Johannes Bitzer

Depression and anxiety during pregnancy: a risk factor for obstetric, fetal and neonatal outcome? A critical review of the literature.

Objective. Research from the past two decades has suggested a link between prenatal maternal psychological distress and adverse obstetric, fetal and neonatal outcome. Comparability of study results, however, is complicated by a diversity of definitions and measurements of prenatal maternal stress and different time points of assessment. Our aim was to critically review studies assessing maternal anxiety and depression during pregnancy and their impact on obstetric, fetal and neonatal outcome. Methods. We carried out a computerized literature search of PubMed, PsycLIT and EMBASE (1990–2005) and a manual search of bibliographies of pertinent articles. In total 35 studies were identified that fulfilled the inclusion criteria. Results. Elevated levels of depression and anxiety were found to be associated with obstetric outcome (obstetric complications, pregnancy symptoms, preterm labor and pain relief under labor), and had implications for fetal and neonatal well-being and behavior. However, prediction of the impact of mood and anxiety disorders during pregnancy is very limited due to methodological problems. Most notably, the majority of the studies included pregnant women with elevated symptoms of depressed mood and anxiety and did diagnose mood and anxiety disorders. Also, potentially confounding and protecting factors as well as biological mechanisms with a possible role in adverse outcome in pregnant women with depression and anxiety disorders have received little attention. Conclusions. Enhanced levels of depression and anxiety symptoms during pregnancy contribute independently of other biomedical risk factors to adverse obstetric, fetal and neonatal outcome. However, conclusions for women with mood or anxiety disorders are limited.

Levels of plasma circulating cell free nuclear and mitochondrial DNA as potential biomarkers for breast tumors

BackgroundWith the aim to simplify cancer management, cancer research lately dedicated itself more and more to discover and develop non-invasive biomarkers. In this connection, circulating cell-free DNA (ccf DNA) seems to be a promising candidate. Altered levels of ccf nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) have been found in several cancer types and might have a diagnostic value.MethodsUsing multiplex real-time PCR we investigated the levels of ccf nDNA and mtDNA in plasma samples from patients with malignant and benign breast tumors, and from healthy controls. To evaluate the applicability of plasma ccf nDNA and mtDNA as a biomarker for distinguishing between the three study-groups we performed ROC (Receiver Operating Characteristic) curve analysis. We also compared the levels of both species in the cancer group with clinicopathological parameters.ResultsWhile the levels of ccf nDNA in the cancer group were significantly higher in comparison with the benign tumor group (P < 0.001) and the healthy control group (P < 0.001), the level of ccf mtDNA was found to be significantly lower in the two tumor-groups (benign: P < 0.001; malignant: P = 0.022). The level of ccf nDNA was also associated with tumor-size (<2 cm vs. >2 cm<5 cm; 2250 vs. 6658; Mann-Whitney-U-Test: P = 0.034). Using ROC curve analysis, we were able to distinguish between the breast cancer cases and the healthy controls using ccf nDNA as marker (cut-off: 1866 GE/ml; sensitivity: 81%; specificity: 69%; P < 0.001) and between the tumor group and the healthy controls using ccf mtDNA as marker (cut-off: 463282 GE/ml; sensitivity: 53%; specificity: 87%; P < 0.001).ConclusionOur data suggests that nuclear and mitochondrial ccf DNA have potential as biomarkers in breast tumor management. However, ccf nDNA shows greater promise regarding sensitivity and specificity.

Hypermethylation of Tumor Suppressor Genes Involved in Critical Regulatory Pathways for Developing a Blood-Based Test in Breast Cancer

Background Aberrant DNA methylation patterns might be used as a biomarker for diagnosis and management of cancer patients. Methods and Findings To achieve a gene panel for developing a breast cancer blood-based test we quantitatively assessed the DNA methylation proportion of 248 CpG sites per sample (total of 31,248 sites in all analyzed samples) on 10 candidate genes (APC, BIN1, BMP6, BRCA1, CST6, ESR-b, GSTP1, P16, P21 and TIMP3). The number of 126 samples consisting of two different cohorts was used (first cohort: plasma samples from breast cancer patients and normal controls; second cohort: triple matched samples including cancerous tissue, matched normal tissue and serum samples). In the first cohort, circulating cell free methylated DNA of the 8 tumor suppressor genes (TSGs) was significantly higher in patients with breast cancer compared to normal controls (P<0.01). In the second cohort containing triple matched samples, seven genes showed concordant hypermethylated profile in tumor tissue and serum samples compared to normal tissue (P<0.05). Using eight genes as a panel to develop a blood-based test for breast cancer, a sensitivity and specificity of more than 90% could be achieved in distinguishing between tumor and normal samples. Conclusions Our study suggests that the selected TSG panel combined with the high-throughput technology might be a useful tool to develop epigenetic based predictive and prognostic biomarker for breast cancer relying on pathologic methylation changes in tumor tissue, as well as in circulation.

Sexual Dysfunction after Premenopausal Stage I and II Breast Cancer: Do Androgens Play a Role?

INTRODUCTION Sexual dysfunction after breast cancer has been attributed to a variety of treatment associated and psychological factors. Data on the role of a treatment-induced decrease of testosterone for the development of sexual problems in breast cancer survivors have remained inconclusive. However, androgen metabolites constitute a more reliable measure for total androgen activity. AIM To measure levels of total androgen activity in breast cancer patients and to investigate relevant predictors of sexual dysfunction after breast cancer. METHODS Twenty-nine patients with a premenopausal diagnosis of Stage I or II breast cancer and terminated adjuvant treatment, completed questionnaires on sexuality, quality of relationship, body image, and depression. In addition, blood samples were taken for the analysis of sex steroids. MAIN OUTCOME MEASURES Female Sexual Function Index (FSFI), Relationship (PFB), Beck Depression Inventory, and European Organization for Research and Treatment of Cancer quality of life questionnaire. Analysis of dihydroepiandrosterone, dihydroepiandrosterone-sulfate, androstenedione, 17beta-diol, testosterone, dihydrotestosterone, androsterone, and ADT-G, 3-alpha-diol-3G, 3-alpha-diol-17G. RESULTS Low levels of sex steroids reflected the medication-induced postmenopausal status independent of the type of chemotherapy treatment. Sexual dysfunction was present in 68% of the study group. Women with a history of chemotherapy were more affected in all of the FSFI-domains. The only predictor for desire was quality of relationship, while chemotherapy was predictive for problems with arousal, lubrication, orgasm, and sexual pain. Sexual satisfaction and higher FSFI sum scores were predicted by better quality of relationship and no history of chemotherapy, together explaining 54.2% and 49.7% of the variance. CONCLUSIONS Sexual dysfunction after breast cancer is common and women should be informed properly at an early stage of treatment. Specific interventions have to be offered considering person-related preexisting factors and couples at risk should be supported in the transition to sexual life after breast cancer.

A Randomized, Double-Blind, Placebo-Controlled Study of Light Therapy for Antepartum Depression

OBJECTIVE Affective disorder during pregnancy is a common condition requiring careful judgment to treat the depression while minimizing risk to the fetus. Following up on promising pilot trials, we studied the efficacy of light therapy. METHOD Twenty-seven pregnant women with nonseasonal major depressive disorder according to DSM-IV (outpatients, university polyclinic) were randomly assigned to 7,000 lux fluorescent bright white or 70 lux dim red (placebo) light administered at home in the morning upon awakening for 1 h/d in a 5-week double-blind trial carried out between October 2004 and October 2008. Clinical state was monitored weekly with the 29-item Structured Interview Guide for the Hamilton Depression Rating Scale (HDRS) with Atypical Depression Supplement (SIGH-ADS). Changes of rating scale scores over time were analyzed with the general linear model. Differences from baseline of SIGH-ADS and 17-item HDRS scores at every time point were the dependent variables, time was the within-subjects factor, and treatment was the between-subjects factor. The model also included baseline score of depression and gestational age at intervention start. RESULTS The superiority of bright light over dim light placebo was shown for both SIGH-ADS (R² = 0.251; F(3,23) = 3.91; P < .05) and HDRS (R² = 0.338; F(3,23) = 5.42; P < .01) when analyzing the week-by-week change from baseline, and HDRS scores showed a significant interaction of treatment with time (F(4,92) = 2.91; P < .05). Categorical analysis revealed that the response rate (HDRS ≥ 50% improvement) at week 5 was significantly greater for bright light (81.3%, n = 16) than for placebo light (45.5%, n = 11) (P < .05). Remission (final score ≤ 8) was attained by 68.6% versus 36.4%, respectively (P < .05). Expectation ratings did not differ significantly between groups. CONCLUSIONS Bright white light treatment for 5 weeks improved depression during pregnancy significantly more than placebo dim red light. The study provides evidence that light therapy, a simple, cost-effective antidepressant modality with minimal side effects for the mother and no known risk for the unborn child, may be a useful nonpharmacologic approach in this difficult situation. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01043289.

Prevalence of Sexual Dysfunction and Impact of Contraception in Female German Medical Students

INTRODUCTION Female sexual dysfunction (FSD) is a very common disorder, with an estimated prevalence of having at least one sexual dysfunction of about 40%. AIM To investigate the prevalence and types of FSD and the relationship between hormonal contraception (HC) and FSD in female German medical students. MAIN OUTCOME MEASURES Female Sexual Function Index (FSFI) with additional questions on contraception, sexual activity, and other factors that may influence sexual function. METHODS An online questionnaire based on the FSFI was completed by students from six medical schools. Obtained data were screened for inconsistencies by programmed algorithms. RESULTS A total of 1,219 completed questionnaires were received, and 1,086 were included in the analyses after screening. The mean total FSFI score was 28.6 +/- 4.5. 32.4% of women were at risk for FSD according to FSFI definitions. Based on domain scores, 8.7% for were at risk for FSD concerning orgasm, 5.8% for desire, 2.6% for satisfaction, 1.2% for lubrication, 1.1% for pain and 1.0% for arousal. The method of contraception and smoking were factors with significant effect on the total FSFI score whereby hormonal contraception was associated with lower total FSFI scores and lower desire and arousal scores than no contraception and non-hormonal contraception only. Other variables such as stress, pregnancy, smoking, relationship and wish for children had an important impact on sexual function as expected according to earlier studies. CONCLUSIONS The prevalence of students at high risk for FSD was consistent with the literature although domain subscores differed from samples previously described. The contraception method has a significant effect on the sexual functioning score and women using contraception, especially hormonal contraception, had lower sexual functioning scores. Stress and relationship among other variables were found to be associated with sexual function and may thus provide insight into the etiology of sexual disorders.

Effects of relaxation on psychobiological wellbeing during pregnancy: A randomized controlled trial

Prenatal maternal stress is associated with adverse birth outcomes and may be reduced by relaxation exercises. The aim of the present study was to compare the immediate effects of two active and one passive 10-min relaxation technique on perceived and physiological indicators of relaxation. 39 healthy pregnant women recruited at the outpatient department of the University Womens Hospital Basel participated in a randomized controlled trial with an experimental repeated measure design. Participants were assigned to one of two active relaxation techniques, progressive muscle relaxation (PMR) or guided imagery (GI), or a passive relaxation control condition. Self-reported relaxation on a visual analogue scale (VAS) and state anxiety (STAI-S), endocrine parameters indicating hypothalamic-pituitary-adrenal (HPA) axis (cortisol and ACTH) and sympathetic-adrenal-medullary (SAM) system activity (norepinephrine and epinephrine), as well as cardiovascular responses (heart rate, systolic and diastolic blood pressure) were measured at four time points before and after the relaxation exercise. Between group differences showed, that compared to the PMR and control conditions, GI was significantly more effective in enhancing levels of relaxation and together with PMR, GI was associated with a significant decrease in heart rate. Within the groups, passive as well as active relaxation procedures were associated with a decline in endocrine measures except epinephrine. Taken together, these data indicate that different types of relaxation had differential effects on various psychological and biological stress systems. GI was especially effective in inducing self-reported relaxation in pregnant women while at the same time reducing cardiovascular activity.

Efficacy and safety of a novel oral contraceptive based on oestradiol (oestradiol valerate/dienogest) : a Phase III trial

OBJECTIVE A novel oral contraceptive (OC) that contains oestradiol valerate (E2V; 1 mg of E2V is equivalent to 0.76 mg of 17beta-oestradiol) and dienogest (DNG) has been developed. The efficacy and safety of this formulation was assessed in the current study. STUDY DESIGN This was a multicentre, open-label, non-comparative, 20-cycle study conducted in Germany, Austria and Spain in healthy women aged 18-50 years. E2V/DNG was administered using an oestrogen step-down and a progestin step-up approach over 26 days (E2V 3 mg on days 1 and 2, E2V 2 mg/DNG 2 mg on days 3-7, E2V 2 mg/DNG 3 mg on days 8-24, E2V 1 mg on days 25 and 26 and placebo on days 27 and 28). The primary outcome measure was the number of pregnancies during treatment in the whole study population and in the subgroup of women aged 18-35 years. Contraceptive efficacy was estimated by calculating the Pearl Index (number of pregnancies per 100 women-years of exposure). At a final examination, treatment satisfaction was assessed. RESULTS In total, 1377 women received study treatment. During the study, thirteen pregnancies occurred (unadjusted Pearl Index: 0.73). Six of these were due to method failure (adjusted Pearl Index: 0.34). In the subgroup of 998 women aged 18-35 years, 12 pregnancies occurred (unadjusted Pearl Index: 0.94), five of which were due to method failure (adjusted Pearl Index: 0.40). The majority of women (79.5%) were satisfied or very satisfied with treatment. Treatment-related adverse events (considered at least possibly treatment-related) occurred in 19.8% of women. Overall, during 20 cycles of treatment, only 10.2% of women prematurely discontinued treatment due to an adverse event. CONCLUSIONS A novel OC based on oestradiol provides highly effective and reliable contraception. This is achieved through the combination of oestradiol valerate (E2V) and dienogest (DNG) administered using an oestrogen step-down and a progestin step-up approach over 26 days of active treatment followed by 2 days of placebo. The preparation is well tolerated and is associated with a high degree of user satisfaction and a low discontinuation rate.

Questionnaires for assessment of female sexual dysfunction: a review and proposal for a standardized screener.

INTRODUCTION There are many methods to evaluate female sexual function and dysfunction (FSD) in clinical and research settings, including questionnaires, structured interviews, and detailed case histories. Of these, questionnaires have become an easy first choice to screen individuals into different categories of FSD. AIM The aim of this study was to review the strengths and weaknesses of different questionnaires currently available to assess different dimensions of womens sexual function and dysfunction, and to suggest a simple screener for FSD. METHODS A literature search of relevant databases, books, and articles in journals was used to identify questionnaires that have been used in basic or epidemiological research, clinical trials, or in clinical settings. MAIN OUTCOME MEASURE Measures were grouped in four levels based on their purposes and degree of development, and were reviewed for their psychometric properties and utility in clinical or research settings. A Sexual Complaints Screener for Women (SCS-W) was then proposed based on epidemiological methods. RESULTS Although many questionnaires are adequate for their own purposes, our review revealed a serious lack of standardized, internationally (culturally) acceptable questionnaires that are truly epidemiologically validated in general populations and that can be used to assess FSD in women with or without a partner and independent of the partners gender. The SCS-W is proposed as a 10-item screener to aid clinicians in making a preliminary assessment of FSD. CONCLUSIONS The definition of FSD continues to change and basic screening tools are essential to help advance clinical diagnosis and treatment, or to slate patients adequately into the right diagnostic categories for basic and epidemiological research or clinical trials.

Current issues and available options in combined hormonal contraception

Development of hormonal contraception marked a revolutionary step in social change that has improved the lives of women and families worldwide. Since the first oral contraceptive was introduced in the 1960s, hormonal contraception has undergone various stages of advancement. Today, oral contraceptive regimens are safer and more tolerable, with equal or improved efficacy, than the early formulations. Incremental decreases in the dose of estrogens have helped to alleviate some of the unwanted estrogenic side effects of combined hormonal contraceptives. Progestogens have also evolved over time, and newer generations of progestins have minimal side effects. New delivery methods have further extended the range of options available to women. Among these, the transdermal patch and vaginal ring are widely used. This review examines available combined hormonal contraceptive options and compares them, where data are available, for efficacy, safety, cycle control, adverse events profiles and associated risks, and user preference and satisfaction. We also examine particular areas of interest, including bone mineral density, venous thrombosis and use of antiepileptic drugs.