Published OnlineFirst November 15, 2017; DOI: 10.1158/1055-9965.EPI-17-0655 Research Article Cancer Epidemiology, Biomarkers Polycystic Ovary Syndrome, Oligomenorrhea, and & Prevention Risk of Ovarian Cancer Histotypes: Evidence from the Ovarian Cancer Association Consortium Holly R. Harris1, Ana Babic2, Penelope M. Webb3,4, Christina M. Nagle3, Susan J. Jordan3,5, on behalf of the Australian Ovarian Cancer Study Group4; Harvey A. Risch6, Mary Anne Rossing1,7, Jennifer A. Doherty8, Marc T.Goodman9,10, Francesmary Modugno11, Roberta B. Ness12, Kirsten B. Moysich13, Susanne K. Kjær14,15, Estrid Høgdall14,16, Allan Jensen14, Joellen M. Schildkraut17, Andrew Berchuck18, Daniel W. Cramer19,20, Elisa V. Bandera21, Nicolas Wentzensen22, Joanne Kotsopoulos23, Steven A. Narod23, † Catherine M. Phelan24, , John R. McLaughlin25, Hoda Anton-Culver26, Argyrios Ziogas26, Celeste L. Pearce27,28, Anna H. Wu28, and Kathryn L. Terry19,20, on behalf of the Ovarian Cancer Association Consortium Abstract Background: Polycystic ovary syndrome (PCOS), and one of its cancer was also observed among women who reported irregular distinguishing characteristics, oligomenorrhea, have both been menstrual cycles compared with women with regular cycles (OR ¼ associated with ovarian cancer risk in some but not all studies. 0.83; 95% CI ¼ 0.76–0.89). No significant association was However, these associations have been rarely examined by observed between self-reported PCOS and invasive ovarian cancer ovarian cancer histotypes, which may explain the lack of clear risk (OR ¼ 0.87; 95% CI ¼ 0.65–1.15). There was a decreased risk associations reported in previous studies. of all individual invasive histotypes for women with menstrual Methods: We analyzed data from 14 case–control studies cycle length >35 days, but no association with serous borderline including 16,594 women with invasive ovarian cancer (n ¼ tumors (Pheterogeneity ¼ 0.006). Similarly, we observed decreased 13,719) or borderline ovarian disease (n ¼ 2,875) and 17,718 risks of most invasive histotypes among women with irregular controls. Adjusted study-specific ORs were calculated using logis- cycles, but an increased risk of borderline serous and mucinous tic regression and combined using random-effects meta-analysis. tumors (Pheterogeneity < 0.0001). Pooled histotype-specific ORs were calculated using polytomous Conclusions: Our results suggest that menstrual cycle charac- logistic regression. teristics influence ovarian cancer risk differentially based on Results: Women reporting menstrual cycle length >35 days had histotype. decreased risk of invasive ovarian cancer compared with women Impact: These results highlight the importance of examining reporting cycle length 35 days [OR ¼ 0.70; 95% confidence ovarian cancer risk factors associations by histologic subtype. interval (CI) ¼ 0.58–0.84]. Decreased risk of invasive ovarian Cancer Epidemiol Biomarkers Prev; 27(2); 174–82. Ó2017 AACR. 1Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, Cancer Research Center, Seattle, Washington. 2Dana Farber Cancer Institute and Massachusetts. 20Department of Epidemiology, Harvard T.H. Chan School of Harvard Medical School, Boston, Massachusetts. 3Population Health Depart- Public Health, Boston, Massachusetts. 21Cancer Prevention and Control Program, ment, QIMR Berghofer Medical Research Institute, Herston, Queensland, Aus- Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. 22Division tralia. 4Australian Ovarian Cancer Study Group, Peter MacCallum Cancer Centre, of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Melbourne, Victoria, Australia. 5The University of Queensland, School of Public Maryland. 23Women's College Research Institute, University of Toronto, Toronto, Health, Herston, Queensland, Australia. 6Department of Chronic Disease Epi- Ontario, Canada. 24Department of Cancer Epidemiology, Moffitt Cancer Center, demiology, Yale School of Public Health, New Haven, Connecticut. 7Department Tampa, Florida. 25Public Health Ontario, Toronto, Canada. 26Department of of Epidemiology, University of Washington, Seattle, Washington. 8Huntsman Epidemiology, University of California Irvine, Irvine, California. 27Department Cancer Institute, Department of Population Health Sciences, University of Utah, of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Salt Lake City, Utah. 9Cancer Prevention and Control, Samuel Oschin Compre- Michigan. 28Department of Preventive Medicine, Keck School of Medicine, hensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California. University of Southern California Norris Comprehensive Cancer Center, Los 10Community and Population Health Research Institute, Department of Biomed- Angeles, California. ical Sciences, Cedars-Sinai Medical Center, Los Angeles, California. 11Division of Note: Supplementary data for this article are available at Cancer Epidemiology, Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproduc- Biomarkers & Prevention Online (http://cebp.aacrjournals.org/). tive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsyl- † vania. 12The University of Texas School of Public Health, Houston, Texas. Deceased. 13Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York. 14Department of Virus, Lifestyle and Genes, Danish Cancer Corresponding Author: Holly R. Harris, Program in Epidemiology, Division of Society Research Center, Copenhagen, Denmark. 15Department of Gynaecology, Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 16Molecular Avenue North, M4-B874, Seattle, WA 98109-1024. Phone: 206-667-2712; Fax: Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, 206-667-4787; E-mail: [email protected] 17 Copenhagen, Denmark. Department of Public Health Sciences, The University doi: 10.1158/1055-9965.EPI-17-0655 of Virginia, Charlottesville, Virginia. 18Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina. 19Obstetrics and Ó2017 American Association for Cancer Research. 174 Cancer Epidemiol Biomarkers Prev; 27(2) February 2018 Downloaded from cebp.aacrjournals.org on September 30, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst November 15, 2017; DOI: 10.1158/1055-9965.EPI-17-0655 PCOS, Oligomenorrhea, and Ovarian Cancer Risk Introduction pants included 16,594 women with invasive ovarian cancer (n ¼ 13,719) or borderline ovarian disease (n ¼ 2,875) and 17,718 Polycystic ovary syndrome (PCOS) is a complex endocrine controls. disorder characterized by oligomenorrhea and abnormal hor- mone levels including hyperandrogenism, hyperinsulinemia, and Exposure and covariate data gonadotropin imbalance. While PCOS has been examined as a History of PCOS, menstrual cycle irregularity, and menstrual – risk factor for ovarian cancer in multiple studies (1 9), results cycle length were self-reported in all studies. The wording of the have been inconsistent, due in part to the inherent limitations in questions for each of the three exposure variables varied between assessing PCOS in a population-based study (10). More objective studies (Table 1). PCOS, polycystic ovary disease, Stein Levanthal measures, like measurement of circulating androgen levels, are syndrome, and polycystic ovaries were reported by the partici- fi not generally available. However, oligomenorrhea, de ned as pants (n ¼ 10 studies). For menstrual cycle irregularity (n ¼ 12 – infrequent or irregular periods, is estimated to occur in 75% studies), we defined women as having irregular cycles if they 85% of women with PCOS and less than 18% of women without reported that their cycles were: "sometimes irregular," "very – PCOS, and can be assessed by questionnaire (10 12). Oligome- irregular," "fairly irregular," "never regular," "variable in length," norrhea has also been examined as an ovarian cancer risk factor or were "unable to predict when next period would start." Men- but results from studies of this association are also inconsistent strual cycle length in days was reported by the participants as a – (2, 4, 7, 13 19). Some studies have reported a reduced risk of continuous variable or in categories (n ¼ 13 studies). When ovarian cancer among women with oligomenorrhea (4, 19), menstrual cycle length was reported in categories the midpoint consistent with the incessant ovulation hypothesis (20), which of the category was used to assign numerical menstrual cycle proposes that repeated damage and repair to the ovarian surface length. Menstrual cycle length was dichotomized into >35 days increases ovarian cancer risk. Thus, among women with infre- and 35 days (reference). Sensitivity analysis were also conducted quent or irregular cycles, the resulting reduction in lifetime excluding women with a cycle length <21 days from the reference ovulations would be expected to reduce ovarian cancer risk. group. When available, individual studies provided information However, other studies have observed increased risks of ovarian on other characteristics associated with PCOS and hyperandro- cancer among women with oligomenorrhea (7, 14). Hormonal genism (11) including amenorrhea (absence of a menstrual – alterations in women with oligomenorrhea (21 23) including period for 3 months or longer; n ¼ 6 studies), hirsutism/excess