Lower placental growth factor and higher free ß-hCG and PAPP-A levels in the fetal circulation of near-term pregnancies complicated with severe preeclampsia.

BACKGROUND: An imbalance between anti- and angiogenic factors during early placentation is key for the development of preeclampsia. Nevertheless, the majority of studies addressing this issue relate to maternal blood and not the fetal circulation. OBJECTIVE: To measure placental growth factor (PlGF), free beta human chorionic gonadotropin (ß-hCG), and pregnancy-associated plasma protein-A (PAPP-A) levels in the fetal circulation of near-term pregnancies complicated with severe preeclampsia (n = 20), and their controls matched for parity, and maternal and gestational age. METHOD: Upon delivery, a blood sample was withdrawn from the umbilical artery and vein of each case and its control in order to measure the proposed analytes using direct fluoroimmunoassay. RESULTS: Preeclampsia cases showed significantly lower median PlGF levels in fetal circulation as compared to controls (25.2 versus 36.9 and 23.6 versus 33.9 pg/mL, artery and vein, respectively, p < 0.05). Contrarily, cases displayed higher concentrations of PAPP-A (1024.0 versus 720.9 [median] and 1027.0 ± 298.4 versus 690.3 ± 401.9 mIU/L, artery and vein, respectively, p < 0.05), and free ß-hCG (mean: 33.9 ± 4.3 versus 17.2 ± 4.0 and 30.1 ± 5.2 versus 13.7 ± 3.3 ng/mL, artery, and vein respectively, p < 0.05). CONCLUSION: Lower PlGF and higher PAPP-A and free ß-hCG levels were found in the fetal circulation of near-term severe preeclamptic pregnancies. There is a need for more research in this regard.

Increased mood symptoms in postmenopausal women related to the polymorphism rs743572 of the CYP17 A1 gene.

BACKGROUND: Menopausal and depressive symptoms are highly prevalent after the menopause; but may vary from one population to another and genetics play a key role. OBJECTIVE: To analyze the intensity of these symptoms in relation to the genetic variants of the rs743572 polymorphism of the CYP17 A1 gene in postmenopausal women. METHODS: DNA was extracted from the whole blood of 168 natural postmenopausal women (40-65 years) and tested for the rs743572 polymorphism of the CYP17 A1 gene. Intensity of menopausal (Menopause Rating Scale, MRS) and depressive symptoms (Hospital Anxiety and Depressive Scale, HADS) were correlated to polymorphism genotypes. RESULTS: Women with the GG genotype of the rs743572 polymorphism displayed significantly higher scores for the MRS (items 5 and 6 [irritability and anxiety] and the psychological subscale) and the HADS (total and subscales). CONCLUSION: The intensity of menopausal symptoms related to mood was found higher among postmenopausal women presenting the GG genotype of the rs743572 polymorphism of the CYP17 A1 gene. There is a need for more research in this regard.

Fetal asphyctic preconditioning in rats results in a preserved placental inflammatory phenotype at birth.

INTRODUCTION: Perinatal asphyxia (PA) is a major cause of neonatal mortality and morbidity. Research has shown that in rats fetal asphyxia (FA) can provoke neuroprotection against a subsequent more severe perinatal asphyctic insult. This is called fetal asphyctic preconditioning (PC). Our objective was to investigate alterations in the placental inflammatory phenotype associated with PC. METHODS: FA was induced in the rat at embryonic day 17 by reversibly clamping the uterine circulation and PA was induced at birth by submersion of the uterine horns in a saline bath for 19 min. The effect of PC was studied by inducing FA at E17, followed by PA at E21. Placental TNF-α, IL-1ß, IL-6 and IL-10 mRNA and protein levels were measured by qPCR and ELISA. RESULTS: IL-1ß mRNA increased in the labouring FA group, but IL-1ß protein decreased after both FA and PA. In the PC group, IL-1ß mRNA and protein levels were similar to controls. IL-6 protein increased 6 h after FA, however decreased 24 h after FA. IL-6 mRNA was higher in the labouring PA group. IL-10 protein decreased 24 h after FA. At birth, IL-10 mRNA increased in the PA group; however, IL-10 protein decreased in both the PA and the FA group. In the PC group, IL-10 mRNA and protein were similar to control levels. DISCUSSION: Depleted protein concentrations of IL-10 and IL-1ß after one single asphyctic insult were reversed after fetal asphyctic PC. In addition, PC placentas showed less up-regulation of IL-6 mRNA compared to the PA ones. This modulated placental inflammatory phenotype might contribute to the improved neonatal outcome showed after fetal asphyctic PC.

Umbilical cord plasma interferon-induced protein 10 (IP-10) and interferon-induced T-cell alpha chemoattractant (ITAC) levels are lower in women with severe preeclampsia.

BACKGROUND: Higher 1st trimester maternal serum levels of interferon-induced protein 10 (IP-10) and interferon inducible T-cell alpha chemoattractant (ITAC) are reported in gestations complicated with preeclampsia. However, parallel results in the fetal circulation are lacking. OBJECTIVE: To compare IP-10 and ITAC levels in neonatal cord blood from gestations complicated by severe preeclampsia vs. gestational age-matched controls. METHOD: Umbilical cord vessels were sampled following delivery of women with severe preeclampsia (n=30) ≥36 weeks to measure plasma IP-10 and ITAC levels and compared to corresponding controls matched for parity as well as maternal and gestational age. Chemokines were measured by specific ELISAs and expressed as pg/mL. Rho Spearman's coefficients were calculated to establish correlations between chemokine values and various numeric variables. RESULTS: Preeclamptic cases displayed significantly lower median plasma umbilical artery and vein levels of both chemokines when compared to controls (IP-10: 23.4 vs. 31.4 and 2.0 vs. 24.6 pg/mL, P<0.05; and ITAC: 2.0 vs. 13.9 and 11.9 vs. 31.6 pg/mL, P<0.05, in artery and vein, respectively). There was a significant correlation between levels of both chemokines (r2=0.616, P=0.0001), but not with other variables. CONCLUSION: In contrast to elevated 1st trimester levels of IP-10 previously found in the maternal serum of women who later developed preeclampsia, this study found lower umbilical cord IP-10 and ITAC plasma levels in near-term gestations with established severe preeclampsia.

Polymorphisms of the methylenetetrahydrofolate reductase gene (C677T and A1298C) in the placenta of pregnancies complicated with preeclampsia.

BACKGROUND: Preeclampsia has been related to single-nucleotide polymorphisms (SNPs) of the methylenetetrahydrofolate reductase (MTHFR) gene; however, data regarding the placenta are still lacking. OBJECTIVE: To determine the frequency of C677T and A1298C SNPs of the MTHFR gene in the placenta of preeclamptic pregnancies and healthy controls. METHODS: Genotyping of C677T and A1298C polymorphisms of the MTHFR gene using RFLP-PCR was performed to the placenta of 100 gestations (n = 50 complicated with preeclampsia and n = 50 normal controls matched for parity and maternal age). RESULTS: Gestational age at birth and neonatal and placental weight were significantly lower in women with preeclampsia as compared to controls. The TT genotype of the C677T polymorphism was threefold more prevalent in preeclamptic placentas as compared to the placenta of controls (24.0% versus 8.0%, p = 0.001). Upon pooled analysis (n = 100), placental and neonatal weights were significantly lower in placentas displaying this genotype (TT, C677T) as compared with the CC genotype. CONCLUSION: This study found that the frequency of the TT mutant genotype of the C677T polymorphism was higher in the placenta of pregnancies complicated with preeclampsia. There is a need for further research in this matter.

Evaluation of the presence and severity of menopausal symptoms among postmenopausal women screened for the metabolic syndrome.

BACKGROUND: The prevalence of the metabolic syndrome (METS) increases after the menopause. Reports indicate that the METS and its components, especially obesity, enhance the intensity of menopausal symptoms. OBJECTIVE: Assess the frequency and severity of menopausal symptoms in postmenopausal women. Factors related to the symptom severity were also analyzed including depressive and metabolic status. METHODS: A total of 204 natural postmenopausal women (40-65 years) participating in a METS screening program were asked to fill out the Menopause Rating Scale (MRS), the Hospital Anxiety and Depression Scale (HADS), and a general socio-demographic questionnaire containing personal and partner data. Criteria of the American Heart Association were used to define the METS. RESULTS: Median age of the whole sample was 56 years. A 52.9% presented the METS, with 37.3% presenting hyperglycemia, 51.5% hypertension, 58.3% abdominal obesity, 45.6% high triglyceride and 56.4% low HDL-C levels. Total and subscale MRS scores did not differ in accordance to the presence or not of the METS. The three top prevalent menopausal symptoms were muscle and joint problems (87.2%), physical and mental exhaustion (72%) and depressive mood (64.7%). A 19.6% of women presented total MRS scores above 16 defined as severe. Multivariate linear regression analysis determined that anxiety (higher HADS anxiety subscale scores) was significantly and positively correlated with all components of the MRS (Total and subscale scores). Higher total MRS scores correlated positively with abdominal perimeter and higher parity. Somatic scores correlated inversely with female education and positively with psychotropic drug use; and psychological MRS scores positively correlated depressed mood (higher HADS depressive subscale scores) and abdominal perimeter. CONCLUSION: In this postmenopausal sample, severity of menopausal symptoms correlated to abdominal obesity, mood and other personal aspects.

Circulating leptin, resistin, adiponectin, visfatin, adipsin and ghrelin levels and insulin resistance in postmenopausal women with and without the metabolic syndrome.

OBJECTIVE: To measure serum levels of adipsin, leptin, resistin, adiponectin, visfatin, ghrelin and insulin in postmenopausal women screened for the metabolic syndrome (METS). METHODS: Serum of 100 postmenopausal women was analyzed using multiplex technology for the mentioned analytes. In addition, values for the homeostasis model assessment of insulin resistance (HOMA-IR) were calculated. Comparisons were performed in accordance to the presence or not of the METS and each of its components. Criteria of the American Heart Association were used to define the METS. RESULTS: Age and time since menopause onset were similar in women with the METS (n=57) as compared to those without the syndrome (n=43). METS women displayed significantly higher levels of adipsin, leptin, resistin, insulin and HOMA-IR values and lower adiponectin levels. These differences were mainly observed among women with abdominal obesity, independent of fulfilling METS criteria or not. In this same sense, lower adiponectin levels significantly related to low HDL-C and high triglyceride levels; and higher insulin and HOMA-IR values related to high triglyceride and glucose levels, respectively. CONCLUSION: In this sample, postmenopausal women with the METS displayed higher insulin and adipokine levels. These were mainly related to abdominal obesity and metabolic and lipid abnormalities. More research is warranted in this regard.

Angiogenesis, inflammation and endothelial function in postmenopausal women screened for the metabolic syndrome.

BACKGROUND: Prevalence of the metabolic syndrome (METS) increases after the menopause; nevertheless, concomitant vascular, inflammatory and endothelial changes have not been completely elucidated. OBJECTIVE: To measure serum markers of angiogenesis, inflammation and endothelial function in postmenopausal women screened for the METS. METHODS: Serum of 100 postmenopausal women was analyzed for angiopoietin-2, interleukin-8 (IL-8), soluble FAS ligand (sFASL), interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-α), soluble CD40 ligand (sCD40L), plasminogen activator inhibitor-1 (PAI-1), and urokinase-type plasminogen activator (uPA). Comparisons were made in accordance to the presence or not of the METS and each of its components. Modified Adult Treatment Panel III criteria were used to define the METS. RESULTS: Women with the METS (n=57) had similar age and time since menopause as compared to those without the syndrome (n=43). In general, women with the METS displayed a trend for higher levels of the analyzed markers. Nevertheless, only IL-6 levels were found to be significantly higher and uPA levels significantly lower among METS women as compared to those without the syndrome. When analyte levels were compared as to presenting or not each of the diagnostic features of the METS, it was found that IL-6 levels were higher among women with abdominal obesity, low HDL-C and high triglyceride levels. Women with low HDL-C and high triglyceride levels presented significantly lower uPA levels and those with high glucose and low HDL-C displayed significantly higher sCD40L levels. CONCLUSION: Postmenopausal women with the METS in this sample displayed higher IL-6 (inflammation) and lower uPA levels (endothelial dysfunction). These were mainly related to metabolic and lipid abnormalities. More research is warranted in this regard.

Polymorphisms of the methylenetetrahydrofolate reductase gene (C677T and A1298C) in nulliparous women complicated with preeclampsia.

OBJECTIVE: To determine the prevalence of C677T and A1298C Single-nucleotide polymorphisms (SNPs) of the MTHFR gene in nulliparous women complicated with preeclampsia (PE). METHODS: One hundred fifty gestations complicated with PE and their corresponding controls without the disease were recruited for the genotyping of C677T and A1298C polymorphisms of the MTHFR gene using restriction fragment length polymorphism polymerase chain reaction. Secondarily, homocysteine (HCy) plasma levels were measured in preeclamptic women displaying the CC genotype of the A1298C polymorphism (homozygous) and compared to HCy levels determined among controls with the normal AA genotype for the A1298C variant. RESULTS: Only the mutant CC genotype of the A1298C polymorphism was associated to higher risk of presenting PE, as frequency of this genotype was significantly higher among cases than controls (15.3% versus 0.7%, p < 0.05). All PE women with a neck circumference ≥32 cm presented the mutant CC A1298C polymorphism as compared to none among preeclamptics with a lower neck circumference (p = 0.0001). Women with the mutant CC A1298C SNP displayed higher plasma HCy levels as compared to controls with normal AA A1298C genotype (8.4 ± 2.6 versus 7.5 ± 2.7 mmoL/L p = 0.04). CONCLUSION: Prevalence of the CC mutant genotype of the A1298C polymorphism was higher among PE women. This mutation among PE women was related to increased neck circumference and higher HCy levels. Future research should aim at linking these gestational findings with obesity and cardiovascular risk.

The metabolic syndrome and its components in postmenopausal women.

BACKGROUND: Prevalence of the metabolic syndrome (METS) increases significantly after the menopause. OBJECTIVE: To assess the prevalence of the METS and its components in postmenopausal women. Factors relating to each of the composing items of the METS were also analyzed. METHODS: Natural postmenopausal women (40-65 years) were invited to participate in this cross-sectional study in order to assess the presence of the METS using modified Adult Treatment Panel III (ATP-III) criteria. Participants were also requested to fill out a general socio-demographic questionnaire. RESULTS: A total of 204 women were surveyed with a median age of 56 years. A 52.9% presented the METS according to modified ATP-III criteria, with 37.3% presenting hyperglycemia, 51.5% hypertension, 58.3% abdominal obesity, 45.6% high triglyceride levels and 56.4% low HDL-C levels. Women with the METS presented a higher rate of dyslipidemia (high triglyceride and low HDL-C levels), hyperglycemia, hypertension and abdominal obesity than those without the syndrome. Those with abdominal obesity and hyperglycemia significantly displayed higher rates of low HDL-C levels (bivariate analysis). Multiple linear regression analysis found a positive correlation between glucose and triglyceride levels. Systolic blood pressure significantly and positively correlated to age and abdominal circumference. Abdominal circumference displayed an inverse correlation with educational level. CONCLUSION: Prevalence of the METS in this postmenopausal female sample was high and associated to metabolic and lipid derangements. As abdominal obesity was significantly associated to lower education, there is an urgent need of implementing educational programs directed to high-risk populations in order to increase awareness of the problem.

Assessment of insomnia and related risk factors in postmenopausal women screened for the metabolic syndrome.

BACKGROUND: Sleep disturbances are common during female mid-life. Nevertheless, there is limited available information linking sleep characteristics to the menopause and the metabolic syndrome (METS). OBJECTIVE: To assess insomnia prevalence and related risk factors in postmenopausal women screened for the METS. METHODS: In this cross sectional study 204 natural postmenopausal women participating in a METS screening program filled out the Athens insomnia scale (AIS), the hospital anxiety and depression scale (HADS) and a general socio-demographic questionnaire. Criteria of the Adult Treatment Panel III (ATP-III) were used to define the METS. RESULTS: Median age of the whole sample was 56 years. A 50.5% of women had the METS, 57.4% hot flushes, 58.3% were abdominally obese, 51.5% hypertension, 25.0% hyperglycemia, 15.7% depressed mood and 29.9% anxiety. A 33.8% presented insomnia according to the AIS (scores 6 or more). The AIS displayed a high internal consistency as computed Cronbach's alpha was determined to be 0.86. Multiple linear regression analysis determined that male premature ejaculation, female psychotropic drug use, hot flush intensity, mood morbidity (higher total HADS scores) and higher parity positively and significantly correlated to higher AIS scores (more insomnia). CONCLUSION: In this postmenopausal sample insomnia was not related to the METS or its components yet to other psycho-somatic female and partner issues.

Feto-placental nitric oxide, asymmetric dimethylarginine and vascular endothelial growth factor (VEGF) levels and VEGF gene polymorphisms in severe preeclampsia.

OBJECTIVE: To measure plasma nitric oxide (NO), asymmetric dimethylarginine (ADMA) and vascular endothelial growth factor (VEGF) levels and VEGF gene polymorphisms in fetal circulation in severe preeclampsia. METHODS: Cord vessels of singleton gestations complicated with severe preeclampsia 36 weeks or more (n = 31) and controls were sampled upon delivery for analyte measuring. Additionally, DNA was extracted from umbilical vein whole blood to determine the frequency of VEGF gene single nucleotide polymorphisms (SNPs): -2578 A/C, -1498 C/T, -1154 A/G, -634 C/G and +936 C/T. Coefficient correlations between analyte levels and placental and neonatal weight were calculated. RESULTS: NO plasma levels in umbilical vessels (artery and vein) were significantly higher in preeclampsia cases as compared to controls (4.67 ± 3.0 vs. 0.82 ± 0.90; 4.46 ± 3.0 vs. 0.82 ± 0.99 mmol/L, respectively, p = 0.0001 both). ADMA levels displayed a similar increased trend in both fetal vessels, but this did not reach statistical significance (2.57 ± 1.03 vs. 2.34 ± 0.57; 2.74 ± 0.94 vs. 2.42 ± 0.59 mmol/L, respectively, p > 0.05). VEGF was significantly lower in artery but not in vein in preeclampsia cases (200.48 ± 225.62 vs. 338.61 ± 287.03 pg/mL, p = 0.04). A significant positive correlation was found between NO and ADMA levels (artery and vein) among preeclampsia cases. Overall, the frequency of the studied VEGF gene SNPs did not differ among pre-eclamptic cases and controls; nevertheless, a significant trend toward lower umbilical vein VEGF levels was observed in pre-eclampsia cases in the presence of -2578 CC and -1154 AG genotypes. CONCLUSION: Near term gestations complicated with severe preeclampsia presented higher NO levels in fetal circulation, which correlated to ADMA and lower artery VEGF values. More research is warranted to confirm that selected VEGF SNPs may be associated with lower umbilical vein VEGF.

Nitric oxide and pro-inflammatory cytokine serum levels in postmenopausal women with the metabolic syndrome.

BACKGROUND: The metabolic syndrome (METS) increases after the menopause which may enhance cardiovascular risk in part explained by a pro-inflammatory state. OBJECTIVE: Measure nitric oxide (NO), tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) serum levels in postmenopausal women with and without the METS (Adult Treatment Panel III criteria). METHODS: Analyte levels were compared among those with and without the syndrome and each of its diagnostic components. Rho Spearman coefficients were also calculated to determine correlations between analyte levels and various numeric variables. RESULTS: Median age of all studied women (n = 88) was 54.4 years, 62.5% had abdominal obesity, 14.8% hyperglycemia, 59.1% high triglycerides (TG) and 44.3% hypertension. Women with the METS (n = 44) displayed higher body mass index values and higher rates of abdominal obesity, hyperglycemia, hypertriglyceridemia, hypertension and low HDL-C levels. Median NO and IL-6 levels were significantly higher in women with the METS as compared to controls (p < 0.05). Independent of presenting the METS, analytes were higher in those displaying abdominal obesity (IL-6), hypertension (IL-6 and TNF-α) and more METS diagnostic criteria and abnormal HDL-C, TG and glucose levels (NO). Both cytokines positively correlated with the number of METS criteria, age and time since menopause, IL-6 positively with waist circumference and TNF-α positively with blood pressure levels. NO levels inversely correlated with HDL-C values and positively with the number of METS criteria, glucose, and TG levels; correlation with the latter being the highest (r² = 0.65, p = 0.0001). CONCLUSION: Postmenopausal women with the METS displayed higher IL-6 and NO levels, with significant correlations found between studied analytes and some of the components of the syndrome.

Pro-inflammatory cytokine levels in postmenopausal women with the metabolic syndrome.

BACKGROUND: Prevalence of the metabolic syndrome (METS) and its components significantly increase after the menopause. Related increased cardiovascular risk may partially be explained by a pro-inflammatory state. OBJECTIVE: To assess pro-inflammatory cytokine serum levels in postmenopausal women with and without the METS. METHODS: Serum of 90 postmenopausal women who previously participated in a METS screening programme was analysed for tumour necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6). Cytokine levels were compared among those with and without the syndrome, and for each of its components. Linear relationships were also assessed between cytokine levels and several continuous variables including each diagnostic METS criteria and menopausal symptoms assessed with the Menopause Specific Quality of Life tool (MENQOL). RESULTS: For all studied women mean age was 55.1 ± 7.3 years with 63.3% having abdominal obesity, 15.6% hyperglycaemia, 58.9% high triglycerides, 44.4% hypertension and 25.6% high total cholesterol levels. Women with the METS (n = 45) significantly had higher body mass index values, and higher rates of abdominal obesity, hyperglycaemia, hypertriglyceridemia, hypertension and lower HDL-C levels. Cytokine levels did not differ among women with or without the METS; however, independent of METS diagnosis those with abdominal obesity displayed significantly higher IL-6 levels and those with hypertension higher levels of both cytokines. Levels of both cytokines positively correlated with age and time since menopause, IL-6 positively correlating with waist circumference values and TNF-α positively with both systolic and diastolic blood pressure levels. A significant positive correlation was also found between the number of positive METS criteria (0-5) and both cytokine levels. Cytokine levels did not correlate with vasomotor and psycho-social MENQOL scores. CONCLUSION: Pro-inflammatory cytokine levels in this postmenopausal series positively correlated with age, time since the menopause, abdominal circumference, blood pressures levels and the number of positive METS diagnostic criteria. There is a need for more research in this regard.

Increased plasma soluble fms-like tyrosine kinase 1 and endoglin levels in pregnancies complicated with preeclampsia.

BACKGROUND: Increased maternal plasma levels of proinflammatory cytokines as well as the anti-angiogenic agents soluble fms-like tyrosine kinase 1 (sFlt-1) and endoglin (sEng) are associated with promoting vascular dysfunction leading to the maternal syndrome of preeclampsia. OBJECTIVE AND METHOD: Nulliparous women complicated with preeclampsia (n = 29) and their corresponding controls (n = 29) delivering at the Enrique C. Sotomayor Obstetrics and Gynecology Hospital, Guayaquil-Ecuador were requested to participate in a study evaluating plasma levels of soluble anti-angiogenic factors (sFlt-1 and sEng) and pro-inflammatory cytokines: interleukin 6 (IL-6), interleukin 8 (IL-8), granulocyte colony stimulating factor (G-CSF), and tumor necrosis factor-alpha (TNF-alpha). Maternal and neonatal data were also assessed and compared among the study groups. RESULTS: No significant differences in either maternal baseline or delivery characteristics were observed among the study groups. Compared with controls, preeclamptic women exhibited higher plasma levels of sFlt-1 (19.0 +/- 15.1 vs. 12 +/- 8.3 ng/mL) and of sEng (20.4 +/- 9.9 vs.15.9 +/- 9.4 ng/mL); respectively, p < 0.05. Women with severe disease displayed higher sFlt-1 and sEng levels when compared with mild ones (34.5 +/- 11.6 vs. 9.5 +/- 1.6 ng/mL, and 29.5 +/- 9.0 vs. 14.8. +/- 5.2 ng/mL, respectively; p < 0.001). In contrast, women with preeclampsia exhibited significant lower IL-8 and G-CSF levels compared with controls. No differences existed between either group in IL-6 levels or TNF-alpha. CONCLUSION: Consistent with previous reports, increased sFlt-1 and Eng levels in maternal plasma is consistent with vascular dysfunction found in gestations complicated with preeclampsia.