BRIEF COMMUNICATION |
Anthropometry, Physical Activity, and Endometrial Cancer Risk: Results From The Netherlands Cohort Study
Leo J. Schouten,
R. Alexandra Goldbohm,
Piet A. van den Brandt
Affiliations of authors: Department of Epidemiology, NUTRIM, Maastricht University, Maastricht, The Netherlands (LJS, PAVDB); TNO Nutrition and Food Research, Zeist, The Netherlands (RAG)
Correspondence to: Leo J. Schouten, MD, PhD, Nutrition and Toxicology Research Institute, Maastricht (NUTRIM) Department of Epidemiology, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands (e-mail: lj.schouten{at}epid.unimaas.nl)
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ABSTRACT
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Although obesity is an established risk factor for endometrial cancer, evidence linking risk to height, weight change since age 20, and physical activity is limited. In this casecohort study, 62 573 women from The Netherlands Cohort Study on Diet and Cancer were followed up from 1986 to 1995, and 226 endometrial cancer case patients were identified. In Cox proportional hazards analyses, women 175 cm or taller had an increased risk of endometrial cancer compared with those less than 160 cm (rate ratio [RR] = 2.57, 95% confidence interval [CI] = 1.32 to 4.99). Compared with women with a body mass index (BMI; kg/m2) between 20 and 22.9, women with a BMI of 30 or greater had a higher risk (RR = 4.50, 95% CI = 2.62 to 7.72; Ptrend<.001). Moreover, BMI at age 20 and BMI gain since age 20 were positively associated with endometrial cancer risk (Ptrend = .02 and <.001, respectively). Women who spent 90 minutes per day or more doing nonoccupational physical activities had a lower risk (RR = 0.54, 95% CI = 0.34 to 0.85; Ptrend = .002) compared with those who spent less than 30 minutes per day. High BMI and low physical activity were strong and independent risk factors for endometrial cancer.
Endometrial cancer ranks as the fourth most frequent cancer among women living in Europe (1). Although being overweight has been established as an important risk factor for endometrial cancer (2,3), the evidence linking risk to body mass at younger ages, weight change, and height is limited (3,4). Several studies (516) found that physical activity is associated with a decreased risk of endometrial cancer. In 2002, the International Agency for Research on Cancer concluded that evidence for the relationship between physical activity and endometrial cancer risk was consistent but limited (3). We studied the association between height, body mass index (BMI), BMI gain during adulthood, and physical activity with the risk of endometrial cancer within The Netherlands Cohort Study on Diet and Cancer. This study started in 1986 and includes 62 573 women from 55 to 69 years of age at enrollment. At baseline, cohort members completed a mailed, self-administered questionnaire on dietary habits, anthropometry, physical activity, and other risk factors for cancer. We used the questionnaire to obtain self-reported information on height (in centimeters) and weight (in kilograms) at baseline, as well as weight at age 20. Baseline BMI and BMI at age 20 were calculated using baseline weight and weight at age 20, respectively, divided by height squared (kg/m2). Baseline nonoccupational physical activity was calculated by adding the number of minutes spent per day on cycling or walking to work, shopping, and walking the dog, and the number of hours spent per week on gardening or odd jobs, recreational cycling or walking, and sports or exercise as reported previously (17). Data were processed and analyzed by using the casecohort approach, in which the case patients were derived from the entire cohort, and the number of person-years at risk in the cohort was estimated from a subcohort. This subcohort of 2589 subjects was randomly sampled from the entire cohort immediately after the baseline measurement and is being followed up biennially for vital status (18). Follow-up for cancer incidence was established by record linkage with The Netherlands Cancer Registry and Pathologisch Anatomisch Landelijk Geautomatiseerd Archief, a nationwide pathology database. After 9.3 years of follow-up, a total of 250 incident invasive epithelial endometrial cancer cases were reported (19,20). Case patients and subcohort members were excluded if they reported cancer other than nonmelanoma skin cancer, reported a hysterectomy at baseline, or had incomplete data for anthropometry, physical activity, or confounders. A total of 1739 subcohort members and 226 endometrial cancer case patients were available for analysis. Incidence rate ratios (RRs) and 95% confidence intervals (CIs) for endometrial cancer were estimated in age-adjusted and multivariable casecohort analyses using the Cox proportional hazards model (21), processed with the Stata statistical software package (22). The proportional hazards assumption was tested using the scaled Schoenfeld residuals (23). Cut points for physical activity and the anthropometric subdivisions were used as previously reported (17,24,25); the combined BMI categories (2526.9 kg/m2 and 2729.9 kg/m2) correspond to being overweight, and a BMI of 30 kg/m2 or greater corresponds to obesity (26). Standard errors were estimated using the robust HuberWhite sandwich estimator to account for additional variance introduced by sampling from the cohort (27). All rate ratios were adjusted for confounders (age, age at menarche, use of oral contraceptives, age at menopause, parity, and cigarette smoking). Tests for doseresponse trends in the risk of endometrial cancer were assessed by fitting ordinal exposure variables as continuous terms. Two-sided P values are reported throughout this report. Height and weight were associated with endometrial cancer risk (Table 1). Although there was not a statistically significant trend with increasing height (Ptrend = .09), the tallest women (
175 cm) had a statistically significantly higher risk than women less than 160 cm tall (RR = 2.57, 95% CI = 1.32 to 4.99). BMI at baseline was strongly associated with endometrial cancer risk (RR = 4.50, 95% CI = 2.62 to 7.72) for obese women (BMI
30 kg/m2) compared with women with a BMI between 20 and 22.9 kg/m2 (Ptrend<.001). Women with a high BMI (
25 kg/m2) at age 20 did not have a higher risk than women with a BMI between 20 and 22.9 kg/m2, but women with a low BMI (<20 kg/m2) had a slightly reduced risk (RR = 0.67, 95% CI = 0.45 to 0.98). BMI gain since age 20 was also associated with endometrial cancer risk (Ptrend<.001); women with BMI loss since age 20 had a rate ratio of 0.50 (95% CI = 0.25 to 0.97) times that of women with a BMI gain of 0 to 3.9 kg/m2. A high level of nonoccupational physical activity was associated with decreased risk of endometrial cancer (Table 2). Women who engaged in nonoccupational physical activity for 90 minutes or more per day had a rate ratio of 0.54 (95% CI = 0.34 to 0.85) times that of women who engaged in such activity for less than 30 minutes (Ptrend = .002). Rates of endometrial cancer decreased with increased daily biking or walking (less than 10 minutes per day to more than 60 minutes per day; Ptrend = .008). Gardening and sports activities were not associated with risk, although most rate ratios were lower than 1. Interactions of BMI or physical activity with other risk factors were also analyzed. No statistically significant interactions were found (supplementary tables available at http://jncicancerspectrum.oupjournals.org/jnci/content/vol96/issue21). Exclusion of case patients with cancer detected in the first 2 years of follow-up did not change the rate ratios related to physical activity and BMI at baseline (data not shown). Previous studies on the relationship between height and endometrial cancer have yielded conflicting results, although most have found increased risks with increasing height (57,2839). De Waard et al. (40) suggested that fat mass, rather than height, explained the relationship. However, when we adjusted for BMI, our results showed that the tallest subgroup of women had a higher rate than the shortest subgroup of women. Among the other studies, some adjusted for weight, while others adjusted for BMI or relative weight. Even if these differences for weight adjustment are taken into account, the outcomes remain heterogeneous. Our study confirms that BMI is strongly related to endometrial cancer risk, a result that is in agreement with those of most studies (3,9,28,31,32,4146). Our results are consistent with a linear doseresponse relationship between BMI (of
20 kg/m2) and endometrial cancer risk. A decrease in BMI during adulthood was associated with a reduced risk. In our study, nonoccupational physical activity for 90 minutes or more per day was associated with a 46% lower risk, compared with less than 30 minutes per day. Several other studies (3) have found similar associations with recreational or occupational physical activity. Several possible biological explanations for the results can be made. It is generally accepted that estrogens unopposed by progestagens increase endometrial cancer risk (47,48). Estrogens stimulate proliferation of the endometrium, whereas progestagens stop cell division and stimulate cell differentiation (48). In obese postmenopausal women, androgens are converted into estrogens in peripheral fat tissues (49,50). Because serum levels of sex-hormone binding globulin are decreased in obese women, the proportion of free estradiol also increases (51). Therefore, women with higher BMIs due to fat accumulation may have higher levels of estrogen than those who have less body fat (51). Because diabetes and insulin resistance have been identified as risk factors for endometrial cancer (52), and insulin-like growth factor and insulin levels are increased in overweight persons and are lowered by physical activity (52), the role of insulin and insulin-like growth factors (e.g., IGF-I) in endometrial tumor development is being explored (5153). This study found that high BMI and low physical activity were strong and independent risk factors for endometrial cancer. One consequence of the increasing epidemic of obesity and the lack of physical activity in Western society may thus be an increasing incidence of endometrial cancer in the coming years.
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Table 1. Multivariable adjusted rate ratios for anthropometric variables in The Netherlands Cohort Study on Diet and Cancer, 19861995*
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Table 2. Multivariable adjusted rate ratios for baseline nonoccupational physical activity in The Netherlands Cohort Study on Diet and Cancer, 19861995*
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NOTES
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We are indebted to the participants of the study and further wish to thank the cancer registries (IKA, IKL, IKMN, IKN, IKO, IKR, IKST, IKW, IKZ, and VIKC) and The Netherlands nationwide registry of pathology (PALGA). We also thank Jan Klerkx for linguistic comments; Dr. Miranda Dirx for methodological advice; Dr. Arnold Kester and Dr. Maurice Zeegers for statistical advice; Sacha van de Crommert, Henny Brants, Jolanda Nelissen, Conny de Zwart, Marijke Moll, Margje Jansen, Willy van Dijk, and Annemie Pisters for assistance; and Harry van Montfort, Ton van Moergastel, Linda van den Bosch, and Ruud Schmeitz for programming assistance.
This study was presented in part at the Annual Meeting of the American Association of Cancer Research (AACR), Orlando, FL, March 27-31, 2004.
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