Anne Staff

Adipokines are predominantly secretory protein hormones from adipose tissue but may also originate in placenta and other organs. Cross-sectionally, we monitored maternal plasma concentration of adiponectin, resistin, and leptin and their mRNA expression in abdominal subcutaneous adipose tissue and placenta from preeclamptic (PE; n = 15) and healthy pregnant (HP; n = 23) women undergoing caesarean section. The study groups were similar in age and BMI, whereas HOMA-IR tended to be higher in the PE group. In fasting plasma samples, the PE group had higher concentrations of adiponectin (18.3 ± 2.2 vs. 12.2 ± 1.1 μg/ml, P = 0.011), resistin (5.68 ± 0.41 vs. 4.65 ± 0.32 ng/ml, P = 0.028), and leptin (34.4 ± 3.2 vs. 22.7 ± 2.1 ng/ml, P = 0.003) compared with the HP group. Adiponectin and leptin concentrations were still different between PE and HP after controlling for BMI and HOMA-IR, whereas resistin concentrations differed only after controlling for BMI but not HOMA-IR. We found similar...

Knowledge on sexual complaints and time to sexual resumption after obstetric anal sphincter injury (OASI) is scarce. The aim of the study was to investigate self-reported sexual activity and coital problems 1 year postpartum in relation to perineal trauma, in addition to delivery mode. Among 2,846 women recruited during pregnancy, all women who delivered with OASI (n = 42, all third-degree perineal tears), in addition to 20 randomly selected controls per OASI case, a total of 882 women, were sent a self-administered questionnaire addressing time to coital resumption after delivery and potential coital difficulty 1 year postpartum. By 8 weeks, half of the 561 responders (51.4 %) had resumed intercourse, increasing to 75.2 % by 12 weeks and 94.7 % 1 year postpartum. In multivariate regression analysis OASI was the strongest predictor for postponed coital onset, defined as after 8 weeks (aOR 5.52, CI 1.59-19.16). OASI was also the only significant predictor for dyspareunia 1 year after...

: Preeclampsia is a multisystemic syndrome during pregnancy that is often associated with intrauterine growth retardation. Immunologic dysregulation, involving T cells, is implicated in the pathogenesis. The aim of this study was to evaluate the effect of upregulating regulatory T cells in an established transgenic rat model for preeclampsia. Application of superagonistic monoclonal antibody for CD28 has been shown to effectively upregulate regulatory T cells. In the first protocol (treatment protocol), we applied 1 mg of CD28 superagonist or control antibody on days 11 and 15 of pregnancy. In the second protocol (prevention protocol), the superagonist or control antibody was applied on days 1, 5, and 9. Superagonist increased regulatory T cells in circulation and placenta from 8.49±2.09% of CD4-positive T cells to 23.50±3.05% and from 3.85±1.45% to 23.27±7.64%, respectively. Blood pressure and albuminuria (30.6±15.1 versus 14.6±5.5 mg/d) were similar in the superagonist or control antibody-treated preeclamptic group for both protocols. Rats treated with CD28 superagonist showed increased pup weights in the prevention protocol (2.66±0.03 versus 2.37±0.05 g) and in the treatment protocol (3.04±0.04 versus 2.54±0.1 g). Intrauterine growth retardation, calculated by brain:liver weight ratio, was also decreased by the superagonist in both protocols. Further analysis of brain development revealed a 20% increase in brain volume by the superagonist. Induction of regulatory T cells in the circulation and the uteroplacental unit in an established preeclamptic rat model had no influence on maternal hypertension and proteinuria. However, it substantially improved fetal outcome by ameliorating intrauterine growth retardation.

The aim of this study was to assess the prevalence and risk factors of anal incontinence in an unselected pregnant population at second trimester. A survey of pregnant women attending a routine ultrasound examination was conducted in a university hospital in Oslo, Norway. A questionnaire consisting of 105 items concerning anal incontinence (including St. Mark's score), urinary incontinence, medication use, and comorbidity was posted to women when invited to the ultrasound examination. Results. Prevalence of self-reported anal incontinence (St. Mark's score ≥ 3) was the lowest in the group of women with a previous cesarean section only (6.4%) and the highest among women with a previous delivery complicated by obstetric anal sphincter injury (24.4%). Among nulliparous women the prevalence of anal incontinence was 7.7% and was associated to low educational level and comorbidity. Prevalence of anal incontinence increased with increasing parity. Urinary incontinence was associate...

To compare the incidence of obstetric anal sphincter injuries (OASIS) in two time periods, before and after implementing a training programme for improved perineal support aimed at reducing the incidence of obstetric anal sphincter injuries. The secondary aim was to study incidence of obstetric anal sphincter injuries in subgroups defined by risk factors for OASIS. Population-based cohort study. University hospital setting in Oslo, Norway. Two cohorts of all delivering women in the largest hospital in Norway during two time periods (2003-2005 and 2008-2010) were studied. After excluding caesarean sections and preterm deliveries (< week 32), the study population consisted of 31 709 deliveries, among which 907 women were identified with obstetric anal sphincter injury. Incidence of OASIS in two time periods. Maternal, obstetrical and foetal risk factors for OASIS were collected from the hospital obstetric database. Univariate analyses and multivariate logistic regression analyses, ...

To explore biomarkers indicating cardiovascular disease in pregnant women with diabetes or preeclampsia, since these women are at increased risk for future cardiovascular disease. EDTA-plasma from 262 women in gestational week 24-42 (healthy pregnancies n=71, preeclampsia n=105, type 2 diabetes n=17, gestational diabetes n=61, diabetes with preeclampsia n=8) was analyzed by immunoassay for neopterin, midregional pro-adrenomedullin (MR-proADM) and C-terminal pro-arginine vasopressin (CT-proAVP). The diabetes groups were also analyzed for midregional pro-atrial natriuretic peptide (MR-proANP), and compared to previously reported MR-proANP concentrations for healthy, normotensive and preeclamptic patients. In contrast to preeclampsia, median plasma MR-proANP was not increased in pregnancies complicated by diabetes, but in fact lower, compared to healthy pregnancies. Neopterin was increased in diabetic pregnancies and in late onset preeclampsia, compared to healthy pregnancies. Median plasma MR-proADM was increased in pregnancies complicated by gestational diabetes or preeclampsia, compared to healthy pregnancies. Median plasma MR-proANP was increased in diabetic pregnancies complicated by preeclampsia compared to pregnant women with diabetes only. Women with pregnancies complicated by diabetes mellitus or preeclampsia are at risk for future cardiovascular disease, but differ in circulating cardiovascular biomarker profile. A cardiovascular biomarker profiling during pregnancy might prove helpful in identifying women at risk for future cardiovascular disease, thus enabling targeted prophylactic interventions and follow-up.

The adipokines adiponectin and leptin may contribute to preeclampsia; however, the reports are conflicting. We explored the issue further. We studied 25 pregnant women with normal pregnancy in first, 25 in second, and 30 in third trimesters, 15 healthy nonpregnant women, and 32 women with preeclampsia. We used enzyme-linked immunosorbent assay to measure human plasma adiponectin (ng/mL) and leptin (ng/mL) concentrations. We also investigated adiponectin and leptin expression by quantitative messenger RNA in fat, decidua, and placenta tissues in a second study. Prepregnancy body mass index was not different in preeclamptic and nonpreeclamptic women. Plasma adiponectin concentrations increased throughout normal pregnancy, compared to nonpregnant women. The values increased in every trimester but were invariably lower in women with preeclampsia. Adiponectin nonetheless correlated inversely with prepregnancy body mass index. Such correlations were not found in women with preeclampsia. Plasma leptin in contrast decreased during pregnancy in every trimester. Leptin values were much higher in preeclamptic than in nonpreeclamptic women. Leptin expression was increased in the uteroplacental unit and in fat tissue of preeclamptic, compared to nonpreeclamptic women, while no differences in adiponectin expression were found. Adiponectin increases in normal pregnancy but remains correlated with prepregnancy body mass index. Plasma leptin decreases in normal pregnancy. In preeclamptic women, the normal adipokine responses are perturbed and this could be of pathophysiological significance.

Autophagy, a mechanism of cell survival during times of stress, may be active in normal placental maintenance, cushioning the fetus from strain during fluctuations in nutrient availability. Moreover, in cases of placental insufficiency, often present in preeclampsia, autophagy may be defective. We used published microarray datasets to analyze differential expression of autophagy pathway genes. No statistically significant difference in autophagy associated gene expression was found in preeclamptic vs. normal placenta samples. Thus although preeclampsia displays many of the features suggestive of altered autophagy, impaired placental autophagy as a cause of preeclampsia is not supported by whole placental tissue differential expression profiling.

The molecular mechanisms leading to preeclampsia are poorly understood. It has been related to certain immune mechanisms, as well as the pathological regulation of the renin-angiotensin system together with perturbed salt and plasma volume regulation. Finally, a non-specific, vascular, inflammatory response is generated, which leads to the clinical syndrome. Here, we present novel findings in salt (NaCl) metabolism implying that salt is not only important in blood pressure control and volume homeostasis, but also in immune regulation. Sodium and chloride can be stored without accumulation of water in the interstitium at hypertonic concentrations through interactions with proteoglycans. Macrophages in the interstitium act as osmosensors for salt, producing increased amounts of vascular endothelial factor C, which increases the density of the lymph-capillary network and the production of nitric oxide in vessels. An increased interstitial salt concentration activates the innate immune system, especially Th17 cells, and may be an important trigger for autoimmune diseases. The novel findings with the idea of sodium storage and local mechanisms of volume and immune regulation are appealing for preeclampsia and may unify the "immune" and "vascular" hypotheses of preeclampsia.

Recommending prophylactic anti-incontinence procedures to continent women undergoing surgery for pelvic organ prolapse (POP) is controversial. We hypothesized that testing for occult incontinence before surgery using four different tests and three defined test combinations would identify individual women at risk for postoperative stress urinary incontinence (POSUI). The diagnostic accuracy of these tests and test combinations were evaluated. We tested 137 women before and after surgery. Fisher's exact test was used when evaluating associations between test results and outcomes. The validity of each test and test combinations was calculated. We found a statistically significant association between occult incontinence and POSUI in two tests and all test combinations. However, all tests and test combinations displayed poor performance when predicting at individual levels. This study confirms a positive association between occult incontinence and POSUI. Occult incontinence does not, however, adequately identify individual women in need of prophylactic anti-incontinence surgery when undergoing POP repair.

Adipose tissue growth depends on angiogenesis. We tested the hypothesis that adipose tissue produces factors relevant to angiogenesis. We obtained fat biopsies in 2 different patient cohorts, cultured adipose-derived stem cells and studied mature adipocytes. We performed microarray, RT-PCR, and Western blotting; studied a rat obesity/metabolic syndrome model; and conducted viral gene transfer experiments in leptin-deficient mice. The microarray identified the splice variant of the vascular endothelial growth factor receptor, the soluble fms-like tyrosine kinase 1 (sFlt-1), as an antiangiogenesis candidate. We verified the expression findings and found that sFlt-1 was secreted by isolated mature human adipocytes. Tumor necrosis factor-α decreased sFlt-1 expression in mature adipocytes, whereas hypoxia had no effect. Separating cells from adipose tissue showed that the highest sFlt-1 expression was present in adipose-tissue nonfat cells rather than in the adipocytes themselves. We also found that sFlt-1 expression and sFlt-1 release by adipose-tissue explants were inversely correlated with body mass index of the corresponding patients but was directly correlated with adiponectin expression. In the obesity/metabolic syndrome rat model, we observed that circulating sFlt-1 levels and sFlt-1 expression in adipose tissue were also inversely correlated with body weight. To model our putative antiangiogenic factor further, we next overexpressed sFlt-1 by viral transfer in a mouse genetic model of leptin deficiency and observed that the transfected mice gained less weight than controls. We suggest that sFlt-1 could act as a paracrine factor inhibiting adipose tissue growth. Local sFlt-1 may regulate angiogenic potential and thereby influence adipose tissue mass.

Isoprostanes are stable markers of oxidative stress. We wanted to assess maternal circulating levels of total 8-isoprostane and indices of antioxidant capacity in preeclampsia compared to uneventful pregnancies. Total 8-isoprostane concentrations, FRAP (ferric reducing ability of plasma), Vitamin E and d-ROM (diacron reactive oxygen metabolites) were measured in maternal venous blood samples from preeclamptic (n=21) and uncomplicated (n=38) pregnancies at cesarean section. Median total 8-isoprostane concentration was elevated in preeclampsia compared to uncomplicated pregnancies (354 and 218 pg/mL, P=0.02). Median FRAP level was also elevated in preeclampsia compared to uncomplicated pregnancies, but to a lesser degree than 8-isoprostane. A positive correlation between 8-isoprostane and previously analyzed placenta-derived sFlt1 (soluble fms-like tyrosine kinase 1) levels in the maternal circulation was found in preeclampsia. We found a relative more increase for the oxidative stress marker (8-isoprostane) than for the antioxidant capacity (FRAP) in preeclampsia compared to uneventful pregnancies.

Alterations in maternal circulating angiogenic factors are proposed to result in hypertension and proteinuria and development of preeclampsia. The aim of this study was to explore whether preeclampsia risk factors are associated with maternal angiogenic profile in normotensive pregnancies.

The study objective was to investigate and validate plasma growth differentiation factor-15 (GDF-15) as a predictor of lymph node metastasis and a poor prognosis in primary endometrial cancer. Plasma samples from 510 women treated for endometrial cancer in a primary investigation cohort (n = 44) and a secondary validation cohort (n = 466) were analyzed for GDF-15. Plasma from healthy premenopausal (n = 20) and postmenopausal (n = 20) women, women with borderline (n = 43), benign (n = 144), and malignant ovarian tumors (n = 125) were used for comparison. Median plasma GDF-15 concentration for the endometrial cancer group was elevated (1,077 ng/L) as compared with pre- and postmenopausal controls (590 and 684 ng/L) and women with benign (591 ng/L) or borderline ovarian tumors (718 ng/L; all P < 0.001), but similar to the ovarian cancer group. In the large validation cohort of endometrial carcinomas, high plasma GDF-15 was significantly associated with International Federation of Gynecology and Obstetrics (FIGO) stage III/IV disease, nonendometrioid histology, high grade, older age, postmenopausal status, and lymph node metastases (all P ≤ 0.001). High GDF-15 was also an independent predictor of poor disease-specific and recurrence-free survival. Based on findings indicated in a primary investigation set and confirmed in the large secondary validation set, we report for the first time plasma GDF-15 as a biomarker for endometrial cancer phenotype, including presence of lymph node metastasis and reduced survival. Its applicability as a predictor of metastatic nodes and in monitoring treatment of endometrial cancer needs to be further studied.

Preeclampsia is associated with an increased risk of hypertension later in life. The regulator of G protein signaling 2 negatively regulates several vasoconstrictors. We recently demonstrated an association between preeclampsia and the CG or GG genotype of the C1114G polymorphism (rs4606) of the regulator of G protein signaling 2 gene. Here, we examined the polymorphism with respect to the development of hypertension after pregnancy. We genotyped 934 women on average 15.1 years after preeclampsia and 2011 age matched women with previous normotensive pregnancy. All women in this study were retrospectively recruited from the Nord-Trøndelag Health Study (HUNT2). Information from HUNT2 was linked to the Medical Birth Registry of Norway to identify women with a history of preeclampsia and women without a history of preeclampsia. No significant association was found between hypertension (blood pressure ≥140/90 mmHg and/or taking antihypertensive drugs) and the polymorphism in crude analysis (OR (95% CI): CG genotype: 1.07 (0.90-1.27); GG genotype: 1.23 (0.90-1.67)). However, in a minimally adjusted model (age and BMI adjusted), a significant association between the GG genotype and hypertension was found (OR (95% CI): 1.49 (1.05-2.11)). This association remained significant also after adjustment for a history of preeclampsia (OR (95% CI): 1.46 (1.02-2.09)), but not in a model adjusted for multiple other variables (OR (95% CI): 1.26 (0.82-1.94)). In multivariate, but not in crude, analysis, the GG genotype of rs4606 (OR (95% CI): 1.93 (1.05-3.53)) was significantly and independently associated with severe hypertension later in life, defined as systolic blood pressure ≥160 mmHg (stage 2 hypertension) and/or taking antihypertensive drugs. A significant association was also found for the merged CG and GG genotypes (OR (95% CI): 1.43 (1.02-2.00)). Moreover, an interaction with physical activity was found. A history of preeclampsia was a significant and independent predictor of either definition of hypertension, both in crude and adjusted analyses. Women carrying the rs4606 CG or GG genotype are at elevated risk for developing hypertension after delivery. Physical activity may interact with the association. Preeclampsia remains an independent risk factor for subsequent hypertension after adjusting for this polymorphism and classical CVD risk factors.

Improved insight into the molecular characteristics of the different ovarian cancer subgroups is needed for developing a more individualized and optimized treatment regimen. The aim of this study was to a) identify differentially expressed miRNAs in high-grade serous ovarian carcinoma (HGSC), clear cell ovarian carcinoma (CCC) and ovarian surface epithelium (OSE), b) evaluate selected miRNAs for association with clinical parameters including survival and c) map miRNA-mRNA interactions. Differences in miRNA expression between HGSC, CCC and OSE were analyzed by global miRNA expression profiling (Affymetrix GeneChip miRNA 2.0 Arrays, n = 12, 9 and 9, respectively), validated by RT-qPCR (n = 35, 19 and 9, respectively), and evaluated for associations with clinical parameters. For HGSC, differentially expressed miRNAs were linked to differentially expressed mRNAs identified previously. Differentially expressed miRNAs (n = 78) between HGSC, CCC and OSE were identified (FDR < 0.01%), of which 18 were validated (p < 0.01) using RT-qPCR in an extended cohort. Compared with OSE, miR-205-5p was the most overexpressed miRNA in HGSC. miR-200 family members and miR-182-5p were the most overexpressed in HGSC and CCC compared with OSE, whereas miR-383 was the most underexpressed. miR-205-5p and miR-200 members target epithelial-mesenchymal transition (EMT) regulators, apparently being important in tumor progression. miR-509-3-5p, miR-509-5p, miR-509-3p and miR-510 were among the strongest differentiators between HGSC and CCC, all being significantly overexpressed in CCC compared with HGSC. High miR-200c-3p expression was associated with poor progression-free (p = 0.031) and overall (p = 0.026) survival in HGSC patients. Interacting miRNA and mRNA targets, including those of a TP53-related pathway presented previously, were identified in HGSC. Several miRNAs differentially expressed between HGSC, CCC and OSE have been identified, suggesting a carcinogenetic role for these miRNAs. miR-200 family members, targeting EMT drivers, were mostly overexpressed in both subgroups, among which miR-200c-3p was associated with survival in HGSC patients. A set of miRNAs differentiates CCC from HGSC, of which miR-509-3-5p and miR-509-5p are the strongest classifiers. Several interactions between miRNAs and mRNAs in HGSC were mapped.