{"paper_id":"5889061d-03aa-4a45-8162-f3ef7eeab2c8","body_text":"ACCEPTED MANUSCRIPT \n \nAnn. Acad. Med. Siles. (Online) 2026; DOI: 10.18794/aams/222342 \nReview \n \nEndometriosis as a systemic disease  \nwith neuroimmunological and tumor-like features:  \nA review of current pathophysiological mechanisms \n \n \nKornelia Gawarecka, Katarzyna Gałka \n \n \n \nStudents of the Faculty of Medical Sciences in Zabrze,  \nMedical University of Silesia, Katowice, Poland \n \n \n \n \nAddress for correspondence: \nKornelia Gawarecka \ne-mail: korneliagawarecka@gmail.com \n \n \n \n \n \n \n \n \n \n \n \n \n \n \nReceived: 08.05.2026, Revised: 11.05.2026, Accepted: 22.05.2026, Published: June 2026 \nThis is an open access article made available under the terms of the Creative Commons Attribution-ShareAlike 4.0 International (CC BY-SA 4.0) \nlicense, which defines the rules for its use. It is allowed to copy, alter, distribute and present the work for any purpose, even commercially, provided \nthat appropriate credit is given to the author and that the user indicates whether the publication has been modified, and when processing or \ncreating based on the work, you must share your work under the same license as the original. The full terms of this license are available at \nhttps://creativecommons.org/licenses/by-sa/4.0/legalcode. \n© Copyright by Author(s) \nPublisher: Medical University of Silesia, Katowice, Poland \n \n \n\n\nABSTRACT  \nEndometriosis is among the most common gynecological disorders, affecting an estimated 10% of \nwomen of reproductive age. In clinical practice, it primarily manifests as chronic pelvic pain and \ninfertility, significantly impairing patients’ daily functioning. Its pathophysiology is complex and \ninvolves both local and systemic processes. The mechanisms underlying pain in endometriosis are \nmultifaceted and not limited solely to the presence of ectopic lesions. Both peripheral \nsensitization and alterations within the central nervous system play a crucial role, often \naccompanied by neurogenic inflammation and the development of new blood vessels and nerve \nfibers. Increasing attention is being paid to immunological mechanisms, particularly the role of \nmacrophages with high phenotypic plasticity, which contribute to the persistence of chronic \ninflammation and support the growth and invasion of endometriotic cells. Endometriosis exhibits \nnumerous features in common with neoplastic processes, including the ability to proliferate under \nhypoxic conditions, invasiveness, and the induction of angiogenesis and neurogenesis. A better \nunderstanding of these mechanisms may, in the future, enable the development of therapies \ntargeting the underlying causes of the disease rather than merely alleviating its symptoms. \nKEYWORDS \nmacrophages, endometriosis, chronic pelvic pain, women’s quality of life, chronic inflammation, \ncentral sensitization, neuroangiogenesis \nIntroduction \nEndometriosis is a chronic, estrogen-dependent gynaecological condition in which tissue similar to \nthe endometrium grows outside the uterine cavity. This ectopic tissue, consisting of both glandular \nand stromal components, can appear in different parts of the body. It is most often found in the \novaries and peritoneum, but may also involve the gastrointestinal and urinary systems, and in \nrarer cases the thoracic cavity [1,2,3]. Although located outside the uterus, these cells remain \nhormonally active and respond to the cyclical changes of the menstrual cycle. This can result in \nrepeated bleeding, ongoing inflammation, progressive fibrosis, and the development of adhesions \nand scar tissue over time. Consequently, the disease is multifocal, polymorphic, and progressive in \nnature, while its ethology remains incompletely understood. In clinical practice, endometriosis is \nestimated to affect approximately 10% of women of reproductive age, corresponding to over 190 \nmillion women worldwide [4]. In Europe, the prevalence is similar; however, the true scale of the \nproblem may be underestimated due to a large number of undiagnosed cases. The incidence is \nhigher in selected patient groups-particularly among women with dysmenorrhea, infertility, and \nchronic pelvic pain [5]. Despite its high prevalence, endometriosis remains a challenging condition \n\nto diagnose. A characteristic feature is a delay in diagnosis, which may range from several to even \nmore than a decade after the onset of symptoms. The delay in diagnosing endometriosis is \ninfluenced by several factors. Symptoms are often non-specific and vary widely in intensity, which \ncan lead to them being overlooked or mistaken as “normal” menstrual discomfort. This is further \nreinforced by persistent social and cultural beliefs that tend to normalise or minimise period pain. \nAnother challenge is the absence of reliable, non-invasive diagnostic markers [6]. As a result, a \ndefinitive diagnosis frequently requires surgical confirmation, even though lesions may also be \npresent in women without any symptoms. It is estimated that endometriosis is identified in up to \n50% of patients investigated for infertility [6]. Traditional explanations of its development mainly \nfocus on the theory of retrograde menstruation, where endometrial cells travel backwards \nthrough the fallopian tubes and implant outside the uterus. However, this theory does not fully \naccount for the wide range of clinical manifestations, particularly chronic pain and the frequent \ncoexistence of other conditions [7]. More recently, endometriosis has increasingly been viewed as \na systemic disorder rather than a purely local one. Research highlights the role of \nneuroimmunological dysregulation, altered pain perception, and biological processes that in some \nways resemble tumour-like behaviour, helping to better explain its complexity. These include, \namong others, uncontrolled cellular proliferation and angiogenesis. In this context, peripheral and \ncentral sensitisation phenomena are of particular importance, as they contribute to pain \npersistence and disease progression [8]. At the same time, endometriosis shares several \ncharacteristics with neoplastic processes, including tissue invasiveness, the ability to establish a \ndistinct local microenvironment, and mechanisms of immune evasion. For this reason, it is \nsometimes described as a pseudoneoplastic condition. The disease also has a profound impact on \npatients’ daily functioning. It can significantly reduce quality of life, limit professional and social \nactivity, and increase the risk of developing emotional disorders [9]. Despite many years of \nresearch, endometriosis remains conceptually fragmented, which highlights the need for a more \ncoherent and integrative framework. In response to this gap, we propose a unified model that \nviews endometriosis as a neuroimmunoendocrine systemic disorder, driven by self-sustaining \nfeedback loops between inflammation, neural sensitisation, and hormonal dysregulation. \nMethodology \nThis narrative review aims to discuss current knowledge regarding the pathophysiological \nmechanisms of endometriosis, with particular emphasis on its potential systemic nature and the \nrole of neuroimmunological and pseudoneoplastic processes in disease development and \nprogression. Particular attention was given to the interactions between chronic inflammation, \nimmune dysregulation, hormonal alterations, and mechanisms of central and peripheral \n\nsensitisation, as well as their influence on the persistence of ectopic endometrial lesions and the \ndevelopment of chronic pain. The review also explores the potential involvement of the \nhypothalamic-pituitary-adrenal (HPA) axis, gut–brain interactions, and cancer-like biological \nbehaviour in the broader understanding of endometriosis as a multi-system disorder. The \nliterature analysed in this review was identified through searches of the PubMed, Scopus, and \nGoogle Scholar databases. Publications from 2008 to 2024 were considered, with particular \nemphasis placed on studies published after 2020 due to the growing body of research concerning \nthe molecular, neuroimmunological, and systemic mechanisms of endometriosis. Earlier \npublications were included primarily to provide historical background and establish the \nfoundations of currently accepted theories of pathogenesis. The literature search was conducted \nbetween 3 and 7 April 2026 using combinations of the following keywords: endometriosis, central \nsensitisation, immune system, chronic pelvic pain, macrophages, multi-system disease, quality of \nlife, IBS, cancer, gut–brain axis, HPA axis, meta-analysis, and pathophysiology review. Additional \nrelevant publications were identified through manual screening of the reference lists of selected \narticles. Only peer-reviewed articles published in English and available in full-text form were \nconsidered. The inclusion criteria were defined according to the PICO framework as illustrated in \nFigure 1. The review included original research articles, clinical and observational studies, review \narticles, systematic reviews, and meta-analyses addressing the pathophysiological mechanisms of \nendometriosis. Studies unrelated to disease mechanisms or focused on unrelated medical \nconditions without a clear connection to endometriosis were excluded. Due to the narrative \nnature of this review, a formal systematic selection process and quantitative risk-of-bias \nassessment were not performed. Instead, the included studies were evaluated qualitatively based \non their relevance, methodological transparency, scientific contribution, and consistency with the \nscope of the review. The collected literature was analysed thematically. The findings were \norganised into major conceptual areas, including inflammatory and immunological mechanisms, \nneuroimmune interactions, central pain sensitisation, endocrine dysregulation, gut–brain axis \ninvolvement, and pseudoneoplastic features of endometriosis. Particular emphasis was placed on \nidentifying recurring biological patterns, overlaps between different pathophysiological pathways, \nand current gaps in understanding the systemic nature of the disease. This review has several \nlimitations. The search was limited to three databases and to English-language full-text \npublications, which may have resulted in the omission of potentially relevant studies. \nFurthermore, the heterogeneity of the included literature and the narrative nature of the review \nmay introduce a degree of interpretative subjectivity. Nevertheless, this approach enabled a broad \nand integrative discussion of the multifactorial mechanisms involved in endometriosis. \n\n \n \nFig. 1. PICO framework used to structure the research question on the pathophysiological mechanisms of \nendometriosis \nPathogenesis of endometriosis – biological basis \nEndometriosis is a disease with a complex and multifactorial ethology, strongly dependent on \nestrogen, and characterised by the presence of endometrium-like tissue outside the uterine cavity \n[6,10]. Contemporary models of pathogenesis indicate that it is not a single disease entity, but \nrather a spectrum of processes involving migration of endometrial cells, metaplastic \ntransformation, and the involvement of progenitor cells [10,11]. The most widely cited pathogenic \n\n\nmodel is retrograde menstruation, which posits that viable endometrial cells are refluxed through \nthe fallopian tubes into the peritoneal cavity during menses, where they can adhere, invade, and \nestablish ectopic lesions [10,12]. However, because retrograde menstruation occurs \nphysiologically in a substantial proportion of menstruating individuals, its presence alone is \ninsufficient to explain disease development. This discrepancy implicates additional contributory \nmechanisms, including impaired immune surveillance and clearance, genetic susceptibility, and \nintrinsic molecular or phenotypic abnormalities of eutopic endometrial tissue that enhance \nectopic implantation and survival [10,12]. The characteristic distribution of lesions in pelvic \ncompartments-particularly the pouch of Douglas, uterosacral ligaments, and ovarian fossa-further \nsupports the hypothesis of gravitational and fluid-dynamic deposition of refluxed cells in \ndependent peritoneal regions where peritoneal fluid tends to accumulate [10]. An alternative \nhypothesis is coelomic metaplasia, which proposes that multi-potent cells within the coelomic \nepithelium or peritoneum may undergo metaplastic transformation into endometrial-like tissue in \nresponse to hormonal signalling or other local microenvironmental stimuli [6,12]. This mechanism \nmay explain the presence of lesions in locations where retrograde transport is unlikely; however, it \ndoes not account for all clinical forms of the disease [12]. Increasing importance is also attributed \nto the stem cell hypothesis, according to which lesions may originate from endometrial progenitor \ncells or bone marrow-derived cells [10,11]. Stem cells have the capacity for self-renewal and \ndifferentiation, which may allow them to survive in ectopic sites and contribute to the formation \nof stable endometriotic lesions [11]. This model may help explain both the biological \nheterogeneity of endometriotic lesions and their presence in distant anatomical locations outside \nthe pelvis [11]. \nAnother explanatory framework is the “tissue injury and repair” (TIAR) hypothesis (Figure 2). \nAccording to this model, endometriosis may originate from repeated injury to the junctional zone \nbetween the endometrium and myometrium, often associated with abnormal uterine peristalsis \n[13]. This tissue damage can trigger a local inflammatory response, increase aromatase expression, \nand enhance estrogen production, thereby promoting the proliferation and persistence of \nendometrial tissue [13]. Hypoxia-related pathways, including activation of hypoxia-inducible factor \n1-alpha (HIF-1α), may further support tissue remodelling, angiogenesis, and lesion survival [13]. \nEndometriosis is also strongly shaped by the hormonal environment, particularly by oestrogens, \nwhich stimulate the growth of ectopic endometrial tissue and amplify inflammatory processes \n[6,11]. In many lesions, estrogen can be produced locally, resulting in increased tissue-level \nestrogen activity that is partly independent of the hypothalamic-pituitary-ovarian (HPO) axis [11]. \nAt the same time, progesterone resistance reduces the normal anti-inflammatory and anti-\n\nproliferative effects of progesterone, thereby favouring the persistence of biologically active \nectopic tissue [11]. According to newer concepts, endometriosis may represent a systemic disease \nin which lesions spread via lymphatic and hematogenous routes, rather than exclusively through \nlocal implantation [13]. The presence of lesions in lymph nodes and distant organs supports this \nhypothesis [13]. It has been demonstrated that endometriotic lesions contain not only \nendometrial cells but also smooth muscle cells, giving them characteristics of structures \nresembling “miniature uteri” responsive to steroid hormones [13]. This suggests the involvement \nof pluripotent cells and processes of smooth muscle metaplasia in disease pathogenesis [13]. \nGenetic and epigenetic factors also play a significant role in susceptibility to endometriosis and its \nclinical course [6,13]. Familial aggregation of the disease has been observed, along with numerous \ngenetic variants associated with increased risk [13]. Environmental factors, particularly exposure \nto endocrine-disrupting chemicals, may further modulate gene expression through epigenetic \nmechanisms [13]. Dysfunction of the immune system plays a pivotal role in this context, serving as \na central nexus that integrates inflammatory, hormonal, and molecular processes. Impaired \nimmune surveillance not only facilitates the survival of ectopic endometrial cells but also actively \nsculpts the disease microenvironment, thereby driving progression and sustaining chronic \ninflammation. \n\n \nFig. 2. Mechanism of the “tissue injury and repair” model. Simplified representation of the local hormonal-\ninflammatory mechanism in endometriosis \nThe role of the immune system in the pathogenesis of endometriosis \nCurrent evidence demonstrates that hormonal mechanisms alone are insufficient to explain the \ndevelopment of the disease, and that dysfunction of the immune system plays a significant role, \nleading to abnormal interactions between endometrial cells and immune cells [14,15]. In the \nperitoneal cavity, a state of chronic activation of inflammatory cells is maintained, accompanied by \nincreased production of mediators that promote the survival and implantation of endometrial cells \nin ectopic locations [14]. A particularly important role is attributed to macrophages, which \nundergo functional reprogramming in the endometriotic environment. They exhibit both increased \nsecretory activity and a reduced capacity for phagocytosis. This leads to a weakening of their \nprotective functions and a shift toward supporting disease processes. These cells also participate \nin tissue remodelling and angiogenesis, thereby promoting the persistence and progression of \nendometrial lesions. They may also acquire properties of long-term immune memory, which may \n\n\ncontribute to the chronicity of inflammation [16,17]. Reduced cytotoxic activity of natural killer \n(NK) cells limits the effectiveness of natural mechanisms for eliminating ectopic cells and enables \ntheir continued survival [14,15]. In endometriosis, disturbances in adaptive immunity are also \nobserved, including impaired activity of T lymphocytes. A shift in the balance between Th1, Th2, \nand Th17 responses is noted, resulting in the predominance of an environment that promotes \nchronic inflammation and weakens the effector mechanisms of the immune response [14]. \nIncreased activity of regulatory T cells (Treg) contributes to suppression of the immune response \nagainst endometrial cells, facilitating their survival in ectopic locations [15]. A key element of \nendometriosis pathogenesis is also the dysregulation of cytokine function. Elevated levels of pro-\ninflammatory cytokines sustain inflammation, support cell proliferation, and enhance angiogenesis \n[15]. Interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) are involved in maintaining \nchronic inflammatory activation and support the survival of endometrial cells, while interleukin-8 \n(IL-8) plays a role in angiogenesis. At the same time, immunosuppressive cytokines such as IL-10 \nand transforming growth factor-beta (TGF-β) promote the formation of a tolerogenic environment \n[14,15]. Endometriosis is also associated with mechanisms that enable endometrial cells to evade \nimmune responses. This includes both impaired function of effector cells and increased activity of \nimmunosuppressive mechanisms, including Treg cells and anti-inflammatory cytokines [14,15]. \nAdditionally, macrophages with an altered phenotype support angiogenesis and tissue \nremodelling processes [16,17]. As a result, the immune system, instead of eliminating ectopic \ncells, contributes to the creation of an environment that favours disease development. Chronic \ninflammation and persistent activation of immune cells significantly affect the nervous system. \nInflammatory mediators present in the endometriotic microenvironment may act on nerve fibres, \nincreasing their excitability and initiating sensitisation processes. Immunological mechanisms thus \nlink disease pathogenesis with the development of chronic pain. \nNeurobiological mechanisms of pain in endometriosis \nThe primary symptom that reduces the quality of life in patients with endometriosis is chronic \npelvic pain [18]. The clinical presentation of pain is heterogeneous and includes, among others, \ndysmenorrhea, dyspareunia, and pain associated with urination or defecation [18]. The severity of \npain symptoms is often not proportional to the extent of pathological lesions, suggesting the \ninvolvement of mechanisms beyond the mere presence of disease foci [19]. The frequent \ncoexistence of other chronic pain syndromes, such as IBS or vulvodynia, suggests a shared \npathophysiological basis related to dysfunction in pain processing [19]. Persistence of pain leads to \nsecondary changes in the central nervous system [20]. Central sensitisation is a key mechanism \nresponsible for the chronic nature of pain and involves increased reactivity of neurones within the \n\ncentral nervous system [20]. This results in enhanced transmission of pain stimuli in the dorsal \nhorns of the spinal cord and a lowered activation threshold [19]. It induces plastic changes in brain \nstructures responsible for pain perception, such as the somatosensory cortex, insula, and \ncomponents of the limbic system [18]. The consequence of these changes is the occurrence of \nallodynia and hyperalgesia [20]. Central sensitisation may persist despite the removal of lesions, \nwhich explains the persistence of symptoms after surgical treatment [18]. The nature of pain in \nendometriosis is complex and includes both nociceptive and neuropathic components [19]. \nDamage or abnormal functioning of nerve fibres within disease lesions promotes the generation of \nspontaneous pain impulses [18]. An increased presence of nerve fibres has been observed in \nendometrial tissue, which may be directly associated with symptom severity [18]. The process of \nneuroangiogenesis further enhances pain signal transmission [19]. Symptoms such as burning, \nstabbing, or radiating pain indicate the involvement of neuropathic mechanisms [20]. Another \nmechanism is cross-sensitisation, in which stimulation of one pelvic organ affects pain perception \nin other organs [19]. Neuroinflammation is a direct consequence of chronic immune system \nactivation observed in endometriosis and plays a key role in pain modulation. In this context, \ninteractions between immune cells and the nervous system are important, leading to the release \nof inflammatory mediators and increased excitability of nociceptors [18]. Inflammatory cells \npresent in lesions secrete mediators such as cytokines and prostaglandins, which increase the \nexcitability of pain receptors [18]. Activated nerve fibres release neuropeptides such as substance \nP and calcitonin gene-related peptide (CGRP), which intensify local inflammation and pain \ntransmission [19]. As a result, peripheral sensitisation occurs, manifested by a lowered activation \nthreshold of nociceptors and an increased response to stimuli [20]. Chronic inflammation \npromotes the persistence of changes in the nervous system and the transition of pain into a \nchronic form [18]. This creates a vicious cycle in which inflammation and pain reinforce each other \n[19]. Available data indicate that the extent of endometrial lesions does not correlate with the \nseverity of pain [18]. In some patients, small lesions may cause severe symptoms, whereas in \nadvanced cases symptoms may be relatively mild [19]. This phenomenon is explained by the \ndominant role of neurobiological mechanisms, such as central and peripheral sensitisation [20]. \nPain perception is also influenced by psychological factors, including stress and anxiety, acting \nthrough the HPA axis [18]. Individual differences in pain processing further determine variability in \nclinical presentation [19]. Therefore, effective pain management in endometriosis requires a \nholistic approach that takes into account both biological mechanisms and neuropsychological \nfactors [18]. \n \n\nNeuroimmunological and neuroendocrine regulatory mechanisms \nThe neuroimmunological axis in endometriosis is a system of interconnections between hormonal \nregulation, the stress response, and immune system activity, in which the HPA axis and the HPO \naxis play a key role [21]. Under normal conditions, hormonal impulses regulating the secretion of \ngonadotropins, such as luteinising hormone (LH), remain in balance with stress-related \nmechanisms. Chronic activation of the HPA axis may disrupt this homeostasis and affect the \nfunctioning of the reproductive system [21]. Studies on women with endometriosis indicate that \nchronic psychological stress and pain may lead to activation of the HPA axis and increased cortisol \nsecretion, which exerts an inhibitory effect on the HPO axis [22]. Cortisol may influence the \nsecretion of gonadotropin-releasing hormone (GnRH), which in turn may modulate the secretion \nof LH and follicle-stimulating hormone (FSH). This leads to disturbances in hormonal balance \nessential for ovarian function [22]. Such changes may be significant in the pathophysiology of \nendometriosis, as disrupted hormonal regulation affects the hormonal environment that \npromotes the persistence of disease lesions [22]. Additionally, it has been shown that patients \nwith endometriosis exhibit alterations in diurnal cortisol levels, which may include abnormal \nmorning values and an impaired stress response [23]. These changes are associated with increased \nchronic pain and reduced quality of life, suggesting that dysregulation of the HPA axis is not \nmerely a consequence of the disease but may also contribute to its maintenance [23]. Cortisol \nfunctions as a stress hormone but also as a factor linking neuroendocrine and immune responses \n[23]. The significance of LH and other gonadotropins in the context of endometriosis results from \ntheir role in regulating the ovarian cycle and estrogen production, which influence the activity of \nendometrial lesions [21]. Disturbances in the HPO axis, resulting from chronic activation of the \nHPA axis, may lead to alterations in LH secretion, indirectly affecting the estrogen–progesterone \nbalance [21]. Cortisol also affects the immune system by modulating the inflammatory response \n[24]. Under physiological conditions, it exerts anti-inflammatory effects; however, its chronic \ndysregulation may lead to impaired control of inflammatory processes and sustained immune \nactivation [24]. As a result, this may promote intensified local inflammatory reactions within \nendometrial lesions and their continued biological activity [24]. Disruptions in the \nneuroimmunological axis indicate that the pathologies present in endometriosis are not solely \nlocal in nature but involve multilevel regulatory mechanisms of the organism. Consequently, \nendometriosis may be viewed as a systemic disease in which immunological, hormonal, and \nneurobiological disturbances are integrated. \n \n \n\nEndometriosis as a systemic disease \nKey importance is attributed to chronic low-grade inflammation and an abnormal immune \nresponse. Additionally, alterations in pain processing led to the persistence and generalization of \nsymptoms [8,10]. Genetic data indicate shared molecular mechanisms between endometriosis and \nother inflammatory and pain-related diseases, confirming its multi-system nature [25]. The clinical \npresentation of endometriosis is heterogeneous and includes numerous non-gynaecological \nsymptoms, which often dominate the disease course and may obscure its actual origin (Figure 3) \n[9]. Particularly significant are gastrointestinal symptoms, such as chronic abdominal pain, \nbloating, altered bowel habits, and painful defecation, which often show cyclically associated with \nthe menstrual cycle [9]. Special attention should be paid to the frequent coexistence of \nendometriosis with irritable bowel syndrome (IBS), which constitutes a significant diagnostic and \ntherapeutic challenge [9,25]. The overlap of symptoms between these two conditions may result \nfrom shared pathophysiological mechanisms, including disturbances in the gut–brain axis, \nhypersensitivity, and chronic activation of the immune system [25]. Additionally, the phenomenon \nof central sensitisation leads to a lowered threshold for pain perception, which promotes the \npersistence of both intestinal and pelvic symptoms [8]. As a consequence, some patients may \ninitially be diagnosed and treated for IBS, which delays the correct diagnosis of endometriosis [9]. \nIn addition to gastrointestinal symptoms, urological complaints are also frequently observed, such \nas urinary frequency, urgency, bladder pain, and dysuria, which may mimic bladder pain syndrome \n[9]. Systemic symptoms are also present in the clinical picture, including chronic fatigue, sleep \ndisturbances, headaches, and generalised hypersensitivity to pain stimuli [8]. Neurobiological \nmechanisms play a key role in the spread of pain beyond the pelvic region and in maintaining its \nchronic nature [8,10]. Comorbidity of endometriosis with IBS and other pain syndromes, such as \nfibromyalgia or migraine, leads to a significant increase in overall disease burden and worsens \nprognosis [25]. Patients with overlapping disorders are characterised by greater symptom severity, \na broader spectrum of symptoms, and a poorer response to standard treatment methods [9]. The \nshared background of these conditions includes both genetic factors and dysregulation of the \nneuroimmunological axis, further emphasising the need for a systemic approach to diagnosis and \ntherapy [25]. Endometriosis affects multiple aspects of life, including physical, psychological, and \nsocial functioning [9,26]. Chronic pain and accompanying somatic symptoms lead to limitations in \ndaily activity and reduced work capacity [9]. Gastrointestinal and urological symptoms further \nimpact quality of life, often causing embarrassment and limiting participation in social life [9]. \nResults of multicenter studies indicate a significant reduction in work productivity, resulting both \nfrom absenteeism and from reduced efficiency while at work [26]. Loss of productivity may \n\nconstitute a substantial burden for both patients and healthcare systems [26]. The disease also \nnegatively affects mental health and interpersonal relationships, including sexual activity, which is \noften impaired due to discomfort [9]. The chronic nature of symptoms, diagnostic delays, and \nlimited effectiveness of causal treatment promote the development of depressive and anxiety \ndisorders [9]. These factors contribute to reduced quality of life and a sense of social isolation [9]. \nConsidering endometriosis as a disorder involving the entire organism allows for integration of \nobserved clinical and pathophysiological phenomena [10,27]. The disease is associated with \nsimultaneous dysregulation of immune, hormonal, and nervous system axes, and its course may \nbe modulated by environmental factors, including lifestyle and diet [27]. Such an approach \nexplains both the multi-organ nature of symptoms and the frequent coexistence of functional \ndisorders [27]. Optimal therapeutic management requires a multidisciplinary approach, taking into \naccount not only gynaecological treatment but also interventions targeting the gastrointestinal \nsystem, pain management, and psychological support [9,27]. \nFig. 3. Symptoms of endometriosis \nPseudoneoplastic nature of endometriosis \nIn endometriosis, particular emphasis is placed on its “pseudoneoplastic” character, resulting from \nthe presence of mechanisms such as uncontrolled cellular proliferation [28,29]. In this context, the \nterm “tumour-like disease” is increasingly used, which does not strictly imply neoplastic \ntransformation, but indicates biological and molecular similarities to oncogenic processes [30]. A \nparticularly important area of research involves somatic mutations detected in endometriotic \n\n\nlesions, especially in the ovarian region. Numerous molecular analyses have demonstrated the \npresence of alterations in genes crucial for regulating cell proliferation and survival, such as \nARID1A, PIK3CA, and KRAS [29,31]. These mutations are not merely passive markers of DNA \ndamage but actively influence signalling pathways, including PI3K/AKT/mTOR and RAS/MAPK, \nleading to dysregulation of the cell cycle, increased cell survival, and enhanced proliferative \npotential [29,31]. Some of these genetic mutations are shared with ovarian cancers associated \nwith endometriosis, which strengthens the hypothesis of a link between endometriosis and \nspecific types of cancer [31]. However, the presence of somatic mutations does not unequivocally \nindicate neoplastic transformation but rather reflects the mosaic nature of lesions and the \nbiological variability of endometrial foci. In certain cases, these mutations may represent an initial \nstep in carcinogenesis. For full transformation to occur, additional microenvironmental \ndisturbances as well as further genetic and epigenetic alterations are required [29]. Consequently, \nendometriosis is progressively being examined as a potential precursor condition, especially \nconcerning ovarian endometriosis [31]. Beyond genetic changes, the inflammatory \nmicroenvironment holds considerable importance, as it may facilitate the selection of cells \nexhibiting more aggressive characteristics. Persistent immune stimulation, elevated levels of pro-\ninflammatory cytokines, and impaired macrophage function establish conditions that support the \nsurvival of cells possessing altered molecular features [17,32]. Within this framework, \nmacrophages additionally amplify the \"tumour-like\" characteristics [17]. The question of malignant \ntransformation potential in endometriosis continues to be a central subject of scientific debate. \nThe most robust epidemiological links involve ovarian cancer, particularly the endometrioid and \nclear cell variants, which are categorised as endometriosis-related malignancies [31,33]. \nPopulation-based cohort research indicates that endometriosis correlates with elevated risk of \ndeveloping these malignancies, though the absolute risk at the population level remains \ncomparatively modest [31,33]. Genomic studies have additionally revealed partial commonality \nbetween genetic variants associated with endometriosis and ovarian cancer susceptibility, \npointing to shared biological mechanisms [34]. Current theoretical frameworks tend to propose \nthe existence of a continuum of alterations, wherein certain endometrial lesions may persist \nunchanged for extended periods, while others through accumulation of somatic genetic changes \nand microenvironmental influences may advance toward precancerous states and eventually \nmalignant transformation [29,31,35]. Endometriosis does not represent a singular disease entity \nbut rather a diverse collection of processes demonstrating variable biological potential [28,35] as \nsummarised in Table I. The strongest correlations pertain to ovarian cancer; nevertheless, certain \nepidemiological investigations also indicate a modest elevation in endometrial cancer and breast \n\ncancer risk among endometriosis patients, although these associations remain less definitive and \nmay be influenced by numerous variables, including hormonal factors [36]. The \"tumour-like \ndisease\" conceptualisation carries important clinical significance, as it redirects the understanding \nof endometriosis from merely a hormonal-inflammatory disorder toward recognition as a \ncondition with a distinctive molecular dimension, necessitating treatment approaches that address \nnot only symptomatic manifestations but also the fundamental biological mechanisms involved \n[28,35]. Nevertheless, the detection of shared mutations should not be interpreted as direct \nevidence that endometriosis constitutes a precancerous condition in a universal or deterministic \nsense. Somatic mutations are increasingly recognised in many benign tissues and may reflect \nclonal expansion, chronic inflammation, oxidative stress, or local tissue adaptation rather than \ninevitable malignant transformation [30,31]. Current evidence suggests that the majority of \nendometriotic lesions remain biologically stable and do not progress to cancer [29,35]. Therefore, \nmolecular overlap between endometriosis and ovarian cancer should be interpreted cautiously \nand primarily as evidence of partially shared biological pathways rather than proof of direct \noncogenic progression. The inflammatory microenvironment characteristic of endometriosis is \nconsidered another important factor contributing to these tumour-like features. Chronic exposure \nto pro-inflammatory cytokines, oxidative stress, altered immune surveillance, and dysregulated \nmacrophage activity may support cellular survival and persistence of ectopic lesions [31,32]. These \nmechanisms may create conditions favouring the accumulation of additional molecular alterations \nover time, particularly in ovarian lesions repeatedly exposed to cyclical haemorrhage and iron-\ninduced oxidative stress [31,35]. However, the presence of such mechanisms alone remains \ninsufficient for malignant transformation, which is understood as a complex, multistep process \nrequiring additional genetic, epigenetic, and microenvironmental events [29,30,31]. \nEpidemiological studies demonstrate that women with endometriosis may have an increased \nrelative risk of specific ovarian cancer histotypes, most notably endometrioid and clear cell ovarian \ncarcinoma [28,29,31,35]. These malignancies are frequently described as endometriosis-\nassociated ovarian cancers. Nonetheless, although relative risk may be elevated, the absolute \nlifetime risk of ovarian cancer among patients with endometriosis remains comparatively low at \nthe population level [29,31,35]. This distinction is clinically important, as relative associations may \noverestimate perceived cancer risk when not interpreted in the context of absolute incidence. \nCurrent genomic and epidemiological data suggest the existence of partially overlapping molecular \nmechanisms between endometriosis and certain ovarian cancer subtypes, rather than a direct \nlinear progression from benign disease to malignancy in most patients [28,30,35]. It has been \nproposed that only a limited subgroup of lesions, particularly ovarian endometriomas displaying \n\nspecific molecular alterations and prolonged inflammatory exposure, may possess increased \nsusceptibility to neoplastic transformation [31,35]. Even within this subgroup, progression to \nmalignancy appears to remain uncommon. Associations between endometriosis and other \nmalignancies, including breast and endometrial cancer, are less consistent. Available meta-\nanalyses indicate that these relationships are generally weaker and may be influenced by shared \nhormonal, reproductive, genetic, or environmental factors rather than direct causal mechanisms \n[33]. Consequently, current evidence does not support the interpretation of endometriosis as a \nbroadly premalignant condition. The concept of endometriosis as a tumour-like disorder therefore \nprimarily reflects selected similarities in cellular behaviour and molecular signalling pathways \nrather than equivalence to malignant disease. Recognition of these shared biological features may \nnevertheless contribute to improved understanding of lesion persistence, recurrence, and \ntherapeutic resistance, while also supporting the development of more targeted molecular and \nanti-inflammatory treatment strategies [30,31,35]. \nTable I. Key pathophysiological mechanisms in endometriosis \nPathway Key mechanisms Main consequences Interactions \nImmunological \nMacrophages lose ability to \nclear ectopic cells and switch \nto pro-inflammatory, pro-\nangiogenic mode [16,17]. NK \ncells show reduced cytotoxic \nactivity [14,15]. Immune \nbalance shifts toward chronic \ninflammation (↑ IL-6, TNF-α, \nIL-8) and immune tolerance \n(↑ IL-10, TGF-β, Treg cells) \n[14,15] \nEctopic cells survive \nand implant. \nChronic inflammation \nis maintained. \nNew blood vessels \nform to sustain \nlesions [14,15,16,17] \nInflammatory \nmediators \nstimulate nerve \nfibres → pain \nsensitisation → \nstress response → \nhormonal \ndisruption \n[14,18,19] \nNeurobiological \nPeripheral and central \nsensitisation develop over \ntime [19,20]. Lesions become \nincreasingly innervated \n(neuroangiogenesis) [18,19]. \nNeuropeptides (substance P , \nCGRP) amplify local \ninflammation [19]. Brain \nChronic pelvic pain \nindependent of lesion \nsize [18,19]. \nHyperalgesia and \nallodynia [20]. Pain \npersists even after \nsurgery [18].  \nPersistent pain \nactivates the HPA \naxis → cortisol \ndysregulation → \nhormonal and \nimmune \nimbalance → \nworsening \n\nstructures involved in pain \nprocessing undergo plastic \nchanges [18] \nCo-occurrence of IBS, \nfibromyalgia, migraine \n[19,25] \nsensitisation \n[21,22,23] \nEndocrine \nLocal oestrogen \noverproduction via ↑ \naromatase in lesions [11,13]. \nProgesterone resistance \nreduces anti-inflammatory \neffects [11]. Chronic stress \ndysregulates HPA axis → \nabnormal cortisol levels \n[22,23]. HPA activation \nsuppresses HPO axis → \naltered LH and FSH secretion \n[21,22] \nOestrogen-driven \nlesion growth [6,11]. \nReduced response to \nhormonal treatments \n[11]. Reproductive \ndysfunction [36]. \nWorsening systemic \nsymptoms [22,23] \nOestrogens fuel \ninflammation and \ncell proliferation \n→ reinforce \nimmune \ndysregulation and \nneural \nsensitisation \n[11,13,24] \nMolecular/ \nPseudoneoplastic \nSomatic mutations (ARID1A, \nPIK3CA, KRAS) activate pro-\nsurvival signalling pathways \n(PI3K/AKT/mTOR, RAS/MAPK) \n[29,31]. Oxidative stress from \ncyclical bleeding promotes \nfurther molecular damage \n[31,35]. Epigenetic changes \nalter gene expression [13]. \nLesions share molecular \nfeatures with certain ovarian \ncancers [28,31,35] \nLesion persistence \nand resistance to \napoptosis [30]. \nCapacity for distant \nspread via lymphatic \nand blood vessels \n[13]. Modestly \nelevated risk of \nendometrioid and \nclear-cell ovarian \ncancer (relative risk \nelevated; absolute \nrisk remains low) \n[29,31,33,35] \nChronic \ninflammation and \noestrogen excess \ndrive molecular \nalterations → \nfurther sustain \ninflammation and \nangiogenesis → \nreinforce all other \npathways \n[17,31,32,35] \nDISCUSSION \nThe available evidence indicates that endometriosis is a complex, systemic, and inherently \nheterogeneous disorder that cannot be fully explained by the classical theory of retrograde \nmenstruation. In light of this, we propose an integrative model that conceptualises endometriosis \nas a neuroimmunoendocrine systemic disorder sustained by self-reinforcing feedback loops \ninvolving inflammation, neural sensitisation, and hormonal dysregulation. Although the traditional \nretrograde menstruation model has been historically influential, it does not adequately account \nfor the multi-system involvement, the wide diversity of clinical phenotypes, or the frequently \nobserved disconnect between lesion burden and symptom severity. It is increasingly recognised \nthat endometriosis should be considered a spectrum of related pathological conditions rather than \na single disease entity. This redefinition is not merely semantic; it reflects the underlying biological \nreality. The absence of a single unifying pathogenic model should be viewed not as a lack of \nknowledge, but as a consequence of genuine biological heterogeneity. This heterogeneity \nconstitutes a central challenge to achieving reliable diagnosis, consistent treatment responses, and \n\ntherapeutic innovation. Among the mechanisms implicated, immune dysregulation appears to play \na particularly important role in disease persistence. Impaired macrophage function, characterised \nby reduced phagocytic capacity and increased pro-angiogenic activity, is thought to sustain the \ninflammatory microenvironment that supports lesion survival. Concurrently, T-cell imbalance and \nenhanced regulatory immune responses may facilitate immune evasion by ectopic endometrial \ntissue. Nevertheless, it remains unclear whether these immune alterations represent a primary \ndriver of the disease or a secondary adaptation, highlighting a significant gap in current \nmechanistic understanding. Neurobiological processes, particularly central sensitisation, are \nequally critical. Chronic pain in endometriosis cannot be explained solely by the physical presence \nof lesions. Rather, it appears to involve altered central pain processing maintained by persistent \nneuroplastic changes. This mechanism helps explain why pain frequently persists despite surgical \nor hormonal interventions. In addition, neuroangiogenesis and increased innervation of lesions \nmay create a self-perpetuating cycle between inflammation and nociception, contributing to a \nchronic pain state that is often independent of ongoing peripheral pathology. Endocrine-immune \ninteractions further increase the complexity of the disorder. Dysregulation of the HPA and HPO \naxes may promote hormonal instability and sustained inflammatory signalling. The persistence of \nsymptoms despite hormonal suppression challenges the traditional estrogen-dependent paradigm \nand suggests that additional mechanisms, including epigenetic reprogramming and autonomous \ncellular behaviour, are likely to be involved. These elements are not yet sufficiently integrated into \nexisting disease models. Endometriotic lesions also exhibit tumour-like features. The presence of \nsomatic mutations (including ARID1A, PIK3CA, and KRAS), together with angiogenic and invasive \nproperties, indicates shared molecular pathways with oncogenic processes. Although this does not \nimply that endometriosis is a premalignant condition, it underscores the importance of examining \nthe disorder within a broader biological context. These overlaps may partly explain the observed \nincreased risk of certain ovarian cancer subtypes and represent an area requiring further \nmechanistic investigation. Despite substantial progress in understanding disease mechanisms, a \nsignificant translational gap remains. Mechanistic insights have not been effectively translated into \nclinically actionable therapeutic strategies. This is reflected in the limited number of high-quality \nclinical trials targeting specific pathogenic pathways. Consequently, current treatment approaches \nremain largely symptom-suppressive rather than disease-modifying. Although hormonal therapies \nand surgical interventions are often necessary, they are associated with high recurrence rates and \nvariable efficacy, indicating that they do not adequately address the underlying drivers of disease \nprogression. Diagnostic limitations are equally important. The continued dependence on invasive \nlaparoscopy for definitive diagnosis highlights the urgent need for reliable non-invasive \n\nbiomarkers. The resulting diagnostic delays, which frequently span several years, have well-\ndocumented negative consequences for disease progression and patient quality of life. \nCollectively, these observations support the conclusion that heterogeneity is not a peripheral \nfeature of endometriosis but its defining characteristic. Management strategies based on uniform \napproaches are therefore inherently limited. Future progress will require the development of \nphenotype-driven classification systems and truly personalised therapeutic strategies. We propose \nthat meaningful advancement depends on the construction of integrative, mechanism-based \nmodels capable of addressing immune dysfunction, neuroangiogenesis, central sensitisation, and \nendocrine imbalance in a coordinated manner. A shift from primarily symptomatic management \ntoward causative, biology-driven interventions is essential if the field is to convert scientific \nprogress into tangible clinical benefit. \nCONCLUSIONS \n1. Current evidence indicates that endometriosis is characterised by complex and multifactorial \npathophysiological mechanisms involving inflammatory, immunological, hormonal, and \nneurobiological pathways. \n2. Despite substantial advances in research, the pathogenesis of endometriosis remains \nincompletely understood, with existing data demonstrating considerable biological and \nclinical heterogeneity among patients and disease phenotypes. \n3. The development of reliable non -invasive biomarkers for endometriosis remains an \nimportant area of ongoing research. Delayed diagnosis continues to be associated with \nincreased disease burden and impaired quality of life. \n4. Contemporary therapeutic strategies are primarily directed towards symptom control, \nparticularly pain reduction and suppression of lesion activity. However, challenges related \nto disease recurrence and long -term treatment effectiveness remain significant c linical \nconcerns. \n5. Phenotype-based classification systems have increasingly been proposed as a means of \nimproving patient stratification and facilitating more individualised therapeutic approaches. \n6. Experimental, molecular, and translational studies have contributed substantially to the \ncurrent understanding of endometriosis pathophysiology; nevertheless, implementation of \nthese findings in routine clinical practice remains limited. \n7. Further interdisciplinary research integrating molecular, immunological, neurobiological, \nand clinical perspectives is required to advance understanding of endometriosis and support \nthe development of more targeted diagnostic and therapeutic strategies. \n\nFunding statement \nThe study did not receive special funding. \nInformed consent statement \nNot applicable. \nConflict of interest \nThe authors declare that there is no conflict of interest. \nUse of AI tools statement \nOpenEvidence was used to search and select scientific literature and to aid in identifying current \npublications. ChatGPT was used for linguistic and stylistic proofreading and translation into English. \nAuthors’ contribution \nStudy design – K. Gawarecka, K. Gałka \nData collection – K. Gawarecka \nManuscript preparation – K. Gawarecka, K. Gałka \nLiterature research – K. Gawarecka \nFinal approval of the version to be published – K. Gawarecka, K. Gałka \nREFERENCES  \n1. Giudice LC. Clinical practice. 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