Novel Associations Between Mid-Pregnancy Cardiovascular Biomarkers and Preeclampsia: An Explorative Nested Case-Control Study.

Prediction of women at high risk of preeclampsia is important for prevention and increased surveillance of the disease. Current prediction models need improvement, particularly with regard to late-onset preeclampsia. Preeclampsia shares pathophysiological entities with cardiovascular disease; thus, cardiovascular biomarkers may contribute to improving prediction models. In this nested case-control study, we explored the predictive importance of mid-pregnancy cardiovascular biomarkers for subsequent preeclampsia. We included healthy women with singleton pregnancies who had donated blood in mid-pregnancy (~ 18 weeks' gestation). Cases were women with subsequent preeclampsia (n = 296, 10% of whom had early-onset preeclampsia [< 34 weeks]). Controls were women who had healthy pregnancies (n = 333). We collected data on maternal, pregnancy, and infant characteristics from medical records. We used the Olink cardiovascular II panel immunoassay to measure 92 biomarkers in the mid-pregnancy plasma samples. The Boruta algorithm was used to determine the predictive importance of the investigated biomarkers and first-trimester pregnancy characteristics for the development of preeclampsia. The following biomarkers had confirmed associations with early-onset preeclampsia (in descending order of importance): placental growth factor (PlGF), matrix metalloproteinase (MMP-12), lectin-like oxidized LDL receptor 1, carcinoembryonic antigen-related cell adhesion molecule 8, serine protease 27, pro-interleukin-16, and poly (ADP-ribose) polymerase 1. The biomarkers that were associated with late-onset preeclampsia were BNP, MMP-12, alpha-L-iduronidase (IDUA), PlGF, low-affinity immunoglobulin gamma Fc region receptor II-b, and T cell surface glycoprotein. Our results suggest that MMP-12 is a promising novel preeclampsia biomarker. Moreover, BNP and IDUA may be of value in enhancing prediction of late-onset preeclampsia.

Maternal and Perinatal Outcomes in Singleton Nulliparous Spontaneous Preterm Birth with and without Preterm Premature Rupture of Membranes-A National Population-Based Cohort Study.

OBJECTIVE: Preterm birth (PTB, birth before 37 gestational weeks) is the leading cause of neonatal death and a major challenge for obstetric and neonatal care. About two-thirds of PTBs are spontaneous PTB (sPTB), of which approximately 30% start with preterm premature rupture of membranes (PPROM). The aim of the study was to investigate risk factors and maternal and perinatal outcomes in sPTB with and without PPROM. STUDY DESIGN: This is a national population-based cohort study including all singleton pregnancies in nulliparous women with spontaneous onset of labor and vaginal births (n = 266,968) registered in the Swedish Medical Birth Register 2005 to 2014. sPTB with PPROM (sPTB-PPROM) and sPTB without PPROM were compared regarding risk factors and maternal and perinatal outcomes. Logistic regression was used to estimate adjusted odds ratios (aORs) with 95% confidence intervals (CIs). Adjustments were made for maternal age, body mass index, country of birth, smoking, chronic hypertension, pregestational and gestational diabetes, and gestational length. RESULTS: sPTB-PPROM (n = 5,037), compared with sPTB without PPROM (n = 8,426), was more common in women with previous spontaneous abortions, prepregnancy urinary tract infections, chronic hypertension, and gestational diabetes and had a higher risk of postpartum endometritis (aOR: 2.78, 95% CI: 1.55-5.00). Infants born to women with sPTB-PPROM had a lower risk of birth asphyxia (aOR: 0.60, 95% CI: 0.43-0.83), respiratory distress syndrome (aOR: 0.86, 95% CI: 0.70-1.00), retinopathy of prematurity (aOR: 0.93, 95% CI: 0.92-0.94), necrotizing enterocolitis (aOR: 0.95, 95% CI: 0.94-0.96), and higher risk of hypoglycemia (aOR: 1.14, 95% CI: 1.01-1.28), and hyperbilirubinemia (aOR: 1.28, 95% CI: 1.19-1.38) compared with infants born to sPTB without PPROM. CONCLUSION: Our findings of risk factors and distinct differences in adverse outcomes after sPTB-PPROM compared with sPTB without PPROM are of vital importance and might serve as a basis when elaborating programs for the prevention and management of PPROM. KEY POINTS: · This is a large cohort study of spontaneous preterm birth (sPTB).. · Singleton nulliparous sPTB with/without preterm premature rupture of membrane (PPROM) were studied.. · Distinct differences in adverse perinatal outcomes in sPTB with and without PPROM were observed..

Ex vivo assessment of cancer drug sensitivity in epithelial ovarian cancer and its association with histopathological type, treatment history and clinical outcome.

Epithelial ovarian cancer (EOC) is divided into type I and type II based on histopathological features. Type I is clinically more indolent, but also less sensitive to chemotherapy, compared with type II. The basis for this difference is not fully clarified. The present study investigated the pattern of drug activity in type I and type II EOC for standard cytotoxic drugs and recently introduced tyrosine kinase inhibitors (TKIs), and assessed the association with treatment history and clinical outcome. Isolated EOC tumor cells obtained at surgery were investigated for their sensitivity to seven standard cytotoxic drugs and nine TKIs using a short­term fluorescent microculture cytotoxicity assay (FMCA). Drug activity was compared with respect to EOC subtype, preoperative chemotherapy, cross­resistance and association with progression­free survival (PFS). Out of 128 EOC samples, 120 samples, including 21 type I and 99 type II, were successfully analyzed using FMCA. Patients with EOC type I had a significantly longer PFS time than patients with EOC type II (P=0.01). In line with clinical experience, EOC type I samples were generally more resistant than type II samples to both standard cytotoxic drugs and the TKIs, reaching statistical significance for cisplatin (P=0.03) and dasatinib (P=0.002). A similar pattern was noted in samples from patients treated with chemotherapy prior to surgery compared with treatment­naive samples, reaching statistical significance for fluorouracil, irinotecan, dasatinib and nintedanib (all P<0.05). PFS time gradually shortened with increasing degree of drug resistance. Cross­resistance between drugs was in most cases statistically significant yet moderate in degree (r<0.5). The clinically observed relative drug resistance of EOC type I, as well as in patients previously treated, is at least partly due to mechanisms in the tumor cells. These mechanisms seemingly also encompass kinase inhibitors. Ex vivo assessment of drug activity is suggested to have a role in the optimization of drug therapy in EOC.

Higher risk of type 2 diabetes in women with hyperandrogenic polycystic ovary syndrome.

OBJECTIVE: To assess the risk of type 2 diabetes (T2D) in women with polycystic ovary syndrome (PCOS) in relation to body mass index (BMI) and the hyperandrogenic (HA) PCOS phenotype. DESIGN: Population-based cohort study. SETTING: Data from six Swedish national registers, with participants being followed for a maximum of 19 years. PATIENT(S): All women with an International Statistical Classification of Diseases and Related Health Problems, version 10, diagnosis of PCOS, androgen excess, or anovulatory infertility born between 1950 and 1999 (n = 52,535) were identified in the Patient Register. The HA PCOS phenotype was defined by two filled prescriptions for anti-androgenic drugs. For each woman with PCOS, five control women (n = 254,624) were randomly chosen from the Total Population Register, matched for age and geographic area. INTERVENTION(S): No interventions were performed. MAIN OUTCOME MEASURE(S): International Statistical Classification of Diseases and Related Health Problems, version 10, diagnosis of T2D or prescription of antidiabetic treatment other than metformin. RESULT(S): The cumulative incidence rates of T2D were 1.3%, 4.4%, and 14.2% in controls (non-PCOS women) and women with normoandrogenic (NA) and HA PCOS, respectively. After adjustment for BMI, women with PCOS had a twofold higher rate of T2D than non-PCOS women (adjusted hazard ratio, 2.52 [95% confidence interval, 2.15-2.96]). Women with HA PCOS had a higher rate of T2D than those with NA PCOS (adjusted hazard ratio, 3.86 [95% confidence interval, 3.16-4.72]). CONCLUSION(S): Polycystic ovary syndrome is an independent risk factor for T2D, even after adjustment for BMI. Women with the HA PCOS phenotype face an even higher risk of T2D than those with the NA PCOS phenotype.

Peritoneal cancer index predicts severe complications after ovarian cancer surgery.

INTRODUCTION: prediction and importance of severe postoperative complications after ovarian cancer surgery is a strong issue in patient selection and evaluation. Pre- and early peroperative predictors of severe 30-days postoperative complications (Clavien-Dindo class ≥3) after surgery for primary ovarian cancer are not fully established, neither their impact on patients' survival. MATERIALS AND METHODS: A prospective observational study included 256 patients with primary ovarian cancer FIGO stages IIB-IV, operated during 2009-2018 in a primary or interval debulking surgery setting. Patient variables were analysed in relation to severe postoperative complications (Clavien-Dindo class ≥3) and overall survival. RESULTS: High-grade postoperative complications occurred in 24.2% patients. Class 3a complications were observed in 12.5% cases. High-grade complications class ≥3 were observed in 31.6% after primary debulking surgery compared to 12.2% after interval debulking surgery (p = 0.0004). Peritoneal cancer index ≥21 and preoperative albumin concentration ≤33 g/L were independent predictors of high-grade complications. Peritoneal cancer index correlated with the surgical complexity score and completeness of cytoreduction. Increased peritoneal cancer index was a negative predictor of overall survival, but high-grade complications did not influence survival negatively. CONCLUSIONS: Peritoneal cancer index ≥21 was an independent predictor of high-grade complications after ovarian cancer surgery. Increased peritoneal cancer index also impacted overall survival negatively, but high-grade complications did not influence overall survival.

Validation of 18F-FDG PET/MRI and diffusion-weighted MRI for estimating the extent of peritoneal carcinomatosis in ovarian and endometrial cancer -a pilot study.

BACKGROUND: The extent of peritoneal carcinomatosis is difficult to estimate preoperatively, but a valid measure would be important in identifying operable patients. The present study set out to validate the usefulness of integrated 18F-FDG PET/MRI, in comparison with diffusion-weighted MRI (DW-MRI), for estimation of the extent of peritoneal carcinomatosis in patients with gynaecological cancer. METHODS: Whole-body PET/MRI was performed on 34 patients with presumed carcinomatosis of gynaecological origin, all scheduled for surgery. Two radiologists evaluated the peritoneal cancer index (PCI) on PET/MRI and DW-MRI scans in consensus. The surgeon estimated PCI intraoperatively, which was used as the gold standard. RESULTS: Median total PCI for PET/MRI (21.5) was closer to surgical PCI (24.5) (p = 0.6), than DW-MRI (median PCI 20.0, p = 0.007). However, both methods were highly correlated with the surgical PCI (PET/MRI: ß = 0.94 p < 0.01, DW-MRI: ß = 0.86, p < 0.01). PET/MRI was more accurate (p = 0.3) than DW-MRI (p = 0.001) when evaluating patients at primary diagnosis but no difference was noted in patients treated with chemotherapy. PET/MRI was superior in evaluating high tumour burden in inoperable patients. In the small bowel regions, there was a tendency of higher sensitivity but lower specificity in PET/MRI compared to DW-MRI. CONCLUSIONS: Our results suggest that FDG PET/MRI is superior to DW-MRI in estimating total spread of carcinomatosis in gynaecological cancer. Further, the greatest advantage of PET/MRI seems to be in patients at primary diagnosis and with high tumour burden, which suggest that it could be a useful tool when deciding about operability in gynaecological cancer.

Pregnancy outcome in women with polycystic ovary syndrome in relation to second-trimester testosterone levels.

RESEARCH QUESTION: Do women with polycystic ovary syndrome (PCOS) have higher testosterone levels during pregnancy and what role does high testosterone play in the development of obstetric complications? DESIGN: Retrospective cohort study from Uppsala University Hospital, Sweden. The study population consisted of women with PCOS (n = 159) and a comparison group of women without PCOS matched for body mass index (n = 320). Plasma testosterone levels were measured in the early second trimester by liquid chromatography with tandem mass spectrometry, and women with PCOS were grouped into tertiles according to their testosterone levels. Possible associations with obstetric complications, maternal metabolic factors and offspring birth weight were explored by multivariable logistic and linear regression models. RESULTS: Compared with women who do not have PCOS, women with PCOS had higher total testosterone (median 1.94, interquartile range [IQR] 1.21-2.64 versus 1.41, IQR 0.89-1.97; P < 0.001), and free androgen index (median 0.25, IQR 0.15-0.36 versus 0.18, IQR 0.11-0.28; P < 0.001). Women with PCOS who had the highest levels of testosterone had increased risk for preeclampsia, even when adjusted for age, parity, country of birth and smoking (adjusted OR 6.16, 95% CI 1.82 to 20.91). No association was found between high testosterone in women with PCOS and other obstetric complications. CONCLUSIONS: Women with PCOS have higher levels of total testosterone and free androgen index during pregnancy than women without PCOS matched for body mass index. Preliminary evidence shows that women with PCOS and the highest maternal testosterone levels in early second trimester had the highest risk of developing preeclampsia. This finding, however, is driven by a limited number of cases and should be interpreted with caution.

The Peritoneal Cancer Index is a Strong Predictor of Incomplete Cytoreductive Surgery in Ovarian Cancer.

BACKGROUND: Extent of tumor load is an important factor in the selection of ovarian cancer patients for cytoreductive surgery (CRS). The Peritoneal Cancer Index (PCI) gives exact information on tumor load but still is not standard in ovarian cancer surgery. The aim of this study was to find a PCI cutoff for incomplete CRS. The secondary aims were to identify reasons for open-close surgery and to compare surgical complications in relation to tumor burden. METHODS: The study included 167 women with stage III or IV ovarian cancer scheduled for CRS. Possible predictors of incomplete surgery were evaluated with receiver operator curves, and a PCI cutoff was identified. Surgical complications were analyzed by one-way analysis of variance and Chi square tests. RESULTS: The median PCI score for all the patients was 22 (range 3-37) but 33 (range 25-37) for the patients with incomplete surgery (n = 19). The PCI predicted incomplete CRS, with an area under the curve of 0.94 (95% confidence interval [CI], 0.91-0.98). Complete CRS was obtained for 67.2% of the patients with a PCI higher than 24, who experienced an increased rate of complications (p = 0.008). Overall major complications were found in 16.9% of the cases. Only 28.6% of the patients with a PCI higher than 33 achieved complete CRS. The reason for open-close surgery (n = 14) was massive carcinomatosis on the small bowel in all cases. CONCLUSION: The study found PCI to be an excellent predictor of incomplete CRS. Due to a lower surgical success rate, the authors suggest that neoadjuvant chemotherapy could be considered if the PCI is higher than 24. Preoperative radiologic assessment should focus on total tumor burden and not necessarily on specific regions.

Pregnancy and neonatal complications in women with polycystic ovary syndrome in relation to second-trimester anti-Müllerian hormone levels.

RESEARCH QUESTION: An association has been found between high anti-Müllerian hormone (AMH) levels during pregnancy and the development of polycystic ovary syndrome (PCOS)-like phenotypic traits in mouse offspring. The aim of this study was to determine whether AMH levels are associated with maternal testosterone levels, and whether high AMH concentration influences the risk of developing PCOS-related adverse pregnancy outcomes. DESIGN: Maternal serum AMH, testosterone and sex hormone binding globulin levels were measured in blood samples taken in early second-trimester pregnancies from women with PCOS (n = 159) and healthy controls matched for body mass index (n = 320). Possible associations with preeclampsia, gestational hypertension, gestational diabetes, preterm birth and birthweight was explored by logistic and linear regression models. RESULTS: Women with PCOS had higher AMH, higher total testosterone levels and higher free androgen index than controls (P < 0.001 for all three parameters). Among women with PCOS, high testosterone levels (B = 2.7; ß = 0.26; P = 0.001) and low first trimester body mass index (B = -0.5; ß = -0.17; P = 0.043) remained independently associated with AMH. High AMH levels were associated with decreased risk of gestational hypertension (adjusted OR 0.55; 95% CI 0.34 to 0.87), but no association was found with other adverse pregnancy outcomes or birthweight. CONCLUSIONS: Women with PCOS had higher AMH levels during pregnancy compared with controls, but high AMH was not associated with increased risk of adverse pregnancy outcomes or birthweight.

Hypothalamic-pituitary-adrenal axis responsiveness, startle response, and sensorimotor gating in late pregnancy.

During pregnancy, the hypothalamic-pituitary-adrenal (HPA) axis, the main regulator of the stress response, undergoes dramatic changes. The acoustic startle response (ASR) and the prepulse inhibition (PPI) of the startle response are neurophysiological research tools and objective measures of an individual's response to an emotional context or stressor. The ASR and PPI are influenced by psychiatric diseases characterized by anxiety symptoms and are sensitive to cortisol. Hence, the ASR and the PPI can be used to investigate the effects of pregnancy-induced endocrine changes and their contribution to affective disorders. The present study sought to investigate the association between measures of HPA-axis responsiveness, startle reactivity and sensorimotor gating during pregnancy that to date remains unknown. The eye-blink component of the ASR, and its prepulse inhibition, were measured in 107 late third trimester pregnant women. Saliva samples were collected to assess the cortisol awakening response (CAR), a measure of HPA-axis activity. Blood was sampled to measure serum levels of cortisol, cortisone and the cortisone to cortisol ratio. Ongoing anxiety disorders, sleep duration, smoking, and age were considered as potential confounders in the statistical analyses. CAR reactivity, measured as area under the curve (AUC) increase and above baseline, was positively associated with baseline startle magnitude [Cohen's d = 0.27; F (1, 105) = 4.99; p = 0.028, and Cohen's d = 0.30; F (1, 105) = 6.25; p = 0.014, respectively] as well as PPI at 86 dB [Cohen's d = 0.29; F (1, 105) = 5.93; p = 0.017; and Cohen's d = 0.34; F (1, 105) = 8.38; p = 0.005, respectively]. The observed positive correlation between startle magnitude in pregnant women and greater increase in cortisol during the awakening response may be interpreted as heightened neurophysiological reactivity, likely associated with dysregulation of the stress system.

Potential Brain Age Reversal after Pregnancy: Younger Brains at 4-6 Weeks Postpartum.

Pregnancy is accompanied by complex biological adaptations, including extreme hormonal fluctuations. Moreover, changes on the endocrine level are accompanied by changes in cerebral anatomy, such as reductions in brain or gray matter volume. Since declining brain and tissue volumes are characteristic for normal aging, the question arises of whether such pregnancy-induced anatomical effects are permanent or transient. To answer this question, we acquired high-resolution brain image data of 14 healthy women in their mid-twenties to late thirties at two time points: within 1-2 days of childbirth (early postpartum) and at 4-6 weeks after childbirth (late postpartum). At both time points, we estimated the brain ages for each woman using a well-validated machine learning approach based on pattern recognition. Ultimately, this algorithm - designed to identify anatomical correlates of age across the entire brain - reveals a single score for each individual: the BrainAGE index. Comparing the BrainAGE indices between both time points, female brains at late postpartum were estimated to be considerably younger than at early postpartum. On average, that difference was about five years (mean ±â€¯SD: 5.4 ±â€¯2.4 years). These findings suggest a substantial restoration/rejuvenation effect after giving birth, which is evident already within the first couple of months.

Treatment of premenstrual dysphoric disorder with the GABAA receptor modulating steroid antagonist Sepranolone (UC1010)-A randomized controlled trial.

CONTEXT: Allopregnanolone is a metabolite from progesterone and a positive modulator of the GABAA receptor. This endogenous steroid may induce negative mood in sensitive women when present in serum levels comparable to the premenstrual phase. Its endogenous isomer, isoallopregnanolone, has been shown to antagonize allopregnanolone effects in experimental animal and human models. OBJECTIVE: The objective was to test whether inhibition of allopregnanolone by treatment with the GABAA modulating steroid antagonist (GAMSA) Sepranolone (UC1010) during the premenstrual phase could reduce symptoms of the premenstrual dysphoric disorder (PMDD). The pharmacokinetic parameters of UC1010 when given as a subcutaneous injection were measured in healthy women prior to the study in women with PMDD. DESIGN: This was an explorative randomized, double-blind, placebo-controlled study. SETTING: Swedish multicentre study with 10 centers. PARTICIPANTS: Participants were 26 healthy women in a pharmacokinetic phase I study part, and 126 women with PMDD in a phase II study part. Diagnosis followed the criteria for PMDD in DSM-5 using Daily Record of Severity of Problems (DRSP) and Endicott's algorithm. INTERVENTION: Subjects were randomized to treatment with UC1010 (10 or 16mg) subcutaneously every second day during the luteal phase or placebo during one menstrual cycle. OUTCOME MEASURES: The primary outcome measure was the sum of all 21 items in DRSP (Total DRSP score). Secondary outcomes were Negative mood score i.e. the ratings of the 4 key symptoms in PMDD (anger/irritability, depression, anxiety and lability) and impairment (impact on daily life). RESULTS: 26 healthy women completed the pharmacokinetic phase I study and the dosing in the following trial was adjusted according to the results. 106 of the 126 women completed the phase II study. Within this group, a significant treatment effect with UC1010 compared to placebo was obtained for the Total DRSP score (p=0.041) and borderline significance (p=0.051) for the sum of Negative mood score. Nineteen participants however showed symptoms during the follicular phase that might be signs of an underlying other conditions, and 27 participants had not received the medication as intended during the symptomatic phase. Hence, to secure that the significant result described above was not due to chance, a post hoc sub-group analysis was performed, including only women with pure PMDD who completed the trial as intended (n=60). In this group UC1010 reduced Total DRSP scores by 75% compared with 47% following placebo; the effect size 0.7 (p=0.006), and for sum of Negative mood score (p=0.003) and impairment (p=0.010) with the effect size 0.6. No severe adverse events were reported during the treatment and safety parameters (vital signs and blood chemistry) remained normal during the study. CONCLUSIONS: This explorative study indicates promising results for UC1010 as a potential treatment for PMDD. The effect size was comparable to that of SSRIs and drospirenone containing oral contraceptives. UC1010 was well tolerated and deemed safe.

Histidine-rich glycoprotein derived peptides affect endometrial angiogenesis in vitro but has no effect on embryo development.

UNLABELLED: Histidine-rich glycoprotein (HRG) is an abundant plasma protein involved in multiple biological processes including immunology, vascularisation, and coagulation. These processes are of importance in regulating embryo development and implantation. A specific polymorphism in the HRG gene, HRG C633T, has an impact on various aspects of fertility, such as oocyte quality, endometrial receptivity, and possibly the capacity of the embryo itself to implant. To further examine the potential role of the HRG C633T polymorphism in regulating endometrial angiogenesis and on embryo development, two HRG peptides were constructed. These HRG peptides correspond to the amino acids 169-203 of the protein which, in turn, reflects the C633T polymorphism in the gene. The HRG proline or serine peptides were added to cultures of primary human endometrial endothelial (HEE) cells and to human embryos in vitro. The HRG peptides inhibited vascular endothelial growth factor (VEGF) induced proliferation and migration and promoted tube formation of HEE cells. The embryos were monitored using a time-lapse system (EmbryoScope®). Except for a prolonged time from first cleavage after thawing to development of the morula, no difference in embryo morphokinetics or embryo quality was noted in human embryos cultured in the presence of the HRG proline peptide. Taken together, these results suggest that treatment with a specific HRG peptide might prime the endometrium for implantation and be beneficial for adequate placentation. However, addition of a specific HRG proline peptide to human embryos has no beneficial effects in terms of embryo development. ABBREVIATIONS: HRG: histidine-rich glycoprotein; HEE: human endometrial endothelial; VEGF: vascular endothelial growth factor; TSP: thrombospondin; SNP; single nucleotide polymorphism; IVF: in vitro fertilization; CLESH-1: CD36 LIMPII Emp structural homology domain-1; ECM: endothelial cell medium; FBS: fetal bovine serum; cDNA: complementary DNA.

Vaginal Gene Expression During Treatment With Aromatase Inhibitors.

BACKGROUND: Aromatase inhibitor (AI) treatment suppresses estrogen biosynthesis and causes genitourinary symptoms of menopause such as vaginal symptoms, ultimately affecting the quality of life for many postmenopausal women with breast cancer. Thus, the aim of this study was to examine vaginal gene expression in women during treatment with AIs compared with estrogen-treated women. The secondary aim was to study the presence and localization of vaginal aromatase. PATIENTS AND METHODS: Vaginal biopsies were collected from postmenopausal women treated with AIs and from age-matched control women treated with vaginal estrogen therapy. Differential gene expression was studied with the Affymetrix Gene Chip Gene 1.0 ST Array (Affymetrix Inc, Santa Clara, CA) system, Ingenuity pathway analysis, quantitative real-time polymerase chain reaction, and immunohistochemistry. RESULTS: The expression of 279 genes differed between the 2 groups; AI-treated women had low expression of genes involved in cell differentiation, proliferation, and cell adhesion. Some differentially expressed genes were found to interact indirectly with the estrogen receptor alpha. In addition, aromatase protein staining was evident in the basal and the intermediate vaginal epithelium layers, and also in stromal cells with a slightly stronger staining intensity found in AI-treated women. CONCLUSION: In this study, we demonstrated that genes involved in cell differentiation, proliferation, and cell adhesion are differentially expressed in AI-treated women. The expression of vaginal aromatase suggests that this could be the result of local and systemic inhibition of aromatase. Our results emphasize the role of estrogen for vaginal cell differentiation and proliferation and future drug candidates should be aimed at improving cell differentiation and proliferation.

Iodine deficiency in a study population of pregnant women in Sweden.

INTRODUCTION: Iodine deficiency in utero may impair neurological development of the fetus. In Sweden, iodine nutrition is considered to be adequate in the general population. The aim of this study was to evaluate iodine nutrition during pregnancy in Sweden. MATERIAL AND METHODS: In this cross-sectional study, the total study population (n = 459) consisted of two cohorts (Värmland County, n = 273, and Uppsala County, n = 186) of pregnant non-smoking women without pre-gestational diabetes mellitus or known thyroid disease before or during pregnancy. Spot urine samples were collected in the third trimester of pregnancy for median urinary iodine concentration (UIC) analysis. RESULTS: The median UIC in the total study population was 98 µg/L (interquartile range 57-148 µg/L). CONCLUSIONS: According to WHO/UNICEF/IGN criteria, population-based median UIC during pregnancy should be 150-249 µg/L. Thus, our results indicate insufficient iodine status in the pregnant population of Sweden. There is an urgent need for further assessments in order to optimize iodine nutrition during pregnancy.

The effect of antenatal depression and selective serotonin reuptake inhibitor treatment on nerve growth factor signaling in human placenta.

Depressive symptoms during pregnancy are common and may have impact on the developing child. Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressant treatment, but unfortunately, these treatments can also negatively affect the behavioral development and health of a child during pregnancy. In addition, serotonin (5-HT) exerts neurotrophic actions with thus far not fully known effects in the offspring. The neurotrophic growth factor (NGF) is involved in neuronal cell survival and differentiation, and altered placenta levels have been found to increase the risk for pregnancy complications, similar to those found in women treated with SSRIs. We therefore investigated whether the NGF signaling pathway was altered in the placenta from women treated with SSRIs (n = 12) and compared them with placenta from depressed (n = 12) and healthy mothers (n = 12). Results from immunohistochemical stainings revealed that placental NGF protein levels of SSRI-treated women were increased in both trophoblasts and endothelial cells compared with depressed and control women. In addition, downstream of the NGF receptor TrkA, increased levels of the signaling proteins ROCK2 and phosphorylated Raf-1 were found in stromal cells and a tendency towards increased levels of ROCK2 in trophoblasts and endothelial cells in SSRI-treated women when compared to healthy controls. SSRI-treated women also displayed increased levels of phosphorylated ROCK2 in all placental cell types studied in comparison with depressed and control women. Interestingly, in placental endothelial cells from depressed women, NGF levels were significantly lower compared to control women, but ROCK2 levels were increased compared with control and SSRI-treated women. Taken together, these results show that the NGF signaling and downstream pathways in the placenta are affected by SSRI treatment and/or antenatal depression. This might lead to an altered placental function, although the clinical relevance of our findings still needs to be investigated.

Aromatase inhibitors affect vaginal proliferation and steroid hormone receptors.

OBJECTIVE: Women with breast cancer who are treated with aromatase inhibitors often experience vaginal atrophy symptoms and sexual dysfunction. This work aims to study proliferation and the presence and distribution of steroid hormone receptors in vaginal biopsies in relation to vaginal atrophy and vaginal pH in women with breast cancer who are on adjuvant endocrine treatment and in healthy postmenopausal women. METHODS: This is a cross-sectional study that compares postmenopausal aromatase inhibitor-treated women with breast cancer (n = 15) with tamoxifen-treated women with breast cancer (n = 16) and age-matched postmenopausal women without treatment (n = 19) or with vaginal estrogen therapy (n = 16). Immunohistochemistry was used to study proliferation and steroid hormone receptor staining intensity. Data was correlated with estrogen and androgen levels, vaginal atrophy scores, and vaginal pH. RESULTS: Aromatase inhibitor-treated women had a lower grade of proliferation, weaker progesterone receptor staining, and stronger androgen receptor staining, which correlated with plasma estrone levels, vaginal atrophy scores, and vaginal pH. CONCLUSIONS: Women with aromatase inhibitor-treated breast cancer exhibit reduced proliferation and altered steroid hormone receptor staining intensity in the vagina, which are related to clinical signs of vaginal atrophy. Although these effects are most probably attributable to estrogen suppression, a possible local inhibition of aromatase cannot be ruled out.

Sexual dysfunction in women on adjuvant endocrine therapy after breast cancer.

OBJECTIVE: The goal of this study was to investigate sexual function in postmenopausal breast cancer patients treated with aromatase inhibitors. METHODS: A population-based, cross-sectional study was conducted among postmenopausal breast cancer patients on adjuvant endocrine treatment and age-matched controls with and without estrogen treatment. Sexual function was assessed with a standardized questionnaire. RESULTS: In all, 42.4% of aromatase inhibitor-treated breast cancer patients were dissatisfied with their sex life in general, and 50.0% reported low sexual interest; this was significantly more common than in tamoxifen-treated patients and controls (P < 0.05). Aromatase inhibitor-treated patients reported insufficient lubrication in 73.9% and dyspareunia in 56.5% of cases, which were significantly more common than in controls, irrespective of hormonal use (P < 0.05). Tamoxifen-treated patients reported significantly more dyspareunia (31.3%; P < 0.05) but resembled controls in all other concerns. CONCLUSIONS: Our findings suggest that sexual dysfunction in aromatase inhibitor-treated women is a greatly underestimated problem.

Thyroid function tests at delivery and risk for postpartum depressive symptoms.

Postpartum depression (PPD) is a common childbirth complication, which can have negative effects on both the newly delivered woman and her family. This condition is underdiagnosed and inadequately treated, while a biological diagnostic test is not yet available. Furthermore, postpartum thyroid dysfunction is common among new mothers, and some evidence point to an association between PPD and thyroid function disturbances. The aim of this study was to evaluate the possible association between serum levels of thyroid hormones at the time of delivery, and the later development of depressive symptoms, using data from a population based cohort of Swedish women. Blood samples were collected during delivery from 347 participating women, delivering at Uppsala University Hospital. The participating women filled in at least one of three structured questionnaires, containing the Edinburgh Postnatal Depression Scale (EPDS), at five days, six weeks and six months postpartum. A cut-off of 12 or more was applied on the EPDS, to identify cases of self-reported PPD and controls. Using a binary logistic regression model (adjusting for previous psychiatric contact, smoking during pregnancy, pre-pregnancy body mass index (BMI) and sleep), having a thyroid stimulating hormone (TSH) level over the clinical cut-off level of 4.0 mU/L was associated with increased risk for depressive symptoms at six months postpartum (OR 11.30, 95% CI 1.93-66.11). A ROC analysis revealed that the predictive variable (PV) had significant predictive ability for PPD at 6 months postpartum, given that the AUC was 0.764, and at a PV cut-off value of 6.33, the sensitivity and specificity were 76.2% and 69.4%, respectively. If these findings are replicated in future studies, they can have important clinical implications, since TSH determination is an inexpensive routine blood test, and its inclusion in a biological screening test for PPD involving other parameters would be tempting.

Long-term reproductive and metabolic consequences of PCOS.

Polycystic ovary syndrome (PCOS) is associated with reproductive and metabolic consequences. The review of findings indicate that the long-term reproductive outcomes of women with PCOS are surprisingly similar compared to women with normal ovaries, and that they have an ovarian reserve possibly superior to women with normal ovaries. The typical features of PCOS, specifically the anovulatory cycles tend to normalize over time, but in spite of a decrease over time, free androgen levels remain elevated compared to age-matched control subjects. Women with PCOS diagnosed at young age continue to display reduced insulin sensitivity in the perimenopausal age, independent from phenotypic expression of PCOS, both at diagnosis and at follow-up. Insulin resistance does not seem to deteriorate further, however. Overall, the accumulated data from several European cohort studies of older women with a previous diagnosis of PCOS suggest an increased incidence of type 2 diabetes, increased prevalence of several features of the metabolic syndrome, but no increased incidence of mortality from CVD.