Table 1.
Observational studies.
| Reference | Sample size | Assay methods | Results | Conclusion | Relevance to fibrosis |
|---|---|---|---|---|---|
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MULTIPLE ENDOMETRIOSIS SUBTYPES | |||||
| Anaf et al., 2000b; Smooth muscles are frequent components of endometriotic lesions (Anaf et al., 2000b) | 21 PER, 13 OMA, 18 DE, 10 control eutopic, 10 healthy peritoneum | IHC and silver staining | PER 75% SMC covered area; OMA 23%; DE 73–79%, peritoneum 0% | Results support transdifferentiation toward smooth muscle cells | Myofibroblasts transdifferentiate toward smooth muscle-like cells in periphery of lesions |
| Bernacchioni et al., 2021; Sphingosine 1-phosphate (S1P) receptors are dysregulated in endometriosis: possible implications in transforming growth factor β-induced fibrosis (Bernacchioni et al., 2021) | 15 OMA, 30 DE, 30 eutopic control | HE, RT-qPCR, WB | Sphingosine kinase (SK) 1 and S1P receptor expression elevated in OMA and DE compared to eutopic control, SK2 not different. TGF-β, α-SMA and collagen 1A expression elevated in OMA and DE versus eutopic control | The S1P signaling axis may represent a useful biomarker or innovative pharmacologic target for endometriosis | Sphingosine signaling axis expression elevated in line with fibrotic markers in endometriosis |
| Haga et al., 2013; immunohistochemical analysis of thoracic endometriosis (Haga et al., 2013) | 84 thoracic endometriosis, 40 diaphragm controls | HE, IHC | Stroma detected in 100%, glands in 25% and SMCs in 1 of the samples. ER staining was positive in the stromal compartment in 88% and PR in 100% of the samples, CD10 in 88% and α-SMA in 55% | Most thoracic endometriosis biopsies stained positive for CD10, ER and PR, half of them for α-SMA. These markers can be useful for diagnosis | Thoracic endometriosis shares high hormonal receptor expression with other endometriosis subtypes, but showed less α-SMA expression |
| Hao et al., 2022; Activation of α7 nicotinic acetylcholine receptor (α7nAChR) retards the development of endometriosis (Hao et al., 2022) | 17 OMA, 14 DE, 18 healthy endometrium | HE, IHC, Masson stain | α7nAChR staining strongest in epithelial cells in all samples. Expression is decreased in DE and OMA versus healthy endometrium, negative correlated with extent of fibrosis, ASRM score, and dysmenorrhea severity | α7nAChR expression is reduced in endometriosis, especially in DE. Pharmacological activation of α7nAChR decelerates lesional progression and fibrogenesis | α7nAChR is suppressed in endometriosis, contributing to disease and can be a potential anti-fibrotic target |
| Huang et al., 2021; Higher fibrotic content of endometriotic lesions is associated with diminished prostaglandin (PG) E2 signaling (Huang et al., 2021) | 41 OMA, 19 DE | HE, IHC, Masson stain, RT-qPCR | DE lesions contained more fibrosis, less COX-2, EP2, and EP4 than OMA lesion. Prostaglandin signaling markers show negative correlation with fibrosis | PGE2 signaling (COX-2, EP2, EP4 staining) attenuated with progressive fibrosis | PGE2 signaling attenuated with progressive fibrosis |
| Khare et al., 1996; A comparative study of ovarian and pelvic wall-infiltrating endometriosis (Khare et al., 1996) | 10 PER, 10 OMA | IHC, Masson stain | Collagen and SMC-like cells were present in bundles around PER lesions, collagen border in OMA lesions | In PER metaplastic reaction without clear delineation observed, in OMA clear delineation with ovary by collagen bundles | Bundles of collagen and smooth muscle-like cells around PER lesions |
| Konrad et al., 2018; Composition of the stroma in the human endometrium and endometriosis (Konrad et al., 2018) | 17 PER, 26 OMA, 22 DE, 47 healthy endometrium | IHC | PER 8%, OMA 19%, DE 9%, patients eutopic 7%, healthy eutopic 9% α-SMA-positive cells among CD10 positive cells, no significant differences between groups | No differences in α-SMA expression in stromal cells | α-SMA expression in stromal cells similar in various endometriosis subtypes |
| Liu et al., 2018; Histological and immunohistochemical characterization of the similarity and difference between ovarian endometriomas and deep infiltrating endometriosis (Liu et al., 2018) | 25 OMA, 25 DE, 20 healthy endometrium | HE, Masson stain, IHC | OMA and DE expressed markers of EMT, FMT, SMM, and fibrosis, more expression in DE. Platelet aggregation in lesions, probably via enhancer of zeste homolog 2. ER-β increased, PR-β decreased in lesions | OMA and DE both undergo EMT, FMT, SMM, fibrosis; DE more extensively, more fibrosis, less vascularity | DE undergo more extensive fibrotic changes compared to OMA |
| Mechsner et al., 2005; Oxytocin receptor expression in smooth muscle cells of peritoneal endometriotic lesions and ovarian endometriotic cysts (Mechsner et al., 2005) | 120 PER (from 80 patients), 40 OMA, 55 distant peritoneum, 11 healthy peritoneum | IHC | Expression of oxytocin receptor, ER and PR among intrastromal α-SMA-positive cells was high, in fully fibrotic areas receptor expression was low. No correlation found between α-SMA and ASRM score | Hormonal and oxytocin receptors present mostly on intrastromal myofibroblasts, ability to contract | Myofibroblasts lose hormonal receptivity toward periphery of lesions |
| Metzger et al., 1993; Histologic features associated with hormonal responsiveness of ectopic endometrium (Metzger et al., 1993) | 196 endometriosis (subtype undefined) and eutopic endometrium | HE | Hormonal responsiveness was defined as ectopic and eutopic endometrium being in phase. Hormonal responsiveness decreased as fibrosis increased. More fibrosis in lesions with hemorrhage signs. Large cystic glands and endometriomas are less often in phase with eutopic endometrium | Hormonal responsiveness correlates with several histologic features of endometriosis | Hormonal responsiveness decreases as fibrosis is more extensive |
| Nezhat and Kalir, 2002; Comparative immunohistochemical studies of endometriotic lesions and endometriotic cysts (Nezhat and Kalir, 2002) | 30 OMA, 35 not defined endometriosis (no OMA) | IHC | 22/30 cystic lesions stained positive for collagen VI compared to 2/35 of non-cystic lesions. BCL-2 staining in 7/30 cysts and 35/35 non-cystic lesions. No p53 staining in both groups. Matrix metalloproteinase IX mostly positive in non-cystic, semi-positive in cystic lesions | Endometriotic cysts have different protein expression patterns. Collagen VI is overexpressed and BCL-2 shows lower expression in cystic lesions versus non-cystic lesions | Collagen VI more overexpressed in cystic lesions versus other lesions |
| Odagiri et al., 2009; Smooth muscle metaplasia and innervation of endometriotic lesions related to pain (Odagiri et al., 2009) | 3 PER, 12 OMA, 5 DE, 5 eutopic endometrium | Masson stain, IHC | Intense α-SMA staining around stromal region, intense neural cell adhesion molecule staining in lesions, and fibrotic interstitium | Smooth muscle cells and nerve cells are extensively present around lesions and fibrosis, suggesting a relationship between contraction and pain | Clustering of nerve cells and myofibroblasts suggesting a role in pain |
| Shin et al., 2023; Single-cell profiling identifies distinct hormonal, immunologic, and inflammatory signatures of endometriosis-constituting cells (Shin et al., 2023) | 6 OMA, 4 PER, 7 DE | scRNA-seq | 11 cell types were assigned. Macrophage (Mac) subpopulations differed between subtypes, nonclassical monocytes in DIE, resident monocytes in OMA and PER, Mac-2 in PER and DE, Mac-4 (MMP9 expressing) in OMA. 5 fibroblasts subpopulations were identified, Myofibroblast (Mfib)-1, Mfib-2 and Mfib-3 abundance in endometriosis, Mfib-1 (Periostin expressing) and Mfib-2 (mesenchymal marker expressing) main fibroblast in PER and DE, Mfib-3 (Transmembrane 19 and Tenascin-C expressing) in OMA | Subpopulations of cell types varied between endometriosis subtypes, estrogen responsiveness is generally high, and distinct cell subpopulations, among which are myofibroblasts, are found in endometriosis, indicating the heterogeneity of endometriosis | Different subpopulations of myofibroblasts are present in the different subtypes of endometriosis and not present in normal endometrium |
| Yan et al., 2019b; Neuropeptides substance P and calcitonin gene-related peptide accelerate the development and fibrogenesis of endometriosis (Yan et al., 2019b) | 30 OMA, 30 DE, 24 healthy endometrium | Masson stain, IHC, WB, RT-qPCR | DE showed more α-SMA expression and fibrosis than OMA. Fibrosis and α-SMA expression showed positive correlation with nerve fiber density and neuropeptides and their receptors. The severity of dysmenorrhea showed a positive correlation with nerve fiber density | Sensory nerves have an important role in promoting fibrogenesis. Substance P, calcitonin-related peptide, and their receptors stimulate EMT, FMT, and SMM. The anatomical link between DE and multiple nerve plexus could explain higher fibromuscular content in DE | Colocalization of nerves, neuropeptides, and fibrosis implies the contribution of fibrosis to pain in endometriosis |
| Yan et al., 2020b; Platelets induce endothelial-mesenchymal transition and subsequent fibrogenesis in endometriosis (Yan et al., 2020b) | 30 OMA, 30 DE, 30 healthy endometrium | Masson stain, IHC | Highest fibrotic content in DE. Fibroblast-specific protein-1 (FSP-1, as a mesenchymal marker) expression is elevated in endometriotic lesions. Fibrosis showed a positive correlation with FSP-1 and FSP1/CD31 ratio. Co-culture of human umbilical vein endothelial cells (HUVECs) and activated platelets increased and fibrosis markers, TGF-β and Platelet-derived growth factor receptor neutralization abolished effect | Evidence for EndoMT with a critical role of platelet activation | EndoMT supports fibrogenesis with a critical role in platelet activation |
| Yan et al., 2020a; Mesothelial cells participate in endometriosis fibrogenesis through platelet-induced mesothelial-mesenchymal transition (Yan et al., 2020a) | 30 OMA, 30 DE, 30 healthy endometrium | Masson stain, IHC, WB, RT-qPCR | Highest fibrotic content and α-SMA expression in DE. Calretinin (mesothelial marker) showed a positive correlation with fibrosis | Mesothelial cells contribute to fibrosis and lesional progression through platelet-induced mesothelial-mesenchymal transition | Mesothelial origin in endometriotic lesions contribute to development of fibrosis |
| Zheng et al., 2023a; Aberrant expression of histone deacetylase (HDAC) 8 in endometriosis and its potential as therapeutic target (Zheng et al., 2023a) | 38 OMA, 20 DE, 24 healthy endometrium | Masson stain, IHC | HDAC2 staining reduced, HDAC8 elevated in lesions. HDAC1 and HDAC6 elevated in DE, HDAC3 reduced, but in OMA these were similar to control endometrium. Extent of fibrosis highest in DE, also elevated in OMA, fibrosis correlated positively with HDAC1, 6 and 8 and negatively with 2 and 3 | Mainly HDAC8 expression is elevated in endometriosis and correlated with fibrosis, suggesting a role in FMT and SMM, which is supported by an anti-fibrotic effect of HDAC8 inhibition in a mouse experiment | HDAC8 overexpression in endometriosis contributes to fibrogenesis and is a potential therapeutic target |
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|
PERITONEAL ENDOMETRIOSIS | |||||
| Barcena de Arellano et al., 2011; Immunohistochemical characterization of endometriosis-associated smooth muscle cells in human peritoneal lesions (Barcena de Arellano et al., 2011) | 60 PER, 60 distant peritoneal biopsies, 10 healthy peritoneal biopsies | IHC | 25% of the stromal region, 65% of the surrounding tissue, and 31% of the peripheral tissue α-SMA positive. Differentiation grade intrastromal SMC 12–15%; 36–44% surrounding SMC; peripheral SMC 77–80%. No differences in SMC amount based on hormonal medication, cycle, or color of lesion | Increased differentiation toward the periphery, SMC has contractile abilities and may be responsible for pain | Myofibroblasts differentiate toward smooth muscle-like cells in the periphery of lesions |
| Ibrahim et al., 2019; Arrangement of myofibroblastic and smooth muscle-like cells in superficial peritoneal endometriosis and a possible role of transforming growth factor beta 1 (TGF-β1) in myofibroblastic metaplasia (Ibrahim et al., 2019) | 23 PER, 5 distant peritoneum biopsies, 10 healthy peritoneum | IHC | Myofibroblasts are present in all compartments of the lesion, contractile calponin-positive cells mostly in intra-stromal region, and differentiated desmin-positive cells in the periphery. TGF-β receptors are highest in the intra-stromal region | Cell maturity increased toward the periphery of lesions. TGF-β involved in metaplasia | Myofibroblasts differentiate into smooth muscle-like cells in the periphery of lesions |
| Matsuzaki et al., 1999; Fibrogenesis in peritoneal endometriosis (Matsuzaki et al., 1999) | 16 PER, 8 healthy eutopic endometrium | IHC | Different part of the stromal compartment of lesions was stained for collagen between different lesion appearances: 61,5% collagen in black; 33,1% in red; 12,5% eutopic. No differences between cycle stages | Collagen is more present in black versus red lesions | Black lesions contain more collagen than red lesions, phase of the menstrual cycle does not affect collagen content |
| Sohler et al., 2013; Tissue remodeling and non-endometrium-like menstrual cycling are hallmarks of peritoneal endometriosis lesions (Sohler et al., 2013) | 18 PER, 22 distant peritoneum, 17 eutopic endometrium | IHC, RT-qPCR | Fibrosis present in metaplastic lesions, not in hyperplastic lesions; α-SMA mRNA overexpression in lesions compared to eutopic endometrium. Metaplasia based on caldesmon expression. SMC hyperplasia not found in combination with fibrosis. No changes in expression of steroid receptors and tissue remodeling factors trough cycle | Endometriotic lesions do not undergo a menstrual cycle based on microarray analysis | Fibrotic endometriosis lesions do not undergo a regular menstrual cycle |
| Stovall et al., 1992; Immunohistochemical detection of type I, III, and IV collagen in endometriosis implants (Stovall et al., 1992) | 10 PER, 10 eutopic endometrium, 6 healthy eutopic endometrium | IHC | Collagen types were similar between eutopic endometrium and intrastromal area of lesions. Type I collagen was dominant in the fibrotic surrounding of lesions | Various collagen types are present in ectopic and eutopic endometrium. Collagen I dominant in lesion-associated fibrosis | Collagen I is the main ECM component in endometriotic lesion-associated fibrosis |
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|
OVARIAN ENDOMETRIOTIC CYST | |||||
| Cao et al., 2019; Plasma high mobility group box 1 (HMGB1), osteopontin (OPN), and hyaluronic acid (HA) as admissible biomarkers for endometriosis (Cao et al., 2019) | 30 OMA, 20 healthy controls. Lesion biopsies and blood plasma | HE, Masson stain, IHC, ELISA | Moderately fibrotic compared to highly fibrotic lesions: lower expression of OPN, Rage, Interleukin-33, higher HMGB1, Toll-like receptor 4, p-p65, and proliferating cell nuclear antigen. Plasma levels of HMGB1, OPN, and HA in patients elevated compared to controls and showed a positive correlation with the extent of fibrosis | Plasma HMGB1, OPN, and HA are promising biomarkers | Positive correlation between plasma markers and the extent of fibrosis in lesions |
| Ding et al., 2020b; Evidence in support for the progressive nature of ovarian endometriosis (Dinget al., 2020b) | 62 OMA: 30 adolescents (15–19 years), 32 adults (35–39 years) | HE, Masson stain, IHC | In lesions from adults more fibrosis and higher expression of α-SMA. Markers of EMT, FMT, and SMM showed further differentiation. Fibrosis showed a positive correlation with time since ultrasound diagnosis and dysmenorrhea severity | OMA endometriosis lesions in adults are more differentiated in terms of EMT, FMT, and SMM and more fibrotic, which supports the progressive nature of the disease | Fibrotic markers increase in older patients, this supports progressive fibrosis. Fibrosis correlates with dysmenorrhea |
| Guo et al., 2015b; Dating endometriotic ovarian cysts based on the content of cyst fluid and its potential clinical implications (Guo et al., 2015b) | 34 OMA | HE, Masson stain, Picrosirius stain, cyst fluid viscosity measurement | White cyst walls contain 68.2% collagen, mostly type I, more than black cyst walls 54.4%, mostly type I and III. Cyst fluid in white cysts had higher viscosity and iron content | Older endometriotic (white) cysts contain more viscous fluid with higher iron content and more fibrosis: suggesting ReTIAR process resulting in fibrotic lesions resistant to hormonal treatment | Fibrotic area increased in white (older) cyst walls, fibrosis is progressive over time in OMA |
| Kitajima et al., 2011; Endometriomas as a possible cause of reduced ovarian reserve in women with endometriosis (Kitajima et al., 2011) | 22 OMA, 11 contralateral ovary biopsies | HE, Masson stain | Follicular density was lower in ovaries with endometriotic cysts. Fibrosis was observed in 80% of ovaries with endometriotic cysts, in 27% without. Fibrosis and presence of cysts independently associated with decreased follicular density | Endometriotic cysts and associated fibrotic tissue may be a cause of reduced ovarian reserve | Fibrosis and endometriotic cysts are independently associated with decreased follicular density |
| Muraoka et al., 2023; Fusobacterium infection facilitates the development of endometriosis through the phenotypic transition of endometrial fibroblasts (Muraoka et al., 2023) | 4 OMA, 4 eutopic endometrium, 4 healthy endometrium | IHC, RT-qPCR, scRNA-seq, FISH | Transgelin (TAGLN) expression was highest in fibroblasts in OMA, also elevated in eutopic endometrium compared to healthy endometrium. Fusobacterium nucleatum was present in 64.3% of eutopic endometrium, 52.4% of ectopic endometrium, 7.1% of healthy endometrium. TGF-β expression was different between F. Nucleatum positive and negative samples | TGF-β promotes myofibroblastic transition, marked by TAGLN expression. TGF-β signaling can be activated by F. nucleatum infection, suggesting a role in pathogenesis. Antibiotic treatment can be a potential therapeutic target | Fusobacterium infection in endometrium triggers myofibroblast activation and thereby attributes to the establishment of endometriotic lesions |
| Nagai et al., 2020; Focal adhesion kinase (FAK)-mediated sequences, including cell adhesion, inflammatory response, and fibrosis as a therapeutic target in endometriosis (Nagai et al., 2020) | 8 OMA, 8 healthy eutopic endometrium | IHC | Focal adhesion kinase (FAK) and monocyte chemoattractant protein-1 expression were upregulated in endometriosis. Co-culture of U937 (macrophage cell line) upregulated TGF-β1 expression | FAK-mediated development of endometriotic lesions is a potential therapeutic target | FAK has a stimulating effect on fibrosis in endometriosis |
| Nie et al., 2022; Identification of lesional attributes of dysmenorrhea severity and the serum antimullerian hormone (AMH) levels in women with ovarian endometriomas (Nie et al., 2022) | 313 OMA | HE, IHC, Masson stain, chemiluminescence for serum hormones | Dysmenorrhea severity correlated negatively with PR-B expression, positively with α-SMA, and lesional fibrosis. AMH levels are not correlated with lesion size, lesional fibrosis, α-SMA, or bilaterality. Adjacent cortical fibrosis varied greatly between patients and correlated negatively with AMH levels | Extent of lesional fibrosis correlated positively with dysmenorrhea severity, not with serum AMH. Ovarian cortical fibrosis correlated negatively with AMH, which argues for early surgical intervention | Lesional fibrosis did not correlate with AMH as a marker for ovarian reserve. Adjacent ovarian cortical fibrosis negatively correlates with AMH. Association between lesional and cortical fibrosis unclear |
| Selcuk et al., 2021; Tumour markers and histopathologic features of ovarian endometriotic cysts (Selcuk et al., 2021) | 97 OMA | HE (thickness fibrosis), blood plasma ELISA | Positive correlation between tumor markers and fibrosis thickness and penetration dept of cyst wall in ovarian tissue. Only CA125 showed a positive correlation with ASRM score | Low levels of tumor markers may permit conservative management, high levels permit surgical intervention based on expected surgical damage on the ovary | Tumor markers are predictive for fibrosis thickness |
| Shi et al., 2017; Transforming growth factor β1 from endometriomas promotes fibrosis in surrounding ovarian tissues via Smad/3 signaling (Shi et al., 2017) | 42 OMA, 29 teratoma controls | HE, Masson stain, IHC, WB, RT-qPCR, FISH | In OMA wall more fibrosis and higher expression of COL1A, α-SMA, TGF-β(R), CTGF, Matrix metalloproteinases, Smad pathway markers | Endometriotic cyst cells produce TGF-β1 leading to fibrosis and adhesions to ovarian tissue via TGF-β1/Smad signaling pathways | Smad pathway is a driver of fibrosis |
| Tsujioka et al., 2009; The efficacy of preoperative hormonal therapy before laparoscopic cystectomy of ovarian endometriomas (Tsujioka et al., 2009) | 96 OMA, 53 untreated, 34 GnRH agonist therapy, 9 danazol | HE, Medical chart review | Hormonal-treated patients had smaller cyst size, no differences in lost primordial follicles, and increased resection time needed. Fibrosis was present in the cyst wall in 45,6% of the untreated group and in all treated patients. More fibrosis between the cyst wall and ovarian tissue | Pre-operative hormonal treatment results in a more favorable pelvic situation. Hormonal treatment did not reduce the loss of primordial follicles. Therapy increases the risk of severe fibrosis and causes difficulties in stripping the cyst wall | Pre-operative hormonal therapy could influence the fibrotic connection between the cyst wall and ovarian tissue |
| Vicino et al., 2009; Fibrotic tissue in the endometrioma capsule: surgical and physiopathologic considerations from histologic findings (Vicino et al., 2009) | 91 OMA | HE (thickness fibrosis), blood plasma ELISA | Negative correlation between fibrotic thickness in cyst wall and CA-125 | High CA-125 correlates with a thinner fibrotic part of the cyst wall and harder stripping removal of the cyst. | CA125 is predictive for thin fibrotic cyst wall |
| Xu et al., 2023; A novel mechanism regulating pyroptosis-induced fibrosis in endometriosis via lnc-MALAT1/miR141-3p/NLRP3 pathway (Xu et al., 2023) | 24 OMA, 24 eutopic endometrium, 26 healthy endometrium | HE, IHC, Masson stain, RT-qPCR, WB | Expression of pyroptosis indicators NLRP3, caspase-1, Gasdermin D and interleukin-1β and fibrotic markers TGF-β1, CTGF, α-SMA, and Fibronectin-1 and extent of fibrosis were increased in OMA versus healthy and patient ectopic endometrium | NLRP3-mediated pyroptosis is upregulated and positively correlated with fibrosis in OMA. Lnc-MALAT1 is increased in endometriosis, which deregulated miR141 expression, leading to increased pyroptosis via NLRP3 expression | NLRP3-mediated pyroptosis via Lnc-MALAT1 regulation promotes fibrosis in endometriosis and is a potential therapeutic target |
| Zhang et al., 2019a; Endometriotic peritoneal fluid promotes myofibroblast differentiation of endometrial mesenchymal stem cells (Zhang et al., 2019a) | 32 OMA, 32 eutopic endometrium, 20 healthy endometrium, Patients and healthy PF | Masson stain, IHC, WB | α-SMA, COL1, CTGF, fibronectin, and the extent of fibrosis increased in OMA compared to eutopic endometrium. Sushi containing domain 2 colocalized with α-SMA in OMA. Patients PF increased fibrotic marker expression in stromal cells | Endometriotic peritoneal fluid promotes myofibroblast differentiation of mesenchymal stem cells | Mesenchymal stem cells are important for fibrosis because they are capable of transdifferentiating to myofibroblasts |
| Zhu et al., 2023; The heterogeneity of fibrogenesis and angiogenesis in endometriosis revealed by single-cell RNA-sequencing (Zhu et al., 2023) | 3 OMA, 3 eutopic endometrium, 3 healthy endometrium | scRNA-seq, HE, IHC, Sirius red stain | Myofibroblasts, pericytes, endothelial cells, and macrophages in abundance in OMA, myofibroblast (MF) C2 dominant MF type (role in ECM organization, TGF-β and Wnt signaling pathway) and derived mainly from FMT | Myofibroblasts, pericytes, and macrophages are potential therapeutic targets | There is an abundance of myofibroblasts in OMA and fibroblasts in eutopic endometrium. Myofibroblasts derived mainly from FMT |
|
DEEP ENDOMETRIOSIS | |||||
| Anaf et al., 2000a; Relationship between endometriotic foci and nerves in rectovaginal endometriotic nodules (Anaf et al., 2000a) | 28 DE | HE, Masson stain, IHC | High pain score groups showed more intrafibrotic and intraglandular nerves and peri- and endoneural invasion of endometriosis | There is a close histological relationship between nerves, endometriotic foci, and their fibrotic environment | Colocalization between fibrosis and nerves implies the role of fibrosis in pain |
| Bonte et al., 2002; Histologic appearance of endometriosis infiltrating uterosacral ligaments in women with painful symptoms (Bonte et al., 2002) | 172 DE | HE | Fibrosis was detected in 59.9% of clinical suspect lesions, and smooth muscle hyperplasia in direct contact with glands in 14,5% of lesions. Connective-muscular tissue in close contact with nerve networks. Typical lesions found in 70,8% of clinical suspect lesions | Histologic appearance of suspect lesions is heterogenous. Fibrosis is often present. Smooth muscle hyperplasia is sometimes present, and could be associated with nerve networks | Fibrosis is often present in endometriotic lesions and sometimes associated with nerve networks |
| Ding et al., 2020a; Diagnosing deep endometriosis using transvaginal elastosonography (TVESG) (Ding et al., 2020a) | 34 DE | HE, IHC, MRI, ultrasound, shear-wave elastosonography | DE lesions detected by: pelvic examination 83,3%; ultrasound 66,7%; MRI 83,3%; TVESG 100%. Missed lesions were smaller, higher stiffness. Fibrosis showed a positive correlation with stiffness, α-SMA, and PR, a negative correlation with ER and vascular density | TVESG could help diagnostics by differentiating tissue stiffness between the lesion and surrounding tissue and estimate the developmental stage of the lesion | Stiffness of fibrotic tissue could be used in the diagnostic process |
| Itoga et al., 2003; Fibrosis and smooth muscle metaplasia in rectovaginal endometriosis (Itoga et al., 2003) | 90 DE | HE, Azan, von Gieson, Berlin blue stains, IHC | Fibrosis is present in 89/90 samples. If mild, fibrosis mainly around glands/stroma, if severe, fibrosis incorporated fat and connective tissue around lesions. Lower fibrosis scores in GnRH-treated patients. Smooth muscle metaplasia in 80/90 samples, positive correlation with fibrosis. No differences in GnRH yes or no groups | Smooth-muscle metaplasia is present in fibrotic areas and becomes more severe correlating with increased fibrosis | Fibrosis and smooth-muscle metaplasia are common features of endometriosis. GnRH treatment might prevent fibrogenesis |
| Roman et al., 2009; Histopathological features of endometriotic rectal nodules and the implications for the management by rectal nodule excision (Roman et al., 2009) | 27 DE | HE | 14/27 cases showed infiltration of fibrosis and glands/stroma in same rectal layer. Deeper infiltration of glands/stroma than fibrosis in 24/27. 3/27 deeper fibrosis than glands/stroma | In majority of lesions, gland/stroma infiltration is deeper than fibrosis. Surgical excision of macroscopic fibrosis will leave glands/stroma intact and may continue natural evolution. Could be cause of recurrence | Fibrosis infiltration depth in bowel follows lesion infiltration dept, might indicate fibrogenesis as a reaction to lesion ingrowth |
| Stratopoulou et al., 2021; Identifying common pathogenic features in deep endometriotic nodules and uterine adenomyosis (Stratopoulou et al., 2021) | 13 DE, 14 adenomyosis, 27 eutopic endometrium, 14 healthy endometrium | HE, Picrosirius red stain, IHC | Collagen/stroma rates: Healthy 20% collagen, DE 60%, adenomyosis 65%. DE showed decreased platelet aggregation and increased macrophage infiltration, comparable with adenomyosis | Macrophage accumulation, fibrosis and irregular angiogenesis are common in DE and adenomyosis. DE and adenomyosis show histologic similarities | Fibrosis common in DE, similarities between adenomyosis and DE |
| van Kaam et al., 2008; Fibromuscular differentiation in deeply infiltrating endometriosis is a reaction of resident fibroblasts to the presence of ectopic endometrium (van Kaam et al., 2008) | 20 DE | IHC | Stroma of lesions showed high vimentin and low α-SMA, desmin and SM-MHC expression, fibromuscular tissue around lesion showed strong α-SMA and SM-MHC expression. Smad colocalized with TGF-β receptors in stroma | Fibromuscular differentiation is present in DE lesions and the result of a reaction of the local environment to the presence of ectopic endometrium | More FMT toward periphery of lesions. Smad and TGF-β receptors showed a connection |
| Xie et al., 2013; Potential role of strain elastosonography for detection of the extent of large-scar endometriosis (Xie et al., 2013) | 8 DE | HE, IHC, MRI, ultrasound, strain elastosonography | Elastosonography showed larger extent of lesions (62.4 mm) than MRI (40.9 mm) and conventional US (41.4 mm). All cases showed strong collagen expression | Strain elastosonography could enhance diagnostic accuracy of scar endometriosis | Stiffness of fibrotic tissue could be used in diagnostics |
Studies assessing multiple endometriosis subtypes are only shown in the first section of the table and not in the subsequent following categories to avoid double information. Studies including both observational and intervention approaches are shown in both tables. Information depicted in each table is specific regarding that particular part of the study. The conclusion column shows a conclusion as stated by the authors, so this is including results from both parts of the study. Sample size of number of biopsies is shown, in some cases multiple biopsies from a single patient were included separately. PER, peritoneal endometriosis; OMA, ovarian endometrioma; DE, deep endometriosis; HE, hematoxylin/eosin staining; IHC, immunohistochemistry; IF, immunofluorescence; WB, western blot; RT-qPCR, real-time qualitative polymerase chain reaction; α-SMA, α-smooth muscle actin; TGF-β, transforming growth factor-β; COL, collagen; CTGF or CCN2, connective tissue growth factor; SM-MHC, smooth muscle-myosin heavy chain; EMT, epithelial-to-mesenchymal transition; FMT, fibroblast-to-myofibroblast transdifferentiation; SMM, smooth muscle metaplasia; SMC, smooth muscle cell; ER, estrogen receptor; PR, progesterone receptor; ASRM score, American Society of Reproductive Medicine score.