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Objective: To identify the physician-, patient- and health-system-related factors that influence gynecologists’ decision to recommend endometrial sampling in young women (less than 40 years) with abnormal uterine bleeding Study methods: A mail-based survey study was conducted using the Salant-Dillman method with 4 points of contact over 9 weeks. All Canadian obstetrician/gynecologists were initially surveyed (N=1746), receiving either French or English questionnaires. Eligible respondents were gynecologists practicing in Canada who treat these young women (N=834). Order response bias was taken into consideration by mailing two versions of the survey. Categorical data were analyzed using Pearson’s Chi-square statistics. A logistic regression with mixed effect model was performed to determine the odds of sampling the endometrium, using physician as random factor. Results: Overall response rate was 56.5%. The majority of respondents were generalists (83.6%). 70.3% of respondents have had young patients with malignant or pre-malignant endometrial conditions. Physicians ≤ 39 years have had less experience with these patients (59.6%, p=0.002) as have physicians practicing in communities without ob/gyn residents (35.2%, p=0.006). Sampling method was predominantly by office pipelle (79.7%), with younger physicians and female respondents employing this method most frequently (p=0.0001). In case scenarios which explored the importance of four patient-related risk factors (obesity, irregular cycles, nulliparity and older age), on the decision to sample, 98.8% of respondents would sample a young woman presenting with all four risk factors, as opposed to 8.8% who would sample if the patient did not have any of these characteristics. Obesity and irregular cycles was the next most important combination of risk factors prompting sampling in 87.3% of physicians. In the logistic regression, the odds ratio to proceed with endometrial sampling was 2.23 (95% CI 1.64-3.03) if a physician had previous experience with young women diagnosed with endometrial cancer or a pre-malignant condition, and was 1.45 (95% CI 1.05-2.01) if the physician was female. Conclusion: Patient and physician factors influenced the decision to proceed with sampling the endometrium of young women with abnormal uterine bleeding, whereas the health-system factors studied in this survey did not seem to play a strong role. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2010-07-14 15:06:07.786

Endometrial adenocarcinoma is the most common gynaecological malignancy in Western countries, affecting mainly post-menopausal women with a frequency of 15-20 per 100 000 women per year. Over-expression of the cyclooxygenase (COX) enzymes and prostaglandin receptors has been demonstrated in endometrial adenocarcinoma as well as other gynaecological pathologies. Increased expression of the prostaglandin F2α (PGF2α) receptor (FP) has been previously demonstrated in endometrial adenocarcinoma. A role for the FP receptor in the promotion of endometrial adenocarcinoma has been shown, with evidence for elevated PGF2α-FP signalling up-regulating angiogenic and tumourigenic genes, and increasing proliferation and migration of neoplastic epithelial cells. This thesis examines signalling pathways regulated by and interacting with the FP receptor that influence chemokine expression and subsequent effects in endometrial adenocarcinoma. To investigate PGF2α-FP interactions in endometrial adenocarcinoma, an endometrial epithelial cell line of adenocarcinoma origin (Ishikawa cells) stably transfected with the FP receptor to levels seen in cancer was used (FPS cells). An antibody array identified the chemokine C-X-C motif Ligand 1 (CXCL1) as a target gene regulated by PGF2α-FP signalling in this cell line. Expression of CXCL1 and its receptor, CXCR2, were elevated in cancer tissue as compared to normal endometrium and localised to glandular epithelium, endothelium and stroma. The induction of CXCL1 expression in FPS cells and endometrial adenocarcinoma explants was determined to be by a signalling pathway involving Gq, the epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK). The infiltration of immune cells into endometrial adenocarcinoma as compared to normal endometrium was then investigated. Increased neutrophils were present in endometrial adenocarcinoma compared with normal endometrium, and the expression of CXCR2 was colocalised to neutrophils. In vitro chemotaxis assays demonstrated that conditioned media from PGF2α-treated FPS cells stimulated human neutrophil chemotaxis which could be abolished by CXCL1 protein immunoneutralisation from the conditioned media or antagonism of CXCR2 on neutrophils. Moreover, xenograft tumours in nude mice arising from inoculation with FPS cells had higher neutrophil infiltration compared to tumours arising from wild-type cells or following treatment of mice bearing FPS tumours with CXCL1-neutralising antibody. Therefore, the up-regulation of CXCL1 by PGF2α promoted neutrophil chemotaxis into endometrial adenocarcinoma. The expression of a further chemokine, CC motif Ligand 20 (CCL20) was determined to be regulated by PGF2α -FP signalling in endometrial adenocarcinoma, and expression of CCL20 and its receptor CCR6 was elevated in endometrial adenocarcinoma. The induction of CCL20 by PGF2α -FP signalling in FPS cells was dependent on the signalling molecules Gq, EGFR, ERK, calcineurin and nuclear factor of activated T-cells (NFAT). The treatment of endometrial epithelial cells with recombinant CCL20 caused a significant increase in proliferation. Finally interactions between the signalling pathway of another pro-inflammatory lipid, lysophosphatidic acid (LPA), and FP receptor signalling in endometrial adenocarcinoma were examined. LPA increased expression of the FP receptor and the FP target genes previously discussed in this thesis, CXCL1 and CCL20, in FPS cells. Expression of the LPA receptors (LPAR) 1, 2 and 3 was localised in endometrial tissue, and LPAR2 and 3 were found to be elevated in endometrial adenocarcinoma compared with normal endometrium, suggesting amplification of the PGF2α -FP signalling pathway by LPA was possible. Collectively, these data demonstrate that inflammatory cytokine signalling pathways regulated by PGF2α-FP activation can promote immune cell infiltration and proliferation of endometrial adenocarcinoma, and that interaction of LPA and PGF2α-FP signalling in endometrial adenocarcinoma may exacerbate the disease.

Abstract Aim: It has been suggested that chronic hyperinsulinemia from insulin resistance is involved in the etiology of endometrial cancer (EC). We performed a systematic review and meta-analysis to assess whether insulin resistance is associated with the risk of EC. Methods: We searched PubMed-Medline, Embase, Scopus, and Web of Science for articles published from database inception through 30th September 2014. We included all observational studies evaluating components defining insulin resistance in women with and without EC. Quality of the included studies was assessed by NewcastleeOttawa scale. Randomeffects models and inverse variance method were used to meta-analyze the association between insulin resistance components and EC. Results: Twenty-five studies satisfied our inclusion criteria. Fasting insulin levels (13 studies, n Z 4088) were higher in women with EC (mean difference [MD] 33.94 pmol/L, 95% confi- dence interval [CI] 15.04e52.85, p Z 0.0004). No differences were seen in postmenopausal versus pre- and postmenopausal subgroup analysis. Similarly, non-fasting/fasting C-peptide levels (five studies, n Z 1938) were also higher in women with EC (MD 0.14 nmol/L, 95% CI 0.08e0.21, p < 0.00001). Homeostatic model assessment - insulin resistance (HOMA-IR) values (six studies, n Z 1859) in EC patients were significantly higher than in women without EC (MD 1.13, 95% CI 0.20e2.06, p Z 0.02). There was moderate-to-high heterogeneity among the included studies. Conclusion: Currently available epidemiologic evidence is suggestive of significantly higher risk of EC in women with high fasting insulin, non-fasting/fasting C-peptide and HOMAIR values.

MSc (Med), Biostatistics and Epidemiology, Faculty of Health Sciences, University of the Witwatersrand, 2009 / Introduction: Endometrial cancer is a gynaecological cancer that mostly affects women in their sixth and seventh decades of life. It is the fourth most common malignancy in women and ranks eighth among all causes of female cancer in terms of age-adjusted mortality. In developed and numerous developing countries endometrial cancer, as well as other types of cancer in women, is an ever-increasing threat that may be explained, among other reasons, by increased life expectancy and a reduction in fertility or birth rates. Conversely, in South Africa and most other African countries, the previous reasons do not exist, because there is a decline in life expectancy due to increased HIV, low income, and a high fertility rate. International epidemiological studies have established significant relationships between endometrial cancer and risk factors such as the woman’s age, race, early menarche and late menopause, parity, a history of breast or ovarian cancer, the use of endogenous estrogens, concomitant diabetes, family history of breast and ovarian cancer, estrogen therapy, obesity, and the use of tamoxifen. The aim of the study was to identify risk factors associated with endometrial cancer among black South African women. Method: The present case control study comprised black South African women diagnosed with a cancer in Johannesburg, between 1995 and 2005. The study included 592 women aged 27 to 90 years who were admitted to three main public hospitals in the city of Johannesburg with histologically confirmed cancers. 148 cases with endometrial cancer and 444 women with other forms of cancer were analysed. Only newly occurring cases (incident) were included. Women in the control group consisted of those with V cancers not associated with reproductive or hormonal factors, i.e. not cancers of the breast or the female reproductive system. Data handling, cleaning and analysis were done using Stata 9 (STATA). Results: Univariate analysis showed that the risk for endometrial cancer was significantly (P<0.05) affected by: miscarriages, the place of former residence, place of current residence, the use of snuff, wine consumption, age of the youngest child, diabetes, age of menarche, age of menopause, and menstrual status. Smoking was found to be a protective factor for endometrial cancer compared to other cancers. After multivariate adjustment, endometrial cancer risk was significantly (P<0, 05) associated with miscarriages, age at menarche, and earlier completion of childbearing. Smoking remained a protective factor against endometrial cancer. Conclusion: The current study reports similar results to those observed in other international investigations. The risk of endometrial cancer was higher among women who were older, women who experienced miscarriages, and those who fell pregnant early in their reproductive lives. Smoking was a protective factor against endometrial cancer compared to other cancers. However, comparing the cases of endometrial cancer with smoking-associated cancer controls (i.e. lung cancer, oesophageal cancer, and mouth cancer) might have distorted the results. A more appropriate control group for confirming the relationship between smoking and endometrial cancer would be subjects with no cancer. Also, it will be important to evaluate the risk factors for cancer among the other race groups in South Africa.

Endometrial cancer (EC) is the most common gynaecological cancer affecting women in developed countries. Improving outcomes for women who are unfit for primary surgery or have advanced disease remains a challenge. Metformin use is associated with reduced cancer risk in several observational studies of patients with type 2 diabetes. Pre-clinical studies in EC show that metformin reduces cellular proliferation. The work described in this thesis tests the hypothesis that metformin reduces cellular proliferation in vitro and in vivo in type I EC through actions on the PI3K/AKT/mTOR pro-proliferative pathway. First, an in vitro model of EC using cell lines was established to determine the effect of metformin on cellular proliferation. Metformin was found to be cytostatic in a dose-dependent manner; these effects were potentiated in combination with carboplatin and paclitaxel. Metformin was shown to modulate mTOR phosphorylation proteins by immunoblot. Flow cytometric and metabolic assays found metformin to increase mitochondrial mass, but conversely, reduce mitochondrial function. These in vitro findings varied according to glucose concentration and were attenuated in hypoxia. Next, staining and scoring protocols for Ki-67, a marker of cellular proliferation, were established using semi-automated scoring on archived EC tumours. Ki-67 correlated with age, tumour grade and myometrial invasion; high Ki-67 expression was associated with an increased risk of disease recurrence, and was thus a prognostic marker. Finally, a presurgical window study of metformin versus no drug in women with EC demonstrated a 17% reduction in tumour Ki-67 with short-term metformin. Ki-67 response varied positively with increased average daily dose of metformin and negatively with increased BMI. High grade tumours were more hypoxic, according to baseline HIF-1alpha and the Ki-67 response to metformin was lower in hypoxic tumours. The effect on tumour mTOR phosphorylation events varied, but was not significant after adjusting for changes in controls. In conclusion, these results demonstrated that short-term oral metformin was associated with reduced cellular proliferation in women with EC. The findings from this study require corroboration with a placebo-controlled trial prior to the introduction of metformin as treatment for EC, both as a sole agent and in combination with existing adjuvant therapy. The response to metformin was heterogeneous; tumour hypoxia and metabolic adaptations of cancer cells may lead to metformin-resistance. Future studies should take these modulating effects into account to help identify patients likely to derive clinical benefit from metformin.

Endometrial cancer is a common gynaecological cancer. Improving outcomes for women with advanced disease remains a challenge and there is also a need to develop preventative strategies in those women at highest risk of developing disease. Peroxisome proliferator-activated receptors (PPARs) comprise of a group of transcription factors belonging to the nuclear hormone receptor subfamily. PPAR sub-types are involved in metabolic homeostasis and have been implicated in malignancy, particularly breast and colo-rectal malignancies both of which are associated with obesity. Endometrial cancer is also closely associated with both obesity and insulin resistance. The work described in this thesis examined the expression of PPARs in endometrioid endometrial cancer and investigated their effects on key pathways implicated in this disease. Immunoblotting revealed over expression of PPARα and loss of PPARγ in human endometrioid endometrial cancer tissues. Pull-down assays also demonstrated differential selectivity of different PPARs for heterodimerisation with different isoforms of the RXR family of transcription factors. PPARα was localized to tumour cells and vascular endothelium and ELISA demonstrated an increase in VEGF-A in PPARα silenced cells suggesting that PPARα may promote tumour angiogenesis. PPARγ was largely seen in epithelial cells and also macrophages within benign endometrium. Reduction of PPARγ expression in cultured endometrial cells led to increased proliferation and decreased apoptosis. Loss of PPARγ was correlated with a loss of the tumour suppressor PTEN in endometrial tissues. Furthermore, PPARγ silencing led to diminished expression of PTEN and a concomitant increase in phosphorylated AKT suggesting that PPARγ is protective against deregulated growth within the endometrium. Synthetic PPAR-specific ligands reduced proliferation and increased apoptosis in endometrial cell lines. These effects were present in PPAR-silenced cells too although reduced in magnitude, indicating that the actions of specific PPAR ligands are mediated via both receptor dependent and receptor independent pathways.In conclusion, this work has demonstrated the differential expression of PPARs and RXRs in endometrial cancers and identified possible mechanisms, both direct and indirect, by which these may modulate endometrial cancer growth. Different PPAR family members may provide targets for therapeutic intervention in endometrial cancer care and require further study in this regard.

Abstract Aim: It has been suggested that chronic hyperinsulinemia from insulin resistance is involved in the etiology of endometrial cancer (EC). We performed a systematic review and meta-analysis to assess whether insulin resistance is associated with the risk of EC. Methods: We searched PubMed-Medline, Embase, Scopus, and Web of Science for articles published from database inception through 30th September 2014. We included all observational studies evaluating components defining insulin resistance in women with and without EC. Quality of the included studies was assessed by NewcastleeOttawa scale. Randomeffects models and inverse variance method were used to meta-analyze the association between insulin resistance components and EC. Results: Twenty-five studies satisfied our inclusion criteria. Fasting insulin levels (13 studies, n Z 4088) were higher in women with EC (mean difference [MD] 33.94 pmol/L, 95% confi- dence interval [CI] 15.04e52.85, p Z 0.0004). No differences were seen in postmenopausal versus pre- and postmenopausal subgroup analysis. Similarly, non-fasting/fasting C-peptide levels (five studies, n Z 1938) were also higher in women with EC (MD 0.14 nmol/L, 95% CI 0.08e0.21, p < 0.00001). Homeostatic model assessment - insulin resistance (HOMA-IR) values (six studies, n Z 1859) in EC patients were significantly higher than in women without EC (MD 1.13, 95% CI 0.20e2.06, p Z 0.02). There was moderate-to-high heterogeneity among the included studies. Conclusion: Currently available epidemiologic evidence is suggestive of significantly higher risk of EC in women with high fasting insulin, non-fasting/fasting C-peptide and HOMAIR values. / Revisión por pares

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第17820号 / 医博第3818号 / 新制||医||999(附属図書館) / 30635 / 京都大学大学院医学研究科医学専攻 / (主査)教授 富樫 かおり, 教授 伊藤 壽一, 教授 楠見 明弘 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18152号 / 医博第3872号 / 新制||医||1002(附属図書館) / 31010 / 京都大学大学院医学研究科医学専攻 / (主査)教授 小川 誠司, 教授 武藤 学, 教授 戸井 雅和 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM