kiss1-protein--human and Pre-Eclampsia

Kisspeptins are the family of neuropeptide products of the

Topics: Abortion, Spontaneous; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Humans; Infant, Newborn; Kisspeptins; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Premature Birth

Kisspeptin and its receptor are central to reproductive health acting as key regulators of the reproductive endocrine axis in humans. Kisspeptin is most widely recognised as a regulator of gonadotrophin releasing hormone (GnRH) neuronal function. However, recent evidence has demonstrated that kisspeptin and its receptor also play a fundamental role during pregnancy in the regulation of placentation. Kisspeptin is abundantly expressed in syncytiotrophoblasts, and its receptor in both cyto- and syncytio-trophoblasts. Circulating levels of kisspeptin rise dramatically during healthy pregnancy, which have been proposed as having potential as a biomarker of placental function. Indeed, alterations in kisspeptin levels are associated with an increased risk of adverse maternal and foetal complications. This review summarises data evaluating kisspeptin's role as a putative biomarker of pregnancy complications including miscarriage, ectopic pregnancy (EP), preterm birth (PTB), foetal growth restriction (FGR), hypertensive disorders of pregnancy (HDP), pre-eclampsia (PE), gestational diabetes mellitus (GDM), and gestational trophoblastic disease (GTD).

Topics: Biomarkers; Female; Humans; Kisspeptins; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Premature Birth

There are contradictory data concerning kisspeptin in gravids with preeclampsia and gestational hypertension (GH).. To conduct a meta-analysis of studies comparing maternal kisspeptin levels in gravids with and without preeclampsia or GH.. We searched PubMed, LILACS, and CNKI list of articles up to 20 August 2021, without language limitations, comparing circulating maternal kisspeptin levels, and maternal and neonatal outcomes in gravids with and without preeclampsia or GH. Meta-analyzed results are reported as standardized mean differences (SMD), and their 95% confidence interval (CI).. Seven studies with a low-to-moderate risk of bias were eligible for meta-analysis. Gravids with preeclampsia or GH displayed significantly lower circulating kisspeptin levels (SMD, -0.68, 95% CI, -1.04 to -0.32), lower gestational ages at delivery (SMD, -2.22, 95% CI, -3.25 to -1.18), and birth weight (SMD, -2.16, 95% CI, -3.15 to -1.17), and significantly higher body mass indices (MD, 0.56, 95% CI, 0.24-0.88), systolic (SMD, 2.87, 95% CI, 2.22-3.53), and diastolic blood pressures (SMD, 2.57, 95% CI, 2.19-2.95).. Gravids with preeclampsia or GH had lower kisspeptin levels as compared to normotensive controls.

Topics: Female; Humans; Kisspeptins; Pre-Eclampsia; Pregnancy

Topics: Apoptosis; Female; Gene Expression Regulation; Humans; Kisspeptins; Pre-Eclampsia; Pregnancy; Trophoblasts

Kisspeptins are a family of neuropeptides that are critical for the puberty initiation and female fertility. Plasma or serum kisspeptin is mainly derived from the placenta during pregnancy and plasma kisspeptin levels significantly increase across pregnancy. Plasma kisspeptin levels could be used as a potential biomarker for the detection of miscarriage, pre-eclampsia, gestational trophoblastic neoplasia (GTN), and fetal development. Kisspeptin may also be involved in the process of parturition by stimulating oxytocin secretion during term pregnancy. This review discussed the potential use of kisspeptin as a marker across pregnancy and highlighted the unresolved problems in this area. Tweetable abstract: Plasma kisspeptin levels could be used as a potential biomarker across pregnancy.

Topics: Abortion, Spontaneous; Biomarkers; Female; Fetal Development; Gestational Trophoblastic Disease; Humans; Kisspeptins; Pre-Eclampsia; Pregnancy

Miscarriage is a major concern in early pregnancy among women having conceived with assisted reproductive treatments. This study aimed to examine potential miscarriage-related biophysical and biochemical markers at 6 weeks' gestation among women with confirmed clinical pregnancy following in vitro fertilization (IVF)/embryo transfer (ET) and evaluate the performance of a model combining maternal factors, biophysical and biochemical markers at 6 weeks' gestation in the prediction of first trimester miscarriage among singleton pregnancies following IVF/ET.. A prospective cohort study was conducted in a teaching hospital between December 2017 and January 2020 including women who conceived through IVF/ET. Maternal mean arterial pressure, ultrasound markers including mean gestational sac diameter, fetal heart activity, crown rump length and mean uterine artery pulsatility index (mUTPI) and biochemical biomarkers including maternal serum soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), kisspeptin and glycodelin-A were measured at 6 weeks' gestation. Logistic regression analysis was carried out to determine significant predictors of miscarriage prior to 13 weeks' gestation and performance of screening was estimated by receiver-operating characteristics curve analysis.. Among 169 included pregnancies, 145 (85.8%) pregnancies progressed to beyond 13 weeks' gestation and had live births whereas 24 (14.2%) pregnancies resulted in a miscarriage during the first trimester. In the miscarriage group, compared to the live birth group, maternal age, body mass index, and mean arterial pressure were significantly increased; mean gestational sac diameter, crown rump length, mUTPI, serum sFlt-1, glycodelin-A, and the rate of positive fetal heart activity were significantly decreased, while no significant differences were detected in PlGF and kisspeptin. Significant prediction for miscarriage before 13 weeks' gestation was provided by maternal age, fetal heart activity, mUTPI, and serum glycodelin-A. The combination of maternal age, ultrasound (fetal heart activity and mUTPI), and biochemical (glycodelin-A) markers achieved the highest area under the curve (AUC: 0.918, 95% CI 0.866-0.955), with estimated detection rates of 54.2% and 70.8% for miscarriage before 13 weeks' gestation, at fixed false positive rates of 5% and 10%, respectively.. A combination of maternal age, fetal heart activity, mUTPI, and serum glycodelin-A at 6 weeks' gestation could effectively identify IVF/ET pregnancies at risk of first trimester miscarriage.

Topics: Abortion, Spontaneous; Biomarkers; Female; Gestational Age; Glycodelin; Humans; Infant; Kisspeptins; Placenta Growth Factor; Pre-Eclampsia; Pregnancy; Prospective Studies; Pulsatile Flow; Reproductive Techniques, Assisted; Uterine Artery; Vascular Endothelial Growth Factor Receptor-1

Maternal Kisspeptin plays role in cell migration which is responsible for trophoblast invasion. We aimed to investigate the role of Kisspeptin as an invasion marker in the early-onset and late-onset preeclampsia cases.. In this case-control study, 125 patients were included: 20 patients with early-onset preeclampsia and 20 gestational-age-matched healthy controls; 45 patients with late-onset preeclampsia and 40 gestational-age-matched controls). Maternal plasma Kisspeptin concentration was measured and compared in groups regarding the presence of early-onset and late-onset preeclampsia.. In the late-onset PE group, significantly higher maternal plasma Kisspeptin values were observed compared with the control group at > 34 weeks of gestation (68.7 ± 93.4 pg/ml vs 68.5 ± 57.9 pg/ml; p = 0.004). Before the 34th week of gestation, plasma Kisspeptin levels did not show a significant difference when patients with early-onset PE and gestational-age matched controls were compared (66.8 ± 87.9 pg/ml vs 48.5 ± 91.3 pg/ml; p = 0.56).. Plasma Kisspeptin levels were significantly higher in women with late-onset preeclampsia, while no significant difference was observed in early-onset preeclampsia when compared with healthy gestational age-matched controls. The role of Kisspeptin proteins is still not clearly defined in the pathogenesis of preeclampsia.

Topics: Case-Control Studies; Female; Gestational Age; Humans; Kisspeptins; Pre-Eclampsia; Pregnancy; Trophoblasts

Antenatal complications such as hypertensive disorders of pregnancy (HDP), fetal growth restriction (FGR), gestational diabetes (GDM), and preterm birth (PTB) are associated with placental dysfunction. Kisspeptin has emerged as a putative marker of placental function, but limited data exist describing circulating kisspeptin levels across all 3 trimesters in women with antenatal complications.. We aimed to assess whether kisspeptin levels are altered in women with antenatal complications.. Women with antenatal complications (n = 105) and those with uncomplicated pregnancies (n = 265) underwent serial ultrasound scans and blood sampling at the Early Pregnancy Assessment Unit at Hammersmith Hospital, UK, at least once during each trimester (March 2014 to March 2017). The women with antenatal complications (HDP [n = 32], FGR [n = 17], GDM [n = 35], PTB [n = 11], and multiple complications [n=10]) provided 373 blood samples and the controls provided 930 samples. Differences in circulating kisspeptin levels were assessed.. Third-trimester kisspeptin levels were higher than controls in HDP but lower in FGR. The odds of HDP adjusted for gestational age, maternal age, ethnicity, BMI, smoking, and parity were increased by 30% (95% CI, 16%-47%; P < 0.0001), and of FGR were reduced by 28% (95% CI, 4-46%; P = 0.025), for every 1 nmol/L increase in plasma kisspeptin. Multiple of gestation-specific median values of kisspeptin were higher in pregnancies affected by PTB (P = 0.014) and lower in those with GDM (P = 0.020), but not significantly on multivariable analysis.. We delineate changes in circulating kisspeptin levels at different trimesters and evaluate the potential of kisspeptin as a biomarker for antenatal complications.

Topics: Adult; Biomarkers; Case-Control Studies; Diabetes, Gestational; Female; Fetal Growth Retardation; Follow-Up Studies; Gestational Age; Humans; Hypertension, Pregnancy-Induced; Infant, Newborn; Kisspeptins; London; Male; Placenta Diseases; Pre-Eclampsia; Pregnancy; Pregnancy Trimesters; Premature Birth; Prognosis

During pregnancy, trophoblast cell invasion needs to be finely controlled. Aberrant trophoblast cell invasion is associated with placental diseases. Epidermal growth factor (EGF) and its receptor, EGFR, are expressed in trophoblast cells. Although the pro-invasive effect of EGF on trophoblast cells has been reported, the underlying mechanism remains largely unknown.. In the present study, we conducted an RNA sequencing (RNA-seq) to HTR-8/SVneo human trophoblast cells in response to EGF and identified KISS1 as a target gene of EGF. The human KISS1 gene encodes kisspeptin, also known as metastin, which can suppress tumor metastasis. Our results showed that EGF treatment downregulated KISS1 expression and secretion by activating the EGFR-mediated PI3K/AKT signaling pathway. In addition, the expression of inhibitor of DNA-binding protein 3 (ID3) was downregulated by EGF and that was required for the EGF-suppressed KISS1 expression. Functionally, transwell invasion assays demonstrated that EGF stimulated human trophoblast cell invasion by downregulating KISS1 expression. Preeclampsia (PE) is a placental disease characterized by insufficient trophoblast cell invasion. Our clinical results revealed that serum levels of EGF were downregulated while serum and placental levels of KISS1 were upregulated in PE patients.. This study demonstrates that downregulation of EGF can lead to poor trophoblast cell invasion by increasing KISS1 expression which subsequently contributes to the pathogenesis of PE. Video Abstract.

Topics: Cell Movement; Epidermal Growth Factor; ErbB Receptors; Female; Humans; Inhibitor of Differentiation Proteins; Kisspeptins; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Phosphatidylinositol 3-Kinases; Placenta; Placenta Diseases; Pre-Eclampsia; Pregnancy; Proto-Oncogene Proteins c-akt; Signal Transduction; Trophoblasts

Kisspeptins regulate the trophoblast invasion. The disturbance of this process might lead to the development of preeclampsia (PE). Diabetes mellitus (DM) is associated with the high rate of this complication. The main hypothesis was to investigate the placental protein expression of kisspeptin-1 (KISS1) and its receptor (KISS1R) in diabetic, preeclamptic, and healthy pregnancies.. Placentae (n = 65) were divided into the following groups: the control group (n = 20), either PE or non-PE type-1 diabetes mellitus (T1DM) (n = 10), either PE or non-PE type-2 diabetes mellitus (T2DM) (n = 10), either PE or non-PE gestational diabetes mellitus (GDM) (n = 10) and preeclampsia without diabetes (PE) (n = 15). Immunohistochemistry analysis was used for demonstrating the presence and location of KISS1/KISS1R in placental tissue and to measure the area of immunopositive expression. Correlation analyses were performed to detect the links between protein expression of these biomarkers and the main obstetric outcomes.. The highest placental protein expressions of KISS1 were detected in the PE (35.4%) and GDM (33.2%) groups. In case of DM, levels of KISS1 expression depended on the presence of PE and were higher compared with DM no PE and control groups: (30.6%) in T1DM + PE and (30.1%) in T2DM + PE group. The lowest expression was detected in the control group (14.1%). The expression of KISS1R was higher in DM and PE compared to the control group. We detected the strong direct link between PE and placental expression of KISS1 (r = 0.81) and KISS1R (r = 0.56), and inverse correlation link between KISS1 and preterm birth weight (r = - 0.73). The low correlation links were found between KISS1 and IUGR (r = 0.29), and preterm birth (r = 0.24). The same trend was detected for KISS1R. We did not find any significant correlations between placental expressions of KISS/KISS1R and placental weight or HbA1c levels.. Increased expression levels of KISS1 and KISS1R in case of diabetes mellitus may play a role in the altered placentation process and lead to the development of preeclampsia.

Topics: Adult; Cohort Studies; Diabetes, Gestational; Female; Humans; Kisspeptins; Pre-Eclampsia; Pregnancy; Receptors, Kisspeptin-1; Retrospective Studies; Young Adult

To evaluate plasma kisspeptin-10 (KP-10) as a marker for preeclampsia and assess its relation to altered reproductive hormones in preeclamptic pregnant women.. First time pregnant women (n = 100) at 20 weeks of gestation participated in this study and divided into preeclamptics (n = 60) and normotensives (n = 40). KP-10, luteinizing hormone (LH), follicle stimulating hormone (FSH), beta-human chorionic gonadotropin (β-hCG), estradiol (E2) and progesterone were evaluated during 2nd and 3rd trimesters of pregnancy for all women.. Kisspeptin-10 levels were reduced in preeclampsia (PE) women compared with normotensive pregnancies. In the 2nd trimester, area under receiver-operator characteristic (ROC) curve was 0.662, positive and negative predictive values were 32.8 and 94.6, and test sensitivity and specificity were 55% and 87.5%, respectively. In the 3rd trimester, area under ROC curve was 0.747 positive and negative predictive values were 22.2 and 97.3, and test sensitivity and specificity were 83.3% and 67.5%, respectively. In PE patients, plasma KP-10 demonstrated an inverse correlation with E2 (during the 2nd trimester), LH and FSH (during the 3rd trimester), and positively correlated with β-hCG (during the 3rd trimester).. This study showed significantly reduced plasma KP-10 levels in PE women. This suggests that KP-10 may play an important role in the pathophysiology of PE. Therefore, combined with previous studies, to diagnose the PE, testing for maternal KP-10 plasma levels may be useful as an effective screening, but because of low positive predictive value and inadequate test sensitivity, screening cannot be recommended. Furthermore, KP-10 in PE patients demonstrated significant positive correlation with β-hCG.

Topics: Adult; Case-Control Studies; Chorionic Gonadotropin, beta Subunit, Human; Estradiol; Female; Follicle Stimulating Hormone; Humans; Kisspeptins; Luteinizing Hormone; Pre-Eclampsia; Predictive Value of Tests; Pregnancy; Pregnancy Proteins; Pregnancy Trimesters; Progesterone; ROC Curve; Sensitivity and Specificity

Topics: Female; Humans; Kisspeptins; Pre-Eclampsia; Pregnancy; Receptors, Kisspeptin-1

To investigate the placental mRNA and protein expression of metastasis suppressor gene Kiss-1 and the transcript expression of its receptor GPR-54 across the maternal-fetal interface of healthy and preeclamptic pregnancies. To furthermore compare placental tissue kisspeptin expression to circulatory kisspeptin levels in these pregnancies.. Secondary and Tertiary Hospital Setting in Cape Town, South Africa.. Patients with and without preeclampsia undergoing elective caesarean delivery.. The placenta, placental bed and decidua parietalis as well as maternal and cord blood in both healthy and preeclamptic pregnancies were simultaneously sampled at elective caesarean delivery. RT-PCR was utilised to determine mRNA expression while immunohistochemistry was employed to investigate protein expression in maternal-fetal tissues. Circulating maternal and cord serum kisspeptin concentrations were determined using ELISA.. Maternal-fetal tissue mRNA expression of Kiss-1 and GPR-54 as well as maternal/cord serum kisspeptin concentrations in healthy and preeclamptic pregnancies.. There was high placental kisspeptin expression but low circulating serum kisspeptin levels in pregnancies complicated by preeclampsia. Kiss-1 mRNA and protein expression was minimal in the maternal tissues (placental bed and decidua parietalis) of both healthy and preeclamptic pregnancies. No difference was found in Kiss-1 receptor (GPR-54) mRNA expression across maternal-fetal tissues of healthy and preeclamptic pregnancies.. Increased placental kisspeptin expression is consistent with reduced trophoblast invasiveness and may represent a molecular mechanism that explains the development of preeclampsia. Decreased circulating kisspeptin concentration has the potential to be utilised as a marker for placental dysfunction.

Topics: Adult; Biomarkers; Case-Control Studies; Cesarean Section; Elective Surgical Procedures; Female; Fetal Blood; Gene Expression Regulation; Humans; Kisspeptins; Placenta; Pre-Eclampsia; Pregnancy; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; RNA, Messenger; South Africa; Young Adult

This study aims to evaluate the role of kisspeptin-10 in preeclampsia and check for possible relationship between its severity and fetal growth well-being. Kisspeptin-10 may participate in implantation of the embryo, placenta formation, and maintenance of pregnancy.. One hundred women who completed 20 weeks of gestation with singleton pregnancies were divided into 60 peeclamptic and 40 normotensive control women. Kisspeptin-10 level estimation, and ultrasound and Doppler ultrasound studies for umbilical artery were performed during their second and third trimesters of pregnancy.. Plasma kisspeptin-10 level was lower in preeclamptic groups and inversely correlated with the severity of the disease. Its level directly correlated with estimated fetal weight in utero during both trimesters in patients with severe preeclampsia and with fetal birth weight in patients with mild preeclampsia, whereas an inverse correlation was observed in those with severe preeclampsia during their second trimester. Kisspeptin-10 level was directly related to the resistance index in the second trimester in patients with severe preeclampsia, while it inversely correlated with the systolic/diastolic ratio and resistance index in the third trimester in patients with mild preeclampsia.. Kisspeptin-10 level is useful in assessing the severity of preeclampsia and can be a novel marker downregulated in pregnant women with preeclampsia, especially in those who also developed impaired uteroplacental perfusion or intrauterine growth restriction.

Topics: Adolescent; Adult; Biomarkers; Case-Control Studies; Female; Fetal Development; Fetal Weight; Gestational Age; Humans; Kisspeptins; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Prospective Studies; Severity of Illness Index; Ultrasonography, Prenatal; Umbilical Arteries; Young Adult

To investigate the association between kisspeptin 10 (Kp-10) levels and early pregnancy bleeding and perinatal outcome.. A total of 20 pregnant women with the complaint of vaginal bleeding during 7-18 gestational weeks and 20 healthy gestational week matched pregnant women were included in the study. Maternal plasma Kp-10 levels were measured with the enzyme immunoassay method. Adverse pregnancy outcomes like intrauterine growth restriction, preterm delivery, preeclampsia and low birth weight were evaluated in both groups.. Maternal plasma Kp-10 levels (p = 0.01) and birth weight (p = 0.06) were found to be lower in women with bleeding. Intrauterine growth restriction, preterm delivery and intrauterine exitus were noted more commonly in women with bleeding (10 vs. 0%, 25 vs. 15% and 20 vs. 0%, p = 0.08). Preeclampsia were developed in 5% of both groups. Kp-10 levels showed positive correlation with gestational week (p = 0.02) and ALT levels (p = 0.02).. [corrected] Kp-10 levels were found lower in women with early pregnancy bleeding.

Topics: Abortion, Threatened; Adult; Alanine Transaminase; Female; Fetal Growth Retardation; Humans; Infant, Low Birth Weight; Infant, Newborn; Kisspeptins; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Premature Birth; Uterine Hemorrhage; Young Adult

Circulating concentrations of the peptide kisspeptin have been proposed as a novel biomarker for early detection of pre-eclampsia. Our aims were to assess analytical and clinical performance characteristics of a commercial kisspeptin assay and to determine sensitivity and specificity of the test for pre-eclampsia.. Prospective, longitudinal study in a United Kingdom tertiary referral Antenatal Metabolic Clinic.. Severely obese (body mass index, BMI > 40 kg/m(2), n = 194) and lean (BMI < 25 kg/m(2), n = 78) pregnant women.. A commercial kisspeptin ELISA (Phoenix Pharmaceuticals) was assessed for analytical sensitivity, specificity, precision, linearity, recovery and stability in maternal plasma samples at 16, 28 and 36 weeks gestation. Pre-eclampsia, defined using International Society for the Study of Hypertension in Pregnancy guidelines; blood pressure; delivery gestation; birthweight.. Kisspeptin concentrations were lower in early pregnancy in obese women (P < 0.001), and in women who later developed pre-eclampsia (P < 0.05), compared with women with uncomplicated pregnancies. For 16-week plasma kisspeptin in prediction of pre-eclampsia, area under the receiver-operator characteristic curve was 0.80 (P < 0.01), positive and negative likelihood ratios were 3.0 and 0.2, and test sensitivity and specificity were 85.7 and 71.4%, respectively. In regression analyses, kisspeptin (16 weeks) associated positively with delivery gestation (P < 0.05) and birthweight (P < 0.0001), and negatively with 28- and 36-week blood pressure (P < 0.0001).. Kisspeptin concentration in early pregnancy is a promising biomarker for pre-eclampsia and low birthweight but cannot be recommended, in isolation, for universal screening because of inadequate test sensitivity and specificity. Large-scale studies are required to assess its potential in a panel of biomarkers.

Topics: Adult; Enzyme-Linked Immunosorbent Assay; Female; Humans; Kisspeptins; Obesity; Pre-Eclampsia; Pregnancy; Prospective Studies; Risk Factors

The aim of this study was to prospectively evaluate plasma kisspeptin levels in 129 singleton pregnancies with diabetes [pregestational insulin-dependent diabetes mellitus (type 1) and gestational diabetes (GD)] and hypertensive disease [chronic hypertension (CH), gestational hypertension, and preeclampsia (PE)] as a potential marker of placental dysfunction and adverse perinatal outcome.. Kisspeptin levels were evaluated in the first, second, and third trimesters in patients with type 1 diabetes (16 patients), H (22), and healthy control (25) and in the second and third trimesters in patients with GD (20), gestational hypertension (18), and PE (28). Maternal kisspeptin levels were correlated with pregnancy outcome, parameters of fetoplacental circulation, ultrasound-detected abnormalities of placental morphology, and placental weight at delivery.. In pregnancies with type 1 diabetes and H, mean kisspeptin levels were significantly lower compared with the control group (p<0.001 in the first and second trimesters and p<0.05 in the third trimester). Decreased plasma kisspeptin levels in the second and third trimesters were found in patients with GD (p<0.001 in the second and third trimesters) and PE (p<0.001 in the second trimester and p<0.05 in the third trimester). In patients with PE and placental dysfunction, low kisspeptin levels in the third trimester were associated with adverse perinatal outcome.. Our study demonstrates reduced kisspeptin levels in pregnancies with diabetes, H, PE, and placental dysfunction. In patients with PE and placental dysfunction, decreased kisspeptin levels were associated with adverse perinatal outcome. Larger studies are needed to investigate the role of kisspeptin as a potential marker of placental dysfunction and adverse perinatal outcome.

Topics: Adult; Diabetes, Gestational; Female; Humans; Hypertension; Kisspeptins; Placenta Diseases; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy in Diabetics; Pregnancy Outcome; Pregnancy Trimester, First; Pregnancy Trimester, Second; Pregnancy Trimester, Third

Kisspeptin, originally identified as metastatin, important in preventing cancer metastasis, has more recently been shown to be important in pregnancy. Roles indicated for kisspeptin in pregnancy include regulating trophoblast invasion and migration during placentation. The pregnancy-specific disorder pre-eclampsia (PE) is now accepted to begin with inadequate trophoblast invasion and the current study therefore sets out to characterise placental expression of both kisspeptin (KISS1) and its receptor (KISS1R) throughout pregnancy and in PE. Placental tissue was obtained from women undergoing elective surgical termination of early pregnancy (n=10) and from women following Caesarean section at term in normal pregnancy (n=10) and with PE (n=10). Immunohistochemistry of paraffin embedded sections and western immunoblotting were performed to assess protein localisation and expression. Quantitative real-time PCR was carried out to evaluate mRNA expression of both KISS1 and KISS1R. Protein and mRNA expression was found to mirror each other with KISS1 expression found to be reduced in PE compared with that in normal term pregnancy. Interestingly, KISS1R expression at both the mRNA and protein levels was found to be increased in PE compared with that in normal term pregnancy. The current findings of increased KISS1R expression may represent a mechanism by which functional activity of KISS1 is higher in PE than in normal pregnancy. Higher levels of activity of KISS1R may be involved in inhibition of trophoblast invasion and angiogenesis, which are associated with PE.

Topics: Adult; Cesarean Section; Female; Gene Expression; Humans; Immunoblotting; Immunohistochemistry; Kisspeptins; Placenta; Pre-Eclampsia; Pregnancy; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Young Adult

To evaluate the role of metastin levels in the pathophysiology of pre-eclampsia and to determine whether there is a relationship between the severity of the disease and Doppler velocimetry measurements.. This cross-sectional study included 89 pregnant women (50 healthy normotensive pregnant women, 15 patients with mild pre-eclampsia, and 24 patients with severe pre-eclampsia) at the third trimester of pregnancy. The maternal levels of plasma metastin were determined by enzyme-linked immunosorbent assay. The umbilical artery and uterine artery blood flow velocities were measured by transabdominal color and pulsed Doppler ultrasound.. Plasma metastin levels were lower in patients with pre-eclampsia than those in the normotensive pregnant women. Four patients with mild pre-eclampsia and seven patients with severe pre-eclampsia had abnormal Doppler velocimetry findings. Metastin levels of pre-eclamptic patients with abnormal Doppler velocimetry findings were significantly lower than those in patients with normal Doppler velocimetry findings. Plasma metastin levels negatively correlated with proteinuria in 24 hours and with mean arterial pressure in the cases of pre-eclampsia.. The findings suggest that decreased maternal concentrations of plasma metastin may be involved in the pathogenesis of pre-eclampsia. Plasma metastin levels may be useful in the assessment of the severity of pre-eclampsia. However, further trials are needed to clarify the role of metastin in pre-eclampsia.

Topics: Adult; Blood Flow Velocity; Cross-Sectional Studies; Female; Humans; Kisspeptins; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Proteinuria; Severity of Illness Index; Ultrasonography, Doppler; Ultrasonography, Prenatal; Umbilical Arteries; Uterine Artery

To investigate whether the serum levels of metastin and PIGF and chitotriosidase activity early in pregnancy differ in women who develop pre-eclampsia from those who remain normotensive.. A retrospective case-control study of prospectively collected data. Thirty healthy pregnant women and 31 women with pre-eclampsia were included in the study. Serum samples were collected at 11-14 weeks and stored at -70°C. Levels of metastin, PIGF and chitotriosidase activity were measured in serum from pregnant women with subsequent development of pre-eclampsia and matched controls.. Mean maternal serum metastin (1554 ± 385 pmol/L vs 1995 ± 375 pmol/L, p<0.001) and PIGF (111.9 ± 7.0 pg/mL vs 124.9 ± 3.5 pg/mL, p<0.001) levels were significantly lower and chitotriosidase activity was significantly higher (681.6 ± 248.3 nmol/mL/h vs 527.7 ± 223.1 nmol/mL/h, p<0.01) in women who subsequently developed pre-eclampsia than in those who remained normotensive. The areas under the curve equal to 0.797, 0.831 and 0.681 (p<0.001, p<0.001 and p<0.01) for metastin, PIGF, and chitotriosidase respectively were determined for the prediction of pre-eclampsia.. Metastin and PIGF levels and chitotriosidase activity are altered in the first trimester serum of women destined to become pre-eclamptic, reflecting placental dysfunction. Metastin, like PIGF, may have a potential to be used as a first-trimester biomarker of pre-eclampsia.

Topics: Adult; Biomarkers; Case-Control Studies; Down-Regulation; Female; Hexosaminidases; Humans; Kisspeptins; Placenta Growth Factor; Pre-Eclampsia; Pregnancy; Pregnancy Proteins; Pregnancy Trimester, First; Retrospective Studies; Up-Regulation

Preeclampsia (PE) is a heterogeneous syndrome affecting 2% to 8% of all pregnancies and is the world's leading cause of fetal and maternal morbidity and mortality. In many cases of PE, shallow trophoblast invasion results in inappropriate maternal spiral artery remodeling and impaired placental function. Multiple genes have been implicated in trophoblast invasion, among which are KiSS-1 and GPR54. The gene product of KiSS-1 is metastin, which is a ligand for the receptor GPR54. Both metastin and GPR54 are expressed in the placenta of normal pregnancy and have been implicated in modulating trophoblast invasion through inhibiting migration of trophoblast cells. We have previously reported that the expression level of KiSS-1 was higher in trophoblasts from women with preeclampsia as compared to normal controls. Here, using quantitative RT-PCR, Western blot analysis and immunohistochemistry, we extend our analysis to demonstrate that elevated KiSS-1 expression occurs only in early-onset preeclampsia (ePE) and not late-onset preeclampsia (lPE). However, no difference in the expression levels of GPR54 is observed between ePE, lPE, and normal controls. Further, we show that KiSS-1 expression is also increased in placenta of intrauterine death and birth asphyxia in comparison to normal newborns of ePE and lPE. Our findings suggest that aberrant upregulation of KiSS-1 expression may contribute to the underlying mechanism of ePE as well as birth asphyxia.

Topics: Adult; Asphyxia Neonatorum; Female; Humans; Infant, Newborn; Kisspeptins; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Trophoblasts

The expression of KiSS-1, MMP-9 and MMP-2 mRNAs and proteins was studied in placentas of women with preeclampsia (PE, n=47) and women of normal pregnancy (NP; n=30). In addition, KiSS-1 mRNA expression as well as cell growth, proliferation and invasion were examined in JAR cells (human trophoblast cell line) transfected with pcDNA3-KiSS-1vector. Expression of KiSS-1 mRNA and protein was higher (p<0.05) in women with PE compared with that of NP women. In contrast, expression of MMP-9 and MMP-2 was lower (p<0.05) in PE than in NP women. KiSS-1 mRNA was detected in JAR cells successfully transfected with pcDNA3-KiSS-1 gene (JAR-K1, JAR-K2, JAR-K3). KiSS-1 mRNA was not detected in JAR cells transfected with pcDNA3 gene (JAR-P1, JAR-P2) and non-transfected JAR cells. No difference (p>0.05) was observed in cell growth among these three cell types. Invasion ability was significantly lower (p<0.01) in JAR-K1, JAR-K2 and JAR-K3 cells compared to JAR-P cells and non-transfected JAR cells. Overexpression of KiSS-1 and insufficient expression of MMP-9 and MMP-2 in placenta were demonstrated in women with PE. The data suggests that KiSS-1 gene plays an important role in inhibiting trophoblast invasion during placental development.

Topics: Cell Line; Female; Gene Expression Regulation; Humans; Kisspeptins; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Placenta; Pre-Eclampsia; Pregnancy; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors; Trophoblasts

The aim of the present work was to look at differences in the placental tissue expression of KiSS-1 and REN genes from preeclamptic and healthy pregnant women, that could account for a possible synergistic function for both genes in the pathogenesis of preeclampsia.. This case-control study involved 27 preeclamptic women and 27 normoevolutive pregnant women. cDNA was obtained from placental tissue to carry out qPCR for both KiSS-1 and REN genes in order to compare mRNA expression levels in the studied groups. Statistical analysis showed expression differences that correlate with clinical and/or biochemical variables.. Higher expression for KiSS-1 in PEE vs. control woman (p=0.001) was observed, whereas no difference was observed for REN expression (p=0.300) when all the subjects were included. However, REN expression was significant higher when the samples were stratified according to preeclampsia severity. For 18 mild preeclamptic patients the p-value was p=0.001 compared to their controls, while for the remaining nine with severe preeclampsia the expression became significant (p=0.001).. Our results suggest that the high KiSS-1 expression seen in preeclamptic patients is in accordance with its role as an inhibitor of trophoblast invasiveness and maintained until the end of gestation. On the other hand, aggressive therapeutic management and/or severity status of patients have a direct effect on placental REN expression levels, masking the natural high expression of this gene on preeclamptic placental tissue. Therefore it was not possible to establish a real concordant expression profile for KiSS-1 and REN genes.

Topics: Adolescent; Adult; Antihypertensive Agents; Case-Control Studies; Cluster Analysis; Female; Genetic Association Studies; Humans; Hypertension; Kisspeptins; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Proteins; Proteinuria; Renin; RNA, Messenger; Severity of Illness Index; Up-Regulation; Young Adult

To investigate (i) if kisspeptin administration alters heart rate (HR) or blood pressure (BP) in healthy male and female volunteers, (ii) whether circulating plasma kisspeptin concentrations in healthy pregnant women and women with hypertensive diseases of pregnancy correlate with BP and (iii) whether women with hypertensive diseases of pregnancy have altered plasma kisspeptin concentrations.. We have previously reported the effects of administration of kisspeptin-54 on gonadotrophin secretion in healthy male and female volunteers. In these studies, cardiovascular parameters were not a primary endpoint. However, data were also collected on BP and HR for 4h post administration of kisspeptin-54. Blood samples were taken from 105 women in the third trimester of pregnancy (27 women with hypertensive diseases of pregnancy and 78 controls). Samples were assayed for plasma kisspeptin immunoreactivity (IR).. Administration of kisspeptin was not associated with significant changes in HR or BP in healthy men or women. There was no significant correlation between plasma kisspeptin concentration and BP in healthy pregnant women or in those with hypertensive diseases of pregnancy. No significant differences in plasma kisspeptin-IR concentrations were observed between women with hypertensive diseases of pregnancy and normotensive pregnant controls, plasma kisspeptin concentrations ±SE: controls 2878 ± 157pmol l(-1) ; pregnancy-induced hypertension 2696 ± 299pmoll(-1) (95% CI vs. controls -514, 878pmoll(-1) ); pre-eclampsia 3519 ± 357 (95% CI vs. controls -1644, 362pmoll(-1) ).. Elevation of plasma kisspeptin-IR is not associated with an alteration in BP in humans.

Topics: Adult; Blood Pressure; Case-Control Studies; Female; Heart Rate; Humans; Hypertension, Pregnancy-Induced; Kisspeptins; Male; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Trimester, Third; Tumor Suppressor Proteins

To investigate whether pregnancies with development of subsequent pre-eclampsia and intra-uterine growth restriction are associated with altered levels of kisspeptin in maternal serum in the second trimester.. Retrospective case-control study of 16-20 week serum samples matched for duration of storage at -70 degrees C. Levels of kisspeptin were measured in serum from women with pregnancies with subsequent development of pre-eclampsia (n = 57), intra-uterine growth restriction (n = 118), and matched controls (n = 317).. Serum kisspeptin levels were significantly lower in those women who subsequently developed pre-eclampsia than in controls [median (quartile range) 1109 (449) vs 1188 (365) pg/mL, p = 0.029] and in those with intra-uterine growth restriction [1164 (386) vs 1188 (365) pg/mL, p = 0.016].. Kisspeptin levels are lower in maternal serum in the second trimester, in pregnancies associated with placental dysfunction. The differences in kisspeptin are modest, so although not forming a single screening marker in pre-eclampsia and intra-uterine growth restriction, measurement of kisspeptin may be useful in combination with other markers. Understanding the role of kisspeptin in the establishment of the placenta may further our knowledge of the mechanisms underlying placental function.

Topics: Adult; alpha-Fetoproteins; Biomarkers; Case-Control Studies; Chorionic Gonadotropin, beta Subunit, Human; Down-Regulation; Female; Fetal Growth Retardation; Gestational Age; Humans; Kisspeptins; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Second; Retrospective Studies; Tumor Suppressor Proteins

The aim of this study was to evaluate whether the quantitative distribution of a panel of circulating mRNAs from maternal whole blood of normal pregnancies is statistically different from those complicated with preeclampsia (PE) with or without intrauterine growth restriction (IUGR).. Maternal whole blood of six subjects with mild or severe PE with or without IUGR and 30 matched controls (1:5 match for gestational age) were retrospectively examined for circulating mRNA markers. Seven specific mRNA markers were identified and chosen based on previous microarray mRNA expressions performed on placental tissue from normal and PE patients. They were human placental lactogen (hPL), inhibin A, KISS-1, pregnancy-associated plasma protein-A (PAPP-A), plasminogen activator inhibitor type 1 (PAI-1), selectin-P and vascular endothelial growth factor receptor (VEGFR), which were therefore quantified for statistical purposes.. Median gestational age was 229 (178-283) and 232 (194-262) days for controls and cases respectively. All mRNA markers but PAPP-A, showed statistically different median values. They were hPL, inhibin A, KISS-1, PAI-1, Selectin-P, and VEGFR. Inhibin A, Selectin-P and VEGFR showed higher values than expected for controls. Instead, hPL, KISS-1 and PAI-1 values of PE patients were lower than those of controls. Selectin-P was the marker with the most aberrant difference, followed by VEGFR and KISS-1.. This preliminary analysis revealed that the median values of a panel of mRNAs from the maternal blood of PE patients were different from those of the same gestational age control group at the third trimester. If prospective studies at the second trimester could detect a related marker sufficiently able to discriminate between affected and unaffected patients and thus detect the disease before its clinical onset, then a screening project using a panel of mRNAs would be feasible.

Topics: Biomarkers; Case-Control Studies; Female; Fetal Growth Retardation; Gestational Age; Humans; Inhibins; Kisspeptins; P-Selectin; Placental Lactogen; Plasminogen Activator Inhibitor 1; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Pregnancy-Associated Plasma Protein-A; Receptors, Vascular Endothelial Growth Factor; Reference Values; RNA, Messenger; Tumor Suppressor Proteins

To investigate the role of KiSS-1 and matrix metalloproteinase (MMP) 9 in trophoblasts in the pathogenesis of preeclampsia and their relation to perinatal outcome of neonates.. RT-PCR and western blot analyses were used to detect the MMP-9 and KiSS-1 expression levels in trophoblast of 40 patients with preeclampsia (15 cases of mild and 25 cases of severe preeclampsia) (preeclampsia group) and 20 cases of term pregnancy (normal pregnancy group) and their correlations with symptoms and perinatal outcome of neonates were analyzed.. (1) The KiSS-1mRNA and metastin expression levels in trophoblasts of preeclampsia group were 1.73 +/- 0.24 (A value) and (78.4 +/- 8.0) microg/100 microg total protein separately, those of mild preeclampsia were (1.50 +/- 0.15) and (72.4 +/- 6.9) microg/100 microg total protein, and severe preeclampsia were (1.87 +/- 0.20) and (83.52 +/- 3.57) microg/100 microg total protein, which were all significantly higher than those of normal pregnancy group [1.24 +/- 0.25, P < 0.01, and (63.4 +/- 2.7) microg/100 microg total protein, P < 0.01], especially those in severe preeclampsia. (2) The MMP-9 mRNA and MMP-9 expression levels in trophoblasts of preeclampsia group were 0.09 +/- 0.06 and (9.6 +/- 4.2) microg/100 microg total protein, those of mild preeclampsia were 0.11 +/- 0.08 and (10.0 +/- 3.2) microg/100 microg total protein, and severe preeclampsia were 0.07 +/- 0.05 and (7.8 +/- 2.0) microg/100 microg total protein, which were all significantly lower than those of normal pregnancy group [0.17 +/- 0.10, P < 0.01, and (17.9 +/- 7.3) microg/100 microg total protein, P < 0.01]. (3) The expression level of KiSS-1mRNA and metastin in preeclampsia group were positively correlated with MAP, urinary protein per 24 hours, the correlation coefficients between KiSS-1mRNA and MAP, urinary protein per 24 hours were 0.610 (P = 0.023), 0.397 (P = 0.003), and between metastin and MAP, urinary protein per 24 hours were 0.713 (P = 0.011), 0.638 (P = 0.002), separately. The expression level of KiSS-1mRNA and metastin in preeclampsia group was significantly positively correlated with the occurrence of fundus oculi artery spasm, correlation coefficients were 0.499 (P = 0.000) and 0.511 (P = 0.000). The MMP-9mRNA and MMP-9 expression levels were negatively correlated with MAP, urinary protein per 24 hours and the occurrence of fundus oculi artery spasm, correlation coefficients between MMP-9mRNA and MAP, urinary protein per 24 hours, the occurrence of fundus oculi artery spasm were 0.561 (P = 0.042), 0.275 (P = 0.039), 0.346 (P = 0.001), between MMP-9 and MAP, urinary protein per 24 hours, the occurrence of fundus oculi artery spasm were 0.571 (P = 0.022), 0.375 (P = 0.048), 0.543 (P = 0.000), separately. (4) The expression level of MMP-9 mRNA and MMP-9 of preeclampsia was positively correlated with neonatal birth weight significantly, Pearson correlation coefficient was 0.651 (P = 0.000) and 0.544 (P = 0.004) separately, while the expression levels of KiSS-1mRNA and KiSS-1 of p. The expression imbalance of MMP-9 and KiSS-1 in trophoblasts may play an important role in the pathogenesis of preeclampsia, and correlate to perinatal outcome of neonates.

Topics: Adult; Blotting, Western; Female; Gene Expression; Humans; Kisspeptins; Matrix Metalloproteinase 9; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Pregnancy Trimester, Third; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Trophoblasts; Tumor Suppressor Proteins