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.

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.

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.

Preventing endometrial cancer risk in polycystic ovarian syndrome (PCOS) women: could metformin help?

Current data indicate that there is a significant risk of endometrial cancer (EC) in women with polycystic ovarian syndrome (PCOS), although further research needed to clarify the exact molecular mechanisms. Endometrial hyperplasia is a premalignant condition that usually heralds EC and it shares identical risk factors with EC. Metabolic syndrome with a triad of obesity, hyperinsulinaemia and diabetes, which is commonly observed in PCOS appears to be a key mechanism in EC pathogenesis. Measures to improve insulin resistance could therefore play a role in reducing the risk of EC in women with PCOS. Metformin is an insulin sensitising agent which is safe, widely available and currently licensed for type-2 diabetes. It has been clearly shown in both animal and human studies that metformin is of value in reversing endometrial hyperplasia. Metformin may therefore prevent EC in PCOS. This article reviews the use of metformin in reducing EC risk in PCOS and makes a case for future research on this topic.

Reviewing the molecular mechanisms which increase endometrial cancer (EC) risk in women with polycystic ovarian syndrome (PCOS): time for paradigm shift?

Endometrial cancer (EC) is the commonest gynaecological cancer in North American and European women. Even though it has been shown that women with polycystic ovary syndrome (PCOS) have a three-fold increase in the risk of developing EC compared to women without PCOS, the precise molecular mechanisms which increase EC risk in women with PCOS remain unclear. Clinical strategies to prevent EC in PCOS are therefore not well researched and understood. Although raised estrogen levels, hyperinsulinaemia and, reduced apoptosis have been suggested as potential mechanisms, there is a lack of clarity about how these factors and other factors may interact to increase EC risk in PCOS. This article reviews the literature, on the potential molecular links between PCOS and EC but argues for a paradigm shift, to a systems biology-based approach in future research into the molecular links between PCOS and EC. The potential challenges of a systems biology-based approach are outlined but not considered insurmountable.

Clinical outcome of atypical endometrial hyperplasia diagnosed on an endometrial biopsy: institutional experience and review of literature.

The aims of this study were: (1) to review the rate of concurrent endometrial cancer in patients with a preoperative diagnosis of atypical endometrial hyperplasia (AEH); and (2) to determine the features of concurrent endometrial carcinoma and their impact on the subsequent management of AEH. We reviewed a retrospective series of 219 AEHs diagnosed locally in routine practice, over 24 years, and followed by a repeat biopsy or hysterectomy. Another series of 65 cases with a malignant diagnosis on preoperative sampling was included as a control group. Clinicopathologic parameters were obtained. In addition, published data on the risk of malignancy and features of malignant tumors after a diagnosis of AEH were collected and analyzed. This study reported on 2571 patients diagnosed in 31 published studies in addition to the current one. This showed a wide variation in the positive predictive value (PPV) of AEH in detecting endometrial cancer (6% to 63%) with an overall PPV of 37%. This variation is not only based on the differences among studies but also on the degree of atypia [mild/moderate (PPV 13%) or severe (PPV 50%)], the type of subsequent intervention (biopsy vs. hysterectomy), and more importantly the time period of diagnosis (around 20% in studies published before 1990s and up to 40% to 48% in recently published cases). Of the benign outcome cases, nearly 40% to 50% showed AEH with a potential risk of progressing to invasive carcinoma in 25% of cases. Malignant tumors after AEH diagnosis are associated with features of good prognosis with endometrioid morphology, lower grade, and early stage. Although the overall PPV of AEH is 37%, a figure of 40% to 48% is expected in the cases currently diagnosed in routine practice. Providing qualifying criteria for AEH will help identify its different associated risks and therefore should be included in routine pathology reports whenever possible. Unless there is a clinical contraindication, hysterectomy should be performed to treat concurrent carcinoma and to reduce the risk of subsequent carcinoma in nonmalignant cases with residual AEH.

Do surgical techniques used in groin lymphadenectomy for vulval cancer affect morbidity rates?

OBJECTIVE: To determine the complication rates associated with differing surgical techniques for groin node dissection for vulval cancer. MATERIALS AND METHODS: We performed a retrospective case note review of patients undergoing groin node dissection for vulval cancer between 2001 and 2009 at Nottingham University Hospitals NHS Trust. RESULTS: Notes for 56 patients undergoing a total of 98 groin node dissections were examined. Sixty-four percent of the patients had at least one complication from surgery. The use of suction drains was not associated with an increase in complications. However, when drains were used, a short duration of use was associated with high rates of wound breakdown and a long duration of use was associated with higher rates of lymphedema. The use of staples for skin closure was associated with an increased risk of lymphocysts and chronic lymphedema. The greater the number of nodes collected at lymphadenectomy, the higher the risk of lymphocysts and lymphedema. CONCLUSIONS: We recommend the use of subcuticular suture for wound closure. Patients who undergo lymphadenectomy with a node count per groin of more than 7 should be closely monitored for lymphedema and referred promptly to specialist services. The prolonged use of suction drainage may increase the risk of lymphedema.

Adenosarcoma of an endometrial polyp in a 27-year-old nulligravida: a case report.

BACKGROUND: Endometrial adenosarcoma is a rare tumor first described by Clement and Scully in 1974. It consists of benign or atypical neoplastic glands within a sarcomatous stroma and represents approximately 8% of all uterine sarcomas. Patients of a variety of ages are affected: the largest series reported 100 cases in patients aged 14-89 years, with the median age at presentation 58 years. Other case reports identified on a literature search also describe patients within this age range. The typical presentation is symptoms of abnormal vaginal bleeding. On examination, tissue protruding from the external cervical os is a common finding, with a smaller number of patients having an enlarged uterus or palpable pelvic mass. The standard management is total abdominal hysterectomy and bilateral salpingo-oophorectomy. However, difficulty arises when one is faced with this condition in a young nullipara wishing to preserve her fertility. CASE: Endometrial polyp adenosarcoma occurred in a 27-year-old, nulligravid woman who presented with intermenstrual and postcoital bleeding. She was managed conservatively but will require close followup subsequently. CONCLUSION: A clinical dilemma was encountered in the management of a young woman with endometrial polyp adenosarcoma because of the necessity to preserve her fertility.

Retinoic acid and retinoid receptors: potential chemopreventive and therapeutic role in cervical cancer.

Retinoids are natural and synthetic derivatives of vitamin A, which can be obtained from animal products (milk, liver, beef, fish oils, and eggs) and vegetables (carrots, mangos, sweet potatoes, and spinach). Retinoids regulate various important cellular functions in the body through specific nuclear retinoic-acid receptors and retinoid-X receptors, which are encoded by separate genes. Retinoic-acid receptors specifically bind tretinoin and alitretinoin, whereas retinoid-X receptors bind only alitretinoin. Retinoids have long been established as crucial for several essential life processes-healthy growth, vision, maintenance of tissues, reproduction, metabolism, tissue differentiation (normal, premalignant cells, and malignant cells), haemopoiesis, bone development, spermatogenesis, embryogenesis, and overall survival. Therefore, deficiency of vitamin A can lead to various unwanted biological effects. Several experimental and epidemiological studies have shown the antiproliferative activity of retinoids and their potential use in cancer treatment and chemoprevention. Emerging clinical trials have shown the chemotherapeutic and chemopreventive potential of retinoids in cancerous and precancerous conditions of the uterine cervix. In this review, we explore the potential chemopreventive and therapeutic roles of retinoids in preinvasive and invasive cervical neoplasia.

Endocervical curettage at the time of colposcopic assessment of the uterine cervix.

UNLABELLED: Colposcopic examination of the uterine cervix remains the gold standard in the evaluation of patients with abnormal cervical cytology. Endocervical curettage (ECC) still forms a limited part of the overall assessment of women with abnormal cervical smears (Pap test) in the United States and in certain other parts of the world. To date, there are no properly randomized trials on the place of ECC in the overall care of women with abnormal Pap test. This review critically appraises the available evidence to look at the possible role of ECC in the complete evaluation of abnormal cervical smears. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to list the proposed indications for endocervical curettage (ECC), to summarize the data in support of the routine use of ECC at the time of colposcopy, and to outline the evidence against the use of routine ECC at colposcopy.