The etiology of endometriosis is complex, involving immune imbalance, hormone alteration, and inflammation[5]. To our knowledge, there is mounting evidence suggesting that certain foods may potentially influence the development of endometriosis in susceptible individuals. However, this is the first MR analysis to evaluate the potential causality between dietary factors and the risk of endometriosis using large-scale summary statistics from food intake GWAS and endometriosis GWAS, which provide unconfounded causal estimates. In our analysis, it has been found that consuming salad / raw vegetable has a protective effect on endometriosis while processed meat intake is associated with a decrease risk factor for the condition. However, there is little evidence supporting an association between endometriosis risk and alcoholic drinks per week, alcohol intake frequency, poultry intake, beef intake, non-oily fish intake, oily fish intake, pork intake, lamb/mutton intake, bread intake, cheese intake, cooked vegetable intake, tea intake, fresh fruit intake, cereal intake, coffee intake and dried fruit intake. The findings of our study can assist clinicians in enhancing their health education for patients with endometriosis, as well as motivating these patients to change their dietary patterns (such as increasing salad / raw vegetable intake and processed meat intake). For those at high risk for endometriosis, changing dietary habits can also decrease the likelihood of onset.
There have been numerous observational studies on the correlation between vegetable intake and the risk of endometriosis. Most of these have shown that increasing vegetable consumption is linked to a reduction in endometriosis risk. Ashrafi M et al. [17]found that people who kept higher green vegetables intake took a lower endometriosis risk (OR = 0.39, 95% CI = 0.21–0.74; p = 0.004) in a retrospective case-control study from Iranian. In another hospital-based case-control study by Parazzini et al., comparing 504 women with endometriosis and 504 women without endometriosis confirmed through laparoscopy, the authors indicated a statistically significant decrease in the consumption of green vegetables among cases (OR = 0.3, 95% CI = 0.2–0.5)[8]. Likewise, several similar studies conducted in other countries also demonstrated a decreased endometriosis risk for those who increased their vegetables consumption[18, 19]. However, not all studies shown the effect of vegetable intake on endometriosis. Based on a population-based case-control study involving 944 participants (284 cases and 660 controls), Trabert et al. reported total vegetable intake was not associated with incident endometriosis[20]. The authors hypothesized that this finding could be attributed to pesticide exposure, which might generate reactive oxygen species and reduce the antioxidant capacity of vegetables. Some studies[21], on the other hand, have demonstrated that certain class of pesticides can cause estrogenic effects, thereby promoting the development of endometriosis lesions. Alternatively, a meta-analysis indicated an insignificant correlation between eating vegetable and the risk of developing endometriosis[22]. Furthermore, Harris et al.[7] reported that a high intake of some vegetables such as cruciferous vegetables, particularly cauliflower, cabbage was related to an increase in endometriosis risk. Through MR analysis, our study indicated that a high level of vegetables intake might be associated with a decreased risk of endometriosis.
Endometriosis is an oestrogen-dependent disease. Typically, populations on a diet rich in green vegetables have higher levels of sex-hormone binding globulin (SHBG), which can attenuate the oestrogenic stimulation of the endometrium and restrict the proliferation of prostaglandin-producing tissues. Additionally, dietary fiber can interrupt enterohepatic circulation of oestrogen conjugates, thereby reducing the risk of endometriosis[17]. Studies have indicated that a number of nutrients found in vegetables potentially benefit endometriosis. First of all, vitamins, especially vitamin C, are important antioxidants that strongly neutralize free radicals and improve oxidative status to reduce the chances of developing endometriosis[23]. This finding aligns with a randomized, triple-blind placebo-controlled clinical study that reported a decrease in systemic indicators of oxidative stress in patients with endometriosis after receiving a boost of vitamin C [24]. Furthermore, the influence of vitamin C on the expression and production of the VEGF gene was investigated in peritoneal macrophages from women diagnosed with endometriosis[25]. Vitamin A can also play a role in influencing aberrant cytokines production in endometriosis, such as suppressing the transcription and translational processes of IL-6 and VEGF[26]. Secondly, vegetables are packed with bioactive plant compounds, especially polyphenols (such as curcumin, resveratrol and epigallocatechin gallate). Natural polyphenols have been proven to possess anti-inflammatory and antioxidative properties, making them a cost-effective and easily accessible treatment option for endometriosis[27]. In addition to these properties, polyphenols can be used as estrogen receptor agonists to combat the condition due to their structural similarity with estradiol[28]. Thirdly, many vegetables contain phytoestrogens that can be classified into three classes: flavonoids, lignans and stilbenes. These compounds are structural and functional homologies with estrogen and act as weak estrogenic factors by binding to the estrogen receptor and interfering with ER mediated responses[29]. Furthermore, the mechanism of action of flavonoids is pleiotropic and includes promoting autophagy, down-regulating nuclear factor (NF)-κB activity, reducing interleukin (IL)-6 and tumor necrosis factor α (TNFα), as well as inhibiting oxidative stress, thereby generating proapoptotic, anti-inflammatory, and anti-proliferative effects[30].
Our MR analysis also indicated a decreased endometriosis risk for those with processed meat intake, which was consistent with the result of a case-control study by Ashrafi M et al.[17](OR = 0.61, 95% CI = 0.41–0.91, P = 0.015). However, different results were obtained by other studies. In a large Italian study, endometriosis risk was notably higher among women in the highest intake of red meat, both processed and unprocessed, compared to those in the lowest (OR = 2.0, 95% CI = 1.4–2.8; P = 0.0004)[8]. In a Nurses’ Health Study II (NHSII) prospective cohort including 81908 participants, red meat consumption, especially non-processed rea meat consumption, was correlated with a greater risk of laparoscopically-confirmed endometriosis by approximately 56% (95% CI = 1.22–1.99; P < 0.0001) [9]. Likewise, a meta-analysis of observational studies reported that women eating red meat had a 17% higher risk in endometriosis[22]. In contrast to these findings, a Washington state based case-control study[20] and a Belgian matched case-control study with prospective recruitment[31] showed no association between red meat intake and incident endometriosis. Owing to the inconsistency between our results and those reported in previous studies, our conclusion must be viewed cautiously. Also, we must correctly understand the correlation between MR analysis and observational studies. MR analysis makes a terrific addition to observational studies because it is not affected by common confounding factors or reverse causation bias but cannot serve as their substitute.
Previous studies provide solid evidence linking red meat consumption to an increased risk of many chronic diseases, including diabetes, hypertension, cardiovascular disease and some cancers[22]. Although the physiological mechanism of how red meat affects endometriosis remains incompletely understood, it has been postulated to involve several ways. On the one hand, a high intake of animal fat in a meat-based diet such as palmitic acid can further increase endogenous estrogens, which stimulate the formation of proinflammatory PGs. These PGs can also induce the release of aromatase P450, promoting inflammatory conditions in endometriosis[9]. On the other hand, diets rich in red meat seem to correlate with decreased SHBG and increased estradiol concentrations, that influence pain in women with endometriosis[32]. Another possible mechanism is iron overload in women with a high intake of red meat, which is related to increased oxidative stress and inflammatory status in endometriosis[9]. Furthermore, iron overload in the peritoneal fluid of women with endometriosis can decrease GPX4 expression, cause embryotoxicity and induce ferroptosis, which probably participates in endometriosis-associated reproductive failure[33].
To date, the dietary structure is complex and the contribution of diet to endometriosis has not been sufficiently studied. Observational studies that assess the relationship between dietary factors and endometriosis have certain limitations, including recall bias, confounding introduced by self-reported food questionnaires, and reverse causation bias. Therefore, more future observational studies and ingenious MR studies are needed to elucidate the role of diet in endometriosis.
Notably, our MR analysis possesses several significant strengths. Firstly, to the best of our knowledge, this MR study is the first to systematically analyze the causality between dietary factors and endometriosis by using genetic variation as IVs, effectively overcoming the reverse causality and confounding bias. Moreover, we utilized European populations as both the exposure and outcome groups to minimize potential biases. Secondly, some of the findings from this study contradict current knowledge, thereby providing valuable insights for future research directions. Thirdly, we took several steps to meet the core assumptions of MR analysis and utilized a large sample size along with SNPs derived from GWAS, thus significantly enhancing the credibility of our findings.
Inevitably, this study also has some limitations. Firstly, this analysis was conducted solely with European participants, which hinders the generalizability of these findings to other populations. Furthermore, we were unable to differentiate the specific effects of different dietary combinations. Secondly, food intake GWAS is still in its early stages due to small sample sizes, which may compromise statistical power. Therefore, the absence of significant associations does not necessarily imply that food intake has no effect. Thirdly, due to the lack of summary-level GWAS data for various ages groups, we cannot conduct an age-stratified analysis further. Lastly, it remains uncertain whether dose-response relationships exist between dietary factors and the risk of endometriosis. Additionally, the food intake data used in our study were obtained through a self-reported questionnaire instead of objective measurements, potentially introducing recall bias.