{"paper_id":"4220373a-a9a0-4ab9-911c-e9084e73acee","body_text":"Endometriosis is an important gynecologic disease\naffecting reproductive-age women ( 1 ). The prevalence\nof endometriosis is approximately 10.8 per 1000 women\nof reproductive age ( 2 ). Endometriosis development\nwas shown to be highly related to prolonged exposure\nto estrogens in the absence of progesterone. The diet\nhas a strong effect on hormonal activity, inflammatory\nmarkers and the immune system, therefore, plays an\nimportant role in the pathogenesis of endometriosis ( 3 -\n 5 ). The results of some studies showed that nutrition\nand diet have a major impact on endometriosis risk ( 6 -\n 9 ). Phytoestrogens are estrogenic components that exist\nin multiple foods of plant origin. Dietary sources of\nphytoestrogens have been identified in various food stuffs\nincluding fruits, vegetables, spinach, sprouts, beans,\ncabbage, soybean, grains, and oilseeds (such as flaxseed).\nMain classes of phytoestrogens consist of isoflavones,\ncoumestans, lignans, and flavonoids. Isoflavones have\nseveral subgroups including genistein, daidzein, glycitein,\nformononetin, biochanin A, and their glycosides.\nMammalian lignans include secoisolariciresinol,\nmatairesinol, pinoresinol, lariciresinol, syringaresinol,\narctigenin, and 7-hydroxy matairesinol ( 10 ). Lignan and\nisoflavonoid glycosides are converted by gut microflora\nto hormone-like substances with poor estrogenic activity\n(0.1% that of estradiol). Therefore, phytoestrogens may\ndemonstrate poor estrogenic activity in low-estrogen environments such as that observed in menopause and\nhave antiestrogenic activity in high-estrogen environments\nsuch as that observed in endometriosis or endometrial\ncancer ( 11 ,  12 ). These substances bind competitively to\nestrogen receptors, thus blocking endogenous estrogens\nbinding ( 11 ). High intake of phytoestrogen is associated\nwith lower C-reactive protein (CRP) concentration ( 13 )\nand suppressed the immune response ( 14 ).\nPhytoestrogens stimulate sex hormone-binding globulin\n(SHBG) production in the liver ( 15 ). High levels of SHBG\nbind to the free estrogen and diminish the concentration of\nestrogens available for binding to estrogen receptors ( 16 ).\nWith regard to the role of inflammatory, immunologic\nand hormonal factors in the pathogenesis of this disease,\nwe hypothesized that phytoestrogen intake can reduce the\nrisk of endometriosis. Our study evaluated the association\nbetween dietary phytoestrogen intake and endometriosis\nrisk using a food frequency questionnaire (FFQ).\n\nBetween May 2016 and February 2017, the present\ncase-control study was conducted on 156 infertile women\nin clinic Arash Hospital, Tehran, Iran. The sample size\nwas determined using the information obtained from a\npilot study with 20 patients and the following formula: all\ninfertile women who underwent diagnostic laparoscopy\nduring the period of the study were allocated. The case\ngroup consisted of 78 endometriosis women for whom\nthe disease was confirmed by laparoscopy and histology\nexaminations. Control group included 78 infertile women\nwith a normal pelvis. Women in the two groups were\ncomparable in demographic and personal characteristics.\nInclusion criteria were as follows: i. Age between 15-45\nyears, ii. The absence of a history of chronic disease (such as\ncancer, diabetes, stroke, heart disease, etc.), iii. Being from\nIranian race, iv. Not being pregnant, v. Not using medications\naffecting food absorption, appetite and basal metabolism of the\nbody, and vi. No smoking and vii. Lack of mental retardation.\nThe medical Ethics Committee of Tarbiat Modares\nUniversity approved the study (IR.TMU.REC.1395.358)\nalso, before enrolment of the participants, a written informed\nagreement was obtained from each one. In the beginning, a\nsocio-demographic questionnaire including questions about\nsocioeconomic status, age, smoking, education, habitat,\nand ethnicity was completed by women, then participants’\ndietary information was obtained using FFQ.\nDietary data were collected using FFQ as a validated\nsemi-quantitative questionnaire with 147 food items.\nTrained dietitians questioned participants regarding their\nintake frequency for each food item consumed during\nthe past year on a daily, weekly, or monthly basis; all\nthese were converted to daily intakes. Then, by applying\nthe manual for household measures, portion sizes of\nthe consumed food were transformed to grams ( 17 ).\nThe validity and reliability of the FFQ for food groups\nintakes were assessed and were found to be acceptable\n( 18 ). Type of phytoestrogen per 100 gram of each dietary\nitem was analyzed by the database from the United States\nDepartment of Agriculture (USDA) ( 19 ) and Tables and\ndatabases available from other studies ( 19 - 25 ). Total\nconsumption of phytoestrogen was calculated as the\nsum of isoflavin, lignan, and coumestrol. We excluded\nindividuals with dissimilar nutrient intake and those with\ndaily energy intake of >4300 or <670 kcal.\nStatistical analysis of data was performed by using\nStatistical Package for Social Science (SPSS, version 21,\nSPSS Inc., Chicago, IL, USA). Odds ratio [adjusted for age,\ntotal energy intake, body mass index (BMI), educational\nlevel, and income], with 95% confidence intervals (95% CIs)\nwere calculated using logistic regression models to assess\nthe strength of the associations between the phytoestrogen\nintake and the risk of endometriosis. Dietary phytoestrogen,\nisoflavin, lignan, and coumestrol intake was categorized\ninto quartile categories, based on the distribution of control\nsubjects. To calculate the linear trend in the odds of dietary\nvariable quartile, median factor score of each quartile was\nentered into the logistic regression analysis, and the lowest\nquartile of intake was used as the reference category for all\nregression analyses. T test, Mann-Whitney, and chi-square\nwere used to compare other variables. A P value below 0.05\nwas considered statistically significant.\n\nTable 1 compares the demographic characteristics of\nhealthy women and subjects with endometriosis. There\nwere no statistically significant differences in the women’s\nage, BMI, parity, educational, marital status, occupation,\nincome, and age at menarche between the two groups.\nDemographic and anthropometric characteristics of women with and without endometriosis\n*; Values are given as mean ± SD and compared using Student’s t test, **; Values are given as a number (%) and compared using Chi-squared test, ***; Values are given as mean ± SD and compared using Mann-Whitney test, and BMI; Body mass index.\nTable 2 summarizes the ORs for endometriosis by daily\nphytoestrogen intake according to quartile of intake.\nWe observed inverse associations between consumption\nof phytoestrogen (OR: 0.68; 95% CI: 0.51-0.91,\nP-trend=0.01) and total isoflavones (OR: 0.38; 95% CI:\n0.33-0.83; P-trend=0.002) and endometriosis risk, but this\ndifference was more related to formononetin (OR: 0.57;\n95% CI: 0.27-0.97; P-trend=0.04) and glycitein (OR:\n0.68; 95% CI: 0.67-0.98; P-trend=0.04).\nHigh consumption of lignan was associated with a\nlower risk of endometriosis (OR: 0.49; 95% CI: 0.46-\n0.52; P-trend=0.01). Among the sub type of lignan,\nonly secoisolariciresinol (OR: 0.54; 95% CI: 0.36-0.77;\nP-trend=0.01), lariciresinol (OR: 0.64; 95% CI: 0.32-\n0.74, P-trend=0.02) and matairesinol (OR: 0.30; 95% CI:\n0.22-0.52; P-trend=0.003) were related to reduced risk\nof endometriosis. The intake of coumestrol in the third\nquartile was associated with reduced risk of endometriosis\n(OR: 0.38; 95% CI: 0.15-0.96; P-trend=0.15).\nTable 3 demonstrates an association between the\nsub-type of phytoestrogen in each food group and risk\nof endometriosis. Among food groups, only isoflavin\n(OR: 0.48; 95% CI: 0.44-0.63), lignan (OR: 0.66;\n95% CI: 0.62-0.94), coumestrol (OR: 0.64; 95% CI:\n0.51-0.99) and phytoestrogen (OR: 0.46; 95% CI:\n0.38-0.83) in dairy products and coumestrol in fruits\n(OR: 0.69; 95% CI: 0.03-0.77) were associated with\nendometriosis.\nAdjusted odds ratios (OR) of endometriosis and corresponding 95% confidence intervals (CI) according to the subtype of phytoestrogen intake\nBMI; Body mass index and *; Odds ratio adjusted for age, energy intake, BMI, educational level, and income. Quartile 1 used as the reference category.\nAdjusted odds ratios (OR)* of endometriosis and corresponding 95% confidence intervals (CI) according to phytoestrogen from the dietary item\nBMI; Body mass index and *; Odds ratio adjusted for age, energy intake, BMI, educational level, and income.\n\nOur findings suggest that higher intake of phytoestrogen\nsuch as isoflavin, lignan, and coumestrol is associated\nwith a reduced risk of endometriosis. All subtypes of\nphytoestrogen in dairy products and coumestrol in fruits\nwere related to reduced endometriosis risk.\nRecently, some studies discussed associations between\nphytoestrogen and endometriosis. One of such studies\n( 26 ), consumption of phytoestrogen (25 to 250 mg/\nday), used for the treatment of endometriosis. Genestein\ninhibits the activity of tyrosine kinase, and in this way,\nplays an important role in growth factors signaling. While\nin another study ( 27 ), soy isoflavones supplementation\nmaintained endometriosis and induced conversion of\nthe disease to the malignant form (i.e. mixed Müllerian\ntumor). Moreover, using an animal model, it was shown\nthat pharmacologic genistein, but not dietary form, helps\nto the maintenance of the implants ( 28 ). In a Japanese\nstudy, higher levels of urinary genistein and daidzein were related to reduced advanced endometriosis risk\n( 29 ). However, to the best of our knowledge, no study\nhas assessed possible associations between dietary\nphytoestrogen intake and women endometriosis risk.\nResults of some studies demonstrated that dietary\nconsumption of phytoestrogens was associated with\nreduced risk of endometrial, breast, colorectal and prostate\ncancer ( 30 - 33 ).\nIt was indicated that increased urinary excretion of\nphytoestrogen was associated with decreased CRP levels\n( 13 ). Soy consumption is associated with a decrease in\nserum nitric oxide, E-selectin, interleukin-18 and CRP\nconcentrations ( 34 ).\nAnimal studies showed that ginstein has an antiproliferative effect on mammary tissue in rats exposed\nto prepubertal estrogens ( 35 ). Diadzein induces\nmitochondrial-dependent apoptosis by increasing\ncaspase-9 activity and decreasing cyclin D expression\nthat can affect cell cycle regulation ( 36 ). Phytoestrogens\nhave antioxidant effects, that lead to reduced production\nof reactive oxygen species (ROS) ( 37 ). Genistein can\nsuppress lymphocyte proliferation and antigen-specific\nimmune response but enhance the cytotoxic responses\nmediated by NK and cytotoxic T cells and production of\ncytokines from T cells ( 38 ).\nRegarding the effect of phytoestrogens on inflammatory,\nimmunological and hormonal factors, phytoestrogen\nconsumption can reduce the risk of endometriosis.\nBioavailability, absorption, and estrogenic characteristics\nof phytoestrogens are dependent on the compound’s\nbioactivity, which metabolized in to compounds by\nintestinal microflora ( 39 ). Also, the phytoestrogen content\nin diet is dependent on environmental and genetic factors\nfor example variety, harvest, food processing, cooking\nand growth locations ( 40 ). Up to now, Iranian dietary\nphytoestrogen has not been measured. Our calculations\nwere done based on the phytoestrogens found in the\nUSDA food composition Table.\nA limitation of this study was the problem of convincing\nthe participants to answer many questions. Also, as it was\na case-control study, the probability of selection and recall\nbias including under- and over-reporting of the specific\nfood items might have affected our results.\n\nPhytoestrogens have a major impact on the level of\nhormones, and immune and inflammatory markers;\nthus, it can play an important role in the control and\nprevention of many diseases. Due to the inflammatory\nnature of endometriosis and the effect of hormones on\nthe progression of the disease, the role of phytoestrogens\nconsumption in the progression and regression of the\ndisease should be assessed in future works.","source_license":"CC0","license_restricted":false}