Combining mammaglobin and carcinoembryonic mRNA markers for early detection of micrometastases from breast cancers - a molecular study of 59 patients

Introduction: As many as 30% of node-negative breast cancer patients relapse within five years, suggesting that current histological detection methods are inadequate for identifying metastatic disease. Detecting small number of cancer cells in the breast tissue or lymph node by reverse transcription-polymerase chain reaction (RT-PCR) assays using a combination of tissue and cancer specific markers might be very useful in the early detection or monitoring of the treatment. Mammaglobin is a member of the uteroglobin gene family and appears to be expressed only in breast tissue. Carcinoembryonic antigen has been the preferred molecular marker for detection of micro metastases in lymph nodes in almost all carcinomas. Materials and Methods: Samples were collected from randomly chosen breast cancer patients undergoing modified mastectomy or breast conserving surgery between September 2003 and July 2004. RT-PCR was applied to study the expression of MMG and CEA markers. Breast cancer micrometastases in axillary lymph nodes were also assessed. Results: The MMG marker was positive in 9/10 normal breast tissues, 3/ 3 breast fibroadenomas and 37/39 of breast carcinoma tissues, giving an overall sensitivity of 94%. The sensitivity was 80% for metastatic lymph node samples. On the other hand CEA showed 95% sensitivity for malignant breast tumors and 100% sensitivity for metastatic lymph nodes. Conclusions: RT-PCR using a combination of MMG and CEA markers is a powerful tool to complement current routine histopathology techniques for detection of breast cancer metastasis in axillary nodes

The effectiveness of high intensity intermittent training on metabolic, reproductive and mental health in women with polycystic ovary syndrome: study protocol for the iHIT- randomised controlled trial

Abstract Background Polycystic ovary syndrome (PCOS) is a reproductive-metabolic condition. Insulin resistance is a hallmark of PCOS and is related to increased hyperandrogenism that drives inherent metabolic, reproductive and psychological features of the syndrome. Insulin resistance in women with PCOS is managed by weight loss, lifestyle interventions (i.e. exercise, diet) and insulin-sensitising medications. This manuscript describes the protocol of our study evaluating the effectiveness of high intensity intermittent training (HIIT) or moderate intensity exercise on cardiometabolic, reproductive and mental health in overweight women with PCOS. Methods/design We will employ a three arm, parallel-group, randomised controlled trial recruiting 60 women diagnosed with PCOS, aged between 18 and 45 years and with a body mass index (BMI) greater than 25 kg/m2. Following screening and baseline testing, women will be randomised by simple randomisation procedure using computer generated sequence allocation to undergo one of two 12-week supervised interventions: either HIIT or moderate intensity exercise (standard supervised exercise), or to standard care [Con] (unsupervised lifestyle advice) at a 1:1:1 allocation ratio. The primary outcome for this trial is to measure the improvements in metabolic health; specifically changes in insulin sensitivity in response to different exercise intensities. Baseline and post-intervention testing include anthropometric measurements, cardiorespiratory fitness testing, reproductive hormone profiles (anti-müllerian hormone and steroid profiles), metabolic health, health-related quality of life and mental health questionnaires and objective and subjective lifestyle monitoring. Reporting of the study will follow the CONSORT statement. Discussion This trial aims to demonstrate the comparative efficacy and maintenance of different exercise intensities to advance the understanding of PCOS management and provide insight into the optimal exercise intensity for improved cardiometabolic outcomes. Secondary outcomes will include the impact of different exercise protocols on reproductive hormone profiles, mental health and health-related quality of life. Trial registration Australian New Zealand Clinical Trials Registry, ACTRN12615000242527. Registered on 17 March 2015

Efficacy of predictive models for polycystic ovary syndrome using serum levels of two antimullerian hormone isoforms (proAMH and AMHN,C)

Objective: To compare total antimüllerian hormone (AMH), proAMH, AMHN,C, and the ratio of the two forms in predictive models for polycystic ovary syndrome (PCOS) diagnosis. Total AMH consists of proAMH (inactive precursor) and AMHN,C (receptor-competent), but neither isoform has been tested individually for their ability to predict PCOS diagnosis. Design: Cross-sectional study using biobanked samples collected between July 2008 and January 2010. Setting: Not applicable. Patient(s): Overweight, premenopausal women aged 18-45 years with PCOS (n = 45, with 21 fulfilling National Institutes of Health diagnostic criteria and 24 fulfilling European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine (ESHRE) criteria, but not National Institutes of Health criteria) and without PCOS (n = 23 controls). Intervention(s): None. Main Outcome Measure(s): Serum concentrations of proAMH and total AMH (proAMH and AMHN,C combined) were determined by immunoassay. The AMHN,C concentrations were calculated by subtraction ([AMHN,C] = [total AMH] - [proAMH]). Relative levels of proAMH were expressed as the AMH prohormone index (API = [ProAMH]/[Total AMH] × 100). Result(s): In women with PCOS, total AMH, proAMH, and AMHN,C levels were higher, and the API was lower (P=.010), than in controls indicating increased conversion of proAMH to AMHN,C. Receiver-operating characteristic analysis for proAMH (area under the curve [AUC] = 0.82), AMHN,C (AUC = 0.86), and API (AUC = 0.70) did not improve the prediction for PCOS when compared with total AMH (AUC = 0.86). Conclusion(s): The proAMH and AMHN,C do not appear to improve the ability to predict a diagnosis of PCOS beyond total AMH assays. However, the ratio of inactive proAMH precursor to receptor-competent AMHN,C (API) differs in women with PCOS relative to unaffected controls indicating that AMH signaling mechanisms may be altered in women with PCOS.Michael W. Pankhurst, Soulmaz Shorakae, Raymond J. Rodgers, Helena J. Teede and Lisa J. Mora

The emerging role of chronic low-grade inflammation in the pathophysiology of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) has become increasingly common over recent years and is associated with reproductive features as well as cardiometabolic risk factors, including visceral obesity, dyslipidemia and impaired glucose homeostasis, and potentially cardiovascular disease. Emerging evidence suggests that these long-term metabolic effects are linked to a low-grade chronic inflammatory state with the triad of hyperinsulinemia, hyperandrogenism, and low-grade inflammation acting together in a vicious cycle in the pathophysiology of PCOS. Dysregulation of the sympathetic nervous system may also act as an important component, potentially creating a tetrad in the pathophysiology of PCOS. The aim of this review is to examine the role of chronic inflammation and the sympathetic nervous system in the development of obesity and PCOS and review potential therapeutic options to alleviate low-grade inflammation in this setting.Soulmaz Shorakae, Helena Teede, Barbora de Courten, Gavin Lambert, Jacqueline Boyle, Lisa J. Mora

Obesity and polycystic ovary syndrome

Obesity is now a major international health concern. It is increasingly common in young women with reproductive, metabolic and psychological health impacts. Reproductive health impacts are often poorly appreciated and include polycystic ovary syndrome (PCOS), infertility and pregnancy complications. PCOS is the most common endocrine condition in women and is underpinned by hormonal disturbances including insulin resistance and hyperandrogenism. Obesity exacerbates hormonal and clinical features of PCOS and women with PCOS appear at higher risk of obesity, with multiple underlying mechanisms linking the conditions. Lifestyle intervention is first line in management of PCOS to both prevent weight gain and induce weight loss; however improved engagement and sustainability remain challenges with the need for more research. Medications like metformin, orlistat, GLP1 agonists and bariatric surgery have been used with the need for large scale randomised clinical trials to define their roles.N. Naderpoor, S. Shorakae, A. Joham, J. Boyle, B. De Courten, H. J. Teed

Inter-related effects of insulin resistance, hyperandrogenism, sympathetic dysfunction and chronic inflammation in PCOS

OBJECTIVE:Insulin resistance, hyperandrogenism, sympathetic dysfunction and chronic low-grade inflammation may act together in a vicious cycle in the pathophysiology of PCOS. However, the inter-relationships of these components are not fully understood. We aimed to study these mechanisms in the pathophysiology of PCOS. PARTICIPANTS AND METHODS:Premenopausal women with PCOS (Rotterdam diagnostic criteria) and without PCOS were recruited from a community setting into a cross-sectional substudy within a randomized control trial. Insulin resistance (fasting insulin and glucose), hyperandrogenism (testosterone, sex hormone-binding globulin [SHBG] and Free Androgen Index [FAI]), muscle sympathetic nerve activity (MSNA) and markers of chronic low-grade inflammation (high sensitivity C-reactive protein [hs-CRP] and high molecular weight adiponectin [HMW-adiponectin]) were measured. RESULTS:Forty-nine women with PCOS (mean age 30 ± 6 mean BMI 29 ± 5) and 23 controls (mean age 29 ± 8 mean BMI 33 ± 7) with included in this analysis. MSNA and testosterone level were most significantly associated with PCOS status, after adjustment for age and BMI. In women with PCOS, markers of sympathetic activity correlated inversely with HMW-adiponectin and HMW-adiponectin correlated inversely with FAI. Testosterone and FAI both correlated positively with insulin resistance in women PCOS. CONCLUSION:Sympathetic dysfunction and hyperandrogenism are significantly associated with PCOS. Chronic low-grade inflammation potentially mediates the effect of sympathetic dysfunction on hyperandrogenism and insulin resistance.Soulmaz ­Shorakae, Sanjeeva­ Ranasinha, Sally­ Abell, Gavin­ Lambert, ­Elisabeth­ Lambert, Barbora­ de­ Courten, Helena ­Teed