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Li M, Cui Y, Wu X, Yang X, Huang C, Yu L, Yi P, Chen C. Integrating network pharmacology to investigate the mechanism of quercetin's action through AKT inhibition in co-expressed genes associated with polycystic ovary syndrome and endometrial cancer. Int J Biol Macromol 2025; 297:139468. [PMID: 39765297 DOI: 10.1016/j.ijbiomac.2025.139468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 12/30/2024] [Accepted: 01/01/2025] [Indexed: 01/30/2025]
Abstract
Endometrial cancer (EC) is a common gynecological malignancy for which polycystic ovarian syndrome (PCOS) has been identified as a significant risk factor. Quercetin, a widely distributed natural flavonoid, has demonstrated potential therapeutic effects in managing both PCOS and EC. However, the specific molecular targets of quercetin in the context of PCOS comorbid with EC (PCOS-EC) remain poorly defined. This study aims to elucidate the therapeutic potential of quercetin for treating PCOS-EC using network pharmacology, molecular dynamics simulations, and in vitro assays. The intersection of 379 PCOS-EC-associated targets with 361 quercetin targets identified 47 potential therapeutic targets of quercetin for PCOS-EC. Gene Ontology enrichment analysis revealed the biological functions, while Kyoto Encyclopedia of Genes and Genomes identified the pathways potentially involved in quercetin's effects against PCOS-EC. Protein-protein interaction network analysis highlighted six overlapping targets, namely, ACTB, AKT1, EGFR, ESR1, PTGS2, and TP53. Molecular docking and molecular dynamics simulations indicated that quercetin bound with high affinity to the hub genes, with AKT1 emerging as a central target. In vitro experiments confirmed that quercetin treatment significantly downregulated AKT expression in EC cells. These findings elucidate potential targets and molecular mechanisms through which quercetin exerts its therapeutic effects.
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Affiliation(s)
- Mengyuan Li
- Department of Obstetrics and Gynecology, Chongqing General Hospital, Chongqing University, Chongqing 401147, China; Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
| | - Yewei Cui
- School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Xingfan Wu
- School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Xunmei Yang
- Department of Orthopedics, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
| | - Chenglong Huang
- Department of Clinical Laboratory, Medical Sciences Research Center, University-Town Hospital of Chongqing Medical University, Chongqing 401331, China
| | - Lili Yu
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
| | - Ping Yi
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China.
| | - Cheng Chen
- Department of Obstetrics and Gynecology, Chongqing General Hospital, Chongqing University, Chongqing 401147, China.
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Pace L, Markovic D, Buyalos R, Bril F, Azziz R. Economic Burden of Endometrial Cancer Associated With Polycystic Ovary Syndrome. J Clin Endocrinol Metab 2024; 110:e168-e176. [PMID: 39106216 DOI: 10.1210/clinem/dgae527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 07/23/2024] [Accepted: 07/29/2024] [Indexed: 08/09/2024]
Abstract
CONTEXT Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive-aged females, and women with PCOS are at increased risk for endometrial cancer (EndoCA), the most common gynecological malignancy. OBJECTIVE Our study sought to assess the economic burden associated with EndoCA in PCOS. METHOD Using PRISMA systematic review guidelines, we evaluated studies on EndoCA rates in patients with PCOS. Excluded studies were reviews and case reports, those with nonhuman subjects, without controls, without full text available, or reporting solely on other conditions. Selected studies were assessed for quality using the Newcastle-Ottawa Scale. Meta-analysis used DerSimonian-Laird random effects model to assess pooled risk ratio (RR). Excess cost was assessed in US dollars (USD). RESULT Of 98 studies screened, 9 were included. Pooled RR for EndoCA in PCOS was 3.46 (95% CI, 2.28-5.23), P ≤ .001. In the United States, prevalence of EndoCA in patients with PCOS in 2020 was 1.712%, compared with a baseline estimated prevalence in all women of 0.489%. The excess prevalence of EndoCA attributable to PCOS was 1.223%, approximately 98 348 affected women. A population attributable fraction of EndoCA for PCOS was 24.4%. Given estimated costs of EndoCA exceeding $1.9 billion (in 2023 USD), the economic burden of EndoCA attributable to PCOS exceeds $467 million/year. CONCLUSION The excess annual US healthcare cost for EndoCA attributable to PCOS exceeds $467 million/year (2023 USD). Although a concerning morbidity of PCOS, it is notable that the economic burden of EndoCA attributable to the disorder represents only a small fraction of its total healthcare burden.
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Affiliation(s)
- Lauren Pace
- Department of Ob/Gyn, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Daniela Markovic
- Division of General Internal Medicine and Health Services Research, The David Geffen School of Medicine, UCLA, Los Angeles, CA 90024, USA
| | - Richard Buyalos
- Department of Ob/Gyn, The David Geffen School of Medicine, UCLA, Los Angeles, CA 90024, USA
| | - Fernando Bril
- Department of Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Ricardo Azziz
- Department of Ob/Gyn, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA
- Department of Ob/Gyn and Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA
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Zanjirband M, Nasr-Esfahani MH, Curtin NJ, Drew Y, Sharma Saha S, Adibi P, Lunec J. A Systematic Review of the Molecular Mechanisms Involved in the Association Between PCOS and Endometrial and Ovarian Cancers. J Cell Mol Med 2024; 28:e70312. [PMID: 39720923 DOI: 10.1111/jcmm.70312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 11/24/2024] [Accepted: 12/10/2024] [Indexed: 12/26/2024] Open
Abstract
Polycystic ovary syndrome (PCOS), a major cause of female infertility, affects 4%-20% of reproductive-age women. Metabolic and hormonal alterations are key features of PCOS, potentially raising the risk of endometrial (EC) and ovarian (OVCA) cancers. This systematic review aims to summarise the proposed molecular mechanisms involved in the association between PCOS and EC or OVCA. This is achieved by conducting a thorough literature review and utilising specific search terms to identify all relevant studies published in English from 2010 to December 2022. PRISMA was followed, and the protocol was registered on PROSPERO (CRD42022375461). The QUADAS-2 tool and Review Manager Software were employed to evaluate study quality and risk of bias respectively. Forty-five eligible studies were selected with molecular signatures based on genomic, transcriptomic, metabolomic, proteomic and epigenetic analyses. Genes and their products deregulated in EC and/or OVCA were identified, including BRCA1, MLH1, NQO1 and ESR1, which were also deregulated in PCOS. Serum levels of IGF1, IGFBP1, SREBP1 and visfatin in women with PCOS were also identified as potential biomarkers of enhanced EC risk. Salusin-β serum levels in individuals with PCOS were identified as a potential biomarker for increased risk of OVCA. Gene signature-based drug repositioning identified several drug candidates: metformin, fenofibrate, fatostatin, melatonin, resveratrol and quercetin, some already established and prescribed for PCOS. In conclusion, this study provides a strong basis for further research to confirm the identified molecular signatures and associated causal links for potential therapeutic prevention strategies for EC and OVCA in women with PCOS.
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Affiliation(s)
- M Zanjirband
- Department of Animal Biotechnology, Reproductive Biomedicine Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - M H Nasr-Esfahani
- Department of Animal Biotechnology, Reproductive Biomedicine Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - N J Curtin
- Translational and Clinical Research Institute, Newcastle University Cancer Centre, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK
| | - Y Drew
- BC Cancer Vancouver and University of British Columbia, Vancouver, British Columbia, Canada
| | - S Sharma Saha
- Translational and Clinical Research Institute, Newcastle University Cancer Centre, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK
| | - P Adibi
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - J Lunec
- Biosciences Institute, Newcastle University Cancer Centre, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK
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Frandsen CLB, Gottschau M, Nøhr B, Viuff JH, Maltesen T, Kjær SK, Jensen A, Svendsen PF. Polycystic ovary syndrome and endometrial cancer risk: results from a nationwide cohort study. Am J Epidemiol 2024; 193:1399-1406. [PMID: 38751314 DOI: 10.1093/aje/kwae061] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 03/11/2024] [Accepted: 05/10/2024] [Indexed: 10/09/2024] Open
Abstract
Most previous studies found an elevated risk of endometrial cancer among women with polycystic ovary syndrome (PCOS). However, these had highly varying methods for ascertainment of PCOS diagnoses and limitations such as few exposed women and short follow-up. In this cohort study, we investigated the association between PCOS and endometrial cancer among women born in Denmark between January 1, 1940, and December 31, 1993 (n = 1 719 121). Data in this study, including PCOS and endometrial cancer diagnoses and covariates, were derived from nationwide registers. We used Cox proportional hazards regression models to calculate hazard ratios (HRs) and 95% CIs. A total of 7862 endometrial cancer cases were identified during 23.7 years of follow-up (IQR, 37.7-61.9). We found an increased risk of endometrial cancer among women with PCOS compared with women without PCOS (HR = 3.02; 95% CI, 2.03-4.49). The risk was increased for premenopausal women (HR = 5.82; 95% CI, 3.64-9.30), whereas no marked association was seen for postmenopausal women. However, for postmenopausal women, results were limited by few cases and young age at the end of follow-up. Mounting evidence of an increased risk for endometrial cancer among women with PCOS reinforces the need for prevention and early detection. This article is part of a Special Collection on Gynecological Cancers.
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Affiliation(s)
- C L B Frandsen
- Virus, Lifestyle and Genes, Danish Cancer Institute, DK-2100 Copenhagen, Denmark
- Department of Obstetrics and Gynecology, University Hospital of Herlev and Gentofte, DK-2730 Herlev, Denmark
| | - M Gottschau
- Virus, Lifestyle and Genes, Danish Cancer Institute, DK-2100 Copenhagen, Denmark
| | - B Nøhr
- Department of Obstetrics and Gynecology, University Hospital of Herlev and Gentofte, DK-2730 Herlev, Denmark
| | - J H Viuff
- Diet, Cancer and Health, Danish Cancer Institute, DK-2100 Copenhagen, Denmark
| | - T Maltesen
- Statistics and Data Analysis, Danish Cancer Institute, DK-2100 Copenhagen, Denmark
| | - S K Kjær
- Virus, Lifestyle and Genes, Danish Cancer Institute, DK-2100 Copenhagen, Denmark
- Department of Gynecology, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark
| | - A Jensen
- Virus, Lifestyle and Genes, Danish Cancer Institute, DK-2100 Copenhagen, Denmark
| | - P F Svendsen
- Department of Obstetrics and Gynecology, University Hospital of Herlev and Gentofte, DK-2730 Herlev, Denmark
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Chen J, Chen W, Wang Z, Zhou L, Lin Q, Huang Q, Zheng L, You H, Lin S, Shi Q. PGD: Shared gene linking polycystic ovary syndrome and endometrial cancer, influencing proliferation and migration through glycometabolism. Cancer Sci 2024; 115:2908-2922. [PMID: 38979884 PMCID: PMC11462980 DOI: 10.1111/cas.16212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 04/22/2024] [Accepted: 05/02/2024] [Indexed: 07/10/2024] Open
Abstract
The relationship among polycystic ovary syndrome (PCOS), endometrial cancer (EC), and glycometabolism remains unclear. We explored shared genes between PCOS and EC, using bioinformatics to unveil their pathogenic connection and influence on EC prognosis. Gene Expression Omnibus datasets GSE226146 (PCOS) and GSE196033 (EC) were used. A protein-protein interaction (PPI) network was constructed to identify the central genes. Candidate markers were screened using dataset GSE54250. Differences in marker expression were confirmed in mouse PCOS and human EC tissues using RT-PCR and immunohistochemistry. The effect of PGD on EC proliferation and migration was explored using Ki-67 and Transwell assays. PGD's impact on the glycometabolic pathway within carbon metabolism was assessed by quantifying glucose content and lactic acid production. R software identified 31 common genes in GSE226146 and GSE196033. Gene Ontology functional classification revealed enrichment in the "purine nucleoside triphosphate metabolism process," with key Kyoto Encyclopedia of Genes and Genomes pathways related to "carbon metabolism." The PPI network identified 15 hub genes. HK2, NDUFS8, PHGDH, PGD, and SMAD3 were confirmed as candidate markers. The RT-PCR analysis validated distinct HK2 and PGD expression patterns in mouse PCOS ovarian tissue and human EC tissue, as well as in normal and EC cells. Transfection experiments with Ishikawa cells further confirmed PGD's influence on cell proliferation and migration. Suppression of PGD expression impeded glycometabolism within the carbon metabolism of EC cells, suggesting PGD as a significant PCOS risk factor impacting EC proliferation and migration through modulation of single carbon metabolism. These findings highlight PGD's pivotal role in EC onset and prognosis.
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Affiliation(s)
- Jia‐ming Chen
- Department of Gynecology and ObstetricsThe Second Affiliated Hospital of Fujian Medical UniversityQuanzhouChina
| | - Wei‐Hong Chen
- Department of Gynecology and ObstetricsThe Second Affiliated Hospital of Fujian Medical UniversityQuanzhouChina
| | - Zhi‐yi Wang
- Department of Gynecology and ObstetricsThe Second Affiliated Hospital of Fujian Medical UniversityQuanzhouChina
| | - Liang‐Yu Zhou
- Department of Gynecology and ObstetricsThe Second Affiliated Hospital of Fujian Medical UniversityQuanzhouChina
| | - Qiu‐ya Lin
- Department of Gynecology and ObstetricsThe Second Affiliated Hospital of Fujian Medical UniversityQuanzhouChina
| | - Qiao‐yi Huang
- Department of Gynecology and ObstetricsThe Second Affiliated Hospital of Fujian Medical UniversityQuanzhouChina
| | - Ling‐tao Zheng
- Department of Gynecology and ObstetricsThe Second Affiliated Hospital of Fujian Medical UniversityQuanzhouChina
| | - Hui‐jie You
- Department of Gynecology and ObstetricsThe Second Affiliated Hospital of Fujian Medical UniversityQuanzhouChina
| | - Shu Lin
- Neuroendocrinology GroupGarvan Institute of Medical ResearchSydneyNew South WalesAustralia
- Centre of Neurological and Metabolic ResearchThe Second Affiliated Hospital of Fujian Medical UniversityQuanzhouChina
| | - Qi‐yang Shi
- Department of Gynecology and ObstetricsThe Second Affiliated Hospital of Fujian Medical UniversityQuanzhouChina
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Cui J, Zhao YC, She LZ, Wang TJ. Comparative effects of progestin-based combination therapy for endometrial cancer or atypical endometrial hyperplasia: a systematic review and network meta-analysis. Front Oncol 2024; 14:1391546. [PMID: 38764577 PMCID: PMC11099254 DOI: 10.3389/fonc.2024.1391546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 04/22/2024] [Indexed: 05/21/2024] Open
Abstract
Objectives The objective of this network meta-analysis is to systematically compare the efficacy of diverse progestin-based combination regimens in treating patients diagnosed with endometrial cancer or atypical endometrial hyperplasia. The primary goal is to discern the optimal combination treatment regimen through a comprehensive examination of their respective effectiveness. Methods We systematically searched four prominent databases: PubMed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials, for randomized controlled trials addressing the efficacy of progestins or progestin combinations in the treatment of patients with endometrial cancer or atypical endometrial hyperplasia. The search spanned from the inception of these databases to December 2023. Key outcome indicators encompassed survival indices, criteria for assessing efficacy, as well as pregnancy and relapse rate. This study was registered in PROSPERO (CRD42024496311). Results From the 1,558 articles initially retrieved, we included 27 studies involving a total of 5,323 subjects in our analysis. The results of the network meta-analysis revealed that the mTOR inhibitor+megestrol acetate (MA)+tamoxifen regimen secured the top rank in maintaining stable disease (SD) (SUCRA=73.4%) and extending progression-free survival (PFS) (SUCRA=72.4%). Additionally, the progestin combined with tamoxifen regimen claimed the leading position in enhancing the partial response (PR) (SUCRA=75.2%) and prolonging overall survival (OS) (SUCRA=80%). The LNG-IUS-based dual progestin regimen emerged as the frontrunner in improving the complete response (CR) (SUCRA=98.7%), objective response rate (ORR) (SUCRA=99.1%), pregnancy rate (SUCRA=83.7%), and mitigating progression (SUCRA=8.0%) and relapse rate (SUCRA=47.4%). In terms of safety, The LNG-IUS-based dual progestin regimen had the lowest likelihood of adverse events (SUCRA=4.2%), while the mTOR inhibitor regimen (SUCRA=89.2%) and mTOR inbitor+MA+tamoxifen regimen (SUCRA=88.4%) had the highest likelihood of adverse events. Conclusions Patients diagnosed with endometrial cancer or atypical endometrial hyperplasia exhibited the most favorable prognosis when undergoing progestin combination therapy that included tamoxifen, mTOR inhibitor, or LNG-IUS. Notably, among these options, the LNG-IUS-based dual progestin regimen emerged as particularly promising for potential application. Systematic review registration https://www.crd.york.ac.uk/PROSPERO, identifier CRD42024496311.
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Affiliation(s)
| | | | | | - Tie-Jun Wang
- Department of Radiation Oncology, The Second Hospital of Jilin University, Changchun, Jilin, China
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7
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Athar F, Karmani M, Templeman N. Metabolic hormones are integral regulators of female reproductive health and function. Biosci Rep 2024; 44:BSR20231916. [PMID: 38131197 PMCID: PMC10830447 DOI: 10.1042/bsr20231916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 11/29/2023] [Accepted: 12/21/2023] [Indexed: 12/23/2023] Open
Abstract
The female reproductive system is strongly influenced by nutrition and energy balance. It is well known that food restriction or energy depletion can induce suppression of reproductive processes, while overnutrition is associated with reproductive dysfunction. However, the intricate mechanisms through which nutritional inputs and metabolic health are integrated into the coordination of reproduction are still being defined. In this review, we describe evidence for essential contributions by hormones that are responsive to food intake or fuel stores. Key metabolic hormones-including insulin, the incretins (glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1), growth hormone, ghrelin, leptin, and adiponectin-signal throughout the hypothalamic-pituitary-gonadal axis to support or suppress reproduction. We synthesize current knowledge on how these multifaceted hormones interact with the brain, pituitary, and ovaries to regulate functioning of the female reproductive system, incorporating in vitro and in vivo data from animal models and humans. Metabolic hormones are involved in orchestrating reproductive processes in healthy states, but some also play a significant role in the pathophysiology or treatment strategies of female reproductive disorders. Further understanding of the complex interrelationships between metabolic health and female reproductive function has important implications for improving women's health overall.
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Affiliation(s)
- Faria Athar
- Department of Biology, University of Victoria, Victoria, British Columbia V8P 5C2, Canada
| | - Muskan Karmani
- Department of Biology, University of Victoria, Victoria, British Columbia V8P 5C2, Canada
| | - Nicole M. Templeman
- Department of Biology, University of Victoria, Victoria, British Columbia V8P 5C2, Canada
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8
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Emons G, Steiner E, Vordermark D, Uleer C, Paradies K, Tempfer C, Aretz S, Cremer W, Hanf V, Mallmann P, Ortmann O, Römer T, Schmutzler RK, Horn LC, Kommoss S, Lax S, Schmoeckel E, Mokry T, Grab D, Reinhardt M, Steinke-Lange V, Brucker SY, Kiesel L, Witteler R, Fleisch MC, Heinrich Prömpeler † 25, Friedrich M, Höcht S, Lichtenegger W, Mueller M, Runnebaum I, Feyer P, Hagen V, Juhasz-Böss I, Letsch A, Niehoff P, Zeimet AG, Battista MJ, Petru E, Widhalm S, van Oorschot B, Panke JE, Weis J, Dauelsberg T, Haase H, Beckmann MW, Jud S, Wight E, Prott FJ, Micke O, Bader W, Reents N, Henscher U, Reina Tholen † 52, Schallenberg M, Rahner N, Mayr D, Kreißl M, Lindel K, Mustea A, Strnad V, Goerling U, Bauerschmitz GJ, Langrehr J, Neulen J, Ulrich UA, Nothacker MJ, Blödt S, Follmann M, Langer T, Wenzel G, Weber S, Erdogan S. Endometrial Cancer. Guideline of the DGGG, DKG and DKH (S3-Level, AWMF Registry Number 032/034-OL, September 2022). Part 1 with Recommendations on the Epidemiology, Screening, Diagnosis and Hereditary Factors of Endometrial Cancer, Geriatric Assessment and Supply Structures. Geburtshilfe Frauenheilkd 2023; 83:919-962. [PMID: 37588260 PMCID: PMC10427205 DOI: 10.1055/a-2066-2051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 06/22/2023] [Indexed: 08/18/2023] Open
Abstract
Summary The S3-guideline on endometrial cancer, first published in April 2018, was reviewed in its entirety between April 2020 and January 2022 and updated. The review was carried out at the request of German Cancer Aid as part of the Oncology Guidelines Program and the lead coordinators were the German Society for Gynecology and Obstetrics (DGGG), the Gynecology Oncology Working Group (AGO) of the German Cancer Society (DKG) and the German Cancer Aid (DKH). The guideline update was based on a systematic search and assessment of the literature published between 2016 and 2020. All statements, recommendations and background texts were reviewed and either confirmed or amended. New statements and recommendations were included where necessary. Aim The use of evidence-based risk-adapted therapies to treat women with endometrial cancer of low risk prevents unnecessarily radical surgery and avoids non-beneficial adjuvant radiation therapy and/or chemotherapy. For women with endometrial cancer and a high risk of recurrence, the guideline defines the optimum level of radical surgery and indicates whether chemotherapy and/or adjuvant radiation therapy is necessary. This should improve the survival rates and quality of life of these patients. The S3-guideline on endometrial cancer and the quality indicators based on the guideline aim to provide the basis for the work of certified gynecological cancer centers. Methods The guideline was first compiled in 2018 in accordance with the requirements for S3-level guidelines and was updated in 2022. The update included an adaptation of the source guidelines identified using the German Instrument for Methodological Guideline Appraisal (DELBI). The update also used evidence reviews which were created based on selected literature obtained from systematic searches in selected literature databases using the PICO process. The Clinical Guidelines Service Group was tasked with carrying out a systematic search and assessment of the literature. Their results were used by interdisciplinary working groups as a basis for developing suggestions for recommendations and statements which were then modified during structured online consensus conferences and/or additionally amended online using the DELPHI process to achieve a consensus. Recommendations Part 1 of this short version of the guideline provides recommendations on epidemiology, screening, diagnosis, and hereditary factors. The epidemiology of endometrial cancer and the risk factors for developing endometrial cancer are presented. The options for screening and the methods used to diagnose endometrial cancer are outlined. Recommendations are given for the prevention, diagnosis, and therapy of hereditary forms of endometrial cancer. The use of geriatric assessment is considered and existing structures of care are presented.
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Affiliation(s)
- Günter Emons
- Universitätsmedizin Göttingen, Klinik für Gynäkologie und Geburtshilfe, Göttingen, Germany
| | - Eric Steiner
- Frauenklinik GPR Klinikum Rüsselsheim am Main, Rüsselsheim, Germany
| | - Dirk Vordermark
- Universität Halle (Saale), Radiotherapie, Halle (Saale), Germany
| | - Christoph Uleer
- Facharzt für Frauenheilkunde und Geburtshilfe, Hildesheim, Germany
| | - Kerstin Paradies
- Konferenz onkologischer Kranken- und Kinderkrankenpfleger (KOK), Hamburg, Germany
| | - Clemens Tempfer
- Frauenklinik der Ruhr-Universität Bochum, Bochum/Herne, Germany
| | - Stefan Aretz
- Institut für Humangenetik, Universität Bonn, Zentrum für erbliche Tumorerkrankungen, Bonn, Germany
| | | | - Volker Hanf
- Frauenklinik Nathanstift – Klinikum Fürth, Fürth, Germany
| | | | - Olaf Ortmann
- Universität Regensburg, Fakultät für Medizin, Klinik für Frauenheilkunde und Geburtshilfe, Regensburg, Germany
| | - Thomas Römer
- Evangelisches Klinikum Köln Weyertal, Gynäkologie Köln, Köln, Germany
| | - Rita K. Schmutzler
- Universitätsklinikum Köln, Zentrum Familiärer Brust- und Eierstockkrebs, Köln, Germany
| | | | - Stefan Kommoss
- Universitätsklinikum Tübingen, Universitätsfrauenklinik Tübingen, Tübingen, Germany
| | - Sigurd Lax
- Institut für Pathologie, LKH Graz Süd-West, Graz, Austria
| | | | - Theresa Mokry
- Universitätsklinikum Heidelberg, Diagnostische und Interventionelle Radiologie, Heidelberg, Germany
| | - Dieter Grab
- Universitätsklinikum Ulm, Frauenheilkunde und Geburtshilfe, Ulm, Germany
| | - Michael Reinhardt
- Klinik für Nuklearmedizin, Pius Hospital Oldenburg, Oldenburg, Germany
| | - Verena Steinke-Lange
- MGZ – Medizinisch Genetisches Zentrum München, München, Germany
- Medizinische Klinik und Poliklinik IV, LMU München, München, Germany
| | - Sara Y. Brucker
- Universitätsklinikum Tübingen, Universitätsfrauenklinik Tübingen, Tübingen, Germany
| | - Ludwig Kiesel
- Universitätsklinikum Münster, Frauenklinik A Schweitzer Campus 1, Münster, Germany
| | - Ralf Witteler
- Universitätsklinikum Münster, Frauenklinik A Schweitzer Campus 1, Münster, Germany
| | - Markus C. Fleisch
- Helios, Universitätsklinikum Wuppertal, Landesfrauenklinik, Wuppertal, Germany
| | | | - Michael Friedrich
- Helios Klinikum Krefeld, Klinik für Frauenheilkunde und Geburtshilfe, Krefeld, Germany
| | - Stefan Höcht
- XCare, Praxis für Strahlentherapie Saarlouis, Saarlouis, Germany
| | - Werner Lichtenegger
- Universitätsmedizin Berlin, Frauenklinik Charité, Campus Virchow-Klinikum, Berlin, Germany
| | - Michael Mueller
- Universitätsklinik für Frauenheilkunde, Inselspital Bern, Bern, Switzerland
| | | | - Petra Feyer
- Vivantes Klinikum Neukölln, Klinik für Strahlentherapie und Radioonkologie, Berlin, Germany
| | - Volker Hagen
- Klinik für Innere Medizin II, St.-Johannes-Hospital Dortmund, Dortmund, Germany
| | | | - Anne Letsch
- Universitätsklinikum Schleswig Holstein, Campus Kiel, Innere Medizin, Kiel, Germany
| | - Peter Niehoff
- Strahlenklinik, Sana Klinikum Offenbach, Offenbach, Germany
| | - Alain Gustave Zeimet
- Medizinische Universität Innsbruck, Universitätsklinik für Gynäkologie und Geburtshilfe, Innsbruck, Austria
| | | | - Edgar Petru
- Med. Univ. Graz, Frauenheilkunde, Graz, Austria
| | | | - Birgitt van Oorschot
- Universitätsklinikum Würzburg, Interdisziplinäres Zentrum Palliativmedizin, Würzburg, Germany
| | - Joan Elisabeth Panke
- Medizinischer Dienst des Spitzenverbandes Bund der Krankenkassen e. V. Essen, Essen, Germany
| | - Joachim Weis
- Albert-Ludwigs-Universität Freiburg, Medizinische Fakultät, Tumorzentrum Freiburg – CCCF, Freiburg, Germany
| | - Timm Dauelsberg
- Universitätsklinikum Freiburg, Klinik für Onkologische Rehabilitation, Freiburg, Germany
| | | | | | | | - Edward Wight
- Frauenklinik des Universitätsspitals Basel, Basel, Switzerland
| | - Franz-Josef Prott
- Facharzt für Radiologie und Strahlentherapie, Wiesbaden, Wiesbaden, Germany
| | - Oliver Micke
- Franziskus Hospital Bielefeld, Klinik für Strahlentherapie und Radioonkologie, Bielefeld, Germany
| | - Werner Bader
- Klinikum Bielefeld Mitte, Zentrum für Frauenheilkunde, Bielefeld, Germany
| | | | | | | | | | | | - Doris Mayr
- LMU München, Pathologisches Institut, München, Germany
| | - Michael Kreißl
- Universität Magdeburg, Medizinische Fakultät, Universitätsklinik für Radiologie und Nuklearmedizin, Germany
| | - Katja Lindel
- Städtisches Klinikum Karlsruhe, Karlsruhe, Germany
| | - Alexander Mustea
- Universitätsklinikum Bonn, Zentrum Gynäkologie und gynäkologische Onkologie, Bonn, Germany
| | - Vratislav Strnad
- Universitätsklinikum Erlangen, Brustzentrum Franken, Erlangen, Germany
| | - Ute Goerling
- Universitätsmedizin Berlin, Campus Charité Mitte, Charité Comprehensive Cancer Center, Berlin, Germany
| | - Gerd J. Bauerschmitz
- Universitätsmedizin Göttingen, Klinik für Gynäkologie und Geburtshilfe, Göttingen, Germany
| | - Jan Langrehr
- Martin-Luther-Krankenhaus, Klinik für Allgemein-, Gefäß- und Viszeralchirurgie, Berlin, Germany
| | - Joseph Neulen
- Uniklinik RWTH Aachen, Klinik für Gynäkologische Endokrinologie und Reproduktionsmedizin, Aachen, Germany
| | - Uwe Andreas Ulrich
- Martin-Luther-Krankenhaus, Johannesstift Diakonie, Gynäkologie, Berlin, Germany
| | | | | | - Markus Follmann
- Deutsche Krebsgesellschaft, Office des Leitlinienprogramms Onkologie, Berlin, Germany
| | - Thomas Langer
- Deutsche Krebsgesellschaft, Office des Leitlinienprogramms Onkologie, Berlin, Germany
| | - Gregor Wenzel
- Deutsche Krebsgesellschaft, Office des Leitlinienprogramms Onkologie, Berlin, Germany
| | - Sylvia Weber
- Universitätsmedizin Göttingen, Klinik für Gynäkologie und Geburtshilfe, Göttingen, Germany
| | - Saskia Erdogan
- Universitätsmedizin Göttingen, Klinik für Gynäkologie und Geburtshilfe, Göttingen, Germany
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Leo J, Dondossola E, Basham KJ, Wilson NR, Alhalabi O, Gao J, Kurnit KC, White MG, McQuade JL, Westin SN, Wellberg EA, Frigo DE. Stranger Things: New Roles and Opportunities for Androgen Receptor in Oncology Beyond Prostate Cancer. Endocrinology 2023; 164:bqad071. [PMID: 37154098 PMCID: PMC10413436 DOI: 10.1210/endocr/bqad071] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 04/25/2023] [Accepted: 05/05/2023] [Indexed: 05/10/2023]
Abstract
The androgen receptor (AR) is one of the oldest therapeutic targets in oncology and continues to dominate the treatment landscape for advanced prostate cancer, where nearly all treatment regimens include some form of AR modulation. In this regard, AR remains the central driver of prostate cancer cell biology. Emerging preclinical and clinical data implicate key roles for AR in additional cancer types, thereby expanding the importance of this drug target beyond prostate cancer. In this mini-review, new roles for AR in other cancer types are discussed as well as their potential for treatment with AR-targeted agents. Our understanding of these additional functions for AR in oncology expand this receptor's potential as a therapeutic target and will help guide the development of new treatment approaches.
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Affiliation(s)
- Javier Leo
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
- The University of Texas MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA
| | - Eleonora Dondossola
- Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Kaitlin J Basham
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Nathaniel R Wilson
- Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Omar Alhalabi
- Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jianjun Gao
- Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Katherine C Kurnit
- Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, The University of Chicago, Chicago, IL 60637, USA
| | - Michael G White
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jennifer L McQuade
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Shannon N Westin
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Elizabeth A Wellberg
- Department of Pathology, Harold Hamm Diabetes Center, and Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Daniel E Frigo
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
- Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204, USA
- Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA
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10
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Johnson JE, Daley D, Tarta C, Stanciu PI. Risk of endometrial cancer in patients with polycystic ovarian syndrome: A meta‑analysis. Oncol Lett 2023; 25:168. [PMID: 36960190 PMCID: PMC10028221 DOI: 10.3892/ol.2023.13754] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 11/30/2022] [Indexed: 03/25/2023] Open
Abstract
While existing literature suggests an association between polycystic ovarian syndrome (PCOS) and endometrial cancer, the sparsity and inconsistency of current evidence indicates a lack of clarity regarding the exact strength of this association. It also remains uncertain whether the degree of risk of disease is affected by confounding factors, such as age and body mass index (BMI). The present meta-analysis is aimed to quantify the risk of endometrial cancer in female subjects with PCOS compared to those without PCOS. PubMed, MEDLINE, EMBASE, Scopus and Cochrane were searched from inception to October 31, 2022, to identify peer-reviewed case-control, cohort and cross-sectional studies that assessed the association between endometrial cancer and PCOS and contained original data. Two researchers independently extracted data and performed quality assessment using the Newcastle-Ottawa criteria. Pooled odds ratios (ORs) were calculated using the random-effect model and inverse variance. The degree of heterogeneity was assessed using I2 statistics. A total of 10 relevant studies were identified and included in the meta-analysis (comprising 12,248 female patients with PCOS and 54,120 controls). Females with PCOS had a significantly increased odds of developing endometrial cancer as compared to those without PCOS [OR, 4.07; 95% confidence interval (CI), 2.13-7.78; P<0.0001]. When postmenopausal subjects (age, >54 years) were excluded from the meta-analysis, the odds increased further (OR, 5.14; 95% CI, 3.22-8.21; P<0.00001). Patients with PCOS are up to 5 times more likely to develop endometrial cancer compared to those without PCOS. Larger, prospective studies that are well-controlled for confounding factors, such as BMI, are required.
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Affiliation(s)
- Jean-Ellen Johnson
- Gynaecological Oncology Department, Watford General Hospital, West Hertfordshire Teaching Hospitals NHS Trust, Watford, West Hertfordshire, WD18 0HB, UK
| | - Diandra Daley
- Gynaecological Oncology Department, Watford General Hospital, West Hertfordshire Teaching Hospitals NHS Trust, Watford, West Hertfordshire, WD18 0HB, UK
- Correspondence to: Dr Diandra Daley, Gynaecological Oncology Department, Watford General Hospital, West Hertfordshire Teaching Hospitals NHS Trust, Vicarage Road, Watford, West Hertfordshire, WD18 0HB, United Kingdom, E-mail:
| | - Cristi Tarta
- Department X, 2nd Surgical Clinic, ‘Victor Babes’ University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Paul I. Stanciu
- Gynaecological Oncology Department, Watford General Hospital, West Hertfordshire Teaching Hospitals NHS Trust, Watford, West Hertfordshire, WD18 0HB, UK
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11
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Violette CJ, Agarwal R, Mandelbaum RS, González JL, Hong KM, Roman LD, Klar M, Wright JD, Paulson RJ, Obermair A, Matsuo K. The potential role of GLP-1 receptor agonist targeting in fertility-sparing treatment in obese patients with endometrial malignant pathology: a call for research. Expert Rev Anticancer Ther 2023; 23:385-395. [PMID: 36944434 DOI: 10.1080/14737140.2023.2194636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/23/2023]
Abstract
INTRODUCTION Most patients diagnosed with endometrial hyperplasia or cancer are obese. Obesity, along with polycystic ovarian syndrome (PCOS) and type-2 diabetes mellitus (T2DM), may act synergistically to increase risk of malignant endometrial pathology. Incidence of malignant endometrial pathology is increasing, particularly in reproductive aged women. In patients who desire future fertility, the levonorgestrel intrauterine device (LNG-IUD) is often utilized. If the first-line progestin therapy fails, there is not an effective second-line adjunct option. Moreover, pregnancy rates following fertility-sparing treatment are lower-than-expected in these patients. AREAS COVERED This clinical opinion provides a summary of recent studies exploring risk factors for the development of malignant endometrial pathology including obesity, PCOS, and T2DM. Studies assessing efficacy of fertility-sparing treatment of malignant endometrial pathology are reviewed and a potential new adjunct treatment approach to LNG-IUD is explored. EXPERT OPINION There is an unmet-need for a personalized treatment approach in cases of first-line progestin treatment failure. Glucagon-like peptide 1 receptor agonists are a class of anti-diabetic agents, but may have a role in fertility-sparing treatment of obese patients with malignant endometrial pathology by reducing weight, decreasing inflammation, and decreasing insulin resistance; these changes may also improve chances of subsequent pregnancy. This hypothesis warrants further exploration.
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Affiliation(s)
- Caroline J Violette
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA
| | - Ravi Agarwal
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA
| | - Rachel S Mandelbaum
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA
| | - José L González
- Department of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Kurt M Hong
- Center of Clinical Nutrition and Applied Health Research, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA
| | - Lynda D Roman
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA
| | - Maximilan Klar
- Department of Obstetrics and Gynecology, University of Freiburg Faculty of Medicine, Freiburg, Germany
| | - Jason D Wright
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - Richard J Paulson
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA
| | - Andreas Obermair
- Queensland Centre for Gynaecological Cancer, The University of Queensland, Herston, Queensland, Australia
- Centre for Clinical Research, University of Queensland, Brisbane, Australia
| | - Koji Matsuo
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
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12
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Allen LA, Shrikrishnapalasuriyar N, Rees DA. Long-term health outcomes in young women with polycystic ovary syndrome: A narrative review. Clin Endocrinol (Oxf) 2022; 97:187-198. [PMID: 34617616 DOI: 10.1111/cen.14609] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 09/22/2021] [Accepted: 10/03/2021] [Indexed: 11/29/2022]
Abstract
Polycystic ovary syndrome (PCOS) has long been recognized as a common disorder in young women leading to reproductive and cutaneous sequelae. However, the associated health risks are now known to extend beyond these familiar manifestations to a range of longer-term comorbidities. Here we review the evidence for an association of PCOS with adverse long-term health outcomes, discussing the pathophysiological mechanisms involved in addition to opportunities for therapeutic intervention. Cross-sectional and longitudinal studies point to an increased risk of type 2 diabetes, hypertension and dyslipidaemia, with recent data confirming that these translate to an increased risk of cardiovascular events independently of obesity. Obstructive sleep apnoea, nonalcoholic fatty liver disease and endometrial cancer are also more prevalent, while mental health disorders, notably anxiety and depression, are common but under-appreciated associations. Uncertainties remain as to whether these risks are apparent in all patients with PCOS or are confined to particular subtypes, whether risks persist post-menopausally and how risk may be affected by ethnicity. Further work is also needed in establishing if systematic screening and targeted intervention can lead to improved outcomes. Until such data are available, clinicians managing women with PCOS should counsel patients on long-term health risks and invest in strategies that limit progression to metabolic and non-metabolic morbidities.
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Affiliation(s)
- Lowri A Allen
- Diabetes Research Group, School of Medicine, Cardiff University, Cardiff, UK
| | | | - Dafydd Aled Rees
- Neuroscience and Mental Health Research Institute, School of Medicine, Cardiff University, Cardiff, UK
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13
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Li Z, Wang YH, Wang LL, Hu DT, Teng Y, Zhang TY, Yan ZY, Wang F, Zou YF. Polycystic ovary syndrome and the risk of endometrial, ovarian and breast cancer: An updated meta-analysis. Scott Med J 2022; 67:109-120. [PMID: 35686317 DOI: 10.1177/00369330221107099] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS This updated meta-analysis aimed to further quantify the risk of endometrial, ovarian, and breast cancer in patients with polycystic ovary syndrome (PCOS), thus providing updated and more reliable estimates. METHODS AND RESULTS We identified relevant articles by searching electronic databases of PubMed, Embase, Web of Science, and Chinese Biological Medical Literature (CBM) published up to March 20, 2021. The pooled effect estimates and their 95% confidence intervals (CIs) were calculated using the random-effect model or the fixed-effect model. A total of 26 eligible studies were included. We found that PCOS was significantly associated with endometrial cancer (odds ratios [OR]: 3.66, 95%CI: 2.05-6.54, P < 0.001), but not with ovarian or breast cancer (OR: 1.23, 95%CI: 0.99-1.53, P = 0.059; OR: 0.94, 95%CI: 0.78-1.14, P = 0.551, respectively). However, in subgroups of high-quality studies, cohort studies, younger women (54 years or less or premenopausal), and studies with unadjusted body mass index (BMI), PCOS patients had a significantly higher risk of ovarian cancer. CONCLUSION These results indicated that PCOS is a significant risk factor for endometrial cancer independent of BMI, but not for breast cancer. PCOS may increase the risk of ovarian cancer in younger women.
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Affiliation(s)
- Zhen Li
- Department of Epidemiology and Biostatistics, School of Public Health, 569061Anhui Medical University, Hefei 230032, Anhui, China
| | - Yu-Hua Wang
- Department of Epidemiology and Biostatistics, School of Public Health, 569061Anhui Medical University, Hefei 230032, Anhui, China
| | - Lin-Lin Wang
- Department of Epidemiology and Biostatistics, School of Public Health, 569061Anhui Medical University, Hefei 230032, Anhui, China
| | - Ding-Tao Hu
- Department of Oncology, 36639The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China
| | - Ying Teng
- Department of Epidemiology and Biostatistics, School of Public Health, 569061Anhui Medical University, Hefei 230032, Anhui, China
| | - Ting-Yu Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, 569061Anhui Medical University, Hefei 230032, Anhui, China
| | - Zi-Ye Yan
- Department of Epidemiology and Biostatistics, School of Public Health, 569061Anhui Medical University, Hefei 230032, Anhui, China
| | - Fang Wang
- Department of Oncology, 36639The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China
| | - Yan-Feng Zou
- Department of Epidemiology and Biostatistics, School of Public Health, 569061Anhui Medical University, Hefei 230032, Anhui, China
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14
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Ali M, Mumtaz M, Naqvi Z, Farooqui R, Shah SA. Assessing Tumor Size by MRI and Pathology in Type I Endometrial Carcinoma to Predict Lymph Node Metastasis. Cureus 2022; 14:e23135. [PMID: 35444870 PMCID: PMC9009998 DOI: 10.7759/cureus.23135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/14/2022] [Indexed: 11/29/2022] Open
Abstract
Introduction Lymphatic spread is the most common route of spread of endometrial carcinoma, and the most frequently involved lymph nodes are those of the external iliac group. MRI is one of the best imaging tools for the preoperative evaluation of patients with endometrial carcinoma. The objective of the current study is to analyze the relationship between tumor size and lymph node metastasis in patients with type I endometrial carcinoma. Methods This is a prospective observational study performed in the Department of Obstetrics and Gynaecology at Liaquat National Hospital, Karachi, Pakistan. The duration of the study was from January 2020 to January 2021. During this period, 86 patients with biopsy-proven type I endometrial carcinoma were selected. Tumor size was measured by MRI. All participants underwent a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and bilateral pelvic lymphadenectomy. Histopathological evaluation was performed according to the College of American Pathologists (CAP) protocols, and staging was performed using the 2009 International Federation of Gynecology and Obstetrics (FIGO) staging system. Lymph nodes were considered positive or negative, irrespective of their number. Result Of the 86 patients, 25 (29.1%) had positive lymph node metastasis. The mean tumor size with positive lymph node metastasis by MRI and histopathology was 7.86 cm and 10.21 cm, respectively. Tumor size determined by MRI and histopathology was significantly associated with lymph node metastasis (p < 0.01 and p < 0.01, respectively). Tumor size was positively correlated with lymph node metastasis (r = 0.715). The cutoff value of >6.5 cm by MRI was established as the statistically significant differentiator of lymph node metastasis. The calculated sensitivity and specificity were 88% and 90.16%, respectively, with an area under the curve (AUC) of 0.920. The cutoff value of >8 cm by histopathology was established as the statistically significant differentiator of lymph node metastasis. The calculated sensitivity and specificity were 80% and 88.52%, respectively, with an AUC of 0.907. Conclusion Our results showed that lymph node metastasis in patients with type I endometrial carcinoma can be predicted by tumor size. This may help incorporate adequate surgical skills and management plans in the treatment course of type I endometrial carcinoma.
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15
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Effect modification of body mass index on the association between ovarian cysts and endometrial cancer. Cancer Epidemiol 2022; 78:102129. [PMID: 35272258 DOI: 10.1016/j.canep.2022.102129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 03/01/2022] [Accepted: 03/03/2022] [Indexed: 11/23/2022]
Abstract
BACKGROUND Ovarian cysts represent a common condition among women. Epidemiologic studies are inconsistent in determining if women with cysts are more likely to develop endometrial cancer (EC) regardless of overweight/obesity. We investigated the combined role of cysts and body mass index (BMI) on EC risk. METHODS We pooled data from three case-control studies conducted in Italy and Switzerland on 920 women with EC and 1700 controls. The prevalence of cysts was 5% among both cases and controls, with 63% of cases being overweight/obese. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression models, adjusting for potential confounders. We conducted stratified analyses according to BMI, and estimated the interaction between cysts and BMI; we carried out additional analyses according to age at diagnosis of cysts. RESULTS Overall, history of cysts was not associated to EC (OR=1.27, 95% CI=0.82-1.97, P = 0.29). Normal weight women reporting cysts had an increased risk of EC (OR=2.49, 95% CI=1.31-4.74), while no such effect was found among overweight/obese women (OR=0.65, 95% CI=0.36-1.18; P for interaction=0.004). The association was limited to women below 65 years of age and was stronger in those who reported cysts at age 48 or older. CONCLUSIONS Cysts appeared to be a risk factor for EC in lean women but not in overweight/obese ones; these results are consistent with an effect of cysts and obesity on EC along common pathways.
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16
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MacLean JA, Hayashi K. Progesterone Actions and Resistance in Gynecological Disorders. Cells 2022; 11:647. [PMID: 35203298 PMCID: PMC8870180 DOI: 10.3390/cells11040647] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/10/2022] [Accepted: 02/11/2022] [Indexed: 02/06/2023] Open
Abstract
Estrogen and progesterone and their signaling mechanisms are tightly regulated to maintain a normal menstrual cycle and to support a successful pregnancy. The imbalance of estrogen and progesterone disrupts their complex regulatory mechanisms, leading to estrogen dominance and progesterone resistance. Gynecological diseases are heavily associated with dysregulated steroid hormones and can induce chronic pelvic pain, dysmenorrhea, dyspareunia, heavy bleeding, and infertility, which substantially impact the quality of women's lives. Because the menstrual cycle repeatably occurs during reproductive ages with dynamic changes and remodeling of reproductive-related tissues, these alterations can accumulate and induce chronic and recurrent conditions. This review focuses on faulty progesterone signaling mechanisms and cellular responses to progesterone in endometriosis, adenomyosis, leiomyoma (uterine fibroids), polycystic ovary syndrome (PCOS), and endometrial hyperplasia. We also summarize the association with gene mutations and steroid hormone regulation in disease progression as well as current hormonal therapies and the clinical consequences of progesterone resistance.
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Affiliation(s)
- James A. MacLean
- Center for Reproductive Biology, School of Molecular Biosciences, Washington State University, 1770 NE Stadium Way, Pullman, WA 99164, USA
| | - Kanako Hayashi
- Center for Reproductive Biology, School of Molecular Biosciences, Washington State University, 1770 NE Stadium Way, Pullman, WA 99164, USA
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17
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Patel VH. Polycystic Ovarian Syndrome: An Autobiographical Case Report of an Often Overlooked Disorder. Cureus 2022; 14:e21171. [PMID: 35165620 PMCID: PMC8835484 DOI: 10.7759/cureus.21171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/12/2022] [Indexed: 12/01/2022] Open
Abstract
Polycystic ovary syndrome (PCOS) is a highly prevalent disease seen in women of reproductive age, and yet a majority of cases go undiagnosed. This autobiographical case report describes a young doctor's experience with PCOS and attempts to highlight the significance of a missed diagnosis. In addition to the endocrine system, PCOS affects the metabolic, reproductive, mental, and psychosocial health of women. Manifested symptoms are just the tip of the iceberg, and addressing what's underneath is the real challenge. The disease in its untreated and undiagnosed forms leads to a series of co-morbidities including, but not limited to, obesity, infertility, diabetes mellitus, cardiovascular disease, and cancer. Additionally, the emotional burden in PCOS women is a major threat to their quality of life and needs separate acknowledgment. PCOS is a pressing issue; the long-term consequences on physical and mental health need to be taken seriously.
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18
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Lai W, He S, Zhou D, Chen L. Managing reproductive problems in women with epilepsy of childbearing age. ACTA EPILEPTOLOGICA 2021. [DOI: 10.1186/s42494-021-00062-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
AbstractGirls and women constitute nearly 50% of all epilepsy cases. Apart from the disease symptoms, epilepsy and antiseizure medications (ASMs) may also affect the reproductive function, pregnancy and even the health of their offspring. Therefore, it is very important to identify and summarize the problems and risks for women with epilepsy (WWE) of childbearing age, and offer internationally recognized methods through multidisciplinary collaboration. In this review, we summarize the reproduction-related problems with WWE and propose multidisciplinary management by epileptologists, gynecologists and obstetricians, as well as other experts, from preconception to delivery. Large, multicenter registries are needed to advance our knowledge on new ASMs and their effects on WWE and their offspring.
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Hutt S, Mihaies D, Karteris E, Michael A, Payne AM, Chatterjee J. Statistical Meta-Analysis of Risk Factors for Endometrial Cancer and Development of a Risk Prediction Model Using an Artificial Neural Network Algorithm. Cancers (Basel) 2021; 13:cancers13153689. [PMID: 34359595 PMCID: PMC8345114 DOI: 10.3390/cancers13153689] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 07/05/2021] [Accepted: 07/09/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary A robust and comprehensive meta-analysis, for the first time, identified definitely that BMI is by far the most influential risk factor in endometrial cancer. Risk factors were previously only studied individually and or in smaller meta-analysis studies which grouped some factors together. BMI was shown to be an important risk factor with other factors less so, but no rank order was established. This work also offers, for the first time, a neural network computer model to predict the overall increase or decreased risk of cancer for individual patients, which is 98.6% accurate. This prediction can be used as a tool to determine if a patient should be considered for testing and to predict diagnosis, as well as to suggest prevention measures to patients. Abstract Objectives: In this study we wished to determine the rank order of risk factors for endometrial cancer and calculate a pooled risk and percentage risk for each factor using a statistical meta-analysis approach. The next step was to design a neural network computer model to predict the overall increase or decreased risk of cancer for individual patients. This would help to determine whether this prediction could be used as a tool to decide if a patient should be considered for testing and to predict diagnosis, as well as to suggest prevention measures to patients. Design: A meta-analysis of existing data was carried out to calculate relative risk, followed by design and implementation of a risk prediction computational model based on a neural network algorithm. Setting: Meta-analysis data were collated from various settings from around the world. Primary data to test the model were collected from a hospital clinic setting. Participants: Data from 40 patients notes currently suspected of having endometrial cancer and undergoing investigations and treatment were collected to test the software with their cancer diagnosis not revealed to the software developers. Main outcome measures: The forest plots allowed an overall relative risk and percentage risk to be calculated from all the risk data gathered from the studies. A neural network computational model to determine percentage risk for individual patients was developed, implemented, and evaluated. Results: The results show that the greatest percentage increased risk was due to BMI being above 25, with the risk increasing as BMI increases. A BMI of 25 or over gave an increased risk of 2.01%, a BMI of 30 or over gave an increase of 5.24%, and a BMI of 40 or over led to an increase of 6.9%. PCOS was the second highest increased risk at 4.2%. Diabetes, which is incidentally also linked to an increased BMI, gave a significant increased risk along with null parity and noncontinuous HRT of 1.54%, 1.2%, and 0.56% respectively. Decreased risk due to contraception was greatest with IUD (intrauterine device) and IUPD (intrauterine progesterone device) at −1.34% compared to −0.9% with oral. Continuous HRT at −0.75% and parity at −0.9% also decreased the risk. Using open-source patient data to test our computational model to determine risk, our results showed that the model is 98.6% accurate with an algorithm sensitivity 75% on average. Conclusions: In this study, we successfully determined the rank order of risk factors for endometrial cancer and calculated a pooled risk and risk percentage for each factor using a statistical meta-analysis approach. Then, using a computer neural network model system, we were able to model the overall increase or decreased risk of cancer and predict the cancer diagnosis for particular patients to an accuracy of over 98%. The neural network model developed in this study was shown to be a potentially useful tool in determining the percentage risk and predicting the possibility of a given patient developing endometrial cancer. As such, it could be a useful tool for clinicians to use in conjunction with other biomarkers in determining which patients warrant further preventative interventions to avert progressing to endometrial cancer. This result would allow for a reduction in the number of unnecessary invasive tests on patients. The model may also be used to suggest interventions to decrease the risk for a particular patient. The sensitivity of the model limits it at this stage due to the small percentage of positive cases in the datasets; however, since this model utilizes a neural network machine learning algorithm, it can be further improved by providing the system with more and larger datasets to allow further refinement of the neural network.
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Affiliation(s)
- Suzanna Hutt
- Academic Department of Gynaecological Oncology, Royal Surrey NHS Foundation Trust Hospital, Guildford GU2 7XX, UK; (S.H.); (A.M.); (J.C.)
- Department of Clinical and Experimental Medicine, Faculty of Health and Medical Sciences, School of Biosciences and Medicine, University of Surrey, Guildford GU2 7XH, UK
| | - Denis Mihaies
- Department of Computer Science, College of Engineering, Design and Physical Sciences, Brunel University, London UB8 3PN, UK;
| | - Emmanouil Karteris
- Department of Life Sciences, Division of Biosciences, College of Health, Medicine and Life Sciences, Brunel University, London UB8 3PN, UK;
| | - Agnieszka Michael
- Academic Department of Gynaecological Oncology, Royal Surrey NHS Foundation Trust Hospital, Guildford GU2 7XX, UK; (S.H.); (A.M.); (J.C.)
| | - Annette M. Payne
- Department of Computer Science, College of Engineering, Design and Physical Sciences, Brunel University, London UB8 3PN, UK;
- Correspondence:
| | - Jayanta Chatterjee
- Academic Department of Gynaecological Oncology, Royal Surrey NHS Foundation Trust Hospital, Guildford GU2 7XX, UK; (S.H.); (A.M.); (J.C.)
- Department of Clinical and Experimental Medicine, Faculty of Health and Medical Sciences, School of Biosciences and Medicine, University of Surrey, Guildford GU2 7XH, UK
- Department of Cancer and Surgery, Imperial College London, London SW7 2BX, UK
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20
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Kho PF, Mortlock S, Rogers PAW, Nyholt DR, Montgomery GW, Spurdle AB, Glubb DM, O'Mara TA. Genetic analyses of gynecological disease identify genetic relationships between uterine fibroids and endometrial cancer, and a novel endometrial cancer genetic risk region at the WNT4 1p36.12 locus. Hum Genet 2021; 140:1353-1365. [PMID: 34268601 DOI: 10.1007/s00439-021-02312-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 07/05/2021] [Indexed: 12/27/2022]
Abstract
Endometriosis, polycystic ovary syndrome (PCOS) and uterine fibroids have been proposed as endometrial cancer risk factors; however, disentangling their relationships with endometrial cancer is complicated due to shared risk factors and comorbidities. Using genome-wide association study (GWAS) data, we explored the relationships between these non-cancerous gynecological diseases and endometrial cancer risk by assessing genetic correlation, causal relationships and shared risk loci. We found significant genetic correlation between endometrial cancer and PCOS, and uterine fibroids. Adjustment for genetically predicted body mass index (a risk factor for PCOS, uterine fibroids and endometrial cancer) substantially attenuated the genetic correlation between endometrial cancer and PCOS but did not affect the correlation with uterine fibroids. Mendelian randomization analyses suggested a causal relationship between only uterine fibroids and endometrial cancer. Gene-based analyses revealed risk regions shared between endometrial cancer and endometriosis, and uterine fibroids. Multi-trait GWAS analysis of endometrial cancer and the genetically correlated gynecological diseases identified a novel genome-wide significant endometrial cancer risk locus at 1p36.12, which replicated in an independent endometrial cancer dataset. Interrogation of functional genomic data at 1p36.12 revealed biologically relevant genes, including WNT4 which is necessary for the development of the female reproductive system. In summary, our study provides genetic evidence for a causal relationship between uterine fibroids and endometrial cancer. It further provides evidence that the comorbidity of endometrial cancer, PCOS and uterine fibroids may partly be due to shared genetic architecture. Notably, this shared architecture has revealed a novel genome-wide risk locus for endometrial cancer.
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Affiliation(s)
- Pik Fang Kho
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.,School of Biomedical Science, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia
| | - Sally Mortlock
- The Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
| | | | | | - Peter A W Rogers
- Department of Obstetrics and Gynaecology, Gynaecology Research Centre, Royal Women's Hospital, University of Melbourne, Parkville, VIC, Australia
| | - Dale R Nyholt
- School of Biomedical Science, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia
| | - Grant W Montgomery
- The Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
| | - Amanda B Spurdle
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Dylan M Glubb
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Tracy A O'Mara
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. .,Molecular Cancer Epidemiology Group, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD, 4006, Australia.
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21
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Hu M, Zhang Y, Li X, Cui P, Li J, Brännström M, Shao LR, Billig H. Alterations of endometrial epithelial-mesenchymal transition and MAPK signalling components in women with PCOS are partially modulated by metformin in vitro. Mol Hum Reprod 2021; 26:312-326. [PMID: 32202622 DOI: 10.1093/molehr/gaaa023] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 02/20/2020] [Indexed: 12/13/2022] Open
Abstract
Growing evidence suggests that epithelial-mesenchymal transition (EMT) and its regulator mitogen-activated protein kinase (MAPK) contribute to endometria-related reproductive disorders. However, the regulation of EMT and MAPK signalling components in the endometrium from polycystic ovary syndrome (PCOS) patients has not been systematically investigated and remains elusive. In humans, how metformin induces molecular alterations in the endometrial tissues under PCOS conditions is not completely clear. Here, we recruited 7 non-PCOS patients during the proliferative phase (nPCOS), 7 non-PCOS patients with endometrial hyperplasia (nPCOSEH), 14 PCOS patients during the proliferative phase (PCOS) and 3 PCOS patients with endometrial hyperplasia (PCOSEH). Our studies demonstrated that compared with nPCOS, PCOS patients showed decreased Claudin 1 and increased Vimentin and Slug proteins. Similar to increased Slug protein, nPCOSEH and PCOSEH patients showed increased N-cadherin protein. Western blot and immunostaining revealed increased epithelial phosphorylated Cytokeratin 8 (p-CK 8) expression and an increased p-CK 8:CK 8 ratio in PCOS, nPCOSEH and PCOSEH patients compared to nPCOS patients. Although nPCOSEH and PCOSEH patients showed increased p-ERK1/2 and/or p38 protein levels, the significant increase in p-ERK1/2 expression and p-ERK1/2:ERK1/2 ratio was only found in PCOS patients compared to nPCOS patients. A significant induction of the membrane ERβ immunostaining was observed in the epithelial cells of PCOS and PCOSEH patients compared to nPCOS and nPCOSEH patients. While in vitro treatment with metformin alone increased Snail and decreased Claudin 1, N-cadherin and α-SMA proteins, concomitant treatment with metformin and E2 increased the expression of CK 8 and Snail proteins and decreased the expression of Claudin 1, ZO-1, Slug and α-SMA proteins. Our findings suggest that the EMT contributes to the switch from a healthy state to a PCOS state in the endometrium, which might subsequently drive endometrial injury and dysfunction. We also provide evidence that metformin differentially modulates EMT protein expression in PCOS patients depending on oestrogenic stimulation.
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Affiliation(s)
- Min Hu
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, 510120 Guangzhou, China.,Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden
| | - Yuehui Zhang
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden.,Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 150040 Harbin, China
| | - Xin Li
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden.,Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 200011 Shanghai, China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, 200011 Shanghai, China
| | - Peng Cui
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden.,Department of Obstetrics and Gynecology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 201203 Shanghai, China
| | - Juan Li
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, 510120 Guangzhou, China.,Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden
| | - Mats Brännström
- Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Sahlgrenska Academy, University of Gothenburg, 41345 Gothenburg, Sweden
| | - Linus R Shao
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden
| | - Håkan Billig
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden
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22
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Bianchi VE, Bresciani E, Meanti R, Rizzi L, Omeljaniuk RJ, Torsello A. The role of androgens in women's health and wellbeing. Pharmacol Res 2021; 171:105758. [PMID: 34242799 DOI: 10.1016/j.phrs.2021.105758] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/30/2021] [Accepted: 07/02/2021] [Indexed: 12/29/2022]
Abstract
Androgens in women, as well as in men, are intrinsic to maintenance of (i) reproductive competency, (ii) cardiac health, (iii) appropriate bone remodeling and mass retention, (iii) muscle tone and mass, and (iv) brain function, in part, through their mitigation of neurodegenerative disease effects. In recognition of the pluripotency of endogenous androgens, exogenous androgens, and selected congeners, have been prescribed off-label for several decades to treat low libido and sexual dysfunction in menopausal women, as well as, to improve physical performance. However, long-term safety and efficacy of androgen administration has yet to be fully elucidated. Side effects often observed include (i) hirsutism, (ii) acne, (iii) deepening of the voice, and (iv) weight gain but are associated most frequently with supra-physiological doses. By contrast, short-term clinical trials suggest that the use of low-dose testosterone therapy in women appears to be effective, safe and economical. There are, however, few clinical studies, which have focused on effects of androgen therapy on pre- and post-menopausal women; moreover, androgen mechanisms of action have not yet been thoroughly explained in these subjects. This review considers clinical effects of androgens on women's health in order to prevent chronic diseases and reduce cancer risk in gynecological tissues.
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Affiliation(s)
- Vittorio E Bianchi
- Endocrinology and Metabolism, Clinical Center Stella Maris, Strada Rovereta 42, Falciano 47891, San Marino.
| | - Elena Bresciani
- School of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, Monza 20900, Italy.
| | - Ramona Meanti
- School of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, Monza 20900, Italy.
| | - Laura Rizzi
- School of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, Monza 20900, Italy.
| | - Robert J Omeljaniuk
- Department of Biology, Lakehead University, 955 Oliver Rd, Thunder Bay, Ontario P7B 5E1, Canada.
| | - Antonio Torsello
- School of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, Monza 20900, Italy.
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23
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Yu Y, Tan P, Zhuang Z, Wang Z, Zhu L, Qiu R, Xu H. DIA proteomics analysis through serum profiles reveals the significant proteins as candidate biomarkers in women with PCOS. BMC Med Genomics 2021; 14:125. [PMID: 33964924 PMCID: PMC8106864 DOI: 10.1186/s12920-021-00962-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 04/14/2021] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND The aim of this study was to apply proteomic methodology for the analysis of proteome changes in women with polycystic ovary syndrome (PCOS). MATERIAL AND METHODS All the participators including 31 PCOS patients and 31 healthy female as controls were recruited, the clinical characteristics data was recorded at the time of recruitment, the laboratory biochemical data was detected. Then, a data-independent acquisition (DIA)-based proteomics method was performed to compare the serum protein changes between PCOS patients and controls. In addition, Western blotting was used to validate the expression of identified proteomic biomarkers. RESULTS There were 80 proteins differentially expressed between PCOS patients and controls significantly, including 54 downregulated and 26 upregulated proteins. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis showed that downregulated proteins were enriched in platelet degranulation, cell adhesion, cell activation, blood coagulation, hemostasis, defense response and inflammatory response terms; upregulated proteins were enriched in cofactor catabolic process, hydrogen peroxide catabolic process, antioxidant activity, cellular oxidant detoxification, cellular detoxification, antibiotic catabolic process and hydrogen peroxide metabolic process. Receiver operating characteristic curves analysis showed that the area under curve of Histone H4 (H4), Histone H2A (H2A), Trem-like transcript 1 protein (TLT-1) were all over than 0.9, indicated promising diagnosis values of these proteins. Western blotting results proved that the detected significant proteins, including H4, H2A, TLT-1, Peroxiredoxin-1, Band 3 anion transport protein were all differently expressed in PCOS and control groups significantly. CONCLUSION These proteomic biomarkers provided the potentiality to help us understand PCOS better, but future studies comparing systemic expression and exact role of these candidate biomarkers in PCOS are essential for confirmation of this hypothesis.
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Affiliation(s)
- Ying Yu
- Institute of Laboratory Medicine, Jiangsu Key Laboratory of Laboratory Medicine, Jiangsu University, No. 301 Xuefu Road, Zhenjiang, Jiangsu, 210013, People's Republic of China
- Department of Laboratory Medicine, Chinese Medicine Hospital of Zhejiang, Hangzhou, Zhejiang, 310006, People's Republic of China
| | - Panli Tan
- Department of Laboratory Medicine, Chinese Medicine Hospital of Zhejiang, Hangzhou, Zhejiang, 310006, People's Republic of China
| | - Zhenchao Zhuang
- Department of Laboratory Medicine, Chinese Medicine Hospital of Zhejiang, Hangzhou, Zhejiang, 310006, People's Republic of China
| | - Zhejiong Wang
- Department of Laboratory Medicine, Chinese Medicine Hospital of Zhejiang, Hangzhou, Zhejiang, 310006, People's Republic of China
| | - Linchao Zhu
- Department of Laboratory Medicine, Chinese Medicine Hospital of Zhejiang, Hangzhou, Zhejiang, 310006, People's Republic of China
| | - Ruyi Qiu
- Department of Laboratory Medicine, Chinese Medicine Hospital of Zhejiang, Hangzhou, Zhejiang, 310006, People's Republic of China
| | - Huaxi Xu
- Institute of Laboratory Medicine, Jiangsu Key Laboratory of Laboratory Medicine, Jiangsu University, No. 301 Xuefu Road, Zhenjiang, Jiangsu, 210013, People's Republic of China.
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24
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Abu Shahin N, Aladily T, Abu Alhaj N, Al-Khader A, Alqaqa S, Aljaberi R, Amer L, Elshebli S. Differential Expression of Androgen Receptor in Type I and Type II Endometrial Carcinomas: A Clinicopathological Analysis and Correlation with Outcome. Oman Med J 2021; 36:e245. [PMID: 33833869 PMCID: PMC8015675 DOI: 10.5001/omj.2021.53] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 08/26/2020] [Indexed: 12/30/2022] Open
Abstract
Objectives Endometrial carcinomas (EC) are the most common gynecological malignancies and are conventionally divided into type I and type II due to diagnostic and prognostic considerations. Female hormone expression in EC is extensively studied; however, data about androgen receptor (AR) expression in EC are sparse. We aimed to study AR expression in different types of EC at our institute and whether it had an impact on patient outcomes. Methods A retrospective analysis of EC cases diagnosed and treated from 2010–2019. AR immunohistochemical expression was tested in 52 EC cases (type I = 40; type II = 12). Histological typing was verified according to conventional diagnostic criteria. Only primary EC were included without neoadjuvant therapy. Histologic score was calculated as: stain intensity (graded 0–3) × positive cells percentage (graded 0–4). Level of expression was scored from 0 to 12. Results The mean age of the selected patients was 60.3 years (range = 31–88 ± 12.6). Recurrence was detected in 11 (21.2%) patients. The outcome was 40 patients were alive without disease, eight alive with disease, three dead of disease, and one dead of other causes. About 62.5% of type I-EC and 25.0% of type II-EC were AR positive. AR expression was analyzed against different clinicopathological parameters including: type (p = 0.005), histotype (p = 0.044); grade (p = 0.035); age group (p = 0.207); menopause (p = 0.086); estrogen receptor (ER) expression (p = 0.284); atypical complex hyperplasia (p = 0.594); tumor stage (p = 0.994); tumor recurrence (p = 0.530); node status (p = 0.110); and outcome (p = 0.202). Conclusion AR expression was higher in type I EC, endometrial endometrioid carcinoma histotype, and with a lower grade. AR expression was not significantly correlated with age, stage, ER, atypical hyperplasia, recurrence, node status, or outcome. Results agree with recent literature that AR expression is associated with better-differentiated EC and may be a potential hormonal therapeutic tool.
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Affiliation(s)
- Nisreen Abu Shahin
- Department of Pathology, Faculty of Medicine, University of Jordan, Amman, Jordan
| | - Tariq Aladily
- Department of Pathology, Faculty of Medicine, University of Jordan, Amman, Jordan
| | - Nezeen Abu Alhaj
- Department of Pathology, Faculty of Medicine, University of Jordan, Amman, Jordan
| | - Ali Al-Khader
- Department of Pathology, Faculty of Medicine, Al-Balqa Applied University, Salt, Jordan
| | - Shefa Alqaqa
- Department of Pathology, Faculty of Medicine, Al-Balqa Applied University, Salt, Jordan
| | | | - Lama Amer
- Faculty of Medicine,University of Jordan, Amman, Jordan
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25
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Hu M, Zhang Y, Li X, Cui P, Sferruzzi-Perri AN, Brännström M, Shao LR, Billig H. TLR4-Associated IRF-7 and NFκB Signaling Act as a Molecular Link Between Androgen and Metformin Activities and Cytokine Synthesis in the PCOS Endometrium. J Clin Endocrinol Metab 2021; 106:1022-1040. [PMID: 33382900 DOI: 10.1210/clinem/dgaa951] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Indexed: 12/19/2022]
Abstract
CONTEXT Low-grade chronic inflammation is commonly seen in polycystic ovary syndrome (PCOS) patients with elevated levels of inflammatory cytokines in the endometrium. OBJECTIVE This work aimed to increase the limited understanding of the mechanisms underlying cytokine synthesis and increased endometrial inflammation in PCOS patients. METHODS Endometrial biopsy samples were collected from non-PCOS (n = 17) and PCOS (n = 22) patients either during the proliferative phase of the menstrual cycle or with hyperplasia. Endometrial explants were prepared from PCOS patients and underwent pharmacological manipulation in vitro. The expression and localization of toll-like receptor 2 (TLR2)/4, key elements of innate immune signal transduction and nuclear factor κB (NFκB) signaling pathways, and multiple cytokines were comprehensively evaluated by Western blotting, immunohistochemistry, and immunofluorescence in endometrial tissues. RESULTS We demonstrated the distribution of protein expression and localization associated with the significantly increased androgen receptor, TLR2, and TLR4-mediated activation of interferon regulatory factor-7 (IRF-7) and NFκB signaling, cytokine production, and endometrial inflammation in PCOS patients compared to non-PCOS patients with and without endometrial hyperplasia. In vitro experiments showed that 5-dihydrotestosterone (DHT) enhanced androgen receptor, TLR4, IRF-7, and p-NFκB p65 protein expression along with increased interferon α (IFNα) and IFNɣ abundance. The effects of DHT on IRF-7, p-NFκB p65, and IFN abundance were abolished by flutamide, an antiandrogen. Although 17β-estradiol (E2) decreased p-IRF-7 expression with little effect on TLR-mediated IRF7 and NFκB signaling or on cytokine protein levels, exposure to metformin alone or in combination with E2 suppressed interleukin-1 receptor-associated kinase 4 (IRAK4), p-IRF-7, IRF-7, IκB kinase α (IKKα), p-NFκB p65, IFNɣ, and tumor necrosis factor α protein expression. CONCLUSION Cytokine synthesis and increased endometrial inflammation in PCOS patients are coupled to androgen-induced TLR4/IRF-7/NFκB signaling, which is inhibited by metformin treatment.
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Affiliation(s)
- Min Hu
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Yuehui Zhang
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Xin Li
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China
| | - Peng Cui
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Amanda Nancy Sferruzzi-Perri
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
| | - Mats Brännström
- Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Linus R Shao
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Håkan Billig
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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26
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Xu XL, Deng SL, Lian ZX, Yu K. Estrogen Receptors in Polycystic Ovary Syndrome. Cells 2021; 10:cells10020459. [PMID: 33669960 PMCID: PMC7924872 DOI: 10.3390/cells10020459] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/17/2021] [Accepted: 02/18/2021] [Indexed: 12/13/2022] Open
Abstract
Female infertility is mainly caused by ovulation disorders, which affect female reproduction and pregnancy worldwide, with polycystic ovary syndrome (PCOS) being the most prevalent of these. PCOS is a frequent endocrine disease that is associated with abnormal function of the female sex hormone estrogen and estrogen receptors (ERs). Estrogens mediate genomic effects through ERα and ERβ in target tissues. The G-protein-coupled estrogen receptor (GPER) has recently been described as mediating the non-genomic signaling of estrogen. Changes in estrogen receptor signaling pathways affect cellular activities, such as ovulation; cell cycle phase; and cell proliferation, migration, and invasion. Over the years, some selective estrogen receptor modulators (SERMs) have made substantial strides in clinical applications for subfertility with PCOS, such as tamoxifen and clomiphene, however the role of ER in PCOS still needs to be understood. This article focuses on the recent progress in PCOS caused by the abnormal expression of estrogen and ERs in the ovaries and uterus, and the clinical application of related targeted small-molecule drugs.
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Affiliation(s)
- Xue-Ling Xu
- College of Animal Science and Technology, China Agricultural University, Beijing 100193, China;
| | - Shou-Long Deng
- Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Ministry of Health, Beijing 100021, China;
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Zheng-Xing Lian
- College of Animal Science and Technology, China Agricultural University, Beijing 100193, China;
- Correspondence: (Z.-X.L.); (K.Y.)
| | - Kun Yu
- College of Animal Science and Technology, China Agricultural University, Beijing 100193, China;
- Correspondence: (Z.-X.L.); (K.Y.)
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Chen H, Zhang Y, Li S, Tao Y, Gao R, Xu W, Yang Y, Cheng K, Wang Y, Qin L. The Genetic Association of Polycystic Ovary Syndrome and the Risk of Endometrial Cancer: A Mendelian Randomization Study. Front Endocrinol (Lausanne) 2021; 12:756137. [PMID: 34803918 PMCID: PMC8602912 DOI: 10.3389/fendo.2021.756137] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 10/22/2021] [Indexed: 12/28/2022] Open
Abstract
The association between polycystic ovary syndrome (PCOS) and endometrial cancer remains unclear. We aimed to investigate the causal association between genetically predicted PCOS and endometrial cancer risk in two ethnic groups through a two-sample Mendelian randomization (MR) approach. Our study includes 13 single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) for PCOS in Europeans, and another 13 SNPs are used as IVs for PCOS in Asians. Outcome data were obtained from the largest published meta-GWAS of European ancestry to date, as well as from the BioBank Japan Project of Asian ancestry. Our study demonstrates that genetically predicted PCOS is not causally associated with the risk of overall endometrial cancer in either Europeans or Asians (odds ratio (OR) = 0.93, 95% confidence interval (CI) = 0.85-1.01, p = 0.09 and OR = 0.98, 95% CI 0.84-1.13, p = 0.75, respectively). Subgroup analyses according to histotype further illustrate that PCOS might not be associated with the risk of either endometrioid endometrial cancer or non-endometrioid endometrial cancer in European ancestry. No pleiotropy is found in our study, and a sensitivity analysis shows similar results. Our results indicate that genetically predicted PCOS might not be associated with the risk of endometrial cancer.
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Affiliation(s)
- Hanxiao Chen
- Reproductive Centre, Department of Obstetrics and Gynaecology, West China Second University Hospital, Sichuan University, Chengdu, China
- West China School of Medicine, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yaoyao Zhang
- Reproductive Centre, Department of Obstetrics and Gynaecology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Shangwei Li
- Reproductive Centre, Department of Obstetrics and Gynaecology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yuanzhi Tao
- Reproductive Centre, Department of Obstetrics and Gynaecology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Rui Gao
- Reproductive Centre, Department of Obstetrics and Gynaecology, West China Second University Hospital, Sichuan University, Chengdu, China
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Wenming Xu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
- Sichuan University-The Chinese University of Hong Kong (SCU–CUHK) Joint Laboratory for Reproductive Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yihong Yang
- Reproductive Centre, Department of Obstetrics and Gynaecology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Kemin Cheng
- Outpatient Department, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yan Wang
- Department of Obstetrics and Gynaecology, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, China
- *Correspondence: Lang Qin, ; Yan Wang,
| | - Lang Qin
- Reproductive Centre, Department of Obstetrics and Gynaecology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
- *Correspondence: Lang Qin, ; Yan Wang,
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Hosseinzadeh P, Barsky M, Gibbons WE, Blesson CS. Polycystic Ovary Syndrome and the Forgotten Uterus. F&S REVIEWS 2021; 2:11-20. [PMID: 34423324 PMCID: PMC8378802 DOI: 10.1016/j.xfnr.2020.12.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Polycystic ovary syndrome (PCOS) is a common disorder that affects various facets of fertility. Although the ovarian and metabolic aspects of the disease is well studied, its role in uterine dysfunction is not well understood. Our objective was to review the features of endometrial and uterine aberrations in women with PCOS. A systematic literature search was performed in PubMed, Medline, and the Cochrane Library databases for papers published in English up to March 2020. The following key words were used for the search: polycystic ovary syndrome, poly cystic ovarian disease, polycystic ovaries, PCOS, PCOD, PCO, PCOM, oligoovulation, anovulation, oligomenorrhea, amenorrhea, hyperandrogenism and this was combined with terms; endometrium, infertility, uterus, progesterone resistance, endometrial hyperplasia, pregnancy outcomes, preterm delivery. In this review, we highlight various uterine pathologies that are associated with PCOS and explore its impact on fertility. We also discuss key uterine molecular pathways that are altered in PCOS that may be related to infertility, endometrial hyperplasia and cancer.
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Affiliation(s)
- Pardis Hosseinzadeh
- Division for Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas 77030
| | - Maya Barsky
- Division for Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas 77030
- Family Fertility Center, Texas Children’s Hospital, Houston, Texas 77030
| | - William E. Gibbons
- Division for Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas 77030
- Family Fertility Center, Texas Children’s Hospital, Houston, Texas 77030
| | - Chellakkan S. Blesson
- Division for Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas 77030
- Family Fertility Center, Texas Children’s Hospital, Houston, Texas 77030
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Cangfudaotan Decoction Alleviates Insulin Resistance and Improves Follicular Development in Rats with Polycystic Ovary Syndrome via IGF-1-PI3K/Akt-Bax/Bcl-2 Pathway. Mediators Inflamm 2020; 2020:8865647. [PMID: 33299379 PMCID: PMC7707997 DOI: 10.1155/2020/8865647] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Revised: 10/26/2020] [Accepted: 11/02/2020] [Indexed: 12/16/2022] Open
Abstract
Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder prevalent in females of reproductive age; insulin resistance (IR) is the major pathogenic driver. Pharmacology is a basic option for PCOS therapy; traditional Chinese medicine (TCM), as a significant part of complementary and alternative medicine, has a long history in the clinical management of PCOS. Cangfudaotan decoction (CFD) has been used clinically for gynaecological diseases especially PCOS. In this study, first, chemical components in CFD were clarified using UPLC-Q/TOF-MS analysis. Then, an animal model of PCOS was established, granular cells were also isolated from the rats with PCOS, and CFD was administrated at different dosages in PCOS rats and granular cells, to investigate the therapeutic effect and mechanisms of CFD for PCOS treatment. The result showed that CFD treatment is effective in PCOS rats and granulosa cells. CFD was able to improve IR, restore the serum hormone levels, inhibit the inflammatory cytokines in PCOS rat, and alleviate ovary morphological injury and apoptosis in PCOS rats. In granulosa cells of PCOS, the result showed that the cell viability was improved, and cell apoptosis was inhibited after CFD administration. Further experiments suggested that CDF improves IR, follicular development, cell apoptosis, and inflammatory microenvironment, and this was associated to the regulation of IGF-1-PI3K/Akt-Bax/Bcl-2 pathway-mediated gene expression. Given that CFD sufficiently suppresses insulin resistance and improves follicular development in this study, exploring these mechanisms might help to optimize the therapeutic treatment of CFD in PCOS patients.
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Yumiceba V, López-Cortés A, Pérez-Villa A, Yumiseba I, Guerrero S, García-Cárdenas JM, Armendáriz-Castillo I, Guevara-Ramírez P, Leone PE, Zambrano AK, Paz-y-Miño C. Oncology and Pharmacogenomics Insights in Polycystic Ovary Syndrome: An Integrative Analysis. Front Endocrinol (Lausanne) 2020; 11:585130. [PMID: 33329391 PMCID: PMC7729301 DOI: 10.3389/fendo.2020.585130] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 10/05/2020] [Indexed: 12/12/2022] Open
Abstract
Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries. Epidemiological findings revealed that women with PCOS are prone to develop certain cancer types due to their shared metabolic and endocrine abnormalities. However, the mechanism that relates PCOS and oncogenesis has not been addressed. Herein, in this review article the genomic status, transcriptional and protein profiles of 264 strongly PCOS related genes (PRG) were evaluated in endometrial cancer (EC), ovarian cancer (OV) and breast cancer (BC) exploring oncogenic databases. The genomic alterations of PRG were significantly higher when compared with a set of non-diseases genes in all cancer types. PTEN had the highest number of mutations in EC, TP53, in OC, and FSHR, in BC. Based on clinical data, women older than 50 years and Black or African American females carried the highest ratio of genomic alterations among all cancer types. The most altered signaling pathways were p53 in EC and OC, while Fc epsilon RI in BC. After evaluating PRG in normal and cancer tissue, downregulation of the differentially expressed genes was a common feature. Less than 30 proteins were up and downregulated in all cancer contexts. We identified 36 highly altered genes, among them 10 were shared between the three cancer types analyzed, which are involved in the cell proliferation regulation, response to hormone and to endogenous stimulus. Despite limited PCOS pharmacogenomics studies, 10 SNPs are reported to be associated with drug response. All were missense mutations, except for rs8111699, an intronic variant characterized as a regulatory element and presumably binding site for transcription factors. In conclusion, in silico analysis revealed key genes that might participate in PCOS and oncogenesis, which could aid in early cancer diagnosis. Pharmacogenomics efforts have implicated SNPs in drug response, yet still remain to be found.
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Affiliation(s)
- Verónica Yumiceba
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Andrés López-Cortés
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Madrid, Spain
| | - Andy Pérez-Villa
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Iván Yumiseba
- Centro de Atención Ambulatorio, Hospital del Día El Batán, Instituto Ecuatoriano de Seguridad Social (IESS), Quito, Ecuador
| | - Santiago Guerrero
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Jennyfer M. García-Cárdenas
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Isaac Armendáriz-Castillo
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Patricia Guevara-Ramírez
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Paola E. Leone
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Ana Karina Zambrano
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - César Paz-y-Miño
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
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Ignatov A, Ortmann O. Endocrine Risk Factors of Endometrial Cancer: Polycystic Ovary Syndrome, Oral Contraceptives, Infertility, Tamoxifen. Cancers (Basel) 2020; 12:E1766. [PMID: 32630728 PMCID: PMC7408229 DOI: 10.3390/cancers12071766] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 06/30/2020] [Accepted: 07/01/2020] [Indexed: 12/15/2022] Open
Abstract
Endometrial cancer is the most common gynecologic cancer and is predominantly endocrine-related. The role of unopposed estrogen in the development of endometrial cancer has been investigated in numerous studies. Different reproductive factors such as younger age at menarche, late age at menopause, infertility, nulliparity, age of birth of the first child, and long-term use of unopposed estrogens during hormone replacement therapy have been associated with an increased risk of endometrial cancer. In contrast, there is a growing body of evidence for a protective role of oral contraceptives. Most of the published data on the association between infertility and polycystic ovary syndrome are inconclusive, whereas the effect of tamoxifen on the risk of endometrial cancer has been well established. With this review, we aim to summarize the evidence on the association between infertility, polycystic ovary syndrome, oral contraceptives, and tamoxifen and the development of endometrial cancer.
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Affiliation(s)
- Atanas Ignatov
- Department of Gynecology and Obstetrics, University Medical Center Regensburg, Landshuter Str. 65, 93053 Regensburg, Germany;
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32
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Meczekalski B, Pérez-Roncero GR, López-Baena MT, Chedraui P, Pérez-López FR. The polycystic ovary syndrome and gynecological cancer risk. Gynecol Endocrinol 2020; 36:289-293. [PMID: 32103691 DOI: 10.1080/09513590.2020.1730794] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
This review updates the knowledge regarding the association between the polycystic ovary syndrome (PCOS) and the risk of gynecological cancer. We performed a literature review of clinical and epidemiological studies concerning PCOS and the risk of breast, endometrial and ovarian cancer after selecting information by quality of scientific methodology. It was found that evidence does not support a link between PCOS and breast cancer risk. There is an increased risk of endometrial cancer, while data concerning ovarian cancer are contradictory. Regarding PCOS and its association to cervical, fallopian tube, and vulvar cancer, the quality of evidence is heterogeneous. In conclusion, women with PCOS should be screened for endometrial cancer and more research is warranted to determine in this population the true risk of developing other gynecological cancers such as breast and ovarian.
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Affiliation(s)
- Blazej Meczekalski
- Department of Gynecological Endocrinology, Poznan University of Medical Sciences, Poznan, Poland
| | - Gonzalo R Pérez-Roncero
- Red de Investigación de Ginecología, Obstetricia y Reproducción, Instituto de Investigaciones Sanitarias de Aragón, Zaragoza, Spain
| | - María T López-Baena
- Red de Investigación de Ginecología, Obstetricia y Reproducción, Instituto de Investigaciones Sanitarias de Aragón, Zaragoza, Spain
| | - Peter Chedraui
- Instituto de Investigación e Innovación en Salud Integral, Facultad de Ciencias Médicas, Universidad Católica de Santiago de Guayaquil, Guayaquil, Ecuador
- Facultad de Ciencias de la Salud, Universidad Católica "Nuestra Señora de la Asunción", Asunción, Paraguay
| | - Faustino R Pérez-López
- Red de Investigación de Ginecología, Obstetricia y Reproducción, Instituto de Investigaciones Sanitarias de Aragón, Zaragoza, Spain
- Department of Obsetrics and Gynecology, University of Zaragoza, Zaragoza, Spain
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Wiwatpanit T, Murphy AR, Lu Z, Urbanek M, Burdette JE, Woodruff TK, Kim JJ. Scaffold-Free Endometrial Organoids Respond to Excess Androgens Associated With Polycystic Ovarian Syndrome. J Clin Endocrinol Metab 2020; 105:5588091. [PMID: 31614364 PMCID: PMC7112974 DOI: 10.1210/clinem/dgz100] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Accepted: 10/02/2019] [Indexed: 12/16/2022]
Abstract
CONTEXT Polycystic ovary syndrome (PCOS) is a prevalent disorder in reproductive aged women associated with a number of endocrine and metabolic complications, including increased risk of endometrial cancer. OBJECTIVE To study the effect of the characteristic increased androgen levels in PCOS on the endometrium, a novel scaffold-free multicellular endometrial organoid was established. DESIGN Human endometrial organoids were constructed using primary endometrial epithelial and stromal cells from endometrial tissues. Organoids were treated for 14 days with physiologic levels of estradiol and testosterone to mimic a normal follicular phase or PCOS hormone profiles. Organoids were harvested for immunostaining and ribonucleic acid sequencing. SETTING Academic institution. PATIENTS Endometrial tissues from 10 premenopausal women undergoing hysterectomy for benign pathologies were obtained following written consent. MAIN OUTCOME MEASURES Organoid architecture, cell specific markers, functional markers, proliferation, and gene expression were measured. RESULTS A method to generate scaffold-free endometrial organoids containing epithelial and stromal cells was established. These organoids exhibited distinct organization with epithelial cells lining the outer surface and stromal cells in the center of the organoids. Epithelial cells were polarized, organoids expressed cell type specific and functional markers, as well as androgen, estrogen, and progesterone receptors. Treatment with PCOS hormones increased cell proliferation and dysregulated genes in endometrial organoids. CONCLUSIONS A new multicellular, scaffold-free endometrial organoid system was established that resembled physiology of the native endometrium. Excess androgens in PCOS promoted cell proliferation in endometrial organoids, revealing new mechanisms of PCOS-associated with risk of endometrial neoplasia.
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Affiliation(s)
- Teerawat Wiwatpanit
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, US
| | - Alina R Murphy
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, US
| | - Zhenxiao Lu
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, US
| | - Margrit Urbanek
- Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, US
| | - Joanna E Burdette
- Department of Medicinal Chemistry and Pharmacology, University of Illinois at Chicago, Chicago, IL, US
| | - Teresa K Woodruff
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, US
| | - J Julie Kim
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, US
- Correspondence and Reprint Requests: J. Julie Kim, PhD, Susy Y. Hung Professor of Obstetrics and Gynecology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, 303 E. Superior Street, 4-117, Chicago, IL 60611. E-mail:
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Ferreira SR, Goyeneche AA, Heber MF, Abruzzese GA, Telleria CM, Motta AB. Prenatally androgenized female rats develop uterine hyperplasia when adult. Mol Cell Endocrinol 2020; 499:110610. [PMID: 31589912 DOI: 10.1016/j.mce.2019.110610] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 09/19/2019] [Accepted: 10/03/2019] [Indexed: 12/20/2022]
Abstract
Prenatal hyperandrogenization (PH) is hypothesized as one of the main factors contributing to the development of polycystic ovary syndrome (PCOS). In this study, we aimed to investigate the impact of prenatal exposure to androgen excess on the uterus when animals reach their adulthood. We found that PH altered the morphology of the uteri that show a hyperplastic morphology with increased total uterine thickness as well as luminal epithelium thickness, with both enhanced and altered distribution of glands as compared with controls. Morphological alterations were associated with an unbalanced homeostasis as assessed by the expression of regulators of cell cycle progression and cell death dynamics. PH also causes disturbances in the cell cycle of the uterine tissue and dysregulates cell death and survival pathways leading to the development of uterine hyperplasia. These findings suggest that PH may have a deleterious effect on the uterus.
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Affiliation(s)
- Silvana Rocío Ferreira
- Laboratorio de Fisio-Patología Ovárica, Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Argentina.
| | - Alicia Alejandra Goyeneche
- Experimental Pathology Unit, Department of Pathology, Faculty of Medicine, McGill University, 3775 University Street, Montreal, QC H3A 2B4, Canada
| | - María Florencia Heber
- Laboratorio de Fisio-Patología Ovárica, Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Argentina
| | - Giselle Adriana Abruzzese
- Laboratorio de Fisio-Patología Ovárica, Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Argentina
| | - Carlos Marcelo Telleria
- Experimental Pathology Unit, Department of Pathology, Faculty of Medicine, McGill University, 3775 University Street, Montreal, QC H3A 2B4, Canada
| | - Alicia Beatriz Motta
- Laboratorio de Fisio-Patología Ovárica, Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Argentina
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35
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Ali AT, Guidozzi F. Midlife women's health consequences associated with polycystic ovary syndrome. Climacteric 2019; 23:116-122. [PMID: 31657237 DOI: 10.1080/13697137.2019.1679111] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Polycystic ovary syndrome (PCOS) is one of the most common female endocrinopathies. Its symptoms may appear as early as adolescence and may include irregular menstrual periods, amenorrhea, hirsutism and obesity. Regardless of their phenotypic appearance, women with PCOS are metabolically obese. PCOS is associated with metabolic syndrome, type 2 diabetes, depression, cardiovascular disease and gynecological cancers. The metabolic disorders in obese women with PCOS are invariably due to insulin resistance, while inflammation, oxidative stress and possible interaction with environmental factors are among the features linking women with PCOS alone to metabolic disorders. The current review aims to highlight the relationship between PCOS and midlife women's health complications.
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Affiliation(s)
- A T Ali
- Department of Chemical Pathology, NHLS, Tygerberg Hospital and Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - F Guidozzi
- Department of Obstetrics and Gynaecology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
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Hu M, Zhang Y, Egecioglu E, Li X, Shao LR, Billig H. Uterine glycolytic enzyme expression is affected by knockout of different estrogen receptor subtypes. Biomed Rep 2019; 11:135-144. [PMID: 31565219 PMCID: PMC6759582 DOI: 10.3892/br.2019.1234] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 07/01/2019] [Indexed: 12/11/2022] Open
Abstract
The estrogen signaling pathway via nuclear estrogen receptors (ER) α and β is considered to be the master regulator of the cellular glucose metabolism in the uterus. While in vivo animal studies have demonstrated that 17β-estradiol (E2) treatment increases the expression levels and activities of several glycolytic enzymes in the uterus, the specific ER subtype-dependent regulation of key glycolytic enzymes in the uterus has not been experimentally verified. In this study, the localization of ERα and ERβ in human and mouse endometria were evaluated using immunohistology. Given that ERα and ERβ are not functionally equivalent, ERα, ERβ and ERαβ knockout (ERα-/-, ERβ-/- and ERαβ-/-) mice were utilized to determine the expression pattern of glycolytic enzymes in the uterus. It was found that the level of ERα was higher than that of ERβ in the human and mouse endometrial epithelial and stromal cells, and both receptors were downregulated by E2 treatment in the mouse uterus. The expression of the hexokinase 1 and GAPDH was increased in ERα-/- and ERβ-/- mice compared with wild-type controls. Increased phosphofructokinase expression was observed in ERα-/- and ERαβ-/- mice, whereas increased pyruvate kinase isozyme M2 and pyruvate dehydrogenase expression was observed in ERβ-/- and ERαβ-/- mice. The findings indicated for the first time that while estrogen regulates ERα and ERβ expression in the uterus, ERα and ERβ selectively regulate uterine glycolytic enzyme expression during glycolysis. Additionally, the link between endometrial ER subtypes and glycolysis in women with polycystic ovary syndrome (PCOS) is discussed. The findings suggested that the E2-dependent ER-mediated regulation of glycolysis may be involved in the disturbance of the glucose metabolism in patients with PCOS with endometrial dysfunction.
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Affiliation(s)
- Min Hu
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, P.R. China.,Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden
| | - Yuehui Zhang
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden.,Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
| | - Emil Egecioglu
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden
| | - Xin Li
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden.,Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, P.R. China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai 200011, P.R. China
| | - Linus R Shao
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden
| | - Håkan Billig
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden
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Ramezani Tehrani F, Amiri M. Polycystic Ovary Syndrome in Adolescents: Challenges in Diagnosis and Treatment. Int J Endocrinol Metab 2019; 17:e91554. [PMID: 31497042 PMCID: PMC6679603 DOI: 10.5812/ijem.91554] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 06/13/2019] [Accepted: 07/02/2019] [Indexed: 02/06/2023] Open
Abstract
CONTEXT Despite the importance of timely diagnosis and treatment of polycystic ovary syndrome (PCOS) among adolescent females, considering the paucity of data focusing on this group and controversies documented on its recognition and management, the purpose of this review was to summarize challenges and recommendations of diagnosis and treatment for adolescents with PCOS. EVIDENCE ACQUISITION This review summarizes papers documented on PCOS among adolescent females. PubMed, Scopus, Web of Science, and Google Scholar databases were searched for retrieving studies conducted on PCOS among adolescent females up to March, 2019. The final selection of papers was made based on their relevancy with the fields of diagnosis and treatment of PCOS in this age group. RESULTS Oligo-anovulation in adolescents, if persistent, is a matter for concern. Hirsutism and moderate to severe acne in adolescent females should be considered as clinical manifestations of hyperandrogenism (HA). Diagnosis of biochemical HA in adolescents with PCOS requires reliable tests using well-defined normal ranges. In adolescent females, an elevated androgen level (hyperandrogenemia) alone is not enough to detect HA, unless it is persistent and associated with anovulation. Metabolic disorders should not be used as diagnostic criteria of PCOS among adolescent females. Re-assessment of all adolescent females with probable PCOS, using reliable diagnostic criteria, is needed to avoid over diagnosis and unnecessary treatment in healthy normal females without HA. In adolescent females with PCOS, the main clinical problem is the control of menstrual irregularity and hirsutism; treatment approaches for these patients are primarily directed at the major clinical manifestations and complaints. Lifestyle modifications are baseline interventions, which can be added to special treatments, such as Oral Contraceptives (OCs), metformin, or antiandrogens for most adolescents with PCOS, particularly those with overweight or obesity. CONCLUSIONS This review emphasizes the use of standard diagnostic criteria for PCOS, developed for adolescents. Although early recognition and management of PCOS in adolescents can prevent long-term complications associated with this syndrome, clinicians should re-evaluate all such patients with features very similar to PCOS to avoid over/incorrect diagnosis using precise criteria, suggested for this age group.
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Affiliation(s)
- Fahimeh Ramezani Tehrani
- Reproductive Endocrinology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Corresponding Author: Reproductive Endocrinology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mina Amiri
- Reproductive Endocrinology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Uterine pathology in transmasculine persons on testosterone: a retrospective multicenter case series. Am J Obstet Gynecol 2019; 220:257.e1-257.e7. [PMID: 30579875 DOI: 10.1016/j.ajog.2018.12.021] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 11/29/2018] [Accepted: 12/12/2018] [Indexed: 01/22/2023]
Abstract
BACKGROUND As part of transition, transmasculine persons often use testosterone gender-affirming hormone therapy; however, there is limited data on its long-term effects. The impact of exogenous testosterone on uterine pathology remains unclear. While testosterone achieves amenorrhea in the majority of this population, persistence of abnormal uterine bleeding can be difficult to manage. Excess androgens in cisgender females are associated with pathologic uterine processes such as polycystic ovary syndrome, endometrial hyperplasia, or cancer. There are no guidelines for management of abnormal uterine bleeding or endometrial surveillance in this population. OBJECTIVE The aim of this study was to describe the characteristics of uterine pathology after the initiation of testosterone in transmasculine persons. MATERIALS AND METHODS A retrospective, multicenter case series was performed. Uterine pathology reports of transmasculine persons who received testosterone and subsequently underwent hysterectomy were reviewed. The endometrial phase and endometrial thickness were recorded. RESULTS A total of 94 subjects met search criteria. The mean age of participants was 30 ± 8.6 years, and the mean interval from initiation of testosterone to hysterectomy was 36.7 ± 36.6 months. Active endometrium was found in the majority of patients (n = 65; 69.1%). One patient had complex hyperplasia without atypia. There were no cases of endometrial cancer. CONCLUSION Despite amenorrhea in the majority of transmasculine persons on testosterone, endometrial activity persists with predominantly proliferative endometrium on histopathology. Individualized counseling for abnormal uterine bleeding is encouraged in this patient population.
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Wang T, Zhang J, Hu M, Zhang Y, Cui P, Li X, Li J, Vestin E, Brännström M, Shao LR, Billig H. Differential Expression Patterns of Glycolytic Enzymes and Mitochondria-Dependent Apoptosis in PCOS Patients with Endometrial Hyperplasia, an Early Hallmark of Endometrial Cancer, In Vivo and the Impact of Metformin In Vitro. Int J Biol Sci 2019; 15:714-725. [PMID: 30745857 PMCID: PMC6367580 DOI: 10.7150/ijbs.31425] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 12/23/2018] [Indexed: 12/21/2022] Open
Abstract
The underlying mechanisms of polycystic ovarian syndrome (PCOS)-induced endometrial dysfunction are not fully understood, and although accumulating evidence shows that the use of metformin has beneficial effects in PCOS patients, the precise regulatory mechanisms of metformin on endometrial function under PCOS conditions have only been partially explored. To address these clinical challenges, this study aimed to assess the protein expression patterns of glycolytic enzymes, estrogen receptor (ER), and androgen receptor (AR) along with differences in mitochondria-dependent apoptosis in PCOS patients with and without endometrial hyperplasia in vivo and to investigate the effects of metformin in PCOS patients with endometrial hyperplasia in vitro. Here, we showed that compared to non-PCOS patients and PCOS patients without hyperplasia, the endometria from PCOS patients with hyperplasia had a distinct protein expression pattern of glycolytic enzymes, including pyruvate kinase isozyme M2 isoform (PKM2) and pyruvate dehydrogenase (PDH), and mitochondrial transcription factor A (TFAM). In PCOS patients with endometrial hyperplasia, increased glandular epithelial cell secretion and infiltrated stromal cells in the glands were associated with decreased PDH immunoreactivity in the epithelial cells. Using endometrial tissues from PCOS patients with hyperplasia, we found that in response to metformin treatment in vitro, hexokinase 2 (HK2) expression was decreased, whereas phosphofructokinase (PFK), PKM2, and lactate dehydrogenase A (LDHA) expression was increased compared to controls. Although there was no change in PDH expression, metformin treatment increased the expression of TFAM and cleaved caspase-3. Moreover, our in vivo study showed that while endometrial ERβ expression was no different between non-PCOS and PCOS patients regardless of whether or not hyperplasia was present, ERα and AR protein expression was gradually increased in women with PCOS following the onset of endometrial hyperplasia. Our in vitro study showed that treatment with metformin inhibited ERα expression without affecting ERβ expression. Our findings suggest that decreased glycolysis and increased mitochondrial activity might contribute to the onset of ERα-dependent endometrial hyperplasia and that metformin might directly reverse impaired glycolysis and normalize mitochondrial function in PCOS patients with endometrial hyperplasia.
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Affiliation(s)
- Tao Wang
- The School of Basic Medical Science, Heilongjiang University of Chinese Medicine, 150040 Harbin, China.,Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 150040 Harbin, China
| | - Jiao Zhang
- Department of Acupuncture and Moxibustion, Second Affiliated Hospital, Heilongjiang University of Chinese Medicine, 150040 Harbin, China
| | - Min Hu
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden.,Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, 510120 Guangzhou, China.,Institute of Integrated Traditional Chinese Medicine and Western Medicine, Guangzhou Medical University, 510120 Guangzhou, China
| | - Yuehui Zhang
- Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 150040 Harbin, China.,Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden
| | - Peng Cui
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden
| | - Xin Li
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden.,Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 200011 Shanghai, China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, 200011 Shanghai, China
| | - Juan Li
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden.,Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, 510120 Guangzhou, China
| | - Edvin Vestin
- The School of Basic Medical Science, Heilongjiang University of Chinese Medicine, 150040 Harbin, China
| | - Mats Brännström
- Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Sahlgrenska Academy, University of Gothenburg, 41345 Gothenburg, Sweden
| | - Linus R Shao
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden
| | - Håkan Billig
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden
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Metformin inhibits estradiol and progesterone-induced decidualization of endometrial stromal cells by regulating expression of progesterone receptor, cytokines and matrix metalloproteinases. Biomed Pharmacother 2018; 109:1578-1585. [PMID: 30551411 DOI: 10.1016/j.biopha.2018.10.128] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 10/20/2018] [Accepted: 10/21/2018] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Polycystic ovary syndrome (PCOS) is a serious threat for reproductive-aged women. Metformin has been used for the treatment of PCOS. However, its molecular mechanism in decidualization process of PCOS has not been well featured. METHODS RT-qPCR analysis was used to detect expression patterns of progesterone receptor (PGR), estradiol receptor alpha (ERα), Cytokeratin 8 and Vimentin in endometrial tissues of PCOS and non-PCOS patients. RT-qPCR assay was also employed to determine mRNA expression of prolactin, Insulin-like growth factor-binding protein 1 (IGFBP-1), matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP9). Cytokine secretion were measured by matching ELISA kits. Protein expression of p-ERK1/2, ERK1/2, p-p38 MAPK, p38 MAPK, and PGR (PGRA and PGRB) was tested by western blot assay. RESULTS PGR expression was upregulated in PCOS patients. Metformin alleviated estradiol (E2) and progesterone (P4) (EP)-induced decidualization of endometrial stromal cells. Abnormal cytokine secretion was observed in EP-stimulated endometrial stromal cells in the absence or presence of metfromin. Metformin suppressed EP-induced MMP-2 and MMP-9 upregulation. Metformin alleviated EP-triggered p38 MAPK inactivation and PGR (PGRA and PGRB) expression. Metfromin had no effect on ERK1/2 signaling in EP-stimulated endometrial stromal cells. CONCLUSION Metformin alleviated EP-induced decidualization of endometrial stromal cells by modulating secretion of multiple cytokines, inhibiting expression of MMP-2 and MMP-9, activating p38-MAPK signaling and reducing PGR expression, providing a deep insight into the molecular basis of metfromin therapy for PCOS patients.
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Emons G, Steiner E, Vordermark D, Uleer C, Bock N, Paradies K, Ortmann O, Aretz S, Mallmann P, Kurzeder C, Hagen V, van Oorschot B, Höcht S, Feyer P, Egerer G, Friedrich M, Cremer W, Prott FJ, Horn LC, Prömpeler H, Langrehr J, Leinung S, Beckmann MW, Kimmig R, Letsch A, Reinhardt M, Alt-Epping B, Kiesel L, Menke J, Gebhardt M, Steinke-Lange V, Rahner N, Lichtenegger W, Zeimet A, Hanf V, Weis J, Mueller M, Henscher U, Schmutzler RK, Meindl A, Hilpert F, Panke JE, Strnad V, Niehues C, Dauelsberg T, Niehoff P, Mayr D, Grab D, Kreißl M, Witteler R, Schorsch A, Mustea A, Petru E, Hübner J, Rose AD, Wight E, Tholen R, Bauerschmitz GJ, Fleisch M, Juhasz-Boess I, Sigurd L, Runnebaum I, Tempfer C, Nothacker MJ, Blödt S, Follmann M, Langer T, Raatz H, Wesselmann S, Erdogan S. Interdisciplinary Diagnosis, Therapy and Follow-up of Patients with Endometrial Cancer. Guideline (S3-Level, AWMF Registry Nummer 032/034-OL, April 2018) - Part 1 with Recommendations on the Epidemiology, Screening, Diagnosis and Hereditary Factors of Endometrial Cancer. Geburtshilfe Frauenheilkd 2018; 78:949-971. [PMID: 30364388 PMCID: PMC6195426 DOI: 10.1055/a-0713-1218] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 08/22/2018] [Indexed: 12/30/2022] Open
Abstract
Summary
The first German interdisciplinary S3-guideline on the diagnosis, therapy and follow-up of patients with endometrial cancer was published in April 2018. Funded by German Cancer Aid as part of an Oncology Guidelines Program, the lead coordinators of the guideline were the German Society of Gynecology and Obstetrics (DGGG) and the Gynecological Oncology Working Group (AGO) of the German Cancer Society (DKG).
Purpose
The use of evidence-based, risk-adapted therapy to treat low-risk women with endometrial cancer avoids unnecessarily radical surgery and non-useful adjuvant radiotherapy and/or chemotherapy. This can significantly reduce therapy-induced morbidity and improve the patientʼs quality of life as well as avoiding unnecessary costs. For women with endometrial cancer and a high risk of recurrence, the guideline defines the optimal surgical radicality together with the appropriate chemotherapy and/or adjuvant radiotherapy where required. The evidence-based optimal use of different therapeutic modalities should improve survival rates and the quality of life of these patients. The S3-guideline on endometrial cancer is intended as a basis for certified gynecological cancer centers. The aim is that the quality indicators established in this guideline will be incorporated in the certification processes of these centers.
Methods
The guideline was compiled in accordance with the requirements for S3-level guidelines. This includes, in the first instance, the adaptation of source guidelines selected using the DELBI instrument for appraising guidelines. Other consulted sources include reviews of evidence which were compiled from literature selected during systematic searches of literature databases using the PICO scheme. In addition, an external biostatistics institute was commissioned to carry out a systematic search and assessment of the literature for one area of the guideline. The identified materials were used by the interdisciplinary working groups to develop suggestions for Recommendations and Statements, which were then modified during structured consensus conferences and/or additionally amended online using the DELPHI method with consent being reached online. The guideline report is freely available online.
Recommendations
Part 1 of this short version of the guideline presents recommendations on epidemiology, screening, diagnosis and hereditary factors, The epidemiology of endometrial cancer and the risk factors for developing endomentrial cancer are presented. The options for screening and the methods used to diagnose endometrial cancer including the pathology of the cancer are outlined. Recommendations are given for the prevention, diagnosis, and therapy of hereditary forms of endometrial cancer.
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Affiliation(s)
- Günter Emons
- Klinik für Gynäkologie und Geburtshilfe, Universitätsmedizin Göttingen, Göttingen, Germany
| | - Eric Steiner
- Frauenklinik, GPR Klinikum Rüsselsheim am Main, Rüsselsheim, Germany
| | | | - Christoph Uleer
- Facharzt für Frauenheilkunde und Geburtshilfe, Hildesheim, Hildesheim, Germany
| | - Nina Bock
- Klinik für Gynäkologie und Geburtshilfe, Universitätsmedizin Göttingen, Göttingen, Germany
| | - Kerstin Paradies
- Konferenz Onkologischer Kranken- und Kinderkrankenpflege, Hamburg, Germany
| | - Olaf Ortmann
- Frauenheilkunde und Geburtshilfe, Universität Regensburg, Regensburg, Germany
| | - Stefan Aretz
- Institut für Humangenetik, Universität Bonn, Zentrum für erbliche Tumorerkrankungen, Universitätsklinikum Bonn, Bonn, Germany
| | | | | | - Volker Hagen
- Klinik für Innere Medizin II, St.-Johannes-Hospital Dortmund, Dortmund, Germany
| | - Birgitt van Oorschot
- Interdisziplinäres Zentrum Palliativmedizin, Universitätsklinikum Würzburg, Würzburg, Germany
| | - Stefan Höcht
- Xcare, Praxis für Strahlentherapie, Saarlouis, Saarlouis, Germany
| | - Petra Feyer
- Klinik für Strahlentherapie und Radioonkologie, Vivantes Klinikum Neukölln, Berlin, Germany
| | - Gerlinde Egerer
- Zentrum für Innere Medizin, Universitätsklinikum Heidelberg, Heidelberg, Germany
| | | | | | | | | | - Heinrich Prömpeler
- Klinik für Frauenheilkunde, Universitätsklinikum Freiburg, Freiburg, Germany
| | - Jan Langrehr
- Klinik für Allgemein-, Gefäß- und Viszeralchirurgie, Martin-Luther-Krankenhaus, Berlin, Germany
| | | | | | - Rainer Kimmig
- Women's Department, University Hospital of Essen, Essen, Germany
| | - Anne Letsch
- Medizinische Klinik mit Schwerpunkt Hämatologie und Onkologie, Charité, Campus Benjamin Franklin, Universitätsmedizin Berlin, Berlin, Germany
| | - Michael Reinhardt
- Klinik für Nuklearmedizin, Pius Hospital Oldenburg, Oldenburg, Germany
| | - Bernd Alt-Epping
- Klinik für Palliativmedizin, Universitätsmedizin Göttingen, Göttingen, Germany
| | - Ludwig Kiesel
- Obstetrics and Gynecology, Reproductive Medicine, University of Muenster, Germany, Münster, Germany
| | - Jan Menke
- Institut für Diagnostische und Interventionelle Radiologie, Universitätsmedizin Göttingen, Göttingen, Germany
| | - Marion Gebhardt
- Frauenselbsthilfe nach Krebs e. V., Erlangen, Erlangen/Forchheim, Germany
| | - Verena Steinke-Lange
- MGZ - Medizinisch Genetisches Zentrum, München und Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, München, Germany
| | - Nils Rahner
- Institut für Humangenetik, Universitätsklinikum Düsseldorf, Düsseldorf, Germany
| | - Werner Lichtenegger
- Frauenklinik Charité, Campus Virchow-Klinikum, Universitätsmedizin Berlin, Berlin, Germany
| | - Alain Zeimet
- Frauenheilkunde, Medizinische Universität Innsbruck, Innsbruck, Austria
| | - Volker Hanf
- Frauenklinik Nathanstift - Klinikum Fürth, Fürth, Germany
| | - Joachim Weis
- Stiftungsprofessur Selbsthilfeforschung, Tumorzentrum/CCC Freiburg, Universitätsklinikum Freiburg, Freiburg, Germany
| | - Michael Mueller
- Universitätsklinik für Frauenheilkunde, Inselspital Bern, Bern, Switzerland
| | | | - Rita K Schmutzler
- Center for Familial Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany
| | - Alfons Meindl
- Frauenklinik am Klinikum rechts der Isar, München, Germany
| | - Felix Hilpert
- Mammazentrum, Krankenhaus Jerusalem, Hamburg, Germany
| | - Joan Elisabeth Panke
- Medizinischer Dienst des Spitzenverbandes Bund der Krankenkassen e. V., Essen, Germany
| | - Vratislav Strnad
- Strahlenklinik, Universitätsklinikum Erlangen, CCC ER-EMN, Universitäts-Brustzentrum Franken, Erlangen, Germany
| | | | - Timm Dauelsberg
- Winkelwaldklinik Nordrach, Fachklinik für onkologische Rehabilitation, Nordrach, Germany
| | - Peter Niehoff
- Strahlenklinik, Sana Klinikum Offenbach, Offenbach, Germany
| | - Doris Mayr
- Pathologisches Institut, LMU München, München, Germany
| | - Dieter Grab
- Frauenklinik Klinikum Harlaching, München, Germany
| | - Michael Kreißl
- Universitätsklinik für Radiologie und Nuklearmedizin, Universitätsklinikum Magdeburg, Magdeburg, Germany
| | - Ralf Witteler
- Obstetrics and Gynecology, Reproductive Medicine, University of Muenster, Germany, Münster, Germany
| | | | | | - Edgar Petru
- Frauenheilkunde, Medizinische Universität Graz, Graz, Austria
| | - Jutta Hübner
- Klinikum für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany
| | | | - Edward Wight
- Frauenklinik des Universitätsspitals Basel, Basel, Switzerland
| | - Reina Tholen
- Deutscher Verband für Physiotherapie, Referat Bildung und Wissenschaft, Köln, Germany
| | - Gerd J Bauerschmitz
- Klinik für Gynäkologie und Geburtshilfe, Universitätsmedizin Göttingen, Göttingen, Germany
| | - Markus Fleisch
- Landesfrauenklinik, HELIOS Universitätsklinikum Wuppertal, Wuppertal, Germany
| | - Ingolf Juhasz-Boess
- Klinik für Frauenheilkunde, Geburtshilfe und Reproduktionsmedizin, Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Homburg, Saar, Germany
| | - Lax Sigurd
- Institut für Pathologie, Landeskrankenhaus Graz West, Graz, Austria
| | | | - Clemens Tempfer
- Marien Hospital Herne - Universitätsklinikum der Ruhr-Universität Bochum, Herne, Germany
| | | | | | - Markus Follmann
- Deutsche Krebsgesellschaft, Office des Leitlinienprogramms Onkologie, Berlin, Germany
| | - Thomas Langer
- Deutsche Krebsgesellschaft, Office des Leitlinienprogramms Onkologie, Berlin, Germany
| | - Heike Raatz
- Institut für Klinische Epidemiologie & Biostatistik (CEB), Basel, Switzerland
| | | | - Saskia Erdogan
- Klinik für Gynäkologie und Geburtshilfe, Universitätsmedizin Göttingen, Göttingen, Germany
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Cooney LG, Dokras A. Beyond fertility: polycystic ovary syndrome and long-term health. Fertil Steril 2018; 110:794-809. [DOI: 10.1016/j.fertnstert.2018.08.021] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 08/08/2018] [Accepted: 08/08/2018] [Indexed: 12/30/2022]
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Ding DC, Chen W, Wang JH, Lin SZ. Association between polycystic ovarian syndrome and endometrial, ovarian, and breast cancer: A population-based cohort study in Taiwan. Medicine (Baltimore) 2018; 97:e12608. [PMID: 30278576 PMCID: PMC6181615 DOI: 10.1097/md.0000000000012608] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Polycystic ovary syndrome (PCOS) is a common endocrine disorder among the women of reproductive age. We conducted a nationwide population-based retrospective cohort study to analyze the association between PCOS and the subsequent development of gynecological cancers, namely endometrial, breast, and ovarian cancer.For this population-based cohort study, we used the Taiwan National Health Insurance Research Database, which contains information on approximately 24.7 million insured individuals. The cohort included women who had received a diagnosis of PCOS between 1998 and 2013. An age-matched systematic random-sampling method with a ratio of 1:4 was used for patient selection for the non-PCOS reference cohort. Multivariate Cox proportional hazard regression analysis was used to determine the effects of PCOS on the risks of gynecologic and breast cancer. The data are presented as hazard ratios (HRs) with 95% confidence intervals (CIs).The PCOS cohort consisted of 8155 patients with PCOS, and the comparison cohort consisted of 32,620 matched patients without PCOS. The incidence of endometrial cancer was 226 and 15 per 100,000 person-years in the PCOS and comparison groups, respectively. A statistically significant higher risk of endometrial cancer was found in the PCOS cohort (adjusted HR [aHR] = 17.7, 95% CI = 4.9-64.2) than in the comparison cohort. However, no association was observed between PCOS and ovarian (aHR = 1.64, 95% CI: 0.63-4.27) or breast cancer (aHR = 0.98, 95% CI: 0.58-1.65).The results of this large population-based cohort study supported the premise that women with PCOS might have an increased risk of endometrial cancer, but no association between PCOS and the risks of ovarian and breast cancer was found.
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Affiliation(s)
- Dah-Ching Ding
- Department of Obstetrics and Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, and Tzu Chi University
- Institute of Medical Sciences, Tzu Chi University, Hualien
| | - Weishan Chen
- Management Office for Health Data, China Medical University Hospital
- College of Medicine, China Medical University, Taichung
| | | | - Shinn-Zong Lin
- Department of Neurosurgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, and Tzu Chi University, Hualien, Taiwan
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Qi J, Wang W, Zhu Q, He Y, Lu Y, Wang Y, Li X, Chen ZJ, Sun Y. Local Cortisol Elevation Contributes to Endometrial Insulin Resistance in Polycystic Ovary Syndrome. J Clin Endocrinol Metab 2018; 103:2457-2467. [PMID: 29618067 DOI: 10.1210/jc.2017-02459] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Accepted: 03/26/2018] [Indexed: 12/22/2022]
Abstract
CONTEXT Endometrial insulin resistance (IR) may account for the endometrial dysfunction in polycystic ovary syndrome (PCOS). The underlying mechanism remains to be elucidated. OBJECTIVE To investigate whether the abundance of 11β-hydroxysteroid dehydrogenases (11β-HSDs) 1 and 2 and cortisol as well as the insulin signaling pathway are altered in PCOS endometrium and to clarify the relationship between endometrial IR and local cortisol. DESIGN We measured cortisol and cortisone concentrations, 11β-HSD1 and 11β-HSD2, and core insulin signaling molecules in endometrial biopsies collected from non-PCOS and PCOS with or without IR patients on the seventh day after human chorionic gonadotropin injection. We also studied the effects of cortisol on glucose uptake and the insulin signaling pathway in primary cultured endometrial epithelial cells (EECs). RESULTS The cortisol concentration was elevated, whereas 11β-HSD2 expression was diminished in endometrial biopsies obtained from PCOS with IR patients compared with those from non-PCOS and PCOS without IR patients. The implantation rate was relatively impaired and the endometrial insulin signaling pathway was defective in PCOS with IR patients. In addition, cortisol attenuated insulin-stimulated glucose uptake in EECs, which was mediated by inhibition of Akt phosphorylation and glucose transporter type 4 translocation via induction of phosphatase and tensin homolog deleted on chromosome ten (PTEN). CONCLUSIONS Decreased oxidation of cortisol and defects of insulin signaling in endometrium were observed in PCOS with IR patients. The excessive cortisol level, derived from the reduction of 11β-HSD2, might contribute to the development of endometrial IR by inhibiting the insulin signaling pathway via induction of PTEN expression in EECs.
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Affiliation(s)
- Jia Qi
- Center for Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China
| | - Wangsheng Wang
- Center for Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China
| | - Qinling Zhu
- Center for Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China
| | - Yaqiong He
- Center for Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China
| | - Yao Lu
- Center for Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China
| | - Yuan Wang
- Center for Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China
| | - Xiaoxue Li
- Center for Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China
| | - Zi-Jiang Chen
- Center for Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China
- Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
- Key Laboratory of Reproductive Endocrinology, Shandong University, Ministry of Education, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Jinan, China
| | - Yun Sun
- Center for Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China
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Zhong Z, Li F, Li Y, Qin S, Wen C, Fu Y, Xiao Q. Inhibition of microRNA-19b promotes ovarian granulosa cell proliferation by targeting IGF-1 in polycystic ovary syndrome. Mol Med Rep 2018; 17:4889-4898. [PMID: 29363717 PMCID: PMC5865948 DOI: 10.3892/mmr.2018.8463] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Accepted: 04/25/2017] [Indexed: 01/03/2023] Open
Abstract
The purpose of the present study was to investigate the functional role of microRNA (miR)-19b in polycystic ovary syndrome (PCOS) and try to elucidate its underlying mechanisms. Expression of miR-19b and insulin-like growth factor 1 (IGF-1) was examined in ovarian cortexes [(from 18 women with PCOS and 10 who did not have PCOS (non-PCOS)] and KGN cells. Cell proliferation assays (cell viability and colony formation assay) were performed following overexpression or inhibition of miR-19b and IGF-1 or following insulin treatment in KGN cells. Expression levels of the cell cycle-associated protein cyclin D1 and cyclin-dependent kinase (CDK) 1 were analyzed following overexpression or inhibition of miR-19b and IGF-1. Potential miR-19b targets were identified by bioinformatics. Luciferase assay, reverse transcription-quantitative polymerase chain reaction and western blotting were performed to determine whether IGF-1 was a target of miR-19b. miR-19b expression was significantly decreased in the PCOS ovarian cortex and KGN cells and its identified target, IGF-1, was upregulated. miR-19b overexpression inhibited cell proliferation at G2/M phrase. Overexpression of IGF-1 promoted cell viability and colony formation ability in KGN cells. The expression of cyclin D1 and CDK1 was statistically increased by inhibition of miR-19b and overexpression of IGF-1. High concentrations of insulin decreased levels of miR-19b, stimulated KGN cell proliferation, and elevated IGF-1 levels. Inhibition of miR-19b promoted ovarian granulosa cell proliferation by targeting IGF-1 in PCOS. Insulin decreased the expression levels of miR-19b and stimulated cell proliferation. The present study suggested that overexpression of miR-19b may be a potential therapeutic approach for PCOS.
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Affiliation(s)
- Zhuohui Zhong
- Department of General Gynaecology, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong 510623, P.R. China
| | - Fang Li
- Department of Obstetrics and Gynecology, Eighth People's Hospital of Guangzhou, Guangzhou, Guangdong 510060, P.R. China
| | - Yingying Li
- Department of General Gynaecology, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong 510623, P.R. China
| | - Shuang Qin
- Department of General Gynaecology, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong 510623, P.R. China
| | - Canliang Wen
- Department of General Gynaecology, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong 510623, P.R. China
| | - Yiyuan Fu
- Department of General Gynaecology, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong 510623, P.R. China
| | - Qing Xiao
- Department of General Gynaecology, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong 510623, P.R. China
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Malignant Transformation of Endometriosis in the Ischioanal Fossa. Case Rep Obstet Gynecol 2018; 2018:5643040. [PMID: 29850315 PMCID: PMC5937550 DOI: 10.1155/2018/5643040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2018] [Accepted: 03/19/2018] [Indexed: 11/29/2022] Open
Abstract
We present the case of a 28-year-old nulliparous female with malignant transformation of an ectopic focus of endometriosis in the right ischioanal fossa. A 28-year-old nulliparous patient with a past medical history of polycystic ovarian syndrome (PCOS) was diagnosed with endometrioid adenocarcinoma in her right ischioanal fossa. Initially, patient presented to an emergency department and underwent a CT scan of the appendix to rule out appendicitis. A multiloculated cystic lesion adjacent to the right obturator internus muscle was found. She underwent surgical resection of the mass, which confirmed FIGO grade 2 endometrioid adenocarcinoma, followed by localized radiation therapy. Malignancy arising in endometriosis is rare, and the influence of PCOS on the rate of malignant transformation is not well established.
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Atiomo W, Shafiee MN, Chapman C, Metzler VM, Abouzeid J, Latif A, Chadwick A, Kitson S, Sivalingam VN, Stratford IJ, Rutland CS, Persson JL, Ødum N, Fuentes‐Utrilla P, Jeyapalan JN, Heery DM, Crosbie EJ, Mongan NP. 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. Clin Endocrinol (Oxf) 2017; 87:557-565. [PMID: 28748640 PMCID: PMC5697576 DOI: 10.1111/cen.13436] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Revised: 05/11/2017] [Accepted: 07/24/2017] [Indexed: 01/28/2023]
Abstract
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.
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Affiliation(s)
- William Atiomo
- Faculty of Medicine and Health SciencesDivision of Obstetrics and Gynaecology and Child HealthSchool of MedicineQueen's Medical CentreNottingham University HospitalNottinghamUK
| | - Mohamad Nasir Shafiee
- Faculty of Medicine and Health SciencesDivision of Obstetrics and Gynaecology and Child HealthSchool of MedicineQueen's Medical CentreNottingham University HospitalNottinghamUK
- Faculty of MedicineDepartment Obstetrics and GynaecologyUKM Medical CentreCherasKuala LumpurMalaysia
| | - Caroline Chapman
- Faculty of Medicine and Health SciencesDivision of Obstetrics and Gynaecology and Child HealthSchool of MedicineQueen's Medical CentreNottingham University HospitalNottinghamUK
| | - Veronika M. Metzler
- Faculty of Medicine and Health SciencesSchool of Veterinary Medicine and ScienceUniversity of NottinghamNottinghamUK
| | - Jad Abouzeid
- Faculty of Medicine and Health SciencesSchool of Veterinary Medicine and ScienceUniversity of NottinghamNottinghamUK
| | - Ayşe Latif
- Faculty of Biology, Medicine and HealthDivision of Pharmacy and OptometrySchool of Health SciencesUniversity of ManchesterManchesterUK
| | - Amy Chadwick
- Faculty of BiologyDivision of Molecular & Clinical Cancer SciencesMedicine and HealthUniversity of ManchesterManchesterUK
| | - Sarah Kitson
- Faculty of BiologyDivision of Molecular & Clinical Cancer SciencesMedicine and HealthUniversity of ManchesterManchesterUK
- Department of Obstetrics and GynaecologyCentral Manchester University Hospitals NHS Foundation TrustManchester Academic Health Science CentreManchesterUK
- Manchester School of PharmacyUniversity of ManchesterManchesterUK
| | - Vanitha N. Sivalingam
- Faculty of BiologyDivision of Molecular & Clinical Cancer SciencesMedicine and HealthUniversity of ManchesterManchesterUK
- Department of Obstetrics and GynaecologyCentral Manchester University Hospitals NHS Foundation TrustManchester Academic Health Science CentreManchesterUK
- Manchester School of PharmacyUniversity of ManchesterManchesterUK
| | - Ian J. Stratford
- Faculty of Biology, Medicine and HealthDivision of Pharmacy and OptometrySchool of Health SciencesUniversity of ManchesterManchesterUK
| | - Catrin S. Rutland
- Faculty of Medicine and Health SciencesSchool of Veterinary Medicine and ScienceUniversity of NottinghamNottinghamUK
| | - Jenny L. Persson
- Clinical Research CenterLund UniversityMalmöSweden
- Department of Molecular BologyUmeå UniversityUmeåSweden
| | - Niels Ødum
- Department of Immunology and MicrobiologyUniversity of CopenhagenKobenhavnDenmark
| | | | - Jennie N. Jeyapalan
- Faculty of Medicine and Health SciencesSchool of Veterinary Medicine and ScienceUniversity of NottinghamNottinghamUK
| | | | - Emma J. Crosbie
- Faculty of BiologyDivision of Molecular & Clinical Cancer SciencesMedicine and HealthUniversity of ManchesterManchesterUK
- Department of Obstetrics and GynaecologyCentral Manchester University Hospitals NHS Foundation TrustManchester Academic Health Science CentreManchesterUK
- Manchester School of PharmacyUniversity of ManchesterManchesterUK
| | - Nigel P. Mongan
- Faculty of Medicine and Health SciencesSchool of Veterinary Medicine and ScienceUniversity of NottinghamNottinghamUK
- Department of PharmacologyWeill Cornell MedicineNew YorkNYUSA
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Harmonisation of biobanking standards in endometrial cancer research. Br J Cancer 2017; 117:485-493. [PMID: 28664917 PMCID: PMC5558683 DOI: 10.1038/bjc.2017.194] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 06/01/2017] [Accepted: 06/01/2017] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Endometrial cancer is the most common gynaecological cancer and its incidence is predicted to escalate by 50-100% in 2025 with a parallel increase in associated mortality. Variations in the collection, processing and storage of biospecimens can affect the generalisability of the scientific data. We aimed to harmonise the collection of biospecimens, clinical data relevant to endometrial cancer and to develop standard operative procedures for the collection, processing and storage of endometrial cancer biospecimens. METHODS We designed research tools, which were evaluated and revised through three consensus rounds - to obtain local/regional, national and European consensus. Modified final tools were disseminated to a panel (n=40) representing all stakeholders in endometrial cancer research for consensus generation. RESULTS The final consensus demonstrated unanimous agreement with the minimal surgical and patient data collection tools. A high level of agreement was also observed for the other remaining standard tools. CONCLUSIONS We here present the final versions of the tools, which are freely available and easily accessible to all endometrial cancer researchers. We believe that these tools will facilitate rapid progress in endometrial cancer research, both in future collaborations and in large-scale multicentre studies.
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Desai A, Madar IH, Asangani AH, Ssadh HA, Tayubi IA. Influence of PCOS in Obese vs. Non-Obese women from Mesenchymal Progenitors Stem Cells and Other Endometrial Cells: An in silico biomarker discovery. Bioinformation 2017; 13:111-115. [PMID: 28539732 PMCID: PMC5429969 DOI: 10.6026/97320630013111] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 04/12/2017] [Accepted: 04/12/2017] [Indexed: 11/23/2022] Open
Abstract
Polycystic ovary syndrome (PCOS) is endocrine system disease which affect women ages 18 to 44 where the women's hormones are imbalance. Recently it has been reported to occur in early age. Alteration of normal gene expression in PCOS has shown negative effects on long-term health issues. PCOS has been the responsible factor for the infertility in women of reproductive age group. Early diagnosis and treatment can improve the women's health suffering from PCOS. Earlier Studies shows correlation of PCOS upon insulin resistance with significant outcome, Current study shows the linkage between PCOS with obesity and non-obese patients. Gene expression datasets has been downloaded from GEO (control and PCOS affected patients). Normalization of the datasets were performed using R based on RMA and differentially expressed gene (DEG) were selected on the basis of p-value 0.05 followed by functional annotation of selected gene using Enrich R and DAVID. The DEGs were significantly related to PCOS with obesity and other risk factors involved in disease. The Gene Enrichment Analysis suggests alteration of genes and associated pathway in case of obesity. Current study provides a productive groundwork for specific biomarkers identification for the accurate diagnosis and efficient target for the treatment of PCOS.
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Affiliation(s)
- Ashvini Desai
- Department of Bioinformatics, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, 632014, Tamil Nadu, India
| | - Inamul Hasan Madar
- Department of Biotechnology & Genetic Engineering and Department of Biochemistry, Bharathidasan University, Tiruchirappalli, 620024, Tamil Nadu, India
| | - Amjad Hussain Asangani
- Department of Biochemistry, Islamiah College, Vaniyambadi 635 752, Vellore Dist, Tamil Nadu India
| | - Hussain Al Ssadh
- School of Biological sciences, University of Essex, Colchester, CO43SQ, United Kingdom
| | - Iftikhar Aslam Tayubi
- Faculty of Computing and Information Technology, King Abdul-Aziz University, Rabigh-21911, Saudi Arabia
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Biological relevance of effects following chronic administration of octamethylcyclotetrasiloxane (D4) in Fischer 344 rats. Toxicol Lett 2017; 279 Suppl 1:42-53. [PMID: 28109826 DOI: 10.1016/j.toxlet.2017.01.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Revised: 01/13/2017] [Accepted: 01/15/2017] [Indexed: 11/21/2022]
Abstract
Octamethylcyclotetrasiloxane (D4) is a cyclic siloxane primarily used as a monomer or intermediate in the production of silicone polymers resulting in potential exposure of workers, and potential low level inhalation or dermal exposure for consumers and the general public. Following a two-year inhalation toxicity study with D4 in rats, increases in uterine endometrial cystic hyperplasia and adenomas were observed at the highest concentration of D4 administered (700ppm). No other neoplasms were increased with D4 treatment. In addition, chronic inhalation exposure of rats to D4 induced changes in relative liver and kidney weights, and produced a chronic nephropathy. This manuscript examines the biological relevance and possible modes of action for the effects observed in the F344 rat following chronic inhalation exposure to D4. D4 is not genotoxic and appears to exert its effects through a nongenotoxic mode of action. An alteration in the estrous cycle in the aging F344 rat was the most likely mode of action for the observed uterine effects following chronic inhalation exposure. Data support the conclusion that D4 acts indirectly via a dopamine-like mechanism leading to alteration of the pituitary control of the estrous cycle in aging F344 rats with a decrease in progesterone and an increase in the estrogen/progesterone ratio most likely induced by a decrease in prolactin concentration. D4 also inhibited the pre-ovulatory LH surge causing a delay in ovulation, persistent follicles and thus a prolonged exposure to elevated estrogen in the adult Sprague Dawely rat. A lengthening of the estrous cycle in the F344 rat with an increase in endogenous estrogen was also induced by D4 inhalation. Although the mode of action responsible for induction of uterine adenomas in the female F344 rat has not been clearly confirmed, the subtlety of effects on the effects of D4 on cyclicity may prevent further assessment and definition of the mode of action. The occurrence of uterine endometrial adenoma in the rat is not relevant for human risk characterization because (1) there are differences in ovulatory cycle regulation in rats compared to humans, (2) cystic hyperplasia without atypia in women is not a cancer precursor, and (3) there is no endometrial lesion in women that is directly analogous to endometrial adenoma in the rat. The effects of D4 on liver are due to a phenobarbital-like mechanism that results in induction of cytochrome P450 and other enzymes of xenobiotic biotransformation. The liver effects are adaptive and not adverse. Kidney findings included chonic progressive nephropathy, a rat lesion that has no counterpart in the human and that should not be used in human risk assessment.
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