Affiliations 

  • 1 Unit of Infections and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO)-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain
  • 2 Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO)-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain
  • 3 Division of Molecular Diagnostics of Oncogenic Infections (F020), Research Program Infection, Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 4 Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
  • 5 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  • 6 Microbiology Department, Universitat Autònoma de Barcelona, Hospital de la Santa Creu i Sant Pau, Barcelona, Catalonia, Spain
  • 7 Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway
  • 8 Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark
  • 9 Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
  • 10 Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute-ISPO, Florence, Italy
  • 11 School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
  • 12 Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark
  • 13 Inserm, Centre for research in Epidemiology and Population Health (CESP), U318, Nutrition, Hormones and Women's Health team, F-94705, Villejuif, France
  • 14 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 15 Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
  • 16 Hellenic Health Foundation, Athens, Greece
  • 17 Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece
  • 18 Cancer Registry and Histopathology Unit, "Civic-M.P. Arezzo" Hospital, Ragusa, Italy
  • 19 Unit of Cancer Epidemiology, University of Turin, Turin, Italy
  • 20 Human Genetics Foundation (HuGeF), Turin, Italy
  • 21 Dipartimento Di Medicina Clinica E Chirurgia, Federico II University, Naples, Italy
  • 22 MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, United Kingdom
  • 23 Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
  • 24 Public Health Directorate, Asturias, Spain
  • 25 CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
  • 26 BBMRI.se Service Center for Southern Sweden, Lund University, Medicon Village, Lund, Sweden
  • 27 Department of Radiation Sciences, Umeå University, Umeå, Sweden
  • 28 Department of Clinical Sciences, Obstetrics and Gynecology, Umeå University, Umeå, Sweden
  • 29 Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
  • 30 Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, United Kingdom
  • 31 International Agency for Research on Cancer, Lyon, France
PLoS ONE, 2016;11(1):e0147029.
PMID: 26808155 DOI: 10.1371/journal.pone.0147029

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).

METHODS AND FINDINGS: 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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.