In this pooled analysis of the individual data from 12 prospective cohort studies, height was associated with a modest increase in the risk of epithelial ovarian cancer, especially in premenopausal women. Height was associated with an increased risk of endometrioid and serous carcinoma but not with mucinous carcinoma, although the difference between histologic subgroups was not statistically significant. BMI at baseline was not associated with the risk of epithelial ovarian cancer overall; however, being obese was associated with an increased risk of premenopausal ovarian cancer.
The association between height and the risk of ovarian cancer has been studied in several epidemiologic studies. Most case-control studies have reported no statistically significant associations between height and risk (9
). Only one case-control study (22
) observed a statistically significant elevated risk. In contrast, most prospective cohort studies have reported positive associations with height. Of the six published prospective studies (13
), three (13
) were included in this analysis. One other report was from a cohort in which we only included the subset of women who completed a dietary assessment in 1992 (32
). The cohorts not included in this analysis have either not assessed diet or did not use a validated assessment of usual dietary intake or been able to control for other ovarian cancer risk factors such as parity and oral contraceptive use. Jonsson et al. (20
) reported an increased risk for the tallest 25% of the women (≥166 cm) compared with the second quartile (159 to <163 cm), which had been defined as the reference category. A Norwegian cohort (21
) of 1.1 million women with 7,882 cases of ovarian cancer reported a positive association between height and ovarian cancer: women taller than 175 cm had a RR of 1.29 (95% CI, 1.11-1.51) compared with women between 160 and 164 cm.
The observation that most case-control studies have not reported statistically significant odds ratios may be caused by a relative lack of power, because 5 (9
) of 10 (9
) have published odds ratios (≥1.3) that are in range with our result (1.37) for the highest category of height. Odds ratios in the other five studies were all above unity, between 1.08 and 1.26 (10
). For the few studies that have investigated whether the association between height and ovarian cancer risk is modified by menopausal status, the association was stronger in or restricted to premenopausal women (21
), which is in agreement with our analysis. Whether height is associated with histologic subtypes has been investigated in a few studies only. In the Norwegian cohort study (21
), height was positively associated with endometrioid ovarian cancer risk, which is in accordance with our findings: the association with other histologic subtypes was not reported. In an Australian case-control study, height was associated with risk of mucinous borderline invasive ovarian cancer, but the 95% CIs were wide because of small numbers (12
); no associations were observed with invasive serous, mucinous, or endometrioid cancers (12
). In our pooled analysis, only invasive ovarian cancers were included, so we were not able to evaluate borderline invasive ovarian cancers.
In this pooled analysis, no association was observed between BMI at baseline and risk of ovarian cancer in all women. This finding is not in agreement with a systematic review from Olsen et al. (28
) who concluded that overweight and obesity were associated with a small to moderately increased risk of ovarian cancer in population-based case-control studies and prospective cohort studies (pooled effect estimate for adult obesity versus normal BMI, 1.3; 95% CI, 1.1-1.5). The association was weaker and not statistically significant in prospective cohort studies in the systematic review (RR, 1.12; 95% CI, 0.95-1.32), and results between cohort studies were heterogeneous (28
). Of the 17 (13
) published cohort studies, 5 (13
) were included in our pooled analysis and 2 were included in part (32
). The 10 cohorts not included in this analysis have published mostly null associations, with the exception of Garfinkel (57
), Wolk et al. (60
), Lukanova et al. (63
), and Reeves et al. (64
) who published positive associations.
However, in our analysis, we observed that BMI was positively associated with ovarian cancer risk in women who were premenopausal. The number of cases in premenopausal women was limited. Heterogeneity with respect to menopausal status, however, has been observed in almost all studies that have investigated whether the association between BMI and ovarian cancer is modified by menopausal status or age (17
). Only one case-control study (69
) has not reported a higher risk in younger women. That BMI has different effects depending on menopausal status is plausible, as this also has been observed with breast cancer, another hormone-dependent cancer (7
Olsen et al. (28
) attributed the weaker association in prospective cohort studies to the fact that some had used a single measurement of body mass and had a very long follow-up. Weight change during the follow-up may have caused attenuation of the risk estimates. In our analysis, the association was stronger in the first 5 years of follow-up but not statistically significant. It is therefore possible that a weak association was attenuated in our analysis because of the single (baseline) measurement of BMI and the long follow-up. Our finding that the association is stronger in premenopausal and younger women may also be an explanation for the time-dependent association. Cases with longer follow-up in the cohort studies are more likely to be postmenopausal at diagnosis than cases with a short follow-up. The difference in risk estimates between study types could also be caused by selection and information bias in the case-control studies.
Because of the small numbers of ovarian cancer cases in most studies, few studies have investigated whether the association with BMI differs among specific histologic subtypes of ovarian cancer and the findings have been inconsistent (31
). In our pooled analysis, we did not observe an association with any of the investigated subtypes of invasive ovarian cancer.
We found no association between BMI in early adulthood and ovarian cancer risk. Four (13
) cohort studies [of which three (13
) are included in this analysis] and six case-control studies (14
) have published inconsistent results. The Norwegian cohort study published increased risks for women with a “high” or “very high” BMI in early adulthood compared with women of medium BMI (21
). Of the case-control studies, one published an inverse association for BMI at age 18 (66
), two published null results (15
), and three published positive associations (14
Height has been associated with several types of cancer, especially breast cancer (8
). Height as such does not cause cancer but probably acts as a marker for some other exposure (8
). Suggested hypotheses include genetic factors, energy intake in early life, and exposure to sex and growth hormones. For instance, insulin-like growth factor-I is associated with height and also inhibits apoptosis of damaged cells and stimulates cell turnover and cell proliferation (8
). Insulin-like growth factor-I was associated with an increased risk of ovarian cancer before age 55 in one study (74
). In a small Italian case-control study, these findings were not confirmed, however (75
), but in this study blood samples were not collected prospectively. A nested case-control analysis within the European Prospective Investigation into Cancer and Nutrition cohort using prediagnostic blood samples observed that insulin-like growth factor-I levels were increased in women that developed ovarian cancer at premenopausal or perimenopausal age (76
). The link between height and increased risk of ovarian cancer therefore seems plausible.
Obesity has multiple effects on the hormonal status of premenopausal and postmenopausal women. In premenopausal women, obesity lowers sex hormone-binding globulin but does not influence levels of estrogens and androgens significantly, because the ovaries produce more steroids than the peripheral fat tissue (23
). A recent publication from the NHS II showed that BMI was inversely associated with sex hormone-binding globulin and progesterone and positively associated with free testosterone in premenopausal women (78
). This is in agreement with the hypothesis of Risch who suggested that high serum levels of androgens increase the risk of ovarian cancer, whereas progestagens protect against ovarian cancer (79
The results from the Pooling Project of Prospective Studies of Diet and Cancer are not likely to have been affected by selection or information bias as only data from prospective cohort studies have been analyzed and the follow-up rate in these studies generally exceeded 90% (41
). Although some cohorts have measured height and weight, all anthropometric results used in this analysis were self-reported, however, and misclassification of exposure is a potential source of bias. Although several studies have reported high correlations (>0.8) between self-reported and measured anthropometric data (80
), other publications have reported that despite high correlations weight tends to be slightly underestimated and height slightly overestimated, thus leading to lower estimates of body mass (83
). Weight at early adulthood was used to calculate BMI in early adulthood, and misclassification might have occurred because this is difficult to remember. Misclassification is expected to be nondifferential and therefore would tend to bias towards the null.
Not all covariates were measured in each study. Within our models, we adjusted for most of the important ovarian cancer risk factors (e.g., age at menarche, oral contraceptive use, and parity) if they were measured in a study; results from age-adjusted and multivariate models were similar, suggesting that any residual or unmeasured confounding was small. A major advantage of the method of pooling primary data compared with a literature-based meta-analysis is the ability to characterize and control for covariates uniformly and classify the main exposures similarly. Due to the inclusion of 12 cohort studies from North America and Europe, we had far greater statistical power than the individual cohort studies to examine specific histologic subtypes or effect modification by menopausal status.
In summary, this prospective study with >2,000 cases found that height was associated with a modestly increased risk of ovarian cancer, especially in premenopausal women. No association was observed between recent BMI or BMI in early adulthood and overall ovarian cancer risk. Being obese was associated with an increased risk of premenopausal ovarian cancer, however. Further research is warranted to investigate possible heterogeneous effects with respect to specific histologic subtypes and menopausal status.