Fruit and Vegetable Consumption and Risk of Endometriosis

H. R. Harris; A. C. Eke; J. E. Chavarro; S. A. Missmer

Disclosures

Hum Reprod. 2018;33(4):715-727. 

In This Article

Discussion

In this cohort, we observed a non-linear inverse association between higher fruit consumption and risk of laparoscopically confirmed endometriosis. This inverse association was particularly evident for citrus fruits. In contrast, intake of cruciferous vegetables, corn and peas/lima beans was associated with an increased risk of endometriosis. No significant associations were observed with any of the nutrients examined after adjustment for intake of food sources of these nutrients. In addition, the observed association with fruits was strongest among ever smokers.

Few human studies have examined the association between diet and endometriosis, yielding conflicting results for the examined dietary factors. Two case–control studies have examined the associations between fruit and vegetable intake and endometriosis risk. An Italian hospital-based case–control study compared 504 cases of laparoscopically confirmed endometriosis and 504 controls admitted with non-gynecological conditions and observed a statistically significant lower consumption of green vegetables among cases (odds ratio [OR] = 0.3; 95% CI = 0.2–0.5) and of fresh fruit (OR = 0.6; 95% CI = 0.4–0.8) when comparing the third to first tertiles of intake. This study did not utilize a validated complete dietary assessment and was unable to adjust for total caloric intake or account for other dietary components (Parazzini et al., 2004). In contrast, a population-based case–control study among 284 cases and 660 controls who were members of a health care organization in WA state, USA, reported a greater odds of endometriosis with greater fruit intake (OR = 1.5; 95% CI = 1.2–2.3 for >2 servings/day versus ≤1/day) and no association with vegetable intake (OR = 1.0; 95% CI = 0.6–1.7 for >3 servings/day versus ≤1/day) (Trabert et al., 2010). A major limitation of both of these studies was the retrospective collection of dietary data that were limited to examining diet in the year preceding endometriosis diagnosis, while our results represent prospectively collected diet over 2 decades. Trabert et al. (2010) speculated that pesticide exposure through fruit intake might explain the increased endometriosis risk observed in their study. Our data do not support this hypothesis as we observed an inverse association with fruits consumed during a time period that overlapped with the WA study. In addition, the vegetables that we observed to be positively associated with endometriosis have a low pesticide residue burden (Chiu et al., 2015). In the WA case population the women reporting infertility (23% of endometriosis cases) may have increased their fruit intake during the previous year in an attempt to improve fertility and could have been diagnosed with endometriosis during an evaluation for prolonged time to conception resulting in the observed association.

In-vitro and in-vivo studies have suggested a number of nutrients that are present in fruits and vegetables that could influence endometriosis risk. Citrus fruits were the most strongly associated with reduced risk of endometriosis in our study and are high in vitamins A and C. Mier-Cabrera et al. (2009) compared antioxidant intake in 83 infertile women with endometriosis to 80 parous women undergoing tubal ligation and observed lower intake of vitamins A, C, and E among women with endometriosis. The growth and adhesion of endometrial cells in the peritoneal cavity may be influenced by free radicals and reactive oxygen species (ROS) and vitamin C may counteract the effect of free radicals and ROS (Jackson et al., 2005). We have previously observed in this NHS II population that vitamin C from foods, but not vitamin C from foods and supplements combined or supplements alone, was associated with endometriosis risk (Darling et al., 2013). This suggests that the vitamin C in citrus foods may not explain the reduced risk observed or that there may be a threshold of intake after which vitamin C does not influence endometriosis risk. Vitamin A intake could also influence risk as Sawatsri et al. (2000) have shown that retinoids may play a role in altering the aberrant production of cytokines in endometriosis, as retinoic acid has been found to suppress IL-6 molecular transcription and translational processes in a time and dose-dependent manner. In addition, vascular endothelial growth factor (VEGF) is thought to contribute to the angiogenesis of endometriosis lesions, and treatment of HL-60 cells differentiated into neutrophil granulocytes with all-trans retinoic acid (atRA) has been shown to suppress VEGF mRNA and protein (Tee et al., 2006). Consumption of citrus fruits that are high in beta-cryptoxanthin has been demonstrated to increase serum retinol (de Pee et al., 1998) suggesting a potential mechanism for our observed associations.

In contrast to the inverse association with citrus fruits, we observed that cruciferous vegetables, particularly cauliflower, cabbage, Brussel sprouts, were associated with increased endometriosis risk. This result was not what we had hypothesized considering that these vegetables contain various phytochemicals and nutrients that have been demonstrated to have health benefits, as well as being a good source of dietary fiber. However, cruciferous vegetables may not be as easily absorbed or digested, and some are high in fermentable oligo-, di- and monosaccharides and polyols (FODMAPs), which have been reported to exacerbate irritable bowel syndrome symptoms (Eswaran et al., 2016). Gastrointestinal symptoms are almost as common as gynecological symptoms in women with endometriosis, and presenting with these symptoms is often the first step toward obtaining a surgical confirmation of endometriosis (Maroun et al., 2009). Thus, the observed association could be due to increased abdominal pain in women consuming cruciferous vegetables that subsequently results in an endometriosis diagnosis. Given the difficulty in accurately quantifying general gastroenterologic distress symptoms and distinguishing them from chronic pelvic pain, we do not have the data necessary to validly stratify by presence or absence of gastrointestinal symptoms. However, the slightly stronger association between cruciferous vegetable intake and the never infertile case group, the case group most likely to have pain as the indication for their surgical diagnosis, provides some support for this hypothesis. In addition, previous studies have observed an increased risk of hypertension among women with higher intake of cruciferous vegetables (Borgi et al., 2016; Wang et al., 2012). The mechanism(s) behind this increased risk are unclear but cooking methods or use of pesticides are possible explanations (Borgi et al., 2016).

Stronger inverse associations were observed between fruit and endometriosis risk among women who were ever smokers. Higher oxidative stress and production of free radicals among smokers may explain the stronger protective association observed in ever smokers. These results are consistent with other studies that have observed stronger inverse associations in smokers between fruit intake and conditions including chronic obstructive pulmonary disease (Kaluza et al., 2017), cholecystectomy (Tsai et al., 2006) and cardiovascular disease (Hung et al., 2004). Further, among women who were ever smokers the risk of endometriosis decreased linearly with increasing fruit consumption while among women who had never smoked the inverse association was non-linear. This may indicate that the ideal level of fruit consumption in relation to endometriosis risk may be mediated by individual-level factors such as oxidative stress and free radical exposure.

Limitations of our study should be considered. Some error in the self-reporting of dietary intake is expected. However, the FFQ has been previously validated for both foods and nutrients (Michaud et al., 1998; Salvini et al., 1989; Willett, 2013; Willett et al., 1985; Yuan et al., 2017). In addition, we had dietary information collected at multiple time points, allowing quantification of cumulative average intake, which reduces measurement error due to within-person variation over time (Hu et al., 1999) and the prospective nature of our study makes it likely that any misclassification would be non-differential. Strengths include its large, prospective design with high follow-up rates over 22 years making it the largest study to date to examine the associations between fruits, vegetables, and related nutrients and laparoscopically confirmed endometriosis. In addition, we were able to apply rigorous modeling to adjust for total caloric intake and quantify the association with fruits and vegetables independent of other dietary components. In addition, we were able to examine varying diet windows in relation to likely endometriosis onset, to examine the associations by case subtype, and to explore potential effect modification by cigarette smoking.

In conclusion, our findings within this cohort of US nurses who had not been diagnosed with endometriosis nor experienced infertility prior to study start, suggest that higher intake of fruits, particularly citrus fruits, are associated with a lower risk of endometriosis and beta-cryptoxanthin in these foods may partially explain this association. In addition, consumption of specific vegetables increased endometriosis risk, which may indicate a role of gastrointestinal symptoms in both the presentation and exacerbation of endometriosis-related pain; however, it is not clear what components of these foods might underlie the observed associations. Future studies examining dietary patterns that consider different combinations of food intake may help clarify these associations.

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