternofetal inflammatory response, immunomodulators may serve as a future intervention in preterm embryos.

Sonographic findings in severe fetomaternal transfusion.

Fetomaternal hemorrhage (FMH) or fetomaternal transfusion syndrome is the leakage of fetal red blood cells into the maternal circulation. Massive FMH can cause substantial fetal morbidity and mortality. Sonographic evidence of severe FMH syndrome includes fetal hydrops and other fetal anemia-related findings. The peak systolic velocity in the middle cerebral artery has extensively been used for the prediction of fetal anemia and for the timing of the first intrauterine intravascular transfusion (IIVT). We present a case of severe FMH syndrome that was diagnosed during the 24th week of pregnancy. A total of eight IIVT were performed. The actual increase in the fetal Hb after each transfusion was much lower than the expected. At 27 weeks of gestation, sonographic evaluation revealed areas of echogenicity around the posterior horns of the lateral ventricles suggesting ischemic damage. Due to these findings, no further IIVTs were offered and the fetus died a week later. The management of fetal anemia caused by severe FMH is difficult, and the anemic fetuses do not respond well to serial IIVTs as the transfer of blood to the maternal circulation continues.

The replacement of cytogenetic analysis by direct chorionic villi sampling preparation with quantitative fluorescence PCR.

AIM: The aim of this study is to assess the replacement of chromosomal analysis of chorionic villi (CV) direct preparation samples (DIR) by quantitative fluorescence PCR (QF-PCR) and to determine its advantages in routine prenatal diagnosis. METHODS: From a total of 4,020 CV samples, rapid results were obtained either by conventional cytogenetic analysis of DIR in 2,770 samples, or by QF-PCR analysis in 1,250 samples. The final results were given after long-term culture (LTC). RESULTS: The frequencies of unbalanced fetal karyotypes were not significantly different, being 4.8% by DIR-LTC and 4.3% by QF-PCR-LTC. No false-negative or false-positive results were obtained from either approach. CONCLUSION: QF-PCR can replace chromosomal analysis of CV-DIR in most cases during routine prenatal diagnosis, requiring smaller CV samples and being more labor effective. Coupled with LTC, it is a robust diagnostic approach with high predictive value for the most frequent fetal trisomies.

Dialkyl phosphates in meconium as a biomarker of prenatal exposure to organophosphate pesticides: a study on pregnant women of rural areas in Crete, Greece.

The authors developed a sensitive analytical method for the determination of dialkyl phosphates (DAPs) in meconium. This method was applied to determine the DAPs, which are non-specific metabolites of the organophosphate pesticides (OPs), in meconium of newborns by mothers who live in rural areas in Crete, Greece. DAPs are considered as biomarkers of exposure to OPs. Meconium is produced in the foetus at approximately 16 weeks of gestation and it acts as a repository of many xenobiotics. The determined organophosphate metabolites were dimethylphosphate (DMP), diethylphosphate (DEP), dimethylthiophosphate (DMTP), diethylthiophosphate (DETP), and diethyldithiophosphate (DEDTP). The DAPs were extracted from meconium by liquid-solid extraction, derivatized, and analysed by gas chromatography-mass spectrometry (GC-MS). The mean percentile recoveries were 76.9%, 65.2%, 94.1%, 109.4%, and 107.2% for DMP, DEP, DMTP, DETP, and DEDTP, respectively. The percentage of positive samples was 92.1% for DMP, 36.8% for DEP, 60.5% for DMTP, 63.2% for DETP, and 57.9% for DEDTP. Mean (+/- standard deviation) and the range concentrations of the positive samples (ng g(-1)) were 126.74 +/- 142.73 (10.64-739.45), 11.46 +/- 20.43 (1.50-79.14), 215.05 +/- 187.34 (8.54-662.16), 4.92 +/- 5.09 (1.25-19.04), and 1.84 +/- 2.07 (0.5-8.04) for DMP, DEP, DMTP, DETP, and DEDTP, respectively. Statistical analysis revealed no significant difference in meconium levels between high- and low-risk groups of exposure of pregnant women. However, the results of this study demonstrate that DAPs in meconium may be considered as a potential biomarker for the assessment of foetal exposure to organophosphate pesticides.

Increased levels of human placental growth hormone in the amniotic fluid of pregnancies affected by Down syndrome.

OBJECTIVE: To evaluate the concentrations of human placental growth hormone (hPGH) in amniotic fluid (AF) at gestational mid-trimester in normal pregnancies and in pregnancies complicated by Down's syndrome. DESIGN: AF samples from 21 women with Down's syndrome pregnancies were analyzed retrospectively. About 47 AF samples from women with singleton, uncomplicated pregnancies, who gave birth to healthy neonates with birth weight appropriate for gestational age were used as controls. All AF samples were obtained during amniocentesis for fetal karyotyping at 16-23 weeks' gestation. hPGH levels were measured by a solid phase immunoradiometric assay using two different epitopes. RESULTS: The mean hPGH values in the AF of the Down's syndrome-affected pregnancies were significantly higher (P<0.05) compared to those of normal pregnancies, at 16-23 weeks' gestation: mean-value+/-SD in the AF was 1.96+/-1.35 microg/l vs. 0.82+/-0.67 microg/l. CONCLUSIONS: Higher hPGH levels in AF were found in pregnancies affected by Down's syndrome as compared to normal pregnancies at gestational mid-trimester. hPGH was detected in all AF samples, and it provides evidence that this pregnancy-specific hormone enters the fetal compartment and is not limited to the maternal circulation. The physiological role and effect of hPGH on fetal growth in normal and pathological pregnancies needs further investigation.

Hydrops fetalis, thickened placenta and other sonographic findings in a low-level trisomy 21 mosaicism: a case report.

We report a case of trisomy 21 mosaicism detected upon amniocentesis in a 36-year-old woman. Ultrasound examination at 23 weeks' gestation showed a fetus with hydrops, pulmonary hypoplasia, oligohydramnios, thickened placenta, and intrauterine growth retardation. Cytogenetic analysis revealed low-percentage (6%) mosaicism for trisomy 21. Hydrops fetalis and thickened placenta are uncommon findings in fetuses affected by trisomy 21 mosaicism. A short review of the literature is given regarding the sonographic findings associated with trisomy 21 mosaicism, and the genetic counseling in such cases.

A stillborn fetus with amniotic band syndrome and elevated levels of alpha-fetoprotein plus beta-human chorionic gonadotropin: a case report.

Amniotic band syndrome is an uncommon, congenital fetal abnormality with multiple disfiguring and disabling manifestations. A wide spectrum of clinical deformities are encountered and range from simple ring constrictions to major craniofacial and visceral defects. We report a case of constriction amniotic bands involving upper extremities and intrauterine fetal death due to strangulation of umbilical cord. Abnormally elevated levels of alpha-fetoprotein and beta-chorionic gonadotropin were detected at 17 weeks' gestation. They were probably caused by the loss of cutaneous integrity of the fetus (alpha-fetoprotein), and by the placental attempt to counteract the fetal growth restriction and hypoxia, due to the strangulation of umbilical cord by the amniotic bands (beta-chorionic gonadotropin).