The link between endometriosis and autoimmune diseases: a myth or reality?

Broadly speaking, endometriosis is defined as a chronic condition in which endometrial-like tissue grows outside of the uterus, primarily affecting women of reproductive age. Although it can be asymptomatic, the main reasons for patients seeking medical attention are pelvic pain and, most notably, infertility. Unfortunately, the diagnosis is often delayed, sometimes by as much as ten years. Recent theories suggest that there may be a link between endometriosis and autoimmune diseases such as Hashimoto’s thyroiditis, lupus or rheumatoid arthritis. In this literary review, we explore these possible connections, with a particular focus on the demonstrated (or not) correlations between specific autoimmune conditions and endometriosis. Nu - merous studies have examined this association, but, unfortunately, the results remain inconclusive. For example, only a few have identified a clear and significant link between endometriosis and a particular autoimmune disease. Many of these studies are limited by small sample sizes, the lack of standardized diagnostic criteria, or retrospective study designs. Some genetic studies have proposed the involvement of shared genes such as PTPN22 or specific HLA alleles, but the evidence in this area is also not yet robust. Still, there is general agreement that both endometriosis and autoimmune diseases involve immune system dysfunctions, particularly chronic inflammation and cytokine production. To gain a better understanding of the rela - tionship between these conditions, larger, prospective and well-controlled studies that follow patients over time are needed. In the future, research may lead to the discovery of shared biological markers or the development of immunological therapies capable of targeting both disorders.

endometriosis, autoimmune diseases, immunological factors REZUMAT În linii mari, definim endometrioza ca fiind o boală cronică în care ţesutul endometrial se dezvoltă în afara uterului, afectând cu predilecţie femeile aflate la vârsta fertilă. Deși poate fi asimptomatică, principalele simptome pentru care se prezintă paci - entele la medic sunt durerile pelviene și în special infertilitatea. Din păcate, diagnosticul este adesea întârziat chiar și cu zece ani. Unele teorii recente susţin că ar putea exista o legătură între endometrioză și bolile autoimune, cum ar fi tiroidita Hashi - moto, lupusul sau artrita reumatoidă. În acest review literar, analizăm aceste aspecte, dar mai ales ne focalizăm pe corelaţia demonstrată dintre anumite boli autoimune și endometrioză. Există numeroase studii care au analizat această asociere, însă rezultatele sunt, din păcate, neconcludente. De exemplu, câteva cercetări au găsit o legătură clară și semnificativă între endometrioză și anumite boli autoimune, iar multe dintre ele sunt limitate de anumiţi factori, cum ar fi dimensiunile mici ale eșantionului, lipsa unor criterii de diagnostic standard și designul retrospectiv al studiului. Alte studii genetice au propus im - plicarea anumitor gene comune, cum ar fi PTPN22 sau anumite alele HLA, dar dovezile nu sunt suficient de solide nici în această privinţă. Totuși, putem ajunge la un acord universal că atât în endometrioză, cât și în bolile autoimune apar dereglări ale siste- mului imunitar, în special inflamaţia cronică și producţia de citokine. Pentru a înţelege mai bine legătura dintre aceste afecţiuni, ar fi necesare studii mai mari, prospective și bine controlate, care să urmărească pacienţii pe termen lung. În viitor, cercetarea ar putea conduce la descoperirea unor markeri biologici comuni sau la dezvoltarea unor terapii imunologice care să trateze ambele afecţiuni. Cuvinte-cheie: endometrioză, boli autoimune, factori imunologici

Endometriosis is a chronic medical condition in which endometrial tissue grows outside the uterus, affecting approximately 8-10% of women of reproductive age. It commonly causes pelvic pain or infertility, although in many cases it may remain asymptomatic (1-3). Despite its high prevalence, the condition is often underdiagnosed, with many women waiting an average of 7 to 10 years before receiving a proper diagnosis (4). The exact cause of endometriosis remains unknown, though potential contributing factors include genetics, immune system dysfunction, and retrograde menstru - ation. It is believed that endometrial cells may change their direction, going backwards through the fallopian 163 obstetrica și ginecologia Rus et al. The link between endometriosis and autoimmune... tubes, adhere to peritoneal surfaces, and begin to proli - ferate wherever they end up, triggering an inflammation reaction in the abdominal cavity (5,6) . These cells are hormone-sensitive and respond to the cyclical hormonal changes during menstruation, leading to inflammation, pain, scarring and, more often, fertility issues. Symp - toms vary depending on the location of the ectopic tissue but typically include pelvic pain, particularly severe dysmenorrhea during menstruation as a hallmark sign. Many women also report pain during intercourse, painful urination and cyclic digestive discomfort. Addi - tionally, endometriosis is linked to heavy or irregular menstrual bleeding, which can lead to complications such as anemia and chronic fatigue. One of the most concerning issues is its well-documented association with infertility, as studies suggest that up to 40% of women experiencing difficulty conceiving may have endometriosis (7), an alarming amount. Other symptoms like chronic fatigue, nausea, bloating and digestive problems, can further complicate diagno - sis, often mimicking other disorders such as irritable bowel syndrome. The impact of endometriosis extends beyond phy - sical symptoms. Chronic pain can drastically reduce the quality of life, interfering with a woman’s ability to work, maintain social relationships and engage in daily activities. Its persistent nature is also linked to increa - sed rates of anxiety, depression and emotional distress. Moreover, endometriosis places a substantial burden on healthcare systems due to the need for frequent me - dical visits, surgeries, and long-term treatment plans. The management typically requires a multidisciplinary approach involving pain control, hormonal therapies and, in severe cases, surgical interventions like lapa - roscopy or even hysterectomy. Given these challenges, early diagnosis and appro - priate management are critical. Increasing awareness and improving access to healthcare resources may help reduce diagnostic delays and improve quality of life for affected individuals. Further research is also essential to better understand the underlying causes of the disease and to develop improved treatment options. An equally important aspect is how endometriosis is diagnosed. The diagnosis generally relies on a com - bination of clinical history, physical examination and imaging studies. While transvaginal ultrasound is often the first-line imaging method, magnetic resonance ima - ging (MRI) has emerged as a valuable tool for confirming diagnosis and assessing disease extent. MRI provides high-resolution images of pelvic structures and can accu - rately identify endometriotic lesions, including deeply infiltrating endometriosis, ovarian endometriomas and rectovaginal nodules. Studies have shown MRI to have a sensitivity exceeding 90% in detecting endometriotic lesions, making it increasingly useful, especially when ultrasound findings are inconclusive, by offering better resolution and a broader field of view. Its multiplanar capabilities allow for detailed mapping of the disease, which is essential for surgical planning and improving patient outcomes.

For the first time in history, in 1987, Gleicher was the first to propose that endometriosis might be classified as an autoimmune disease, noting that it fulfills many diagnostic criteria: polyclonal B cell activation, immu - nologic abnormalities in T and B cell function, increased apoptosis, tissue damage and multiorgan involvement (9). Epidemiological studies suggest a higher prevalence of autoimmune disorders among women with endo - metriosis (10), pointing toward a shared mechanisms such as hormonal influences, systemic inflammation and genetic predisposition (11,12) . Sadly, the diagnosis is often delayed by up to 10 years from the onset of pelvic pain (13). Autoimmune conditions frequently associated with endometriosis are widely discussed in the scientific literature due to their overlapping pathogenic features, primarily involving immune dysregulation and chronic inflammation. Among these, Hashimoto’s thyroiditis, an autoimmune condition in which the immune system attacks the thyroid gland, leading to hypothyroidism, is commonly observed in women with endometriosis. Several studies have reported a significantly higher pre - valence of Hashimoto’s disease in this patient population, suggesting a possible immunological link between the two diseases. Chronic inflammation and the presence of autoantibodies are hallmarks of both conditions, which may account for their increased co-occurrence (14). Moreover, research has highlighted a distinct cytokine profile, with significantly elevated production of IL-1 β, IL-6 and TNF- α in both endometriotic and endometrial tissues. These differences between tissue types indicate a dysregulated cytokine environment in women with endometriosis, compared to healthy controls, mediators that play a central role in the pathophysiology of both autoimmune thyroiditis (15) and endometriosis (16). Systemic lupus erythematosus (SLE), another well- known autoimmune disorder characterized by wide - spread inflammation and immune dysfunction, is also more commonly seen in women with endometriosis. This may be due to overlapping immune dysregulati - on, including abnormal T cell activity and cytokine production. SLE is marked by a hyperactive immune response, which may align with the mechanisms driving ectopic endometrial growth (17). The chronic inflamma - tory environment, elevated autoantibody levels, and immune complexes may contribute to the progression of both diseases, suggesting that immune modulation could serve as a potential therapeutic target (18). Notably, both SLE and endometriosis have been associated with pregnancy complications such as miscarriage and in - trauterine fetal demise (19). One of the largest cohort studies, based on Taiwan’s National Health Insurance Database and including over one million participants, found a clear association betwe - en endometriosis and SLE, strengthening the case for a link between the two (20) . Rheumatoid arthritis (RA), a systemic autoimmune disorder that primarily affects the joints but also in - volves systemic inflammation, has also been linked to endometriosis. The connection likely stems from shared 164 Revista Societăţii Române de Obstetrică și Ginecologie • Vol. LXXII • Nr. 4 • octombrie-decembrie 2024 review inflammatory pathways, particularly involving cytokines such as TNF- α and IL-6, which are the core to the patho - genesis of both diseases. Studies suggest that women with RA are more likely to have endometriosis and vice versa. Research by Gogacz et al. (2021) found elevated levels of IL-6 and TNF- α in patients with endometriosis – key markers also implicated in RA (21). Both diseases also share associations with HLA gene polymorphisms, indicating a potential genetic susceptibility (22). Multiple sclerosis (MS), a neuroinflammatory auto - immune disease affecting the central nervous system, has also been linked to endometriosis in several epi - demiological studies. Sinaii et al. (2002) showed that women with endometriosis are up to seven to 24 times more likely to develop autoimmune diseases, including MS, compared to the general population (23) . While the phenotypes of these conditions differ, they share an underlying autoimmune foundation. Macrophages, for instance, play a critical role in the initiation and progres - sion of endometriosis by mistakenly promoting repair of ectopic endometrial tissue rather than clearing it. Si - milarly, in MS, macrophages contribute to pathogenesis by attacking the myelin sheath and oligodendrocytes (24). Moreover, there is clear evidence confirming that both diseases are characterized by systemic inflammation and immune dysregulation, including an elevated Th1/ Th2 cell ratio and increased IFN- γ activity, factors that suggest a potential link between them (25) . Nonetheless, there is still limited evidence in the medical field expla - ining the molecular, immunological, or defense mecha - nisms shared by these two conditions, and assessing the common molecular pathways and their components may help clarify the association between endometriosis and MS (26) . Some studies also explore a potential link betwe - en Sjögren’s syndrome and endometriosis. Sjögren’s syndrome is an autoimmune disorder that primarily affects the exocrine glands, leading to dryness of the eyes and mouth. Research has shown a higher prevalence of Sjögren’s syndrome among women with endometriosis. Both conditions are associated with systemic inflamma - tion, autoantibody production, and immune dysfunction. A study by Dmowski et al. (1994) suggested that the two diseases share a similar immune profile, with elevated levels of anti-SSA and anti-SSB antibodies commonly found in both (27) . Additionally, both endometriosis and Sjögren’s syndrome involve dysregulated T cell activity and cytokine production, which may help explain their connection. More recent studies further support the bidirectional relationship between endometriosis and Sjögren’s syndrome, potentially driven by dendritic cell maturation and fibrosis signaling pathways (28) . Gastrointestinal symptoms such as bloating, con - stipation and diarrhea are commonly reported among women with endometriosis. Research also indicates a higher prevalence of irritable bowel syndrome (IBS) and celiac disease in these patients. Sinaii et al. (2002) observed that women with endometriosis often present with gastrointestinal symptoms likely exacerbated by immune-mediated intestinal inflammation (29). The over - lap between celiac disease and endometriosis may be explained by shared immune dysfunction, particularly involving T cell activation and inflammatory cytokine production. Santoro et al. (2014), in their study on celiac disease in Italian women with endometriosis, reported a potential association between the two conditions, highlighting an increasing trend in the prevalence of celiac disease among women affected by endometriosis. Although the results were not statistically significant (30), it is noteworthy that numerous studies in recent years have explored this connection and yielded similar fin - dings (31,32) . The growing interest in this relationship stems from the shared characteristics of both celiac disease and endometriosis, particularly with respect to their un - derlying etiology and ongoing inflammatory processes. Common pathogenic mechanisms between endometriosis and autoimmune diseases To summarize the information presented above re - garding each pathology, we first note the shared mecha - nism between endometriosis and autoimmune disea - ses: immune system dysfunction. In endometriosis, the immune system fails to eliminate ectopic endometrial tissue, leading to its persistence and proliferation outside its normal location. Similarly, autoimmune diseases are characterized by the immune system attacking autoan - tigens, causing tissue damage. Key immune dysfunctions observed in both conditions include: n Impaired natural killer (NK) cell function, leading to inadequate elimination of abnormal cells (33). n Hyperactivation of macrophages, contributing to ex - cessive inflammatory responses (34). n Dysregulation of T-helper (Th1, Th17) cells and regula - tory T cells (Tregs), resulting in chronic inflammation and immune imbalance (35) . Secondly, both pathologies are marked by chronic inflammation, a distinctive feature of both endometri - osis and autoimmune diseases. In endometriosis, the peritoneal fluid and ectopic lesions show elevated levels of inflammatory mediators, and, similarly, auto immune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, are driven by persistent in flam - mation. Chronic inflammation plays a central role in both conditions. In endometriosis, this inflammation is characterized by increased cytokine levels and heighte - ned macrophage activity in the peritoneal fluid, contri - buting to the proliferation and implantation of ectopic endometrial cells. A study published in the Journal of Reproductive Immunology highlighted elevated concen - trations of proinflammatory cytokines in the peritoneal fluid of endometriosis patients, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF- α), which can stimulate endometrial cell proliferation (36). Additi - onally, research has also shown increased macrophage activity in the peritoneal fluid of women suffering from this disease, with cells secreting growth factors and cytokines that promote the implantation and growth of endometrial lesions (37). Cytokine imbalances also play a crucial role in both conditions, causing immune dysregulation and accelera - 165 obstetrica și ginecologia ting inflammation. Specific cytokines involved include IL-17 and IL-23, both elevated in both endometriosis and autoimmune diseases, contributing to chronic activation of the immune system, TNF- α and IL-1 β, which promote inflammation and tissue destruction. Additionally, oxi - dative stress leads to cellular damage, DNA mutations, and perpetuates inflammatory responses (38). In endometriosis, over time, multiple theories have emerged, one of which is the autoimmune theory. Emer - ging evidence supports the hypothesis that endometri - osis may have an autoimmune component. Features of autoimmune diseases observed in endometriosis include the presence of autoantibodies, such as anti-nuclear antibodies and anti-endometrium antibodies (39). Another link between the two studied pathologies is the genetic and epigenetic factors that contribute to the development of both endometriosis and autoimmune diseases through shared genetic susceptibility, with specific gene variants related to immune function and inflammation (e.g., HLA genes, IL-6, TNF genes). Family clustering suggests a hereditary predisposition to both conditions. Epigenetic changes, such as DNA methylation and histone acetylation, influence immune cell behavior and cytokine production. Controversies and limitations of existing research A systematic review conducted in 2019 examined 26 cross-sectional, case-control and cohort studies pu - blished on the association between endometriosis and autoimmune diseases. The studies that quantified the association between endometriosis and multiple auto - immune diseases generally had poor quality of evidence due to a high risk of bias in most study designs and sta - tistical analyses. Only five of the 26 studies supported a statistically significant association between endometri - osis and at least one autoimmune disease (40) . Since endometriosis is a potentially hereditary di - sease, several genetic studies have been conducted to investigate the association between autoimmune ge - nes and endometriosis (41). Among these studies, genes such as PTPN22 have been associated with rheumatoid arthritis (RA) and, by extension, with endometriosis. Additionally, HLA alleles, commonly associated with autoimmune diseases, have been reported in association with endometriosis. However, these studies generally included small sample sizes, poorly defined ethnicities, and limited genotyping. It is important to note that these autoimmune genes have not been reported in robust, large-scale genome-wide association studies of endometriosis (42). Regarding the association between endometriosis and autoimmune thyroiditis (Hashimoto’s disease), a study published in Gynecologic and Obstetric Investestigation in 2024 showed that, while higher rates of Hashimoto’s thyroiditis were found in women with endometriosis compared to those without, and women with higher TSH levels, there was no significant impact on fertility and reproductive outcomes related to the coexistence of endometriosis and thyroid disease (43). Furthermore, regarding the association with systemic lupus erythema - tosus (SLE), studies have shown that women diagnosed with endometriosis, regardless of whether they received surgical treatment, did not show a statistically signifi - cant difference in the risk of SLE (44) . In a controversial state, a Danish cohort study did not support the same association as the studies mentioned before. This study analyzed 9191 patients whose endome - triosis was diagnosed by laparoscopy or laparotomy (45) , and no significant associations were found between endometriosis and SLE (standardized incidence ratio = 1.1; 95% CI; 0.6-2.1). However, the study did report a modest increase in the risk of SLE. Current studies exploring the relationship between endometriosis and autoimmune diseases face several limitations, which influence their results and validity. Some limitations include small sample sizes, which re - duce the statistical power of findings. A limited number of participants makes it difficult to generalize findings to the broader population, especially for identifying rare autoimmune diseases or associations with endometrio - sis. Another issue is the lack of consistent diagnostic cri - teria, as there is no universally accepted set of diagnostic criteria for endometriosis or autoimmune diseases. This inconsistency between studies can lead to variability in how these conditions are identified, classified and evaluated, contributing to differing results and inter - pretations in the literature. Many studies examining the relationship between endometriosis and autoimmune diseases are retrospective, relying on the review of past medical data or patient records, which may introduce recall bias and confounding factors. These studies often lack the control over variables that prospective studies would provide, affecting the clarity of findings. On a different note, most studies fail to account for other potential confounding factors such as environmental exposure, genetic predisposition, or hormonal influences that may contribute to the development of autoimmu - ne diseases and endometriosis, and these factors are crucial for understanding the underlying mechanisms and potential interactions but are often not sufficiently controlled. Another limitation we were able to identify is the cross-sectional nature of many studies, meaning they only capture the relationship between endometri - osis and autoimmune diseases at a single point in time, which limits the ability to establish causality or to track the progression of both conditions over time.

and future research directions Current studies suggest an association between en - dometriosis and various autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis and autoimmune thyroiditis. These autoimmune con - ditions occur more frequently in women diagnosed with endometriosis, suggesting a potential link between the two. However, most studies do not provide sufficient evidence to establish a direct causality between the two conditions, and much of the research is limited by factors such as small sample sizes and the lack of uniform diagnostic criteria. Rus et al. The link between endometriosis and autoimmune... 166 Revista Societăţii Române de Obstetrică și Ginecologie • Vol. LXXII • Nr. 4 • octombrie-decembrie 2024 review An important point is that immune dysfunctions ob - served in endometriosis, such as immune cell activation and the production of inflammatory cytokines, may contribute to the development of autoimmune diseases. It is also possible that the presence of endometriosis may worsen or alter the course of preexisting autoimmune conditions. In this regard, it is proposed that endo - metriosis and autoimmune diseases may interact in a bidirectional manner, with each condition influencing the pathogenesis of the other. To address the limitations of current studies, more research is needed with a more thorough and controlled approach. The first step should be to make sure future studies are prospective and long-term, so that we can track the progress of patients with endometriosis and better understand whether these women are at a higher risk of developing autoimmune conditions as they age. Such a study design could provide valuable insights into risk factors and help identify the critical moments when these conditions might develop. Additionally, to ensure consistency in future research, it is crucial that diagnostic criteria for both endometri - osis and autoimmune diseases are standardized. This would make it easier to compare different studies and help avoid significant differences in how these conditi - ons are diagnosed. Another important direction is exploring the shared immunological mechanisms between endometriosis and autoimmune diseases. In-depth studies of the immune response at the cellular level, particularly on how chronic inflammation and uncontrolled immune system activa - tion contribute to the progression of both conditions, could lead to the identification of new biomarkers for diagnosis and treatment. Furthermore, this research could pave the way for novel immunomodulatory ther - apies that could improve both endometriosis and auto - immune diseases. Large, well-designed cohort studies with confounding control and mediation quantification, as well as genetic and biological studies, are needed to provide additional insights into whether endometriosis is a risk factor for or a consequence of autoimmune diseases, and whether these two types of disorders share pathophysiological mechanisms despite appearing independently. Such per - spectives could offer opportunities for the development of new nonhormonal drugs, such as immunomodulators, or the repurposing of existing immunomodulatory ther - apies for endometriosis (46) . Although current research suggests a link between endometriosis and autoimmune diseases, many unresol - ved questions remain. Future studies must address the current limitations, include larger participant groups, and use standardized diagnostic methods to better understand the interaction between these conditions. Identifying common mechanisms and developing tar - geted therapies could have a significant impact on the treatment of patients with concurrent endometriosis and autoimmune diseases. In our opinion, the relationship between endometriosis and autoimmune diseases is an extremely important yet complex area of research that requires further studies to clearly understand the mechanisms linking them. It is evident that there is a correlation between the two conditions, and women with endometriosis seem to have an increased risk of developing autoimmune diseases. However, it is still challenging to establish a direct causality, and research to date is limited due to small sample sizes, the lack of uniform diagnostic criteria, and the retrospective design of many studies. Despite these limitations, we believe that the existing studies provide a promising direction for the future, es - pecially regarding exploring the shared immunological mechanisms between endometriosis and autoimmune di - seases. Immune mechanisms such as chronic inflamma - tion and immune dysregulation may play a crucial role in the development of both conditions, and identifying new biomarkers and immunomodulatory therapies co - uld significantly improve the available treatments. n

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