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Objectives: To compare soluble-ST2 (sST2) concentrations in patients with severe features of preeclampsia and healthy pregnant controls before as well as 1 year after delivery. Another objective wa...

A low Apgar score is associated with increased risk of cerebral palsy (CP) in term infants, while such association remains controversial in preterm neonates. The objective of this study was to assess association between 5-minute Apgar scores and CP in different subcategories of preterm birth based on gestational age. The Slovenian National Perinatal Information System was used to identify singleton children without congenital malformations live-born at 22 to 37 weeks of gestation between 2002 and 2010. Data were linked to the Slovenian Registry of Cerebral Palsy in children born between 2002 and 2010. CP was diagnosed at a minimum of 5 years of age. Of 11,924 children included, 241 (2.0%) died before discharge and 153 (1.3%) were diagnosed with CP. Five-minute Apgar scores 32 weeks a low 5-minute Apgar score was associated with CP.

Objective: To examine the correlation between plasma cerebral biomarkers (S100B and neuron-specific enolase (NSE)) and ultrasonographic optic-nerve-sheath-diameter (ONSD) in preeclampsia. Methods: ...

Adequate levels of folates are essential for homeostasis of the organism, prevention of congenital malformations, and the salvage of predisposed disease states. They depend on genetic predisposition, and therefore, a pharmacogenetic approach to individualized supplementation or therapeutic intervention is necessary for an optimal outcome. The role of folates in vital cell processes was investigated by translational pharmacogenetics employing lymphoblastoid cell lines (LCLs). Depriving cells of folates led to reversible S-phase arrest. Since 5,10-methylenetetrahydrofolate reductase (MTHFR) is the key enzyme in the biosynthesis of an active folate form, we evaluated the relevance of polymorphisms in the MTHFR gene on intracellular levels of bioactive metabolite, the 5-methyltetrahydrofolate (5-Me-THF). LCLs (n = 35) were divided into low- and normal-MTHFR activity groups based on their genotype. They were cultured in the presence of folic acid (FA) or 5-Me-THF. Based on the cells' metabolic activity and intracellular 5-Me-THF levels, we conclude supplementation of FA is sufficient to maintain adequate folate level in the normal MTHFR activity group, while low MTHFR activity cells require 5-Me-THF to overcome the metabolic defects caused by polymorphisms in their MTHFR genes. This finding was supported by the determination of intracellular levels of 5-Me-THF in cell lysates by LC-MS/MS. FA supplementation resulted in a 2.5-fold increase in 5-Me-THF in cells with normal MTHFR activity, but there was no increase after FA supplementation in low MTHFR activity cells. However, when LCLs were exposed to 5-Me-THF, a 10-fold increase in intracellular levels of this metabolite was determined. These findings indicate that patients undergoing folate supplementation to counteract anti-folate therapies, or patients with increased folate demand, would benefit from pharmacogenetics-based therapy choices. Nasl. z nasl. zaslona. Opis vira z dne 18. 9. 2020. Članek št. 2836. Abstract. Bibliografija: str. 15-18. ARRS ARRS ARRS ARRS

Purpose: To determine whether high-dose intravenous vitamin C reduces oxidative stress in patients with severe preeclampsia in the first days postpartum. Methods: Biomarkers of oxidative stress were assessed as secondary outcomes of a single-center, randomized, placebo-controlled trial. Thirty-four patients with singleton pregnancies complicated by severe features of preeclampsia were randomized into two groups: intravenous vitamin C (1.5 g/6 h) (n = 17) or placebo (n = 17). Urinary concentrations of dityrosine, 8-hydroxy-2-deoxyguanosine (8-OHdg), 8-isoprostane, and N epsilon-(hexanoyl) lysine (HEL) were measured at days one and three after delivery and normalized for urinary creatinine in 22 of patients included (12 in vitamin C and 10 in placebo group). The Mann&ndash, Whitney U-test was used to compare values of oxidative stress biomarkers at days one and three after delivery in vitamin C vs. placebo groups (p &le, 0.05 significant). Results: Dityrosine and 8-OHdg values did not differ significantly between the two study groups at day one after delivery (p = 0.23 and p = 0.77, respectively), but were significantly lower in the vitamin C group compared to the placebo group at day three after delivery (p = 0.04 and p = 0.03, respectively). Values of 8-isoprostane and HEL did not differ significantly between the two study groups at day one (p = 0.41 and p = 0.42, respectively), as well as at day three, after delivery (p = 0.25 and p = 0.24, respectively). Conclusion: High-dose intravenous vitamin C treatments in patients with severe preeclampsia reduced urinary levels of dityrosine and 8-OHdg (markers of protein and DNA oxidative damage, respectively) on day three after delivery. Vitamin C treatment had no significant effect on lipid peroxidation biomarkers, i.e., 8-isoprostane and HEL.

Aiming at triggering in-depth research of the problem of Premature Ovarian Insufficiency (POI) in Slovenia, we assessed the regional differences in POI incidence emphasising the relationship with social and physical environmental factors at the population level using a mapping approach. The differences in POI incidence between regions were tested by goodness-of-fit chi-square test, while Pearson correlation coefficient was used to assess the ecological relationship between POI incidence and selected environmental indicators. Significant indicators were mapped. The results showed highly significant interregional differences in POI incidence (p

Inadequate folate status is detrimental to human development. Deficiency has been implicated in congenital birth defects and cancer, whereas excess has been linked to various negative neurocognitive development outcomes. We developed a method for translational studies involving lymphoblastoid cell models for studying role of folates in vital cell processes. We describe a simple, sensitive, and fast liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of intracellular concentrations of clinically important metabolites of folate-homocysteine cycle; namely, folic acid (FA), 5-methyltetrahydrofolate (5-Me-THF), and homocysteine (Hcy). The method was validated for specificity, linearity, limits of quantification, repeatability, reproducibility, matrix effects, and stability. Method had a wide linear range between 0.341 and 71.053 ng Hcy/mg protein for Hcy, 0.004-0.526 ng FA/mg protein for FA and 0.003-0.526 ng 5-Me-THF/mg protein for 5-Me-THF. The method overcomes challenges associated with the quantification of endogenous molecules, poor stability, and extremely small amounts of the analytes. The method was successfully applied to evaluate the effects of FA and 5-Me-THF treatment of cells in vitro mimicking supplement therapy with various metabolically active species, and showed that 5-Me-THF is more effective than FA in increasing intracellular levels of the biologically active form of folate. Št. članka: 113830. Bibliografija: str. 11-12. Abstract. ARRS ARRS ARRS European Regional Development Fund, EATRIS-TRI.si

AIM The effectiveness of vaginal progesterone for maintenance tocolysis after arrested preterm labor remains controversial. Myometrial contractility can be assessed objectively and non-invasively after progesterone treatment by monitoring uterine electromyography (EMG). We examined the effects of vaginal progesterone on uterine EMG after successful acute tocolysis. METHODS This was a randomized, double-blind, single-center study performed between 2012 and 2015. Thirty women who experienced preterm labor between 24 0/7 and 33 6/7 weeks were randomly allocated to groups administered either 400 mg vaginal progesterone or a placebo 48 h after acute tocolysis. EMG measurements were taken prior to and 1 h and 2 h following treatment. Mann-Whitney U tests were used to compare EMG power density spectrum peak frequency and peak amplitude, propagation velocity of EMG signals, and duration and number of EMG bursts in 30 min recordings between the groups (P

Objective: It has been shown that noninvasive uterine electromyography (EMG) can identify true preterm labor more accurately than methods available to clinicians today. The objective of this study was to evaluate the effect of body mass index (BMI) on the accuracy of uterine EMG in predicting preterm delivery. Materials and Methods: Predictive values of uterine EMG for preterm delivery were compared in obese versus overweight/normal BMI patients. Hanley–McNeil test was used to compare receiver operator characteristics curves in these groups. Previously reported EMG cutoffs were used to determine groups with false positive/false negative and true positive/true negative EMG results. BMI in these groups was compared with Student t test (p

Less than 10% of medicines approved by the FDA since 1980 have provided enough information as regards risks for birth defects associated with their use (Adam et al. (2011) [1]). Nevertheless, it is estimated that over 90% of pregnant women take over-the-counter (OTC) or prescription medication (Ke et al., 2014 [2]). Considering the fact that the use of medication in the period before conception and during lactation can also influence the development of the child, information on the impact of their usage during reproductive life is important for everyone. The lack of clear information on this topic results in situations where life-saving medication is discontinued, withheld or used in a reduced dosage by pregnant women, while on the other hand medicines with (potential) toxic effects are taken. This is unacceptable and it is a major public concern that must be addressed. Currently, Europe lacks a robust and comprehensive information system about medication use in reproductive life (from preconception, during pregnancy and during lactation). In order to improve maternal health, and subsequently the health of our next generation, reliable and up to date information should be made available. It should be readily accessible for both health care providers and women who are considering getting pregnant or who are already pregnant. In order to tackle this gap in public health, this paper describes current knowledge of the use of medicines before and during pregnancy. It calls upon all stakeholders involved in medical care, research and medicine regulation, such as policy makers, regulators and governmental agencies, to take action to protect patients and improve public health.

Objective: To determine the levels of 8-isoprostane (8-IP) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) in urine and in amniotic fluid (AF) of pregnant women and to assess the correlation between oxidative status in the maternal and fetal compartment in the second trimester of pregnancy. Methods: One hundred and forty-six women with singleton pregnancies, undergoing amniocentesis at the Department of Obstetrics and Gynaecology at the University Medical Centre Ljubljana, were prospectively enrolled. AF and maternal urine were collected in the second trimester of pregnancy. Paired urinary and AF 8-IP and 8-OHdG were measured and evaluated cross-sectionally. Results: 8-IP and 8-OHdG concentrations were higher in maternal urine compared to AF and the ratios were 47:1 and 50:1, respectively. AF 8-OHdG was very low and in 74% was below the limit of detection (LOD). We found a positive correlation between 8-IP in maternal and fetal compartment (ρ=0.217, P=0.008), which stayed unchanged also after adjustment for possible confounding factors. Conclusions: Oxidative damage to lipids and DNA is also a part of physiologic processes during healthy pregnancy. 8-IP and 8-OHdG are constantly present in urine and AF. A weak positive correlation between maternal and fetal unit suggests a weak reflection of fetal oxidative status in maternal urine in the mid-trimester.

Background Identifying the risk factors for preeclampsia (PE) is essential for the implementation of preventive actions. In the present study, we aimed at exploring the association between total gestational weight gain (GWG) and PE. Methods We performed a population-based cohort survey of 98,820 women with singleton pregnancies who delivered in Slovenia from 2013 to 2017. Aggregated data were obtained from the National Perinatal Information System (NPIS). The main outcome measure was the incidence of PE. The main exposure variable was total GWG standardized for the gestational duration by calculating the z-scores. The associations between total GWG and PE stratified by pre-pregnancy body mass index (BMI) categories adjusted for a variety of covariates were determined using multivariable logistic regression. We calculated the crude odds ratio (OR) and adjusted odds ratio (aOR) with a 95% confidence interval using a two-way test. Results Excessive GWG was associated with increased odds of PE in all pre-pregnancy BMI categories. The increase in the odds of PE by 445% was the highest in underweight women and by 122% was the lowest in obese women. Low GWG was associated with decreased odds of PE in all pre-pregnancy BMI categories except in normal-weight women with a GWG below −2 standard deviation (SD) and underweight women. The decrease in the odds of PE by 67% was the highest in obese women and by 41% was the lowest in normal-weight women. Conclusion Excessive GWG is a significant risk factor for PE, especially in underweight women, while low GWG is an important protective factor against PE, especially in obese women.

Objective To explore correlations between the sFlt-1/PlGF ratio and uterine arteries (UtA) Doppler indexes in placental dysfunction-related disorders (PDD). Methods We prospectively included women with a singleton pregnancy with preeclampsia (PE) only (n = 22), preeclampsia with fetal growth restriction (FGR) (n = 32), FGR only (n = 12), or normal pregnancy (n = 29). Results In PDDs, significantly positive correlations between the sFlt-1/PlGF ratio and the mean UtA pulsatility (mPI-UtA), as well as the resistance index (mRI-UtA) were found (p = 0.015, p = 0.019, respectively), but not in normal pregnancies. PDD with signs of impaired placentation, evidenced by the increased sFlt-1/PlGF ratio and mPI-UtA, was found in 50.0%, and, by the increased sFlt-1/PlGF ratio and mRI-UtA, in 65.2%. PDD without signs of impaired placentation, evidenced by the increased sFlt-1/PlGF ratio but normal mPI-UtA, was found in 24.2%, and, by the increased sFlt-1/PlGF ratio but normal mRI-UtA, in 7.6%. A substantial proportion of women with signs of impaired placentation were diagnosed with FGR with or without PE. Conclusion In PDD, the sFlt-1/PlGF ratio and UtA Doppler indexes increase proportionally. Correlations between the sFlt-1/PlGF ratio and UtA Doppler indexes might help to distinguish between PDDs with and without impaired placentation. However, further studies are needed to explore the correlations in different phenotypes of PDD.

Folate is vital for cell development and growth. It is involved in one-carbon transfer reactions essential for the synthesis of purines and pyrimidines. It also acts in conjunction with cobalamin (vitamin B12) as a fundamental cofactor in the remethylation cycle that converts homocysteine to methionine. A deficiency in folate or vitamin B12 can lead to elevated homocysteine level, which has been identified as an independent risk factor in several health-related conditions. Adequate folate levels are essential in women of childbearing age and in pregnant women, and folate deficiency is associated with several congenital malformations. Low folate levels can be caused by dietary deficiencies, a genetic predisposition or treatment with medicines that affect folate concentration. Women who are pregnant or of child-bearing age commonly use medicines, so it is important to identify the basic biochemical mechanisms by which medicines interfere with the folate–homocysteine–methionine pathway. This review focuses on prescription medicines associated with folate disruption. It also summarizes their undesirable/toxic effects. Recommendations regarding folate supplementation during medical therapy are also reviewed.

The objective of this study was to identify new environmental and genetic risk factors for orofacial clefts that arise during early foetal development. In this retrospective, case-control, mother-child pair study, 172 orofacial clefts cases and 199 healthy controls, and their respective mothers, were genotyped for common variants in relevant genes obtained by text and database mining using STRING 10.0. Exposure to environmental risk factors was evaluated using questionnaires. Variant glycine N-methyltransferase (odds ratio (OR) 2.1, 95% confidence interval (95% CI) 1.0-4.4) and dihydrofolate reductase (OR 2.4, 95% CI 1.3-4.5) genotypes were identified as risk factors for cleft lip with or without cleft palate formation. Furthermore, synergy was detected between variant glycine N-methyltransferase and dihydrofolate reductase genotypes in promoting cleft lip with or without cleft palate formation (OR 7, 95% CI 2-23). This study is novel in finding that common glycine N-methyltransferase variant genotypes increase the risk of cleft lip with or without cleft palate.

INTRODUCTION In a prospective study in a tertiary university hospital we wanted to determine whether uterine electromyography (EMG) can differentiate between the active and latent phase of labor. MATERIAL AND METHODS Thirty women presenting at ≥37(0/7) weeks of gestation with regular uterine contractions, intact membranes, and a Bishop score

Estrogens and antioxidants indirectly alleviate telomere attrition. However, available clinical data on the association between hormone exposure and telomere length are inconclusive. In the present study, we examined the effects of exogenous estrogen use and of some genetic factors implicated in estrogen metabolism and oxidative stress response on mean leukocyte telomere length. We studied 259 postmenopausal women. Genotyping was conducted for CYP1B1 (rs1056836), COMT (rs4680), GSTP1 (rs1695), MnSOD (rs4880), KRAS (rs61764370), and MTHFR (rs1801133 and rs1801131) polymorphisms. Mean leukocyte telomere length was measured using a quantitative real-time PCR assay. In multivariate analysis we found no association between oral contraceptives or hormone replacement therapy (HRT) and mean leukocyte telomere length. The presence of variant alleles in CYP1B1, KRAS and MTHFR genes was statistically significantly associated with shorter mean leukocyte telomere length. Further, the data provided evidence for the effect modification of the association between HRT and mean leukocyte telomere length by the CYP1B1, KRAS and MTHFR genotypes. Our findings suggest that functionally relevant genetic variants within estrogen and folate metabolic pathways may influence telomere length. We propose these genetic factors should be taken into consideration when interpreting associations between hormone exposure and telomere length.

Estrogens are known to selectively influence cell proliferation. Physiological variations of blood hormone concentration might play a role in regulating the level of X chromosome aneuploidy. In this study we observed the percentages of X aneuploid cells in standard lymphocyte cultures from blood samples obtained in relation to the menstrual cycle, noting whether collection occurred during either the follicular or the luteal phase.A study consisting of 28 women with X mosaicism and recurrent pregnancy loss, and 28 age-matched healthy controls. Cytogenetic studies were carried out on peripheral blood samples according to standard procedures.A significant difference in the percentage of X aneuploidy was found in blood samples obtained during different phases of the menstrual cycle. In the case group, the mean value of aneuploid cells in the follicular and luteal phase samples was 10.0 and 6.3 % respectively and in the control group, it was 2.8 and 1.0 % (P 0.0001). The difference in the case group varied between 0 and 8 % (3.6 ± 2.1 %) and in the control group between 0 and 4 % (1.7 ± 1.1 %). The specificity for detecting true X mosaicism was 0.875. We estimate that the initial diagnosis of X mosaicism could be correct in 68 % of patients with recurrent pregnancy loss.This observational study establishes that the time of blood sampling in relation to the menstrual cycle can influence lymphocyte X chromosome mosaicism. The results, further proven by additional controlled studies, would have practical implications for genetic counselling and fertility treatment.

Background: To date there are no known data about the use and administration of medicine in the postpartum period in Slovenia.Methods: We included 1,070 women after they gave birth in a prospective cross-sectional study while they were routinely admitted to the Maternal and Neonatal Unit of the Department of Perinatology at the University Medical Centre Ljubljana’s, from October 2011 to February 2012. Data were collected through written questionnaires and finally statistically analysed. The same questionnaires were given at time points of 3, 6, and 12 months after giving birth.Results: Three days after giving birth 96.5% of women were breastfeeding fully or partially. The most commonly used medications during this period were analgetics, laxatives and iron supplements. In the period of up to 3 months after giving birth, 84.0% of women were breastfeeding fully or partially, whereas the number decreased to 72.4% in the period from 3 to 6 months after giving birth. Analgetics, vitamins and/or minerals and folic acid supplements were the most used medications in both periods. From 6 to 12 months after giving birth 51.5% of women were breastfeeding. Vaginally administered antimycotics were most commonly used medicines in this time period in addition to analgetics, vitamins and/or mineral supplements.Conclusions: No significant difference could be determined in the frequency of medicine use in all three time periods after giving birth between both groups of breastfeeding and non-breastfeeding mothers. Moreover, no difference could be observed in the frequency of medicine use between the fully and partially breastfeeding mothers. This study has also shown that the most frequent used medicinal substances were folic acid, vitamins and/or minerals, analgetics, and antimycotics in the form of vaginal tablets.

The importance of folates in human physiology is well known, as are various pathologies associated with low folate status. Folate deficiency can occur due to low dietary intake, genetic predisposition or treatment with medicines affecting the folate status. The aim of this paper is to explore the importance of determining genetic polymorphisms which influence the levels of biologically active folate. MTHFR is involved in the transformation of 5,10-methylene-THF to 5-methyl-THF. Polymorphisms of the MTHRF gene are associated with decreased enzymatic activity.Only 9.3 % of the population in Slovenia displays full activity of the MTHFR enzyme; these subjects are non-mutated homozygotes (wild-type alleles). In contrast, the average enzymatic activity in subjects with mutated alleles is between 50 and 60 %. MTHFR polymorphism is associated with an increased risk of hyperhomocysteinemia and cardiovascular diseases, neurological disorders and various types of cancer. There is also an increased risk for congenital malformations. Folic acid food fortification was introduced in some countries in order to assure an adequate folate status in the population. However, this approach does not address the decreased activity of MTHFR.Polymorphism in the key enzymes of the folate cycle is common. Determination of the genetic predisposition is therefore plausible in the most vulnerable groups of the population, such as pregnant women and patients receiving medicines influencing the folate cycle in various ways, e.g. 5-fluorouracil, methotrexate and 6-mercaptopurine. Genotyping would allow the identification of patients at high risk for suboptimal folate status.

Aims: To evaluate the prevalence of congenital heart defects (CHDs) in live-born infants with Down syndrome (DS) and to investigate whether these CHDs might be detected during routine second trimester ultrasound screening performed at the primary level. Methods: A retrospective analysis of 66 cases of DS in live-born infants. The infants with DS underwent a detailed echocardiographic examination to evaluate cardiac morphological characteristics and function. Results: Thirty-six live-born DS infants (54.5%) had associated CHDs. According to the apical four-chamber view at the first postnatal echocardiographic examination, we estimated that 20 (55.6%) of the 36 patients with associated CHDs should have been identified during the routine second-trimester prenatal scan [17 infants with complete atrioventricular septal defect (AVSD), two with partial AVSD, and one with non-restrictive perimembranous ventricular septal defect] if the results had been correctly interpreted. An additional seven patients with associated CHDs should have been identified if the evaluation of both outflow tracts had been included into the screening protocol. Conclusion: Our data suggest that the prenatal DS detection rate can be significantly increased by improving obstetricians’ skills of performing adequate foetal cardiac examination as part of the routine 18- to 23-week ultrasound examination at the primary level.

Smoking, laryngopharyngeal reflux and voice misuse/overuse are known possible etiological factors for the development of Reinke’s edema (RE) on vocal folds. RE is found more frequently in women. The disparity between the incidence of RE in women and men suggests that endogenous sex hormones such as estrogens, progesterone and/or testosterone may have a significant influence on vocal folds. The aim of the study was to investigate the level of sex hormones such as estradiol (E), progesterone (P), and testosterone (T) in men with RE in comparison with men without laryngeal pathology. Fifty-six men with RE and 48 men without laryngeal pathology participated in the study. All participants received a questionnaire for assessing possible risk factors for the development of RE. The serum levels of T, E and P were determined and the ratios between hormones (T/E, T/P, P/E) were calculated. T and P serum levels were significantly higher in patients with RE (p = 0.002, p = 0.017). No differences were found in the hormone ratio values. Smoking was the only known risk factor for RE (p < 0.001). In conclusion, the difference in the level of sex hormones implies that hormones may affect both, the development and the maintenance of the edema in the lamina propria of vocal folds. The authors suppose that the possible mode of action of sex hormones is through enzymatic activity of nitric oxide synthase in the endothelial cell wall.

Hyperandrogenemia has been the most consistent feature of polycystic ovary syndrome (PCOS). Androgens exert their effects through androgen receptors (ARs). The expansion of the codon CAG trinucleotide repeat polymorphism in exon 1 of the AR gene represents a type of genetic alteration associated with changes in the AR gene function. The purpose of this study was to establish a possible association of the AR gene CAG repeat length polymorphism with PCOS, and its influence on clinical and biochemical androgen traits. Two hundred and fourteen Croatian women with PCOS and 209 healthy control women of reproductive age were enrolled. Phenotypic hyperandrogenism, BMI and waist to hip ratio were recorded. Hormonal profiles, fasting insulin and glucose levels were measured on cycle days 3–5. Genotyping of the CAG repeat polymorphism in the AR gene was performed. We found no significant difference in the mean CAG repeat number between the PCOS patients and controls (22.1 ± 3.4 vs. 21.9 ± 3.2, P = 0.286). There was a positive correlation between the CAG repeat length and total testosterone (TT) in the PCOS group (R = 0.225, P = 0.015). A multiple linear regression model using mean CAG repeat length, BMI, age and HOMA-IR as predictors explained 8.5% (adjusted R2) of the variability in serum TT levels. In this model the CAG repeat polymorphism was found to be a significant predictor of serum TT levels in PCOS patients (P = 0.015). The logistic regression analysis revealed that the CAG repeat length is not a significant predictor of hirsutism and acne status (P = 0.921 and P = 0.437, respectively). The model was adjusted for serum TT, free testosterone, androstendione and DHEAS levels as independent variables, which were also not found to be significant predictors of hirsutism (P = 0.687, P = 0.194, P = 0.675 and P = 0.938, respectively) or acne status (P = 0.594, P = 0.095, P = 0.290 and P = 0.151, respectively). In conclusion, the AR CAG repeat polymorphism is not a major determinant of PCOS in the Croatian population, but it is a predictor of serum TT level variability in women with PCOS.

The study aimed to investigate the influence of some generally recognized risk factors for hormone receptor (HR)- and human epidermal growth factor receptor 2 (HER2)-defined breast cancer among Slovenian postmenopausal women.Eligible women diagnosed with breast cancer were compared with 709 controls of the same age and ethnicity. Immunohistochemistry and FISH analyses were used to classify cases into molecular subtypes: 454 HR(+), 106 HR(-), 81 HER2(+) and 603 HER2(-). Adjusted odds ratios and 95% confidence intervals were estimated using multivariate logistic regression analysis.Overweight and obese women were at increased risk of HR(+), HER2(-) and of HR(+), HR(-), HER2(-) tumors, respectively. Women who started menstruating at the age of 11 years or earlier were at decreased risk of ER(-)PR(-) tumors. Users of hormone replacement therapy (HRT) were negatively associated with HR(+) and HER2(-) tumors. The inverse effect was most pronounced with the use of estrogen-only HRT, and longer duration of HRT use did not result in a significant change in risk. In contrast, combined HRT decreased the risk of HER2(+) tumors. Having a first-degree relative with breast and/or ovarian cancer increased the risk of HR(+) and HER2(-) tumors.We conclude that certain breast cancer risk factors may vary by molecular subtypes. According to our results, HRT use may have a greater influence on HR (+) and HER2(-) breast cancers and the risk of HER2-defined breast cancer may differ with respect to the regimen of HRT.

The aim of the study was to analyze the impact of the rs2747648 genetic variant in the estrogen receptor alpha (ER1) gene affecting a putative miR-453-binding site on the risk of breast cancer in postmenopausal women. Furthermore, we examined if the risk changes in a subset of women on hormone replacement therapy (HRT).We studied 530 breast cancer cases and 270 controls of the same age and ethnicity. Duration of HRT use was ascertained through a postal questionnaire. Genotyping was accomplished by TaqMan® allelic discrimination assay. The associations with breast cancer risk were assessed using logistic regression models.The analysis did not reveal any association between the ER1 genetic variant and postmenopausal breast cancer risk, either ER-positive or ER-negative disease. Also, there was no association between the ER1 genetic variant and breast cancer risk in postmenopausal women receiving HRT.There may be an inverse association between the premenopausal women carrying the variant allele and breast cancer, but it was not detected in our analysis for the postmenopausal women, or for those on HRT.

Objective The aim of the study was to examine the influence of the use of hormone replacement therapy (HRT) and of some generally recognized risk factors on breast cancer risk among Slovenian postmenopausal women. Methods Eligible women diagnosed with breast cancer and a control group of women of the same age and ethnicity were invited to participate in the case‐control study via a personal letter and asked to complete a written questionnaire. Adjusted odds ratios and 95% confidence intervals were estimated using multivariate logistic regression analysis. Results A total of 784 cases and 709 controls aged 50‐69 years were enrolled. HRT use was inversely associated with breast cancer risk. The effect was most pronounced with the use of estrogen-only replacement therapy (odds ratio (OR) 0.51, 95% confidence interval (CI) 0.30‐0.87). Longer duration of HRT use did not result in a significant change in risk (1 to55 years of HRT use: OR 0.44, 95% CI 0.26‐0.73;5 years of HRT use: OR 0.51, 95% CI 0.30‐0.87). Obesity (25body mass index530 kg/m 2 : OR 1.34, 95% CI 1.04‐1.73; body mass index30 kg/m 2 : OR 1.89, 95% CI 1.36‐2.63), smoking10 cigarettes per day (OR 1.70, 95% CI 1.20‐2.43), and any first-degree relative with breast or ovarian cancer (OR 1.52, 95% CI 1.11‐2.08) were positively associated with breast cancer risk. Conclusions Our analysis revealed some differences from the previously published literature, which might reflect underlying demographic changes. Comprehensive medical care in HRT users without pre-existing breast abnormalities probably reduces the incidence of new breast cancer cases in Slovenia.

Genetic causes of premature ovarian failure (POF) comprise less than one-third of all cases, among them X chromosome abnormalities, mutations and polymorphisms in some genes. The frequency of X-chromosome mosaicism in women with sporadic POF has been found to range between 3 and 10%, whereas the prevalence of POF in carriers of the FMR1 premutation is estimated to range between 13 and 25%. We report two successful pregnancy outcomes after in vitro fertilization-embryo transfer with donated oocytes in a woman with severe POF of a complex genetic origin. Chromosome analysis, fluorescence in situ hybridization on cultured peripheral blood lymphocytes and buccal mucosal cells, and molecular genetic studies, using autosomal, Y-chromosomal polymorphic microsatellite or short tandem repeat markers and CGG repeats in the FMR1 gene, were performed. FMR1 premutation, sex chromosome mosaicism and blood lymphocyte microchimerism were found. Assisted reproduction techniques can be safely used in POF women after a thorough clinical evaluation and genetic counselling.

Objectives To present cases exhibiting possible effects of angiotensin II receptor blockers (ARBs) received in pregnancy on the fetus. Methods Retrospective analysis included women who delivered between 2002 and 2006 at Department of Obstetrics and Gynaecology Ljubljana. Results Antihypertensive medications were prescribed to 346 of the 26,735 women. ARBs were given in only five pregnancies: two women received losartan, and three irbesartan. The therapy was stopped between 5 and 23 weeks of gestation. Two women delivered healthy babies at term; another term baby had one additional finger and toe. Other two pregnancies were complicated with oligohydramnios and ended in preterm delivery. One preterm infant had transient abnormal renal function tests. Conclusion Women should be informed that ARB-antihypertensive therapy must be replaced/stopped before planning their pregnancy or at least as soon as the pregnancy is confirmed. Fetal morphology scan and monitoring of amniotic fluid volume should be obligatory, if ARBs are prescribed accidentally.

Literature data concerning thyroid enlargement during pregnancy are not conclusive. Our aim was to systematically follow the thyroid volume changes during pregnancy and after delivery in an iodine-sufficient area.Prospective study of healthy pregnant women living in an iodine-sufficient area. We followed 118 pregnant women with the mean age 30.9+/-4.1 years in the first trimester (mean 11.2+/-2.5 weeks of pregnancy), in the third trimester (mean 31.6+/-1.7 weeks of pregnancy), and 4 months after delivery (mean 15.9+/-3.9 weeks). Additionally, 71 women were also evaluated 14 months after delivery (mean 13.3+/-1.1 months). All women were negative for thyroid autoantibodies. We measured urinary iodine concentration (UIC), thyroid volume, serum TSH, and body mass index (BMI). After delivery, in a subgroup of women we also estimated the colour flow Doppler sonography (CFDS) patterns 0, I, II and III, where thyroid vascularity increased from pattern 0 to III, and the peak systolic velocity (PSV) using a 7.5 mHz linear transducer.Median UIC in the third trimester (176 microg/g creatinine) was significantly higher than 4 and 14 months after delivery (P=0.030, P0.001, respectively). Thyroid volume in the third trimester (11.3+/-3.1 mL) was significantly greater (P0.001) than in the first trimester (8.7+/-2.5 mL), 4 months after delivery (8.6+/-2.5) and 14 months after delivery (7.8+/-2.4 mL). TSH concentration was significantly higher in the third trimester than in the first trimester and 4 months after delivery (P=0.007, P=0.006, respectively). As expected, BMI was the highest in the third trimester. CFDS pattern I was more frequent 4 months after delivery than 14 months after delivery (P0.001). Similarly, PSV was significantly higher 4 months after delivery than 14 months after delivery (P0.001). Linear regression analysis revealed TSH and BMI as significant independent predictors for thyroid volume.In an iodine-sufficient area, thyroid volume increases during pregnancy and decreases after delivery, and the changes in volume are associated with changes in TSH and BMI. They may be viewed as indicators for metabolic and haemodynamic changes during pregnancy.

Pregnancy is a physiological state accompanied by excessive levels of oxidative stress (OS), due to the increased demand and utilisation of oxygen. There is increasing evidence that maternally augmented OS exerts an adverse effect on pregnancy outcome. The aim of the present prospective study was to determine the association between the urinary concentration of relatively novel OS markers measured in the second trimester of pregnancy and the infant characteristics at birth. The maternal levels of urinary hexanoyl-lysine (HEL), propanoyl-lysine (PRL), dityrosine (DiY) and 3-nitrotyrosine (NY) were evaluated in generally healthy pregnant subjects to determine their association with birth weight, gestation at delivery and Apgar score. The observed levels of the markers were in agreement with those measured in healthy non-pregnant subjects in a previous study. A positive correlation was detected between HEL and PRL, as well as between HEL and DiY. Although the absence of a correlation between NY and the other markers has been previously noted in a non-pregnant population, a positive correlation in the pair PRL-NY (r=0.367; P

Purpose :Women with ultrasonic evidence of polycystic ovaries are at higher risk of ovarian hyperstimulation syndrome (OHSS). We focused on investigating a possible association of the (TTTTA) n microsatellite polymorphism in the promoter of the CYP11A gene with OHSS during controlled ovarian hyperstimulation (COH). Methods :We evaluated 58 patients at high risk of OHSS (study group) and 58 control patients undergoing controlled ovarian hyperstimulation. Results :The difference in the allele distribution between both groups of patients was not statistically significant. The genotype distribution of 4+ (with at least one copy of the four-repeat-unit allele) and 4− (without the four-repeat-unit allele) genotypes was identical in the two groups. Conclusion :An association between the (TTTTA) n microsatellite polymorphism in the promoter of the CYP11A gene and the pathogenesis of OHSS could not be confirmed.

Inhibin is an important glycoprotein that is involved in folliculogenesis. INHA, the gene encoding the inhibin alpha subunit, was recently proposed as a candidate for premature ovarian failure (POF), a syndrome that leads to the cessation of ovarian function under the age of 40 years. 70 POF patients and 70 controls were screened for the previously identified INHA -16CT transition mutation. The T allele was found in 31/70 (44.3%) of controls, but only 18/70 (25.7%) of POF patients. This result indicates that the T allele is significantly underrepresented in the POF patient population (Fisher's exact test, two-tail: P = 0.033). Sequence analysis of the INHA promoter in 50 POF patients and 50 controls identified a highly polymorphic imperfect TG repeat at approximately -300 bp, that consisted of four common haplotypes (A, B, C and D). The -16T allele is linked to the shortest repeat haplotype (haplotype C). Despite the association between haplotype C and POF, no significant difference was found between the promoter activity of a luciferase reporter construct containing haplotype C, and most of the other haplotypes tested. Interestingly, haplotype B failed to show any promoter activity. We conclude that the inheritance of specific INHA promoter haplotypes predispose to the development of premature ovarian failure.

Premature ovarian failure (POF) affects approximately 1% of women and is known to be caused by sex chromosome abnormalities, iatrogenic agents and autoimmune diseases, but in the majority of cases the cause is unknown. However, several families have been identified as having an inherited predisposition to POF, suggesting a genetic component to the condition in these cases. The FOXL2 gene of 70 POF patients from New Zealand and Slovenia was screened for mutations. In a Slovenian POF patient, a novel 30 bp deletion was identified that was predicted to remove 10 out of 14 alanines (A221_A230del), from the polyalanine tract downstream of the winged helix/forkhead domain of the FOXL2 protein. A novel single nucleotide substitution, 772(1009)T>A, which is predicted to change amino acid 258 from tyrosine to asparagine (Y258N), was identified in a New Zealand POF patient. Neither mutation was identified in 200 normal control chromosomes from 100 control samples. Three previously unreported single nucleotide substitutions, considered to be non-functional polymorphisms, were also identified.

Objective: To determine whether hCG and IGFBP-1 appear in the same or different cells and in what sequence. Design: Retrospective analysis of laboratory data. Setting: University medical center. Patient(s): Twenty-five women undergoing IVF-ET with natural cycles and 25 women having stimulated IVF-ET. Intervention(s): Cells were obtained from dominant follicles in women with natural cycles and from the follicles from hMG- and hCG-stimulated cycles. Main Outcome Measure(s): Detection and localization of hCG and IGFBP-1 in granulosa-luteal cells using double immunocytochemical staining. Measurement of hCG and IGFBP-1 in follicular fluid and serum. Result(s): Three types of hCG staining were found: on the cell surface, on the cell surface and in the cytoplasm, and in the cytoplasm alone. IGFBP-1 stained diffusely in the cytoplasm and was found only in those cells that were luteinized and contained hCG. IGFBP-1 and hCG were colocalized in the same cells. There was a positive correlation between follicular fluid hCG and IGFBP-1 levels, but only in natural IVF-ET cycles. Conclusion(s): HCG-driven luteinization is required for IGFBP-1 synthesis to take place in granulosa cells.

Purpose: Our purpose was to find the differences in granulosa—luteal cells obtained from gonadotropin- versus gonadotropin-releasing hormone (GnRH) agonist/gonadotropintreated follicles in in vitro fertilization-embryo transfer (IVF-ET) cycles. Methods: Granulosa-luteal cells were obtained from 45 follicles of women undergoing IVF-ET with gonadotropin releasing hormone (GnRH) agonist and human menopausal gonadotropin (hMG) and from 45 follicles of women with hMG IVF-ET cycles. Subpopulations of granulosa-lut eal cells were observed by computerized image analysis in which human chorionic gonadotropin (hCG) was localized using immunoperoxidase staining. Results: The luteinized granulosa-luteal cells from hMGtreated follicles were larger than those from GnRH agonist/ hMG-treated follicles. The hMG-treated follicles contained more hCG-stained cells, particularly those with cytoplasmic hCG localization. Conclusions: We found differences in morphometric characteristics and hCG localization in granulosa-lut eal cells obtained from hMG- versus GnRH agonist/hMG-treated follicles. We presume that the results indicate the influence and importance of luteal-phase support on the clinical pregnancy rate in GnRH agonist/hMG-treated IVF-ET cycles.