POLYCYSTIC OVARY SYNDROME COAGULATION AND METABOLIC STUDIES

The polycystic ovary syndrome (PCOS) is a heterogeneous disorder in women characterised by chronic ovulatory failure, hyperandrogenaemia, and insulin resistance. Some women are completely asymptomatic and others present with extreme menstrual disturbance, severe hirsutism, infertility and recurrent miscarriage. The pathophysiology of PCOS is not completely understood, but it is thought that insulin resistance plays a central role. In normal subjects, non-diabetic obese patients and patients with non-insulin dependent diabetes, insulin resistance is associated with elevated plasminogen activator inhibitor-1 (PAI-1) levels. PAI-1 is a glycoprotein, which inhibits the formation of plasmin (a proteolytic enzyme). Plasmin aids fibrinolysis and extracellular proteolysis. High PAI-1 and low plasmin levels increase the risk of thrombosis and impair extracellular proteolysis required in ovarian follicle growth, ovulation and embryo implantation. This study was designed to determine whether elevated plasminogen activator inhibitor-1 (PAI-1) was associated with the insulin resistance present in PCOS, investigate its possible role in the causation of anovulation and recurrent pregnancy loss in these women and ascertain whether it was an additional thrombotic risk factor so that clinicians and patients could take appropriate measures to reduce this risk In a pilot study, systemic PAI-1 activity was significantly elevated in oligomenorrhoiec women with PCOS. A larger study supported these findings, but demonstrated that obesity was a significant confounding factor, as the increase in PAI-1activity disappeared when standardised for weight. Activated Protein-C (APC) resistance was subsequently tested in these women because of the unexpected finding of an increased prevalence of a positive family history of thrombosis in women with PCOS compared with controls, but there was no increase in the prevalence of APC-resistance in PCOS. In another project, the cellular distribution of PAI-1 protein in human ovaries was described for the first time using immunohistochemistry. It was localised to the granulosa and theca cell compartments in both polycystic and normal ovaries, however there was no significant difference in the intensity of PAI-l staining between both groups on image analysis. PAI-1 messenger RNA expression was also evaluated in these biopsies by in-situ hybridisation, but no signal was detected suggesting that there was either a low overall RNA preservation in the tissues, or an insufficient sensitivity of the cocktail of oligonucleotide probes used. This study did not support the hypothesis that elevated PAI-1 was a feature of PCOS, however the in-situ location of PAI-1 protein was demonstrated for the first time in the human ovary and consistent with a previously suspected role in ovulation. The results did not support a role for PAI-1 in anovulation, recurrent miscarriage or increased thrombosis in PCOS

Overlap of proteomics biomarkers between women with pre-eclampsia and PCOS: a systematic review and biomarker database integration

Study question: Do any proteomic biomarkers previously identified for pre-eclampsia (PE) overlap with those identified in women with polycystic ovary syndrome (PCOS). Summary answer: Five previously identified proteomic biomarkers were found to be common in women with PE and PCOS when compared with controls. What is known already: Various studies have indicated an association between PCOS and PE; however, the pathophysiological mechanisms supporting this association are not known. Study design, size, duration: A systematic review and update of our PCOS proteomic biomarker database was performed, along with a parallel review of PE biomarkers. The study included papers from 1980 to December 2013. Participants/materials, setting, methods: In all the studies analysed, there were a total of 1423 patients and controls. The number of proteomic biomarkers that were catalogued for PE was 192. Main results and the role of chance: Five proteomic biomarkers were shown to be differentially expressed in women with PE and PCOS when compared with controls: transferrin, fibrinogen a, b and g chain variants, kininogen-1, annexin 2 and peroxiredoxin 2. In PE, the biomarkers were identified in serum, plasma and placenta and in PCOS, the biomarkers were identified in serum, follicular fluid, and ovarian and omental biopsies. Limitations, reasons for caution: The techniques employed to detect proteomics have limited ability in identifying proteins that are of low abundance, some of which may have a diagnostic potential. The sample sizes and number of biomarkers identified from these studies do not exclude the risk of false positives, a limitation of all biomarker studies. The biomarkers common to PE and PCOS were identified from proteomic analyses of different tissues. Wider implications of the findings: This data amalgamation of the proteomic studies in PE and in PCOS, for the first time, discovered a panel of five biomarkers for PE which are common to women with PCOS, including transferrin, fibrinogen a, b and g chain variants, kininogen-1, annexin 2 and peroxiredoxin 2. If validated, these biomarkers could provide a useful framework for the knowledge infrastructure in this area. To accomplish this goal, a well co-ordinated multidisciplinary collaboration of clinicians, basic scientists and mathematicians is vital

A systematic review of the literature describing the outcomes of near-peer mentoring programs for first year medical students

BackgroundTransition into higher education has been identified as one of the most stressful periods for learners. Interventions targeting the transition phase such as near- peer mentoring might help address some of these challenges. We were however unable to identify a published systematic review of the literature describing outcomes of near-peer mentoring of medical students during the transition phase into medical school. The aim of this paper is to review the literature and describe the outcomes of near-peer mentoring schemes for first-year medical students in the transition phase.MethodsA search of different electronic databases was carried out, using the search terms peer, buddy, mentor*, counsel*, advise*, tutor*, student, medical, school. 1861 articles were identified, however only 5 studies met the inclusion criteria- primary mentees should be first-years, and mentors must be inclusive of second-years but not limited to them. In reporting this paper, the PRISMA guidelines were followed.ResultsPublished material on near-peer mentoring for medical students is scarce. Three outcomes for peer mentoring were identified- professional and personal development, stress reduction, and ease of transitioning. Incidentally, peer-mentoring was also found to have facilitated the development of personal and professional attitudes in the mentors. The quality of the evaluation methods in the studies was however low to moderate.ConclusionNear-peer-mentoring is a way of promoting professional and personal development. It is also promising to aid transition and maintain well-being of first-year medical students. However, larger, better quality longitudinal studies, are needed to ascertain its true value for these students

Evaluating an obstetrics and gynecology teaching program for medical students incorporating simulation-based education underpinned by cognitive load theory

Although there have been previous publications on curriculum innovations in teaching O&G to medical students, especially utilizing simulation-based education, there have been none, as far as we know, incorporating and evaluating the outcomes using cognitive load theory. The aim of this article was to describe the introduction, implementation, and evaluation of an innovative teaching program in O&G, incorporating simulation-based education, underpinned by cognitive load theory. Cognitive load is defined as the amount of information a working memory can hold at any one time and incorporates three types of cognitive load—intrinsic, extraneous, and germane. To optimize learning, educators are encouraged to manage intrinsic cognitive load, minimize extraneous cognitive load, and promote germane cognitive load. In these sessions, students were encouraged to prepare in advance of each session with recommended reading materials; to limit intrinsic cognitive load and promote germane cognitive load, faculty were advised ahead of each session to manage intrinsic cognitive load, an open-book MCQ practice session aimed to reduce anxiety, promote psychological safety, and minimize extraneous cognitive load. For the simulation sessions, the faculty initially demonstrated the role-play situation or clinical skill first, to manage intrinsic cognitive load and reduce extraneous cognitive load. The results of the evaluation showed that the students perceived that they invested relatively low mental effort in understanding the topics, theories, concepts, and definitions discussed during the sessions. There was a low extraneous cognitive load. Measures of germane cognitive load or self-perceived learning were high. The primary message is that we believe this teaching program is a model that other medical schools globally might want to consider adopting, to evaluate and justify innovations in the teaching of O&G to medical students. The secondary message is that evaluation of innovations to teaching and facilitation of learning using cognitive load theory is one way to contribute to the high-quality training of competent future healthcare workers required to provide the highest standard of care to women who are crucial to the overall health and wellbeing of a nation

Evaluating the impact of the reconfiguration of gynaecology services at a University Hospital NHS trust in the United Kingdom

Background: The project aim was to investigate the impact of reconfiguring gynaecology services on the keyperformance indicators of a University Hospital NHS Trust in the UK. The reconfiguration involved the centralisationof elective gynaecology on one hospital site and emergency gynaecology on the other.Methods: Data measuring outcomes of the Trust’s performance indicators (clinical outcomes, patient experience,staff satisfaction, teaching/training, research/development and value for money) were collected. Two time periods,12 months before and after the reconfiguration in March 2011, were compared for all outcome measures exceptpatient experience. Retrospective data from the hospitals audit department on clinical activity/outcomes andemergency gynaecology patient’s feedback questionnaires were analysed. Staff satisfaction, teaching/training andresearch/development were measured through an online survey of gynaecology consultants.Results: Post reconfiguration, the total number of admissions reduced by 6% (6,867 vs 6,446). There was a 14%increase in elective theatre sessions available (902.29 vs 1030.57) and an 84% increase in elective theatre sessionscancelled (44.43 vs 81.71). However, the average number of elective operations performed during each theatresession remained similar (2.63 vs 2.5). There was a significant increase in medical devices related clinical incidents(2 vs 11). With patient experience, there was a significant reduction in patient’s overall length of stay on theemergency gynaecology ward and waiting times for investigations. For staff satisfaction, Consultants weresignificantly more dissatisfied with workload (3.45 vs 2.85) and standards of care (3.75 vs 2.93). With research anddevelopment, consultants remained dissatisfied with time/funding/opportunities for research. No significantimpact on undergraduate/postgraduate teaching was found. No financial data on gynaecology was provided forthe assessment of value for money.Conclusions: Reconfiguration of gynaecology services at this Trust may have resulted in a reduction ingynaecological activity and increased cancellation of elective operations but did not significantly reduce thenumber of elective operations performed. Although consultants expressed increased dissatisfaction withstandards of clinical care, clinical incident reports did not significantly increase apart from medical devicesincidents. Patient experience of emergency gynaecology services was improved. This manuscript provides aframework for similar exercises evaluating the impact of service redesign in the NHS

Up-regulation of genes involved in the Insulin signaling pathway (IGF1, PTEN and IGFBP1) in the endometrium may link Polycystic Ovarian Syndrome and endometrial cancer

BACKGROUND Endometrial cancer (EC) is the most common gynaecological cancer amongst women in the UK. Although previous studies have found that women with polycystic ovary syndrome (PCOS) have at least a three-fold increase in endometrial cancer (EC) risk compared to women without PCOS, the precise molecular mechanisms which link between PCOS and EC remain unclear. It has been suggested that insulin resistance may contribute to the increased risk of EC in PCOS. The specific expression of genes related to the insulin-signalling pathway including the IGF system in the endometrium of women with PCOS has however never been measured and compared to that in women with EC without PCOS and control women without EC or PCOS. . OBJECTIVES To test the hypothesis that insulin signaling plays a key role in the development of EC in women with PCOS by measuring and comparing the expression of three key genes involved in the insulin signaling pathway (IGF1, PTEN and IGFBP1) in endometrial tissue obtained from three groups of women; PCOS without EC, women with EC without PCOS and non-PCOS women without EC (controls). We also aimed to determine the correlation between the gene expressions to various clinical variables among participants. METHODS This was a cross-sectional study of 102 women in 3 groups (PCOS, EC and controls) at a University teaching hospital in the United Kingdom. Clinical assessment (blood pressure, body mass index (BMI) and waist-hip-circumference ratio), venepuntures (fasting blood sugar, insulin, lipid profile, hormones) and endometrial tissue biopsies were taken in all participants. Endometrial tissue RNA extraction was performed before real time polymerase-chain-reaction for the genes of interest (IGF1, IGFBP1 and PTEN) was carried out. To compare the baseline characteristics of the study population, One-Way-ANOVA test or the Independent t-test was used. For variables that were not normally distributed, the Spearman correlation test was used to calculate the r value. A "p" value of <0.05 was considered statistically significant. RESULTS IGF1, IGFBP1 and PTEN gene expression were significantly up-regulated in the endometrium of PCOS and EC women compared to controls. However there was no significant difference in the expression of these genes in PCOS compared to EC endometrium. The BMI of women with PCOS and controls, were not significantly different (29.28 (±2.91) vs 28.58 (±2.62) kg/m(2)) respectively, women with EC however had a higher mean BMI (32.22 (±5.70) kg/m(2)). PCOS women were younger (31.8 (±5.97) years) than women with EC (63.44 (±10.07) years) and controls (43.68 (±13.12) years). The changes in gene expression were independent of BMI, waist hip ratio, estradiol and androgen levels. Protein validation test in the serum samples in the three groups were consistent with the gene findings. CONCLUSION Women with PCOS and EC have an increased endometrial expression of genes (IGF1, IGFBP1 and PTEN) involved in the insulin signaling pathway compared with control women. This may explain the increased risk of EC in PCOS women. This study provides a strong basis for clinical trials aiming to prevent EC in women with PCOS by investigating drugs targeting the insulin signaling pathway. This panel of genes may also serve as clinically useful early biomarkers which predict which women with PCOS will go on to develop EC

Vibrational Biospectroscopy: An Alternative Approach to Endometrial Cancer Diagnosis and Screening

Endometrial cancer (EC) is the sixth most common cancer and the fourth leading cause of death among women worldwide. Early detection and treatment are associated with a favourable prognosis and reduction in mortality. Unlike other common cancers, however, screening strategies lack the required sensitivity, specificity and accuracy to be successfully implemented in clinical practice and current diagnostic approaches are invasive, costly and time consuming. Such limitations highlight the unmet need to develop diagnostic and screening alternatives for EC, which should be accurate, rapid, minimally invasive and cost-effective. Vibrational spectroscopic techniques, Mid-Infrared Absorption Spectroscopy and Raman, exploit the atomic vibrational absorption induced by interaction of light and a biological sample, to generate a unique spectral response: a “biochemical fingerprint”. These are non-destructive techniques and, combined with multivariate statistical analysis, have been shown over the last decade to provide discrimination between cancerous and healthy samples, demonstrating a promising role in both cancer screening and diagnosis. The aim of this review is to collate available evidence, in order to provide insight into the present status of the application of vibrational biospectroscopy in endometrial cancer diagnosis and screening, and to assess future prospects

Metformin for endometrial hyperplasia (Review)

Background Endometrial cancer is one of the most common gynaecological cancers in the world. Rates of endometrial cancer are rising, in part because of rising obesity rates. Endometrial hyperplasia is a precancerous condition in women that can lead to endometrial cancer if left untreated. Endometrial hyperplasia occurs more commonly than endometrial cancer. Progesterone tablets currently used to treat women with endometrial hyperplasia are associated with adverse effects in up to 84% of women. The levonorgestrel intrauterine device (Mirena Coil, Bayer HealthCare Pharmaceuticals, Inc., Whippany, NJ, USA) may improve compliance, but it is invasive, is not acceptable to all women, and is associated with irregular vaginal bleeding in 82% of cases. Therefore, an alternative treatment for women with endometrial hyperplasia is needed. Metformin, a drug that is often used to treat people with diabetes, has been shown in some human studies to reverse endometrial hyperplasia. However, the effectiveness and safety of metformin for treatment of endometrial hyperplasia remain uncertain. Objectives To determine the effectiveness and safety of metformin in treating women with endometrial hyperplasia. Search methods We searched the Cochrane Gynaecology and Fertility Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL),MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PubMed, Google Scholar,OpenGrey, Latin American Caribbean Health Sciences Literature (LILACS), and two trials registers from inception to 10 January 2017. We searched the bibliographies of all included studies and reviews on this topic. We also handsearched the conference abstracts of the European Society of Human Reproduction and Embryology (ESHRE) 2015 and the American Society for Reproductive Medicine (ASRM) 2015. Selection criteria We included randomised controlled trials (RCTs) and cross-over trials comparing metformin (used alone or in combination with other medical therapies) versus placebo or no treatment, any conventional medical treatment, or any other active intervention for women with histologically confirmed endometrial hyperplasia of any type. Data collection and analysis Two review authors independently assessed studies for eligibility, extracted data from included studies, and assessed the risk of bias of included studies. We resolved disagreements by discussion or by deferment to a third review author. When study details were missing, review authors contacted study authors. The primary outcome of this review was regression of endometrial hyperplasia histology (with or without atypia) towards normal histology. Secondary outcome measures included recurrence of endometrial hyperplasia, progression of endometrial hyperplasia to endometrial cancer, hysterectomy rate, abnormal uterine bleeding, health-related quality of life, and adverse effects during treatment. Main results We included three RCTs in which a total of 77 women took part. We rated the quality of the evidence as very low for all outcomes owing to very serious risk of bias (associated with poor reporting, attrition, and limitations in study design) and imprecision. We performed a meta-analysis of two trials with 59 participants. When metformin was compared with megestrol acetate in women with endometrial hyperplasia, we found insufficient evidence to determine whether there were differences between groups for the following outcomes: regression of endometrial hyperplasia histology towards normal histology (odds ratio (OR) 3.34, 95% confidence interval (CI) 0.97 to 11.57, two RCTs, n = 59, very low-quality evidence), hysterectomy rates (OR 0.91, 95% CI 0.05 to 15.52, two RCTs, n = 59, very low-quality evidence), and rates of abnormal uterine bleeding (OR 0.91, 95% CI 0.05 to 15.52, two RCTs, n = 44 , very low quality evidence). We found no data for recurrence of endometrial hyperplasia or health-related quality of life. Both studies (n = 59)provided data on progression of endometrial hyperplasia to endometrial cancer as well as one (n = 16) reporting some adverse effects in the metformin arm, notably nausea, thrombosis, lactic acidosis, abnormal liver and renal function among others. Another trial including 16 participants compared metformin plus megestrol acetate versus megestrol acetate alone in women with endometrial hyperplasia. We found insufficient evidence to determine whether there were differences between groups for the following outcomes: regression of endometrial hyperplasia histology towards normal histology (OR 9.00, 95% CI 0.94 to 86.52, one RCT, n = 16, very low-quality evidence), recurrence of endometrial hyperplasia among women who achieve regression (OR not estimable, no events recorded, one RCT, n = 8, very low-quality evidence), progression of endometrial hyperplasia to endometrial cancer (OR not estimable, no events recorded, one RCT, n = 13, very low-quality evidence), or hysterectomy rates (OR 0.29, 95% CI 0.01 to 8.37,one RCT, n = 16, very low-quality evidence). Investigators provided no data on abnormal uterine bleeding or health-related quality of life. In terms of adverse effects, three of eight participants (37.5%) in the metformin plus megestrol acetate study arm reported nausea. Authors’ conclusions At present, evidence is insufficient to support or refute the use of metformin alone or in combination with standard therapy - specifically, megestrol acetate - versus megestrol acetate alone, for treatment of endometrial hyperplasia. Robustly designed and adequately powered randomised controlled trials yielding long-term outcome data are needed to address this clinical question

Lipidomic analysis of plasma samples from women with polycystic ovary syndrome

Abstract Polycystic ovary syndrome (PCOS) is a common disorder affecting between 5 and 18 % of females of reproductive age and can be diagnosed based on a combination of clinical, ultrasound and biochemical features, none of which on its own is diagnostic. A lipidomic approach using liquid chromatography coupled with accurate mass high-resolution mass-spectrometry (LCHRMS) was used to investigate if there were any differences in plasma lipidomic profiles in women with PCOS compared with control women at different stages of menstrual cycle. Plasma samples from 40 women with PCOS and 40 controls aged between 18 and 40 years were analysed in combination with multivariate statistical analyses. Multivariate data analysis (LASSO regression and OPLSDA) of the sample lipidomics datasets showed a weak prediction model for PCOS versus control samples from the follicular and mid-cycle phases of the menstrual cycle, but a stronger model (specificity 85 % and sensitivity 95 %) for PCOS versus the luteal phase menstrual cycle controls. The PCOS vs luteal phase model showed increased levels of plasma triglycerides and sphingomyelins and decreased levels of lysophosphatidylcholines and phosphatidylethanolamines in PCOS women compared with controls. Lipid biomarkers of PCOS were tentatively identified which may be useful in distinguishing PCOS from controls especially when performed during the menstrual cycle luteal phase

Evaluating compliance to a low glycaemic index (GI) diet in women with polycystic ovary syndrome (PCOS)

<p>Abstract</p> <p>Background</p> <p>A low Glycaemic Index (GI) diet may decrease some long-term health risks in Polycystic Ovary Syndrome (PCOS) such as endometrial cancer. This study was performed to assess compliance to a low GI diet in women with PCOS. Food diaries prospectively collected over 6 months from women on a low GI diet or healthy eating diet were analysed retrospectively. The women were recruited for a pilot randomised control trial investigating whether a low GI diet decreased the risk of Endometrial Cancer. Nine women with PCOS completed 33 food diaries (17 from women on a low GI diet and 16 from women on a healthy eating diet) recording 3023 food items (low GI group:n = 1457; healthy eating group:n = 1566). Data was analysed using Foster-Powell international values inserted into an SPSS database as no scientifically valid established nutrition software was found. The main outcome measures were mean item GI and Glyacemic Load (GL), mean meal GL, percentage high GI foods and mean weight loss.</p> <p>Findings</p> <p>Women allocated the low GI diet had a statistically significant lower GI of food items (33.67 vs 36.91, p < 0.05), lower percentage of high GI foods (4.3% vs 12.1%, p < 0.05) and lower GL of food items and meals.</p> <p>Conclusion</p> <p>Women with PCOS on a low GI diet consumed food items with a significantly lower mean GI and GL compared to the healthy eating diet group. Longer term compliance needs evaluation in subsequent studies to ascertain that this translates to reduced long term health risks.</p> <p>Trial Registration</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN86420258">ISRCTN86420258</a></p