In this study we found a suggestion of an inverse association between phytoestrogen consumption and ovarian cancer risk. However, confidence intervals included the null value after adjusting for covariates, including physical activity and smoking. Estimates were stronger when combined intake from foods and supplements was evaluated. Similarly, there was some suggestion of an inverse association with tofu and combined soy product consumption, but confidence intervals included one.
Few epidemiologic studies have evaluated the association between phytoestrogens and ovarian cancer and, to our knowledge, this is the first population-based study to undertake a detailed analysis of lignans, isoflavones, and total phytoestrogens in relation to ovarian cancer risk in the United States, as well as attempting to compute total phytoestrogens from foods and supplements. Total isoflavone intake was previously evaluated in two cohort studies in California [16
] and Sweden [21
] and two hospital-based studies conducted in China [15
] and Italy [18
]. Three of these studies [15
] found an inverse association with isoflavone intake, with approximately 50% reduced risk for the highest category of consumption compared to the lowest. However, in the cohort study in Sweden [21
], like in our study, there was little evidence of an association. Tofu was also evaluated in the California Teachers Cohort [16
] and in the Japan Collaborative Cohort (JACC) Study [17
]. Similar to our findings, both studies found risk estimates below one, but the confidence interval included the null. Tofu and meat substitutes were uncommonly used in both our study and in the California Teachers Cohort, and that may have affected our ability to detect an association. In the Chinese hospital-based case-control study [15
], which had a wider range of intake, soy foods were also found to decrease ovarian cancer risk, with an OR of 0.50 (95% CI: 0.31-0.82) [15
We are aware of two other studies reporting on lignan intake and ovarian cancer risk, with conflicting results. The first is a case-control study in Western New York, which evaluated two lignans combined, secoisolariciresinol and matairesinol, and found a strong inverse association with intake [20
]. The second study, is a cohort study in Sweden [21
] which, like ours, found no indication of an association with lignan consumption. Lignan calculations were computed using different databases in the three studies and this, together with possibly different food sources, may have explained, at least in part, the discrepant findings.
Several mechanisms have been postulated to explain the potential protective effect of soy and phytoestrogens on ovarian carcinogenesis. They have been shown to inhibit enzymes that synthesize and metabolize estrogens and increase sex hormone-binding globulin synthesis [22
]. In addition, they are capable of binding to the estrogen receptor (ER), particularly ER beta, which has been involved in the differentiation of proliferating tissue [22
]. Other anticarcinogenic properties that have been attributed to phytoestrogens include inhibiting tumor angiogenesis, cell proliferation, tyrosine kinase, and topoisomerase II [22
Our study is subject to the limitations of case-control studies, such as potential recall bias, as cases may report or recall dietary intake in a different way than controls. However, because the relationship of ovarian cancer with soy foods is largely unknown, and lignans are widely distributed in the diet, this is unlikely. The response rate in our study was low. However, it is well known that participation rates in population-based studies have been decreasing over the past years, and rates around 50% are not unusual, particularly among controls [31
]. To evaluate possible selection bias, we compared the characteristics of women consenting to participate in the study to all women diagnosed with epithelial ovarian cancer using New Jersey State Cancer Registry data in the same counties during a similar time period [32
]. Race and ethnic distribution was similar, while the cases consenting tended to be younger, with a median age of 56 years at diagnosis, compared to a median age of 61 years at diagnosis for the total population of cases. The distribution by histology, stage, and grade was generally similar. For controls, like most epidemiologic studies, we do not have information on those who could not be reached or did not participate. However, the distribution of the main risk factors for ovarian cancer in cases and controls is similar to that reported in other studies. Furthermore, non-response bias would only affect the study validity if willingness to participate is related to the factors under evaluation [31
]. The possible role of dietary factors in the etiology of ovarian cancer is not well known, and even less so that of phytoestrogens and soy foods. This reduces the possibility of response bias. Also, the fact that our results are in agreement with the current literature in this area lessens even further the concern over possible non-response bias.
Our sample size was relatively small and we may have lacked power to detect a significant association. Nevertheless, our results were in general agreement with other studies. A major strength of our study is that it was specifically designed to evaluate the association between phytoestrogen intake from foods and supplements and ovarian cancer risk. For example, we expanded the questionnaire to include important sources of these compounds. We also computed all the major phytoestrogens for a detailed assessment.
Future studies should conduct a comprehensive assessment by including all major sources of phytoestrogens (including a detailed assessment of phytoestrogens in supplements) and should have sufficient power to evaluate the association, preferably using a prospective design, which avoids the major biases inherent to the case-control approach (such as recall and selection bias).