{"paper_id":"dbe913f9-2b35-43a2-9d49-3199b829222a","body_text":"https://doi.org/10.1530/JME-17-0227\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nCellular signal dysfunction in \nendometriosis\nY J Cho et al.Journal of Molecular \nEndocrinology\nR97–R113\n60 3:\nREVIEW\nDysfunctional signaling underlying \nendometriosis: current state of knowledge\nYeon Jean Cho1,2, Seung Hyun Lee1, Jung Woo Park1, Myoungseok Han1, Mi Jin Park2 and Sang Jun Han2,3,4,5\n1Department of Obstetrics and Gynecology, Dong-A University, College of Medicine, Busan, Republic of Korea\n2Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA\n3Center for Reproductive Medicine, Baylor College of Medicine, Houston, Texas, USA\n4Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA\n5Center for Drug Discovery, Baylor College of Medicine, Houston, Texas, USA\nCorrespondence should be addressed to S J Han: sjhan@bcm.edu\nAbstract\nEndometriosis is defined as the presence of endometrial tissue outside the uterine \ncavity. It affects approximately 5–10% of women of reproductive age. Endometriosis is \nassociated with dysmenorrhea, dyspareunia and, often, severe pelvic pain. In addition \nto pain, women with endometriosis often experience infertility. Defining the molecular \netiology of endometriosis is a significant challenge for improving the quality of women’s \nlives. Unfortunately, the pathophysiology of endometriosis is not well understood. Here, \nwe summarize the potential causative factors of endometriosis in the following three \ncategories: (1) dysregulation of immune cells in the peritoneal fluid and endometriotic \nlesions; (2) alteration of apoptotic signaling in retrograde menstrual tissue and cytotoxic \nT cells involved in endometriosis progression and (3) dysregulation of oxidative \nstress. Determining the molecular etiology of these dysregulated cellular signaling \npathways should provide crucial clues for understanding initiation and progression \nof endometriosis. Moreover, improved understanding should suggest new molecular \ntherapeutic targets that could improve the specificity of endometriosis treatments and \nreduce the side effects associated with current approaches.\nIntroduction\nEndometriosis, defined as the presence of endometrial \ntissue outside the uterine cavity, results in severe \npelvic pain and infertility in up to 5–10% of women of \nreproductive age (Eskenazi & Warner 1997, Giudice 2010). \nUnderstanding the molecular etiology of endometriosis is \nessential to providing better treatment for this disease. \nThere are many unresolved side effects of treatment, \nincluding adverse consequences for normal reproductive \nfunction, because current systemic estrogen deficiency \ntherapy using gonadotropin-releasing hormone agonists \n(Descamps & Lansac 1998), oral contraceptives, synthetic \nprogestins and/or aromatase inhibitors prevents \npregnancy ( Attar & Bulun 2006 ). To minimize these \nside effects, new and essential pathological pathways \ninvolved in endometriosis and endometriosis-associated \ndysfunction need to be evaluated.\nThere are several hypotheses regarding how \nendometriosis is initiated and progresses ( Bulun 2009 ). \nThe most widely accepted hypothesis involves retrograde \nmenstruation (Sampson’s hypothesis), wherein viable \nendometrial tissue fragments move into the pelvic cavity \nthrough the fallopian tubes during menstruation (Sampson \n1927). These refluxed endometrial cells subsequently \nadhere to various tissues (such as the ovary, peritoneum, \nJournal of Molecular \nEndocrinology  \n(2018) 60, R97–R113\nKey Words\n f endometriosis\n f inflammation\n f apoptosis\n f oxidative stress\n f estrogen receptor\n10.1530/JME-17-0227\n360\nDownloaded from Bioscientifica.com at 06/18/2026 11:06:46PM\nvia free access\n\n\nhttps://doi.org/10.1530/JME-17-0227\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nR98\nY J Cho et al. Cellular signal dysfunction in \nendometriosis60 3:\nJournal of Molecular \nEndocrinology\nintestine and uterus), invade them and then proliferate \nuntil they become endometriotic lesions. Abnormalities \nof the genital tract, genetic predispositions, hormonal \nimbalances, altered immune surveillance, inflammatory \nresponses and abnormal regulation of endometrial cells are \npotential causative drivers of endometriosis progression \n(Sourial et  al. 2014 ). Although numerous studies have \nsought to determine the causative factors underlying the \ninitiation and progression of endometriosis, the precise \npathogenesis of endometriosis remains unknown. To \nhelp address this crucial question, we have summarized \nhow the dysregulation of inflammation, apoptosis and \noxidative stress signaling in immune cells, endometriotic \nlesions and peritoneal fluid drives the initiation and \nprogression of endometriosis ( Gupta et  al. 2006 , Barrier \n2010, Taniguchi et al. 2011). A review of the literature was \nconducted to identify the most relevant studies reported \nin the English language. We searched the PubMed \nMEDLINE electronic database ( https://www.ncbi.nlm.\nnih.gov/pubmed) for articles published between 1996 \nand 2017. The major keywords used were as follows: \n‘endometriosis and inflammation’, ‘endometriosis and \nimmune dysregulation’, ‘endometriosis and apoptosis’ \nand ‘endometriosis and oxidative stress’. Here, our \ngoal was to present relevant research related to the \npathophysiology of endometriosis, and we considered \nboth in vitro  studies using human samples and animal \nmodel studies. To specify our purpose, we have included \nadditional keywords as follows: ‘T-cell/B-cell dysfunction’, \n‘macrophage’, ‘natural killer cells’, ‘cytokine signal’ \nand ‘inflammation and estrogen receptor’ along with \nendometriosis. Moreover, references in each article were \nsearched to identify studies potentially overlooked in our \ninitial search.\nDysregulation of immune signaling during \nendometriosis progression\nDuring each menstrual cycle, viable endometrial \nfragments are transported into the peritoneal area by \nretrograde menstruation. Several studies have indicated \nthat endometriosis patients have dysregulated immune \nsystems that allow retrograde menstrual tissue to survive. \nFor example, endometriosis patients have elevated levels \nof activated macrophages, T and B cells, but reduced \nlevels of cytotoxic natural killer (NK) cells compared \nto healthy women ( Jeung et  al. 2016 ). They also show \nsignificant upregulation of stem cell growth factor b \n(SCGFB), interleukin (IL) 8, human growth factor (HGF) \nand monocyte chemoattractant protein 1 (MCP1) and \ndownregulation of IL13 ( Jorgensen et  al. 2017 ). These \ndysregulated immune cells and their cytokine networks \ncould stimulate the initiation and progression of \nendometriosis.\nAlterations of macrophages and their \ncytokine profiles in endometriosis\nMacrophages, the internal components of the \nmononuclear phagocyte system, are derived from \nbone marrow progenitors and enter the bloodstream \nas monocytes. In peripheral tissues, macrophages are \nmatured and activated in response to various external \nstimuli (such as lineage-determining growth factors, \nT helper (Th) cell cytokines and microbial products) to \nmodulate the immune system (Santanam et al. 2002).\nAre macrophages required for the progression \nof endometriosis?\nSignificantly increased numbers of macrophages \nare detected in eutopic endometria in women with \nendometriosis ( Berbic et  al. 2009 ), raising questions \nregarding their role during endometriosis progression. \nA rat endometriosis model showed that macrophage \ndepletion using liposomal alendronate (LA) effectively \ninhibited the initiation and growth of endometriotic \nlesions, as determined by reduced implantation rates, \nadhesion scoring, implant size and weight and numbers \nof infiltrating macrophages in implants following LA \ntreatment compared to vehicle treatment ( Haber et  al. \n2009). Another study revealed that endometrial fragments \nadhered to and implanted in the peritoneal wall, whereas \nendometriotic lesions failed to organize and develop in \nthe absence of macrophages because blood vessels failed \nto reach the inner layers of endometriotic lesions, which \nsubsequently stopped growing ( Bacci et al. 2009). These \nobservations suggest an important role for macrophages \nin endometriosis progression.\nHow do macrophages drive \nendometriosis progression?\nAs macrophages secrete various cytokines to modulate \nnormal cell functions, dysregulated macrophage-secreted \ncytokines have been associated with several diseases (Arango \nDuque & Descoteaux 2014 ). An abundance of peritoneal \nneutrophils and macrophages in the peritoneal fluid of \nendometriosis patients increases the levels of vascular \nendothelial growth factor (VEGF), which stimulates \nendometriosis progression ( Lin et  al. 2006 ). Higher \nDownloaded from Bioscientifica.com at 06/18/2026 11:06:46PM\nvia free access\n\n\nhttps://doi.org/10.1530/JME-17-0227\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nR99\n60 3:\nY J Cho et al. Cellular signal dysfunction in \nendometriosis\nJournal of Molecular \nEndocrinology\nlevels of macrophages may play a role in endometriosis \nby increasing the levels of cytokines responsible for \namplifying the angiogenic signal. Interleukin 24 (IL24) is \na novel tumor suppressor gene active in a broad range of \nhuman cancer cells. In decidual stromal cells, IL24 also \nsignificantly restricts the stimulatory effects of estrogen \n(Shao et  al. 2013 ). Interestingly, macrophages markedly \nreduce the expression of IL24 in endometrial stromal \ncells to limit the inhibitory effects of IL24 on cell viability \nand invasion, as well as on the expression levels of the \nproliferation-related gene Ki-67, proliferating cell nuclear \nantigen (PCNA) and cyclooxygenase 2 (COX2) (Shao et al. \n2016). Macrophage-mediated downregulation of IL24 \nleads to the increased proliferation and invasiveness of \nendometrial stromal cells and contributes to endometriosis \nprogression.\nTumor growth factor (TGF)β levels are also elevated in \nendometriotic lesions and macrophages in women with \nendometriosis compared to healthy women ( Omwandho \net  al. 2010 ). TGF β-mediated autocrine and paracrine \nsignaling in peritoneal macrophages plays an essential role \nin endometriosis progression by stimulating macrophage \nDNA synthesis, macrophage cell–cell interactions and the \nexpression of macrophage cell surface adhesion molecules, \nsuch as integrin-α/β (Dou et al. 1997).\nIs there any difference in the macrophage \npopulations between the normal endometrium \nand endometriotic lesions?\nMacrophages are activated into classic (M1) or alternative \n(M2) phenotypes depending on the type of stimulation \n(Martinez & Gordon 2014 ). Lipopolysaccharides (LPS), \ninterferon-γ (IFN-γ) and granulocyte-macrophage colony-\nstimulating factor (GM-CSF) induce macrophages toward \nthe M1 phenotype. M1 macrophages produce significant \nlevels of pro-inflammatory cytokines, such as IL1 β, \ntumor necrosis factor (TNF), IL12, IL18 and IL23 ( Wang \net  al. 2014a). These help drive antigen-specific Th1 and \nTh17 cell inflammatory responses that suppress tumor \ncell growth ( Roberts et  al. 2015 ). In addition to pro-\ninflammatory cytokines, M1 macrophages upregulate \nthe expression of intracellular protein suppressor of \ncytokine signaling 3 (SOCS3) and activate inducible \nnitric oxide synthase (NOS2 or iNOS) to produce NO \nfrom L-arginine and inhibit tumor growth ( Arnold et al. \n2014). Macrophages are guided toward the M2 type by \nfungal cells, immune complexes, helminth infections, \ncomplement components, apoptotic cells, macrophage \ncolony-stimulating factor (MCSF), IL4, IL13, IL10 and \ntransforming growth factor (TGF)- β (Martinez & Gordon \n2014). Activated M2 macrophages secrete high levels \nof IL10, IL1, IL1ra and IL6 to stimulate tumor growth \n(Arango Duque & Descoteaux 2014).\nA rhesus macaque model of endometriosis revealed \nthat, compared to controls, the activation state of \nmacrophages in endometriosis tissues in nonhuman \nprimates was skewed toward the M2 phenotype ( Smith \net  al. 2012 ). Large peritoneal macrophages (LPMs) and \nsmall peritoneal macrophages (SPMs) have been found \nto polarize toward either M1 or M2 cells, respectively, \nin a murine model. Accordingly, the proportion of \nSPMs increased immediately after peritoneal injection \nof endometrial tissue, whereas LPMs exhibited the \nopposite trend (Yuan et al. 2017). Thus, it is possible that \nretrograde menstrual tissues could stimulate peritoneal \nmacrophage polarization to the M2 type. In human \nendometriosis patients, there is high M2 macrophage \npolarization, and in vitro  co-culture analyses have \nshown that M2 macrophages significantly upregulate \nproliferation of endometrial stromal cells by activating \nsignal transducer and activator of transcription 3 (STAT3) \nsignaling (Itoh et al. 2013). STAT3 signaling is aberrantly \nactivated in epithelial and endometrial stromal cells in \nhuman endometriotic lesions (Kim et al. 2015). Therefore, \nendometriosis-associated M2 macrophages may stimulate \nSTAT3 signaling in endometriotic lesions and thereby \nstimulate endometriosis.\nWhat causative factors drive M2 macrophage \npolarization in endometriotic cells?\nM2 macrophage polarization is regulated by the \nendometrium. Abnormal expression of indoleamine \n2,3-dioxygenase-1 (IDO1) in endometrial stromal cells \npromotes an inflammatory response that subsequently \ninitiates M2 macrophage polarization, which may \nfacilitate the survival of retrograde menstrual tissues (Mei \net al. 2017). Fractalkine (FKN), which is secreted by eutopic \nendometrial stroma cells, also stimulates M2 macrophage \npolarization and enhances endometriosis progression \n(Wang et  al. 2014 b). FKN induces M2 macrophage \npolarization by decreasing CD86 expression. In addition, \nFKN increases the expression of matrix metalloproteinase \n9 (MMP9) by decreasing the expression of tissue inhibitor \nof MMP1 and 2. This promotes the invasiveness of \nendometrial stromal cells by activating p38 mitogen-\nactivated protein kinases (MAPKs) and the integrin β1 \nsignaling pathway to stimulate endometriosis progression \n(Collette et al. 2006, Wang et al. 2014b).\nDownloaded from Bioscientifica.com at 06/18/2026 11:06:46PM\nvia free access\n\n\nhttps://doi.org/10.1530/JME-17-0227\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nR100\nY J Cho et al. Cellular signal dysfunction in \nendometriosis60 3:\nJournal of Molecular \nEndocrinology\nExposure to endocrine-disrupting chemicals interferes \nwith the endocrine system, causing cancerous tumors, \nbirth defects and other developmental disorders, resulting \nin the progression of several human diseases ( Mallozzi \net al. 2017, Ribeiro et al. 2017). For example, exposure to \n2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) compounds \nstimulate endometriosis progression ( Smarr et  al. 2016 ). \nTo induce endometriosis, TCDD alters patterns of \nmacrophage activation. Combining 17 β-estradiol with \nTCDD has a synergistic effect on the induction of M2 \nmacrophage activation when macrophages are co-cultured \nwith endometrial stromal cells, because it activates STAT3 \nand p38 MAPK signaling pathways ( Wang et al. 2015). In \naddition to in vitro assays, the combination of TCDD and \nhigh levels of local 17β-estradiol in endometriotic lesions \nhas been shown to synergistically induce M2 macrophage \npolarization and stimulate endometriosis in humans \n(Delvoux et al. 2009).\nAnnexin A2 is involved in various cellular processes, \nsuch as cell motility, cytoskeletal regulation and \nendocytosis. Levels of annexin A2 are markedly reduced in \nperitoneal macrophages from women with endometriosis \ncompared to controls, and downregulation of annexin A2 \ninhibits the phagocytic capacity of macrophages (Wu et al. \n2013). The level of annexin A2 mRNA in macrophages \nis reduced by prostaglandin E2 (PGE2) via the EP2/EP4 \nreceptor-dependent signaling pathway. Indeed, elevated \nlevels of PGE2 have been detected in endometriotic \nlesions (Rakhila et al. 2015), where they may reduce the \nratio of M1/M2 peritoneal macrophages and stimulate the \nprogression of endometriosis.\nEndometriotic lesions exhibit high levels of the \nC–C chemokine regulated on activation, normal T-cell \nexpressed and secreted (RANTES). During osteogenesis, \nRANTES stimulates the transition of M1 to M2 \nmacrophages in osteoprogenitors ( Cordova et  al. 2017 ). \nElevated RANTES levels has been linked to endometriosis \nprogression ( Hornung et  al. 2001 , Wang et  al. 2010 ) \nand is likely involved in M2 peritoneal macrophage \npolarization in endometriosis patients. TCDD promotes \nRANTES expression, and a combination of 17 β-estradiol \nand TCDD significantly enhanced RANTES secretion \nin an endometriosis-associated human endometrial \ncell co-culture system, recruiting greater numbers \nof  macrophages ( Wang et  al. 2010 ). RANTES could be \na molecular therapeutic target for endometriosis, as \nsuggested by the action of shikonin, an anti-inflammatory \nphytocompound derived from Lithospermum erythrorhizon, \nthat mediates the inhibition of RANTES secretion and \nreduces endometriosis progression (Yuan et al. 2014).\nThe activation of TGF β signaling in endometriosis \nalso induces M2 macrophage polarization to stimulate \ninflammatory signaling and tissue repair ( Gong et  al. \n2012).\nDysregulation of T-cell-mediated cytokine  \nprofiling in endometriosis\nLymphocyte subpopulations in endometriotic lesions are \nmarkedly different from those in normal endometrial \ntissue. Specifically, endometriotic lesions display increased \nnumbers of CD4 and CD8 cells and activated T cells \ncompared to normal endometrial tissue ( Witz et  al. \n1994). Additionally, T-cell subtypes are also differentially \nregulated. The proportion of Th1 lymphocytes is \nsignificantly lower, whereas the Th17 lymphocyte fraction \nis significantly elevated in endometriotic lesions (Takamura \net al. 2015). One recent study has shown that IL-10 +Th17 \ncell population is significantly elevated in the peritoneal \nfluid of endometriosis patients as compared to the women \nwithout endometriosis (Chang et al. 2017). Interestingly, \nelevation of IL-10+Th17 cell population is associated with \nincreased levels of IL-27, IL-6 and TGF-β. Especially, TGF-β  \nstimulates IL-10 production in Th17 cells in vitro and in \nvivo in human endometrial stromal cells to stimulate the \nproliferation and implantation of ectopic lesions and \naccelerate the progression of endometriosis ( Chang et al. \n2017). Although these patterns are not fully understood, \nthis differential T lymphocyte activation appears to clearly \nbe involved in the pathophysiology of endometriosis.\nAltered ratios of Th1/Th2 cells in \nendometriotic lesions\nCD4+ T lymphocytes, or Th cells, can be further \nsubdivided into Th1 and Th2 cells, and the cytokines \nthey produce are referred to as Th1-type and Th2-type, \nrespectively ( Berger 2000 ). Th1-type cytokines tend to \ngenerate pro-inflammatory responses, whereas Th2-type \ncytokines, such as IL4, IL5, IL10 and IL13, tend to elicit \nanti-inflammatory responses. A well-balanced Th1 and \nTh2 response is important for various immune challenges \n(Berger 2000). In endometriotic lesions, the levels of IFN-\nγ, IL10 and the ratios of IL4/IFN-γ, IL4/IL2 IL10/IFN-γ, and \nIL10/IL2 are significantly elevated in the peritoneal fluid \nof endometriosis patients compared to healthy controls \n(Podgaec et  al. 2007 ), which reflects a shift toward the \nTh2 immune response. Endometriosis progression may be \nassociated with a reduced Th1/Th2 ratio among T cells in \nthe peritoneal fluid.\nDownloaded from Bioscientifica.com at 06/18/2026 11:06:46PM\nvia free access\n\n\nhttps://doi.org/10.1530/JME-17-0227\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nR101\n60 3:\nY J Cho et al. Cellular signal dysfunction in \nendometriosis\nJournal of Molecular \nEndocrinology\nRole and determinants of Th2 cytokine  \nproduction during endometriosis progression\nIn humans, cytokines secreted from Th2 cells stimulate \nendometriosis progression. For example, IL4, a typical Th2 \ncytokine, has been shown to increase the mRNA expression \nof 3 β-hydroxysteroid dehydrogenase (HSD3B2) in a dose-\ndependent manner (Urata et al. 2013). HSD3B2 is a pivotal \nenzyme for estrogen production. IL4 increases local estrogen \nlevels to stimulate endometriosis progression. In addition, \nIL4 increases the proliferation of endometriotic stromal cells \nby activating p38 MAPK, stress-activated protein kinase/c-\nJun kinase and p42/44 MAPK to stimulate endometriosis \nprogression (OuYang et  al. 2008b). Similar changes have \nbeen observed in mouse models. The weights and areas of \nendometriotic lesions have been found to be significantly \nreduced following treatment with INF- γ and IL2 (Th1 \ncytokines) compared to treatment with IL4 and IL10 (Th2 \ncytokines) or saline solution (controls) (Mier-Cabrera et al. \n2013). Th1 cytokine milieus suppress the progression of \nendometriosis in a murine endometriosis model.\nEutopic endometrial tissues from patients with \nendometriosis have higher mRNA levels of GATA-binding \nprotein 3 ( GATA3) compared to normal endometrial \ntissue (Chen et al. 2012). Expression of GATA3 is regulated \nby estrogen, and their synergistic action regulates Th2 \ncytokine (e.g., IL6, IL8 and IL10) expression in eutopic \nendometrial cells ( Chen et  al. 2016 ). Therefore, GATA3 \nintegrates estrogen signaling to induce Th2 cytokine \nexpression in endometriotic lesions, thereby promoting \nendometriosis progression.\nIL6 levels are also elevated in endometrial stromal \ncells isolated from women with endometriosis compared \nto healthy controls ( Tsudo et al. 2000). IL6 expression in \nendometriotic cells is induced by IL1β and TNF-α (Akoum \net  al. 1996 ). IL6 promotes CD4+ Th2 differentiation \nand inhibits Th1 differentiation via two independent \nmolecular mechanisms ( Diehl et  al. 2000 ). Elevated \nIL6 levels promote Th2 differentiation by activating \ntranscription mediated by nuclear factor of activated \nT cells (NFAT) ( Diehl & Rincon 2002 ). Additionally, IL6 \ninhibits Th1 differentiation by interfering with IFN- γ \nsignaling and the expression of suppressor of cytokine \nsignaling 1 (SOCS1). These findings may support a role for \nIL6 in Th2 differentiation and Th2 cytokine production in \nendometriotic lesions.\nAlteration of Treg cells in endometriosis\nIn addition to Th1 and Th2 cells, naïve T cells can \ndifferentiate into regulatory T (Treg) cells (Josefowicz et al. \n2012). Treg cells suppress a range of immune responses, \nsuch as T-cell proliferation and activation (Giatromanolaki \net  al. 2008), as well as macrophage, B-cell, dendritic cell \nand NK-cell function ( Thornton 2005 ). Because of its \nimmunosuppressive function, the infiltration of large \nnumbers of Treg cells into tumor tissues is associated with \na poor prognosis (Enokida & Nishikawa 2017). Consistent \nwith tumor progression, a higher concentration of Treg cell \nphenotypes and/or expression markers has been detected \nin  peritoneal fluid and endometriotic lesions but not in \nsamples from healthy control women (Bellelis et al. 2013, \nSlabe et  al. 2013 , de Barros et  al. 2017 ). To initiate and \nestablish endometriosis, retrograde menstrual tissues in the \nperitoneal region must escape the host immune surveillance \nsystem. To achieve this, the large numbers of Treg cells in \nthe T-cell population and endometriotic lesions decrease \nthe recruitment of immune cells to prevent the recognition \nand targeting of retrograde menstrual tissues, thus allowing \ntheir survival and implantation into ectopic sites.\nTh17 cells and IL23 levels in endometriosis\nIn addition to Th2 cytokines, the levels of IL23 and the \nTh17 cytokine IL17 are highly elevated in the peritoneal \nfluid of women with minimal or mild  endometriosis \n(Andreoli et  al. 2011 ). Th17 cells are involved in the \npathogenesis of several autoimmune diseases, and \nendometriosis is associated with a higher risk (20–60%) of \nautoimmune disease, such as multiple sclerosis, systemic \nlupus erythematosus and Sjögren syndrome ( Ouyang \net  al. 2008 a, Nielsen et  al. 2011 ). In vitro stimulation of \nendometrial epithelial carcinoma cells, Ishikawa cells \nand HUVECs with IL17A revealed that IL17A treatment \nsignificantly increased angiogenic (VEGF and IL8), pro-\ninflammatory (IL6 and IL1 β) and chemotactic cytokine \nlevels (G-CSF, CXCL12, CXCL1 and CX3CL1) ( Ahn et al. \n2015). The levels of IL23 were significantly higher in the \nperitoneal fluid of women with endometriosis compared \nto normal controls (Andreoli et al. 2011). Activated naïve T \ncells produce IL23, which then increases the levels of IL10 \nand IL17, both of which are required for endometriosis \nprogression (Vanden Eijnden et al. 2005). Dysregulation of \nIL23 is also involved in several endometriosis-associated \nendometrial dysfunctions, such as infertility ( Andreoli \net al. 2011, Frazer et al. 2013).\nAltered T-cell activation and autoimmune properties \nof endometriosis\nEndometriosis is not itself an autoimmune disease; however, \nwomen with endometriosis may have been reported to \nDownloaded from Bioscientifica.com at 06/18/2026 11:06:46PM\nvia free access\n\n\nhttps://doi.org/10.1530/JME-17-0227\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nR102\nY J Cho et al. Cellular signal dysfunction in \nendometriosis60 3:\nJournal of Molecular \nEndocrinology\nhave a higher risk of developing several autoimmune \ndiseases, such as systemic lupus erythematosus, Sjögren’s \nsyndrome, multiple sclerosis and rheumatoid arthritis \n(Haga et  al. 2005 , Harris et  al. 2016 ). This is somewhat \ncontroversial, however, as another study reported no \ncorrelation between them ( Nielsen et al. 2011). In many \nautoimmune diseases, altered activation of CD4 + T cells \nplays a critical role in activating B cells to stimulate the \nproduction of autoantibodies ( Palmer & Weaver 2010 ). \nConsistent with autoimmune disease, the elevated levels \nof autoantibodies against the endometrium and ovary \nare highly elevated in endometriosis patient ( Mathur \net al. 1982). Therefore, altered activation of CD4 + T cells, \nas  described earlier, might be involved in the elevation  \nof autoimmune disease properties in endometriotic \nlesions.\nDysfunction of NK cells in endometriosis patients\nNK cells secrete lytic granules containing granzyme, \nperforin and cytotoxins (such as IFN- γ) to destroy \nother cells ( Topham & Hewitt 2009 ). Cytotoxic NK \ncells therefore play a critical role in innate immunity \nto activate the host immune surveillance system \nfollowing exposure to pathogens. Because of the crucial \nrole of NK cells in innate immunity, dysregulation of \nNK cells causes immune-related disease progression \n(Smyth et  al. 2005 , Mandal & Viswanathan 2015 ). \nThe levels of molecular markers of cytotoxic NK \ncells, such as markers of activation (granzyme B, \nperforin, TRAIL, CD107a and CD69) and cell surface \nmarkers (NKp46, NKp44, NKG2D and CD16), are \nsignificantly reduced, but the proportion of immature \nNK cells (CD272CD11b2+) in the NK cell population \n(CD32CD56+) is elevated in the peritoneal fluid of \nendometriosis patients compared to normal women \n(Oosterlynck et al. 1991 , Jeung et al. 2016 ).\nHow are cytotoxic NK cells downregulated in \nendometriotic lesions compared to normal \nendometrial tissue?\nCytokines with inhibitory effects on cytotoxic NK \ncells, such as inflammatory cytokines (IL6, IL8, IL1 β, \nIFN-γ and TNF- α) and non-inflammatory cytokines \n(CXCL3, CCL2, CCL5), are significantly elevated in the \nperitoneal fluid of endometriosis patients compared \nto controls ( Malutan et al. 2015 ). Moreover, peritoneal \nfluid from endometriosis patients also shows elevated \nlevels of antigens (HLA-G and HLA-E), immunoreceptor \ntyrosine-based inhibitory motif killer cell inhibitory \nreceptors (ITIM-KIRs), inhibitory NK cell receptors \ncontaining Ig domains (KIR2DL1, KIR3DL1), EB6 and \nsoluble intracellular adhesion molecule-1 (I-CAM), \nwhich also suppress cytotoxic NK cells ( Jeung et  al. \n2016). In addition, HLA-G expression is detected in \neutopic endometrial tissue of endometriosis patients \nduring the menstrual phase ( Thiruchelvam et al. 2015). \nRetrograde menstrual tissues show elevated levels of \nHLA-G in the peritoneal cavity, where they can interact \nwith the immune surveillance system and counteract \nthe cytotoxicity of NK cells. This would allow retrograde \nmenstrual tissues to survive and implant, eventually \ndeveloping into endometriotic lesions. Therefore, \nincreased levels of inflammatory cytokines, antigens \nand inhibitory receptors in the peritoneal fluid and \nendometrium downregulate cytotoxic NK activity during \nthe progression of endometriosis.\nActivation of B cells in endometriosis\nB cells underlie humoral immune responses by producing \nantibodies against antigens. Increased numbers of B \ncells are found in the blood and peritoneal fluids of \nendometriosis patients compared to healthy women \n(Osuga et  al. 2011 ). Interestingly, transcriptional factors \nregulating B-cell function are differentially expressed in \nendometriosis patients compared with healthy women. \nFor example, B lymphocyte inducer of maturation \nprogram (Blimp)-1, which is a crucial regulator of plasma \ncell differentiation, is significantly increased; the levels \nof B-cell leukemia lymphoma (Bcl)-6, its antagonist, \nare significantly reduced in the peritoneal cavities of \nendometriosis patients ( Yeol et  al. 2015). In addition to \ntranscription factors, endometriotic lesions also have \nhigher levels of cytokines that activate B cells, such as B \nlymphocyte stimulator (BLys) ( Hever et  al. 2007 ). BLys \nplays an important role in the normal development of B \ncells and their differentiation into plasma cells (Schiemann \net al. 2001). Therefore, these factors can stimulate B-cell \nfunction in endometriosis patients.\nThese hyperactivated B lymphocytes appear to \ncontribute to the pathogenesis of endometriosis by \nproducing autoantibodies against the endometrium, DNA \nand phospholipids, as well as antinuclear antibodies (Osuga \net al. 2011). A similar elevation of autoantibodies has also \nbeen observed in autoimmune diseases (Eggert et al. 2010). \nBecause of the many similarities between endometriosis \nand autoimmune diseases, endometriosis may be treatable \nas an autoimmune disease (Nothnick 2001).\nDownloaded from Bioscientifica.com at 06/18/2026 11:06:46PM\nvia free access\n\n\nhttps://doi.org/10.1530/JME-17-0227\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nR103\n60 3:\nY J Cho et al. Cellular signal dysfunction in \nendometriosis\nJournal of Molecular \nEndocrinology\nAlteration of cytokine profiling in \nendometriotic lesions\nIn addition to immune cells, endometriotic lesions \nare themselves a source of secreted cytokines that \nstimulate endometriosis progression. For example, \nendometriotic epithelial cells have increased levels of \nTNF-α compared to normal endometrial tissue during \nendometriosis progression. Epithelial TNF- α activates the \nphosphoinositide 3-kinase (PI3K), MAPK, c-Jun N-terminal \nkinase (JNK), p38 and I κB kinase signaling pathways \nvia autocrine responses to stimulate inflammation and \ninvasion of endometriotic epithelial cells, thus favoring \ntheir proliferation ( Grund et  al. 2008 ). Endometriotic \nepithelial TNF- α also induces IL6 and IL8 expression in \nendometriotic stromal cells via nuclear factor-kappa-B \n(NF-κB) and activator protein (AP)1 through paracrine \nresponses to stimulate proliferation of endometriotic \nstromal cells (Sakamoto et al. 2003, Yamauchi et al. 2004). \nThese dysregulated autocrine or paracrine cytokine \nsignaling networks in endometriotic lesions are also \ninvolved in endometriosis progression.\nIn addition to TNF α, endometriotic lesions are a \nsource of various cytokines, such as ENA78, RANTES, IL6 \nand IL8 (Akoum et al. 2001, Bertschi et al. 2013). IL6 plays \na significant role in CD4+ T-cell differentiation ( Dienz & \nRincon 2009), and IL8 induces T lymphocyte infiltration \nin target tissues (Taub et al. 1996). Therefore, IL6 and IL8 in \nendometriotic lesions might generate T-cell milieus specific \nfor endometriotic lesions to enhance their survival.\nInflammatory and estrogen receptor (ESR) signaling \nin endometriotic lesions and macrophages\nPeritoneal macrophages are activated by exposure to \n17β-estradiol ( Hong & Zhu 2004 ). Because a higher \nactivity of the 17β-estradiol axis stimulates endometriosis-\nassociated macrophage activation to synergistically \ninduce endometriosis, endometriosis has been considered \nan estrogen-dependent inflammatory disease. In addition \nto higher local estradiol concentrations, ESR levels are \nalso differentially regulated in endometriotic lesions in \nresponse to increased estradiol signaling. Accordingly, \nelevated levels of ESR2 but not ESR1 have been detected \nin endometriotic tissues compared to normal endometrial \ntissues. Elevated ESR2 stimulates prostaglandin \nproduction in endometriotic tissues through COX2 to \npromote endometriosis progression (Wu et al. 2010, Bulun \net  al. 2012 ). Increased prostaglandin levels suppress the \nimmune system, allowing retrograde menstrual tissues to \nescape the immune surveillance system and develop into \nendometriotic lesions. In addition, ESR2 interacts with \ncomponents of the cytoplasmic inflammasome to increase \nIL1β in endometriotic lesions, stimulating their adhesion \nand proliferation properties ( Han et al. 2015). Therefore, \nincreases in ESR2 function modulate the immune response \nto retrograde menstrual tissues, which can subsequently \ndevelop into endometriotic lesions. Hypomethylation of \nthe ESR2 gene promoter region might contribute to higher \nESR2 levels in endometriotic lesions (Xue et al. 2007), but \ndetailed molecular mechanisms underlying ESR2 function \nin endometriosis progression remain unclear.\nPeritoneal macrophages are activated upon \n17β-estradiol treatment to stimulate endometriosis \nprogression (Hong & Zhu 2004), and expression levels of \nESR2 are significantly increased in peritoneal macrophages \nof women with  endometriosis ( Montagna et  al. 2008 ). \nPretreatment of peritoneal macrophages with ERB-041, \na selective ESR2 agonist, results in significant inhibition \nof LPS-induced iNOS expression by suppressing NF- κB \nactivation and endometriosis progression ( Harris et  al. \n2005, Xiu-li et al. 2009). Collectively, the alteration of the \nESR2-estradiol axis in macrophages is another driver of \nendometriosis progression.\nCommunication between immune cells and \nendometriotic lesions drives \nendometriosis progression\nWe have discussed dysregulated immune signaling in both \nimmune cells and endometriotic lesions. Interestingly, \naltered inflammatory signaling in immune cells induces \nendometriotic lesions to enhance endometriosis \nprogression (Fig. 1 ). During the initiation of endometriosis, \naltered immune cells release pro-inflammatory cytokines \n(IL1, IL6, IL8, IL10, IL12, IL13, TNF-α, VEGF and platelet-\nderived growth factor (PDGF)) by activating the STAT, \np38, extracellular signal-regulated kinase (ERK) and JNK \nsignaling pathways. These cytokines bind to their receptors \nin endometriotic lesions and mediate further downstream \nsignaling via NF-kB to initiate and establish endometriosis \nprogression. For example, mRNA expression levels of \nsteroidogenic acute regulatory protein (StAR), COX2, \nMMP9 and other pro-inflammatory cytokines is increased \nin endometriotic lesions as a result of NF-kB-mediated \npro-inflammatory cytokines ( Tsai et  al. 2001 ). Elevated \nStAR expression is involved in estradiol production in \nendometriotic lesions, further promoting endometriosis \nprogression. Moreover, increased local E2 levels directly \ninduce COX2 expression to promote PGE2 production \nDownloaded from Bioscientifica.com at 06/18/2026 11:06:46PM\nvia free access\n\n\nhttps://doi.org/10.1530/JME-17-0227\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nR104\nY J Cho et al. Cellular signal dysfunction in \nendometriosis60 3:\nJournal of Molecular \nEndocrinology\nand activate inflammasomes via ESR2 to induce IL1β, thus \nenhancing the adhesion and proliferation of endometriotic \nlesions and endometriosis progression.\nDysregulated apoptosis signaling \nin endometriotic lesions\nImpaired apoptosis in retrograde menstrual tissues and \nabnormal apoptosis in immune cells are associated \nwith endometriosis progression ( Taniguchi et  al. 2011 ). \nUnderstanding the molecular mechanisms governing the \ndysregulation of apoptosis in endometriotic tissues and \nimmune cells is crucial for determining the molecular \netiology of endometriosis and providing new molecular \ntherapeutic treatments. Here, we discuss how dysregulated \napoptosis is involved in the progression of endometriosis.\nReduced apoptosis in endometriotic lesions\nCompared to healthy women, apoptosis is significantly \nreduced in eutopic endometrial tissue in patients \nwith endometriosis ( Gebel et  al. 1998 ). Specifically, \nendometriotic lesions show higher BCL2 (anti-apoptotic \nsignaling) staining than normal endometrial tissue \n(Harada et  al. 2004 ), as well as increased expression of \nc-myc (a cell-cycle regulator) and TGF- β; in contrast, \nreduced levels of the pro-apoptotic BCL2-associated X \nprotein (BAX) are found ( Meresman et al. 2000, Vetvicka \net al. 2016, Yu et al. 2017). Collectively, the reduction of \napoptosis in endometriotic lesions represents a concerted \neffort by retrograde menstrual tissues to evade immune \nsurveillance and develop into endometriotic lesions.\nDysregulation of intrinsic apoptosis \nsignaling in endometriosis\nApoptotic signaling occurs via two different pathways: \nintrinsic (or mitochondrial) and extrinsic (or death \nreceptor-mediated) (Schleich & Lavrik 2013). Suppression \nof the intrinsic apoptotic pathway has been detected in \nendometriotic lesions. The ratio of anti- to pro-apoptotic \nmolecules, such as BCL2/BAX, is higher in mitochondria \nFigure 1\nCytokine signaling networks involving endometriotic lesions and peritoneal macrophages. Activated peritoneal macrophages express inducible nitric \noxide synthase (iNOS) and COX2 through interferon regulatory factors (IRFs), NF-κB and nuclear factor (Nrf)2 through activation of STAT, p38, ERK and \nJNK signaling cascades. Activated macrophages then release cytokines (including IL1, IL6, IL8, IL10, IL12, IL13 and TNFα), growth factors and angiogenic \nfactors (VEGF and platelet-derived growth factor (PDGF)). The secreted TNFα, IL1β and IL6 bind their membrane receptors in endometriotic lesions. The \ncytokine/cytokine receptor complex then activates PI3K, MKK, JNK, p38 and IKK pathways to induce the expression of inflammation and invasion \nmediators, such as StAR, COX2 and MMP9, through NF-Κ B and AP1 transcription factors to stimulate local estradiol formation, PEG2 formation and \ntissue remodeling and NCOA-1 isoform generation, which enhances the growth of endometriotic lesions. The estradiol/ESR2/NCOA-1 complex interacts \nwith the cytoplasmic inflammasome to increase IL1β levels to induce monocyte differentiation into macrophages (Schenk et al. 2014). Therefore, \ncytokine crosstalk between endometriotic cells and macrophages is the main driver for the initiation, maintenance and progression of endometriosis.\nDownloaded from Bioscientifica.com at 06/18/2026 11:06:46PM\nvia free access\n\n\nhttps://doi.org/10.1530/JME-17-0227\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nR105\n60 3:\nY J Cho et al. Cellular signal dysfunction in \nendometriosis\nJournal of Molecular \nEndocrinology\nof eutopic endometrial tissues ( Meresman et  al. 2000 ) \nand in macrophages from endometriotic lesions. The \nBCL2 family of proteins constitutes a critical intracellular \ncheckpoint of the intrinsic apoptotic pathway; increased \nBCL2 but decreased BAX expression levels are found in \nthe proliferative phase of eutopic endometrial tissues \nfrom patients with endometriosis compared with normal \nendometrial tissue. Women with endometriosis have \na large BCL2-positive macrophage population in the \nperitoneal fluid, whereas women without endometriosis \nhave a peritoneal macrophage population that has \nelevated levels of BAX (McLaren et al. 1997). Interestingly, \nthe expression profile of apoptosis-related proteins in \nendometriotic lesions is regulated in a location-dependent \nmanner. For example, p53 and p21 are higher in ovarian \nendometriosis, whereas BCL2 expression is higher in \nperitoneal and colorectal endometriosis ( Dufournet \net al. 2006). A different mechanism of suppression of the \nintrinsic apoptotic pathway might be involved in the \ndevelopment of each type of endometriotic lesion, and \ntargeting specific anti-apoptotic pathways may be useful \nas a component of endometriosis treatment for specific \nendometriotic lesions.\nAlteration of extrinsic apoptosis signaling \nin endometriosis\nFas/FasL\nThe Fas/FasL axis is the traditional extrinsic apoptosis \nsignaling cascade (Curtin & Cotter 2003). Fas (DR2/CD95/\nApo-1) is a type I cell membrane protein (mFas), with an \nextracellular domain that binds FasL (CD95L/CD178/\nApo-1L) and a cytoplasmic domain that transduces the \ndeath signal ( Peter et al. 2007, Strasser et al. 2009). Cell \ndeath signaling mediated by the Fas/FasL interaction \nplays an essential role in the immune system and in \nmaintaining immune-privileged sites in the body. For \nexample, Fas/FasL-mediated apoptosis kills cytotoxic T \ncells ( Waring & Mullbacher 1999 ). FasL is expressed in \nnormal human endometrial cells, where it is stimulated by \nmacrophage cytokines, such as PDGF and TGF-β1 (Garcia-\nVelasco et al. 1999). Higher levels of IL8 in the peritoneal \nfluid of endometriosis patients cause an increase in FasL \nexpression in endometrial cells ( Selam et  al. 2002 ) and \nendometrial stromal cells. However, increased FasL does \nnot induce apoptosis in endometrial stromal cells ( Selam \net  al. 2006 a). Ectopic epithelial cells of endometriotic \nlesions have simultaneously increased FasL expression \nand reduced Fas expression, irrespective of the menstrual \ncycle phase ( Sbracia et  al. 2016). Collectively, induction \nof FasL in endometrial cells may induce apoptosis in \ncytotoxic T cells expressing the Fas receptor, thus allowing \nthem to evade immune surveillance and develop into \nendometriotic lesions.\nTNFα-mediated apoptosis\nChanges in TNF- α-mediated cell death signaling are \nalso involved in endometriosis progression ( Iwabe et  al. \n2000). During retrograde menstruation, the influx of \nretrograde menstrual tissues into the peritoneal cavity \nactivates macrophages to secrete cytotoxic cytokines, such \nas TNF- α, inducing apoptosis signaling in extrauterine \nendometrial fragments that need to be removed ( Leavy \n2015). In endometriosis patients, however, the molecular \nproperties of retrograde menstrual tissues are altered in a \nway that allows escape from TNF-α-mediated apoptosis. As \nendometriosis is an estrogen-dependent disease, nuclear \nreceptor coactivator (NCOA)s may play an important role \nin endometriosis progression. Interestingly, endometriotic \nlesions have an elevated level of the NCOA-1 isoform, but \nnot full-length NCOA-1 ( Han et  al. 2012 ). The NCOA-1 \nisoform is proteolytically generated from full-length \nNCOA-1 by MMP9 in endometriotic lesions. There, the \nNCOA-1 isoform, but not full-length NCOA-1, interacts \nwith caspase 8 to prevent TNF- α-mediated apoptosis by \ndisrupting apoptosis complex II formation. Endometriotic \nlesions also express high levels of ESR2 ( Hudelist et  al. \n2005), which then interacts with caspase 8 or components \nof the cell death machinery in endometriotic cells to block  \nTNF-α-induced apoptosis (Han et al. 2015). Specifically, high \nESR2 induces the formation of apoptosis signal-regulating \nkinase 1 (ASK1), serine/threonine kinase receptor-associated \nprotein and the 14-3-3 protein complex to inhibit ASK1 \nactivity required for TNF-α-mediated apoptosis. Moreover, \nESR2 disrupts apoptosome formation by interacting  \nwith and preventing the activation of caspase 9 in \nendometriotic lesions. Taken together, induction of \nthe  endometriosis-specific NCOA-1 isoform/ESR2 axis \nactively prevents TNF- α-induced apoptosis signaling in \nendometriotic lesions by interacting with the apoptotic  \nmachinery (Fig. 2 ).\nTargeting the dysregulation of apoptosis  \nsignaling in endometriotic tissues\nIn addition to endometriosis progression, the sophisticated \nregulation of apoptosis also plays an important role in \nembryonic development via the appropriate formation of \nvarious organs and structures ( Haanen & Vermes 1996 ).  \nDownloaded from Bioscientifica.com at 06/18/2026 11:06:46PM\nvia free access\n\n\nhttps://doi.org/10.1530/JME-17-0227\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nR106\nY J Cho et al. Cellular signal dysfunction in \nendometriosis60 3:\nJournal of Molecular \nEndocrinology\nTherefore, defective apoptosis signaling during \nembryogenesis may cause developmental abnormalities \n(Haanen & Vermes 1996). Dysregulation of apoptosis is a \nkey driver of many human diseases and may serve as an \neffective molecular therapeutic target for the treatment of \nmany human diseases.\nPGE2 levels are elevated in endometriosis patients; \nPGE2 promotes the survival of human endometriotic \nlesions through EP2 and EP4 receptors and activation of \nthe ERK1/2, AKT, NF-κB and β-catenin signaling pathways \n(Banu et  al. 2009 ). Selective inhibitors of EP2 (AH6809) \nand EP4 (AH23848) suppress these cell survival pathways \nand enhance interactions between anti-apoptotic and \npro-apoptotic proteins, thereby activating the intrinsic \napoptotic pathways in human endometriotic cells.\nPro-inflammatory cytokines also regulate apoptotic \nsignaling in various cells to modulate their cellular function \n(Grunnet et  al. 2009 ). In endometriosis, dysregulated \ncytokines prevent apoptosis and promote the survival of \nendometriotic lesions. For example, secretion of CXCL8 \nis significantly higher in eutopic endometrial stromal \ncells of women with endometriosis compared to normal \nendometrial tissues, and elevated CXCL8 reduces apoptosis \nby upregulating BCL2 expression in these cells in an \nautocrine manner ( Li et  al. 2012 ). Anti-human CXCL8-\nneutralizing antibodies suppress endometriosis progression \nby inducing apoptosis in endometriotic lesions. RANTES \nand IL8 attenuate apoptosis in endometriotic lesions \n(Selam et  al. 2006 b); shikonin-mediated inhibition of \nRANTES secretion reduces endometriosis progression (Yuan \net al. 2014). Treatment with an IL8-neutralizing antibody \nalso suppresses endometriosis progression by inhibiting the \nattachment of retrograde menstrual tissues and reactivating \napoptosis in these cells (Arici 2002). Collectively, molecules \nthat induce anti-apoptotic pathways in endometriotic \nlesions could be molecular therapeutic targets for alternative \nendometriosis treatments.\nDysregulation of oxidative stress \nin endometriosis\nHealthy women exhibit balanced levels of reactive oxygen \nspecies (ROS) and antioxidants. An overabundance of ROS \ninduces oxidative stress, impacting women throughout \ntheir reproductive lifespan, including in the initiation \nof endometriosis ( Carvalho et  al. 2012 ). Oxidative \nFigure 2\nDysregulation of apoptotic signaling in endometriosis. The decreased apoptosis of endometriotic cells and increased apoptosis of immune cells leads to \nimmune privilege. TNFα, elevated by retrograde menstruation, binds to tumor necrosis factor receptor (TNFR) to induce caspase 8- and caspase \n9-mediated apoptosis in retrograde menstrual tissues. In endometriosis patients, however, elevated NCOA-1 isoform/ESR2 complex binds to ASK1 \n(apoptosis complex I), caspase 8 (apoptosis complex II) and caspase 9 (apoptosome) and suppresses extrinsic apoptosis signaling in retrograde menstrual \ntissues. The elevation of PGE2 in endometriosis patients increases the ratio of BCL2/BAX in mitochondria to inhibit intrinsic apoptosis signaling. The \nendometriotic lesions also exhibit elevated levels of FasL, which binds to Fas in cytotoxic T cells, causing cell death in cytotoxic T cells. This represents a \ncritical defense mechanism of endometriotic lesions against destruction by cytotoxic T cells during retrograde menstruation.\nDownloaded from Bioscientifica.com at 06/18/2026 11:06:46PM\nvia free access\n\n\nhttps://doi.org/10.1530/JME-17-0227\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nR107\n60 3:\nY J Cho et al. Cellular signal dysfunction in \nendometriosis\nJournal of Molecular \nEndocrinology\nstress results in damage to cellular lipids, proteins and \nDNA, changing their molecular properties and possibly \nleading to disease. Importantly, ROS overproduction \nimpairs cellular functions by inducing redox-sensitive \ntranscription factor (such as NF- κB)-mediated expression \nof genes required for the initiation and progression of \nendometriosis (Fig. 3 ) (Defrere et al. 2011).\nErythrocytes, apoptotic endometrial tissue and cell \ndebris transplanted into the peritoneal cavity by menstrual \nreflux, as well as macrophages, have all been cited as \npotential inducers of oxidative stress. Iron overload has \nbeen detected in the cells and peritoneal fluid of women \nwith endometriosis compared to normal endometrial \ntissues (Van Langendonckt et al. 2002, Carvalho et al. 2012). \nExcessive iron induces deleterious ROS in the peritoneal \nenvironment, which enhances the attachment and growth \nof retrograde menstrual tissues ( Alizadeh et  al. 2015 , \nDonnez et al. 2016). In a murine model, iron overload has \nbeen shown to further expand endometriosis by promoting \nepithelial cell proliferation at lesion sites (Defrère et  al. \n2006). Additionally, excessive iron levels may favor nitric \noxide production, resulting in the impaired clearance of \nendometrial cells by macrophages ( Pirdel & Pirdel 2014 ). \nAt present, it remains unclear why iron-mediated oxidative \nstress is maintained at high levels in endometriosis patients \ncompared to healthy women. One possibility is that it is \nassociated with alterations in ROS detoxification pathways \nand reductions in catalase levels, as observed in cancer \npatients (Ngo et  al. 2009). Retrograde menstruation-mediated \nhyperactivated oxidative stress leads to stimulation of the \nERK and PI3K/AKT/mTOR signaling pathways ( Fig.  3 ), \nthus promoting adhesion, angiogenesis and proliferation \nof endometriotic lesions and subsequent endometriosis \nprogression (McKinnon et al. 2016).\nDevelopment of alternative endometriosis \ntreatments based on drugs targeting \nthe dysregulated immune system,  \napoptosis and oxidative stress\nThe goal of endometriosis treatment is to relieve pain and/\nor achieve successful pregnancies in infertile patients. \nMost current medical treatments induce systemic estrogen \ndepletion, because estrogen signaling is an essential \ndriver of endometriosis. However, many current clinical \nendometriosis treatments are not sufficiently effective and \nhave unacceptable side effects, because the specific molecular \netiology of endometriosis has not yet been elucidated. \nHere, we have discussed endometriosis-associated \nprocesses, including dysregulation of inflammation, anti-\napoptosis and oxidative stress in endometriosis patients. \nTherefore, these dysregulated cellular pathways provide \nFigure 3\nAlterations of oxidative stress pathways in endometriosis. An overload of erythrocytes, apoptotic endometrial tissue and cell debris in the peritoneal \ncavity stimulate the generation of ROS in mitochondria. The hyperactivated ROS stimulate ERK and PI3K/AKT/mTOR signaling pathways in endometriotic \nlesions to enhance adhesion, angiogenesis, and proliferation. Overproduction of ROS also impairs cellular function by altering gene expression profiles \nthrough the NF-κB signaling cascade to increase inflammatory cytokine production in endometriotic lesions, which enhances endometriosis progression.\nDownloaded from Bioscientifica.com at 06/18/2026 11:06:46PM\nvia free access\n\n\nhttps://doi.org/10.1530/JME-17-0227\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nR108\nY J Cho et al. Cellular signal dysfunction in \nendometriosis60 3:\nJournal of Molecular \nEndocrinology\nimportant clues to understanding the molecular etiology of \nendometriosis and could offer new molecular therapeutic \ntargets to improve the specificity of endometriosis therapy \nand reduce side effects of current treatments. Based on \nthese findings, several drugs targeting endometriosis-\nspecific inflammation, anti-apoptosis and oxidative stress \npathways, as well as alternative hormonal agents, have \nbeen developed and examined using in vitro and in vivo \nendometriosis models. The most recently studied drugs are \nsummarized in Table 1 .\nConclusion\nRetrograde menstruation occurs in all women of \nreproductive age. For reasons that remain unknown, \nretrograde menstrual tissues develop into endometriotic \nlesions in 5–10% of cases. Here, we have discussed how \ndysregulation of the immune system, apoptosis and \noxidative stress are closely associated with endometriosis \nprogression. The dysregulated status of these signaling \npathways may predispose women to developing \nendometriosis, although it remains to be determined \nwhat causes such dysregulation in the endometrial \ntissues to develop into endometriotic lesions. Epigenetic \nchanges caused by nutrition and environmental variables \nor genetic changes might be potential factors that can \ninitiate endometriosis ( Borghese et  al. 2017 ). Moreover, \nfurther studies on functional correlation between the \ndysregulated signals and the severity of endometriosis \nare clearly needed but, taken together, the dysregulated \nsignals herein we have reviewed may also be connected \nto disease severity. Future studies must determine \nhow these potential endometriosis initiation factors \ndysregulate the immune system, apoptosis and oxidative \nstress pathways, leading to the initiation and progression \nof endometriosis.\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be \nperceived as prejudicing the impartiality of this review.\nTable 1 Emerging medical therapies in endometriosis with human data: alternative hormonal agents as well as agents targeting \nendometriosis-specific inflammation, anti-apoptosis and oxidative stress.\nTarget site Drug name Results in human study Main effect\nHormonal agents\n Aromatase inhibitor Block androstenedione to \nestrone\nLetrozole Retrospecitve analysis (Abushahin et al. 2011) Reduce pain with \nGnRh agonist\n GnRH antagonist Direct pituitary gonadotropin \nsuppression\nElagolix RCT (Taylor et al. 2017) Reduce pain\n SERMs Nonsteroid selective agonist or \nantagonist effects in different \nestrogen target tissues\nRaloxifene RCT (Stratton et al. 2008) Early termination \nBazedoxifene None\nERB-041 None\n SPRMs Progesterone receptor \nantagonist/agonist\nAsoprisnil RCT (Chwalisz et al. 2005) Reduce pain and \ndysmenorrhea \nNon-hormonal agents\n Antiangiogenic agents Anti-VEGF antibody Avastatin None\n3-Hydroxy-3-methyl glutaryl \ncoenzyme A inhibitor\nSimvastatin RCT (Almassinokiani et al. 2013) Reduce pain\nDopamine receptor 2 agonist Quinagolide Observational study (Gomez et al. 2011) Reduce lesion size\nCOX-2 inhibitors Celecoxib Case-control study (Cobellis et al. 2004) Reduce pain\nEpigallocatechin-3-gallate None\n Antioxidant agents Melatonin Melatonin RCT (Schwertner et al. 2013) Reduce pain and \ndysmenorrhea\nPentoxifylline Pentoxifylline RCT (Alborzi et al. 2007) No effect on pain \nor recurrence\n TNF- α blockers Anti-TNF-α antibody Infliximab RCT (Koninckx et al. 2008) No effect \n Immunomodulators mTOR inhibitor Rapamycin None\nEndogenous eicosanoid, inhibit \nMMP-9\nLXA4 None\n Apoptotic agent Natural polyphenolic compound, \ninduce p53 mediated apoptosis\nCurcumin None\n Metformin Insulin sensitizer from the family \nof the biguanides\nMetformin None\n MMP inhibitor Doxycycline None\nONO-4817 None\nSERMs, selective estrogen receptor modulators; SPRMs, selective progesterone receptor modulators; MMP, matrix metalloproteinase.\nDownloaded from Bioscientifica.com at 06/18/2026 11:06:46PM\nvia free access\n\n\nhttps://doi.org/10.1530/JME-17-0227\nhttp://jme.endocrinology-journals.org © 2018 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nR109\n60 3:\nY J Cho et al. Cellular signal dysfunction in \nendometriosis\nJournal of Molecular \nEndocrinology\nFunding\nThis work was supported by the Eunice Kennedy Shriver National Institute \nof Child Health and Human Development (NICHD, 5 U24 DK097748-04 Pilot \nGrant), the Mike Hogg Foundation, the Basic Science Research Program \nthrough the National Research Foundation of Korea (NRF) funded by the \nMinistry of Science, ICT & Future planning (NRF-2016R1C1B1006976) and \nthe Dong-A University Research Fund (2017).\nReferences\nAbushahin F, Goldman KN, Barbieri E, Milad M, Rademaker A & \nBulun SE 2011 Aromatase inhibition for refractory endometriosis-\nrelated chronic pelvic pain. Fertility and Sterility 96 939–942. (https://\ndoi.org/10.1016/j.fertnstert.2011.07.1136)\nAhn SH, Edwards AK, Singh SS, Young SL, Lessey BA & Tayade C 2015 \nIL-17A contributes to the pathogenesis of endometriosis by \ntriggering proinflammatory cytokines and angiogenic growth factors. \nJournal of Immunology 195 2591–2600. 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