Circulating concentrations of 25(OH)D were not associated with risk of endometrial cancer in this nested case-control study based on seven cohorts. Though there was some indication of a trend of decreasing risk with increasing concentrations of 25(OH)D in crude analyses, no trend was observed after adjusting for body mass index. Obesity plays an important role in endometrial cancer etiology because it is associated with increased exposure to estrogen unopposed by progesterone, leading to increased mitotic activity of endometrial cells and greater opportunity for the occurrence of DNA replication errors (3
). Consistent with results from other studies (23
), the prevalence of obesity was greater among cases than among controls (). Body mass index was also inversely associated with 25(OH)D (cohort-adjusted Spearman correlation coefficient = −0.16 in controls and −0.28 in cases), as was observed in the overall population of controls included in VDPP (25
); this was expected since vitamin D tends to be sequestered in adipose tissue (26
). These associations led to negative confounding of the 25(OH)D - endometrial cancer risk relationship by body mass index. Such negative confounding, if ignored, will lead to a spurious association as was observed in our study prior to adjusting for body mass index.
This study is the first to examine the association of endometrial cancer risk with circulating 25(OH)D, which is considered the best marker of vitamin D status (15
). The results of this study are in agreement with a review of the literature on vitamin D intake in relation to endometrial cancer which concluded that the limited evidence available regarding vitamin D did not support an association (10
). These studies, though, did not take into account vitamin D obtained from ultraviolet B exposure. An ecological study of 107 countries reported that endometrial cancer incidence rates were higher at higher latitudes and concluded that low ultraviolet B irradiance, which is associated with lower vitamin D exposure, was associated with endometrial cancer risk (6
). However, although the authors adjusted for the proportion of the population who were overweight as well as for some other risk factors, the observed association could be due to ecological fallacy since control for body mass index and other risk factors at the individual level was not possible.
A strength of the present study was the availability of individual data, collected prospectively, on known risk factors for endometrial cancer. For most of these risk factors, differences between cases and controls were as expected. Hormone replacement therapy use, though, was less common in cases than in controls. This result appears inconsistent with the known positive association between estrogen-only replacement therapy and endometrial cancer risk. However, our study did not have the ability to assess the association of this variable with disease risk because most participating cohorts matched on use of hormone replacement therapy at entry. In addition, we were not able to distinguish between estrogen-only and estrogen plus progestin formulations, nor to take into account the recency of use, both factors which impact the association of hormone replacement therapy with endometrial cancer risk (23
Because sun exposure is the main source of vitamin D, circulating concentrations of 25(OH)D are lower in the winter than in the summer months and it is important to take into account such variations to avoid bias (30
). In addition to matching on date of blood draw, this issue was addressed using various statistical methods. There was no evidence of a protective effect of vitamin D in any of these analyses.
Interactions of vitamin D and vitamin D analogs with estrogens have been reviewed (31
). Although, to our knowledge, there are no data specific to the endometrium, it has been proposed, based on an animal model of breast cancer, that 1,25(OH)2
D opposes estrogen-driven proliferation (33
). In this study, the test for interaction by hormone replacement therapy use was statistically significant (P
for heterogeneity = 0.04); however, there was no evidence of a protective effect of vitamin D in either ever or never users of hormone replacement therapy (). In addition, no association was observed between circulating 25(OH)D and risk of endometrioid endometrial cancer, a subtype strongly associated with estrogen (34
). Because of the data collection procedures of some of the cohorts and in order to have sufficient numbers of cases, non-endometrioid subtypes (mucinous, serous, clear cell, squamous-cell, mixed) were excluded in this analysis but adenocarcinomas not-otherwise -specified (ICD-O codes 8140 and 8010) (n
= 462) were combined with endometrioid tumors (n
= 223). It is therefore likely that some tumors of non-endometrioid subtype were included. However, since endometrioid tumors represent about 80% of all endometrial carcinomas, it is unlikely that an association was missed in this subgroup. Because of small numbers, the association of 25(OH)D with other subtypes of endometrial cancer could not be examined.
The concentrations of circulating 25(OH)D observed in this study were similar to concentrations observed in women in the United States (35
). Few women, though, had high concentrations and the highest category that could be studied was was ≥100 nmol/L, and for stratified and subgroup analyses, ≥75 nmol/L. Therefore, conclusions cannot be drawn regarding the potential protective effect of higher concentrations of 25(OH)D. However, although a threshold effect is possible, the complete lack of a dose-response relationship in this study argues against a protective role of vitamin D.
Strengths of this study include the prospective assessment of vitamin D status and possible confounders, the inclusion of women living in a wide range of latitudes, a large number of cases and the use of the same laboratory to assay all samples. Only one serum/plasma sample was used for each participant which leads to some measurement error regarding the exposure of interest, i.e. the long-term average circulating level of 25(OH)D. However, circulating concentrations of 25(OH)D appear relatively stable when collected during the same season. A pilot study conducted in the NYU-WHS using the same assay in the same laboratory found an intraclass correlation coefficient of 0.78 (95% CI: 0.64, 0.88) in 30 healthy women who contributed three samples each at yearly intervals (unpublished data). Likewise, in the Nurses’ Health Study, the intraclass correlation coefficient for 25(OH)D was 0.72 (95% CI: 0.62, 0.80) in 71 women over a 2–3 year period using a similar assay (unpublished data). These results are comparable to those observed in 144 middle-aged men for whom the Pearson correlation between samples collected 4 years apart was 0.70 (36
). Such temporal reliability compares favorably to that of other biomarkers that have been found to be associated with disease, such as circulating estrogens (e.g., intraclass correlation coefficient in the 0.50–0.70 range for estradiol over a 2–3 year period (37
)), which have been consistently found to be associated with breast cancer risk (39
In conclusion, after taking into account the effect of body mass index, circulating concentrations of 25(OH)D do not appear to be associated with risk of endometrial cancer.