Characteristics of menstruation and pregnancy and the risk of lung cancer in women Anita Koushik 1,2 * , Marie-  Elise Parent 2,3 and Jack Siemiatycki 1,2 1 D epartement de m edecine sociale et pr eventive, Universit  e de Montr eal, Montr eal, QC, Canada 2 Axe Sant  e des populations, Centre de recherche du CHUM, Montr eal, QC, Canada 3 INRS—Institut Armand-Frappier, Universit  e du Qu ebec, Laval, QC, Canada Lung tissue, both normal and cancerous, has been found to express estrogen receptors and patterns of expression have dif- fered between men and women, suggesting a possible role for hor- mone-related factors in lung carcinogenesis in women. Few epide- miological studies have examined hormone-related variables and lung cancer risk and the findings have not been consistent. We investigated the association between characteristics of menstrua- tion and pregnancy in relation to lung cancer risk in a population- based case–control study carried out in Montreal, Canada, in- cluding 422 women with lung cancer and 577 controls. For each variable, odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression modeling. Asso- ciations were also examined according to level of smoking and by lung cancer histology. All statistical tests were two-sided. Most characteristics of menstruation and pregnancy were not associ- ated with lung cancer risk. However, an increased risk was observed for women who had had a non-natural menopause, which predominantly included women who had had a bilateral oophorectomy, compared with women who had had a natural menopause (OR 5 1.92, 95% CI: 1.22–3.01). An inverse associa- tion with age at menopause was suggested. These results did not vary by level of smoking and they were similar for adenocarcino- mas compared with other histological types. Our results suggest that hormonal factors, related to early menopause and/or ovary removal, may play a role in the risk of lung cancer. Further stud- ies are needed to confirm these findings, and to assess the possible contribution of hormone replacement therapy. ' 2009 UICC Key words: lung cancer; hormones; reproductive factors; menopause; case–control study Worldwide, lung cancer is the most frequently diagnosed cancer and the most common cause of cancer death. 1 Between 80 and 90% of lung cancers are attributable to smoking in North Ameri- can populations. 2 However, only 15% of smokers eventually de- velop lung cancer, 3 suggesting that other factors may modify the increased risk associated with tobacco carcinogens. Also, lung cancer occurs among individuals who have never smoked 4,5 —the proportion of all lung cancers that occur among lifetime never smokers is approximately 15–25% among women, whereas just 10% among men. 4 The distribution of lung cancers by histology also varies by sex, with the most frequent histological type being squamous cell carcinomas in men and adenocarcinomas in women. 6 These differences between men and women suggest that the profile of etiologic factors for lung cancer may differ by sex. Both normal and cancerous lung tissue have been found to express estrogen receptors, 4,5 and patterns of expression have dif- fered between men and women, 4 leading to speculation about a possible role for hormone-related factors in lung carcinogenesis in women. The first epidemiological evidence of a potential role of hormonal factors in lung cancer risk was from a study of women in China where it was observed that women with shorter menstrual cycle lengths were at an increased risk of adenocarcinoma. 7 Other hormone-related variables that have been examined include age at menarche, menopausal status, use of hormone replacement ther- apy, oral contraceptive use, and parity. 8–27 Overall, very few stud- ies have been conducted on any one factor and the findings have not been consistent. In the context of a population-based case– control study of lung cancer carried out in Montreal, Canada, in- formation was collected on a number of personal, lifestyle, and environmental factors, including characteristics of menstruation and pregnancy. The present analysis is intended to explore the possible role of these latter factors in the etiology of lung cancer in women. Material and methods Study population This study, which has been described previously, 28 included men and women aged 35 years and older who were Canadian citi- zens and resided in the greater Montreal area. Newly diagnosed lung cancer cases occurring between January 1996 and December 1997 were identified at 18 Montreal-area hospitals either through hospital tumor registries or active monitoring of pathology records. The 18 participating hospitals together diagnose 98% of the cases that occur in the greater Montreal area. 28 A total of 1,429 men and women with histologically confirmed incident lung cancer were eligible and were approached for interview, of which 569 were women. The participation rate among the 569 eligible women was 81.7% (n 5 465) and interviews with the woman her- self, or her next of kin if she had died before the interview or was too ill (approximately 30%), were conducted an average of 12.1 months after diagnosis. Lung cancer histology was obtained from the pathology reports and coded according to the classification provided by the International Agency for Research on Cancer. 29 Population controls were selected from electoral lists of the Province of Quebec, which provide a nearly complete listing of all Quebec residents who are Canadian citizens aged 18 or greater. Women residing in Montreal, the largest city in Quebec, were ran- domly selected, stratified to the expected age and sex distribution of cases. Among 885 eligible potential female controls that were approached for interview, the participation rate was 69.4% (n 5 614). Approximately 4% of the interviews among female controls were conducted with proxy respondents due to illness, travel, or difficulties with communication. Written informed consent was obtained from all participants, and the study was approved by the Institutional Review Boards of the INRS-Institut Armand-Frap- pier, McGill University and the 18 participating hospitals. Exposure assessment Data was collected with an in-person interviewer-administered questionnaire that assessed various factors including detailed smoking history, sociodemographic characteristics, residential his- tory, occupational exposures, and medical history. For women, the questionnaire included items on hormone-related factors including age at first and last menstrual period, reason for cessation of men- strual periods, ovary removal (oophorectomy) status, age at Grant sponsors: National Health Research and Development Program, Canadian Institutes of Health Research. *Correspondence to: Axe Sant e des populations, Centre de recherche du CHUM, 3875 rue Saint-Urbain, 3e  etage, Montr eal, QC H2V 1W1, Canada. E-mail: anita.koushik@umontreal.ca Received 29 January 2009; Accepted after revision 29 April 2009 DOI 10.1002/ijc.24560 Published online 11 May 2009 in Wiley InterScience (www.interscience. wiley.com). Int. J. Cancer: 125, 2428–2433 (2009) ' 2009 UICC Publication of the International Union Against Cancer