1 Department of Epidemiology, NUTRIM, Maastricht University, Maastricht, the Netherlands.
2 Department of Nutritional Epidemiology, TNO Nutrition and Food Research Institute, Zeist, the Netherlands.
Received for publication July 11, 2002; accepted for publication September 24, 2002.
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ABSTRACT |
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body constitution; body height; body mass index; body weight; cohort studies; ovarian neoplasms
Abbreviations: Abbreviations: CI, confidence interval; RR, rate ratio.
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INTRODUCTION |
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An American Cancer Society study linked obesity to increased risk of ovarian cancer (3, 4). This relation is plausible, because several clinical conditions (e.g., polycystic ovarian syndrome, infertility, and so on) have been linked to both obesity and ovarian cancer (59). However, the results of other epidemiologic studies evaluating the relation between obesity and ovarian cancer have been inconsistent. Comparing their results is difficult because different methods were used, some studies using a clinical diagnosis of obesity from medical discharge registries as the exposure variable (10, 11) and other studies comparing mean values or presenting only the results for the top exposure category compared with the reference category.
The results of hospital-based case-control studies have been heterogeneous (1220). These studies might suffer from selection bias, however, because it cannot be excluded that obesity was overrepresented in the control group (21, 22). Almost all population-based case-control studies have reported a positive relation (although not always statistically significant) between body mass and ovarian cancer risk (2234). Very few prospective studies have been conducted (3, 10, 11, 3537). Most of them showed a small positive effect of body mass on the risk of ovarian cancer. Only two studies were able to control for confounding by other important risk factors (36, 37). The Iowa Womens Health Study cohort found the rate ratio of the highest category to be only very marginally elevated. Another anthropometric measurement, waist/hip ratio, was positively correlated with ovarian cancer (36). A recent nested case-control study within a multicenter cohort study observed an inverse association (37).
The number of studies evaluating the relation between height and ovarian cancer has been much smaller. Some case-control studies reported a greater average height among cases than among controls (13, 18), although the difference was not statistically significant. Some studies reported elevated rate ratios for the highest categories, although again the differences were not significant (31, 38, 39).
Considering the lack of evidence on this topic and the heterogeneity of the published results, we decided to study anthropometry in relation to ovarian cancer in a prospective cohort study, allowing adjustment for the main potential confounders. We therefore examined the association of height and (relative) weight with ovarian cancer in the Netherlands Cohort Study on Diet and Cancer, which provides information on many potential confounders. We also evaluated whether dynamic anthropometric measures, such as (relative) weight gain during adulthood, are predictors of ovarian cancer risk.
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MATERIALS AND METHODS |
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The present analysis is restricted to cancer incidence in the 7.3-year follow-up period from September 1986 to December 1993. The completeness of cancer follow-up was estimated to be at least 96 percent (42), and no subcohort members were lost to follow-up. After a follow-up period of 7.3 years, 202 incident, microscopically confirmed, primary ovarian carcinomas were detected. After the exclusion of nonepithelial tumors (n = 14) and borderline invasive tumors (n = 2), 186 cases remained available. Women in the subcohort who had reported at baseline to have undergone an oophorectomy (n = 16) were excluded, leaving 1,700 subcohort members for analysis.
Questionnaire data
Self-reported information on height (in cm) and weight (in kg) at baseline, as well as weight at age 20 years (in kg), was obtained from the questionnaire. Questionnaire data of all cases and subcohort members were key entered twice and processed in a manner blinded with respect to case/subcohort status to minimize observer bias in the coding and interpretation of data. The baseline body mass index and the body mass index at age 20 years were calculated using baseline weight and weight at age 20 years, respectively, divided by height at baseline squared (kg/m2). Body mass index was classified into the categories recommended by the National Institutes of Health (43). Because very few women in the subcohort fell into the three highest National Institutes of Health categories (30.034.9, 35.039.9, and 40.0 kg/m2), these categories were combined. The following categories were thus used for body mass index: normal (
24.9 kg/m2), overweight (2529.9 kg/m2), and obese (
30 kg/m2). The change in body mass index from age 20 years was calculated as the body mass index at baseline minus the body mass index at age 20 years.
Women with incomplete anthropometric data were excluded, leaving 172 cases and 1,636 subcohort members for analysis. The analysis of weight at age 20 years was based on 152 cases and 1,477 subcohort members with complete data.
Data analysis
The mean values of the anthropometric variables were compared between cases and subcohort members. Other factors were considered as confounders if they were associated with ovarian cancer risk, if they were clearly associated with the anthropometric variables, and if rate ratios changed by more than 10 percent after adjustment. The confounders considered were age (continuous), use of oral contraceptives (ever vs. never), parity (no children, one or two children, or three or more children), use of postmenopausal hormones (ever vs. never), hysterectomy (yes or no), and family history of breast and/or ovarian cancer (yes or no). Family history was considered positive if breast and/or ovarian cancer was reported in a first-degree relative, that is, mother, sister, or daughter.
Incidence rate ratios and corresponding 95 percent confidence intervals for ovarian cancer were estimated in the age-adjusted and multivariate case-cohort analyses with categorized and continuous anthropometric variables, using exponentially distributed failure time regression models (44) processed with the Stata statistical software package (Stata Corporation, College Station, Texas). Standard errors were estimated using the robust Hubert-White sandwich estimator to account for additional variance introduced by sampling from the cohort. This method is equivalent to the variance-covariance estimator presented by Barlow (45). Tests for dose-response trends in the risk of ovarian cancer were assessed by fitting ordinal exposure variables as continuous terms and performing likelihood-ratio tests between regression models with and without these variables. Two-sided p values are reported throughout the paper. Because preclinical disease might influence weight, we repeated the analyses for weight and body mass after excluding cases occurring in the first year of follow-up.
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RESULTS |
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Table 1 lists the anthropometric variables for cases and subcohort members. The mean height and weight differed between cases and subcohort members, in that cases were both taller and heavier. The difference in body mass index between cases and subcohort members was not great. Cases were also somewhat heavier than subcohort members at age 20 years. A comparison of subcohort members whose information on weight at age 20 years was missing with those who did report their weight at age 20 years yielded no significant differences in mean height, baseline weight, and body mass index (data not shown).
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Table 2 shows age-adjusted and multivariate-adjusted rate ratios of ovarian cancer for height, baseline weight, and body mass index at baseline. Height was positively correlated with the risk of ovarian cancer in both the univariate and multivariate analyses (p trend = 0.01). Weight was also positively associated with the risk of ovarian cancer but not significantly so (p trend = 0.18). Women who were obese at baseline (body mass index, 30 kg/m2) had an increased risk of ovarian cancer compared with women who had a normal body mass (rate ratio (RR) = 1.69, 95 percent confidence interval (CI): 1.00, 2.86; p trend = 0.06).
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DISCUSSION |
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These results from the Netherlands Cohort Study on Diet and Cancer are not likely to have been affected by selection or information bias. Selection bias is unlikely given the high level of follow-up of cases and subcohort person-years (42, 46). All of the anthropometric results were self-reported, however, and misclassification of exposure is a potential source of bias. Although several studies have reported high correlations (r > 0.8) between self-reported and measured anthropometric data (4749), other publications reported that, despite high correlations, weight tends to be underestimated and height overestimated, thus leading to lower estimates of body mass (50, 51). Mean values for the self-reported height and weight, however, were comparable with those of a representative sample of Dutch women 5069 years of age measured in 1986 (52). The mean measured height and weight of the latter group (n = 3,377) were 165.6 cm and 68.9 kg, respectively, compared with 165.1 cm and 68.6 kg for our subcohort of women from the Netherlands Cohort Study on Diet and Cancer. Weight at age 20 years was used to calculate body mass index at age 20 years, and misclassification might have occurred because weight at age 20 years is difficult to remember. However, misclassification is expected to be nondifferential, and therefore, a possible effect on the risk estimates tends toward zero. Data regarding weight (and body mass index) at age 20 years were missing for 12 percent and 10 percent of the cases and the subcohort members, respectively. Subcohort members with and without information regarding weight at age 20 years did not differ significantly in baseline anthropometric measures. We were able to control for confounding by the most important risk factors (7). However, all covariates were measured at baseline only, and it is conceivable that use of postmenopausal hormone therapy had changed since then.
Obesity may have hampered diagnostics, causing delay in diagnosis, which would lower the risk estimates in the highest weight category. It is also conceivable that preclinical disease causes weight loss and may confound an association with body weight (2).
The relation between height and the risk of ovarian cancer has been studied in a few case-control studies. Two of these studies reported that cases were slightly more than 1 cm taller than controls, although the difference was not statistically significant (13, 18). This difference is in exact agreement with the findings of the present study. Another case-control study, however, reported no difference in mean height between cases and controls (24). In Greece, women with a height of 165 cm or more had a risk of 1.8 (95 percent CI: 0.8, 3.9) compared with women with a height of 154 cm or less (38). A more recent study in the same geographic location did show a much lower risk estimate: Women with a height of 165 cm or more had a rate ratio of 1.13 (95 percent CI: 0.67, 1.90) compared with women with a height of 159 cm or less (53). The observed difference in outcome might be explained by the different reference category, but also by cohort effects. Polychronopoulou et al. (53) did not exclude an effect of height and suggested that the increasing trend in ovarian cancer mortality in Greece could be caused in part by the dramatic increase in adult height in that country. Two case-control studies in China and Japan found nonsignificantly increased risk estimates for the highest category compared with the lowest: 1.3 (95 percent CI: 0.6, 3.1) and 1.4 (95 percent CI: 0.6, 3.0), respectively (31, 39). Only one prospective study has provided results on the relation between height and risk of ovarian cancer (54). The power of this study (only nine cases) was too small to yield any meaningful results. A recent multicenter nested case-control study reported some evidence of a direct association of ovarian cancer and height in cancers diagnosed before the age of 55 years (37), but precise rate ratios were not published.
Height has been associated with several types of cancer, especially breast cancer (55). Height as such does not cause cancer but probably acts as a biomarker for some other exposure (55). Suggested hypotheses include genetic factors, calorie restriction in early life, and an increased exposure to sex and growth hormones. Several investigators have noted that height-cancer associations are strongest in birth cohorts exposed to periods of food shortages during prepubertal growth (5659). This may also be a possible clue to the apparent discrepancy in outcomes between the two Greek studies (38, 53). Women in the Dutch cohort of the Netherlands Cohort Study on Diet and Cancer experienced the economic crisis of the 1930s in their youth, as well as the German occupation during the Second World War, including particularly the famine in the winter of 1944 (60). Food restriction during youth may restrict serum levels of insulin-like growth factor I (61, 62), which inhibits apoptosis of damaged cells and stimulates cell turnover and cell proliferation (63, 64). The link between height and increased risk of ovarian cancer therefore does not seem implausible, and insulin-like growth factor I must be considered as one of the factors involved in this relation.
Although several studies have published results on the relation between weight or body mass and the risk of ovarian cancer, interpretation is hampered by differences in methodology and presentation of the results. A study by the American Cancer Society was the first to publish results on the relation between anthropometric data and the risk of ovarian cancer (3, 4). Women whose weight was 40 percent higher than the mean (adjusted for age and height) had a rate ratio of 1.63 compared with women of average weight. Several case-control studies have reported a higher average weight or body mass index among cases than among controls (18, 29) or reported a higher prevalence or increased rate ratio for excess (relative) weight or clinical obesity among cases (12, 23, 25, 65). On the other hand, several other case-control studies have reported lower average weight for cases than for controls (13, 17, 18) or decreased rate ratios for the highest category of (relative) weight (14, 15, 19, 66, 67).
As noted by Whittemore et al. (68) and Purdie et al. (22), all these studies that found a negative or no association used hospital-based controls (1320). Selection bias has been suggested as an explanation for the lack of association or the negative associations found in hospital-based case-control studies (21, 22). It was suggested that obese persons are overrepresented in a series of hospital controls. Most case-control studies, however, including almost all population-based case-control studies, published a positive, albeit moderate association between weight and/or body mass index and the risk of ovarian cancer (22, 24, 2628, 30, 31, 34). A few case-control studies reported no association or a very small association (odds ratio 1.1): Two of these were hospital based (16, 20), and two were population based (32, 39). A recent systematic review concluded that there is a small-to-moderate positive relation between high body mass index and the occurrence of ovarian cancer (22). Overall, the hospital-based case-control studies observed no relation (summary RR = 1.1, 95 percent CI: 0.9, 1.2), while the population-based case-control studies yielded positive relations (summary RR = 1.4, 95 percent CI: 1.2, 1.6) (22). Since the study by the American Cancer Society, only a few prospective cohort studies have published results with respect to the relation between weight or body mass index and ovarian cancer risk. Törnberg and Carstensen (35) analyzed the risk of increasing body mass index and found a positive association in women below the age of 55 years (RR = 1.66 for body mass index of 28 or higher compared with body mass index below 22) but no association in women who were more than 55 years of age. These rate ratios were not adjusted for the major potential confounders. Moller et al. (10) and Wolk et al. (11) studied the incidence of ovarian cancer in women who had been recorded in the hospital discharge registry with a diagnosis of obesity (International Classification of Diseases, Ninth Revision, code 277) and compared the observed incidence rates with the expected rates based on the general population. Moller et al. found a small and statistically nonsignificant risk (RR = 1.1, 95 percent CI: 0.8, 1.4), while Wolk et al. found a rate ratio of 1.2 (95 percent CI: 1.1, 1.5). These studies could not adjust for confounders. Mink et al. (36) were able to adjust for confounders and found no statistically significant association for women who had a body mass index higher than 29.5 compared with those who had a body mass index lower than 23.5 (RR = 1.1, 95 percent CI: 0.64, 1.93). The waist/hip ratio, however, was significantly increased in the highest quartile compared with the lowest quartile (RR = 1.92, 95 percent CI: 1.03, 3.60). Overall, Purdie et al. (22) calculated a summary rate ratio of 1.2 (95 percent CI: 1.1, 1.3) for the cohort studies. These results are in agreement with our findings.
The review by Purdie et al. did not include the study by Lukanova et al. (37). In a multicenter nested case-control study with 122 cases, they observed an inverse association between increasing weight and risk of ovarian cancer. The highest body mass index category (28.4 kg/m2) had a multivariate-adjusted relative risk of 0.46 compared with women who had a body mass below 23.1. The age at recruitment in this multicenter cohort was lower than in our cohort, and the mean age at diagnosis was 59.4 years (compared with 62.1 years in our study). This means that a considerable proportion of the cases must have been premenopausal at diagnosis, and that the measured weight and body mass reflected mainly premenopausal exposure.
As regards the etiology of ovarian cancer, several hypotheses have been put forward. Fathalla (69) and Casagrande et al. (23) have proposed the "incessant ovulation" hypothesis, assuming that ovulation causes trauma to the ovarian epithelium and that the higher the number of ovulations the greater the risk of ovarian cancer. Cramer and Welch (70) suggested that excessive amounts of gonadotropins stimulate ovarian carcinogenesis. A more recent hypothesis by Risch (71) suggests that high serum levels of androgens increase the risk of ovarian cancer, while progestagens protect against ovarian cancer.
Obesity has multiple effects on the hormonal status of pre- and postmenopausal women. In premenopausal women, it lowers sex hormone-binding globulin and increases the serum levels of insulin-like growth factor I, but it does not influence levels of estrogens and androgens significantly, because the ovaries produce more steroids than the peripheral fat tissue (2, 72). In postmenopausal women, the levels of estrogens and androgens are increased because the main production is by peripheral fat tissue, while serum levels of free progestagens are decreased (2). According to the hypothesis by Risch this would predict a positive relation between weight or body mass and the risk of ovarian cancer in the postmenopausal period.
Only a limited number of case-control studies have considered the influence of weight (or body mass index) at a young adult age. Purdie et al. (22) reported little deviation from zero across the range of body mass index at age 20 years. Farrow et al. (26) reported an increasing trend for body mass index according to categories at age 30 years (p < 0.05). Mori et al. (31) reported an increased risk for women heavier than 55 kg compared with women lighter than 45 kg (odds ratio = 1.52, 95 percent CI: 0.78, 2.96). Our study found no consistent increasing trend. The rate ratio was nonsignificantly decreased in the highest category of body mass index at age 20 years, while the rate ratio in the second category was nonsignificantly increased. Purdie et al. (22) reported a significantly elevated risk for the highest category of change in weight since age 20 years. This observation was not confirmed in our study. Clinical obesity (>30 kg/m2) in the fertile age is known to increase the frequency of anovulatory menstrual cycles (73). The Nurses Health Study found the risk of ovulatory infertility to be increased in women with a body mass index less than 20 or greater than 24 (74). According to the theory by Fathalla (69), fewer ovulatory cycles would decrease the risk of ovarian cancer. As regards weight and body mass index at age 20 years, we observed that the risks were smallest in the lowest and the highest categories (although the differences were not statistically significant). According to Fathallas theory, this is in agreement with the results of the Nurses Health Study.
The findings of the present prospective study support a positive association between height (and to a lesser extent weight) and ovarian cancer risk in this population of postmenopausal women. Confirmation of these results in other well-designed prospective studies is warranted, while the relation with body mass at age 20 years and weight gain since then needs further research.
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ACKNOWLEDGMENTS |
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NOTES |
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REFERENCES |
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