Effects of metformin and ganirelix on subcutaneous endometriosis in a mouse model of autophagy-related cell death.

Objective: This study aimed to investigate the efficacy of metformin and ganirelix on subcutaneous endometriotic tissues created in an experimental mouse model. Materials and Methods: Five groups were formed with eight animals in each group. One of the groups was set as the control group. Endometriotic lesions were created by transplanting 40 mouse autologous endomyometrial tissues into the mouse subcutaneous tissue to a highly vascular surface. Gene expression analyzes of tissues were performed as HIF-1α, ATG5, ATG12, Beclin2, Beclin1, LC3BII, CateninB, GSK3b, TCF, WNT2, WNT7α, and WNT10α gene analyzes. Drug effects were examined by histological examination. HIF1a and WNT2 protein expressions were examined immunohistochemically. Gene expression coefficients of control, metformin day 1 (Met1g), metformin day 7 (Met7g), ganirelix day 1 (Gnx1g), and ganirelix day 7 (Gnx7g) groups are shown in tables. Data are presented as mean and standard error. Results: Beclin2 gene expression coefficients of metformin 1st day, metformin 7th day, ganirelix 1st day, and general 7th day groups were found to have significantly decreased compared with the control group coefficient. Beclin1 gene expression coefficients of metformin 1st day, metformin 7th day, ganirelix 1st day, and genirelix 7th day groups were found to have significantly decreased compared with the control group coefficient. LC3BII gene expression coefficients of metformin 1st day and metformin 7th day groups were found to have significantly decreased compared with LC3BII gene expression coefficients of control, genirelix 1st day, and genirelix 7th day groups. These findings were supported by histological and immunohistochemical staining. Conclusion: These genes are actively involved in the autophagy pathway, and we think that the use of metformin in endometriosis might create an autophagy-based suppression mechanism.

Zonulin as a potential biomarker for diminished ovarian reserve: A prospective study.

Objective: The purpose of this research is to investigate the relationship between zonulin levels and diminished ovarian reserve (DOR), and to evaluate the potential role of autoimmunity in the development of DOR. The study contributes to the understanding of the pathogenesis of DOR, which can be an unexpected diagnosis often associated with infertility and unpleasant physical symptoms in women. Materials and Methods: This cross-sectional study was conducted by scanning 224 patients. The demographic characteristics of the patients were recorded. Antral follicle counts of the patients were determined by ultrasound, and Anti-Mullerian hormone (AMH) levels were examined. Follicle-stimulating hormone (FSH), luteinizing hormone, estradiol, AMH measurement, and antral follicle counts were made on the 2nd or 3rd day of menstrual bleeding. The zonulin levels of the participants were measured by the ELISA method. The patients were divided into two groups according to the presence of DOR. The patients' demographic characteristics and hormone levels were compared between these two groups, serum zonulin levels were examined, and the relationship between other hormone parameters and zonulin was investigated. Results: When the median ages of the patients in both groups were compared, the median age of patients with DOR was 38 years, significantly higher (p<0.001) than the median age of those without DOR, which was 27 years. The median zonulin levels of both groups were compare; it was observed that it was 19.71 ng/mL in the group with DOR and 11.03 ng/mL without DOR, and a statistically significant difference was found between the zonulin levels of the patients in both groups (p<0.001). A moderate inverse correlation (p<0.001) between patients' zonulin and AMH levels, and a moderate correlation between FSH levels (p<0.001). Conclusion: In conclusion, zonulin levels of patients with DOR were higher than women without DOR. Evaluation of zonulin levels may also be considered during the diagnosis of DOR.

Perinatal and neonatal outcomes of adolescent pregnancies over a 10-year period.

OBJECTIVES: Poor overall neonatal outcomes, small neonatal head circumference, neonatal hypoglycemia, need for Neonatal Intensive Care Unit and late-onset neonatal sepsis are more common in adolescents. The aim of this study is to draw attention to the outcomes of adolescent pregnancies. MATERIAL AND METHODS: This retrospective study was conducted in adolescent singleton pregnancies with maternal age < 15 years (n = 20, group 1), 16-19 years (n = 1929, group 2), and 20 years (n = 866, group 3). Age, gravidity, parity, and body mass index (BMI) measurements of mothers; mode of delivery, maternal and neonatal outcomes were evaluated and compared. RESULTS: The rate of preterm birth, postpartum hemorrhage, asymmetrical intra-uterine growth restriction (IUGR, as 3% percentile), macrosomia, and height of newborn of Group 3 was significantly higher. The rate of asymmetrical IUGR (as 10% percentile) was significantly lower in Group 3. The rate of severe preeclampsia and cesarean section was significantly higher in Group 3. The rate of Small for Gestational Age newborn, neonatal hypoglycemia, and late-onset neonatal sepsis was significantly higher in Group 1. CONCLUSIONS: Neonatal problems with poor obstetric outcomes are common in adolescent pregnant women, so that a family planning and baby care social trainings are important in achieving good long-term maternal and neonatal outcomes.

Clinical Value of Serum BMP-4, BMP-2, GDF-15, MMP-9, GP39 Levels in Pregnant Women with Obesity and the Related Comorbidities Diabetes Mellitus and Gestational Hypertension.

AIMS: We evaluated the clinical value of selected serum biomarkers BMP-4, BMP-2, GDF-15, MMP-9, and GP39 in pregnant women with obesity and the comorbidities diabetes mellitus (DM) and gestational hypertension (GHT). METHODS: This observational study had groups of controls, including healthy pregnant women; women with only obesity, including pregnant women with BMI≥30 kg/m2; women with gestational DM (GDM) with obesity, including pregnant women with GDM and obesity; women with pregestational DM (PGDM) with obesity, including pregnant women with PGDM and obesity; and women with GHT with obesity, including pregnant women with GHT and obesity. We measured serum levels of selected biomarkers by ELISA. RESULTS: Obesity increased serum levels of all the biomarkers; GDM developed in obese women caused a more pronounced increase in the serum levels of BMP-4 and BMP-2, and GHT developed in obese women caused a more pronounced increase in the serum levels of GDF-15. In the women with GDM-, PGDM-, and GHT-complicated obesity, serum levels of MMP-9 and GP39 did not change meaningfully. CONCLUSIONS: Obesity and its comorbidities DM and GHT lead to meaningful changes in the studied serum biomarkers. Since obesity has a causal effect on developing numerous conditions, reliable clinical biomarkers are needed to improve the early prediction and diagnosis of high-risk conditions during pregnancy.

Predictive and diagnostic value of serum sVEGFR-1 level in women with preeclampsia: A prospective controlled study.

Objective: Pre-eclampsia (PE), a pregnancy-specific syndrome consisting of hypertension and proteinuria occurring de novo after the 20th week of gestation, remains the leading cause of maternal and fetal morbidity and mortality worldwide. Endothelial dysfunction is proposed to be a central feature of the pathophysiology of preeclampsia. However, the mechanism by which this endothelial dysfunction occurs remains uncertain. We investigated the predictive and diagnostic value of serum soluble vascular endothelial growth factor receptor-1 (VEGFR-1) with by comparison of its prepartum and postpartum serum levels in the management of women with PE. Materials and Methods: This prospective case-controlled study was composed of pre-eclamptic (n=44) and normal, healthy pregnant (n=44) women. Blood samples were collected before any intervention at the first antenatal examination of the women in the control group and at the admission of the women to the hospital in the PE group, additionally, from all women in the study groups within six hours of the postpartum period, and used for the serum VEGFR-1 analyses. Results: Within both groups, prepartum serum levels of sVEGFR-1 were higher than postpartum levels (p<0.05). In PE, pre-partum and postpartum serum levels of sVEGFR-1 were higher than levels in the control group (p<0.05). Serum sVEGFR-1 levels of preeclamptic women were positively correlated with the degree of proteinuria (p<0.05, r=0.25), systolic (p<0.05, r=0.25), and diastolic blood pressure (p<0.05, r=0.31). Conclusion: These findings seem to point to an involvement of sVEGFR-1 in the pathophysiology of PE. Serum sVEGFR-1 has the potential to be used as a valuable biomarker in the prediction, diagnosis, and risk management of women with subtypes of PE including mild and severe PE, HELLP syndrome, and eclampsia. There is a need to study serum sVEGFR-1 as a biomarker in pregnant women with different subtypes of PE.

Predictive and Prognostic Value of Plasma Zonulin for Gestational Diabetes Mellitus in Women at 24-28 Weeks of Gestation.

OBJECTIVE: We aimed to examine the predictive and prognostic value of plasma zonulin for gestational diabetes mellitus (GDM) in women at 24-28 weeks of gestation. METHODS: This retrospective study was carried out with pregnant women with GDM (n=98) and normal glucose tolerance (control group) (n=132). GDM was diagnosed according to American Diabetes Association (ADA) criteria with a one-step 75-g OGTT at 24-28 gestational weeks. Their serum zonulin levels measured during one-step 75-g OGTT and perinatal outcomes were compared, and the cut-off value of plasma zonulin for the prediction of GDM was calculated with receiver operating characteristic curve analysis. RESULTS: Plasma zonulin level was significantly higher in women with GDM compared to controls (28.8±24.9 and 7.3±11.3 ng/mL, respectively). According to logistic regression analysis, plasma zonulin levels and GDM were statistically significant. The plasma zonulin cut-off value was>45.2 ng/mL. The rate of cesarean section, the rate of meconium in the amniotic fluid, and the need for admission to the neonatal intensive care unit significantly differed between women with GDM and controls. CONCLUSION: In pregnant women with GDM, plasma zonulin increases, and with the cut-off level of>45.2 ng/mL, it can predict GDM with values of sensitivity and specificity levels significantly higher in pregnant women with GDM, suggesting that it can be used as a tool for its screening and early diagnosis.

Prediction of gestational diabetes mellitus and perinatal outcomes by plasma zonulin levels.

PURPOSE: Zonulin has been shown to be associated with many metabolic disorders, including type 2 diabetes mellitus, metabolic syndrome, and obesity. In this study, we aimed to evaluate the association between maternal plasma zonulin levels and gestational diabetes mellitus (GDM) and its perinatal outcomes. MATERIALS: A total of 100 pregnant women, 56 with GDM and 44 controls, were included in this prospective case-control study. Maternal plasma zonulin levels were evaluated in each trimester. The association between zonulin levels and GDM, body mass index (BMI) and adverse perinatal outcomes was evaluated. The GDM predictability of zonulin levels for each trimester was analyzed with the receiver operator curve (ROC). RESULTS: Plasma zonulin levels were significantly higher in pregnant with GDM in all trimesters (p < 0.001; for all). Optimum cut-off values of plasma zonulin levels in predicting GDM: first trimester: 6.27 ng/mL, second trimester: 12.71 ng/mL, and third trimester: 18.38 ng/mL. BMI was significantly higher in pregnant women with GDM (30.5 vs 26.1; p < 0.001). Zonulin levels were significantly higher in pregnant women with GDM with overweight BMI [≥ 25-30 (kg/m2)] in all trimesters (p < 0.05; for all). Zonulin levels were significantly higher in pregnant women with composite adverse outcomes that included at least one of neonatal intensive care unit (NICU) admission, meconium-stained amniotic fluid, and 1st minute APGAR score < 7. CONCLUSION: Increased maternal plasma zonulin levels were associated with increased risk of GDM and adverse perinatal outcomes. Zonulin may be a potential marker to predict GDM risk and perinatal outcomes.

Relationship between serum cadherin 6 and 11 levels and severe and early-onset preeclampsia: A pilot study.

Objective: Preeclampsia is a highly morbid disease of placental origin, life-threatening condition for both a pregnant woman and her fetus. Cadherin 6 and 11 are adhesion molecules that play an important role in trophoblastic development and placentation. In our study, we investigated the change in serum cadherin 6 and 11 levels in pregnant women with preeclampsia. Materials and Methods: Pregnant women with preeclampsia were selected and compared with healthy women (as a control group) for a one-year study. The serum alanine aminotransferase, aspartate aminotransferase, and cadherin levels 6 and 11 of participants were analyzed and compared. Results: A total of 189 pregnant women were subdivided into 2 groups as preeclamptic (n=94) and women with healthy pregnancy (n=95). The cadherin 6 and cadherin 11 levels of the preeclamptic patients were significantly higher than those in the control group (p=0.001), and they were found to be significantly higher mainly in patients with early-onset and severe preeclampsia group (p=0.001). The cut-off cadherin 6 and 11 values for severe preeclampsia were found as 98.174 ng/mL and 1.92 ng/mL; with sensitivity of 88.3% and 84% respectively (p=0.001). Conclusion: The data analysis showed elevated serum cadherin 6 and 11 levels associated with the severity and early onset of pre-eclampsia. Serum cadherin 6 and 11 levels can be a candidate marker for the prediction of preeclampsia.

Predictive and Diagnostic Value of Serum Adipokines in Pregnant Women with Intrahepatic Cholestasis.

The objective of this study was to assess the value of serum leptin, adiponectin, apelin, and ghrelin as biomarkers for the prediction and diagnosis of intra-hepatic cholestasis (ICP). This prospective study included pregnant women in the third trimester of pregnancy: 63 with ICP, 48 and 15 of whom had mild and severe disease, respectively, and 32 as controls. ICP women had increased median levels of serum leptin, adiponectin, apelin, and ghrelin compared to the controls (p < 0.05). These biomarkers meaningfully changed regarding the severity of ICP: While leptin was reduced, apelin and ghrelin were increased, and adiponectin was increased somewhat. To predict and diagnose ICP, the predictive values of serum leptin, adiponectin, and apelin need to be accepted as comparable, with moderate to high sensitivity and specificity; however, the predictive value of serum ghrelin was somewhat lower. More research is needed to clarify the potential properties of adipokines to gain acceptance as a predictive or diagnostic biomarker for ICP.

Derangements of vaginal and cervical canal microbiota determined with real-time PCR in women with recurrent miscarriages.

Balanced vaginal microbiota and, as a continuum, cervical canal microbiota help prevent reproductive disorders, including recurrent miscarriage (RM). In a significant proportion of couples with RM, routine diagnostic workup cannot find any manageable cause, leading to a requirement for new diagnostic tools. In the present study, we determined the quantitative composition of the microbiota of the vagina and cervical canal, assessed by real-time polymerase chain reaction, in women with RM. It also evaluated their derangements related to the pathogenesis of RM, and thus the suitability of this test as a diagnostic tool for managing RM. Vaginal and cervical canal specimens of 25 women with RM and 25 healthy volunteers were collected. The test results revealed information about the total vaginal bacterial biomass by measuring the abundance of Lactobacillus spp.; other bacteria; and pathogens, including Mycoplasma hominis, Mycoplasma genitalium, Ureaplasma (urealyticum + parvum), and Candida spp. Overall, the findings of this study implied the abundance of Lactobacillus spp. decreased in women with RM with an increase in the abundance of other microorganisms in accordance with the reduction in the abundance of Lactobacillus spp. due to aerobic vaginitis and bacterial vaginosis. Vaginal and cervical canal microbiota need to be considered during the diagnostic workup of women with RM.IMPACT STATEMENTWhat is already known on this subject? Recurrent miscarriage (RM) is a well-known reproductive disorder. Its diagnostic workup is not successful in determining the underlying problem in many cases. Hence, novel diagnostic tools based on real-time polymerase chain reaction (PCR) are needed for evaluating reproductive microbiota, which are considerably reliable, to satisfy the expectations of women with RM.What do the results of this study add? Overall, the decrease in the abundance of Lactobacillus spp. was found to be related to RM, and the patterns of the presence of other microorganisms were in accordance with the reduction in the abundance of Lactobacillus spp. These findings suggested an important role of vaginal and cervical canal microbiota in the pathogenesis of RM.What are the implications of these findings for clinical practice and/or further research? Additional research is warranted to elucidate the functional impact of altered components of the microbiota of vaginal and cervical canals on the physiology of the local cervical canal and its participation in the microbiota of the endometrial cavity, especially regarding unsuccessful pregnancies as a result of the disturbed physiology of the local endometrial microenvironment. However, possible applications of real-time PCR-based tests for the screening of subclinical infections in clinical practice require the performance of further investigations in patients with RM.

Assessment of vaginal and endometrial microbiota by real-time PCR in women with unexplained infertility.

AIM: Microbiota of the reproductive tract may be associated with unexplained infertility in women. We aimed to determine the derangements of vaginal and endometrial microbiota related to unexplained infertility by real-time polymerase chain reaction (real-time PCR) microbiota analyses of vaginal and endometrial samples of the unexplained infertility patients and fertile women. MATERIALS AND METHODS: Twenty-six women with unexplained infertility and 26 age-matched fertile women were included. Vaginal and endometrial samples were obtained in the mid-menstrual cycle for analysis by quantitative real-time PCR method. RESULTS: The proportion of lactobacilli-impaired microbiota was significantly higher in the vaginal samples of unexplained infertility patients (76.9% vs. 26.9%; p < 0.001). Those with impaired lactobacilli microbiota of vaginal samples had an increased risk of 9.048 times for infertility than those with normal lactobacilli microbiota. In addition, the mean lactobacilli/total bacterial mass (TBM) ratio in the vaginal samples was significantly lower in the unexplained infertility patients (38.2% vs.76.3%; p = 0.001). CONCLUSION: The present study results supported the role of vaginal and endometrial microbiota derangements in unexplained infertility. Many time-consuming and invasive methods are currently used in the diagnosis of infertility. Our study showed that the quantitative determination of lactobacilli/TBM ratio in vaginal specimens, a less invasive and easily obtainable method, could be used as a diagnostic test during the workup of couples with unexplained infertility.

Predictive value of pregnancy of follicular fluid fetuin-A and -B levels in infertile women after intra-cytoplasmic sperm injection.

AIM: We aimed to investigate the value of follicular fluid fetuins-A and -B to predict successful IVF and pregnancy outcomes in infertile women with poor, normal, and high ovarian reserve. METHODS: The follicular fluid of 96 infertile women who underwent intra-cytoplasmic sperm injection (ICSI) procedure was analyzed. Fetuins-A and -B levels were examined and compared in those who could achieve pregnancy and those who could not. Receiver operating characteristic curve analyzes were used to determine cut-off and statistically significant associations for fetuins-A and -B. RESULTS: Follicular fluid fetuin-A levels were higher in cases with weak ovarian reserve (OR) (p < 0.05) and higher in patients who did not achieve clinical pregnancy (p < 0.05). Conversely, the follicular fluid fetuin-B levels were lower in cases with poor OR (p < 0.05) and were lower in patients who did not achieve a clinical pregnancy (p < 0.05). A follicular fluid fetuin-A concentration ≤ 19.12 ng/mL had a sensitivity and specificity of 94.74% and 93.1%, respectively, at predicting clinical pregnancy. While the follicular fluid fetuin-B concentration >24.7 ng/mL had sensitivity and specificity of 71.1% and 51.7%, respectively, for clinical pregnancy prediction. CONCLUSION: Overall, high levels of follicular fluid fetuin-A may be independently associated with unsuccessful IVF irrespective of OR grouping. A low level of follicular fetuin-B was also associated with failed IVF. The sensitivity and specificity were found to be higher for fetuin-A in predicting clinical pregnancy. Therefore, the follicular fluid fetuin-A may be more predictive for successful IVF and clinical pregnancy outcomes than follicular fluid fetuin-B.

Serum Melatonin as a Biomarker for Assessment of Late-term and Postterm Pregnancies in Women without Spontaneous Onset of Labor.

We conducted a prospective study to assess serum melatonin as a biomarker to predict the development of late-term and postterm pregnancies and spontaneous beginning of labor in women with term pregnancies. Population of this prospective study included pregnant women with late-term and postterm pregnancies and term pregnancies as controls. In these study groups, serum melatonin concentrations were measured in women with or without labor and their perinatal data were collected. In the postterm pregnancies without labor, the lowest median melatonin concentrations were measured (p<0.05). In the late-term and postterm pregnancies with and without labor, the median serum melatonin concentrations were significantly lower than term ones (p<0.05). In the term pregnancies with labor, the highest median melatonin concentration was measured (p<0.05). A serum melatonin concentration≤34 pg/mL as a cut-off value determines late-term and postterm pregnancy with a sensitivity of 80.4% and a specificity of 81.4%. A serum melatonin concentration>29.35 pg/mL as a cut-off value determines presence of labor with a sensitivity of 82.1% and a specificity of 55.0%. In women with term pregnancies, with the measurement of serum melatonin, it is possible to predict the development of late-term and postterm pregnancies and whether these pregnancies undergo spontaneous labor. With further studies, these findings need to be supported before their routine clinical use.

Comparison of effects of formoterol and BRL 37344 on isolated term-pregnant rat myometrial strips in vitro.

This study was designed to compare the effects of beta-adrenoceptor agonists formoterol and BRL 37344 on spontaneous contractions and the levels of cAMP and cGMP of myometrial strips isolated from timed-pregnant rats. Myometrial strips were obtained from term-pregnant Wistar albino rats (n=12), mounted in organ baths and tested for changes in isometric tension in response to formoterol and BRL 37344. We evaluated the effect of increasing concentrations of formoterol and BRL 37344 on oxytocin-induced myometrial contractions and on contractions of myometrial smooth muscle pretreated with metoprolol, ICI 118.551 and SR 59230A (beta1, beta2, beta3-adrenoceptor antagonist, respectively, 10(-6) M). Effects of formoterol and BRL 37344 on cAMP and cGMP levels in isolated myometrial strips (n=6) were evaluated by radioimmunoassay kits. Formoterol (10(-12)-10(-8) M) and BRL 37344 (10(-11)-10(-5) M) concentration-dependently decreased the amplitude of oxytocin-induced contractions. E(max) value (100%) of formoterol was increased significantly more than E(max) value (70.6%) of BRL 37344 (P<0.05), with no change in pD(2) value (9.54+/-0.12 and 9.12+/-0.12, respectively). The inhibition of the amplitude of oxytocin-induced contractions by formoterol was antagonized with ICI 118.551 (10(-6) M), but they were not changed by metoprolol (10(-6) M) or SR 59230A (10(-6) M). The inhibition of the amplitude of oxytocin-induced contractions by BRL 37344 were antagonized with SR 59230A (10(-6) M), but they were not changed by metoprolol (10(-6) M) or ICI 118.551 (10(-6) M). Formoterol and BRL 37344 increased cAMP levels. BRL 37344 increased cGMP levels in BRL 37344 group more than control group, but this increase is less significant than cAMP levels (P>0.05). Formoterol and BRL 37344 decreased amplitude of myometrial contractions with similar potency, but efficacy of formoterol was better than BRL 37344.

The effect of glyceryl trinitrate on hypertension in women with severe preeclampsia, HELLP syndrome, and eclampsia.

OBJECTIVE: The goal of this study is to evaluate the effect of glyceryl trinitrate (GTN) in the management of hypertension in women with preeclampsia, eclampsia, and HELLP syndrome. STUDY DESIGN: Fifty five women with preeclampsia, eclampsia, and HELLP syndrome administered GTN infusion for the management of hypertension were studied. Demographic, clinical, and perinatal outcome findings were collected for analyses. We recorded initial and maintenance doses of GTN, and duration of its use in prepartum and postpartum periods. We collected systolic and diastolic blood pressures (BPs) at admission and before the administration of GTN infusion. During the GTN infusion, we calculated average diastolic and systolic blood pressures 6 hours apart on the first day, 12 hours apart on the second day, and 24 hours apart on the third day. RESULTS: Of 55 women, 24 with severe preeclampsia, 16 with HELLP syndrome, and 15 with eclampsia were included in this study. In severe preeclampsia group, GTN infusion significantly reduced systolic and diastolic BPs beginning from the second quarter and third quarter, respectively, of first day (p < 0.05). In the HELLP syndrome group, GTN infusion significantly decreased systolic and diastolic blood pressures beginning from the third quarter and second quarter, respectively, of the first day (p < 0.05). In the eclampsia group, GTN infusion significantly reduced systolic and diastolic blood pressures beginning from the third quarter and first quarter, respectively, of the first day (p < 0.05). CONCLUSION: In women with severe preeclampsia, eclampsia, and HELLP syndrome, infusion of GTN can be used as an alternative agent to well-known drugs and causes no significant adverse effect to the mother and fetus.