The interplay between endometriosis and obesity

Endometriosis is a complex disorder where tissue resembling the uterine lining grows outside the uterus, leading to chronic pain, inflammation, and infertility challenges. Despite being documented for over two millennia, its pathophysiology remains only partially understood, with no single hypothesis fully capturing its diverse manifestations. The primary theory, retrograde menstruation (see Glossary ), suggests that menstrual fluid flows into the pelvic cavity, leading to ectopic lesions development on the peritoneal and intestinal mucosa, fallopian tubes, and ovaries [ 1 ]. Yet, this does not explain cases in distant locations ( e . g ., lungs, skin) or in individuals without a uterus, like those with Mayer-Rokitansky-Küster-Hauser syndrome [ 2 ]. Alternative hypotheses, including extrauterine stem cells, hematogenous spread, coelomic metaplasia , and Müllerian remnants , also offer only partial insights [ 3 ]. The development of endometriosis relies on immune evasion , cell adhesion, neurovascular remodeling, and angiogenesis to establish and sustain ectopic growth [ 4 ]. Impaired immune clearance contributed to endometriosis progression, with ectopic tissue inhibiting the cytotoxic activity of natural killer (NK) cells [ 5 ]. Additionally, peritoneal fluid and eutopic endometrial tissue in affected women also exhibited enhanced immunosuppressive properties, further compromising NK cell function compared to controls [ 5 ]. However, the mechanisms by which endometrial cells evade immune surveillance and survive in ectopic lesions remain elusive. Reduced NK cell function, possibly modulated by cytokines such as interleukin-6 (IL-6), IL-10, IL-12, IL-15, and transforming growth factor beta (TGF-β), appears to support ectopic lesions survival [ 6 ]. Altered functions in macrophages, T-cells, and B-cells also suggest an immune dysfunction underlying endometriosis [ 7 ]. In addition, eutopic endometrium from women with endometriosis exhibited increased cellular proliferation and reduced apoptosis, especially during the late secretory and early proliferative phase s of the menstrual cycle [ 8 ], likely due to elevated B-cell lymphoma 2 ( Bcl-2 ) and decreased BCL2-associated X ( BAX ) expression [ 9 ]. This selective inhibition of apoptosis may involve genetic or local cytokine factors. Further survival of ectopic lesions requires adherence to target tissues and vascular support. Endometrial stromal cells readily adhere to the peritoneal mesothelial surface [ 10 ], facilitated by increased expression of adhesion molecules such as integrins and E-cadherin/catenin complexes in affected women [ 11 ]; once adhered, elevated matrix metalloproteinases (MMPs) and reduced MMP inhibitors in endometrial cells promoted invasion into mesothelial tissue [ 12 ]. After attachment and invasion, these cells rely on a new blood supply through angiogenesis to survive. Ectopic lesions have reduced apoptosis and enhanced angiogenic potential, driven by genes like vascular endothelial growth factor-A (VEGF-A), Bcl-2, and Bcl-xL, which support their persistence and growth [ 13 ]. Thus, the role of adhesion molecules in ectopic tissue stability and the therapeutic potential of targeting these molecules warrants further exploration. Beyond cellular adhesion and invasion, systemic, metabolic, and inflammatory factors also influence the endometriotic microenvironment. Growing evidence suggests that body composition, both low body mass index (BMI) and obesity, influences disease progression by modulating chronic inflammation, hormonal balance, and immune responses [ 14 ]. As research continues to uncover these complex interactions, integrating metabolic health into the broader understanding of endometriosis provides a more comprehensive view of its pathophysiology. As such, this review will summarize emerging epidemiological, molecular, and clinical findings, providing critical insights that may refine the diagnosis, management, and treatment of endometriosis. Endometriosis development results from a complex interplay of reproductive, environmental, lifestyle, and molecular factors. An overview of these factors, along with the associated hormonal and molecular changes, is compiled in Figure 1 . Early menarche, severe cramps, and heavy menstrual flow have been linked to increased risk, whereas multiparity may reduce the prevalence [ 15 ]. Additionally, increased ovulation frequency has been correlated with the disease [ 16 ]. However, these associations remain inconsistent, highlighting the need for further studies with larger, more diverse samples, including asymptomatic cases, to clarify their significance. Several environmental and lifestyle factors also impact endometriosis risk. While height, waist/hip ratio, and caffeine intake showed no link, age, race, body composition, and alcohol use were associated with increased risk [ 17 ]. Endometriosis affects an estimated 5% to 15% of individuals of reproductive age, with a lower occurrence in postmenopausal women ranging from 2% to 5% [ 18 ]. Body composition plays a complex role, as both low BMI and obesity potentially influence disease risk through mechanisms explored in later sections. Conversely, smoking demonstrated an inverse association, potentially due to its anti-estrogenic effects, manipulation of prostaglandin production, and activation of cholinergic receptors [ 19 ]. Physical activity shows mixed associations, with one study [ 20 ] finding up to an 80% reduced risk of endometriosis with regular exercise, while another [ 21 ] observed a modest inverse association. It has been suggested that most of the earlier case-control studies may have been biased, as symptoms could reduce activity levels [ 21 ]. Despite this, regular exercise remains beneficial, and practices like Hatha yoga and muscle relaxation are suggested to reduce pain and stress in patients with endometriosis. Emerging evidence highlights the impact of endocrine-disrupting chemicals (EDCs) such as bisphenol A (BPA), dioxins (TCDD), polychlorinated biphenyls (PCBs), and phthalates on endometriosis risk, as these environmental pollutants disrupt the hormonal balance by mimicking or antagonizing endogenous estrogen and other steroid hormones [ 22 ]. Exposure to TCDD and PCBs is associated with an increased prevalence of endometriosis, potentially through their ability to promote inflammation and alter immune function [ 23 ]. Similarly, BPA, a common plasticizer, has been linked to epigenetic changes that may contribute to establishing and progressing endometriotic lesions [ 22 ]; epidemiological studies have shown a significant association between high BPA exposure and increased odds of endometriosis [ 24 ]. At the molecular level, both BPA and phthalates disrupt estrogen signaling and inflammatory pathways, which are critical in the pathogenesis of endometriosis [ 24 ]. Given that endometriosis is an estrogen-dependent disease, the role of EDCs in disrupting hormonal signaling and promoting aberrant inflammatory responses requires further investigation. Sun exposure and skin sensitivity are additional factors, with individuals with endometriosis reported higher photosensitivity and sun avoidance [ 25 ]. Similarly, another study linked endometriosis risk to skin sensitivity, freckles, and naevi, suggesting a genetic links between endometriosis and pigmentation traits, warranting further investigation [ 26 ]. Familial and genetic factors further contribute to endometriosis risk, as seen in both humans and Rhesus monkeys [ 27 ]. The risk is estimated to be seven times higher for mothers and sisters of affected individuals [ 28 ], while daughters face a two-fold increased risk [ 29 ]. Genome-wide association studies have identified polygenic risk factors, with multiple single nucleotide polymorphisms contributing modest effects [ 27 ]. It is important to note that the increased hereditary risk of endometriosis likely arises from a variety of genetic variations, each with modest individual effects. While genetic factors play a complex role, recent research underscores the growing importance of epigenetics in endometriosis. Epigenetic enzymes, including DNA methyltransferases and histone deacetylases, impact molecular changes in the eutopic endometrium and ectopic lesions, especially in sex steroid signaling pathways [ 30 ]. miRNAs are also increasingly recognized for their regulatory roles in these changes [ 30 ]. Since epigenetic changes are heritable yet reversible, understanding these mechanisms could provide promising therapeutic strategies for endometriosis treatment. There is still no cure for endometriosis, making it essential to understand its risk factors to guide informed decisions based on evidence rather than assumptions. While obesity is a well-known health risk, an exceptionally low BMI may also indicate underlying health concerns, including an increased susceptibility to endometriosis. But how does body composition shape the narrative of endometriosis? The relationship is far from straightforward. Research reveals intriguing patterns: a low BMI appears linked to a higher risk of endometriosis, while obesity correlates with a lower incidence but more advanced disease stages. Adding to the complexity, some studies find no clear connection between BMI and endometriosis at all. Although BMI is widely used, alternative anthropometric measures such as waist-to-hip ratio and body adiposity content may provide further insights into the relationship between obesity and endometriosis [ 31 ]. However, current studies remain limited, underscoring the need for further research into these parameters. Table 1 comprehensively summarizes human and preclinical animal studies, highlighting the complex relationship between obesity, BMI, and endometriosis. Earlier studies report an inverse relationship between BMI and endometriosis [ 32 ], with very low BMI (<18.5) linked to a higher risk of deep infiltrating endometriosis [ 33 ]. However, many of these studies rely on self-reported diagnoses, introducing potential bias [ 34 ], and the lack of ideal control groups also complicates the interpretation. Chronic pain associated with endometriosis may suppress appetite, while gastrointestinal side effects of non-steroidal anti-inflammatory drugs , a common therapy, could reduce food tolerance and contribute to weight loss [ 35 ]. These observations suggest that the BMI-endometriosis relationship is more complex than a simple inverse association, inquiring a reevaluation of whether low BMI is causal or consequential. Conversely, population-based studies from Australia, Sweden, Israel, and China have reported fewer endometriosis cases in individuals with low BMI than those with normal or high BMI ( Table 1 ). Some studies found no correlation, while others suggest obesity correlates with a lower incidence of endometriosis ( Table 1 ). This is debated since endometriosis is an estrogen-dependent condition, and excess body fat elevates estrogen levels, potentially fueling the inflammatory processes involved in its progression [ 36 ]. By contrast, it was hypothesized that elevated estrogen in obesity might disrupt ovulation, shortening menstrual cycles and reducing endometriosis risk; however, no statistical link between BMI and cycle length was found [ 37 ]. A possible mechanism linking obesity, dysfunctional adipose tissue, and endometriosis is presented in Figure 2 . Hospital-based studies further complicate the picture. In the Korean population, low BMI was associated with increased endometriosis-related pain [ 38 ], suggesting women with obesity may experience fewer symptoms and undergo fewer surgical procedures, reducing laparoscopic diagnoses. Women with obesity often exhibit higher revised American Society for Reproductive Medicine (rASRM) scores and increased post-operative recurrence rates [ 39 ]. The evidence further supports the link between body composition and endometriosis severity, showing that severe ureteral endometriosis is more common in women with lower BMI [ 40 ]. While obesity is often linked to advanced disease stages, lower BMI may also contribute to increased risk in specific subtypes of endometriosis, such as deep infiltrating endometriosis with ureteral compression. These findings emphasize the complexity of the obesity-endometriosis relationship and the need for a nuanced understanding of how body composition influences disease progression. Diagnostic delays further affect the overall outcomes of the disease. In an analysis of surgically diagnosed patients, categorized by BMI and time to diagnosis, patients with obesity faced the longest delays, averaging 18.4 months, compared to 9.0 months for overweight and 3.8 months for normal/underweight patients [ 41 ]. This highlights a potential link between increasing BMI and longer diagnostic times, possibly reflecting more severe disease. Supporting this, patients with a BMI > 30 kg/m 2 often have more severe forms of the disease [ 42 ], potentially due to hesitancy to undergo surgery or less detectable lesions on ultrasound. Moreover, women with obesity are more frequently diagnosed with superficial peritoneal endometriosis, while underweight women were more likely to have deep infiltrating endometriosis [ 43 ]. Endometriosis is linked to a hyperestrogenic state, with adipose tissue playing a critical role in estrogen production. Although lower BMI is often linked to endometriosis, obesity is not protective and may exacerbate symptoms through adipose tissue dysfunction, inflammation, and altered immune responses. Animal models offer a controlled environment to investigate how obesity and dietary factors drive endometriosis progression, providing valuable insights that enhance and broaden our understanding of this complex relationship. In mice, a high-fat diet worsens endometriosis by increasing lesion numbers and inflammation, independent of weight gain [ 44 ]. Moreover, endometriosis has been linked to liver metabolic dysregulation, contributing to reduced body weight and fat, similar to patterns observed in affected women [ 45 ]. Furthermore, endometriosis-related microRNAs disrupt adipocyte metabolism, reducing fat storage and contributing to disease progression [ 46 ]. Obesity-induced metabolic changes, such as altered adipocyte function and inflammation, exacerbate endometriosis by initiating a pro-inflammatory environment that accelerates lesion development [ 47 ]. Obesity can further disrupt key physiological processes, impairing endometrial repair by reducing cell proliferation and promoting inflammation [ 48 ]. It also affects decidualization in both mice and human endometrial cells, linking high BMI to poor reproductive outcomes [ 14 ]. Collectively, these findings underscore the complex interplay between diet, obesity, and disease mechanisms in endometriosis. Although low BMI is common in women with endometriosis due to disease-driven metabolic changes, higher BMI exacerbates outcomes by promoting inflammation and impairing reproductive health. This highlights the need for further research into how metabolic dysfunction influences endometriosis progression and severity. Identifying transcriptomic and proteomic overlaps between endometriosis and obesity is key to understanding molecular interactions that worsen disease severity. Shared pathways and biomarkers, such as inflammation, immune response, and metabolic dysregulation, offer insights for early detection and therapeutic intervention. Pro-inflammatory cytokines such as IL-6 and TNF-α, elevated in obesity, are also found in the ectopic microenvironment, while oxidative stress links adipose tissue dysfunction in obesity to ectopic endometrial tissue in endometriosis [ 61 ]. On the other hand, genes involved in lipid metabolism, insulin resistance, and adipogenesis are dysregulated in both diseases, further highlighting a metabolic connection [ 62 ]. Proteomic studies have identified upregulated proteins involved in extracellular matrix remodeling and angiogenesis—key processes in both conditions [ 63 ]. These findings suggest obesity may worsen endometriosis via shared inflammatory and metabolic pathways. Moreover, genetic loci ( e . g ., 7p15.2, KIFAP3, WNT4) have been linked to both endometriosis and obesity-related fat distribution, emphasizing fat distribution as a key factor influencing both conditions [ 64 ]. Although limited, emerging research highlights the potential of targeting shared pathways to mitigate the reciprocal impact of obesity and endometriosis, facilitating the development of personalized treatments. Leptin, a cytokine secreted by adipose tissue, regulates energy balance by suppressing hunger and reflects body fat mass under stable weight conditions [ 65 ]. Beyond energy regulation, leptin influences immune, inflammatory, and angiogenic responses, potentially contributing to the pathophysiology of endometriosis [ 66 ], though the mechanisms remain unclear. Table 2 highlights evidence from human studies linking obesity-driven leptin signaling to endometriosis progression. It is important to note that while elevated leptin levels were frequently observed in patients with endometriosis, results varied, and BMI differences were generally minor. Common limitations included small sample sizes and inconsistent inclusion of healthy controls, emphasizing the need for standardized, large-scale studies. Comparing women with endometriosis to controls, elevated leptin levels were reported in the peritoneal and follicular fluids of those with endometriosis, though no significant differences were observed in serum or plasma leptin levels [ 67 ]. Further analysis of peritoneal fluid samples revealed no variation in leptin concentrations between stages 1–2 and 3–4 of endometriosis, suggesting leptin acts locally regardless of disease severity [ 67 ]. A sub-analysis of 14 studies adjusting for BMI showed significantly higher leptin levels in endometriosis patients, with an increased leptin/BMI ratio in peritoneal fluid [ 68 ], while other studies reported no overall difference [ 49 ]. Notably, a lower leptin/BMI ratio was observed in patients with primary infertility, though this was limited by a small sample size [ 49 ]. These findings highlight the complex role of leptin in endometriosis, emphasizing its localized activity in the peritoneal environment and its potential links to BMI and infertility. The leptin/BMI ratio, a measure of leptin efficiency relative to body fat, is useful for identifying leptin resistance. Elevated leptin levels may indicate increased inflammatory responses or metabolic stress, while leptin resistance may stem from downregulated leptin receptor (Ob-R) genes in endometriosis [ 69 ]. Despite its potential clinical value, limited research has produced inconsistent findings, emphasizing the need for further studies to understand the leptin/BMI ratio’s role in disease progression and therapeutic applications. Leptin signals through its receptor, Ob-R, primarily via the JAK-STAT pathway. Upon binding, JAK2 activates STAT3, which regulates genes involved in inflammation, cell proliferation, and angiogenesis [ 70 ]. In endometriosis, excessive STAT3 activation may drive abnormal endometrial cell proliferation and invasion [ 70 , 71 ]. Additionally, leptin-induced VEGF expression and PI3K-Akt pathway activation contribute to angiogenesis and disease progression, while inflammatory responses in adipose tissue and immune cell activation exacerbate the condition [ 72 ]. Additionally, the shift in macrophage polarization from an anti-inflammatory to a pro-inflammatory phenotype, along with increased adipocytokines such as TNF-α and IL-6 and systemic metabolic dysfunction, further contributes to disease progression [ 73 ]. A proposed model illustrating the Ob-R, its downstream signaling pathways, and their association with endometriosis is shown in Figure 2 . Animal models also highlight the role of leptin in endometriosis and obesity. Leptin and its receptor are essential for disease progression, with obesity exacerbating endometriosis by increasing leptin levels [ 74 ]. Leptin produced by ectopic endometrial tissue contributes to chronic pain in an estrogen-dependent manner, underscoring the interplay between reproductive hormones, leptin’s inflammatory effects, and the increased severity of endometriosis in individuals with obesity [ 75 ]. Moreover, leptin receptor overexpression in ectopic tissues drives cell proliferation via the JAK2/STAT3 and ERK pathways [ 76 ]. Additionally, disrupting leptin signaling reduced lesion formation, angiogenesis, and inflammation in murine models, underscoring leptin’s role in lesion development and maintenance [ 77 ]. In conclusion, evidence from human and preclinical studies proposes leptin as a key mediator linking obesity and endometriosis. Leptin contributes to lesion formation, maintenance, pain, and inflammation, highlighting obesity as a significant risk factor for disease progression. Therefore, targeting leptin pathways, such as JAK2/STAT3 and ERK, may offer promising therapeutic opportunities to mitigate obesity’s impact on endometriosis and enable personalized treatment based on metabolic profiles. Exploring obesity as a modifiable factor presents a compelling strategy to improve endometriosis management and outcomes. Therapeutic interventions such as lifestyle changes, bariatric surgery, and pharmacotherapy can alleviate endometriosis symptoms by reducing systemic inflammation, correcting metabolic imbalances, and regulating hormonal profiles. Structured diet and exercise programs not only promote weight loss but also lower inflammation and improve insulin sensitivity, both critical in endometriosis pathophysiology [ 92 ]. These interventions can also alleviate chronic pain and enhance overall well-being. Bariatric surgery, often recommended for severe obesity, has demonstrated significant weight loss, reduced estrogen levels, and improved inflammatory markers [ 93 ]. These metabolic shifts may help reduce lesion progression and pain severity in endometriosis [ 93 ], though further clinical research is warranted to establish direct benefits. Similarly, pharmacological therapies such as glucagon-like peptide-1 receptor agonists aid in weight management, modulate metabolic health, and decrease adipose-driven inflammation and leptin levels, key contributors to endometriosis progression [ 94 ]. Targeting JAK2/STAT3 and ERK signaling is a promising therapeutic strategy for endometriosis and obesity-related inflammation [ 95 ]. Obesity-driven leptin overexpression activates these pathways, promoting chronic inflammation, angiogenesis, and lesion growth. JAK2/STAT3 inhibition with Tofacitinib reduces lesion size and adhesion formation by suppressing STAT3 phosphorylation, HIF-1α, and VEGF, key regulators of vascularization and lesion progression [ 71 ]. Given that obesity-induced adipose tissue dysfunction fosters a pro-inflammatory state and elevated estrogen production [ 73 ], controlling obesity-related inflammatory pathways may help mitigate lesion development and disease severity. Additionally, nanoceria, non-steroidal anti-inflammatory nano-drugs, mitigate oxidative stress and inflammation while shifting macrophages from a pro-inflammatory to an anti-inflammatory phenotype, thereby regulating immune-driven disease progression [ 70 ]. Since obesity amplifies STAT3 activation, chronic inflammation, and macrophage dysregulation, therapies like nanoceria and JAK2/STAT3 inhibitors could counteract obesity-driven inflammation and reduce lesion burden in individuals with endometriosis ( Figure 2 ). Further, WP1066, another JAK2/STAT3 inhibitor, has demonstrated to suppress endometrial stromal cell proliferation and invasion by inhibiting hypoxia-induced angiogenesis [ 96 ]. Similarly, ERK pathway inhibitors (PD98059 and U0126) effectively reduce endometriotic cell proliferation, presenting an additional viable approach for controlling disease progression [ 97 ]. Given the overlapping inflammatory pathways in obesity and endometriosis, these targeted interventions hold the potential for modulating systemic inflammation and improving patient outcomes. However, further clinical validation is required to confirm their long-term efficacy and safety. Future research should elucidate the molecular connections between obesity, immune modulation, and endometriosis pathogenesis. Special emphasis should be placed on leptin signaling, adipokines, and macrophage-driven inflammation as potential therapeutic targets. Investigating the direct impact of these interventions on lesion size, pain, and fertility will be essential for optimizing personalized treatment strategies. Integrating obesity management into comprehensive endometriosis care may provide a multifaceted approach to improving patient outcomes. Endometriosis is a complex disease influenced by immune dysfunction, metabolic alterations, and chronic inflammation. While research has advanced our understanding, significant gaps remain in uncovering the immune evasion mechanisms of ectopic lesions, the role of adipose tissue dysfunction, and the metabolic interplay between obesity and disease progression (see Outstanding Questions ). Body composition significantly impacts disease severity, with both low BMI and obesity contributing through distinct mechanisms. Obesity-driven metabolic dysfunction intensifies systemic inflammation, while leptin signaling promotes angiogenesis, lesion survival, and chronic pain. Therefore, investigating how adipose tissue-derived cytokines and oxidative stress sustain lesion persistence is essential for identifying new metabolic and immunomodulatory targets. Additionally, the long-term effects of obesity-targeted interventions on endometriosis outcomes remain unclear and warrant further investigation. Future research should explore how ectopic lesions escape immune clearance, focusing on cytokine networks, immune cell dysfunction, and genetic factors that drive chronic inflammation. Investigating leptin-mediated JAK-STAT and ERK pathways could provide new opportunities for endometriosis therapy. Large-scale, population-based studies are also needed to better define the relationships among BMI, lifestyle factors, and disease risk, particularly in understanding diagnostic delays and cultural differences in disease perception. Indeed, a multidisciplinary approach integrating molecular research, metabolic profiling, and personalized medicine is essential for advancing new treatment strategies. Expanding knowledge of the complex interactions between metabolism, immunity, and endometriosis will enable more precise and effective therapeutic interventions. Ultimately, combining scientific research, clinical innovation, and holistic care is critical for improving patient outcomes and enhancing the quality of life for those affected by endometriosis.