{"paper_id":"279ffff6-80ff-4fff-9454-a32523e93992","body_text":"Endometriosis is characterized as a chronic, inflammatory gynecological disease that affects approximately\n10% of women of reproductive age worldwide. Despite\nadvancements in diagnostic and therapeutic modalities,\nthe global incidence of endometriosis continues to rise.\nThis trend is likely underestimated, particularly in low-\nand middle-income countries, due to pervasive underdiagnosis and undertreatment ( 1 ). Endometriosis refers to\nthe growth of endometrium-like tissue outside the uterus,\nwhich results in debilitating symptoms including dysmenorrhea, dyspareunia, dyschezia, dysuria, infertility, and\nchronic pelvic pain. Moreover, a significant proportion of\npatients with endometriosis also reported depression and\nanxiety, as well as a lower quality of life ( 2 ).\nRecent studies revealed that diet and nutrition may signif\nicantly influence the progression of endometriosis. Several\ndietary components have been associated with the exacer\nbation of the disease, while others appear to offer protective\neffects ( 3 ,  4 ). Growing evidence suggests that consuming\nthe right diet may play a significant role in managing endometriosis. Encouragingly, a survey by Mazza et al. ( 5 ) found that as many as 64.4% of women with endometriosis\ndecided to change their dietary composition and habits after receiving the diagnosis. This shows a high interest from\nthe general public in the potential role of nutrition in health\nand diseases, particularly in relation to endometriosis.\nDespite growing interest, the precise influence of specific\nmacronutrients and micronutrients on the pathogenesis of\nendometriosis remains inadequately defined. Moreover, it\nis still uncertain whether dietary modifications can be sufficiently effective to serve as a standalone therapeutic intervention. One such dietary strategy is referred to as the orthomolecular approach, which involves the therapeutic use\nof naturally occurring substances-nutrients endogenous to\nthe human body-to restore optimal physiological function.\nThis review aims to comprehensively summarize the most\nrecent updates on the relationship between various food\nsubstances and endometriosis in a comprehensive manner.\nThis literature review aims to synthesize current research findings on the association between dietary factors\nand endometriosis. The literature search was conducted\nusing multiple electronic databases, including PubMed,\nGoogle Scholar, and ScienceDirect, supplemented by\nmanual searches of relevant journals. Targeted keywords\nused during the search process included “endometriosis,” “diet,” “food,” “nutrition,” “inflammatory factors,”\n“protective factors,” and “dietary recommendations.” The\nsearch focused on peer-reviewed studies published between 2000 and 2024. The inclusion criteria were: i. Studies investigated the association between endometriosis\nand nutrition, ii. Both primary data from original research\nand secondary data from past reviews or meta-analysis\nwere included, iii. Studies employing either qualitative or\nquantitative methodologies. Articles that were not written\nin English and did not provide full texts were excluded.\nEndometriosis is widely recognised as an estrogen-dependent condition with several hypotheses proposed to explain its etiology. The most established theories include retrograde menstruation, coelomic metaplasia theory, tissue\ninjury and repair theory, and hematogenous or lymphogenous spread ( 6 ). The pathogenesis of endometriosis involves a complex interplay of several mechanisms. According to Sampson's accepted theory, menstrual blood containing endometrial cells regurgitates into the peritoneal cavity\nvia the fallopian tubes, leading to implantation of these\ncells ( 7 ). Risk factors such as shortened menstrual cycles\nand obstructed uterine outflow may increase the quantity\nof retrogradely flushed cells, contributing to endometriosis\ndevelopment ( 6 ,  7 ). In addition to mechanical and hormonal factors, immune dysregulation plays a pivotal role in\nendometriosis, with various immune cells implicated in lesion formation ( 8 ). Macrophages, neutrophils, natural killer\ncells (NK cells), dendritic cells, and T cells contribute to\ninflammation and lesion progression through altered function and cytokine release ( 8 ). A previous study found that\nthere is inhibition of immune response in the endometriosis\nmicroenvironment, particularly through suppression of NK\ncell activity and T-cell response ( 9 ). Hormonal imbalance,\nepigenetic modifications, and environmental exposures\nsuch as dietary factors and pollutants are also believed to\nmodulate susceptibility to endometriosis ( 10 )\nIn summary, understanding the multifaceted mechanisms\ninvolved in endometriosis pathogenesis is crucial for developing effective diagnostic and therapeutic strategies for\nthis condition. Key contributors include retrograde menstruation, immune dysregulation, hormonal imbalance,\ngenetic and epigenetic factors, stem cell dynamics, and\nenvironmental influences ( 6 ,  11 ). These diverse and interrelated factors underscore the complexity of endometriosis\nand highlight the necessity for integrated, multidisciplinary\napproaches in its clinical management and future research.\nCurrent diagnostic and therapeutic approaches for endometriosis present significant challenges due to symptom\nvariability and the absence of a universally accepted non-invasive diagnostic tool. Although clinical assessment and\npelvic examination may suggest endometriosis, the presence of asymptomatic cases and the poor correlation between symptom severity and disease extent complicate accurate diagnosis. While pelvic examination abnormalities\noften correlate with endometriosis, laparoscopic confirmation reveals the disease in over 50% of women with normal\npelvic exams, highlighting limitations in relying solely on\nphysical examination ( 12 ,  13 ). Conventional diagnostic\nmodalities, including imaging techniques and blood-based\nbiomarkers, offer limited diagnostic sensitivity and specificity. However, emerging research on microRNAs (miR-\nNAs) shows promise as potential non-invasive diagnostic\nbiomarkers. Dysregulated expression patterns of specific\nmiRNAs have been identified in endometriosis, suggesting\npotential for adjunctive tools in the diagnostic evaluation.\nHowever, further validation and standardization are essential to fully exploit the potential of miRNAs in improving\ndiagnostic accuracy for endometriosis ( 14 ).\nRecent advancements in analytical methodologies and artificial intelligence have significantly contributed to the identification of promising biomarkers and therapeutic targets\nfor endometriosis management. Machine techniques, such\nas support vector machine (SVM) algorithms, have been\nemployed to construct predictive diagnostic models, identifying five key biomarkers with potential clinical relevance.\nConcurrently, molecular investigations utilizing single-gene\ngene set enrichment analysis (GSEA) have elucidated critical pathways involved in the pathogenesis of endometriosis.\nThe development of a competing endogenous RNA (ceRNA) regulatory network further elucidates the complex interactions among these biomarkers. Potential therapeutic\ndrugs targeting these biomarkers are also highlighted, offering novel avenues for endometriosis treatment. Clinical validation of biomarker expression reinforces the significance of\nthese findings in advancing both the diagnosis and treatment\nof endometriosis ( 15 ). Minimally invasive surgery, particularly laparoscopy, offers substantial advantages, including\nreduced rates of surgical complications and shorter hospital\nstays ( 13 ). While robotic-assisted laparoscopy yields comparable perioperative outcomes, it may provide additional\nadvantages in advanced-stage (stage III and IV) endometriosis cases requiring complex and extensive resection. Certain\naspects of endometriosis surgery, such as lesion heterogene\nity and difficulty predicting surgical complexity, may benefit from robotic technology, emphasizing its potential to\nenhance patient care in challenging cases ( 16 ).\nAlcohol consumption has long been associated with vari\nous chronic inflammatory conditions. In relation to endometriosis, alcohol may contribute to elevated circulating estrogen levels in the blood through increasing aromatase activity,\nan enzyme responsible for converting testosterone to estrogen. Frydenberg et al. ( 17 ) reported that women consuming\nmore than 10 g of alcohol per day exhibited an 18% higher\nmean 17β-estradiol level compared with those consuming\nless than 10 g per day. These findings suggest that alcohol\nconsumption affects the cumulative estrogen level in the\nbody throughout a woman’s life cycle ( 4 ,  17 ,  18 ).\nA recent systematic review and meta-analysis conducted by Li Piani et al. ( 19 ) found that there was a significant\nassociation between moderate alcohol intake and endometriosis [unadjusted odds ratio (OR): 1.22, 95% confidence interval (CI): 1.03-1.45, P=0.02].\nThe metabolism of alcohol also upregulates pro-inflammatory and oxidative stress-related pathways, which\nfurther lead to the production of persistent inflammatory\nmediators and free radicals ( 4 ). Excessive reactive oxygen species (ROS) lead to upregulation of transcription\nfactor nuclear factor kappa B (NFkB), which is implicated in the pathogenesis of endometriosis. Following this\ntranscription factor regulation, activated peritoneal macrophages will express many genes associated with proinflammatory cytokines, growth factors, angiogenic factors,\nchemokines, and others. This chain of events eventually\nresults in endometrial fragment implantation, proliferation, and neovascularization ( 20 - 22 ).\nAnother concerning issue is how alcohol is often viewed\nas a coping mechanism by populations affected by chronic conditions, including endometriosis patients ( 19 ). Gao\net al. ( 23 ) reported that individuals with endometriosis are\nat significantly higher risk of developing alcohol or substance use disorders compared to other psychiatric conditions [hazard ratio (HR): 1.93; 95% CI: 1.71-2.18]. Rather\nthan offering pain relief or a sense of liberation, this actually creates a vicious cycle that further aggravates the disease progression. However, considering the many types\nof alcohol and varying alcohol percentages in a drink, the\ndose-response relationship between alcohol and endometriosis remains unclear. Further research is warranted to\ndetermine a definitive threshold for alcohol intake that may be considered unsafe in this patient population.\nRed meat and processed animal products such as bacon or\nbutter all contain high are rich sources of saturated fats. Excessive intake of saturated fats has been associated with higher\nlevels of estradiol and steroid hormones in the blood. In addition, trans fats, which can be naturally found in meat and\ndairy and in industrially processed foods such as deep-fried\nitems, have been shown to stimulate the production of tumor\nnecrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and C-reactive protein (CRP) ( 4 ,  24 ). These inflammatory mediators\nare believed to contribute to the chronic inflammatory milieu\nobserved in endometriosis. Despite this theoretical framework, in practice their role in endometriosis progression is not\nfully clear. A meta-analysis of randomized controlled trials by\nO’Connor et al. ( 25 ) found that red meat consumption, particularly unprocessed beef and pork, did not significantly affect levels of glycemic control and inflammation biomarkers\n[fasting glucose, insulin, homeostatic model assessment for\ninsulin resistance (HOMA-IR), HbA1c, IL-6, CRP, TNF-α],\nwithin a 16-week observation period. The authors suggested\nthat consuming a balanced, healthy, and nutrient-dense diet in\naddition to weight loss help achieve control of cardiometabolic\ndisease risk factors independent of total red meat intake ( 25 ).\nIn addition, red meat intake can increase risk of endometriosis\nthrough other mechanisms. Red meat consumption has been\nlinked with lower sex hormone binding globulin (SHBG) and\nelevated estradiol levels. High iron content in red meat can\nalso amplify oxidative stress and inflammation. How meat\nis processed may also influence endometriosis risk; red meat\ngrilled at high temperature can undergo pyrolysis and produce\npolycyclic aromatic hydrocarbon (PAH), a harmful compound\nthat has been associated with increased risk of endometriosis.\nPAH can dysregulate levels of reproductive hormones such as\nestradiol, testosterone, follicle-stimulating hormone (FSH),\nand luteinizing hormone (LH) ( 26 - 28 ).\nOne of the few studies that has confirmed a significant correlation between red meat intake and endometriosis is the\nNurses’ Health Study II by Yamamoto et al. ( 26 ), who revealed that women who consumed more than two portions\nof red meat a day were 56% more likely to develop endometriosis compared to women who consumed red meat once a\nweek. Similarly, an earlier Italian study reported a significantly increased in risk of endometriosis among women who\nregularly consumed ham, beef, and other red meats ( 29 ). Al\nthough several other studies have also reported associations\nbetween red meat and endometriosis, but none of the results\nwere significant ( 30 ,  31 ). Regarding saturated fats consumption, while older studies comparing the risk of acquiring\nendometriosis from high intake with low intake found no\nsignificant correlation ( 32 - 34 ), a recent meta-analysis found\nthat an increased risk for endometriosis was significantly\nassociated with red meat [relative risk (RR): 1.17, 95% CI:\n1.08 to 1.26, P<0.001, I2=82.4%], saturated fats (RR: 1.06,\n95% CI: 1.04 to 1.09, P<0.001, I2=57.3%), and trans fats\n(RR: 1.12, 95% CI: 1.02 to 1.23, P=0.019, I2=73.0%) ( 35 ).\nAdditionally, one study specifically examining trans fat intake found that women in the highest consumption group\nwere 48% more likely to be diagnosed with endometriosis\ncompared to those with the lowest intake ( 33 ).\nMost dietary guidelines endorsed by the government or\nclinicians generally restrict the intake of red meat, saturated\nfats, and trans fats for better health, such as the dietary approaches to stop hypertension (DASH) and the Mediterranean diet. Although there has been no universally accepted\ndietary guideline for endometriosis patients, it is good practice to switch to healthier alternatives such as white meat,\nlow-fat diet, and food high in polyunsaturated fats. These\ndietary modifications and their potential implications for\nendometriosis will be discussed in the following sections.\nCaffeine has been implicated in the modulation of estrogen-dependent disorders such as endometriosis, although\nthe underlying mechanisms remain poorly understood. This\nactive substance can increase plasma levels of steroid hormones, sex hormone-binding protein (SHBG), and therefore\nlower concentration of free testosterone and estradiol. Caffeine is believed to inhibit aromatase activity, which catalyzes the conversion of androgens to estrogens. Alterations\nof the hormonal balance are hypothesized to promote endometriosis progression ( 4 ,  36 ). A meta-analysis conducted\nby Chiaffarino et al. ( 37 ) found no statistically significant\ncorrelation between caffeine intake and risk of endometriosis [total RR: 1.26, 95% CI: 0.95 -1.66 for caffeine and 1.13\n(95% CI: 0.46 -2.76) for coffee consumption] ( 37 ). Similarly,\na more recent meta-analysis by Kechagias et al. ( 36 ) corroborated the findings that caffeine was not significantly associated with endometriosis (RR: 1.12, 95% confidence interval (CI): 0.97-1.28, I2=70%) ( 36 ). However, it suggested\nthat higher intake of caffeine (more than 300 mg/day) could\npotentially increase the risk of endometriosis (RR: 1.30, 95%\nCI: 1.04-1.63, I2=56%) ( 36 ).\nInterestingly, the impact of caffeine on estrogen levels appears to vary across racial groups. For example, one study\nreported that caffeine consumption was associated with\ndecreased levels in white women, whereas it led increased\nestrogen concentration among Asian women. These differences are hypothesised to result from genetic polymorphism\nand gene-environment interactions which may vary between\nraces ( 38 ). This warrants further research for clarification.\nWomen with endometriosis are often advised to limit\ncaffeine intake, as it may potentially aggravate their symptoms, such as pelvic pain and cramps. Previous studies\nhave documented self-reported symptom improvement\namong endometriosis patients who reduced their intake of\ncertain foods, including coffee ( 5 ,  39 ). However, there is\nstill limited evidence regarding this relationship between\ncaffeine and endometriosis-associated pain.\nEmerging evidence suggests that patients with endome\ntriosis exhibit lower serum concentration of vitamin A,\nC, and E than the normal population ( 40 ,  41 ). This deficiency \nis believed to be linked to oxidative stress. Oxidative stress has been shown to be crucial in endometriosis pathogenesis as it promotes ectopic implantation of\nendometrial cells ( 42 ,  43 ). Vitamins A, C, and E possess\nantioxidant properties that neutralize ROS and mitigate\noxidative damage within metabolic pathways ( 40 ). In\naddition to their antioxidative function, vitamin C and E\nhave exert anti-inflammatory activity, in which they can\ndownregulate the production of inflammatory mediators\nsuch as IL-1 and IL-6. These vitamins may also attenuate\nendometriosis-associated pain by inhibiting cyclooxygenase activity, thereby reducing prostaglandin E2 synthesis\n( 44 ). A randomized controlled trial conducted by Amini et\nal. ( 45 ) demonstrated that supplementation with vitamin\nC and E resulted in significant improvements in dysmenorrhea, dyspareunia, and pelvic pain associated with endometriosis after 8 weeks intervention period.\nVitamin A and its metabolites have been shown to positively regulate gut microbiome-derived butyrate, which\nplays a role in gut barrier maintenance, suppression of\ninflammation and cytokine storm, mitochondria optimization, melatoninergic pathway activation, and histone\ndeacetylase (HDAC) inhibition. Butyrate is a short-chain\nfatty acid (SCFA) that is believed to be decreased in endometriosis due to gut dysbiosis. This observation has contributed to the emerging concept of a \"gut–uterus axis,\"\nwhich suggests that endometriosis may be influenced by\nintestinal health and microbial composition ( 42 ). Nevertheless, these findings support the idea that endometriosis\nshould be viewed as a systemic disease rather than a local\nestrogen-mediated uterine disorder. Furthermore, all-trans\nretinoic acid (ATRA), a bioactive metabolite of vitamin\nA, has demonstrated potential in inhibiting the progression of endometriosis by decreasing estrogen levels and\npreventing endometrial tissue cysts’ proliferation ( 46 ).\nSelenium is a trace element with potent antioxidant\nwhich can be found in a variety of dietary sources, including seafood, meat, nuts, some fruits and vegetables, and\neggs. Its antioxidative capacity enables it to neutralize\nROS, which are implicated in the pathogenesis of endometriosis. Beyond its role in oxidative stress mitigation,\nselenium also exhibits anti-apoptotic and anti-angiogenic\neffects, which may further contribute to its protective role\nin endometriosis ( 3 ,  47 ). Similarly, zinc is an essential\nmineral with known antioxidant effects that appears to be\ndecreased in patients with endometriosis. Dietary sources\nof zinc include meat, seafood, dairy products, and supplements. Zinc is involved in DNA synthesis for oocyte formation as well as the proliferation and differentiation of\nreproductive system cells ( 3 ,  47 ). Zinc deficiency has been\nlinked to several reproductive disorders, including polycystic ovarian syndrome (PCOS), abnormal LH and FSH\nbalance, preeclampsia, and endometriosis ( 48 ,  49 ). A study\nby Singh et al. ( 50 ) showed that the follicular fluid of women with endometriosis had increased concentration of ROS\nand decreased levels of antioxidant molecules, including selenium and zinc, compared to that of women with tubal\ninfertility ( 50 ). Furthermore, clinical studies have reported\nthat the severity of endometriosis is inversely correlated\nwith oral intake of antioxidant nutrients, including vitamin\nC, vitamin E, selenium, and zinc ( 47 ).\nVitamin B-complex has been proposed as a component\nof both preventive and therapeutic strategies for endometriosis. A case-control study in Iran demonstrated that consuming a diet rich in vitamins B2, B6, B12, and C, as well\nas calcium and potassium, may reduce the risk of endometriosis ( 3 ). Vitamin B6 plays a critical role in activating the\npathways to break down estrogen to prevent excessive levels that can lead to endometriosis proliferation. Consuming\nvitamin B6 and B9 along with antioxidant nutrients may\nalso alter gene expression or DNA methylation related to\nendometriosis risk ( 51 ). Higher intake of vitamin B12 has\nbeen inversely associated with lower plasma concentration\nof homocysteine, which is a thiol-containing amino acid\nthat promotes oxidative stress and inflammation responsible for endometriosis progression ( 52 ). A previous study\ndiscovered that endometriosis patients had significantly\nhigher levels of homocysteine in the blood and follicular\nfluid compared to those without endometriosis ( 53 ). Overall, consumption of B-complex vitamins such as vitamin\nB6, B9, and B12 may contribute to reducing endometriosis\nrisk via multiple biochemical and molecular pathways.\nOne potential strategy to increase vitamin B levels\nin patients with endometriosis is through the consumption of more probiotics. Probiotics are natural producers\nof vitamin B; not only that, but they also maintain gut\nhealth, increase the absorption of vitamins and minerals,\nand boost the immune system ( 47 ,  54 ). Moreover, women\nwith endometriosis should augment their animal protein\nand vegetable intake as these are the primary food sources\nfor vitamin B12 and B9 respectively ( 55 ).\nVitamin D is widely recognized not only for its role in\ncalcium homeostasis but also as a key modulator of immune system function ( 56 ). Vitamin D can be found in\ndairy products, seafood, and meat, although it is mainly\nobtained through adequate sunlight exposure. It is one of\nthe many micronutrients that have been largely studied\nfor its role in endometriosis. Evidence from past studies\nindicated that the endometrial tissue naturally contains vitamin D receptor (VDR), and it was also revealed that ectopic endometrial tissue had higher VDR levels ( 57 ,  58 ).\nUp to present, very limited data can be found regarding\ntissue expression levels of VDR in endometriosis patients.\nNevertheless, a recent study by Matasariu et al. ( 59 ) was\nable to find that women with endometriosis who did not\nreceive hormonal treatment exhibited VDR overexpression in parallel with reduced serum levels of 25(OH) vitamin D. Regarding vitamin D serum concentration, many\nstudies have demonstrated that patients with endometriosis had significantly lower vitamin D levels compared\nto controls ( 60 ,  61 ). As a result, vitamin D deficiency in\nendometriosis has emerged as an increasingly prominent\narea of investigation. Typically, vitamin D insufficiency\nis defined as serum levels between 20-30 ng/mL, while\ndeficiency is classified as levels below 20 ng/mL ( 56 ).\nVDR acts as both a receptor and a transcription factor that mediates many vitamin D-associated metabolic\npathways. Through these signaling pathways, vitamin D\nis able to suppress key processes involved in the pathogenesis of endometriosis, including inflammation, angiogenesis, cellular adhesion, invasion, and proliferation.\nIt also modulates the immune response by influencing\nCD4-positive T cells, specifically enhancing T helper 2\n(Th2)-mediated anti-inflammatory pathways while inhibiting T helper 1 (Th1)-mediated pro-inflammatory\nresponses ( 62 ). Additionally, vitamin D acts on variety\nof immune cells expressing VDR which include B lymphocytes, monocytes, macrophages, and Langerhans cells\n( 56 ). However, despite the demonstrated beneficial effect\nof vitamin D therapy in animal and  in vitro  studies, this\neffect still lacks conclusive evidence from human trials.\nHence, further studies are needed to investigate the effect\nof vitamin D supplementation using various doses and in\nvarious subtypes of endometriosis. Although endometriosis alone may not be sufficient to justify the use of vitamin\nD supplementation should still be strongly recommended\nin all women diagnosed with vitamin D deficiency ( 56 ).\nVDR acts as both a receptor and a transcription fac\ntor that mediates many vitamin D-associated metabolic\npathways. Through these signaling pathways, vitamin D\nis able to suppress key processes involved in the patho\ngenesis of endometriosis, including inflammation, an\ngiogenesis, cellular adhesion, invasion, and proliferation.\nIt also modulates the immune response by influencing\nCD4-positive T cells, specifically enhancing T helper 2\n(Th2)-mediated anti-inflammatory pathways while in\nhibiting T helper 1 (Th1)-mediated pro-inflammatory\nresponses ( 62 ). Additionally, vitamin D acts on variety\nof immune cells expressing VDR which include B lym\nphocytes, monocytes, macrophages, and Langerhans cells\n( 56 ). However, despite the demonstrated beneficial effect\nof vitamin D therapy in animal and  in vitro  studies, this\neffect still lacks conclusive evidence from human trials.\nHence, further studies are needed to investigate the effect\nof vitamin D supplementation using various doses and in\nvarious subtypes of endometriosis. Although endometrio\nsis alone may not be sufficient to justify the use of vitamin\nD supplementation should still be strongly recommended\nin all women diagnosed with vitamin D deficiency ( 56 ).\nCalcium absorption relies upon adequate vitamin D levels\nin the blood. It was suggested that calcium’s protective role\nagainst endometriosis may involve the prevention of retrograde menstruation through smooth muscle contraction. A\ncase-control study by Roshanzadeh et al. ( 3 ) found a significant inverse association between total calcium intake and risk\nof endometriosis. Similarly, another case-control study based\nin Korea found that patients with endometrioma had a sig\nnificantly lower calcium intake than the control group ( 63 ).\nEndometrioma refers to cystic lesions commonly found in\nthe ovaries, also known as deep ovarian endometriosis, which\nshares a similar etiopathogenesis with endometriosis ( 64 ).\nWhile saturated and trans fats are associated with an increased risk of endometriosis, it is important to note that not\nall dietary fats exert the same biological effects. PUFAs,\nabundant in fish, nuts, seeds, and dietary supplements, play\na beneficial role in reproductive health. Since the human\nbody’s capacity for producing PUFAs is limited, dietary in\ntake is essential. The two primary categories of PUFAs are\nomega-3 and omega-6 fatty acids, both of which have been\nextensively studied in relation to endometriosis.\nPUFAs have demonstrated anti-proliferative, anti-angiogenic, and anti-inflammatory properties in both  in vitro \nand  in vivo  models of endometriosis. These mechanisms\ncontribute to the suppression of lesion development and\nprogression. Furthermore, PUFA supplementation has\nbeen associated with symptomatic improvement, particularly in the reduction of dysmenorrhea ( 4 ,  47 ,  65 ,  66 ).\nHuman studies have also demonstrated positive results\nregarding the role of PUFAs in the prevention of endometriosis. For instance, Savaris et al. ( 34 ) reported that\nwomen diagnosed with endometriosis had significantly\nlower omega-3 consumption than women in the control\narm. Similarly, Missmer et al. ( 33 ) also showed that wom\nen with the highest consumption of omega-3 in their study\nwere 22% less likely to develop endometriosis.\nA recent study by Akyol et al. ( 67 ) compared the effects of vitamin D supplementation versus omega-3 supplementation on endometriosis lesions in a rat model. The\nfinding concluded that omega-3 was significantly more\neffective than vitamin D in reducing the volume of the\nlesion. In the rats given omega-3 supplementation, levels of IL-6, TNF-alpha, and vascular endothelial growth\nfactor (VEGF) in the peritoneal fluid were significantly\ndecreased. Whereas in the rats given vitamin D supplementation, only IL-6 was significantly decreased ( 67 ).\nDietary fiber consists of complex carbohydrate compounds that are resistant to complete digestion in the\ngastrointestinal tract. It can mainly be found in fruits,\nvegetables, whole grains, and beans. The protective role\nof dietary fiber against endometriosis has been suggested to be mediated by its anti-proliferative effect. This\nanti-proliferative effect is brought by the role of fiber in\nestrogen metabolism ( 4 ). In contrast, diets rich in simple\ncarbohydrates or low-fiber food have a high glycemic\nindex, leading to a spike in glucose in the bloodstream\nand subsequent rapid insulin release. Since insulin can\nact as a growth factor that promotes proliferation and\ninhibits apoptosis of certain cell types, hyperinsulinism\ncan contribute to endometrial lesion growth. In particular, hyperinsulinism also reduces the level of sex-hormone binding globulin in the blood, which in turn increases the number of circulating free estrogen. Overall,\nhyperestrogenism due to hyperinsulinism may lead to\nworsening of endometriosis. This state of hyperestrogenism, driven by hyperinsulinemia, may exacerbate the\nprogression of endometriosis ( 4 ,  68 - 70 ). Previous studies have shown that low fiber intake is associated with\nother estrogen-dependent disorders which include breast\ncancer and endometrial cancer ( 71 ). Thus, adopting a\nhigh-fiber diet may mitigate the effect of unopposed estrogen. In fact, the concentration of estrogen in the blood\ncan be lowered by 10 to 25 percent by consuming less\nfats and more fiber ( 24 ). Additionally, high fiber consumption may also exert anti-inflammatory effects, further contributing to its protective role ( 72 ).\nA prospective cohort study by Schwartz et al. ( 72 ) observed that women who consumed more food with high\nglycemic index were more likely to receive a diagnosis of\nendometriosis. Conversely, although an inverse association\nwas noted between higher fruit fiber intake and endometriosis risk, the finding did not reach statistical significance ( 72 ).\nDespite promising  in vitro  and  in vivo  findings, many clinical\nstudies have struggled to establish statistically significant associations ( 31 ). Therefore, more research is needed to clarify\nthis matter regarding the role of fiber in endometriosis prevention. A summary of aggravating versus protective dietary\nfactors in endometriosis can be found in Table 1.\nDietary factors and nutrients associated with endometriosis\nTo date, there is no universally accepted nutritional\nguideline specifically established for patients with endometriosis. Such consensus may be difficult to formulate\nsince there is evidence that endometriosis is influenced\nby genetic and epigenetic factors, in which they may differ according to an individual’s ethnicity and geographic\nlocation ( 73 ). The variety of food sources available and\nthe cost of food in each country may also differ from one\nanother. Nonetheless, there remains a critical need for\nmore comprehensive, evidence-based dietary guidelines\ntailored to endometriosis patients, with consideration of\nboth global findings and regional feasibility.\nSince endometriosis is a chronic condition, it is essential for patients to adopt dietary habits that enables them\nto cope with their symptoms and may also help reduce the\ndisease severity. A study conducted in Australia reported\nthat a change in dietary habit is one of the most popular\nself-management strategies for women with endometriosis,\nwith 44% of all patients employing it ( 74 ). According to\nMazza et al. ( 5 ), some of the most popular diet regimens\nchosen by endometriosis patients included gluten-free diet\n(15%), anti-inflammatory diet (8%), Mediterranean diet\n(7.1%), and ketogenic diet (4%). Moreover, participants in\nthe study started to eat more fruits and vegetables (10%),\ncereals and legumes (6.6%), and fish (4.5%). They also\ncut back on dairy products (18.4%), soy-containing food\n(6.7%), and saturated fats (8%). Successful adherence to\nthese dietary habit modifications requires the patients to be\naware of the role of nutrition in endometriosis prevention\nand management, which is why health promotion and patient education for this matter are essential.\nAn Italian study found that 52% of endometriosis patients who adhered to a gluten-free diet for 12 months\nreported a significant reduction in pain severity ( 75 ).\nSimilarly, an Austrian study investigated the benefits of\nMediterranean diet for endometriosis and observed notable improvements in pain, dysmenorrhea, dyspareunia,\ndyschezia, and overall well-being ( 76 ). The Mediterranean diet has been associated with reduced homocysteine\nlevels and increased serum concentrations of folate and\nvitamin B12, nutrients that are believed to attenuate inflammation and oxidative stress, both of which are implicated in the pathophysiology of endometriosis ( 55 ).\nOverall, current evidence indicates that individuals with\nendometriosis may benefit from adopting a diet rich in\nantioxidants and anti-inflammatory nutrients while minimizing the intake of pro-inflammatory foods. The consumption of alcohol and trans fats, and saturated fats\nshould be limited and patients with endometriosis are en\ncouraged to replace them with PUFAs. Any dietary modifications should be made in consultation with a healthcare\nprovider, and referral to a clinical nutritionist should be\nconsidered as part of a comprehensive management plan.\nEstablishing and maintaining a healthy dietary pattern is\na long-term commitment that requires ongoing monitoring, individualised assessment, and sustained motivation.\nIn a study by Youseflu et al. ( 77 ), the impact of endometriosis on the sleep quality of women was investigated,\nwith a focus on the potential influence of lifestyle factors.\nThe study revealed that endometriosis adversely affects\nsleep quality (SQ), as patients report lower scores in subjective sleep quality, sleep latency, and sleep disturbance\ncompared to healthy controls. Lifestyle modifications\nsuch as diet and physical activity play a crucial role in\nmodifying SQ in endometriosis patients. The consumption\nof dairy products and nuts, which are rich in tryptophan,\nhas been associated with better SQ due to their influence\non melatonin production and regulation of inflammation.\nRegular physical activity enhancing melatonin secretion\nand improves SQ, although issues such as pain or abnormal menstrual cycles may decrease patients' tendency for\nexercise. In summary, counseling on diet strategies and\npromoting regular physical activity are recommended to\nimprove SQ and overall well-being in endometriosis patients ( 77 ).\nAnother study reported that lifestyle interventions, particularly regular physical exercise, may exert protective\nbenefits against the progression and severity of endometriosis symptoms ( 78 ). The discussion highlights the potential\nrole of regular physical exercise in mitigating inflammatory conditions, including endometriosis. Despite evidence\nsuggesting an association between endometriosis and inflammation, the role of exercise in managing the condition\nremains unclear due to a lack of well-designed, controlled\nclinical trials. While observational studies suggest a positive inverse relationship between exercise and endometriosis risk, these associations have yet to be confirmed through\nrobust empirical evidence. In addition to physical activity,\nother lifestyle strategies such as stress reduction techniques\nand improved sleep hygiene may also contribute to better\nsymptom management. However, further research is necessary to validate their effectiveness and to determine their\nspecific impact on symptom burden and quality of life in\npatients with endometriosis ( 78 ).\nThis review is subject to several limitations. First, the\nfindings presented were based on data from observational\nstudies, case-control studies, and a limited number of randomized controlled trials, which may not necessarily reflect causal relationship. Furthermore, as the studies took\nplace in different countries and used self-reported dietary\ninstruments, there could be some extent of recall bias. Future research must therefore consider the effect of socio\ncultural and geographical diversity on dietary pattern and\nsubsequent endometriosis risk.\n\nThe relationship between diet and endometriosis is\ncomplex, with certain foods either worsening or potentially protecting against the condition. Consumption of alcohol, red meat, processed foods, and excessive caffeine may increase inflammation and hormonal imbalance,\nwhich may worsen endometriosis symptoms. On the other\nhand, nutrition such as antioxidants, B vitamins, vitamin\nD, calcium, omega-3 and omega-6 fatty acids, and fiber\nmay help suppress inflammation and protect against the\ndisease. Healthcare providers should promote a balanced\ndiet rich in anti-inflammatory foods while limiting proinflammatory substances. A diet focused on fruits, vegetables, lean proteins, whole grains, and healthy fats is\nbeneficial. Other lifestyle changes like exercise, stress\nmanagement, and good sleep hygiene should also be part\nof treatment. Further research is required to elucidate the\nmechanisms by which dietary factors influence endometriosis and to establish evidence-based, individualized dietary guidelines for affected patients.","source_license":"CC0","license_restricted":false}