Maternal serum Sortilin-1 level as a potential biomarker for intrahepatic cholestasis of pregnancy.

Objective: Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease related to pregnancy in women. Sortilin-1 is a sorting receptor belonging to the vacuolar protein sorting 10 (Vps10p) domain family, and recent studies have shown that Sortilin-1 has a distinct role in the pathogenesis of biliary fibrosis and cirrhosis. We aimed to evaluate maternal serum Sortilin-1 level as a potential biomarker in pregnant women with intrahepatic cholestasis.Materials and methods: A prospective observational cohort study was conducted. We enrolled 80 pregnant women, 49 with the diagnosis of intrahepatic cholestasis of pregnancy and 31 healthy controls. Then, we measured maternal serum Sortilin-1 levels using an enzyme-linked immunosorbent assay method and compared them between groups.Results: The mean Sortilin-1 level in the ICP group was higher than control group (3.3 ± 1.7 ng/mL vs. 2.0 ± 0.6 ng/mL, respectively, p < .001). The receiver operating characteristic curve (ROC) analysis based on maternal serum Sortilin-1 levels to predict the presence of ICP was 85.3% controls [area under the curve (AUC), 0.853; 95% CI, 0.738-0.938, p < .001]. The optimal cutoff value of Sortilin-1 was 2.24 ng/mL (71.4% sensitivity and 74.2% specificity) to detect intrahepatic cholestasis of pregnancy.Conclusion: Elevated maternal serum Sortilin-1 levels are associated with ICP and can be used as a disease biomarker. Sortilin-1 levels can be combined with total bile acids, transaminases, and blood coagulation profile in the follow-up of ICP.

Maternal Serum Placental Protein-13 Levels in the Prediction of Pregnancies with Abnormal Invasive Placentation.

OBJECTIVE: To evaluate whether placental protein-13 (PP-13) measured in the serum of pregnant women could predict abnormal invasive placentation (AIP) detected by color Doppler ultrasound (US) and magnetic resonance imaging scan in addition to the routine US scan during the third trimester. MATERIALS AND METHODS: The prospective case-control study included patients subdivided in 2 groups: 42 pregnant women with a singleton pregnancy at 28-32 weeks of gestation with only suspected AIP, and 32 healthy pregnant women. The serum PP-13 levels were measured in both groups using an enzyme-linked immunosorbent assay (ELISA) method and statistically compared. The cases of AIP were confirmed by placental histopathological examination and/or the uterus removed by hysterectomy after elective caesarean section. RESULTS: Serum PP-13 levels of pregnant women with AIP were significantly higher (p<0.001) than those of controls (650.32±387.33 vs. 231.43±94.33). Statistical analysis of maternal serum PP-13 levels above the threshold of 312 pg/ml (measured in the early third trimester) predicted AIP with 76.2% sensitivity and 75% specificity. CONCLUSION: Maternal serum PP-13 may have a role in the pathophysiology of AIP owing to its high serum value in the AIP group. The maternal serum dosage of PP-13 levels could improve pregnancy management in those patients suspected of having AIP.

A novel biochemical marker -OKL38- with its apoptotic and antioxidant properties for the development of PCOS and its related clinical implications.

Aim: To investigate the role of serum OKL38 levels in the development of polycystic ovary syndrome (PCOS) and clinical implications related to PCOS.Method: PCOS (n = 33) and ovulatory controls (n = 48) were recruited for the study. Anthropometric measurements were recorded, and blood samples for hormonal and biochemical parameters including serum OKL38 levels were obtained. The potential role of OKL38 on the development of PCOS, metabolic syndrome and cardiovascular disease (CVD) were investigated. Framingham risk score (FRS) was used for the determination of CVD risk.Results: Mean Ferriman-Gallway (FG) score, insulin, low-density lipoprotein (LDL), total cholesterol (TC) levels, and the homeostasis model assessment of insulin resistance index (HOMA-IR) were significantly increased (p < .05) in women with PCOS compared to controls. PCOS group had lower mean OKL38 level compared to controls (p < .0001) and OKL38 was negatively predictive for the diagnosis of PCOS after adjustment of variables that were significantly different between two groups. A negative association between OKL38 and metabolic syndrome in PCOS women was evident after adjustment for age, obesity, and abdominal obesity. OKL38 level was also negatively correlated with body mass index, waist-to-hip-ratio, fat composition, serum TC, LDL, free testosterone levels, FRS, and FG scores.Conclusion: OKL38 may have a partial role in the etiopathogenesis of PCOS and may protect development of metabolic syndrome and CVD in women with PCOS.

Gremlin-1 and gremlin-2 levels in polycystic ovary syndrome and their clinical correlations.

Objective: Gremlin 1 and 2 regulate oocyte primordial follicle transition in animal models. The main objective of this study is to measure the blood levels of Gremlin 1 and 2 in the women with Polycystic Ovary Syndrome (PCOS). We also aimed to evaluate the association of these markers with hormonal and biochemical parameters of PCOS as interrupted folliculogenesis in those women is related to metabolic dysfunction. Material and methods: Fifty women with PCOS were diagnosed according to Rotterdam criteria, and thirty age-matched female controls were included in this prospective study. Gremlin 1 and 2 levels along with hormonal and metabolic parameters were compared between PCOS and control groups. Results: Serum Gremlin 1 levels were significantly higher in the PCOS group than in the control group (p = .001). Gremlin 2 levels were similar between the groups. Besides, there was a significant positive correlation between Gremlin 1 and insulin levels, Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) and waist to hip ratio (WHR) (r = 0.305; r = 0.297; r = 0.303, respectively). Conclusion: Our data suggest that Gremlin 1 may be the key regulator in the pathogenesis of PCOS. In future, Gremlin 1 may be a novel therapeutic target for the treatment of PCOS.

Increased maternal serum aquaporin 9 levels in pregnancies complicated with gestational diabetes mellitus.

INTRODUCTION: This study aimed to examine maternal serum aquaporin 9 levels in pregnant women with gestational diabetes mellitus and to compare them with non-diabetic pregnant women. METHODS: Forty-one pregnant women between 37 and 39 weeks of gestation complicated with gestational diabetes mellitus and 39 non-diabetic pregnant women at similar gestational weeks without additional obstetric complications were included in this cross-sectional study. Maternal serum aquaporin 9 levels and leptin levels of the cases were measured. RESULTS: Maternal serum leptin and aquaporin 9 levels in pregnant women with GDM were found to be significantly higher than in the control group (p < .001). In the study group, first-minute Apgar scores were significantly lower and birth weight significantly higher (p = .001 and .005, respectively). A weak but significant positive correlation between aquaporin 9 levels and maternal body mass index (r = 0.279, p = .012), birth weight (r = 0.433, p < .001), and hemoglobin A1c (r = 0.354, p = .001) levels was detected. A significant positive correlation was detected between maternal serum aquaporin 9 levels and leptin levels (r = 0.331, p = .003). CONCLUSION: The increased aquaporin 9 levels detected in cases with gestational diabetes mellitus might be a marker of the poor maternal metabolic environment specific to diabetes and might contribute to the pathophysiology of gestational diabetes.

Insulin-like Peptide-6 Levels in Non-obstructive Azoospermia.

OBJECTIVE: To investigate the serum versus insulin-like peptide-6 (INSL-6) levels in men with non-obstructive azoospermia (NOA) and normospermia. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Department of Urology, Balikligol State Hospital and Harran University, Sanliurfa, Turkey, between July and October 2020. METHODOLOGY: The serum and seminal levels of INSL-6 were measured in men with NOA, and normospermia using a commercially available enzyme-linked immunosorbent assay. Age, body mass index (BMI), hormone profile, testicular volumes and seminal and serum INSL-6 levels were compared between the study groups. RESULTS: In total, 80 men were included in the study, 40 of whom have NOA and 40 have normospermia. No significant difference was found in the mean age and BMI between the groups (p >0.05). Seminal INSL-6 levels were higher in the normospermia group, although serum and seminal INSL-6 levels were not significantly different in this group (p >0.05). No significant correlation was observed between serum INSL-6 levels and age, BMI,testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and varicocele presence (p >0.05). No significant association was found between seminal INSL-6 levels and age, BMI, FSH, LH, and testosterone levels (p >0.05). However, a significant negative association observed between seminal INSL-6 levels and testicular volume (p <0.05). CONCLUSION: The seminal INSL-6 levels were approximately 5.5 times higher than the serum INSL-6 levels and survival level of INSL-6 were higher in the normospermia. This suggests that INSL-6 plays an active role in the male reproductive system. However, the mechanism and extent of this effect remain to be elucidated. KEY WORDS: Infertility, Non-obstructive azoospermia, Insulin-like peptide-6.

Circulating levels of Elabela in pregnant women complicated with intrauterine growth restriction.

OBJECTIVE: This study aimed to detect Elabela concentrations in the serum of normotensive pregnant women complicated with intrauterine growth restriction (IUGR) and compare them with the uncomplicated healthy pregnancies. MATERIAL AND METHODS: This prospective case-control study was performed from May 1, 2020 to September 30, 2020. Of the 92 pregnant patients included in the study, we enrolled 49 normotensive patients complicated with IUGR as the study group, and 43 normotensive healthy gestational age-matched and body mass index (BMI)-matched patients without IUGR or additional pregnancy complication as the control group. Demographic and clinical characteristics, and maternal serum Elabela concentrations were recorded. RESULTS: Maternal serum Elabela levels were significantly lower in IUGR pregnancies (4.02±3.42 ng/mL) compared to healthy pregnant women (14.01±18.38 ng/mL, p<0.001). There was a positive intermediate correlation between maternal serum Elabela levels and the birth weight (r = 0.308, p = 0.004). CONCLUSION: Maternal circulating levels of Elabela were significantly lower in IUGR pregnancies than in healthy pregnant women. Also, birth weight was positively correlated with maternal serum Elabela levels. We consider that Elabela might be a crucial biomarker of the pathophysiologic process in pregnancies complicated by IUGR.

Lysyl oxidase like protein-2 (LOXL-2); a novel marker for prediction of intrahepatic cholestasis of pregnancy.

OBJECTIVE: Lysyl oxidase like protein 2 (LOXL-2) is an enzyme that is involved in the development of hepatic fibrosis and bile duct epithelial injury in hepatic cholestasis. Our aim was to investigate maternal serum levels of LOXL-2 and their relationship with fasting total bile acid (FTBA) levels in patients with intrahepatic cholestasis of pregnancy (ICP). MATERIALS AND METHODS: Thirty-five pregnant women with ICP and 35 healthy women with uncomplicated pregnancies as the control group, were included in this cross-sectional study. Maternal serum LOXL-2, FTBA and other liver function test levels were compared between the two groups. The predictive cutoff value for LOXL-2 level in ICP was specified. RESULTS: Serum LOXL-2 levels were found to be higher in the ICP group compared to the control group (225.699 ± 142.453 vs. 127.731 ± 63.419 pg/mL, p = .001). There was a significant positive correlation between serum LOXL-2 levels and FTBA levels (r = 0.330, p = .003). The optimal cutoff point for LOXL-2 for identifying increased risk of ICP was found to be ≥102 pg/mL, for which the sensitivity and specificity were 96.87% and 48.57%, respectively (p < .001). CONCLUSIONS: Maternal serum LOXL-2 levels were significantly higher in women with ICP. LOXL-2 may be both an initiating factor in the pathophysiology of ICP and a marker in the prediction. It may also be a target in terms of preventing strategies in ICP.

Maternal serum IL-22 concentrations are significantly upregulated in patients with preterm premature rupture of membranes.

OBJECTIVES: This study aimed to compare the serum IL-22 levels between preterm premature rupture of membranes (PPROM) patients and the control group with intact membranes. We also hypothesized whether serum IL-22 upregulation might contribute to defense against inflammatory responses and improve the pregnancy outcomes. MATERIAL AND METHODS: We performed this prospective case-control study between 24-34 weeks of pregnancy. We enrolled 40 singleton pregnant patients with PPROM and 40 healthy gestational age- and gravidity-matched patients without PPROM. The degree of association between variables and IL-22 were calculated by Spearman correlation coefficients where appropriate. Scatter plots were given for statistically significant correlations. ROC curve was constructed to illustrate the sensitivity and specificity performance characteristics of IL-22, and a cutoff value was estimated by using the index of Youden. RESULTS: Maternal serum IL-22 levels were significantly higher in PPROM patients (60.34 ± 139.81 pg/mL) compared to the participants in the control group (20.71 ± 4.36 pg/mL, p < 0.001). When we analyze the area under the ROC curve (AUC), the IL-22 value can be considered a statistically significant parameter for diagnosing PPROM. According to the Youden index, a 23.86 pg/mL cut-off value of IL-22 can be used to diagnosing PPROM with 72% sensitivity and 61.5% specificity. There was no positive correlation between serum IL-22 levels and maternal C-reactive protein (CRP) value, procalcitonin value, latency period, birth week, birth weight, and umbilical cord blood pH value. CONCLUSIONS: Maternal serum IL-22 levels were significantly higher in PPROM patients than healthy pregnant women with an intact membrane. We suggest that IL-22 might be a crucial biomarker of the inflammatory process in PPROM.

Maternal serum galectin-1 and galectin-3 levels in pregnancies complicated with preterm prelabor rupture of membranes.

Objective: To investigate maternal serum galectin-1 and galectin-3 levels in pregnancies complicated with preterm prelabor rupture of membranes (PPROM) and to compare with pregnancies delivered at term.Materials and methods: In this cross-sectional study, 40 women with singleton pregnancies complicated with PPROM between 24 and 34 weeks of gestation were compared with gestational age-matched 40 pregnant women with no obstetrics complications, who delivered at term. The maternal serum galectin-1 and galectin-3 levels were measured.Results: Patients complicated with PPROM had significantly higher levels of galectin-1 (p = .001) and galectin-3 (p = .003) than the control group. Maternal serum galectin-3 levels were found significantly negatively correlated with the gestational age at delivery and birth weight.Conclusion: Maternal serum galectin-1 and galectin-3 levels were significantly higher in pregnancies complicated with PPROM. Galectin-1 and galectin-3, with their regulatory effects in key biological processes, may be both an initiating factor in the pathophysiology of PPROM, a marker in the prediction, and a target of preventing strategies of PPROM.

Increased maternal C1q/TNF-related protein-1 (CTRP-1) serum levels in pregnancies with preeclampsia.

Objective: Metabolic changes and inflammation are involved in the pathogenesis of preeclampsia. Complement C1q tumor necrosis factor-related protein-1 (CTRP-1) is a pleiotropic molecule that possesses insulin-sensitizing effects and is also involved in lipid metabolism and inflammatory responses. The aim of the study was to investigate CTRP-1 levels in pregnancies with preeclampsia.Material and methods: Serum concentrations of CTRP-1 were measured in 29 pregnant women with early-onset preeclampsia (EOPE), 24 pregnant women with late-onset preeclampsia (LOPE), and 26 women with uncomplicated pregnancies using an enzyme-linked immunosorbent assay method.Results: Patients with both EOPE and LOPE had significantly higher serum concentrations of CTRP-1 compared to the healthy controls (p < .001). However, no significant difference was found between the EOPE and LOPE groups regarding CTRP-1 levels (p = 1.000). Correlation analysis showed that CTRP-1 levels were positively correlated with systolic blood pressure (p < .001), diastolic blood pressure (p < .001), and mean UtA PI (p < .001) but negatively correlated with gestational age at delivery (p = .001) and birth weight (p < .001).Conclusions: Serum CTRP-1 levels were significantly higher in patients with both EOPE and LOPE than in healthy pregnant women.

Maternal serum TXNDC5 levels and thiol/disulfide homeostasis in preeclamptic pregnancies.

Objective: To investigate thiol/disulfide homeostasis (TDH) and thioredoxin domain-containing 5 (TXNDC5) level in early and late-onset preeclampsia.Material and methods: In this cross-sectional study, 24 pregnant women with early-onset preeclampsia and 26 pregnant women with late-onset preeclampsia were compared with 30 pregnant women with no obstetric complications. The serum TXNDC5 levels and thiol/disulfide homeostasis were measured.Results: Serum TXNDC5 levels were significantly higher in the early-onset and late-onset preeclampsia groups compared with the control group (p < .05). Native thiol and total thiol levels were significantly lower in the early-onset and late-onset preeclampsia groups than control group. The disulfide levels were found as significantly high in early preeclamptic patients compared to control group (p < .05). The highest levels of TXNDC5 and the lowest levels of native thiol and total thiol were found in early-onset preeclampsia group. No significant difference was found between the patients with early onset and late onset preeclampsia regarding TXNDC5 levels and thiol/disulfide homeostasis (p > .05).Conclusion: Serum TXNDC5 levels were significantly higher in patients with early-onset and late-onset preeclampsia. The dynamic thiol/disulfide homeostasis was impaired in favor of the oxidized state in patients with preeclampsia.

Maternal serum AMP-activated protein kinase levels in mild and severe preeclampsia.

OBJECTIVE: To investigate Phosphorylated adenosine monophosphate activated protein kinase (AMPK) levels in healthy pregnant women and pregnant women with preeclampsia (PE). METHODS: Twenty-eight women with mild-PE, 22 with severe-PE, and 30 normotensive controls were included in this cross-sectional study. The serum AMPK levels of these patients were analyzed. The patients were followed up to delivery. RESULTS: No statistically significant difference was found between the groups for age, gravida, parity, and gestational age at the time the blood samples were obtained (p > .05). No significant difference between the group with mild-PE and the control group was found, while in the severe-PE group, serum AMPK levels were significantly higher relative to both the mild-PE and control groups (p < .001 and p < .001, respectively). No correlation was detected between serum AMPK levels and age, body mass index (BMI), and gestational age at the time the blood samples were collected. A negative correlation was found between AMPK levels and gestational week and birthweight at delivery, while a positive correlation was detected between systolic and diastolic blood pressures and AMPK levels. CONCLUSIONS: Serum AMPK was higher in patients with severe-PE compared with healthy pregnant women and patients with PE without severe features so it might be a new biomarker for the prediction of disease and its severity.

Increased levels of the novel hepatokine fetuin B in patients with intrahepatic cholestasis of pregnancy.

OBJECTIVES: To investigate liver-derived plasma protein fetuin B levels in healthy pregnant women and pregnant women with intrahepatic cholestasis of pregnancy (ICP). MATERIALS AND METHODS: Forty women with ICP and 40 healthy pregnant women were included in this cross-sectional study. The serum fetuin B levels of these patients were analyzed. The patients were followed up to delivery. RESULTS: Maternal age, gravida, parity, BMI at assessment, and gestational age at blood sampling were similar between the ICP and control groups (p > .05). However, the gestational age at delivery and the birth weight were significantly lower in the ICP group (p < .05). Total bile acid (TBA) levels and liver function tests were significantly higher in the ICP group than in the control group (p < .0001 and < .0001, respectively). In addition, serum fetuin B concentrations were significantly higher in the ICP group than in the control group (p < .0001). The best cutoff for fetuin B serum concentration was 5540.2 pg/mL. Serum values greater than this threshold had 80% sensitivity and 65% specificity for the diagnosis of ICP. CONCLUSIONS: Serum fetuin B was higher in patients with ICP compared to healthy pregnant women and might be a new biomarker.

Maternal cytoglobin (CYGB) serum levels in normal and preeclamptic pregnancies.

OBJECTIVE: To investigate cytoglobin levels in women with preeclampsia and women with uncomplicated pregnancies. MATERIALS AND METHODS: A cross-sectional study including 26 pregnant women complicated with early-onset preeclampsia (EO-PE) and 26 pregnant women complicated with late-onset preeclampsia (LO-PE) were recruited for the study group. Twenty-seven healthy pregnant women selected randomly were included in the control group. The serum CYGB concentrations were measured using an enzyme-linked immunosorbent assay. RESULTS: Gestational age at delivery and mean birth weight were significantly lower in the preeclampsia groups than in the control group and were found to be the lowest in the EO-PE group (p < .001). Serum CYGB levels were significantly higher in the EO-PE and LO-PE groups as compared with the control group (9.99 (6.08) ng/ml (EOPE), 10.04 (7.04) ng/ml (LOPE) versus 2.84 (0.82) ng/ml), (p < .001). However, a significant difference was not found between the EO-PE and LO-PE groups regarding CYGB levels (p = 1.000). CONCLUSIONS: Serum CYGB levels were significantly higher in patients with EO-PE and LO-PE as compared to healthy pregnant women.

Maternal serum sestrin 2 levels in preeclampsia and their relationship with the severity of the disease.

OBJECTIVE: To investigate sestrin 2 (SESN2) levels in preeclampsia (PE) cases and uncomplicated pregnancies. METHODS: Cross-sectional study including 26 pregnant women with PE, 24 with severe-PE, and 30 randomly selected healthy pregnant women. RESULTS: The mean arterial pressure, severe proteinuria, number of HELLP syndrome cases, and serum SESN2 levels in the severe PE group were significantly higher than those in the other groups (p < 0.001, p < 0.001, p = 0.006, and p = 0.004, respectively). Negative correlation was found between the birth interval (r = -.262, p = 0.019) and the SESN2 level. CONCLUSION: SESN2 seems to play a role in the pathophysiology of PE, especially in severe PE cases.

Evaluation of FGF-19 and ß-klotho as biomarkers in patients with intrahepatic cholestasis of pregnancy.

INTRODUCTION: Fibroblast growth factor-19 (FGF-19) and its co-receptor, beta-klotho, regulate bile acid synthesis in the liver as an enterohepatic feedback mechanism. In this study, our aim was to investigate the circulating FGF-19 and ß-klotho levels in intrahepatic cholestasis of pregnancy (ICP) cases. MATERIAL AND METHODS: A cross-sectional study including 40 women whose pregnancies were complicated with ICP were recruited for the study group. Forty randomly selected healthy pregnant women comprised the control group. The patient characteristics, including maternal age, gravidity, parity, gestational age at the time of diagnosis, body mass index (BMI), and obstetric history, were recorded. The serum FGF-19 and ß-klotho concentrations were measured using an enzyme-linked immunosorbent assay. RESULTS: Maternal age, gravidity, parity, body mass index at assessment, and gestational age at blood sampling were similar between the two groups (p > 0.05). Moreover, there were no significant differences in the FGF-19 and ß-klotho concentrations between the two groups (p = 0.341 and p = 0.086, respectively). A positive correlation was detected between the ß-klotho and FGF-19 levels, as well as between the FGF-19 level and BMI (r = 0.368, p = 0.020 and r = 0.389, p = 0.013, respectively). CONCLUSIONS: The serum FGF-19 and ß-klotho concentrations did not differ between the pregnancies with ICP and the healthy controls. However, in some cases, abnormalities in the FGF-19, ß-klotho, and FGFR4 signaling system may play roles in the pathogenesis of ICP.