Endometriosis: pathophysiology and the potential role of diet

Endometriosis is a complex, estrogen-dependent condition marked by a multifaceted pathophysiology and a broad spectrum of symptoms, particularly chronic pelvic pain. Pain arises through overlapping mechanisms, including systemic inflammation. Given the prevalence of ENDO and the lack of effective mitigation strategies, exploring dietary interventions to control inflammation and manage pain are necessary. While dietary interventions such as the Mediterranean Diet and low FODMAP diet show promise in reducing inflammation and symptom burden from observational studies, significant gaps remain in understanding their mechanistic effects and long-term efficacy in ENDO management. Since pain is acyclic and subjective, future research should focus on the identification of biomarkers that predict individual responses to dietary or pharmacological interventions, exploring the gut-immune-endocrine axis, and developing personalized treatment strategies that target specific pain pathways. A more comprehensive, mechanistic approach is essential to improve quality of life and clinical outcomes for individuals living with ENDO.

Endometriosis (ENDO) affects over 190 million females worldwide ( 1 ). It is considered an inflammatory chronic gynecologic disease characterized by the development and presence of histological alterations in endometrial-like epithelial and/or stroma tissue (referred to as lesions) on organs and areas outside the uterine cavity ( 2 ). The main clinical characteristics are chronic pelvic pain and infertility, which affects up to 30–50% of patients ( 3 , 4 ). Over 70% of females diagnosed with ENDO report severe acyclic pelvic pain ( 5 ). Other common symptoms that are often undermined are painful menstrual periods, painful urination, painful defecation, and painful intercourse ( 6 ). The pain experienced with ENDO detrimentally affects daily quality of life. Indeed, in a prospective study of 104 females with ENDO, 86% of those with chronic pelvic pain also reported symptoms of depression, compared to 38% of those without chronic pelvic pain ( 7 ). Females with ENDO are 2.6 times more likely to have anxiety and 3.6 times more likely to have depression compared to females without ENDO ( 8 ). Furthermore, a survey of 5,879 females ( 77.2% White; 59.1% employed) demonstrated ENDO leads to increased work absenteeism ( 9 ) and an estimated 1.9 hours loss per week of productivity with mild cases growing to 15.8 hours per week with severe cases ( 9 ). Females with endometriosis report missing work 74% of the time ( 10 ), a substantially higher proportion than those with other chronic conditions such as polycystic ovary syndrome, where 50% report work absences ( 11 ). Despite its prevalence, no permanent cure or treatment exists for ENDO. The estrogen-mediated mechanism often disguises ENDO as usual menstrual-like symptoms ( 12 ). Hence, its diagnosis is challenging. Dysmenorrhea is highly prevalent among adolescents (20–90%) ( 13 ), yet many do not seek care because it is commonly perceived as normal ( 14 , 15 ), a belief often reinforced by peers, parents, and healthcare providers. Furthermore, health care providers may have limited knowledge of ENDO symptoms, with only 60% of general practitioners specialized in gynecology feeling that they knew enough about ENDO for their routine clinical practice ( 16 ). There are no effective, non-invasive diagnostic tools and many healthcare providers are accused of normalizing female pelvic pain ( 12 ). Females living with ENDO experience an average diagnostic delay of 7–9 years ( 17 ). This delay prolongs disease progression by increasing the severity of both endometrial lesions ( 18 ) and adhesions ( 19 ). Only short-term treatments such as pain medication, hormonal therapy, and neuromodulators are available to manage symptoms ( 20 ). Longer-term management requires more invasive options including excision or ablation of the uterine tissue, though 40–50% of females experience symptoms recurrence in as little as 5 years ( 1 ). Previous studies have shown that females with greater awareness of ENDO are more likely to seek medical attention for their symptoms ( 21 – 23 ); however, despite having high health literacy, patients with ENDO reported it was difficult to “find information about treatments for diseases” and “use information given by the doctor to take decisions about the illness”( 24 ). Because effective treatment options remain limited, many also readily adopt self-management strategies. A survey of over 200 females with ENDO found that 44% reported dietary modifications to manage symptoms, ranking dietary changes ahead of exercise (42%), stretching (40%), and yoga/Pilates (35%) ( 25 ). Those who adopted dietary changes often followed anti-inflammatory or elimination-style diets, yet few clinical studies have systematically evaluated the effectiveness, feasibility, or long-term impact of these dietary approaches. In this review, we provide a brief overview of the diagnosis and pathophysiology of ENDO. We then explore the perceived role of diet in managing pain among females with ENDO. Finally, we call for further research examining dietary interventions to mitigate pain associated with inflammation in ENDO. Early identification of ENDO is key to improving outcomes and optimizing the long-term management of ENDO ( 20 , 26 , 27 ). However, the criterion standard for ENDO diagnosis is visualization and biopsy of lesion histology (using surgical laparoscopy) in the abdomen and pelvic regions. The reliance on surgery for diagnosis contributes to delays in care ( 28 , 29 ). As such, assessment of ENDO can begin with a physical examination of the pelvic region to identify palpable thickening, ovarian masses, or tenderness ( 30 ). Physical examinations prior to surgery demonstrated 67 – 95% detection of endometrium thickening and ovarian masses ( 30 ). International guidelines recommend transvaginal pelvic ultrasounds or magnetic resonance imaging (MRI) of the pelvic organs as an initial diagnostic test ( 20 , 31 , 32 ). Yet, a systematic review of 49 studies involving 4807 females found none of the evaluated imaging modalities were able to detect overall pelvic ENDO with enough accuracy that they would be suggested to replace surgery ( 33 ). There has been a call to action to identify non-invasive markers of ENDO such as markers of immune function, glycoproteins, and miroRNA signatures, to expediate diagnosis ( 34 ). Diagnosis also includes an assessment of disease severity with the appearance of lesions and adhesions classified into four subtypes: superficial peritoneal, deep, ovarian (endometriomas), and extrapelvic ( 35 ). Each subtype has distinct pathological features and clinical implications that can influence diagnosis and treatment strategies. Superficial peritoneal lesions , found in 15–50% of diagnosed cases, occur on top of the peritoneal surface of abdominal or pelvic organs and have been histologically categorized into red (active, vascularized), black (advanced), and white (quiescent or healed) lesions, representing stages of disease progression ( 36 ). In Deep infiltrating ENDO , which is estimated to affect 20% of individuals with ENDO, lesions penetrate the pelvic peritoneal surface and/or muscle tissue of pelvic organs such as the bowel or bladder. These lesions have unique histological patterns ranging from well-differentiated to undifferentiated cells types ( 35 , 36 ) and are thought to resist suppression and demonstrate higher expression of estrogen receptor α (ERα). Ovarian endometriomas are endometrial-lined cysts filled with thick, brown fluid and these cysts are observed in 17 to 44% of females with ENDO and up to 50% of those with infertility ( 35 – 37 ). Their origin is unclear but most likely involves complex histologic mechanisms. Extrapelvic ENDO , though rare, has been documented in nearly every organ system, including the diaphragm, abdominal wall, thoracic cavity, and even the brain ( 35 , 36 ). The true prevalence of each subtype of ENDO is unclear due to reliance on surgical diagnosis. The Revised American Society for Reproductive Medicine (rASRM) classification is the most widely used system for grading the pathological severity of endometriosis. It relies on surgical laparoscopy to assess anatomical factors, such as implant size, location, depth, and adhesion characteristics, across four stages from minimal (I) to severe (IV) using a weighted point system ( 38 ). Although comprehensive in describing lesion appearance and distribution, rASRM does not account for symptoms or reliably predict patient-centered outcomes, including pain or fertility ( 39 – 41 ). This is especially true for legions locations outside of the endometrium, which often lead to misdiagnoses. More recent systems, such as the #Enzian classification and the Endometriosis Fertility Index, provide additional detail on deep infiltrating disease and fertility prognosis, respectively, and are intended to complement rather than replace rASRM staging ( 2 , 42 ). ENDO is a complex, multisystem, and multipathway condition, making it difficult to identify a single underlying cause. No current theory fully explains the wide range of clinical presentations seen in the disease ( 43 ). Although its precise origin remains unclear, research suggests that genetic predisposition, early menarche (before age 12), anatomical differences, and environmental exposures all contribute to its development and progression ( 44 – 46 ). The most widely accepted explanation for disease development is Samson’s theory of retrograde menstruation, which posits that menstrual blood containing endometrial and stem cells flows backward through the fallopian tubes into the peritoneal cavity leading to the adhesion and growth of endometrial tissue in ectopic locations ( 17 ). Another potential mechanism called Celomic Metaplasia Theory, involves the differentiation of the outer layer of the peritoneal epithelium into endometrial-like tissue, likely stimulated by cytokines and growth factors released from endometrial-like stroma cells, eventually leading to the formation of lesions ( 47 ). An additional proposed theory is lymphatic and vascular metastasis, which suggests that endometrial-like cells from the uterine cavity spread through the blood or lymphatic system to distant tissues ( 43 ). Emerging evidence also points to the role of endometrial stem cells in driving both the development and progression of the disease ( 19 ). The pathogenesis of ENDO involves complex, estrogen-dependent inflammatory processes ( 28 ). ENDO lesions develop from an estradiol-mediated mechanism. Elevated levels of systemic estrogen increase activation of ERα and estrogen receptor β (ERβ) ( 12 , 18 ). The activation of these receptors promotes ENDO cellular proliferation and adhesion, which triggers downstream effects including localized fibrosis and chronic inflammation, impaired immune surveillance, and the coordinated growth of blood vessels and nerve fibers ( 12 , 18 ). When estrogen binds to ERβ, anti-apoptotic signaling pathways are activated, allowing endometrial cells to evade programmed cell death thereby enhancing lesion formation. Furthermore, ERβ binding increases cell adhesion and invasion and bolsters localized immune system activity ( 18 ). When bound to ERα, estrogen promotes angiogenesis within endometriotic lesions ( 12 , 18 , 48 ). This vascularization delivers oxygen and nutrients necessary for lesion growth, yet the immature vasculature often results in persistent hypoxia. This hypoxic environment exacerbates inflammation and recruits activated macrophages, which contribute to lesion survival and initiate macrophage-mediated neurogenesis (the development of new nerve fibers within lesions) ( Figure 1 ) ( 6 , 49 ). ENDO-associated pain is now recognized as involving a combination of mechanisms, including pain, fatigue, and psychological distress ( 50 ). Nociceptive pain arises from localized inflammation that activates peripheral sensory neurons near developing lesions ( 50 ). Neuropathic pain , occurs when nerve fibers form on lesions or when nerves are affected by surgical injury ( 50 ). The innervation of the ENDO tissue heightens pain sensitivity across internal organs, leading to chronic pelvic pain, painful periods, painful urination, and painful stools; up to 40% of individuals with ENDO exhibit a neuropathic-like pain component ( 51 ). Additionally, systemic inflammation, mediated by activated white blood cells, can alter central pain processing, resulting in nociplastic pain ( 50 ). This type of pain is associated with widespread body discomfort, fatigue, sleep disturbances, and cognitive impairments ( 52 ). Fibrous adhesions further exacerbate ENDO symptoms by tethering lesions to pelvic organs, increasing both inflammation and mechanical pain ( 12 , 18 ). Given the potential for multiple pain mechanisms to coexist within the same individual, further research is critical to improve clinical assessment and inform tailored, mechanism-specific treatment strategies. This is especially important as pain severity is often not correlated with ENDO stage. The first-line treatment for symptom management of ENDO is hormonal medications, such as combined oral contraceptives and progestin-only options ( 35 ). If these are ineffective or not recommended, second-line treatments include surgical lesion removal (typically via laparoscopy) or other hormonal therapies like gonadotropin-releasing hormone (GnRH) agonists and antagonists. Third-line options involve aromatase inhibitors or hysterectomy with surgical excision of lesions ( 35 ). A meta-analysis of 45 studies examining 16 treatments found GnRH agonists provided the greatest pain relief, followed by combined oral contraceptives with or without GnRH agonists or aromatase inhibitors ( 19 ). However, when these medical treatments were assessed for their efficacy, a substantial proportion of female experienced little to no reduction in pain, with 5%–59% reporting persistent symptoms at the end of treatment and 17%–34% experiencing recurrence after cessation ( 53 ). Discontinuation rates of 5%–16% due to adverse events or lack of efficacy further highlight the burden of side effects and suboptimal therapeutic response. Together, these findings emphasize the shortcomings of existing treatments and reinforce the urgent need for new, more effective approaches to ENDO management. Clinical guidelines and systematic reviews encourage providers to discuss nonmedical strategies that may improve quality of life, including pelvic floor physical therapy, psychological pain interventions, pain education, exercise, dietary changes (e.g., antioxidant use), and acupuncture ( 31 , 54 ). A meta-analysis examining randomized controlled trials found that only two studies provided adjunctive therapies of acupuncture, exercise, electrotherapy, and yoga to complement medical pelvic pain treatment ( 54 ). Despite having limited sample sizes, these trials showed a significant benefit in pain reduction compared with control. Indeed, the adoption of patient-initiated interventions to mitigate pain and/or relief of medication side effects are becoming more common ( 25 ). More than 7 in 10 patients reported using heat and dietary choices such as gluten free or vegan to provide pain relief ( 25 ). However, due to limited evidence with randomized trials, current guidelines do not offer specific recommendations regarding such adjunct treatments. Dietary modifications have emerged as an alternative method to improve ENDO pain. It is postulated that diets with anti-inflammatory properties could reduce systemic inflammation thereby lessen pain ( 25 ). Anti-inflammatory diets, such as the Mediterranean Diet, incorporate nutrient-dense foods rich in antioxidants, omega-3 fatty acids, and polyphenols, all of which reduce pro-inflammatory cytokines and oxidative stress ( 55 ). Additionally, diets that eliminate specific food groups, such as the Low-FODMAP Diet, which restricts consumption of short-chain carbohydrates to support gut health and modulate the immune response, may help to reduce pelvic pain severity. A systematic review of nine dietary interventions in females with ENDO found the Mediterranean diet, low-FODMAP diet, and gluten free diet significantly reduced pain by 25%−50% in as little as 4 weeks; yet these studies were limited with small sample sizes and lack of randomized controlled trials with dietary patterns ( 56 ). However, the Mediterranean Diet and low-FODMAP diet are promising for managing endometriosis because they target key mechanisms underlying pain and inflammation, and, as described in the sections below, each has been shown to offer distinct levels and patterns of pain relief. A summary of the potential mechanisms by which these diets could be used to mitigate ENDO-associated systemic inflammation is illustrated in Figure 2 . The Mediterranean Diet may help reduce inflammation and alleviate pain associated with ENDO through several biologically plausible mechanisms. Rich in omega-3 fatty acids, polyphenols, antioxidants, and fiber, the Mediterranean Diet modulates inflammatory pathways by decreasing pro-inflammatory cytokines, such as IL-6 and TNF-α, while increasing anti-inflammatory mediators ( 57 ). High intake of fruits, vegetables, whole grains, and olive oil also supports gut microbiota diversity, which plays a key role in regulating systemic inflammation ( 57 ). Additionally, omega-3s from fatty fish may compete with arachidonic acid in cell membranes, reducing the synthesis of prostaglandins, a lipid compound elevated in ENDO that promotes pain and lesion growth ( 58 ). The Mediterranean Diet style is known for its anti-inflammatory and antioxidant properties, and is beneficial in mitigating symptoms of various chronic conditions ( 57 , 59 ). Initially recognized for cardiovascular benefits, a Mediterranean Diet also reduces the risk of stroke, obesity, diabetes, cancer, and neurodegenerative diseases ( 59 ). More recently, the Mediterranean Diet has shown promising benefits for patients living with chronic pain ( 60 ). For example, in 84 patients with fibromyalgia, a condition characterized by chronic pain and a notable comorbidity of females with ENDO, a randomized controlled trial reported that adhering to the Mediterranean Diet for 8 weeks resulted in a significant decrease in pain-related disability [F (2,74)=5.5, p<0.01] ( 61 ). Another study in 45 patients (90% female) with rheumatic diseases such as rheumatoid arthritis, fibromyalgia, and osteoarthritis found following a modified Mediterranean Diet (excluding red meat, gluten, and cow’s milk) for four months decreased pain’s perceived effect on physical disability by 60% (p=0.014) and effect on stress by 70% (p=0.01) ( 62 ). Additionally, pain was negatively correlated with anti-inflammatory diet score (rho= −0.32, p=0.03) and the overall dietary score (rho= −0.42, p=0.004). Additionally, the Mediterranean Diet often increases Vitamin D intake, which may be important as a recent analysis of National Health and Nutrition Examination Survey data found a negative correlation between serum 25-hydroxyvitamin D₃ levels and the risk of ENDO ( 63 ). These findings suggest a Mediterranean Diet pattern was significantly associated with reduced pain and stress in diseases associated with chronic pain, suggesting they could aid in managing symptoms of ENDO ( 62 ). Studies testing the effectiveness of Mediterranean Diets in females with ENDO are limited. A meta-analysis of eleven randomized controlled trials involving 716 females with ENDO examined the effectiveness of dietary supplements (i.e., vitamins and minerals) on pain ( 64 ). Of the six randomized controlled trials, including 457 females with ENDO, antioxidant use compared with placebo was associated with a reduction in dysmenorrhea (mean difference [95% CI]: −1.95 [CI 95%, −3.78 to −0.13]). Antioxidant supplementation did not significantly reduce chronic pelvic pain (−2.22 [95% CI, −4.99 to 0.55] or painful urination (−2.56 [95% CI, - 5. 22 to 0.10] ( 64 ). Another prospective observational study of 35 females with ENDO showed that following a personalized Mediterranean Diet prescription for six months significantly reduced dyspareunia in 42% of the sample (p=0.04), non-menstrual pelvic pain in 20% (p=0.06), dyschezia in 60% (p<0.001), and dysuria in 25% (p=0.04) at three months with outcomes remaining stable at six months ( 65 ). The study also demonstrated a significant negative correlation between oxidative stress and Mediterranean Diet score (Neutrophil-Reactive Oxygen Species: rho = −0.55, p = 0.03; Monocyte- Reactive Oxygen Species: rho = −0.66, p = 0.007; Lymphocyte- Reactive Oxygen Species: rho = −0.55, p = 0.03) ( 65 ). These results suggest a potential relationship between adherence to the Mediterranean Diet and pain relief in endometriosis, indicating it may be an effective long-term strategy for managing chronic ENDO-related pain; however, randomized controlled trials are needed to confirm these findings. The low-FODMAP diet may help alleviate inflammation and pain in individuals with ENDO by reducing the intake of short-chain fermentable carbohydrates that contribute to gastrointestinal distress. These short-chain carbohydrates, such as oligosaccharides, disaccharides, monosaccharides, and polyols, can increase gastric water content and gas production through bacterial fermentation ( 66 ). This often leads to bloating, pressure, and visceral hypersensitivity and inflammation. Additionally, the most common location outside of the endometrium for lesion growth is surrounding the intestinal organs, often leading to symptoms like painful bowel movements, constipation, or diarrhea ( 51 ). These symptoms overlap with irritable bowel syndrome (IBS), a chronic digestive disorder causing abdominal pain, bloating, and changes in bowel habits, such as diarrhea or constipation ( 67 ). Approximately 23.4– 47.8% of females with ENDO will have been diagnosed with IBS ( 68 , 69 ), and the similarities in symptoms can impact accurately diagnosing ENDO. By minimizing food triggers, the low-FODMAP diet may reduce gut-related inflammation and lessen the overall pain burden. The Low-FODMAP diet follows three stages: restriction, reintroduction, and personalization to identify individual tolerances ( 67 ). Patients with IBS report significant abdominal pain improvement when adhering to the low-FODMAP diet with 72.1% of patients reporting satisfaction with their symptom reduction ( 67 ). A recent randomized controlled trial in patients with IBS found that following a low-FODMAP diet for 4 weeks led to greater relief of gut symptoms (52% vs. 16%, p=0.007) and significantly higher health-related quality of life scores (81.9 ± 1.2 vs. 78.3 ± 1.2, p=0.042), compared to a control diet ( 70 ). Given that females with ENDO are three times more likely to develop IBS ( 69 ), researchers have explored its potential for ENDO-related symptom relief. An single-arm, non-randomized control study prescribing the Low-FODMAP diet for 4 weeks in 160 patients with IBS with (n=59) or without ENDO (n=101) found that 72% of participants with ENDO reported a >50% improvement in bowel symptoms compared to 49% of participants without ENDO (odds ratio 3.11, [1.5, 6.2]; p=0.001) ( 71 ). Another prospective study in 20 females with ENDO following the LOW-FODMAP for 6 months demonstrated a reduction in bloating (p<0.001), reduced pain during urination (p=0.015), and improvements in overall pain (p=0.007) and work-life quality (p=0.013), suggesting the diet may aid ENDO-associated pain management and improvements in quality of life ( 72 ). These findings highlight the promise of the Low-FODMAP diet as a targeted nutritional strategy for managing gastrointestinal and pain-related symptoms in individuals with endometriosis, though randomized controlled trials are needed to establish its efficacy and long-term benefits. While both the Mediterranean Diet and low-FODMAP diet show promise in managing ENDO-related inflammation and pain, significant gaps remain in our understanding of their long-term efficacy and feasibility in this population ( 73 ). Most existing evidence is observational, with limited randomized controlled trials evaluating whole-diet interventions specific to ENDO. Adoption of the Mediterranean Diet and Low-FODMAP diet is supported mechanistically as they target systemic inflammation, gut permeability, immune dysregulation, and visceral hypersensitivity, key contributors to ENDO-associated pain ( 73 ). However, clinical trials and observational studies are needed to clarify how these dietary strategies modulate these mechanisms in ENDO specifically. Implementing dietary strategies for ENDO requires considering the target population (e.g., disease stage, pain severity), study design, and treatment goals such as pain or fertility outcomes. Because dietary change can be difficult and highly individualized, involvement of a multidisciplinary team, including dietitians, is essential to ensure feasibility, adherence, and effectiveness. Future studies should prioritize appropriately powered, patient-centered trials that assess clinical outcomes, dietary adherence and while also exploring individualized nutrition approaches that integrate these diets into sustainable, long-term management plans.