Association between MIND diet its components with endometriosis risk: secondary results from a case-control study

In line with the principles outlined in the Declaration of Helsinki 20 authorization for the study was provided by the Medical Ethical Committee of the National Nutrition and Food Technology Research Institute at Shahid Beheshti University of Medical Sciences in Iran (IR.SBMU.NNFTRI.REC.1399.062, Approval Date: 2021-01-27). All participants provided explicit written consent to ensure the confidentiality of data. A detailed account of the study design, participant demographics, and the evaluation of exposures and outcomes was previously delineated in a separate investigation 21 . Specifically, a case-control study conducted in hospitals, involving interviews with 115 individuals recently diagnosed with endometriosis and 230 control subjects in Tehran, Iran, from February to September 2021 (Obstetrics and Gynecology clinics in Imam Hossein, Taleghani, Shohada Tajrish and Mahdieh hospitals). Female participants, aged 18 to 49, were free of any underlying health conditions that could impact the study findings, as elucidated in the preceding research (non-pregnant and lactating, non-menopausal not afflicted with diet related chronic diseases such as cancer, diabetes, cardiovascular disease and etc.). Any endometriosis patient that diagnosed by surgery, macroscopically or with histological examination, considered as case group. Also, for the control group, the same criteria was considered, except for the presence of endometriosis. All participants in both case and control groups were confirmed by a blinded gynecologist 21 . Patients were excluded if they were unable to complete at least 60% of the food frequency questionnaire (FFQ) items, reporting energy intake outside of ± 3SD of the mean energy intake, and failure to cooperate for any reason. As elaborated in the previous study 21 the assessment of dietary intake relied on a validated 168-item Food Frequency Questionnaire (FFQ) 22 and a validated food album 23 supplemented with visuals of household measurements. Interviews and surveys were conducted by an impartial interviewer, blinded to the participants’ outcomes, to minimize potential information bias. Dietary intake of study participants were assess by their intakes through the year prior to interview (controls) or endometriosis diagnosis (cases). The interview participants were provided with information regarding the typical size of each food item. Following this, they shared how frequently they consumed each food item on a daily, weekly, or monthly basis. These consumption frequencies were then converted into grams using a reference scale for home food measurements. Then, calculation of daily energy and macronutrient intake was carried out using either the USDA food composition table 24 or the Iranian food composition table 25 . The MIND diet calculation was done based on food intake of FFQ items. At first, 15 good groups created based on 168 items of FFQ: 10 healthy food (green leafy vegetables, other vegetables, nuts, legumes, berries, whole grains, poultry, fish and olive) and 5 unhealthy groups (red meat, butter and margarine, cheese, desserts and fast foods). In this study, wine consumption was excluded due to the absence of relevant data in the original dataset. Dietary intakes were then divided into tertiles, and healthy food groups were scored as follows: a score of 0 for the first tertile, 0.5 for the second tertile, and 1 for the third tertile. For unhealthy food groups, reverse scoring was applied: a score of 1 for the first tertile, 0.5 for the second tertile, and 0 for the third tertile. Finally, the overall score was calculated by summing the scores of 14 food groups, resulting in a total score ranging from 0 to 14. MIND diet components and food items are provided in Supplementary File 1 . Data collection on various information (age, age at menarche, marriage ststus, familial history of Endometriosis, pregnancy history, menstrual history, education and cigarette smoking) and anthropometric parameters (weight, height, body mass index and waist circumference) were performed by the researchers 21 while levels of physical activity were assessed using a reliable questionnaire developed by Aadahl et al. 26 . The sample size was calculated using the standard formula for unmatched case-control studies, assuming an odds ratio (OR) of 2, a 95% confidence level, 80% power, and a case-to-control ratio of 1:2. Based on previous data from Mirmiran et al., the prevalence of high trans fatty acid intake (> 1% of daily energy) was estimated at 55% among adult women in Tehran. Accordingly, a minimum of 105 cases and 210 controls was required. To account for potential nonresponse or incomplete data, the final sample size was increased to 115 cases and 230 controls 27 – 29 . The statistical analysis was conducted using SPSS (Statistical Package for the Social Sciences program; version 22; Chicago, IL, USA). Two-tailed analyses were performed, and p-values < 0.05 were considered statistically significant. Prior to further analysis, continuous variables were checked for normal distribution through skewness, histogram, Q-Q plots, and the Kolmogorov-Smirnov test. Normally distributed quantitative variables were expressed as mean (SD), and non-normally distributed ones as median (25 th −75 th). Categorical demographic characteristics were presented as frequency and percentages. The Chi-square test was utilized to compare qualitative data between endometriosis patients and controls. The Mann-Whitney U test was employed to compare non-normally distributed quantitative variables, respectively, between the two groups. Logistic regression was used to estimate odds ratios (OR) for endometriosis, with a 95% confidence interval (CI). Multivariable logistic regression models were adjusted for age (years), age at menarche (years), physical activity (MET-hours/day), body mass index (kg/m²), total energy intake (kcal/day), menstrual history (regular vs. irregular), cigarette smoking status (never, past, or current smoker), family history of endometriosis (yes/no), OCP (yes/no) and number of pregnancy (0, 1–2 and ≥ 3). Confounding variables were selected based on prior literature, biological plausibility, and significant differences between cases and controls.

The general characteristics of the participants have been detailed in a previous publication 21 . Out of 317 participants, 4 were excluded due to discrepancies in energy intake. The final analysis included 105 cases of endometriosis and 208 healthy controls, with no significant age differences between the groups 21 . General characteristics of participants with endometriosis and healthy controls, separated according to the MIND diet median score are show in Table  1 . Education level was significantly differenet between two groups of lowest and highest adherence to the MIND diet in participants with endometriosis (p-value < 0.001). Also, in the healthy controls, the mean of BMI (p-value < 0.001) and WC (p-value = 0.008) were significantly higher in the group of lowest adherence to the MIND diet in comparision to the other group. Table 1 General characteristics of participants with endometriosis and healthy controls, separated according to the MIND diet median score. Variables Healthy controls ( n  = 208) Participants with endometriosis ( n  = 105) Lower than median ( n  = 81) Higher than median ( n  = 127) P -value Lower than median ( n  = 89) Higher than median ( n  = 16) P -value Age (years) 1 30.00 27.00–35.50 31.00 28.00–35.00 0.827 36.00 30.00–40.00 35.00 30.00–36.75 0.708 Age at menarche (years) 1 13.00 11.50–14.00 13.00 12.00–14.00 0.078 13.00 11.00–15.00 13.00 11.25–15.00 0.943 Physical activity (MET/hour/day) 1 11.00 0.00–60.00 20.00 0.00–60.00 0.936 35.00 7.50–77.50 21.00 0.00–53.75 0.166 Body mass index (kg/m 2 ) 1 23.91 21.41–27.64 24.03 21.61–26.70 0.637 28.25 24.49–30.29 23.30 21.92–25.987 <0.001 Waist circumference (cm) 1 85.00 75.00–96.00 84.00 75.00–92.00 0.204 85.00 78.00–93.00 78.50 75.25–83.25 0.008 Marriage ststus, married 2 45 59.3 85 66.9 0.301 50 56.2 12 75.0 0.180 OCP use (yes) 2 12 14.8 12 9.4 0.269 30 33.7 4 25.0 0.574 Familial history of Endometriosis (yes) 2 1 1.2 5 3.9 0.408 47 52.8 5 31.3 0.174 Pregnancy history (yes) 2 36 44.4 68 53.5 0.255 42 47.2 5 31.3 0.284 Number of pregnancy 2 0 1–2 ≥ 3 45 25 11 55.6 30.8 13.6 58 52 16 46.0 41.3 12.7 0.307 47 31 11 52.8 34.8 12.4 11 4 1 68.8 25.0 6.2 0.482 Menstrual history 2 Regular Irregular 60 21 74.1 25.9 89 38 70.1 29.9 0.636 74 15 83.1 16.9 14 2 87.5 12.5 1.000 Education 2 Primary/secondary school Diploma Bachelor’s degree Master’s/doctoral degree 13 26 25 17 16.0 32.1 30.9 21.0 7 23 76 21 5.5 18.1 59.8 126.5 <0.001 12 20 44 13 13.5 22.5 49.4 14.6 1 3 7 5 6.3 18.8 43.8 31.3 0.401 Cigarette smoking 2 Never smokers Past smokers Current smokers 65 1 15 80.2 1.2 18.6 101 7 19 79.5 5.5 15.0 0.254 44 23 22 49.4 25.8 24.7 12 2 2 75.0 12.5 12.5 0.169 Abbreviation: MET, metabolic equivalent of task; kg, kilogram; m, meter; OCP, oral contraceptive pill. 1 Using Mann-Whitney U-test and values are median (25 th −75 th ). 2 Using chi-square tests for categorical variables and values are number and precent. General characteristics of participants with endometriosis and healthy controls, separated according to the MIND diet median score. Number of pregnancy 2 0 1–2 ≥ 3 45 25 11 55.6 30.8 13.6 58 52 16 46.0 41.3 12.7 47 31 11 52.8 34.8 12.4 11 4 1 68.8 25.0 6.2 Menstrual history 2 Regular Irregular 60 21 74.1 25.9 89 38 70.1 29.9 74 15 83.1 16.9 14 2 87.5 12.5 Education 2 Primary/secondary school Diploma Bachelor’s degree Master’s/doctoral degree 13 26 25 17 16.0 32.1 30.9 21.0 7 23 76 21 5.5 18.1 59.8 126.5 12 20 44 13 13.5 22.5 49.4 14.6 1 3 7 5 6.3 18.8 43.8 31.3 Cigarette smoking 2 Never smokers Past smokers Current smokers 65 1 15 80.2 1.2 18.6 101 7 19 79.5 5.5 15.0 44 23 22 49.4 25.8 24.7 12 2 2 75.0 12.5 12.5 Abbreviation: MET, metabolic equivalent of task; kg, kilogram; m, meter; OCP, oral contraceptive pill. 1 Using Mann-Whitney U-test and values are median (25 th −75 th ). 2 Using chi-square tests for categorical variables and values are number and precent. Nutrients and food groups intake based on the MIND diet median score are presented in Table  2 . In the group by highest adherence to the MIND diet score, higher intake of energy (p-value = 0.006), protein (p-value = 0.006), green leafy vegetables (p-value = 0.015), other vegetables (p-value = 0.001), nuts (p-value < 0.001), berries (p-value = 0.029), whole grains (p-value = 0.003), poultry (p-value = 0.005), fish (p-value = 0.010), olive (p-value = 0.001) and MIND diet total score (p-value < 0.001), and lower intake of red meat (p-value < 0.001), desserts (p-value = 0.003) and fats foods (p-value = 0.031) were seen in participants with endometriosis. Also, in the control group, higher intake of fiber (p-value = 0.007), green leafy vegetables (p-value < 0.001), other vegetables (p-value = 0.003), nuts (p-value < 0.001), berries (p-value < 0.001), poultry (p-value < 0.001), fish (p-value = 0.019), olive (p-value < 0.001) and MIND diet total score (p-value < 0.001), and lower intake of cheese (p-value = 0.008) and desserts (p-value = 0.025) were vobserved in the group by highest adherence to the MIND diet score. Also, box-plot of energy, macronutrients and food groups are shown in Supplementary File 2 . Table 2 Nutrients and food groups intake based on the MIND diet median score. Variables Healthy controls ( n  = 208) Participants with endometriosis ( n  = 105) Lower than median ( n  = 81) Higher than median ( n  = 127) P -value Lower than median ( n  = 89) Higher than median ( n  = 16) P -value Energy intake (kcal/day) 1 2009.25 1419.68–2484.28 2048.96 1677.57–2610.68 0.095 2302.69 1785.49–3187.65 1794.20 1493.48–2144.83 0.006 Protein intake (g/day) 1 62.46 45.89–88.91 71.19 56.96–90.46 0.063 82.49 61.03–104.12 67.16 53.45–75.65 0.006 Fat intake (g/day) 1 59.12 49.61–83.39 62.63 46.21–85.06 0.508 95.38 69.73–148.77 62.37 51.23–84.37 0.001 Carbohydrate intake (g/day) 1 288.15 196.90–372.36 318.10 233.51–411.53 0.089 278.74 205.81–387.60 235.60 180.80–287.22 0.132 Fiber intake (g/day) 1 21.83 13.14–34.16 27.05 18.16–35.96 0.007 13.69 10.77–19.31 16.74 13.92–20.59 0.075 MIND diet total score 1 7.50 7.00–8.00 9.50 8.50–10.00 <0.001 6.00 4.50–7.00 9.25 8.50–10.37 < 0.001 Green leafy vegetables, servings/day 1 0.65 0.28–0.96 0.99 0.60–1.65 < 0.001 0.23 0.07–0.39 0.39 0.16–0.83 0.015 Other vegetables, servings/day 1 2.37 0.98–4.26 3.19 1.80–5.00 0.003 1.05 0.53–1.68 1.80 1.17–2.33 0.001 Nuts, servings/day 1 0.30 0.05–0.84 1.35 0.43–2.68 < 0.001 0.06 0.00–0.28 1.03 0.43–2.70 < 0.001 Legumes, servings/day 1 2.07 0.95–4.34 2.21 1.24–3.99 0.466 1.01 0.40–2.18 1.61 0.67–2.68 0.230 Berries, servings/day 1 0.02 0.01–0.08 0.07 0.02–0.36 < 0.001 0.01 0.00–0.07 0.09 0.01–0.25 0.029 Whole grains, servings/day 1 0.10 0.01–0.35 0.11 0.02–0.35 0.362 0.10 0.00–0.74 2.08 0.20–3.02 0.003 Poultry, servings/day 1 0.28 0.13–0.71 0.57 0.42–0.85 < 0.001 0.28 0.00–0.71 0.78 0.46–1.64 0.005 Fish, servings/day 1 0.34 0.16–0.69 0.59 0.28–0.94 0.019 0.00 0.00–0.34 0.31 0.04–0.45 0.010 Red meat, servings/day 1 0.34 0.05–1.01 0.43 0.18–0.87 0.193 3.16 1.87–4.67 0.91 0.50–1.39 < 0.001 Olive, servings/day 1 0.00 0.00–0.01 0.02 0.00–0.12 < 0.001 0.00 0.00–0.06 0.09 0.01–0.31 0.001 Butter & margarine, servings/day 1 0.00 0.00–0.09 0.01 0.00–0.06 0.679 0.28 0.02–1.00 0.15 0.03–0.53 0.345 Cheese, servings/day 1 0.57 0.20–1.71 0.42 0.10–0.85 0.008 0.33 0.00–2.00 0.28 0.00–0.96 0.379 Desserts, servings/day 1 2.01 0.89–3.84 1.30 0.53–2.85 0.025 2.82 1.25–5.65 0.94 0.22–2.35 0.003 Fast Foods, servings/day 1 0.87 0.31–1.86 0.52 0.26–1.85 0.446 1.10 0.39–2.21 0.45 0.18–1.10 0.031 Abbreviation: kcal, kilocalorie; g, gram. 1 Using Mann-Whitney U-test and values are median (25 th −75 th ). Nutrients and food groups intake based on the MIND diet median score. Abbreviation: kcal, kilocalorie; g, gram. 1 Using Mann-Whitney U-test and values are median (25 th −75 th ). As shown in Table  3 , in continuous association, a lower odds of endometriosis were found by each unit increase in MIND diet score in both crude (OR: 0.446; 95% CI: 0.369–0.540, p-value < 0.001) and adjusted models (OR: 0.530; 95% CI: 0.421–0.666, p-value < 0.001). Also, in categorical association, lower odds of endometriosis were seen in the highest than median score of MIND diet in comparision to the lowest one in both crude (OR: 0.115; 95% CI: 0.063–0.209, p-value < 0.001) and adjusted models (OR: 0.175; 95% CI: 0.080–0.381, p-value < 0.001). Table 3 The association between MIND diet and its components with the odds of endometriosis. Variables Case/Control Crude model Adjusted model OR CI 95% P -value OR CI 95% P -value MIND diet total score Lower than median Higher than median 89/81 16/127 0.446 Ref. 0.115 0.369–0.540 Ref. 0.063–0.209 <0.001 Ref. < 0.001 0.530 Ref. 0.175 0.421–0.666 Ref. 0.080–0.381 < 0.001 Ref. < 0.001 Green leafy vegetables, servings/day Lower than median Higher than median 87/67 18/141 0.071 Ref. 0.098 0.033–0.150 Ref. 0.055–0.176 < 0.001 Ref. < 0.001 0.105 Ref. 0.104 0.041–0.268 Ref. 0.046–0.234 < 0.001 Ref. < 0.001 Other vegetables, servings/day Lower than median Higher than median 83/73 22/135 0.430 Ref. 0.143 0.338–0.547 Ref. 0.083–0.248 < 0.001 Ref. < 0.001 0.415 Ref. 0.205 0.295–0.582 Ref. 0.097–0.436 < 0.001 Ref. < 0.001 Nuts, servings/day Lower than median Higher than median 78/78 27/130 0.701 Ref. 0.208 0.569–0.863 Ref. 0.123–0.349 0.001 Ref. < 0.001 0.710 Ref. 0.275 0.549–0.919 Ref. 0.135–0.555 0.009 Ref. < 0.001 Legumes, servings/day Lower than median Higher than median 69/87 36/121 0.682 Ref. 0.375 0.579–0.803 Ref. 0.230–0.611 < 0.001 Ref. < 0.001 0.650 Ref. 0.339 0.519–0.815 Ref. 0.166–0.691 < 0.001 Ref. 0.003 Berries, servings/day Lower than median Higher than median 62/94 43/114 0.455 Ref. 0.572 0.199–1.044 Ref. 0.356–0.920 0.063 Ref. 0.021 0.252 Ref. 0.482 0.064–0.991 Ref. 0.245–0.949 0.049 Ref. 0.035 Whole grains, servings/day Lower than median Higher than median 49/108 56/100 1.302 Ref. 1.234 1.090–1.555 Ref. 0.771–1.975 0.004 Ref. 0.380 1.357 Ref. 1.887 1.101–1.672 Ref. 0.937–3.797 0.004 Ref. 0.075 Poultry, servings/day Lower than median Higher than median 56/109 49/99 1.268 Ref. 0.963 0.967–1.662 Ref. 0.602–1.542 0.086 Ref. 0.876 1.452 Ref. 1.721 0.96–2.192 Ref. 0.874–3.338 0.076 Ref. 0.116 Fish, servings/day Lower than median Higher than median 72/69 33/139 0.564 Ref. 0.228 0.363–0.876 Ref. 0.138–0.376 0.011 Ref. < 0.001 0.579 Ref. 0.151 0.361–0.928 Ref. 0.070–0.323 0.023 Ref. < 0.001 Red meat, servings/day Lower than median Higher than median 19/138 86/70 2.735 Ref. 8.923 2.148–3.483 Ref. 5.026–15.843 < 0.001 Ref. < 0.001 3.313 Ref. 7.060 2.159–4.545 Ref. 3.168–15.733 < 0.001 Ref. < 0.001 Olive, servings/day Lower than median Higher than median 54/102 51/106 1.029 Ref. 0.909 0.336–3.152 Ref. 0.568–1.453 0.960 Ref. 0.690 1.558 Ref. 1.104 0.377–6.449 Ref. 0.570–2.136 0.541 Ref. 0.770 Butter & margarine, servings/day Lower than median Higher than median 28/137 77/71 13.536 Ref. 5.306 5.469–33.499 Ref. 3.158–8.915 < 0.001 Ref. < 0.001 9.885 Ref. 4.357 3.629–26.922 Ref. 2.131–8.907 < 0.001 Ref. < 0.001 Cheese, servings/day Lower than median Higher than median 57/106 48/102 1.202 Ref. 0.875 0.945–1.529 Ref. 0.547–1.401 0.134 Ref. 0.578 0.958 Ref. 0.524 0.670–1.371 Ref. 0.263–1.045 0.817 Ref. 0.066 Desserts, servings/day Lower than median Higher than median 40/116 65/92 1.164 Ref. 2.049 1.066–1.271 Ref. 1.268–3.310 0.001 Ref. 0.003 1.085 Ref. 1.252 0.975–1.207 Ref. 0.612–2.563 0.134 Ref. 0.538 Fast Foods, servings/day Lower than median Higher than median 44/112 61/96 1.008 Ref. 1.617 0.887–1.146 Ref. 1.007–2.598 0.897 Ref. 0.047 1.015 Ref. 1.296 0.838–1.229 Ref. 0.624–2.692 0.881 Ref. 0.488 Abbreviation: OR, odds ratio; CI, confidence interval. Significant values are shown in bold. These values are odds ratio (95% CIs). Obtained from logistic regression. Adjusted model: adjusted for age (years), age at menarche (year), physical activity (MET/hour/day), body mass index (kg/m 2 ), energy intake (kcal/day), menstrual history (regular/irregular), cigarette smoking (never smokers/past smokers/current smokers), familial history of endometriosis (yes/no), OCP (yes/no) and number of pregnancy (0, 1–2 and ≥ 3). The association between MIND diet and its components with the odds of endometriosis. MIND diet total score Lower than median Higher than median 89/81 16/127 0.446 Ref. 0.115 0.369–0.540 Ref. 0.063–0.209 <0.001 Ref. < 0.001 0.530 Ref. 0.175 0.421–0.666 Ref. 0.080–0.381 < 0.001 Ref. < 0.001 Green leafy vegetables, servings/day Lower than median Higher than median 87/67 18/141 0.071 Ref. 0.098 0.033–0.150 Ref. 0.055–0.176 < 0.001 Ref. < 0.001 0.105 Ref. 0.104 0.041–0.268 Ref. 0.046–0.234 < 0.001 Ref. < 0.001 Other vegetables, servings/day Lower than median Higher than median 83/73 22/135 0.430 Ref. 0.143 0.338–0.547 Ref. 0.083–0.248 < 0.001 Ref. < 0.001 0.415 Ref. 0.205 0.295–0.582 Ref. 0.097–0.436 < 0.001 Ref. < 0.001 Nuts, servings/day Lower than median Higher than median 78/78 27/130 0.701 Ref. 0.208 0.569–0.863 Ref. 0.123–0.349 0.001 Ref. < 0.001 0.710 Ref. 0.275 0.549–0.919 Ref. 0.135–0.555 0.009 Ref. < 0.001 Legumes, servings/day Lower than median Higher than median 69/87 36/121 0.682 Ref. 0.375 0.579–0.803 Ref. 0.230–0.611 < 0.001 Ref. < 0.001 0.650 Ref. 0.339 0.519–0.815 Ref. 0.166–0.691 < 0.001 Ref. 0.003 Berries, servings/day Lower than median Higher than median 62/94 43/114 0.455 Ref. 0.572 0.199–1.044 Ref. 0.356–0.920 0.063 Ref. 0.021 0.252 Ref. 0.482 0.064–0.991 Ref. 0.245–0.949 0.049 Ref. 0.035 Whole grains, servings/day Lower than median Higher than median 49/108 56/100 1.302 Ref. 1.234 1.090–1.555 Ref. 0.771–1.975 0.004 Ref. 0.380 1.357 Ref. 1.887 1.101–1.672 Ref. 0.937–3.797 0.004 Ref. 0.075 Poultry, servings/day Lower than median Higher than median 56/109 49/99 1.268 Ref. 0.963 0.967–1.662 Ref. 0.602–1.542 0.086 Ref. 0.876 1.452 Ref. 1.721 0.96–2.192 Ref. 0.874–3.338 0.076 Ref. 0.116 Fish, servings/day Lower than median Higher than median 72/69 33/139 0.564 Ref. 0.228 0.363–0.876 Ref. 0.138–0.376 0.011 Ref. < 0.001 0.579 Ref. 0.151 0.361–0.928 Ref. 0.070–0.323 0.023 Ref. < 0.001 Red meat, servings/day Lower than median Higher than median 19/138 86/70 2.735 Ref. 8.923 2.148–3.483 Ref. 5.026–15.843 < 0.001 Ref. < 0.001 3.313 Ref. 7.060 2.159–4.545 Ref. 3.168–15.733 < 0.001 Ref. < 0.001 Olive, servings/day Lower than median Higher than median 54/102 51/106 1.029 Ref. 0.909 0.336–3.152 Ref. 0.568–1.453 0.960 Ref. 0.690 1.558 Ref. 1.104 0.377–6.449 Ref. 0.570–2.136 0.541 Ref. 0.770 Butter & margarine, servings/day Lower than median Higher than median 28/137 77/71 13.536 Ref. 5.306 5.469–33.499 Ref. 3.158–8.915 < 0.001 Ref. < 0.001 9.885 Ref. 4.357 3.629–26.922 Ref. 2.131–8.907 < 0.001 Ref. < 0.001 Cheese, servings/day Lower than median Higher than median 57/106 48/102 1.202 Ref. 0.875 0.945–1.529 Ref. 0.547–1.401 0.134 Ref. 0.578 0.958 Ref. 0.524 0.670–1.371 Ref. 0.263–1.045 0.817 Ref. 0.066 Desserts, servings/day Lower than median Higher than median 40/116 65/92 1.164 Ref. 2.049 1.066–1.271 Ref. 1.268–3.310 0.001 Ref. 0.003 1.085 Ref. 1.252 0.975–1.207 Ref. 0.612–2.563 0.134 Ref. 0.538 Fast Foods, servings/day Lower than median Higher than median 44/112 61/96 1.008 Ref. 1.617 0.887–1.146 Ref. 1.007–2.598 0.897 Ref. 0.047 1.015 Ref. 1.296 0.838–1.229 Ref. 0.624–2.692 0.881 Ref. 0.488 Abbreviation: OR, odds ratio; CI, confidence interval. Significant values are shown in bold. These values are odds ratio (95% CIs). Obtained from logistic regression. Adjusted model: adjusted for age (years), age at menarche (year), physical activity (MET/hour/day), body mass index (kg/m 2 ), energy intake (kcal/day), menstrual history (regular/irregular), cigarette smoking (never smokers/past smokers/current smokers), familial history of endometriosis (yes/no), OCP (yes/no) and number of pregnancy (0, 1–2 and ≥ 3). Furthermore, based on the results of the adjusted model, lower odds of endometriosis were found in the group by the highest intake of green leafy vegetables (OR: 0.104; 95% CI: 0.046–0.234, p-value < 0.001), other vegetables (OR: 0.205; 95% CI: 0.097–0.436, p-value < 0.001), nuts (OR: 0.275; 95% CI: 0.135–0.555, p-value < 0.001), legumes (OR: 0.339; 95% CI: 0.166–0.691, p-value = 0.003), berries (OR: 0.482; 95% CI: 0.245–0.949, p-value < 0.001), and fish (OR: 0.151; 95% CI: 0.070–0.323, p-value < 0.001) in comparision to the other group. But, in comparison to the lowest intake group, higher odds of endometriosis were seen in the group by the highest intake of red meats (OR: 7.060; 95% CI: 3.168–15.733, p-value < 0.001) and butter and margarine (OR: 4.357; 95% CI: 2.131–8.907, p-value < 0.001).

Adhering to a healthy diet, particularly the MIND diet, which focuses on higher consumption of healthy ingredients such as nuts, fish and vegetables and lower consumption of inflammatory foods, could help reduce the incidence of endometriosis. The consideration of the origin and quality of the food is also noteworthy. Further studies are necessary to clarify these associations and understand the potential mechanisms involved.

In this case-control study, we aimed to determine whether following the MIND diet, in addition to each individual food group, leads to a lower odds of endometriosis. The results showed that high adherence to the MIND diet, as well as higher consumption of green leafy vegetables, other vegetables, nuts, legumes, berries and fish are associated with a lower odds of endometriosis, while higher intake of whole grains, red meat, butter and margarine increases the likelihood of endometriosis. Notably, no clear association has been found between endometriosis and the consumption of berries, poultry, olives, cheese, desserts, and fast food. The results of our study show that greater adherence to the MIND diet is associated with a reduction in the odds of endometriosis. Studies suggest that specific foods and eating habits can either alleviate or worsen the symptoms and prevalence of endometriosis. A prospective study underscored the importance of dietary patterns in understanding endometriosis, highlighting the necessity for further investigation in this field 30 . In our earlier case-control study, we observed that following a fertility diet notably decreased the likelihood of endometriosis by 66%. The consumption of vegetable proteins and multivitamins was found to be protective, whereas foods with a high glycemic load were associated with an increased risk 21 . Research suggests that dietary factors can impact immune and angiogenic processes, which are crucial in the development of endometriosis 31 . A literature review found that dietary changes could help alleviate symptoms and enhance the quality of life for patients, though this field remains under-researched and findings are occasionally inconsistent 32 . It is found that a balanced diet rich in fruits, vegetables, and omega-3 fatty acids, may be protective for endometriosis 33 . Despite these studies indicating a notable connection between diet and endometriosis, the complexity of dietary interactions and individual differences requires further research to establish clear causal relationships. The results of our study showed an inverse association between vegetables intake with endometriosis, however, the association between vegetables and endometriosis odds is controversial according to previous observational research. Some studies represented a modifiable association between vegetable consumption and endometriosis 34 , 35 . Interestingly, Harris et al. showed that certain types of vegetables, especially cruciferous ones like broccoli, brussels sprouts, and cabbage, have been associated with an increased risk of endometriosis. They found that women who consumed one or more servings of cruciferous vegetables daily had a 13% higher risk of developing endometriosis compared to those who ate less than one serving per week. This observation suggests that specific compounds in these vegetables might contribute to the condition 36 . Furthermore, the meta-analysis carried out by Arab et al. 37 suggests that there is no significant link between overall vegetables intake and the risk of developing endometriosis, indicating that merely increasing vegetables intake may not help in preventing the condition. These controversies highlight the need for more research. Probable mechanisms for the protective role of vegetables may be due to the effects on the inflammatory pathways in the body. The increase in the production of C-reactive protein (CRP), followed by the production of other inflammatory mediators such as interleukin (IL)−6, IL1-β, and tumor necrosis factor alpha, as well as the increase in body oxidants, worsen inflammatory conditions and the likelihood of developing endometriosis. However, the antioxidant capacity created by vitamins E and C in vegetables by reducing the production of reactive oxygen and nitrogen species, as well as the production of CRP as key to the inflammatory cascade 38 is effective in reducing the occurrence of endometriosis 39 , 40 . Besides, certain vegetables are a good source of beta-cryptoxanthin, an antioxidant chemical which has been shown protective role for the risk of endometriosis 36 . Red meat consumption was shown to be a risk factor for endometriosis in our study which is similar to previous studies. According to previous studies, high red meat consumption is considered as a risk factor for endometriosis 30 , 37 . According to a prospective cohort study, consumption of more than two servings of red meat daily is linked with a 56% higher risk of developing endometriosis 41 . It may be due to the high amounts of trans fatty acids and saturated fats in red meat which has been shown to be linked to an increased risk of endometriosis 37 . Besides red meat is a rich source of dietary advanced glycation end-products. These components lead to an increase in CRP and white blood cells levels as inflammatory markers 42 , 43 . Also, red meat is a heme-iron source and increased intake of it could induce the oxidizing effect of iron in the body by increasing the reactive oxygen species 44 . On the other hand, increased heme iron consumption could play a negative role in epithelial cell proliferation through DNA damage 45 and worsen the uterine lesions that occur in endometriosis 46 . Furthermore, red meat consumption influences estrogen levels in the body. Increased intake is linked to lower sex hormone-binding globulin levels and higher estradiol concentrations. Elevated estrogen levels can worsen inflammatory conditions, which are typical of endometriosis 37 . The observed association between fish and nut consumption with endometriosis, as well as the impact of butter and margarine on the odds of endometriosis, may be attributed to their respective fatty acid profiles. We found the protective effect of fish consumption in our study. In consistant with our results, research indicates that fish oil, rich in omega-3 fatty acids, may alleviate endometriosis-related symptoms and reduce inflammation, which is crucial given the chronic inflammatory nature of the condition 9 , 47 . A prospective study found that women in the highest quintile of long-chain omega-3 fatty acid consumption had a 22% lower risk of endometriosis compared to those with the lowest intake 48 . Some research suggests that diets high in omega-3 fatty acids, especially from fatty fish like salmon, mackerel, and sardines, may benefit endometriosis due to their anti-inflammatory properties, which could help alleviate symptoms and potentially lower the risk 33 , 41 . However, a large study of 81,908 women found no connection between the intake of fish and the risk of endometriosis, indicating that merely increasing fish consumption may not directly affect endometriosis risk 33 , 41 . Omega-3 fatty acids, particularly EPA and DHA, can lower the production of inflammatory substances, potentially alleviating endometriosis symptoms 33 , 41 . Fish oil has been linked to lower levels of certain prostaglandins and reduced inflammatory symptoms, as well as decreased dysmenorrhea (painful menstruation). Dietary changes, including the addition of fatty fish, may complement conventional endometriosis management strategies 33 , 41 . Additionally, higher EPA intake increases the ratio of omega-3 to omega-6, especially in form of arachidonic acid (AA) which leads to a shift of the inflammatory pathway to the non-inflammatory pathway and alleviates disease symptoms 49 , 50 . Fish oil has been linked to symptom improvement in dysmenorrhea, which may indirectly suggest benefits for endometriosis 51 . More research is needed to fully understand the relationship between fish consumption, omega-3 fatty acids, and endometriosis. We found protective role of nuts on endometriosis; However, the association between nut intake and endometriosis has not been extensively studied, and the existing literature presents limited and inconclusive findings. Examining the link between nut consumption and the risk of endometrial and ovarian cancer found no significant relationship between total nut intake (including tree nuts and peanuts) and the risk of endometrial cancer. This implies that nut consumption may not directly affect reproductive system conditions, such as endometriosis 52 . Although specific studies on nuts and endometriosis are limited, nuts are generally considered part of a healthy diet due to their high content of healthy fats, protein, fiber, vitamins, and minerals. These nutrients may contribute to overall health and potentially offer anti-inflammatory benefits, which could be advantageous for women with endometriosis 37 , 53 . Nuts are also a good source of omega-3 fatty acids in diet. Like eicosapentaenoic acid (EPA) in fish, alpha-linolenic acid (ALA) in nuts 54 decreases the intra lesionary mediators responsible for cell proliferation and immune signaling such as cyclooxygenase 2 (Cox-2) and IL-6 resulting in decreasing the adhesion and lesion of endometrial tissue and pelvic pain 55 . In summary, there is currently no strong evidence directly linking nut consumption to the risk of endometriosis. While nuts are nutritious and may positively contribute to overall health, more targeted research is needed to explore their specific role in relation to endometriosis. As part of a balanced diet, nuts may offer indirect benefits, but their direct impact on endometriosis remains unclear. We found the negative impact of butter and margarin on endometriosis odds. Similarly, A meta-analysis found that females with high butter intake might have an increased risk of endometriosis compared to those with low butter intake 56 . Content of SFA and trans fatty acid (TFA) in butter and margarin has a negative effect on endometriosis. Palmitic acid, known as a source of SFA in butter and margarine 57 stimulates prostaglandins, lipopolysaccharides and other mediators as well as TFAs through estrogenic and inflammatory pathways by decreasing peroxisome proliferator-activated receptor-γ (PPAR γ), in addition to afore mentioned signaling pathways lead to the pathogenesis of the disease 58 and increase the risk of this by 48% 48 . We found the potential protective effect of eating legumes against endometriosis. Similar to our study, a case-control study have suggested that women consuming two or more portions of grain legumes per week had a lower risk of endometriosis compared to those with lower intake levels, with a significant trend suggesting that increased legume consumption is associated with decreased risk. Specifically, the odds ratio (OR) for those consuming fewer portions was greater than one, indicating a potential risk factor for lower legume intake 34 . Although, the previous meta-analysis did not show a significant association between legumes and endometriosis 37 . Legumes are considered non-animal dietary protein, fiber and phytoestrogen sources 59 . Increasing the consumption of legumes, by increasing the intake of fiber, thereby reducing the amount of circulating estrogen 60 and on the other hand, increasing the intake of dietary phytoestrogens, which can balance the circulating amount of esterogen through binding to estrogen receptors with their selective binding properties 61 and also improve the pathogenesis of endometriosis by reversing cell proliferation and modifying the inflammatory mediators 62 . Besides, their high fiber content may help regulate insulin levels and reduce inflammation, both of which are relevant factors in the context of endometriosis 53 . Higher intake of phytoestrogens, particularly isoflavones and lignans found in legumes, is associated with a reduced risk of endometriosis (OR: 0.48 for isoflavones) 53 . Phytoestrogens may modulate inflammatory responses and hormonal levels, which are critical in the pathophysiology of endometriosis 53 . Furthermore, the incidence of the disease would be lower in this group because individuals who consume more legumes have a greater interest in maintaining a healthy, balanced diet and controlling their body weight 63 although obesity may also be a trigger for endometriosis 64 . We also found positive association between whole grain intake with odds of endometriosis, which is an emerging area of research. Some studies found no significant link between whole grain intake and endometriosis 35 . In contrast to our study, an inverse association between whole grain intake and endometrial cancer among women not using hormone replacement therapy, suggest the protective role of this food group 65 . Whole grain products are the source of gluten in the diet. Because the signs of endometriosis overlap with some other inflammatory and immune diseases such as celiac disease 66 limiting gluten intake could help reduce pain, physical function, and mental health 67 . On the other hand, the most common sources of whole grains in the Iranian diet are traditional breads, which contain significant amounts of sodium salt and baking soda powder as effective ingredients in the baking process 68 , 69 . In addition, sodium is responsible for inflammation, which is crucial for the onset and progression of endometriosis 46 , 70 . Our study had some limitations. It is plausible that the knowledge endometriosis diagnosis before FFQ completion might have affected the dietary consumption recall in a manner that differed from that of the control group. Despite the researchers’ endeavors to mitigate bias, certain forms of bias, including selection bias, recall bias, and measurement bias, could still result in misleading conclusions when employing a case-control methodology. Although we used a validated FFQ to assess long-term dietary intake, the possibility of recall bias remains, particularly since endometriosis is a chronic condition with often delayed diagnosis. In spite of including only newly diagnosed patients to minimize reverse causation, the retrospective nature of dietary assessment may still influence the accuracy of reported intake. An additional limitation was the inadequacy of clinical stage data available for all participants, underscoring the potential ramifications it may have on comprehending the association between dietary habits and the disease trajectory in endometriosis patients. Furthermore, the exclusion of data pertaining to infertility or the utilization of assisted reproductive technologies in our analysis was another limitation. Although our study focused on dietary factors, we acknowledge that medical history, including hypertension, hyperlipidemia, diabetes, and cardiovascular disease, could also influence endometriosis risk. Future studies should consider including these variables to provide a more comprehensive understanding of the factors contributing to endometriosis. In addition, although cases and controls were not matched based on age or sampling location, age was adjusted for in the analysis; however, the lack of matching may still introduce residual confounding. Conversely, our research possessed notable strengths. The participation rates was high in both groups, and several potential variables were available for the adjustment of regression models. To ensure the integrity of the data, we eliminated participants who supplied inaccurate or excessive energy intake data, as well as patients who had not received a diagnosis within the preceding six months. Our selection of incident cases mitigated recall bias and enhanced the interpretation of causal relationships. We utilized a validated FFQ to assess exposure, and interviews were conducted by a professional dietitian who remained blinded to the participants’ diagnostic status.

Endometriosis is a chronic disease with inflammatory nature defined by detecting ectopic glands and stroma, similar to endometrial tissue 1 . This condition is estimated to impact between six and ten% of women, with a prevalence believed to exceed 33% in patients experiencing acute pelvic pain 2 . Common symptoms associated with endometriosis include severe menstrual pain, increased menstrual bleeding, chronic and intense pelvic pain, painful intercourse, and decreased fertility 3 . Risk factors such as early menarche, shorten menstrual cycle duration, and nulliparity, are all associated with elevated levels of circulating estrogen concentrations and are also linked to an increased risk of developing endometriosis 4 . Several recognized risk factors for endometriosis share a common thread of increased exposure to estrogens. This heightened exposure, coupled with insitu estrogen secretion and circulating estrogen, can stimulate the proliferation of ectopic endometrial tissue, which may be a potent risk factor for endometriosis 5 . The pathogenesis of endometriosis have been reviewed by several hypotheses, with retrograde menstruation being the most widely accepted theory 6 , 7 . However, the exact cause of endometriosis remains unknown 8 , 9 . The treatment of these symptoms lacks a standardized approach, and the disease has the potential to recur even after appropriate surgical or pharmacological interventions 10 . So, affected women may advantage from research on lifestyle factors or potential strategies for prevention, modification, or treatment of the condition 11 , 12 . The impact of nutrition on the development and progression of endometriosis has been reviewed recently. The disease nature, such as inflammatory and estrogen activity, menstrual cycles, and the biochemistry of prostaglandin, can be influenced by dietary choices 8 . Studies have suggested that consuming fiber may enhance the elimination of estrogen, potentially reducing the risk of endometriosis. Besides, lowering the intake of dietary fat can also decrease serum estrogen levels. Furthermore, plant-based diets, with theit anti-inflammatory nature, have been found to be associated with an increased level of sex-hormone binding globulin, reducing the amount of bio-available estrogen present in the body 13 . On the other hand, meat intake is shown to be related with a higher risk of endometriosis 14 . In addition, recent research indicated that following an anti-inflammatory diet is a viable option for managing endometriosis symptoms 15 . Finally, when comparing the foods and drinks recommended in most national dietary guidelines to the components of inflammatory indices, they closely resemble an anti-inflammatory diet 16 . Although there is insufficient evidence to support a superior diet for management of endometriosis; however, the Mediterranean diet may have the most benefit without nutrition concerns 17 . MIND diet (Mediterranean-dietary approach to stop hypertension (DASH) diet intervention for neurodegenerative delay), which benefits from the principals of the Mediterranean and DASH diets, is a low fat, anti inflammatory dietary pattern, rich in high fiber food items 18 , 19 . In addition to share similarities with the Mediterranean diet, MIND diet is stricter about avoiding red meat, butter, fried foods, and sweets, which are high fat inflammatory food items 18 , 19 . Therefore, it appears that the MIND dietary pattern has the necessary components to protect an individual against odds of endometriosis, based on the literature, and even has advantages over the Mediterranean diet in terms of meat and fat restriction. However, to our knowledge, no study had previously investigated the correlation between the MIND diet and the risk of endometriosis. Therefore, we investigated the association between the MIND diet and the odds of endometriosis.

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