Whereas positive aspects of isoflavone supplementation are rarely factored into the extrapolation of a carcinogenic risk of isoflavones, the hypothesis of an increased risk of hormone-sensitive cancer is almost entirely based on the study of Unfer et al. (2004). The authors had reported observations from a five-year double-blind supplementation of 298 women with a daily dose of 150 mg of isoflavones. At the end of the study the authors had found endometrial hyperplasia in 3.37 % of the women of the isoflavone group (five cases of simple, reversible hyperplasia, one case of complex hyperplasia), in contrast to not a single case in the placebo group (Unfer et al. 2004).
The study was criticized for various reasons (Foth and Nawroth 2005; Mahady 2005; Messina 2009):
- - The complete absence of endometrial hyperplasia in the placebo group is highly unlikely (Messina 2009). The natural incidence rate of endometrial hyperplasia in menopausal women not treated with hormonal replacement therapy is approximately 5 %.
- - Hyperplasia was only observed after 5 years, but not after 30 months (Mahady 2005). Supposed the isoflavones do in fact have an estrogen-like effect on the proliferation of the endometrium, why would such an effect only become apparent after a minimum duration of supplementation of 2.5 years?
- - Unfer et al. did not give information on possible relations between endometrial hyperplasia and body weight. Due to the endogenous production of estrogens in fat tissue, endometrial hyperplasia occurs much more frequently in overweight women than in normal weight subjects. Unfer et al. (2004) mention that a part of the study population was in fact overweight, but do not correlate the two observations (Mahady 2005).
- - All but one of the cases of hyperplasia observed in the study were reversible and thus not cancer. The occurrence of hyperplasia as such does not allow concluding on the development of cancer. Simple hyperplasia is usually reversible, and only rarely progresses to endometrial carcinoma (Münstedt et al. 2004).
- - The observations of Unfer et al. (2004) stand in contrast to all clinical trials where the safety at the endometrium was measured after the intake of isoflavones. Thus, no histological or structural changes were detected in placebo-controlled randomized studies (Mahady 2005). In contrast, epidemiological studies point to an inverse correlation between isoflavone intake and the risk of endometrial cancer (Goodman et al. 1997b; Goodman et al. 1997a; Mahady 2005; Xu et al. 2004).
- - On inclusion into the trial the average age of the women examined by Unfer et al. was 49±4.3 and 50±3.9 years in the isoflavone and placebo group, respectively. The average age of beginning menopausal complaints was indicated with 50.2±6.5 and 49.8±6.3 years in the isoflavone and the placebo group, respectively. According to these figures only women just shifting into menopause were included. The study details, however, mention an average duration of menopause of 5.6±4.3 years (isoflavone group) and 58±4.5 years (placebo group) on inclusion into the trial! Correspondingly one of the figure sets must have been wrong: either the average time of duration of menopausal symptoms was incorrect, or women at an age of 45 years were included, an average which seems to be unusually early for the onset of menopause.
- The most important point, however, was the lack of comparability of pre/post data at the endometrium. Both on inclusion and at the end of the study approximately one quarter of biopsies could not be assessed (26.8 % and 24.8 % for isoflavones and placebo on inclusion, and 19.5 % and 24.8 % for isoflavones and placebo on termination of the study). Apparently all women were included into the study, whether there was an assessable biopsy or not. Following the data given in the publication, no distinction was made between women with and without starting values at the end of the study. Although a comparison of women with pre/post data would have been the obvious thing to do, the results were pooled. Correspondingly, it is impossible to know whether the cases of hyperplasia in the isoflavone group were not already pre-existing on inclusion (albeit this seems rather unlikely), or whether there was really no case of hyperplasia in the 24.8 % of women of the placebo group with unassessable biopsies. The observations of Unfer et al. (2004) may have been a result of chance.
Especially the review of Wuttke et al. (2007) refers to the Unfer study with words for which there is no scientific backing when the source material is taken into consideration. Wuttke uses the words
- - „… has clearly adverse effects on the endometrium“,
- „… clearly stimulate the human endometrium” and
- „alarming“ (Wuttke et al. 2007).
None of these interpretations can be found in the study of Unfer et al. (2004). This example – one of many – was chosen to highlight that the extrapolation of risks of isoflavones does mostly not originate from primary data sources, but from secondary interpretations.
All available clinical and epidemiological data taken together, the potential risk observed by Unfer et al. (2004) is not reproducible. In view of the flaws of the study and the overall clinical data available on the safety of isoflavones at the breast and endometrium the study of Unfer should no longer be used as an argument for assumed safety problems with isoflavones.
One might, however, argue that no other study has as yet reproduced the 5 years of continuous intake. All other safety studies published to date had a maximum duration of three years. Even then the results must be questioned for the mentioned reasons. In contrast, the dose of 150 mg/day applied by Unfer et al. (2004) was not highly unusual: other safety studies not confirming the effect on breast and endometrium used doses up to 160 mg daily.
References
Mahady, G. B. (2005). Do soy isoflavones cause endometrial hyperplasia? Nutr. Rev. 63 (11): 392-397.
Messina, M. (2009). Effects of isoflavones on endometrial tissue and endometrial cancer risk. Symposium on Evaluating the Efficacy and Safety of Isoflavones for Postmenopausal Women, 13-14 May. Milan (Italy): Council for Responsible Nutrition.
Safety 