Metformin for endometrial hyperplasia.

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 that are currently used to treat women with endometrial hyperplasia are associated with adverse effects in up to 84% of women. A levonorgestrel intrauterine device 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. This is an update of a review first published in 2017. 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, CENTRAL, MEDLINE, PubMed, Embase, Google Scholar, OpenGrey, LILACS, and two trials registers from inception to 5 September 2022. We searched the bibliographies of all relevant studies, and contacted experts in the field for any additional trials. 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, 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, assessed the risk of bias in the included studies, and assessed the certainty of the evidence for each outcome. We resolved disagreements by discussion or by deferring to a third review author. When study details were missing, review authors contacted the study authors. The primary outcome of this review was regression of endometrial hyperplasia histology (with or without atypia) towards normal histology. MAIN RESULTS: We included seven RCTs, in which a total of 387 women took part. In the comparison, Metformin plus megestrol versus megestrol alone, we rated the certainty of the evidence as low for the outcome, regression of endometrial hyperplasia. We rated the quality of the evidence as very low for the rest of the outcomes, in all three comparisons. Although there was a low risk of selection bias, there was a high risk of bias in the blinding of personnel and outcome assessment (performance bias and detection bias) in many studies. This update identified four new RCTs and six ongoing RCTs. Metformin versus megestrol We are uncertain whether metformin increases the regression of endometrial hyperplasia towards normal histology over megestrol (odds ratio (OR) 4.89, 95% confidence interval (CI) 1.56 to 15.32; P = 0.006; 2 RCTs, 83 participants; I² = 7%; very low-certainty evidence). This evidence suggests that if the rate of regression with megestrol is 61%, the rate of regression with metformin would be between 71% and 96%. It is unresolved whether metformin results in different rates of abnormal uterine bleeding or hysterectomy compared to megestrol. No study in this comparison reported progression of hyperplasia to endometrial cancer, recurrence of endometrial hyperplasia, health-related quality of life, or adverse effects during treatment. Metformin plus megestrol versus megestrol monotherapy The combination of metformin and megestrol may enhance the regression of endometrial hyperplasia towards normal histology more than megestrol alone (OR 3.27, 95% CI 1.65 to 6.51; P = 0.0007; 4 RCTs, 258 participants; I² = 0%, low-certainty evidence). This suggests that if the rate of regression with megestrol monotherapy is 54%, the rate of regression with the addition of metformin would be between 66% and 84%. In one study, 3/8 (37.5%) of participants who took metformin had nausea that settled without further treatment. It is unresolved whether the combination of metformin and megestrol results in different rates of recurrence of endometrial hyperplasia, progression of endometrial hyperplasia to endometrial cancer, or hysterectomy compared to megestrol monotherapy. No study in this comparison reported abnormal uterine bleeding, or health-related quality of life. Metformin plus levonorgestrel (intrauterine system) versus levonorgestrel (intrauterine system) monotherapy We are uncertain whether there is a difference between groups in the regression of endometrial hyperplasia towards normal histology (OR 0.29, 95% CI 0.01 to 7.56; 1 RCT, 46 participants; very low-certainty evidence). This evidence suggests that if the rate of regression with levonorgestrel monotherapy is 96%, the rate of regression with the addition of metformin would be between 73% and 100%. It is unresolved whether the combination of metformin and levonorgestrel results in different rates of abnormal uterine bleeding, hysterectomy, or the development of adverse effects during treatment compared to levonorgestrel monotherapy. No study in this comparison reported recurrence of endometrial hyperplasia, progression of hyperplasia to endometrial cancer, or health-related quality of life. AUTHORS' CONCLUSIONS: Review authors found insufficient evidence to either support or refute the use of metformin, specifically megestrol acetate, given alone or in combination with standard therapy, for the treatment of women with endometrial hyperplasia. Robustly designed and adequately powered randomised controlled trials, yielding long-term outcome data are still needed to address this clinical question.

Prevalence and Diagnosis of PCOS Using Electronic Health Records: A Scoping Review and a Database Analysis.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age. It increases the risk of type 2 diabetes, cardiovascular disease, endometrial cancer, infertility, gestational diabetes, preeclampsia, and preterm birth. Accurately identifying predictors of these health risks is crucial. Electronic health records (EHRs) offer an affordable approach, however, the validity and reliability of EHRs for PCOS diagnosis are unclear. A scoping review of the literature on the prevalence and reliability of the diagnosis of PCOS using EHRs was performed. An analysis of the feasibility of obtaining diagnostic variables from a PCOS patient database was also carried out. Eight studies met the criteria. The prevalence of PCOS ranged from 0.27% to 5.8%. Reliability varied, with one study reporting a sensitivity of 50% and a specificity of 29%. Another study found a 74.4% agreement between international classification of disease (ICD) codes and clinical criteria. The database analysis found only 13.7%, 8%, and 7.5% of women had all the necessary variables for an objective diagnosis of PCOS using the Rotterdam, National Institutes of Health (NIH), and Androgen Excess and PCOS Society (AEPCOS) criteria, respectively. Using EHRs results in an underestimation of PCOS prevalence compared to other diagnostic criteria, and many women identified may not meet the complete diagnostic criteria. These findings have implications for future research studies on PCOS prevalence and related health risks.

Deciphering the Role of Insulin-Like Growth Factor 1 in Endometrial Cancer in Patients With Polycystic Ovary Syndrome: Protocol for a Methodological Approach Using Cell Culture Experiments.

BACKGROUND: Endometrial cancer (EC) is the most common gynecological cancer in women globally. It is linked to increasing obesity rates and longer life spans. The molecular mechanisms leading to EC are unclear; however, women with polycystic ovary syndrome (PCOS) have a 3- to 5-fold increased EC risk. According to a pilot study conducted in the United Kingdom, insulin-like growth factor-1 (IGF-1) gene and protein were raised in the endometrium and blood of women with EC and PCOS, compared with those without PCOS (controls). Therefore, raised serum IGF-1 levels may contribute to an increased EC risk in women with PCOS, but it is necessary to test this hypothesis since not all studies have demonstrated this association. OBJECTIVE: This study aims to investigate the role of IGF-1 in mediating EC risk in PCOS. This will be achieved by evaluating the proliferative effects of PCOS serum, IGF-1, and IGF-1 antagonist on human endometrial cancer 1-A and 1-B cell lines, with a comparison to controls (using serum from women without PCOS and cell culture media). The study will also identify differentially expressed genes and pathways activated by various treatments. METHODS: We intend to recruit 20 women with PCOS and 20 women without PCOS for this cross-sectional study. All experiments will be carried out 4 times to ensure consistency. We will perform transcriptomic and phosphoproteomic profiling to identify differentially expressed genes and phosphoproteins between different treatments using RNA sequencing and phosphoproteomics. We will also perform bioinformatics pathway analysis to identify whether any unique collection of genes or phosphoproteins explains increased EC risk in PCOS. The primary outcome measure will be the cell proliferation (growth) difference measured by cell index values. Our protocol stands out due to its unique approach; no previous study has used this approach to investigate the oncogenic effect of serum from women with PCOS. Additionally, no previous study has considered the differential mutations of genes related to the insulin signaling pathway across various types of human EC cell lines and the potential impact of these variations on their experimental findings. RESULTS: Participants are currently being recruited. It is expected that preliminary findings suitable for analysis and publication will be available by the summer of 2024. CONCLUSIONS: Although we currently do not have any results to report, sharing our protocol at this stage will aid in research collaboration, provide an opportunity for early feedback, and help reduce duplication of effort by other research groups. The findings of our study will have broader implications. A deeper understanding of the mechanisms underlying the regulation of the IGF system in PCOS and EC will improve our ability to develop effective treatment modalities for EC and will be a vital step toward reducing EC in women globally. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/48127.

Transcriptomic analysis identifies four novel receptors potentially linking endometrial cancer with polycystic ovary syndrome and generates a transcriptomic atlas.

Polycystic Ovary Syndrome (PCOS) is associated with a 3 to 4-fold increased risk of endometrial cancer (EC), but molecular mechanisms are unclear. Upregulation of the IGF1 gene in PCOS endometrium may increase EC risk, but this is uncertain. We aimed to investigate links between EC and PCOS, by analysing publicly available transcriptomic data. The NCBI Gene Expression Omnibus was used to identify relevant studies. Differentially expressed genes (DEGs) were identified and analysed using Metascape to identify pathways of interest. PCOS DEGs that encode proteins secreted into blood were identified using the Human Protein Atlas blood protein database. EC DEGs that are cellular receptors were identified using EcoTyper. These were intersected to identify which EC receptors interact with PCOS secreted proteins. Seven receptors were identified in EC but only PTPRF, ITGA2, ITGA3 and ITGB4 genes were expressed on epithelial cells. Pathway enrichment of these genes showed that the major and common pathway involved was that of the PI3K-AKT signalling pathway which was consistent with a link between PCOS and EC. However, IGF1 was down regulated in PCOS and EC. These findings hold significant promise for improving our understanding of mechanistic pathways leading to EC in PCOS.

Obesity and female infertility.

Infertility is a significant global health issue, with a negative impact on people's wellbeing and human rights. Despite the longstanding association between obesity and infertility, there remains uncertainty, about the precise mechanisms underpinning this association and best management strategies. In this article, we aimed to address these uncertainties by reviewing the recent literature, and focusing on studies which evaluated live birth rates. We found that just over half of the studies, investigating the relationship between preconception maternal weight and live birth rates found an inverse correlation. There was, however, insufficient evidence, that preconception maternal lifestyle or pharmacological interventions in obese women with infertility, resulted in improved live birth rates. The implications for clinical practice and future research are highlighted. For example, the need to consider some flexibility in applying strict preconception body mass index targets, limiting access to fertility treatment, and a need for large clinical trials of new pharmacological options and bariatric surgery.

Prevalence of Polycystic Ovary Syndrome amongst Females Aged between 15 and 45 Years at a Major Women's Hospital in Dubai, United Arab Emirates.

Objective criteria have been scarce in published data on the occurrence of polycystic ovary syndrome (PCOS) in the United Arab Emirates (UAE). It is crucial that we enhance our comprehension of PCOS prevalence in the UAE to inform key stakeholders about the disease's burden and enable comparisons with other nations. This research aimed to examine the PCOS prevalence at a large academic tertiary centre in Dubai, UAE, called Latifa Women and Children's Hospital. We performed a cross-sectional study by reviewing the electronic medical records of patients accessing care between 2017 and 2022 (5 years). By utilizing the international classification of diseases codes (ICD-10), we discovered a period prevalence of PCOS of 1.6% among 64,722 women aged between 15 and 45 years. It is worth noting that the estimated annual point prevalence rose from 1.19% in 2020 (at the beginning of the COVID19 pandemic) to 2.72% in 2022 (after the start of the COVID-19 pandemic). Therefore, the odds ratio of the risk of a PCOS diagnosis in 2022 compared to 2020 was 2.28. The majority of the women diagnosed with PCOS in this study had an ICD-10 code of E28.2. Women with PCOS were younger than the controls, less likely to be pregnant, and had a higher body mass index and systolic and diastolic blood pressure. This is the most extensive research to date examining PCOS prevalence in the UAE, and it emphasizes the significance of this condition. It is crucial to prioritize PCOS to prevent morbidity and mortality from reproductive and long-term health consequences, including infertility, type 2 diabetes and endometrial cancer, which is presently the most frequent gynecological cancer in the UAE.

Polycystic Ovarian Syndrome (PCOS): Does the Challenge End at Conception?

Polycystic ovary syndrome (PCOS) is a prevalent condition that not only has the potential to impede conception but also represents the most common endocrine dysfunction in fertile women. It is considered a heterogeneous and multifaceted disorder, with multiple reproductive and metabolic phenotypes which differently affect the early- and long-term syndrome's risks. Undoubtedly, the impact of PCOS on infertility has attracted most of the attention of healthcare providers and investigators. However, there is growing evidence that even after conception is achieved, PCOS predisposes the parturient to several adverse pregnancy outcomes including a high risk of pregnancy-induced hypertension, spontaneous abortion, gestational diabetes, preeclampsia, and preterm birth, which increase the risks of stillbirth and neonatal death. Fetal growth abnormalities may also be more common, but the relationship is less well defined. This narrative review aims to summarize current knowledge regarding these conditions as they interplay with PCOS and concludes that although there appears to be an increase in these complications during the pregnancy of women with PCOS, there is a need for further research to clarify the possible confounding impact of obesity. Implications for clinical practice and future research are outlined.

Polycystic Ovary Syndrome and Endometrial Cancer: A Scoping Review of the Literature on Gut Microbiota.

Gut dysbiosis has been associated with polycystic ovary syndrome (PCOS) and endometrial cancer (EC) but no studies have investigated whether gut dysbiosis may explain the increased endometrial cancer risk in polycystic ovary syndrome. The aim of this scoping review is to evaluate the extent and nature of published studies on the gut microbiota in polycystic ovary syndrome and endometrial cancer and attempt to find any similarities between the composition of the microbiota. We searched for publications ranging from the years 2016 to 2022, due to the completion date of the 'Human Microbiome Project' in 2016. We obtained 200 articles by inputting keywords such as 'gut microbiome', 'gut microbiota', 'gut dysbiosis', 'PCOS', and 'endometrial cancer' into search engines such as PubMed and Scopus. Of the 200 identified in our initial search, we included 25 articles in our final review after applying the exclusion and inclusion criteria. Although the literature is growing in this field, we did not identify enough published studies to investigate whether gut dysbiosis may explain the increased EC risk in PCOS. Within the studies identified, we were unable to identify any consistent patterns of the microbiome similarly present in studies on women with PCOS compared with women with EC. Although we found that the phylum Firmicutes was similarly decreased in women with PCOS and studies on women with EC, there was however significant variability within the studies identified making it highly likely that this may have arisen by chance. Further research pertaining to molecular and microbiological mechanisms in relation to the gut microbiome is needed to elucidate a greater understanding of its contribution to the pathophysiology of endometrial cancer in patients with polycystic ovarian syndrome.

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.

Coenzyme A Restriction as a Factor Underlying Pre-Eclampsia with Polycystic Ovary Syndrome as a Risk Factor.

Pre-eclampsia is the most common pregnancy complication affecting 1 in 20 pregnancies, characterized by high blood pressure and signs of organ damage, most often to the liver and kidneys. Metabolic network analysis of published lipidomic data points to a shortage of Coenzyme A (CoA). Gene expression profile data reveal alterations to many areas of metabolism and, crucially, to conflicting cellular regulatory mechanisms arising from the overproduction of signalling lipids driven by CoA limitation. Adverse feedback loops appear, forming sphingosine-1-phosphate (a cause of hypertension, hypoxia and inflammation), cytotoxic isoketovaleric acid (inducing acidosis and organ damage) and a thrombogenic lysophosphatidyl serine. These also induce mitochondrial and oxidative stress, leading to untimely apoptosis, which is possibly the cause of CoA restriction. This work provides a molecular basis for the signs of pre-eclampsia, why polycystic ovary syndrome is a risk factor and what might be done to treat and reduce the risk of disease.

Lipidomic Biomarkers in Polycystic Ovary Syndrome and Endometrial Cancer.

Women with polycystic ovary syndrome (PCOS) are more likely to develop endometrial cancer (EC). The molecular mechanisms which increase the risk of EC in PCOS are unclear. Derangements in lipid metabolism are associated with EC, but there have been no studies, investigating if this might increase the risk of EC in PCOS. This was a cross-sectional study of 102 women in three groups of 34 (PCOS, EC and controls) at Nottingham University Hospital, UK. All participants had clinical assessments, followed by obtaining plasma and endometrial tissue samples. Lipidomic analyses were performed using liquid chromatography (LC) coupled with high resolution mass spectrometry (HRMS) and the obtained lipid datasets were screened using standard software and databases. Using multivariate data analysis, there were no common markers found for EC and PCOS. However, on univariate analyses, both PCOS and EC endometrial tissue samples showed a significant decrease in monoacylglycerol 24:0 and capric acid compared to controls. Further studies are required to validate these findings and investigate the potential role of monoacylglycerol 24:0 and capric acid in the link between PCOS with EC.

Metformin for endometrial hyperplasia.

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.

Expression of NAD(P)H quinone dehydrogenase 1 (NQO1) is increased in the endometrium of women with endometrial cancer and women with polycystic ovary syndrome.

OBJECTIVE: Women with a prior history of polycystic ovary syndrome (PCOS) have an increased risk of endometrial cancer (EC). AIM: To investigate whether the endometrium of women with PCOS possesses gene expression changes similar to those found in EC. DESIGN AND METHODS: Patients with EC, PCOS and control women unaffected by either PCOS or EC were recruited into a cross-sectional study at the Nottingham University Hospital, UK. For RNA sequencing, representative individual endometrial biopsies were obtained from women with EC, PCOS and a woman unaffected by PCOS or EC. Expression of a subset of differentially expressed genes identified by RNA sequencing, including NAD(P)H quinone dehydrogenase 1 (NQO1), was validated by quantitative reverse transcriptase PCR validation (n = 76) and in the cancer genome atlas UCEC (uterine corpus endometrioid carcinoma) RNA sequencing data set (n = 381). The expression of NQO1 was validated by immunohistochemistry in EC samples from a separate cohort (n = 91) comprised of consecutive patients who underwent hysterectomy at St Mary's Hospital, Manchester, between 2011 and 2013. A further 6 postmenopausal women with histologically normal endometrium who underwent hysterectomy for genital prolapse were also included. Informed consent and local ethics approval were obtained for the study. RESULTS: We show for the first that NQO1 expression is significantly increased in the endometrium of women with PCOS and EC. Immunohistochemistry confirms significantly increased NQO1 protein expression in EC relative to nonmalignant endometrial tissue (P < .0001). CONCLUSIONS: The results obtained here support a previously unrecognized molecular link between PCOS and EC involving NQO1.

Sterol regulatory element binding protein-1 (SREBP1) gene expression is similarly increased in polycystic ovary syndrome and endometrial cancer.

INTRODUCTION: Women with polycystic ovary syndrome have a three-fold higher risk of endometrial cancer. Insulin resistance and hyperlipidemia may be pertinent factors in the pathogenesis of both conditions. The aim of this study was to investigate endometrial sterol regulatory element binding protein-1 gene expression in polycystic ovary syndrome and endometrial cancer endometrium, and to correlate endometrial sterol regulatory element binding protein-1 gene expression with serum lipid profiles. MATERIAL AND METHODS: A cross-sectional study was performed at Nottingham University Hospital, UK. A total of 102 women (polycystic ovary syndrome, endometrial cancer and controls; 34 participants in each group) were recruited. Clinical and biochemical assessments were performed before endometrial biopsies were obtained from all participants. Taqman real-time polymerase chain reaction for endometrial sterol regulatory element binding protein-1 gene and its systemic protein expression were analyzed. RESULTS: The body mass indices of women with polycystic ovary syndrome (29.28 ± 2.91 kg/m2 ) and controls (28.58 ± 2.62 kg/m2 ) were not significantly different. Women with endometrial cancer had a higher mean body mass index (32.22 ± 5.70 kg/m2 ). Sterol regulatory element binding protein-1 gene expression was significantly increased in polycystic ovary syndrome and endometrial cancer endometrium compared with controls (p < 0.0001). Sterol regulatory element binding protein-1 gene expression was positively correlated with body mass index (r = 0.017, p = 0.921) and waist-hip ratio (r = 0.023, p = 0.544) in polycystic ovary syndrome, but this was not statistically significant. Similarly, statistically insignificant positive correlations were found between endometrial sterol regulatory element binding protein-1 gene expression and body mass index in endometrial cancer (r = 0.643, p = 0.06) and waist-hip ratio (r = 0.096, p = 0.073). Sterol regulatory element binding protein-1 gene expression was significantly positively correlated with triglyceride in both polycystic ovary syndrome and endometrial cancer (p = 0.028 and p = 0.027, respectively). Quantitative serum sterol regulatory element binding protein-1 gene correlated with endometrial gene expression (p < 0.05). CONCLUSIONS: Sterol regulatory element binding protein-1 gene expression is significantly increased in the endometrium of women with polycystic ovary syndrome and women with endometrial cancer compared with controls and positively correlates with serum triglyceride in both polycystic ovary syndrome and endometrial cancer.

Metformin for endometrial hyperplasia: a Cochrane protocol.

INTRODUCTION: Endometrial hyperplasia is a precancerous lesion of the endometrium, commonly presenting with uterine bleeding. If managed expectantly, it frequently progresses to endometrial carcinoma, rates of which are increasing dramatically worldwide. However, the established treatment for endometrial hyperplasia (progestogens) involves multiple side effects and leaves the risk of recurrence. Metformin is the most commonly used oral hypoglycaemic agent in type 2 diabetes mellitus. It has also been linked to the reversal of endometrial hyperplasia and may therefore contribute to decreasing the prevalence of endometrial carcinoma without the fertility and side effect consequences of current therapies. However, the efficacy and safety of metformin being used for this therapeutic target is unclear and, therefore, this systematic review will aim to determine this. METHODS AND ANALYSIS: We will search the following trials and databases with no language restrictions: Cochrane Gynaecology and Fertility Specialised Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; EBSCO Cumulative Index to Nursing and Allied Health Literature; PubMed; Google Scholar; ClinicalTrials.gov; the WHO International Trials Registry Platform portal; OpenGrey and the Latin American and Caribbean Health Sciences Literature (LILACS). We will include randomised controlled trials (RCTs) of use of metformin compared with a placebo or no treatment, conventional medical treatment (eg, progestogens) or any other active intervention. Two review authors will independently assess the trial eligibility, risk of bias and extract appropriate data points. Trial authors will be contacted for additional data. The primary review outcome is the regression of endometrial hyperplasia histology towards normal histology. Secondary outcomes include hysterectomy rate; abnormal uterine bleeding; quality of life scores and adverse reactions to treatments. ETHICS AND DISSEMINATION: Dissemination of the completed review will be through the Cochrane Library as well as through presenting the results at appropriate conferences.

Up-regulation of genes involved in the insulin signalling 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 signalling 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 signalling 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 signalling 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 signalling 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.

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 α, ß and γ 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 α, ß and γ 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. STUDY FUNDING/COMPETING INTERESTS: No financial support was obtained for this project. There are no conflicts of interest.

The effect of Metformin on endometrial tumor-regulatory genes and systemic metabolic parameters in polycystic ovarian syndrome--a proof-of-concept study.

The aim of this proof-of-concept study was to determine the effects of three-month Metformin therapy on the expression of tumor-regulatory genes (p53, cyclin D2 and BCL-2) in the endometrium of women with polycystic ovary syndrome (PCOS). A total of 40 women, aged between 21 and 45 years with PCOS (Rotterdam criteria) were recruited. The participants were assessed at pre- and 3-month-post-Metformin therapy for the menstrual regularities, weight reduction, Ferriman Galway scores, fasting blood glucose (FBG), total cholesterol, LDL, HDL and p53, BCL-2 and cyclin D2 gene expression. Five participants conceived spontaneously after the initial recruitment. Majority (68%) resumed regular menstrual cycles after Metformin. There were significant reduction in BMI (p = 0.001), weight (p = 0.001) and Ferriman Galway scores (p = 0.001). A significant improvement was seen in mean FBG (p = 0.002), total cholesterol (p = 0.001), LDL (p = 0.003) and HDL cholesterol levels (p = 0.015). Tumor suppressor gene (p53) was significantly up-regulated after Metformin (10 out of 14 women), with p value 0.016. BCL-2 and cyclin D2 (oncogenes) were slightly up-regulated without significant difference (p = 0.119 and 0.155, respectively). In conclusion, Metformin therapy improved clinical and metabolic parameters in women with PCOS and up-regulated p53 tumor suppressor gene significantly. Further studies are however required to independently validate our findings.

Validation of proteomic biomarkers previously found to be differentially expressed in women with polycystic ovary syndrome: a cross-sectional study.

OBJECTIVES: The aim of this study was to independently validate proteomic biomarkers previously reported to be differentially expressed in women with Polycystic Ovary Syndrome (PCOS) compared with controls. This study focused on plasma proteomic biomarkers. METHODS: This was a cross-sectional study at the University of Nottingham, in which samples from 30 PCOS and 30 control women were analysed by Western blotting. RESULTS: Mean abundance ratios from Western blots of plasma total haptoglobin and haptoglobin beta proteins were 1.25 (CI 1.11-1.4) and 1.24 (CI 1.04-1.44). The mean abundance ratio from the blots of alpha-2 macroglobulin was however 1.05 (CI, 1-1.1). The mean PCOS/control BMI ratio was 1.18 (CI 1.17-1.20). There was no correlation between PCOS/control BMI ratio and alpha-2 macroglobulin, total haptoglobin and haptoglobin beta abundance ratios. There was also no correlation between PCOS/control insulin ratio and alpha-2 macroglobulin, total haptoglobin and haptoglobin beta abundance ratios. CONCLUSIONS: Total haptoglobin and haptoglobin beta chain protein abundance was found to be elevated in women with PCOS compared with controls. We were unable to confirm decreased alpha-2 macroglobulin levels as reported in a previous study. Independent validation studies are required to validate early promising proteomic biomarkers in PCOS.