title: The Influence of Hormonal Factors on the Risk of Developing Cervical Cancer and Pre-Cancer: Results from the EPIC Cohort.
abstract: BACKGROUND
  In addition to HPV, high parity and hormonal contraceptives have been associated with cervical cancer (CC). However, most of the evidence comes from retrospective case-control studies. The aim of this study is to prospectively evaluate associations between hormonal factors and risk of developing cervical intraepithelial neoplasia grade 3 (CIN3)/carcinoma in situ (CIS) and invasive cervical cancer (ICC).
  
  
  RESULTS
  We followed a cohort of 308,036 women recruited in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study. At enrollment, participants completed a questionnaire and provided serum. After a 9-year median follow-up, 261 ICC and 804 CIN3/CIS cases were reported. In a nested case-control study, the sera from 609 cases and 1,218 matched controls were tested for L1 antibodies against HPV types 11,16,18,31,33,35,45,52,58, and antibodies against Chlamydia trachomatis and Human herpesvirus 2. Multivariate analyses were performed to estimate hazard ratios (HR), odds ratios (OR) and corresponding 95% confidence intervals (CI). The cohort analysis showed that number of full-term pregnancies was positively associated with CIN3/CIS risk (p-trend = 0.03). Duration of oral contraceptives use was associated with a significantly increased risk of both CIN3/CIS and ICC (HR = 1.6 and HR = 1.8 respectively for ≥ 15 years versus never use). Ever use of menopausal hormone therapy was associated with a reduced risk of ICC (HR = 0.5, 95%CI: 0.4-0.8). A non-significant reduced risk of ICC with ever use of intrauterine devices (IUD) was found in the nested case-control analysis (OR = 0.6). Analyses restricted to all cases and HPV seropositive controls yielded similar results, revealing a significant inverse association with IUD for combined CIN3/CIS and ICC (OR = 0.7).
  
  
  CONCLUSIONS
  Even though HPV is the necessary cause of CC, our results suggest that several hormonal factors are risk factors for cervical carcinogenesis. Adherence to current cervical cancer screening guidelines should minimize the increased risk of CC associated with these hormonal risk factors.
authors.affiliation: Unit of Infections and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO)-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.|CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
authors.forename: Esther
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authors.lastname: Roura
authors.affiliation: Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO)-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.
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authors.lastname: Travier
authors.affiliation: Division of Molecular Diagnostics of Oncogenic Infections (F020), Research Program Infection, Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Tim
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authors.lastname: Waterboer
authors.affiliation: Unit of Infections and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO)-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.|CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
authors.forename: Silvia
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authors.lastname: de Sanjosé
authors.affiliation: Unit of Infections and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO)-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.
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authors.affiliation: Division of Molecular Diagnostics of Oncogenic Infections (F020), Research Program Infection, Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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authors.affiliation: Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
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authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway.|Department of Research, Cancer Registry of Norway, Oslo, Norway.|Genetic Epidemiology Group, Folkhälsan Research Center, Helsinki, Finland.
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authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
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authors.affiliation: Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway.
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authors.affiliation: Inserm, Centre for research in Epidemiology and Population Health (CESP), U318, Nutrition, Hormones and Women's Health team, F-94705, Villejuif, France.|Université Paris Sud, UMRS 318, F-94705, Villejuif, France.|Institut Gustave Roussy, F-94705, Villejuif, France.
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authors.affiliation: Inserm, Centre for research in Epidemiology and Population Health (CESP), U318, Nutrition, Hormones and Women's Health team, F-94705, Villejuif, France.|Université Paris Sud, UMRS 318, F-94705, Villejuif, France.|Institut Gustave Roussy, F-94705, Villejuif, France.
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authors.affiliation: Inserm, Centre for research in Epidemiology and Population Health (CESP), U318, Nutrition, Hormones and Women's Health team, F-94705, Villejuif, France.|Université Paris Sud, UMRS 318, F-94705, Villejuif, France.|Institut Gustave Roussy, F-94705, Villejuif, France.
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authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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authors.affiliation: Hellenic Health Foundation, Athens, Greece.
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authors.affiliation: Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece.|Department of Epidemiology, Harvard School of Public Health, Boston, United States of America.
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authors.affiliation: Hellenic Health Foundation, Athens, Greece.|Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece.
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authors.affiliation: Unit of Cancer Epidemiology, University of Turin, Turin, Italy.|Centre for Cancer Epidemiology and Prevention (CPO Piemonte), Turin, Italy.
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authors.affiliation: MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, United Kingdom.|Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
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authors.affiliation: CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.|Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain.|Department of Health and Social Sciences, Universidad de Murcia, Murcia, Spain.
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authors.affiliation: Unit of Infections and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO)-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.|CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
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mesh_terms: D000328:Adult; D000368:Aged; D000914:Antibodies, Viral / Q000097:blood; D002294:Carcinoma, Squamous Cell / Q000453:epidemiology* / Q000503:physiopathology; D016022:Case-Control Studies; D002690:Chlamydia Infections / Q000097:blood / Q000453:epidemiology; D002692:Chlamydia trachomatis / Q000276:immunology; D003278:Contraceptives, Oral, Hormonal / Q000009:adverse effects; D005260:Female; D005500:Follow-Up Studies; D012739:Gonadal Steroid Hormones / Q000009:adverse effects / Q000502:physiology*; D006558:Herpes Genitalis / Q000097:blood / Q000453:epidemiology; D018258:Herpesvirus 2, Human / Q000276:immunology; D020249:Hormone Replacement Therapy / Q000009:adverse effects; D006801:Humans; D007434:Intrauterine Devices; D008875:Middle Aged; D027383:Papillomaviridae / Q000276:immunology; D030361:Papillomavirus Infections / Q000097:blood / Q000453:epidemiology; D011247:Pregnancy; D011446:Prospective Studies; D017584:Reproductive History; D012306:Risk; D002583:Uterine Cervical Neoplasms / Q000453:epidemiology* / Q000503:physiopathology; D055815:Young Adult; D002578:Uterine Cervical Dysplasia / Q000453:epidemiology* / Q000503:physiopathology
chemical_list: D000914:Antibodies, Viral; D003278:Contraceptives, Oral, Hormonal; D012739:Gonadal Steroid Hormones