{"paper_id":"8f5ea9cf-d507-4c81-9071-c96361e00fc5","body_text":"https://doi.org/10.1530/JOE-19-0248\nhttps://joe.bioscientifica.com © 2019 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nJournal of \nEndocrinology\n243:3\nR47–R57R C M Simmen et al. Co-morbid endometriosis and \ntype 1 diabetes\n-19-0248\nREVIEW\nCo-morbidity of type 1 diabetes and \nendometriosis: bringing a new paradigm \ninto focus\nRosalia C M Simmen1, Dustin M Brown1, Charles M Quick2, Iad Alhallak1, Tyler Rose1, Shi J Liu3 and Angela S Kelley4\n1Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA\n2Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA\n3Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA\n4Department of Obstetrics and Gynecology, The University of Michigan Health System, Ann Arbor, Michigan, USA\nCorrespondence should be addressed to R C M Simmen: simmenrosalia@uams.edu\nAbstract\nType 1 diabetes mellitus and endometriosis separately affect millions of women \nworldwide. Reproductive-age women diagnosed with type 1 diabetes may also suffer \nfrom endometriosis, but the asymptomatic pre-clinical period of highly variable duration \nfor each condition can lead to challenges in the timely recognition of co-morbid disease \nonset and misdiagnosis. While knowledge of the pathogenesis of each condition has \ngrown substantially, co-morbid endometriosis and type 1 diabetes has not been widely \nconsidered and much less addressed. This review discusses the molecular rationale \nfor the likelihood of their co-existence, and prospects for improvements in therapeutic \nstrategies and reduced complications, if this paradigm is included as a significant \nvariable in disease management.\nIntroduction\nType 1 diabetes mellitus (T1DM) is an autoimmune disease, \nresulting from the destruction of insulin-producing β-cells \nof the pancreatic islets of Langerhans, which leads to a \nstate of hypoinsulinemia and hyperglycemia. In 2015, \n1.25 million Americans suffered from T1DM, with an \nannual economic cost of ~$14B (https://beyondtype1.org/\ntype-1). With 40,000 new cases diagnosed annually, the \nprediction that 5 million people will have T1DM by 2020 \nis disconcerting. The incidence of T1DM has also increased \nby ~3% per year globally, albeit with some geographical \npreferences (Maahs et al.  2010). Mortality risks are higher \nin individuals with T1DM than in the general population \n(Collier et  al.  2018 ). While T1DM is often diagnosed at \nchildhood and may have early life origins ( Knip et  al.  \n2017), the condition has later onset in many adults. In such \ncases, the condition is often mistaken for type 2 diabetes,  \nleading to inappropriate management and a life-\nthreatening state (Thomas et al.  2019).\nEndometriosis (ENDO), a chronic estrogen-dependent \ndisease, characterized by the implantation and growth \nof endometrial tissues predominantly in the peritoneal \ncavity and the ovary, affects 6–10% of all reproductive-\nage women (average age 13–45 years) ( Burney & Giudice \n2012). Debilitating pelvic pain, infertility in 50% of \nafflicted patients, considerable morbidity, and an \neconomic burden of ~$50B a year in the United States \nalone accompany this condition. ENDO is often subject \nto delayed diagnosis, has no known effective treatment \nand is recurrent.\nT1DM and ENDO share similar pathophysiology \nsince both are associated with chronic inflammation \ntriggered by overactivation of the immune response  \n3\nKey Words\n f endometriosis\n f type 1 diabetes\n f inflammation\n f cancers\nJournal of Endocrinology  \n(2019) 243, R47–R57\n243\nDownloaded from Bioscientifica.com at 06/09/2026 09:58:57PM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-19-0248\nhttps://joe.bioscientifica.com © 2019 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR48\nCo-morbid endometriosis and \ntype 1 diabetes\nR C M Simmen et al.243:3\nJournal of \nEndocrinology\n(Cabrera et al.  2016, Symons et al.  2018). The predominance \nof ENDO in women with T1DM remains unknown; \nhowever, women (and young girls upon initiation of \nmenses) with T1DM may suffer from ENDO during \ntheir reproductive years. Considering the significant \nhealth and economic burdens related to T1DM and \nENDO singly and the prospect of their co-incidence, an \nincreased understanding of their risks and predisposition \nare imperative. This review aims to address why these \ntwo conditions may co-exist and how awareness of this \npossibility may improve clinical management and quality \nof life in affected women.\nCommonalities between T1DM and ENDO\nInflammatory status\nSubstantial evidence from human and animal studies \nindicates that dysfunction in local immune signaling \ncontributes to the development and maintenance of \nectopic lesions (EC) in ENDO ( Ulukus & Arici 2005 , \nPabona et al.  2012, Greaves et al.  2014). A review on this \ntopic (Symons et al.  2018) summarizes the cell populations \nof the innate immune system implicated in ENDO \npathophysiology. Neutrophils, macrophages, and natural \nkiller cells recruited to EC may promote ENDO in two \nways. One mechanism for which the estrogen receptor- β \n(ESR2) signaling cascade has been implicated ( Han et al.  \n2015), results in increased secretion of various cytokines \nthat support the growth, invasion and angiogenic \nproperties of lesions ( Capobianco et al.  2011). A second \nmechanism occurs via the reduction in the phagocytic \nabilities of macrophages and natural killer cells, thus \ninhibiting the clearance of endometrial cells in the \nimmediate environment of lesions (Chuang et al.  2010). In \na murine model of ENDO, EC growth was associated with \ndendritic cells, which can attenuate ( Stanic et  al.  2014 ) \nor enhance ( Pencovich et al.  2014) the process. Toll-like \nreceptors (TLRs) are essential components of the innate \nimmune system owing to their roles in mediating pattern \nrecognition of and response toward pathogens and host-\nrelated antigens. In patients with peritoneal ENDO, higher \nexpression of TLR3 and TLR4 in glandular epithelium of \nEC than of corresponding EU were noted ( Allhorn et al.  \n2008, Hayashi et  al.  2013 ). A potential mechanism for \nTLR4 promotion of ENDO has been described ( Luo et al.  \n2015). In this scenario, TLR4 activation causes increased \nsecretion of pro-inflammatory interleukin-8 (IL-8) and \nenhanced expression of IL-8 receptor C-X-C motif \nchemokine receptor-1 in endometriotic stromal cells, to \nbolster these cells’ invasive and proliferative potential.\nIn recent years, innate immunity in the pathogenesis \nof T1DM has gained substantial support and has linked \nTLRs in mediating islet inflammation ( Lien & Zipris \n2009, Alkanani et  al.  2012 , Cabrera et  al.  2016 ). TLRs \nimplicated in T1DM include TLR1, TLR2, TLR3, TLR7 \nand TLR9. Nonetheless, distinct TLRs may be protective \nor supportive of T1DM, suggesting contextual effects and \ndiffering mechanisms. For example, in non-obese diabetic \nmice, TLR4 deficiency accelerated the development of \nT1DM ( Devaraj et  al.  2011 , Gülden et  al.  2013 ), while \nloss of TLR9 reduced incidence of T1DM ( Tai et al.  2013). \nSimilar to ENDO, T1DM pathogenesis is associated with \naberrant dendritic cell function. Many polymorphic \nloci identified by genome-wide and disease-association \nstudies and which can potentially underlie susceptibility \nto T1DM have been linked to immune dysfunctions in \ndendritic cells such as in cytokine signaling, development \nand activation, all of which disrupt their tolerogenic \nproperties ( Hotta-Iwamura & Tarbell 2016 ). The recent \nidentification of an insulin B peptide as a trigger of \nT-regulatory cells in the pancreas provides a promising \nprospect for targeting TLRs and dendritic cells to suppress \nautoimmunity in T1DM (Wang et al.  2019).\nRisk for ovarian and other cancers\nEpidemiological and molecular evidence indicate that \nwhile benign in its initial stages, ENDO is an independent \nrisk factor for both clear-cell and endometroid ovarian \ncarcinoma (reviewed in Lee et  al.  2016 , Bulun et  al.  \n2019). Somatic mutations in key genes, primarily \nphosphatidylinositol 4,5-bisphosphate 3-kinase catalytic \nsubunit alpha ( PIK3CA) and Kirsten rat sarcoma ( KRAS) \nin endometriotic epithelial cells have been suggested to \ncontribute to the development of ovarian cancers ( Er \net al.  2016). However, mutations in these same genes have \nbeen detected in endometriosis with and without cancers \n(Anglesio et al.  2017). Moreover, epithelial cells isolated \nfrom ovarian endometriotic lesions and normal/benign \nuterine endometrium displayed mutations in both PIK3CA \nand KRAS, albeit at different allele frequencies, suggesting \nthat these mutations are not sufficiently causal for \novarian cancers (Suda et al.  2018). In a comparison of gene \nexpression patterns of normal (non-diseased) endometria \nwith those of endometriosis (benign, atypical, concurrent \nwith endometriosis) and endometriosis-associated \novarian cancer, Andersen et al . (2018) implicated the loss \nof estrogen receptor- α signaling and the development of \nDownloaded from Bioscientifica.com at 06/09/2026 09:58:57PM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-19-0248\nhttps://joe.bioscientifica.com © 2019 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR49\nReview\nR C M Simmen et al. Co-morbid endometriosis and \ntype 1 diabetes\n243:3\nJournal of \nEndocrinology\nendocrine resistance as contributing to the progression \nof ENDO to endometriosis-associated ovarian carcinoma. \nMore detailed examination of coincident and multi-\ngene mutations occurring in endometriosis and ovarian \ncancers is undoubtedly needed to reinforce the ENDO-\nOvarian cancer link.\nT1DM patients of both genders show increased risks \nfor several cancers (stomach, kidney, liver, and pancreas) \n(Shu et al.  2010, Carstensen et al.  2016). In women, T1DM \nincreased predisposition to ovarian and endometrial \ncancers, but unlike type 2 diabetes, did not influence \nbreast cancer risk (Liaw et al.  2015, Wise 2016). Two recent \nepidemiological studies provide support for an association \nbetween T1DM and increased ovarian cancer risk. In a \nstudy conducted in the United Kingdom, ovarian cancer \nrisk was significantly elevated in younger-onset T1DM \npatients (standard incidence ratio of 2.14) ( Swerdlow \net al.  2005). Another study conducted in Taiwan of 14,610 \nfemale patients with T1DM showed a significant positive \nassociation between T1DM patients and risk for ovarian \ncancer (Hsu et al.  2015). Mechanistically, the association \nmaybe explained in part, by high levels of glucose that \npromote tumor growth ( Kellenberger & Petrik 2018 ). \nHowever, no studies to date have linked ovarian cancer \nrisk in women with co-morbid T1DM and ENDO.\nVascular dysfunctions\nENDO is an independent risk factor for venous \nthromboembolism, a major cause of maternal mortality, \nduring pregnancy and post-partum ( Abe et  al.  2019 , \nSugiura-Ogasawara et  al. 2019). Increased cardiovascular \ndisease is also associated with infertility ( Mahalingaiah \net al.  2017), a co-morbidity of ENDO.\nCardiovascular disease is the leading cause of death in \nT1DM patients. Serum concentrations of cardiovascular \ndisease biomarkers (e.g., soluble intracellular adhesion \nmolecule 1, soluble endothelial selectin) are higher in \nT1DM than in healthy women ( Lebkowska et  al. 2017). \nBranchial distensibility, an independent risk factor for \ncardiovascular disease, showed a steeper decline with age \nin T1DM that in non-diabetic, women ( Ljunggren et al.  \n2016). Interestingly, women with T1DM have higher risks \nof fatal and non-fatal vascular events than males with \nT1DM (Huxley et al.  2015).\nCompromised reproductive health\nInfertility, dysmenorrhea and pelvic pain are \ncommon symptoms of reproductive-age women with  \nENDO ( Burney & Giudice 2012 ). Women with ENDO \nare predisposed to increased early pregnancy loss and \nlater pregnancy complications such as placenta previa, \nantepartum and post-partum hemorrhage, small-for-\ngestational-age births and cesarean delivery ( Saraswat \net al.  2017, Zullo et al.  2017).\nWomen with T1DM manifest delayed puberty and \nmenarche, oligomenorrhea, mild hyperandrogenism, \nand in some cases, earlier menopause ( Codner et  al.  \n2012). Increased risk of infertility in women with T1DM \ncompared to women without T1DM, was also noted, \ndespite adjustments for irregular menses (Kim et al.  2018). \nThe compromised reproductive function in T1DM females \nmay have early developmental origins since diabetic girls \nshowed delayed uterine development (length and volume \nof uterus) at puberty relative to non-diabetic counterparts, \nalthough this difference largely equalized post puberty \n(Gurr et al.  1986). Perturbations in leptin and kisspeptin \nsignaling have been associated with defective reproductive \nfunction in women with T1DM (Castellano et al.  2009).\nT1DM complicates a relatively small percentage \nof pregnancies (~1 of 200). Nevertheless, women with \nT1DM experience fewer livebirths (Lin et al.  2018), higher \nearly pregnancy terminations ( Sjöberg et  al.  2017 ) and \na greater risk for preterm births ( Ludvigsson et al.  2019) \nthan the general population. Increased infiltration and \nadhesion of monocytes to placental bed endothelium \nleading to inflammation and reduction of placental blood \nflow have been suggested to partly underlie these poor \nbirth outcomes in women ( Galettis et al.  2004) and were \nmechanistically confirmed in non-obese diabetic mice \n(Burke et al.  2007).\nIn a number of T1DM patients, islets transplantation \nis a course of treatment, and patients undergo \nimmunosuppression therapy ( Cure et  al.  2004 ). Adverse \noutcomes of these regimen include menstrual cycle \nalterations and emergence of ovarian cysts ( Alfadhli \net al.  2009), which can further contribute to diminished \nreproductive status of TIDM patients.\nNeuropathy\nA predominant clinical feature of ENDO is chronic pelvic \npain during menstruation. The mechanism(s) underlying \nthe origin of this pain remains unknown, although \nendometriotic lesions display increased expression of \nneurotrophic and angiogenic factors and higher density \nof nerve fibers ( Morotti et  al.  2014 ). Moreover, women \nsuffering from deep infiltrating ENDO and bowel ENDO, \nwho experience more pelvic pain, present greater nerve \nDownloaded from Bioscientifica.com at 06/09/2026 09:58:57PM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-19-0248\nhttps://joe.bioscientifica.com © 2019 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR50\nCo-morbid endometriosis and \ntype 1 diabetes\nR C M Simmen et al.243:3\nJournal of \nEndocrinology\nfiber densities in ectopic lesions than women with \nperitoneal ENDO and endometrioma ( Morotti et  al.  \n2014). A rat model for leg pain in ENDO showed that \nthe complexes (cysts) formed from the fusion of nerve \nfibers with endometrial tissues are highly infiltrated \nwith macrophages, indicating inflammation and are \nprominently innervated by small diameter axons, which \ntogether could result in persistent neural discharge and \nthus, pain (Bove 2016).\nNeuropathy and neuropathic pain are common \ncomplications of T1DM. In adults with longstanding \nT1DM, neuropathic pain was more prevalent in females \nthan in males ( Cardinez et  al.  2018 ). Similar to ENDO-\nassociated pain, the pathophysiology of neuropathic pain \nin T1DM is not well understood, although hyperglycemia \nis highly considered to play an important role in its \ndevelopment. A recent review on this topic provides a \ncomprehensive summary of plausible mechanisms, which \ninclude stress, microvascular changes and glial activation \n(Schreiber et al.  2015).\nDifferences between TIDM and ENDO\nLinks with polycystic ovary syndrome (PCOS)\nPCOS is a condition associated with insulin resistance, \nhyperandrogenism, oligomenorrhea and other \nmorbidities including reduced fertility ( Escobar-Morreale \n2018). While both PCOS and ENDO are associated with \ncompromised fertility, an increased risk for ENDO with \nPCOS and vice-versa, has not been established, supporting \nthe notion of their differing pathogenesis and underlying \nmechanisms. A prime example of these differences relates \nto pro-inflammatory cytokines, whose systemic levels \nare elevated predominantly in PCOS as opposed to more \nlocally in ENDO (Younis et al.  2014). Moreover, while the \nearly events in ENDO are highly dependent on the innate \nimmune system (Burns et al.  2012, 2018), those of PCOS \nare largely initiated by hyperandrogenism with epigenetic \nunderpinnings (Escobar-Morreale 2018).\nPCOS incidence is higher in T1DM women than in the \ngeneral population ( Escobar-Morreale & Roldán-Martín \n2016). Adolescent girls with T1DM also displayed a greater \nprevalence of PCOS (Busiah et al.  2017). Insulin therapy in \nT1DM may result in hyperinsulinemia that can aggravate \nPCOS through hyperandrogenism (Shigiyama et al.  2016). \nOne study compared the phenotypic characteristics, \nincluding general hormonal patterns, of PCOS women \nwith and without T1DM. No differences were noted, \nsuggesting that the enhanced subfertility of women with \ncoincidence of T1DM and PCOS, relative to PCOS alone \nmay not be directly dependent on mechanisms related to \nglycemic/metabolic control ( Amato et al.  2014, Escobar-\nMorreale & Roldán-Martín 2016). However, another study \nreported that while hirsutism and hyperandrogenism as \nwell as ovarian volume were comparable between PCOS \nwomen with and without T1DM (and higher than shown \nfor the control group), T1DM/PCOS women displayed \nlower anti-mullerian hormone levels (which were \ncorrelated with ovarian follicle numbers) and higher ratios \nof luteinizing hormone to follicle-stimulating hormone, \nthan PCOS women without T1DM ( Codner et al.  2007). \nThe resolution of these differences is yet to be addressed.\nPredisposition and body mass index\nENDO is inversely associated with BMI across the life \ncourse and with more favorable morphometric indicators \nand body composition (Backonja et al.  2017, Farland et al.  \n2017). Specifically, lower BMI is suggested to constitute a \nrisk factor for the development of ENDO and a predictive \nfactor for severe ENDO. This association is counter-\nintuitive to the substantially supported and largely \nacknowledged notion that obesity is a risk factor for many \nchronic diseases and compromises fertility. Given that a \ncausal association is yet to be established between ENDO \nand BMI, numerous studies continue to address this \nseeming paradoxical relationship. Taylor and colleagues \n(Goetz et  al.  2016 ) showed that in a mouse model of \nENDO, the presence of EC promoted low BMI due to \ndysregulation of hepatic metabolism, suggesting ENDO as \na cause rather than a consequence of low BMI. In another \nmouse model of ENDO from our group ( Heard et  al.  \n2016), EC growth was increased by high-fat diet, in the \nabsence of changes in body weight. Further, genome-wide \nenrichment analyses between ENDO and obesity-related \ntraits indicated that body fat distribution rather than BMI \nis associated with ENDO (Rahmioglu et al.  2015).\nT1DM individuals, in the absence of insulin therapy, \nexperience poor metabolic control, which can lead \nto early death ( Collier et  al.  2018 ). With appropriate \nclinical management, however, T1DM females can lead \nrelatively normal lives, despite the condition’s associated \nmorbidities. T1DM patients typically have lower BMI than \ntype 2 diabetes patients ( Thomas et  al. 2018 ). Sustained \nobesity (cumulative excess BMI ≥ 5 kg/m2) enhanced \nthe risk for T1DM in pediatric and young women  \n(<35 y-o) but the risk diminished with increasing age (Ferrara \net  al.  2017 ). While insulin resistance in T1DM patients \nDownloaded from Bioscientifica.com at 06/09/2026 09:58:57PM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-19-0248\nhttps://joe.bioscientifica.com © 2019 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR51\nReview\nR C M Simmen et al. Co-morbid endometriosis and \ntype 1 diabetes\n243:3\nJournal of \nEndocrinology\noccurs regardless of accompanying obesity or metabolic \nsyndrome (Cree-Green et  al.  2018 ), recent data indicate \nthat a significant fraction (30%) of girls and adolescent \nfemales with T1DM are overweight or obese (Maffeis et al.  \n2018), which may have bearing on ENDO risk.\nMolecular correlates in T1DM and ENDO\nTable 1  provides a list of molecules independently \nimplicated in ENDO and T1DM, based on studies with \nhuman patients and animal disease models. The parallel \ninvolvement of these molecules in both conditions \nreinforces the notion that T1DM and ENDO may not \nonly co-exist but may promote each other’s occurrence. \nPro-inflammatory molecules predominate the list, \nconsistent with the inflammatory status associated with \neach condition. A recent review (Ahn et al.  2016) presents \na comprehensive description of immune-inflammation \ngenes associated with ENDO. Interferon-γ is a key molecule \nin ENDO (Mier-Cabrera et al.  2011, Gueuvoghlanian-Silva \net al.  2018) and in T1DM ( Driver et al.  2017, Osum et al.  \n2018), given its regulation of Th-1 cell development in \nautoimmunity. Tumor necrosis factor-alpha (TNF- α) is \nimplicated in the pathogenesis of ENDO, since its levels \nare increased in peritoneal fluids of ENDO women by \nvirtue of activated peritoneal macrophages infiltrating \nlesions and correlate with disease severity and with size \nand numbers of active lesions ( Birt et  al.  2013 , Kocbek \net al.  2016). Similarly, serum TNF- α levels are elevated in \nT1DM patients, regardless of age, disease duration, and \nethnicity (Qiao et al.  2017). By using non-obese diabetic \nmice, Lee et al . (2005) demonstrated that TNF- α initiates \nT1DM autoimmunity by regulating the maturation of \ndendritic cells, leading to the activation of islet-specific \npancreatic lymph node T-cells. Macrophage migration \ninhibitor factor-1 (MIF-1), another pro-inflammatory \ncytokine implicated in the innate immune system, \nshowed significantly higher expression in EU of women \nwith ENDO than in normal (control) endometrium, and \nits levels were highly upregulated by estrogen ( Veillat \net  al.  2012 , Rakhila et  al.  2014 ). Expression of MIF’s \nspecific receptor CD74 is also higher in human EC, where \nit is postulated to contribute to epithelial cell survival \nand enhanced IL-8 expression ( Nothnick et  al.  2018 ). \nMIF-1 is also associated with T1DM, where it is involved \nin the activation of macrophages and dendritic cells \nfor inflammatory Th-1 response. By using wildtype and  \nMif-1 knockout mice administered streptozotocin to \ninduce T1DM, Sánchez-Zamora et al . (2016) provided direct \nevidence to support MIF’s role in inducing hyperglycemia, \ninflammation, production of specific pancreatic \nantigen, and regulation of TLR expression, all of which \ncharacterize T1DM in humans. The transcription factor \nNF-κB is similarly implicated in the pathogenesis of ENDO \nand of T1DM, albeit in opposing manner. In pancreatic \nislet cells, NF-κB prevents TNF-α induced apoptosis by its \nupregulation of the anti-apoptotic protein TNF-induced \nprotein 3 ( Liuwantara et al.  2006, Kim et al.  2007), thus \nserving a protective role. By contrast, NF- κB promotes \nEC establishment, maintenance and progression by \nstimulating the synthesis of pro-inflammatory cytokines \nin ectopic endometrial cells and in macrophages that \nsubsequently infiltrate these lesions ( Veillat et  al.  2009 , \nKaponis et  al.  2012 ); these mechanisms were shown to \nbe mediated by ESR2 ( Gou et  al.  2019 ). Nevertheless, it \nis currently unknown which condition (ENDO or T1DM) \nmay occur first in the case of co-morbidity, since the \ndiagnosis of each is subject to delay, owing in part to a \nlack of reliable non-intrusive biomarkers for ENDO and to \nthe increasing adult onset of T1DM.\nPotential therapeutic complications in \nco-morbid T1DM and ENDO\nTo date, no systematic studies have addressed the \nquestion of whether treatments administered to singly \nTable 1 Immune/inflammatory molecules implicated in endometriosis (ENDO) and type 1 diabetes mellitus (T1DM).\nMolecules ENDO T1DM\nIFN-γ Mier-Cabrera et al. (2011), Gueuvoghlanian-Silva et al. (2018) Driver et al. (2017), Osum et al. (2018)\nTNFα Birt et al. (2013), Kocbek et al. (2016) Lee et al. (2005), Qiao et al. (2017)\nMIF Rakhila et al. (2014), Zhang & Mu (2015), Nothnick et al. (2018) Sánchez-Zamora et al. (2016)\nNF-κβ Veillat et al. (2009), Kaponis et al. (2012), Gou et al. (2019) Liuwantara et al. (2006), Kim et al. (2007)\nIL-8 Jørgensen et al. (2017), Burns et al. (2018) Devaraj et al. (2011), Purohit et al. (2015)\nIL-6 Burns et al. (2018), Woo et al. (2017) Hundhausen et al. (2016)\nMCP-1 Grandi et al. (2016), Younis et al. (2014) Waugh et al. (2017)\nIFN-γ, interferon gamma; IL-6, interleukin 6; IL-8, interleukin 8; MCP-1, monocyte chemotactic protein-1; MIF, macrophage migration inhibitory factor; \nNF-κβ, nuclear factor- kappa β; TNFα, tumor necrosis factor α.\nDownloaded from Bioscientifica.com at 06/09/2026 09:58:57PM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-19-0248\nhttps://joe.bioscientifica.com © 2019 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR52\nCo-morbid endometriosis and \ntype 1 diabetes\nR C M Simmen et al.243:3\nJournal of \nEndocrinology\nmanage ENDO or T1DM in women with either condition \nmight influence the efficacy of agents in patients with \nboth conditions. Nevertheless, published studies provide \nsupport for this possibility. Gonadotropin-releasing \nhormone (GnRH) agonists and progestins are standard \ntreatments for ENDO. In women with ENDO (but without \nT1DM), intake of the GnRH agonist leuprorelin or use \nof subdermal progestin implant for symptoms of pelvic \nendometriosis decreased insulin sensitivity and glucose \nutilization ( Cagnacci et  al.  2005 ). A causal effect of \nprogestin intake on disruption of glucoregulatory function \nwas confirmed in adult rhesus macaques undergoing \ntreatment for ENDO with medroxy-progesterone acetate \n(MPA) ( Cruzen et  al.  2011 ). Further, in a retrospective \nstudy of rhesus macaques with ENDO, treatment with \ndepot MPA increased the risk of incident T1DM (Connolly \net al.  2016). In a randomized trial of non-ENDO women \nwith uncomplicated (i.e., managed) T1DM, the use of \nprogestin levonorgestrel for contraception showed no \nadverse effect on glucose metabolism as measured by \nglycosylated hemoglobin, fasting serum-glucose levels \nand daily insulin dose requirements ( Rogovskaya et  al.  \n2005). However, in a case report, progestin administration \nto prevent preterm delivery and miscarriage in a pregnant \nwoman with T1DM, elicited a decline in glycemic control, \nwhich necessitated the adjustment of the patient’s basal \ninsulin rate ( Sasaki et al.  2013). Danazol is an androgen \nantagonist used to treat ENDO since it normalizes \naromatase cytochrome P450 expression in EU from \nwomen with ENDO (Ishihara et al.  2003). In a comparison \nof non-T1DM women with and without ENDO, danazol \ndecreased the response of glucose to insulin in women \nwith ENDO, indicating its promotion of insulin resistance \n(Bruce et al.  1992, Matalliotakis et al.  1997). Collectively, \nthe results suggest that current clinical management of \nENDO may compromise women with accompanying \nT1DM and thus, advocate for physicians to recognize \npatients with ENDO and T1DM co-morbidities for \nprovision of appropriate and optimal care.\nGiven increasing support for the role of specific diets \nin the promotion of a pro-inflammatory state that is \nassociated with T1DM (Vaarala 2011, Knip et al.  2012, van \nBussel et al.  2013) and ENDO (Saguyod et al.  2018, Simmen \n& Kelley 2018), it is prudent to consider dietary changes, \nwhich can significantly impact the intestinal microbiota, \nfor management of co-morbid ENDO and T1DM \n(Henschel et  al.  2018 ). Similarly, the use of metformin \nfor targeting co-morbid T1DM and ENDO may have \nvalue, given recent evidence for its efficacy in reducing \nT1DM (Bjornstad et al.  2018, Cree-Green et al.  2019) and \nhindering the progression of ENDO lesions and associated \nsignaling pathways ( Takemura et  al.  2007 , Yilmaz et  al.  \n2010). Additionally, therapies that reduce inflammation \ncould prove beneficial, given the pro-inflammatory status \nof T1DM and ENDO. Further investigations into these \npossibilities are warranted.\nConcluding remarks\nENDO and of T1DM are complex conditions due \nto their polygenic nature and their susceptibility to \nenvironmental triggers. Figure 1 is a schematic summary \nof how immune dysfunction and enhanced inflammatory \nFigure 1\nA schematic summary of immune system \ncomponents potentially involved in co-morbid \nendometriosis and type 1 diabetes. Also shown \nare the substantial overlaps in clinical disorders \nassociated with each condition.\nDendritic Cells Macrophages Natural Killer Cells Neutrophils\nEctopic Lesions\nGrowth\nAngiogenesis\nInflammation\nEndometriosis\nPancreatic β- cells \nβ- cell Destruction\nType 1 Diabetes\nIL-8\nIL-6\nIFN-γ\nTNFα\nMIF\nMCP-1\nOvarian/Endometrial\nCancer\nVascular Dysfunction\nReproductive Health\nNeuropathy\nDownloaded from Bioscientifica.com at 06/09/2026 09:58:57PM\nvia free access\n\n\nhttps://doi.org/10.1530/JOE-19-0248\nhttps://joe.bioscientifica.com © 2019 Society for Endocrinology\nPublished by Bioscientifica Ltd.\nPrinted in Great Britain\nR53\nReview\nR C M Simmen et al. Co-morbid endometriosis and \ntype 1 diabetes\n243:3\nJournal of \nEndocrinology\nstatus may promote ENDO and T1DM in high-risk women \nand the overlaps in the association of each condition to \nmany clinical disorders. Reproductive-age women with \nco-morbid ENDO and T1DM may suffer from infertility \nat a higher rate than those with either condition yet pre-\nconception counseling for this cohort of women is likely \nnon-existent, given their asymptomatic nature at early \nstages. Moreover, current therapies addressing ENDO to \nmitigate infertility can exacerbate T1DM via their negative \neffects on glucose control. Thus, there is a current unmet \nneed to identify and develop novel therapeutic strategies \nthat are safe and effective to address these co-morbid \nconditions. Relevant and convenient animal models that \nconcomitantly recapitulate T1DM and ENDO are crucial \nfor the design of mechanistic studies to address how \nT1DM can promote ENDO and conversely, how ENDO \nmay complicate T1DM. The provision of these animal \nmodels will advance current understanding of biomarkers \nfor predicting disease development and therapeutically \ntargetable pathways to ameliorate disease pathogenesis. \nFinally, ENDO and T1DM should continue to be at \nthe forefront of future research since there remains a \nlarge gap in knowledge on how genetic, endocrine and \nimmunological factors contribute to their onset and \nprogression.\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be \nperceived as prejudicing the impartiality of this review.\nFunding\nWork described in this review from our laboratory was supported in part \nby the National Institutes of Health (HD21961), the Sturgis Foundation and \nthe Development Enhancement Awards for Proposals Grant Program of \nthe University of Arkansas for Medical Sciences.\nReferences\nAbe K, Kuklina EV , Hooper WC & Callaghan WM 2019 Venous \nthromboembolism as a cause of severe maternal morbidity and \nmortality in the United States. 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