The impact of GnRH agonists in patients with endometriosis on prolactin and sex hormone levels: a pilot study.

OBJECTIVE: Gonadotropin releasing hormone agonists (GnRHa) decrease the expression of growth factors involved in the development of human endometriotic tissue. As endometriosis has been found to be associated with a mild increase in prolactin (PRL) serum levels, we aimed to evaluate changes in PRL serum levels as well as other hormones relevant to endometriosis and infertility during long-term administration of GnRHas in women with endometriosis. STUDY DESIGN: In this prospective pilot study we obtained blood samples on the first day of leuporeline administration and then subsequently after 4, 8 and 12 weeks in 22 patients. RESULTS: Median PRL levels were unchanged after 4 weeks, but significantly decreased 8 and 12 weeks after the first leuporeline administration (p1=0.085, p2=0.020, p3=0.001). There was no significant decrease in serum anti-Mullerian hormone (AMH) levels over the whole period of down regulation with leuporeline (p1-3>0.05). CONCLUSION: Our data support the hypothesis that the decrease of PRL levels might contribute to the known effect of GnRH treatment in patients with endometriosis via suppression of VEGF expression in endometriotic lesions. Moreover this study lends support to the thesis that AMH remains stable under GnRHa therapy and therefore can be also used as a marker of ovarian function prior to IVF-stimulation during down regulation.

Global and single gene DNA methylation in umbilical cord blood cells after elective caesarean: a pilot study.

OBJECTIVE: To evaluate global and single gene methylation patterns as a sign for epigenetic modulation of the immune system in infants born by elective cesarean section (CS) and vaginal delivery (VD). STUDY DESIGN: For this prospective pilot study a two step approach was chosen. Initially 41 newborn infants comprising 23 delivered by VD and 18 delivered by elective CS were included. Global DNA methylation of umbilical cord blood was determined. In a second step, methylation status of 96 single genes linked to T cell activation, cytokine production, inflammatory response, and stem cell transcription was evaluated in 48 newborn infants, 20 delivered by VD and 28 delivered by CS. RESULTS: Global methylation did not differ significantly between CS and VD (p=0.732). The methylation status was low (threshold: ≤3%) for the majority of single genes (n=92) in both groups. FOXP3, CD7, ELA2, and IRF1 showed hypermethylation in both groups. In the CS group, ELA2 (p<0.001) and IRF1(p =0.017) showed significantly higher methylation compared to the VD group. CONCLUSION: We found no difference in global methylation between newborn infants in the VD group compared to the elective CS group. Methylation of single genes was significantly higher in newborn infants delivered by elective CS. Further research is needed to determine the significance of theses findings.

Augmentation index and pulse wave velocity in normotensive and pre-eclamptic pregnancies.

OBJECTIVE: Hypertensive disorders during pregnancy remain a major health burden. Normal pregnancy is associated with systemic cardiovascular adaptation. The augmentation index and pulse wave velocity measures may serve as surrogate markers of cardiovascular pathology, including pre-eclampsia. We evaluated these parameters during and after normotensive and pre-eclamptic pregnancies. DESIGN: Longitudinal cohort trial involving a case-control analysis of healthy women and women with pre-eclampsia. SETTING: University hospital. POPULATION: Fifty-three healthy pregnant women between 11(+6) and 13(+6) gestational weeks, as well as 21 patients with pre-eclampsia. METHODS: The augmentation index and pulse wave velocity were measured seven times during pregnancy and postpartum. MAIN OUTCOME MEASURES: Changes in augmentation index and pulse wave velocity during and after healthy pregnancies were measured. The influence of early-onset and late-onset pre-eclampsia on these measurements both during and after pregnancy was evaluated. RESULTS: The normotensive pregnancies exhibited a significant decrease in the augmentation index from the first trimester to the end of the second trimester; however, the normotensive pregnancies showed an increase in the augmentation index during the third trimester as term approached. The patients with early-onset and late-onset pre-eclampsia displayed a significantly elevated augmentation index during pregnancy. The postpartum augmentation index and pulse wave velocity were significantly elevated in the early-onset pre-eclampsia group. CONCLUSION: After pregnancy, early-onset and late-onset pre-eclamptic patients exhibit differences in vascular function. This result indicates the presence of a higher cardiovascular risk in patients after early-onset pre-eclampsia.

Small GTPases are involved in sprout formation in human granulosa lutein cells.

INTRODUCTION: The corpus luteum (CL), develops from the ruptured follicle after gonadotropin stimulation. Based on intracellular reorganization of the cytoskeleton an human chorionic gonadotropin (hCG) dependent sprouting and migration of luteinizing granulosa cells (LGCs) and endothelial cells is observed. Rho-GTPases are shown to be key regulators of cytoskeletal restructuring. In the present study we analyzed the role of Rho-GTPases in the sprouting activity of LGCs. METHODS: We used the Rho-GTPase-inhibitors Toxin A and -B and the Cdc42-activator Bradykinin in a LGC-spheroid sprouting assay to determine the effect of these modulators in LGCs. RESULTS: Toxin A and Toxin B reduces sprout formation in LGC spheroids. However, the reduction is less than in hCG treated cells. The usage of Bradykinin demonstrates both, a reduction of sprouts in untreated spheroids and an increase of sprouting in previous hCG treated spheroids. CONCLUSIONS: The presented results let us suggest that small Rho-GTPases may regulate the sprouting activity of LGCs after stimulation by hCG and that this mechanism may play a role in CL formation.

N-terminal-pro-brain natriuretic peptide is decreased in insulin dependent gestational diabetes mellitus: a prospective cohort trial.

BACKGROUND: N-terminal-pro-brain natriuretic peptide (NT-proBNP) is elevated in gestational hypertension and preeclampsia. This trial aimed to generate data for gestational diabetes mellitus patients, who are at risk to develop these complications. METHODS: We have measured NT-proBNP in 223 otherwise healthy women between gestational week 24 and 32 referred to the outpatient diabetes unit in a cross-sectional study. RESULTS: 88 control subjects, 45 patients with indication for medical nutrition therapy (MNT) alone and 90 patients who required insulin therapy were included. Groups of women were comparable regarding gestational week. Body mass index before pregnancy and at blood draw was significantly higher in subjects with insulin dependent gestational diabetes mellitus compared to MNT controlled gestational diabetes mellitus. NT-proBNP was significantly lower in patients with insulin dependent gestational diabetes mellitus (35 ± 25 pg/ml) compared to controls (53 ± 43 pg/ml, p = 0.012). CONCLUSIONS: NT-proBNP is within the reference range of normal subjects in women with gestational diabetes mellitus. Differences in body mass index, changes in glomerular filtration rate and haemodynamics may explain lower NT-proBNP concentrations in insulin dependent gestational diabetes mellitus. A false negative interpretation needs to be considered in these women.

Obstetrical management of the older gravida.

In developed countries, an increase in the average age of the gravida has been documented. The mean age of primiparous women in Austria rose from 25 years in 1991 to 28 years in 2008. In Germany in 2006, most gravidas were between the ages of 30 and 34 years whereas in the 1970s, most babies were born to women aged 20-24 years. Delayed childbearing and increased maternal age are associated with increased obstetrical and perinatal complications and, therefore, require adjustments in obstetrical management. Increasing maternal age is associated with pre-existing maternal risk factors such as diabetes mellitus, hypertension, myomas or obesity. In addition to lower fecundability and higher rates of chromosomal aberrations, higher rates of spontaneous early abortion are also common complications in early pregnancy among older women. In ongoing pregnancies, complications such as gestational diabetes, hypertensive disorders and low birth weight are associated with increasing maternal age. Furthermore, gravidas of advanced age are at a higher risk for stillbirth and perinatal morbidity and mortality. At delivery, increased maternal age is associated with an increased rate of malpresentation and represents an independent odds ratio for cesarean section. Owing to these facts, obstetric management in the older gravida needs to be adapted in order to manage the possible complications.

NT-proBNP is increased in healthy pregnancies compared to non-pregnant controls.

Serum concentrations of the amino-terminal pro-B-type natriuretic peptide (NT-proBNP) may be used to monitor cardiac function during pregnancy but normal values are not established for this purpose. Therefore, we investigated NT-proBNP in normotensive healthy pregnancies compared to a non-pregnant control group. Serum NT-proBNP was measured in 94 normotensive, healthy pregnant women (32+/-6 years) every five weeks beginning from 12th gestational week (GW) in a longitudinal study and compared to a non-pregnant control group of 521 women (32+/-7 years). Pooled median serum NT-proBNP levels (25th; 75th percentile) were significantly higher in pregnant women compared to non-pregnant women (56 (33; 95) pg/ml vs. 38 (22; 62) pg/ml (p<0.001)). NT-proBNP increased during pregnancy to 73 (51; 124) pg/ml in the 11+6 to 15+6 GW (p<0.001). However, NT-proBNP levels from 23+0 GW towards term were comparable to non-pregnant controls. NT-proBNP is significantly elevated in healthy pregnancies until mid-pregnancy. As preeclampsia and gestational hypertension are associated with increased NT-proBNP, our results have to be considered in future diagnostic approaches using NT-proBNP for these pathologic conditions.

Stillbirth following previous cesarean section in Bavaria/Germany 1987-2005.

BACKGROUND: An elevated risk for unexplained stillbirth in subsequent pregnancies after cesarean section was reported in 2003. This finding would imply renewed discussions about stronger indications for cesarean sections. OBJECTIVE: To find out whether there is an elevated risk for stillbirth in subsequent pregnancies after cesarean section in our cohort in Bavaria. METHODS: As data linkage of records is not possible in Germany, we devised a suitable adjustment for bias correction. Second pregnancies in Bavaria/Germany after previous vaginal birth and previous cesarean section from 1987 to 2005 were analyzed. Risk of unexplained stillbirth was estimated by time-to-event analysis. RESULTS: In our cohort of 629,815 second pregnancies, no elevated stillbirth risk in pregnancies after previous cesarean section compared to previous vaginal birth was noted (crude risk 0.22% in both groups; hazard ratio (HR) 1.00; P = 1.0). A slightly decreased risk for stillbirth after previous cesarean section for the period of 1994-2005 (HR 0.674; P = 0.04) could be shown. CONCLUSION: We found no elevated stillbirth risk in pregnancies after previous cesarean section. The significantly lower risk for stillbirths after previous cesarean section in the period 1994-2005 is interpreted as consequence of improved obstetric surveillance. With our adjustment for bias correction, we hope to have found a way to make our data largely comparable with other sources reported in the literature. However, because of the strict German data protection act, the Bavarian birth register is only of limited use for the presented study.

Pro-B-type natriuretic peptide as a marker of pulmonary embolism in pregnancy: a case report.

Pulmonary embolism in pregnancy is difficult to diagnose because of the technical limitations. We report on a diagnosis of severe pulmonary embolism during pregnancy using the serum parameter NT-proBNP as a marker for right ventricular dysfunction following pulmonary embolism.