In this large prospective study, we observed a significantly lower rate of laparoscopically confirmed endometriosis among women with greater predicted plasma 25(OH)D levels and among women with a higher intake of dairy foods. Calcium, vitamin D, and magnesium intakes from foods (including fortified foods) were also inversely related to endometriosis.
The epidemiologic data regarding the relationship between diet and endometriosis are limited. Only 2 case-control studies have examined the association between dairy foods and nutrients. Parazzini et al. (14
) examined 504 laparoscopically confirmed endometriosis cases and 504 controls with acute nongynecological, nonhormonal, nonneoplastic conditions and reported no association between milk or cheese intake and endometriosis (for the top tertile of intake, odds ratio (OR) = 1.4 (95% CI: 0.9, 2.0) for milk and OR = 0.8 (95% CI: 0.6, 1.2) for cheese). Differences between that study and ours include our prospectively collected data and our ability to adjust for total caloric intake. Furthermore, although that study did use laparoscopically confirmed cases of endometriosis, the associations were not examined separately by the fertility status of the cases. Finding results similar to ours, Trabert et al. (15
) reported inverse associations between dairy foods and calcium intake from foods and endometriosis (for the top quartile of intake, OR = 0.7 (95% CI: 0.4, 1.2) for dairy foods and OR = 0.7 (95% CI: 0.4, 1.2) for calcium). However, they did not observe an association with vitamin D intake from foods.
Abnormal levels of proinflammatory cytokines have been observed in the peritoneal fluid and serum of women with endometriosis (29
). Mouse models examining the development of endometriosis have suggested that interleukin-6 and tumor necrosis factor α may play a role through their influence on inflammatory angiogenesis (4
). Accordingly, dietary factors such as dairy foods and specific nutrients may be related to the physiological processes associated with endometriosis through effects on inflammation. Our results are supported by mouse models in which a milk diet reduced markers of oxidative and inflammatory stress, including tumor necrosis factor α and interleukin-6 (7
). Moreover, data in humans suggest that high magnesium intake may be associated with lower levels of inflammatory markers, including interleukin-6 and tumor necrosis factor α-R2 (32
Previous studies have found that magnesium deficiency is common among women with premenstrual syndrome (33
) and among women with a history of miscarriage (34
). This may indicate a role of magnesium in reproductive function. In a recent study, Mathias et al. (35
) observed that the fallopian tubes of women with endometriosis contract not at regular intervals but more spasmodically, exhibiting “seizure activity.” Magnesium has also been shown to relax smooth muscles (8
) and as a result may influence endometriosis through its effect on retrograde menstruation. Consistent with these findings, we observed a decreased risk of endometriosis with increasing magnesium intake, with the strongest association being with magnesium intake from foods.
Only a portion of vitamin D comes from diet; thus, plasma 25(OH)D is a more relevant indicator of vitamin D levels than dietary vitamin D, as it reflects not only dietary intake of vitamin D but also adiposity, skin pigmentation, and vitamin D produced from exposure to ultraviolet B radiation. To our knowledge, we are the first investigators to report an inverse association between predicted plasma 25(OH)D levels and endometriosis. In contrast, 2 previous studies found elevated levels of serum 1,25-dihydroxyvitamin D (36
) and 25-hydroxyvitamin D3
), while a third study found no differences in 25(OH)D serum levels between women with endometriosis and healthy controls (38
). These studies measured vitamin D levels after (36
) and at the time of (37
) endometriosis diagnosis; thus, in these studies it was unknown whether serum vitamin D levels influenced the development of endometriosis or whether the presence of endometriosis influenced serum vitamin D levels. We used predicted plasma levels prior to endometriosis diagnosis, which may represent the long-term average 25(OH)D level of an individual better than a single plasma measurement (25
). In addition, using predicted levels had the benefit of increasing our statistical power by allowing us to examine the association with a larger sample size than if we had been limited to only those subjects with plasma 25(OH)D measurements.
The biological mechanism through which vitamin D may affect endometriosis risk is not yet fully understood, though it is hypothesized to involve immune system regulation, since there is strong circumstantial evidence that endometriosis is dependent not only on circulating steroid hormone levels but also on aberrant immunological response (39
). Women with endometriosis have been demonstrated to exhibit altered immune surveillance, with depressed cell-mediated immunity and heightened humoral immune response (40
). Vitamin D may influence endometriosis through suppression of proinflammatory processes. In vitro studies have demonstrated that 1,25-dihydroxyvitamin D3
inhibits proliferation of T helper 1 cells (41
) and production of interleukin-2 and interferon γ (42
) and stimulates development of T helper 2 cells (41
), suggesting a role of vitamin D in diseases such as endometriosis.
Our results suggest dissimilar associations between dietary intakes of total milk, skim/low-fat milk, and magnesium and endometriosis risk between the 2 subtypes of endometriosis. In contrast, the inverse association between predicted plasma(OH)D levels and endometriosis risk was quite consistent in both women who had never reported infertility and women who reported concurrent infertility. This may suggest that these foods and nutrients may play different roles in chronic pelvic pain symptoms and/or the etiology of endometriosis. Among women who have had laparoscopically diagnosed endometriosis, the infertile women who are diagnosed with endometriosis during an infertility evaluation will include women who are “asymptomatic,” while women with no infertility are all “symptomatic” with respect to pain; otherwise a surgical evaluation would not have been conducted. Thus, the stronger protective association for milk and magnesium intakes in women who have never reported infertility may be due to these factors’ influence on chronic pelvic pain symptoms or due to differing endometriosis etiologies in women without infertility and women with infertility.
It is likely that there was some misclassification of predicted plasma 25(OH)D levels in our data. However, the prediction model has been validated among participants in 3 prospective cohort studies, including NHS II, providing evidence that it is appropriate for assessing an individual's long-term vitamin D status (26
). Previous studies have found significant inverse associations between vitamin D estimates from this prediction model and Crohn's disease (43
), pancreatic cancer (44
), digestive-system cancer mortality (25
), total cancer incidence (25
), and total cancer mortality (25
). We expect that any misclassification would have been random and would probably have caused attenuation of the true effect.
We observed stronger associations with intakes of calcium, vitamin D, and magnesium from foods than with total intake. This may indicate residual or unmeasured confounding by other dietary factors. However, we explored the association for foods that were the top contributors of these nutrients and observed an association with milk consumption. In addition, confounding by other lifestyle factors is a possibility. However, we adjusted for physical activity, cigarette smoking, and alcohol intake, and the associations did not materially change. Because the participants were primarily white nurses, it is unlikely that confounding by socioeconomic characteristics or access to health care influenced the results.
To our knowledge, this is the largest study to have examined the relationship between dairy foods and nutrients and endometriosis risk, allowing us the power to examine whether the association varied according to the fertility status of endometriosis cases. We also had high follow-up rates, cases that had been laparoscopically confirmed, and information on many important covariates, including known endometriosis risk factors on which data were collected and updated at 2-year intervals.
In conclusion, our findings suggest that greater predicted plasma 25(OH)D levels and higher intake of dairy foods are associated with a lower risk of endometriosis. While these findings need to be confirmed in future studies, dairy foods and vitamin D may be some of the first identifiable modifiable risk factors for endometriosis.