This chapter should be cited as follows:
Greaves E, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.417633
The Continuous Textbook of Women’s Medicine Series – Gynecology Module
Volume 3
Endometriosis
Volume Editors:
Professsor Andrew Horne, University of Edinburgh, UK
Dr Lucy Whitaker, University of Edinburgh, UK
Chapter
The Etiology of Endometriosis
First published: November 2023
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INTRODUCTION
Endometriosis is a chronic and (currently) incurable inflammatory disorder defined by the growth of endometrial-like tissue outside the uterus as ‘lesions’. Endometriotic lesions can be found on the peritoneal lining of visceral organs and the abdominal wall and can invade muscular structures. Endometriosis lesions have also been identified in extra-pelvic sites (e.g., inguinal, thoracic, and in the nervous system).1 Although this definition simply describes the pathology, it does not encompass the complex symptomatic and multisystemic nature of the disorder.2 Worldwide it affects 190 million women and people assigned female at birth. Rare cases affecting men have been documented.3,4,5
Endometriotic lesions are grouped into three main subtypes: (i) superficial peritoneal lesions; (ii) ovarian cysts (endometriomas); and (iii) deeply infiltrating nodules (depth of penetration exceeding 5 mm). Lesions are often accompanied by scarring and adhesions within the pelvic cavity. Currently the gold-standard method to diagnose endometriosis is via laparoscopic visualization of lesions, and the ‘stage’ (minimal – severe) of endometriosis following examination of the intra-peritoneal environment is recorded. Most commonly, the revised scoring system of the American Society for Reproductive Medicine (ASRM) is used (although several others are also in use), and this encompasses the types, location, appearance, depth of invasion, and extent of lesions and adhesions.6 Imaging methods (ultrasound and MRI) for detection of endometriomas and deep infiltrating lesions are now gaining popularity. It is important to note that the severity of symptoms most frequently, does not correlate with disease stage.7
Endometriosis lesions are complex multicellular tissue deposits composed of endometrial-like stromal cells, +/− epithelial glands, extracellular matrix deposition, including fibrosis, scarring, and sometimes evidence of hemorrhage.8,9 They are infiltrated by blood vessels and nerve fibers as well as abundant immune cells, yielding a highly inflammatory microenvironment.10,11,12,13,14 The local cellular niche of a lesion is regulated by estrogen, which has significant impacts on endometrial-like cell types15 as well as processes such as neuroangiogenesis and neuroinflammation.16,17 Histological appearance of lesions varies significantly, with different contributions of extracellular matrix/fibrosis,18 presence of endometrial-like cells8 and their synchronicity with the menstrual cycle,19 and extent of immune and nerve infiltration.20 It is likely that disease processes vary in each lesion microenvironment, as suggested in the extreme variation in disease presentation, response to treatment, and evident ‘life-cycle’ of lesions that yield deposits of different colors.2
Currently, the etiology of endometriosis is not clearly defined. Instead, multiple origins have been proposed (which may give rise to different subtypes), and it is acknowledged that endometriosis is multifactorial in nature, with a complex interplay of genetic, hormonal, immunological, and environmental factors contributing to its development.
ORIGINS OF ENDOMETRIOSIS
Retrograde menstrual bleeding
Retrograde menstruation occurs when some menstrual fluid, instead of exiting the body through the cervix and vagina, flows backward through the fallopian tubes into the pelvic cavity. This phenomenon is thought to be a relatively common occurrence (up to 90%)21 in menstruating women and is usually cleared by the immune system.
The theory suggests that retrograde bleeding leads to the dissemination of shed endometrial tissue containing viable endometrial cells.22 These cells can attach to the peritoneal lining and pelvic organs, such as the ovaries, fallopian tubes, and bladder. Once attached, endometrial cells can continue to grow and proliferate, forming lesions and causing localized inflammation. The identification of endometrial progenitors in peritoneal fluid23 and an increased prevalence of endometriosis in young people with obstructive genital tract malformations24 adds weight to this theory.
The neonatal uterine bleeding theory proposes that endometriosis may develop following dissemination of endometrial cells into the pelvic cavity that are shed shortly after birth. Studies have indicated that, towards the end of gestation the fetus could become sufficiently exposed to placental progesterone in utero to produce secretory and decidual changes that precede menstrual shedding. The prevalence of visible neonatal uterine bleeding (NUB) is thought to be between 3–5%, whereas discrete/occult bleeding may be prevalent in up to 60% of newborns,25 providing a mechanism for seeding endometrial cells early in life that are then activated in adolescence. It is also suggested that this mechanism may be responsible for rare cases of endometriosis that present prior to menarche.26
An additional concept that can be merged with the theories of retrograde menstruation and NUB is the theory that endometrial stem/progenitor cells can give rise to lesions. N-Cadherin+ and SUSD2+ endometrial mesenchymal stem cells have been identified in menstrual fluid and in peritoneal fluid.23,27 It has also been postulated that in NUB, potent fetal endometrial stem cells might seed the peritoneal cavity, remaining dormant until estrogen levels begin to rise during thelarche and menarche when they become activated and initiate endometriosis lesions.28
Furthermore, the disrupted eutopic endometrium theory suggests that alterations in the endometrium of women with endometriosis may be responsible for an increased propensity for endometrial cells to survive once they are shed into the peritoneal cavity. Numerous studies have demonstrated that in the eutopic endometrium processes including proliferation, apoptosis, adhesion and invasion, angiogenesis and lymphangiogenesis are altered in women with endometriosis compared to those without. Moreover, hormone production, hormone responsiveness, and immune regulation also exhibit disruption.29,30,31 The single cell transcriptomics revolution has also led to the discovery of multiple subpopulations of stromal fibroblasts (decidual and senescent).32 Adverse pregnancy outcomes, specifically recurrent pregnancy loss is associated with an imbalance of these subpopulations. It may also be hypothesized that such imbalances increase the possibility of refluxed endometrial cells giving rise to endometriosis lesions.
Müllerian duct remnants and coelomic metaplasia
The Müllerian remnants' theory proposes that endometriosis arises from remnants of the Müllerian ducts, which are structures that develop during fetal life and give rise to the female reproductive organs. Müllerian duct anomalies (MDAs) are the manifestations of aberrant uterine and vaginal embryologic development and are seen in higher association in women with endometriosis, particularly in women with anomalies leading to obstructed flow, adding weight to the retrograde menstruation theory. However, increased endometriosis prevalence is also observed in women with anomalies that result in agenesis (functional endometrial tissue without a connected outflow tract), suggesting that residue from the developing Müllerian structures can give rise to lesions.33
Coelomic metaplasia is a phenomenon where the cells that line the peritoneal cavity, undergo a transformation into endometrial-like cells, either spontaneously or after some unknown stimulus.33 The coelomic metaplasia and Müllerian remnants' theory share similar concepts whereby they have embryonic origins and produce cells/tissues that resemble the endometrium and can respond to hormones.
Lymphatic dissemination
According to the lymphatic spread theory, endometrial cells from the shed uterine lining may gain access to the lymphatic vessels present in the uterus or pelvic cavity. Once inside the lymphatic vessels, these endometrial cells can be transported to other areas of the body, away from the uterus. This may include distant sites within the pelvic cavity or even beyond, and may be the main origin of extra-pelvic endometriosis. The theory was postulated to explain the observations of endometrial cells and endometriotic tissue in lymphatic vessels of some women.18,22,34 More recently, additional evidence has demonstrated that pro-lymphangiogenic factors and lymphatic vessel densities are increased in lesions compared to the eutopic endometrium suggesting a mechanism by which endometriotic cells can spread via lymphatics.35
In summary, multiple origins of endometriosis have been proposed and it is extremely likely that not all endometriosis has a common origin. By definition, endometriosis is the presence of endometrial-like cells that occur ectopically (via one or several of the proposed origins) and persist due to a combination of factors. The contribution of factors that potentiate the development of endometriosis is likely different in each case, ultimately leading to the multitude of presentations and disease heterogeneity that is consistently observed. Although the origins described above explain a conduit for the appearance of ectopic endometrial cells, they do not describe the persistence and progression of cells into lesions and advanced disease. Below is a summary of factors that may act to confer a selective advantage to ectopic endometrial-like cells in women with endometriosis.
ETIOLOGIC FEATURES OF ENDOMETRIOSIS
Genetic factors
Endometriosis has a significant heritable component, with familial aggregation, indicating a high risk for first-degree relatives of those affected. Studies performed on twins suggest that heritability may be as high as 50% indicating a strong genetic predisposition.36 Genome-wide association studies (GWAS) and candidate gene studies have identified several genetic variants associated with endometriosis. Prominent genetic susceptibility includes single gene polymorphisms (SNPs) within the following: (i) WNT4, WNT2, and WNT7B; (ii) endometrial receptivity genes (e.g., HOXA10 and HOXA1); (iii) immune-related genes (e.g., IL1A, IL1B, and IL1RN); and (iv) estrogen metabolism genes (GREB1, ESR1, FSHB, CYP1A1, and CYP19A1).37,38,39
Understanding the functional consequences of genetic variants associated with endometriosis is an ongoing area of research. These genetic variations may influence gene expression, protein function, or immune response pathways, ultimately contributing to the persistence of ectopic endometrial-like cells and development of endometriotic lesions. For example, altered Wnt signaling due to genetic variants in WNT4, WNT2, and WNT7B may promote cell proliferation and migration, enhancing the invasive properties of endometriotic lesions. Similarly, variations in immune-related genes may affect the inflammatory microenvironment in the pelvic cavity or altered immune cell profiles, facilitating the establishment and persistence of endometriosis. Mutations in endometrial receptivity genes may contribute to implantation defects and fertility issues observed in endometriosis, whilst conferring selective advantage to refluxed cells. Polymorphisms in genes involved in estrogen metabolism may lead to an imbalance between estrogen and progesterone, promoting the growth of endometriotic lesions.
Gene regulation
Expression quantitative trait locus (eQTL) studies have begun to link the genetic variant (identified via GWAS) regulation of transcriptomic expression.40 Future studies employing this approach should aid in the identification of those genes most likely to be involved in disease risk.
Epigenetic modifications
Epigenetic modifications are reversible and dynamic modulations that regulate how DNA is expressed and are highly influenced by environmental and lifestyle factors. Differences in DNA methylation signatures have been identified in endometriotic tissue compared to normal endometrium. Studies have also evaluated methylation sites in stromal cells derived from endometriosis patients. These methylation sites map to genes that are involved in endometriosis and in the process of endometrial stromal cell decidualization and include HOX genes, nuclear receptors, GATA transcriptional factors and WNT genes.27 Endometriosis has been postulated to be an ‘epigenetic disease’ given the key findings that the promoters for HOXA10 (implicated in the decidualization process), and PR-B are hypermethylated and that DNA methyltransferases (central to DNA methylation) are over expressed in endometriosis.41
Somatic mutations
Somatic cancer-driver mutations have now been described in a range of endometriosis lesions and most of them are recurrent mutations in KRAS, PIK3CA as well as loss of PTEN and ARID1A. They are mostly restricted to the glandular epithelium. Some of these mutations are also observed in the eutopic endometrium but at lower mutant alle frequencies than lesions.42,43 Recently, it has been determined that KRAS mutations were associated with greater anatomic severity of endometriosis, and it has been postulated that cancer-driver mutations may inform a future molecular classification of endometriosis.44
Hormonal imbalances
Steroid-dependence is recognized as a key hallmark of endometriosis. Evidence for de novo steroid synthesis within lesions and increased expression of estrogen receptors (specifically ERb) in lesion resident cells has been well documented and collectively contribute to an estrogen dominant environment. Suppressed expression of progesterone receptor isoforms (PR-A and PR-B) resulting from hypermethylation of the PR promoter has been detected in endometrium as well as lesions from women with endometriosis and contributes to progesterone resistance in the disorder. This is evidenced by decreased progesterone responsiveness in endometriotic cells. Dysregulated progesterone action leads to attenuated endometrial expression of progesterone responsive genes during the window of implantation and impaired decidualization.15,45 As progesterone acts to restrain estrogen-driven proliferation and inflammation in endometrial cells, attenuated progesterone responsiveness compounds the estrogendominant environment in endometriosis.45,46 Estrogen acts on several cell types (including but not limited to stromal cells, endothelial cells, and macrophages) within endometriosis lesions to drive key process central to disease pathophysiology.16,17
Repeated tissue injury and repair and the contribution of previous surgery
The concept that endometriosis lesions are perceived by the body as wounds that undergo repeated tissue injury and repair (reTIAR) is documented in the literature. This theory proposes that, as the ectopic endometrial-like tissue proliferates in response to estrogen, it may undergo a cycle of tissue damage, inflammation, and healing, which ultimately contributes to the formation and persistence of endometriotic lesions and adhesions. It has been proposed that during menstruation, as the normal endometrium exhibits cyclic bleeding, so does ectopic endometrial-like tissue.47 Whilst the eutopic endometrium has the capacity to undergo scarless healing and regeneration, bleeding of ectopic tissue results in aberrant repair, deposition of extracellular matrix and lesional fibrogenesis.9,48 Although cyclic bleeding of lesions has been suggested and observed in some cases, it is not clear what proportion of lesions mirror the cyclicity of the endometrium or exhibit evidence of bleeding.19
Previous pelvic surgeries, such as cesarean sections, laparoscopic procedures, or hysterectomies, can potentially impact the development of endometriosis. It is thought that surgical interventions may inadvertently disperse endometrial tissue into the pelvic cavity. This is seen, for example, in occurrences of umbilical endometriosis following cesarean sections.49,50,51 Surgical trauma, including the formation of adhesions (scar tissue) following surgery, may also play a role in endometriosis.
Immune system dysfunction
Immune cell dysfunction is intrinsically linked with the pathogenesis of endometriosis. It is characterized by excessive immune cell infiltration (into the peritoneal cavity and lesions), heightened immune response (including low-grade systemic inflammation), and altered immune-cell profiles. Ectopic endometrial-like tissue is infiltrated by abundant immune cells that include macrophages, natural killer cells, dendritic cells, T and B cells, and mast cells. These immune cells contribute to the local inflammatory microenvironment.
Macrophages are central to the survival of ectopic endometrial-like tissue and pathogenesis of endometriosis lesions. Not only do they contribute to the inflammatory microenvironment, but they also act to promote lesion growth and vascularization.52 It is also well documented that they play a key role in recruiting nerve fibers, promote the activation of recruited nerves and the generation of pain.10,17 Macrophages exhibit a predominantly pro-repair and tolerogenic phenotype.52,53 Attenuated phagocytic capacity is also reported in peritoneal macrophages in endometriosis.54 Recently, it has been demonstrated that multiple subpopulations of macrophages are present in endometriosis12,53 and that they can exhibit different functions depending on their origin; with some populations exhibiting pro-disease roles and others being protective against the development of endometriosis.12
T-cell dysregulation has also been reported in endometriosis and this includes increased levels of activated CD4+ T cells and regulatory T cells (Tregs). It is thought that these changes may contribute to immune tolerance towards ectopic endometrial-like tissue. There is also evidence that macrophages cooperate with Tregs via CD86 (macrophages) and CTLA4 (Tregs), which may be important in establishing an immunomodulatory microenvironment in endometriosis.53
Peritoneal and lesion-resident immune cells in endometriosis provide an inflammatory microenvironment that allows ectopic endometrial-like tissue to thrive. This includes pro-inflammatory factors that perpetuate recruitment of additional immune cells, further inflammation, tissue damage, and fibrosis. Paradoxically, anti-inflammatory cytokines [e.g., transforming growth factor-beta (TGF-β)] are also expressed in endometriosis and likely contribute to immune evasion and the immunosuppressive environment. Angiogenic (e.g., VEGF) and neurogenic factors (e.g., IGF-1, BDNF) are also significant contributors to the endometriotic milieu and act to recruit blood vessels and nerves fibers.55
Environmental factors
Toxicants
Exposure to certain toxicants that act as endocrine disruptors have been linked to an increased risk of developing endometriosis. Dioxins are environmental pollutants that are released into the air during the burning of waste and other processes. They can accumulate in the food chain and are found in high levels in some animal products, such as meat, dairy, and fish. Epidemiological studies have shown some association between exposure to dioxins and an increased risk of endometriosis in women.56 Animal studies have demonstrated that exposure to dioxins can promote the development of endometrisois,57 it has also been demonstrated that exposure to dioxin in utero reduces fertility and has a significant negative impact on fertility and pregnancy outcomes across generations.58 Other toxicants that have been linked to endometriosis include thalates, polychlorinated biphenyls (PCBs), which are industrial chemicals, widely used in the past, and bisphenol A (BPA), a chemical found in some plastics and other consumer products. PCBs and BPAs also act as endocrine disruptors and interfere with immune function, and cause inflammation, all of which contribute to the development of endometriosis. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that integrates environmental and metabolic cues to control complex transcriptional programmes in a ligand-specific, cell-type-specific context. It is the primary target for endocrine disruptors and has been reported to interact with the estrogen receptor resulting in the recruitment of the AHR-ESR complex to estrogen response elements59 and providing a mechanism for further activation of estrogen-regulated pathways in the context of endometriosis. Whilst the impact of endocrine disrupting toxicants on endometriosis and fertility in model systems has been demonstrated, currently the literature remains too polarized to ascertain a strong correlation between exposure and endometriosis in women.60
Developmental programming
The concept of developmental programming and the fetal origins of health and disease is well established and documented.61 The theory of endometriosis having origins in utero is also gaining traction. The reproductive morphology and physiology of the female reproductive system begins to develop in utero during the first 12 weeks of gestation. It is characterized by development of the hypothalamus-pituitary-gonadal (HPO) axis, which coordinates neurological, hormonal, homeobox-based systems and transcription factor signaling, an aberrant in utero environment during this critical window of development will determine how the system will function in later life. Prenatally, testosterone is active in females, being produced from maternal and fetal sources (lower levels than males). Levels vary prenatally amongst females, and this is responsible for a variety of phenotypes evidenced in facial morphology, anogenital distance and 2D4D digit (finger) ratio. Some females develop under conditions of lower or higher prenatal testosterone with notable effects on development of the HPO axis. This is evidenced in the association between high in utero testosterone exposure and the development of polycystic ovary syndrome (PCOS). It is proposed that endometriosis is in fact the opposite of PCOS, exhibiting hormonal markers and risk factors (including a shorter anogenital distance in women with endometriosis) suggesting that they are diametric opposed disorders.62
SUMMARY
- Endometriosis has several proposed origins, with retrograde menstruation being the most widely accepted.
- A variety of other factors contribute to disease pathophysiology to confer a selective advantage and ability for immune evasion to ectopic endometrial-like cells.
- Endometriosis in different women may arise via different mechanisms and contributing factors.
- In the future, stratification of patients based on their phenotype (disease symptom presentation and peritoneal and lesion biochemistry) and precision diagnostics will hopefully allow patient-specific management and treatment strategies.
CONFLICTS OF INTEREST
The author(s) of this chapter declare that they have no interests that conflict with the contents of the chapter.
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