Mohamad Nasir Shafiee1, Claire Seedhouse2, Nigel Mongan3, Caroline Chapman4, Suha Deen5, Jafaru Abu6, William Atiomo7. 1. Division of Obstetrics and Gynaecology and Child Health, School of Medicine, Faculty of Medicine and Health Sciences, Queen's Medical Centre, Nottingham University Hospital, Derby Road, Nottingham, NG7 2UH, UK; Department of Obstetrics and Gynaecology, Universiti Kebangsaan Malaysia, Faculty of Medicine, Cheras, Kuala Lumpur, 56000, Malaysia. Electronic address: mgxmnsh@nottingham.ac.uk. 2. Department of Haematology, Clinical Sciences Building, University of Nottingham, Hucknall Road, Nottingham, NG5 1PB, UK. 3. School of Veterinary Medicine and Science, University of Nottingham, LE12 5RD, UK. 4. Division of Medical Sciences and Graduate Entry Medicine, Faculty of Medicine and Health Sciences, University of Nottingham, NG5 1PB, UK. 5. Department of Pathology, Queen's Medical Centre, Nottingham University Hospital, Nottingham, NG7 2UH, UK. 6. Department of Obstetrics and Gynaecology, City Hospital, Nottingham University Hospital, Nottingham, NG5 1PB, UK. 7. Division of Obstetrics and Gynaecology and Child Health, School of Medicine, Faculty of Medicine and Health Sciences, Queen's Medical Centre, Nottingham University Hospital, Derby Road, Nottingham, NG7 2UH, UK.
Abstract
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.
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-PCOSwomen 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)). PCOSwomen 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 PCOSwomen. 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.
Authors: Maryam Kazemi; Brittany Y Jarrett; Stephen A Parry; Anna E Thalacker-Mercer; Kathleen M Hoeger; Steven D Spandorfer; Marla E Lujan Journal: J Clin Endocrinol Metab Date: 2020-09-01 Impact factor: 5.958
Authors: William Atiomo; Mohamad Nasir Shafiee; Caroline Chapman; Veronika M Metzler; Jad Abouzeid; Ayşe Latif; Amy Chadwick; Sarah Kitson; Vanitha N Sivalingam; Ian J Stratford; Catrin S Rutland; Jenny L Persson; Niels Ødum; Pablo Fuentes-Utrilla; Jennie N Jeyapalan; David M Heery; Emma J Crosbie; Nigel P Mongan Journal: Clin Endocrinol (Oxf) Date: 2017-08-18 Impact factor: 3.478
Authors: Joseph A Dottino; Qian Zhang; David S Loose; Bryan Fellman; Brenda D Melendez; Mikayla S Borthwick; Laurie J McKenzie; Ying Yuan; Richard K Yang; Russell R Broaddus; Karen H Lu; Pamela T Soliman; Melinda S Yates Journal: Am J Obstet Gynecol Date: 2020-08-21 Impact factor: 8.661