Co-morbidity of type 1 diabetes and endometriosis: bringing a new paradigm into focus

Type 1 diabetes mellitus and endometriosis separately affect millions of women worldwide. Reproductive-age women diagnosed with type 1 diabetes may also suffer from endometriosis, but the asymptomatic pre-clinical period of highly variable duration for each condition can lead to challenges in the timely recognition of co-morbid disease onset and misdiagnosis. While knowledge of the pathogenesis of each condition has grown substantially, co-morbid endometriosis and type 1 diabetes has not been widely considered and much less addressed. This review discusses the molecular rationale for the likelihood of their co-existence, and prospects for improvements in therapeutic strategies and reduced complications, if this paradigm is included as a significant variable in disease management.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease, resulting from the destruction of insulin-producing β-cells of the pancreatic islets of Langerhans, which leads to a state of hypoinsulinemia and hyperglycemia. In 2015, 1.25 million Americans suffered from T1DM, with an annual economic cost of ~$14B (https://beyondtype1.org/ type-1). With 40,000 new cases diagnosed annually, the prediction that 5 million people will have T1DM by 2020 is disconcerting. The incidence of T1DM has also increased by ~3% per year globally, albeit with some geographical preferences (Maahs et al. 2010). Mortality risks are higher in individuals with T1DM than in the general population (Collier et  al. 2018 ). While T1DM is often diagnosed at childhood and may have early life origins ( Knip et  al. 2017), the condition has later onset in many adults. In such cases, the condition is often mistaken for type 2 diabetes, leading to inappropriate management and a life- threatening state (Thomas et al. 2019). Endometriosis (ENDO), a chronic estrogen-dependent disease, characterized by the implantation and growth of endometrial tissues predominantly in the peritoneal cavity and the ovary, affects 6–10% of all reproductive- age women (average age 13–45 years) ( Burney & Giudice 2012). Debilitating pelvic pain, infertility in 50% of afflicted patients, considerable morbidity, and an economic burden of ~$50B a year in the United States alone accompany this condition. ENDO is often subject to delayed diagnosis, has no known effective treatment and is recurrent. T1DM and ENDO share similar pathophysiology since both are associated with chronic inflammation triggered by overactivation of the immune response 3 Key Words f endometriosis f type 1 diabetes f inflammation f cancers Journal of Endocrinology (2019) 243, R47–R57 243 Downloaded from Bioscientifica.com at 06/09/2026 09:58:57PM via free access https://doi.org/10.1530/JOE-19-0248 https://joe.bioscientifica.com © 2019 Society for Endocrinology Published by Bioscientifica Ltd. Printed in Great Britain R48 Co-morbid endometriosis and type 1 diabetes R C M Simmen et al.243:3 Journal of Endocrinology (Cabrera et al. 2016, Symons et al. 2018). The predominance of ENDO in women with T1DM remains unknown; however, women (and young girls upon initiation of menses) with T1DM may suffer from ENDO during their reproductive years. Considering the significant health and economic burdens related to T1DM and ENDO singly and the prospect of their co-incidence, an increased understanding of their risks and predisposition are imperative. This review aims to address why these two conditions may co-exist and how awareness of this possibility may improve clinical management and quality of life in affected women. Commonalities between T1DM and ENDO Inflammatory status Substantial evidence from human and animal studies indicates that dysfunction in local immune signaling contributes to the development and maintenance of ectopic lesions (EC) in ENDO ( Ulukus & Arici 2005 , Pabona et al. 2012, Greaves et al. 2014). A review on this topic (Symons et al. 2018) summarizes the cell populations of the innate immune system implicated in ENDO pathophysiology. Neutrophils, macrophages, and natural killer cells recruited to EC may promote ENDO in two ways. One mechanism for which the estrogen receptor- β (ESR2) signaling cascade has been implicated ( Han et al. 2015), results in increased secretion of various cytokines that support the growth, invasion and angiogenic properties of lesions ( Capobianco et al. 2011). A second mechanism occurs via the reduction in the phagocytic abilities of macrophages and natural killer cells, thus inhibiting the clearance of endometrial cells in the immediate environment of lesions (Chuang et al. 2010). In a murine model of ENDO, EC growth was associated with dendritic cells, which can attenuate ( Stanic et  al. 2014 ) or enhance ( Pencovich et al. 2014) the process. Toll-like receptors (TLRs) are essential components of the innate immune system owing to their roles in mediating pattern recognition of and response toward pathogens and host- related antigens. In patients with peritoneal ENDO, higher expression of TLR3 and TLR4 in glandular epithelium of EC than of corresponding EU were noted ( Allhorn et al. 2008, Hayashi et  al. 2013 ). A potential mechanism for TLR4 promotion of ENDO has been described ( Luo et al. 2015). In this scenario, TLR4 activation causes increased secretion of pro-inflammatory interleukin-8 (IL-8) and enhanced expression of IL-8 receptor C-X-C motif chemokine receptor-1 in endometriotic stromal cells, to bolster these cells’ invasive and proliferative potential. In recent years, innate immunity in the pathogenesis of T1DM has gained substantial support and has linked TLRs in mediating islet inflammation ( Lien & Zipris 2009, Alkanani et  al. 2012 , Cabrera et  al. 2016 ). TLRs implicated in T1DM include TLR1, TLR2, TLR3, TLR7 and TLR9. Nonetheless, distinct TLRs may be protective or supportive of T1DM, suggesting contextual effects and differing mechanisms. For example, in non-obese diabetic mice, TLR4 deficiency accelerated the development of T1DM ( Devaraj et  al. 2011 , Gülden et  al. 2013 ), while loss of TLR9 reduced incidence of T1DM ( Tai et al. 2013). Similar to ENDO, T1DM pathogenesis is associated with aberrant dendritic cell function. Many polymorphic loci identified by genome-wide and disease-association studies and which can potentially underlie susceptibility to T1DM have been linked to immune dysfunctions in dendritic cells such as in cytokine signaling, development and activation, all of which disrupt their tolerogenic properties ( Hotta-Iwamura & Tarbell 2016 ). The recent identification of an insulin B peptide as a trigger of T-regulatory cells in the pancreas provides a promising prospect for targeting TLRs and dendritic cells to suppress autoimmunity in T1DM (Wang et al. 2019). Risk for ovarian and other cancers Epidemiological and molecular evidence indicate that while benign in its initial stages, ENDO is an independent risk factor for both clear-cell and endometroid ovarian carcinoma (reviewed in Lee et  al. 2016 , Bulun et  al. 2019). Somatic mutations in key genes, primarily phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha ( PIK3CA) and Kirsten rat sarcoma ( KRAS) in endometriotic epithelial cells have been suggested to contribute to the development of ovarian cancers ( Er et al. 2016). However, mutations in these same genes have been detected in endometriosis with and without cancers (Anglesio et al. 2017). Moreover, epithelial cells isolated from ovarian endometriotic lesions and normal/benign uterine endometrium displayed mutations in both PIK3CA and KRAS, albeit at different allele frequencies, suggesting that these mutations are not sufficiently causal for ovarian cancers (Suda et al. 2018). In a comparison of gene expression patterns of normal (non-diseased) endometria with those of endometriosis (benign, atypical, concurrent with endometriosis) and endometriosis-associated ovarian cancer, Andersen et al . (2018) implicated the loss of estrogen receptor- α signaling and the development of Downloaded from Bioscientifica.com at 06/09/2026 09:58:57PM via free access https://doi.org/10.1530/JOE-19-0248 https://joe.bioscientifica.com © 2019 Society for Endocrinology Published by Bioscientifica Ltd. Printed in Great Britain R49 Review R C M Simmen et al. Co-morbid endometriosis and type 1 diabetes 243:3 Journal of Endocrinology endocrine resistance as contributing to the progression of ENDO to endometriosis-associated ovarian carcinoma. More detailed examination of coincident and multi- gene mutations occurring in endometriosis and ovarian cancers is undoubtedly needed to reinforce the ENDO- Ovarian cancer link. T1DM patients of both genders show increased risks for several cancers (stomach, kidney, liver, and pancreas) (Shu et al. 2010, Carstensen et al. 2016). In women, T1DM increased predisposition to ovarian and endometrial cancers, but unlike type 2 diabetes, did not influence breast cancer risk (Liaw et al. 2015, Wise 2016). Two recent epidemiological studies provide support for an association between T1DM and increased ovarian cancer risk. In a study conducted in the United Kingdom, ovarian cancer risk was significantly elevated in younger-onset T1DM patients (standard incidence ratio of 2.14) ( Swerdlow et al. 2005). Another study conducted in Taiwan of 14,610 female patients with T1DM showed a significant positive association between T1DM patients and risk for ovarian cancer (Hsu et al. 2015). Mechanistically, the association maybe explained in part, by high levels of glucose that promote tumor growth ( Kellenberger & Petrik 2018 ). However, no studies to date have linked ovarian cancer risk in women with co-morbid T1DM and ENDO. Vascular dysfunctions ENDO is an independent risk factor for venous thromboembolism, a major cause of maternal mortality, during pregnancy and post-partum ( Abe et  al. 2019 , Sugiura-Ogasawara et  al. 2019). Increased cardiovascular disease is also associated with infertility ( Mahalingaiah et al. 2017), a co-morbidity of ENDO. Cardiovascular disease is the leading cause of death in T1DM patients. Serum concentrations of cardiovascular disease biomarkers (e.g., soluble intracellular adhesion molecule 1, soluble endothelial selectin) are higher in T1DM than in healthy women ( Lebkowska et  al. 2017). Branchial distensibility, an independent risk factor for cardiovascular disease, showed a steeper decline with age in T1DM that in non-diabetic, women ( Ljunggren et al. 2016). Interestingly, women with T1DM have higher risks of fatal and non-fatal vascular events than males with T1DM (Huxley et al. 2015). Compromised reproductive health Infertility, dysmenorrhea and pelvic pain are common symptoms of reproductive-age women with ENDO ( Burney & Giudice 2012 ). Women with ENDO are predisposed to increased early pregnancy loss and later pregnancy complications such as placenta previa, antepartum and post-partum hemorrhage, small-for- gestational-age births and cesarean delivery ( Saraswat et al. 2017, Zullo et al. 2017). Women with T1DM manifest delayed puberty and menarche, oligomenorrhea, mild hyperandrogenism, and in some cases, earlier menopause ( Codner et  al. 2012). Increased risk of infertility in women with T1DM compared to women without T1DM, was also noted, despite adjustments for irregular menses (Kim et al. 2018). The compromised reproductive function in T1DM females may have early developmental origins since diabetic girls showed delayed uterine development (length and volume of uterus) at puberty relative to non-diabetic counterparts, although this difference largely equalized post puberty (Gurr et al. 1986). Perturbations in leptin and kisspeptin signaling have been associated with defective reproductive function in women with T1DM (Castellano et al. 2009). T1DM complicates a relatively small percentage of pregnancies (~1 of 200). Nevertheless, women with T1DM experience fewer livebirths (Lin et al. 2018), higher early pregnancy terminations ( Sjöberg et  al. 2017 ) and a greater risk for preterm births ( Ludvigsson et al. 2019) than the general population. Increased infiltration and adhesion of monocytes to placental bed endothelium leading to inflammation and reduction of placental blood flow have been suggested to partly underlie these poor birth outcomes in women ( Galettis et al. 2004) and were mechanistically confirmed in non-obese diabetic mice (Burke et al. 2007). In a number of T1DM patients, islets transplantation is a course of treatment, and patients undergo immunosuppression therapy ( Cure et  al. 2004 ). Adverse outcomes of these regimen include menstrual cycle alterations and emergence of ovarian cysts ( Alfadhli et al. 2009), which can further contribute to diminished reproductive status of TIDM patients. Neuropathy A predominant clinical feature of ENDO is chronic pelvic pain during menstruation. The mechanism(s) underlying the origin of this pain remains unknown, although endometriotic lesions display increased expression of neurotrophic and angiogenic factors and higher density of nerve fibers ( Morotti et  al. 2014 ). Moreover, women suffering from deep infiltrating ENDO and bowel ENDO, who experience more pelvic pain, present greater nerve Downloaded from Bioscientifica.com at 06/09/2026 09:58:57PM via free access https://doi.org/10.1530/JOE-19-0248 https://joe.bioscientifica.com © 2019 Society for Endocrinology Published by Bioscientifica Ltd. Printed in Great Britain R50 Co-morbid endometriosis and type 1 diabetes R C M Simmen et al.243:3 Journal of Endocrinology fiber densities in ectopic lesions than women with peritoneal ENDO and endometrioma ( Morotti et  al. 2014). A rat model for leg pain in ENDO showed that the complexes (cysts) formed from the fusion of nerve fibers with endometrial tissues are highly infiltrated with macrophages, indicating inflammation and are prominently innervated by small diameter axons, which together could result in persistent neural discharge and thus, pain (Bove 2016). Neuropathy and neuropathic pain are common complications of T1DM. In adults with longstanding T1DM, neuropathic pain was more prevalent in females than in males ( Cardinez et  al. 2018 ). Similar to ENDO- associated pain, the pathophysiology of neuropathic pain in T1DM is not well understood, although hyperglycemia is highly considered to play an important role in its development. A recent review on this topic provides a comprehensive summary of plausible mechanisms, which include stress, microvascular changes and glial activation (Schreiber et al. 2015). Differences between TIDM and ENDO Links with polycystic ovary syndrome (PCOS) PCOS is a condition associated with insulin resistance, hyperandrogenism, oligomenorrhea and other morbidities including reduced fertility ( Escobar-Morreale 2018). While both PCOS and ENDO are associated with compromised fertility, an increased risk for ENDO with PCOS and vice-versa, has not been established, supporting the notion of their differing pathogenesis and underlying mechanisms. A prime example of these differences relates to pro-inflammatory cytokines, whose systemic levels are elevated predominantly in PCOS as opposed to more locally in ENDO (Younis et al. 2014). Moreover, while the early events in ENDO are highly dependent on the innate immune system (Burns et al. 2012, 2018), those of PCOS are largely initiated by hyperandrogenism with epigenetic underpinnings (Escobar-Morreale 2018). PCOS incidence is higher in T1DM women than in the general population ( Escobar-Morreale & Roldán-Martín 2016). Adolescent girls with T1DM also displayed a greater prevalence of PCOS (Busiah et al. 2017). Insulin therapy in T1DM may result in hyperinsulinemia that can aggravate PCOS through hyperandrogenism (Shigiyama et al. 2016). One study compared the phenotypic characteristics, including general hormonal patterns, of PCOS women with and without T1DM. No differences were noted, suggesting that the enhanced subfertility of women with coincidence of T1DM and PCOS, relative to PCOS alone may not be directly dependent on mechanisms related to glycemic/metabolic control ( Amato et al. 2014, Escobar- Morreale & Roldán-Martín 2016). However, another study reported that while hirsutism and hyperandrogenism as well as ovarian volume were comparable between PCOS women with and without T1DM (and higher than shown for the control group), T1DM/PCOS women displayed lower anti-mullerian hormone levels (which were correlated with ovarian follicle numbers) and higher ratios of luteinizing hormone to follicle-stimulating hormone, than PCOS women without T1DM ( Codner et al. 2007). The resolution of these differences is yet to be addressed. Predisposition and body mass index ENDO is inversely associated with BMI across the life course and with more favorable morphometric indicators and body composition (Backonja et al. 2017, Farland et al. 2017). Specifically, lower BMI is suggested to constitute a risk factor for the development of ENDO and a predictive factor for severe ENDO. This association is counter- intuitive to the substantially supported and largely acknowledged notion that obesity is a risk factor for many chronic diseases and compromises fertility. Given that a causal association is yet to be established between ENDO and BMI, numerous studies continue to address this seeming paradoxical relationship. Taylor and colleagues (Goetz et  al. 2016 ) showed that in a mouse model of ENDO, the presence of EC promoted low BMI due to dysregulation of hepatic metabolism, suggesting ENDO as a cause rather than a consequence of low BMI. In another mouse model of ENDO from our group ( Heard et  al. 2016), EC growth was increased by high-fat diet, in the absence of changes in body weight. Further, genome-wide enrichment analyses between ENDO and obesity-related traits indicated that body fat distribution rather than BMI is associated with ENDO (Rahmioglu et al. 2015). T1DM individuals, in the absence of insulin therapy, experience poor metabolic control, which can lead to early death ( Collier et  al. 2018 ). With appropriate clinical management, however, T1DM females can lead relatively normal lives, despite the condition’s associated morbidities. T1DM patients typically have lower BMI than type 2 diabetes patients ( Thomas et  al. 2018 ). Sustained obesity (cumulative excess BMI ≥ 5 kg/m2) enhanced the risk for T1DM in pediatric and young women (<35 y-o) but the risk diminished with increasing age (Ferrara et  al. 2017 ). While insulin resistance in T1DM patients Downloaded from Bioscientifica.com at 06/09/2026 09:58:57PM via free access https://doi.org/10.1530/JOE-19-0248 https://joe.bioscientifica.com © 2019 Society for Endocrinology Published by Bioscientifica Ltd. Printed in Great Britain R51 Review R C M Simmen et al. Co-morbid endometriosis and type 1 diabetes 243:3 Journal of Endocrinology occurs regardless of accompanying obesity or metabolic syndrome (Cree-Green et  al. 2018 ), recent data indicate that a significant fraction (30%) of girls and adolescent females with T1DM are overweight or obese (Maffeis et al. 2018), which may have bearing on ENDO risk. Molecular correlates in T1DM and ENDO Table 1 provides a list of molecules independently implicated in ENDO and T1DM, based on studies with human patients and animal disease models. The parallel involvement of these molecules in both conditions reinforces the notion that T1DM and ENDO may not only co-exist but may promote each other’s occurrence. Pro-inflammatory molecules predominate the list, consistent with the inflammatory status associated with each condition. A recent review (Ahn et al. 2016) presents a comprehensive description of immune-inflammation genes associated with ENDO. Interferon-γ is a key molecule in ENDO (Mier-Cabrera et al. 2011, Gueuvoghlanian-Silva et al. 2018) and in T1DM ( Driver et al. 2017, Osum et al. 2018), given its regulation of Th-1 cell development in autoimmunity. Tumor necrosis factor-alpha (TNF- α) is implicated in the pathogenesis of ENDO, since its levels are increased in peritoneal fluids of ENDO women by virtue of activated peritoneal macrophages infiltrating lesions and correlate with disease severity and with size and numbers of active lesions ( Birt et  al. 2013 , Kocbek et al. 2016). Similarly, serum TNF- α levels are elevated in T1DM patients, regardless of age, disease duration, and ethnicity (Qiao et al. 2017). By using non-obese diabetic mice, Lee et al . (2005) demonstrated that TNF- α initiates T1DM autoimmunity by regulating the maturation of dendritic cells, leading to the activation of islet-specific pancreatic lymph node T-cells. Macrophage migration inhibitor factor-1 (MIF-1), another pro-inflammatory cytokine implicated in the innate immune system, showed significantly higher expression in EU of women with ENDO than in normal (control) endometrium, and its levels were highly upregulated by estrogen ( Veillat et  al. 2012 , Rakhila et  al. 2014 ). Expression of MIF’s specific receptor CD74 is also higher in human EC, where it is postulated to contribute to epithelial cell survival and enhanced IL-8 expression ( Nothnick et  al. 2018 ). MIF-1 is also associated with T1DM, where it is involved in the activation of macrophages and dendritic cells for inflammatory Th-1 response. By using wildtype and Mif-1 knockout mice administered streptozotocin to induce T1DM, Sánchez-Zamora et al . (2016) provided direct evidence to support MIF’s role in inducing hyperglycemia, inflammation, production of specific pancreatic antigen, and regulation of TLR expression, all of which characterize T1DM in humans. The transcription factor NF-κB is similarly implicated in the pathogenesis of ENDO and of T1DM, albeit in opposing manner. In pancreatic islet cells, NF-κB prevents TNF-α induced apoptosis by its upregulation of the anti-apoptotic protein TNF-induced protein 3 ( Liuwantara et al. 2006, Kim et al. 2007), thus serving a protective role. By contrast, NF- κB promotes EC establishment, maintenance and progression by stimulating the synthesis of pro-inflammatory cytokines in ectopic endometrial cells and in macrophages that subsequently infiltrate these lesions ( Veillat et  al. 2009 , Kaponis et  al. 2012 ); these mechanisms were shown to be mediated by ESR2 ( Gou et  al. 2019 ). Nevertheless, it is currently unknown which condition (ENDO or T1DM) may occur first in the case of co-morbidity, since the diagnosis of each is subject to delay, owing in part to a lack of reliable non-intrusive biomarkers for ENDO and to the increasing adult onset of T1DM. Potential therapeutic complications in co-morbid T1DM and ENDO To date, no systematic studies have addressed the question of whether treatments administered to singly Table 1 Immune/inflammatory molecules implicated in endometriosis (ENDO) and type 1 diabetes mellitus (T1DM). Molecules ENDO T1DM IFN-γ Mier-Cabrera et al. (2011), Gueuvoghlanian-Silva et al. (2018) Driver et al. (2017), Osum et al. (2018) TNFα Birt et al. (2013), Kocbek et al. (2016) Lee et al. (2005), Qiao et al. (2017) MIF Rakhila et al. (2014), Zhang & Mu (2015), Nothnick et al. (2018) Sánchez-Zamora et al. (2016) NF-κβ Veillat et al. (2009), Kaponis et al. (2012), Gou et al. (2019) Liuwantara et al. (2006), Kim et al. (2007) IL-8 Jørgensen et al. (2017), Burns et al. (2018) Devaraj et al. (2011), Purohit et al. (2015) IL-6 Burns et al. (2018), Woo et al. (2017) Hundhausen et al. (2016) MCP-1 Grandi et al. (2016), Younis et al. (2014) Waugh et al. (2017) IFN-γ, interferon gamma; IL-6, interleukin 6; IL-8, interleukin 8; MCP-1, monocyte chemotactic protein-1; MIF, macrophage migration inhibitory factor; NF-κβ, nuclear factor- kappa β; TNFα, tumor necrosis factor α. Downloaded from Bioscientifica.com at 06/09/2026 09:58:57PM via free access https://doi.org/10.1530/JOE-19-0248 https://joe.bioscientifica.com © 2019 Society for Endocrinology Published by Bioscientifica Ltd. Printed in Great Britain R52 Co-morbid endometriosis and type 1 diabetes R C M Simmen et al.243:3 Journal of Endocrinology manage ENDO or T1DM in women with either condition might influence the efficacy of agents in patients with both conditions. Nevertheless, published studies provide support for this possibility. Gonadotropin-releasing hormone (GnRH) agonists and progestins are standard treatments for ENDO. In women with ENDO (but without T1DM), intake of the GnRH agonist leuprorelin or use of subdermal progestin implant for symptoms of pelvic endometriosis decreased insulin sensitivity and glucose utilization ( Cagnacci et  al. 2005 ). A causal effect of progestin intake on disruption of glucoregulatory function was confirmed in adult rhesus macaques undergoing treatment for ENDO with medroxy-progesterone acetate (MPA) ( Cruzen et  al. 2011 ). Further, in a retrospective study of rhesus macaques with ENDO, treatment with depot MPA increased the risk of incident T1DM (Connolly et al. 2016). In a randomized trial of non-ENDO women with uncomplicated (i.e., managed) T1DM, the use of progestin levonorgestrel for contraception showed no adverse effect on glucose metabolism as measured by glycosylated hemoglobin, fasting serum-glucose levels and daily insulin dose requirements ( Rogovskaya et  al. 2005). However, in a case report, progestin administration to prevent preterm delivery and miscarriage in a pregnant woman with T1DM, elicited a decline in glycemic control, which necessitated the adjustment of the patient’s basal insulin rate ( Sasaki et al. 2013). Danazol is an androgen antagonist used to treat ENDO since it normalizes aromatase cytochrome P450 expression in EU from women with ENDO (Ishihara et al. 2003). In a comparison of non-T1DM women with and without ENDO, danazol decreased the response of glucose to insulin in women with ENDO, indicating its promotion of insulin resistance (Bruce et al. 1992, Matalliotakis et al. 1997). Collectively, the results suggest that current clinical management of ENDO may compromise women with accompanying T1DM and thus, advocate for physicians to recognize patients with ENDO and T1DM co-morbidities for provision of appropriate and optimal care. Given increasing support for the role of specific diets in the promotion of a pro-inflammatory state that is associated with T1DM (Vaarala 2011, Knip et al. 2012, van Bussel et al. 2013) and ENDO (Saguyod et al. 2018, Simmen & Kelley 2018), it is prudent to consider dietary changes, which can significantly impact the intestinal microbiota, for management of co-morbid ENDO and T1DM (Henschel et  al. 2018 ). Similarly, the use of metformin for targeting co-morbid T1DM and ENDO may have value, given recent evidence for its efficacy in reducing T1DM (Bjornstad et al. 2018, Cree-Green et al. 2019) and hindering the progression of ENDO lesions and associated signaling pathways ( Takemura et  al. 2007 , Yilmaz et  al. 2010). Additionally, therapies that reduce inflammation could prove beneficial, given the pro-inflammatory status of T1DM and ENDO. Further investigations into these possibilities are warranted. Concluding remarks ENDO and of T1DM are complex conditions due to their polygenic nature and their susceptibility to environmental triggers. Figure 1 is a schematic summary of how immune dysfunction and enhanced inflammatory Figure 1 A schematic summary of immune system components potentially involved in co-morbid endometriosis and type 1 diabetes. Also shown are the substantial overlaps in clinical disorders associated with each condition. Dendritic Cells Macrophages Natural Killer Cells Neutrophils Ectopic Lesions Growth Angiogenesis Inflammation Endometriosis Pancreatic β- cells β- cell Destruction Type 1 Diabetes IL-8 IL-6 IFN-γ TNFα MIF MCP-1 Ovarian/Endometrial Cancer Vascular Dysfunction Reproductive Health Neuropathy Downloaded from Bioscientifica.com at 06/09/2026 09:58:57PM via free access https://doi.org/10.1530/JOE-19-0248 https://joe.bioscientifica.com © 2019 Society for Endocrinology Published by Bioscientifica Ltd. Printed in Great Britain R53 Review R C M Simmen et al. Co-morbid endometriosis and type 1 diabetes 243:3 Journal of Endocrinology status may promote ENDO and T1DM in high-risk women and the overlaps in the association of each condition to many clinical disorders. Reproductive-age women with co-morbid ENDO and T1DM may suffer from infertility at a higher rate than those with either condition yet pre- conception counseling for this cohort of women is likely non-existent, given their asymptomatic nature at early stages. Moreover, current therapies addressing ENDO to mitigate infertility can exacerbate T1DM via their negative effects on glucose control. Thus, there is a current unmet need to identify and develop novel therapeutic strategies that are safe and effective to address these co-morbid conditions. Relevant and convenient animal models that concomitantly recapitulate T1DM and ENDO are crucial for the design of mechanistic studies to address how T1DM can promote ENDO and conversely, how ENDO may complicate T1DM. The provision of these animal models will advance current understanding of biomarkers for predicting disease development and therapeutically targetable pathways to ameliorate disease pathogenesis. Finally, ENDO and T1DM should continue to be at the forefront of future research since there remains a large gap in knowledge on how genetic, endocrine and immunological factors contribute to their onset and progression. Declaration of interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review. Funding Work described in this review from our laboratory was supported in part by the National Institutes of Health (HD21961), the Sturgis Foundation and the Development Enhancement Awards for Proposals Grant Program of the University of Arkansas for Medical Sciences.

Abe K, Kuklina EV , Hooper WC & Callaghan WM 2019 Venous thromboembolism as a cause of severe maternal morbidity and mortality in the United States. Seminars in Perinatology 43 200–204. (https://doi.org/10.1053/j.semperi.2019.03.004) Ahn SH, Khalaj K, Young SL, Lessey BA, Koti M & Tayade C 2016 Immune-inflammation gene signatures in endometriosis patients. Fertility and Sterility 106 1420.e7–1431.e7. (https://doi.org/10.1016/j. fertnstert.2016.07.005) Alfadhli E, Koh A, Albaker W, Bhargava R, Ackerman T, McDonald C, Ryan EA, Shapiro AM & Senior PA 2009 High prevalence of ovarian cysts in premenopausal women receiving sirolimus and tacrolimus after clinical islet transplantation. Transplant International 22 622–625. (https://doi.org/10.1111/j.1432-2277.2009.00839.x) Alkanani AK, Rewers M, Dong F, Waugh K, Gottlieb PA & Zipris D 2012 Dysregulated toll-like receptor-induced interleukin-1β and interleukin-6 responses in subjects at risk for the development of type 1 diabetes. Diabetes 61 2525–2533. (https://doi.org/10.2337/db12- 0099) Allhorn S, Böing C, Koch AA, Kimmig R & Gashaw I 2008 TLR3 and TLR4 expression in healthy and diseased human endometrium. Reproductive Biology and Endocrinology 6 40. (https://doi.org/10.1186/1477-7827- 6-40) Amato MC, Guarnotta V , Ciresi A, Modica R, Pantò F & Giordano C 2014 No phenotypic differences for polycystic ovary syndrome (PCOS) between women with and without type 1 diabetes mellitus. Journal of Clinical Endocrinology and Metabolism 99 203–211. (https://doi. org/10.1210/jc.2013-2669) Andersen CL, Boisen MM, Sikora MJ, Ma T, Tseng G, Suryawanshi S, Vlad A, Elishaev E, Edwards RP & Oesterreich S 2018 The evolution of estrogen receptor signaling in the progression of endometriosis to endometriosis-associated ovarian cancer. Hormones and Cancer 9 399–407. (https://doi.org/10.1007/s12672-018-0350-9) Anglesio MS, Papadopoulos N, Ayhan A, Nazeran TM, Noë M, Horlings HM, Lum A, Jones S, Senz J, Seckin T, et al . 2017 Cancer- associated mutations in endometriosis without cancer. New England Journal of Medicine 376 1835–1848. (https://doi.org/10.1056/ NEJMoa1614814) Backonja U, Hediger ML, Chen Z, Lauver DR, Sun L, Peterson CM & Buck Louis GM 2017 Beyond body mass index: using anthropometric measures and body composition indicators to assess odds of an endometriosis diagnosis. Journal of Women’s Health 26 941–950. (https://doi.org/10.1089/jwh.2016.6128) Birt JA, Nabli H, Stilley JA, Windham EA, Frazier SR & Sharpe-Timms KL 2013 Elevated peritoneal fluid TNF-α incites ovarian early growth response factor 1 expression and downstream protease mediators: a correlation with ovulatory dysfunction in endometriosis. Reproductive Sciences 20 514–523. (https://doi.org/10.1177/1933719113477479) Bjornstad P, Schäfer M, Truong U, Cree-Green M, Pyle L, Baumgartner A, Garcia Reyes Y, Maniatis A, Nayak S, Wadwa RP, et al . 2018 Metformin improves insulin sensitivity and vascular health in youth with type 1 diabetes mellitus. Circulation 138 2895–2907. (https://doi. org/10.1161/CIRCULATIONAHA.118.035525) Bove GM 2016 A model for radiating leg pain of endometriosis. Journal of Bodywork and Movement Therapies 20 931–936. (https://doi. org/10.1016/j.jbmt.2016.04.013) Bruce R, Godsland I, Stevenson J, Devenport M, Borth F, Crook D, Ghatei M, Whitehead M & Wynn V 1992 Danazol induces resistance to both insulin and glucagon in young women. Clinical Science 82 211–217. (https://doi.org/10.1042/cs0820211) Bulun SE, Wan Y & Matei D 2019 Epithelial mutations in endometriosis: link to ovarian cancer. Endocrinology 160 626–638. (https://doi. org/10.1210/en.2018-00794) Burke SD, Dong H, Hazan AD & Croy BA 2007 Aberrant endometrial features of pregnancy in diabetic NOD mice. Diabetes 56 2919–2926. (https://doi.org/10.2337/db07-0773) Burney RO & Giudice LC 2012 Pathogenesis and pathophysiology of endometriosis. Fertility and Sterility 98 511–519. (https://doi. org/10.1016/j.fertnstert.2012.06.029) Burns KA, Rodriguez KF, Hewitt SC, Janardhan KS, Young SL & Korach KS 2012 Role of estrogen receptor signaling required for endometriosis- like lesion establishment in a mouse model. Endocrinology 153 3960–3971. (https://doi.org/10.1210/en.2012-1294) Burns KA, Thomas SY, Hamilton KJ, Young SL, Cook DN & Korach KS 2018 Early endometriosis in females is directed by immune-mediated estrogen receptor α and IL-6 cross-talk. Endocrinology 159 103–118 (https://doi.org/10.1210/en.2017-00562) Busiah K, Colmenares A, Bidet M, Tubiana-Rufi N, Levy-Marchal C, Delcroix C, Jacquin P, Martin D, Benadjaoud L, Jacqz-Aigrain E, et al . 2017 High prevalence of polycystic ovary syndrome in type 1 diabetes Downloaded from Bioscientifica.com at 06/09/2026 09:58:57PM via free access https://doi.org/10.1530/JOE-19-0248 https://joe.bioscientifica.com © 2019 Society for Endocrinology Published by Bioscientifica Ltd. Printed in Great Britain R54 Co-morbid endometriosis and type 1 diabetes R C M Simmen et al.243:3 Journal of Endocrinology mellitus adolescents: is there a difference depending on the NIH and Rotterdam criteria? Hormone Research in Paediatrics 87 333–341. (https://doi.org/10.1159/000471805) Cabrera SM, Henschel AM & Hessner MJ 2016 Innate inflammation in type 1 diabetes. Translational Research 167 214–227. (https://doi. org/10.1016/j.trsl.2015.04.011) Cagnacci A, Tirelli A, Cannoletta M, Pirillo D & Volpe A 2005 Effect on insulin sensitivity of Implanon vs. GnRH agonist in women with endometriosis. Contraception 72 443–446. (https://doi.org/10.1016/j. contraception.2005.05.021) Capobianco A, Monno A, Cottone L, Venneri MA, Biziato D, Di Puppo F, Ferrari S, De Palma M, Manfredi AA & Rovere-Querini P 2011 Proangiogenic Tie2(+) macrophages infiltrate human and murine endometriotic lesions and dictate their growth in a mouse model of the disease. American Journal of Pathology 179 2651–2659. (https://doi. org/10.1016/j.ajpath.2011.07.029) Cardinez N, Lovblom LE, Bai JW, Lewis E, Abraham A, Scarr D, Lovshin JA, Lytvyn Y, Boulet G, Farooqi MA, et al . 2018 Sex differences in neuropathic pain in longstanding diabetes: results from the Canadian Study of Longevity in Type 1 Diabetes. Journal of Diabetes and its Complications 32 660–664. (https://doi.org/10.1016/j. jdiacomp.2018.05.001) Carstensen B, Read SH, Friis S, Sund R, Keskimäki I, Svensson AM, Ljung R, Wild SH, Kerssens JJ, Harding JL, et al . 2016 Cancer incidence in persons with type 1 diabetes: a five-country study of 9,000 cancers in type 1 diabetic individuals. Diabetologia 59 980–988. (https://doi.org/10.1007/s00125-016-3884-9) Castellano JM, Navarro VM, Roa J, Pineda R, Sánchez-Garrido MA, García-Galiano D, Vigo E, Dieguez C, Aguilar E, Pinilla L , et al . 2009 Alterations in hypothalamic KiSS-1 system in experimental diabetes: early changes and functional consequences. Endocrinology 150 784–794. (https://doi.org/10.1210/en.2008-0849) Chuang PC, Lin YJ, Wu MH, Wing LY, Shoji Y & Tsai SJ 2010 Inhibition of CD36-dependent phagocytosis by prostaglandin E2 contributes to the development of endometriosis. American Journal of Pathology 176 850–860. (https://doi.org/10.2353/ajpath.2010.090551) Codner E, Iñíguez G, Villarroel C, Lopez P, Soto N, Sir-Petermann T, Cassorla F & Rey RA 2007 Hormonal profile in women with polycystic ovarian syndrome with or without type 1 diabetes mellitus. Journal of Clinical Endocrinology and Metabolism 92 4742–4746. (https://doi. org/10.1210/jc.2007-1252) Codner E, Merino PM & Tena-Sempere M 2012 Female reproduction and type 1 diabetes: from mechanisms to clinical findings. Human Reproduction Update 18 568–585. (https://doi.org/10.1093/humupd/ dms024) Collier A, Connelly PJ, Hair M, Cameron L, Ghosh S & Waugh N 2018 Mortality risk remains higher in individuals with type 1 diabetes: a population-based cohort study (the Ayrshire diabetes follow-up cohort [ADOC]). Diabetes, Obesity and Metabolism 20 1965–1971. (https://doi.org/10.1111/dom.13334) Connolly MA, Trentalange M & Zeiss CJ 2016 Long-term clinical outcomes in diabetic rhesus macaques (Macaca mulatta) treated with medroxyprogesterone acetate for endometriosis. Comparative Medicine 66 343–348. Cree-Green M, Stuppy JJ, Thurston J, Bergman BC, Coe GV , Baumgartner AD, Bacon S, Scherzinger A, Pyle L & Nadeau KJ 2018 Youth with type 1 diabetes have adipose, hepatic, and peripheral insulin resistance. Journal of Clinical Endocrinology and Metabolism 103 3647–3657. (https://doi.org/10.1210/jc.2018-00433) Cree-Green M, Bergman BC, Cengiz E, Fox LA, Hannon TS, Miller K, Nathan B, Pyle L, Kahn D, Tansey M, et al . 2019 Metformin improves peripheral insulin sensitivity in youth with type 1 diabetes. Journal of Clinical Endocrinology and Metabolism 104 3265–3278. (https://doi. org/10.1210/jc.2019-00129) Cruzen CL, Baum ST & Colman RJ 2011 Glucoregulatory function in adult rhesus macaques (Macaca mulatta) undergoing treatment with medroxyprogesterone acetate for endometriosis. Journal of the American Association for Laboratory Animal Science 50 921–925. Cure P, Pileggi A, Froud T, Norris PM, Baidal DA, Cornejo A, Hafiz MM, Ponte G, Poggioli R, Yu J, et al . 2004 Alterations of the female reproductive system in recipients of islet grafts. Transplantation 78 1576–1581. (https://doi.org/10.1097/01.tp.0000147301.41864.c0) Devaraj S, Tobias P & Jialal I 2011 Knockout of toll-like receptor-4 attenuates the pro-inflammatory state of diabetes. Cytokine 55 441–445. (https://doi.org/10.1016/j.cyto.2011.03.023) Driver JP, Racine JJ, Ye C, Lamont DJ, Newby BN, Leeth CM, Chapman HD, Brusko TM, Chen YG, Mathews CE, et al . 2017 Interferon- γ limits diabetogenic CD8 + T-cell effector responses in type 1 diabetes. Diabetes 66 710–721. (https://doi.org/10.2337/db16- 0846) Er TK, Su YF, Wu CC, Chen CC, Wang J, Hsieh TH, Herreros- Villanueva M, Chen WT, Chen YT, Liu TC, et al . 2016 Targeted next-generation sequencing for molecular diagnosis of endometriosis- associated ovarian cancer. Journal of Molecular Medicine 94 835–847. (https://doi.org/10.1007/s00109-016-1395-2) Escobar-Morreale HF 2018 Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment. Nature Reviews: Endocrinology 14 270–284. (https://doi.org/10.1038/nrendo.2018.24) Escobar-Morreale HF & Roldán-Martín MB 2016 Type 1 diabetes and polycystic ovary syndrome: systematic review and meta-analysis. Diabetes Care 39 639–648. (https://doi.org/10.2337/dc15-2577) Farland LV , Missmer SA, Bijon A, Gusto G, Gelot A, Clavel-Chapelon F, Mesrine S, Boutron-Ruault MC & Kvaskoff M 2017 Associations among body size across the life course, adult height and endometriosis. Human Reproduction 32 1732–1742. (https://doi. org/10.1093/humrep/dex207) Ferrara CT, Geyer SM, Evans-Molina C, Libman IM, Becker DJ, Wentworth JM, Moran A, Gitelman SE, Redondo MJ & Type 1 Diabetes TrialNet Study Group 2017 The role of age and excess body mass index in progression to type 1 diabetes in at-risk adults. Journal of Clinical Endocrinology and Metabolism 102 4596–4603. (https://doi. org/10.1210/jc.2017-01490) Galettis A, Campbell S, Morris JM, Jackson CJ, Twigg SM & Gallery ED 2004 Monocyte adhesion to decidual endothelial cells is increased in pregnancies complicated by type 1 diabetes but not by gestational diabetes. Diabetes Care 27 2514–2515. (https://doi.org/10.2337/ diacare.27.10.2514) Goetz LG, Mamillapalli R & Taylor HS 2016 Low body mass index in endometriosis is promoted by hepatic metabolic gene dysregulation in mice. Biology of Reproduction 95 115 (https://doi.org/10.1095/ biolreprod.116.142877) Gou Y, Li X, Li P, Zhang H, Xu T, Wang H, Wang B, Ma X, Jiang X & Zhang Z 2019 Estrogen receptor β upregulates CCL2 via NF-κB signaling in endometriotic stromal cells and recruits macrophages to promote the pathogenesis of endometriosis. Human Reproduction 34 646–658. (https://doi.org/10.1093/humrep/dez019) Grandi G, Mueller M, Bersinger N, Papadia A, Nirgianakis K, Cagnacci A & McKinnon B 2016 Progestin suppressed inflammation and cell viability of tumor necrosis factor-α-stimulated endometriotic stromal cells. American Journal of Reproductive Immunology 76 292–298. (https://doi.org/10.1111/aji.12552) Greaves E, Cousins FL, Murray A, Esnal-Zufiaurre A, Fassbender A, Horne AW & Saunders PT 2014 A novel mouse model of endometriosis mimics human phenotype and reveals insights into the inflammatory contribution of shed endometrium. American Journal of Pathology 184 1930–1939. (https://doi.org/10.1016/j. ajpath.2014.03.011) Gueuvoghlanian-Silva BY, Bellelis P, Barbeiro DF, Hernandes C & Podgaec S 2018 Treg and NK cells related cytokines are associated with deep rectosigmoid endometriosis and clinical symptoms related to the disease. Journal of Reproductive Immunology 126 32–38. (https:// doi.org/10.1016/j.jri.2018.02.003) Downloaded from Bioscientifica.com at 06/09/2026 09:58:57PM via free access https://doi.org/10.1530/JOE-19-0248 https://joe.bioscientifica.com © 2019 Society for Endocrinology Published by Bioscientifica Ltd. Printed in Great Britain R55 Review R C M Simmen et al. Co-morbid endometriosis and type 1 diabetes 243:3 Journal of Endocrinology Gülden E, Ihira M, Ohashi A, Reinbeck AL, Freudenberg MA, Kolb H & Burkart V 2013 Toll-like receptor 4 deficiency accelerates the development of insulin-deficient diabetes in non-obese diabetic mice. PLoS ONE 8 e75385. (https://doi.org/10.1371/journal.pone.0075385) Gurr S, Kobs K & Steindel E 1986 Ultrasonic measurements of the uterus in adolescents. Zentralblatt für Gynakologie 108 1420–1424. Han SJ, Jung SY, Wu SP, Hawkins SM, Park MJ, Kyo S, Qin J, Lydon JP, Tsai SY, Tsai MJ, et al . 2015 Estrogen receptor β modulates apoptosis complexes and the inflammasome to drive the pathogenesis of endometriosis. Cell 163 960–974. (https://doi.org/10.1016/j. cell.2015.10.034) Hayashi C, Chishima F, Sugitani M, Ichikawa G, Nakazawa-Watanabe T, Sugita K, Suzuki M, Nemoto N & Yamamoto T 2013 Relationship between Toll-like receptor-4 and mPGES-1 gene expression in local lesions of endometriosis patients. American Journal of Reproductive Immunology 69 231–239. (https://doi.org/10.1111/aji.12056) Heard ME, Melnyk SB, Simmen FA, Yang Y, Pabona JM & Simmen RC 2016 High-fat diet promotion of endometriosis in an immunocompetent mouse model is associated with altered peripheral and ectopic lesion redox and inflammatory status. Endocrinology 157 2870–2882. (https://doi.org/10.1210/en.2016-1092) Henschel AM, Cabrera SM, Kaldunski ML, Jia S, Geoffrey R, Roethle MF, Lam V , Chen YG, Wang X, Salzman NH, et al . 2018 Modulation of the diet and gastrointestinal microbiota normalizes systemic inflammation and β-cell chemokine expression associated with autoimmune diabetes susceptibility. PLoS ONE 13 e0190351. (https:// doi.org/10.1371/journal.pone.0190351) Hotta-Iwamura C & Tarbell KV 2016 Type 1 diabetes genetic susceptibility and dendritic cell function: potential targets for treatment. Journal of Leukocyte Biology 100 65–80. (https://doi.org/10.1189/jlb.3MR1115- 500R) Hsu PC, Lin WH, Kuo TH, Lee HM, Kuo C & Li CY 2015 A population- based cohort study of all-cause and site-specific cancer incidence among patients with type 1 diabetes mellitus in Taiwan. Journal of Epidemiology 25 567–573. (https://doi.org/10.2188/jea.JE20140197) Hundhausen C, Roth A, Whalen E, Chen J, Schneider A, Long SA, Wei S, Rawlings R, Kinsman M, Evanko SP, et al . 2016 Enhanced T cell responses to IL-6 in type 1 diabetes are associated with early clinical disease and increased IL-6 receptor expression. Science Translational Medicine 8 356ra119. (https://doi.org/10.1126/scitranslmed.aad9943) Huxley RR, Peters SA, Mishra GD & Woodward M 2015 Risk of all-cause mortality and vascular events in women versus men with type 1 diabetes: a systematic review and meta-analysis. Lancet: Diabetes and Endocrinology 3 198–206. (https://doi.org/10.1016/S2213- 8587(14)70248-7) Ishihara H, Kitawaki J, Kado N, Koshiba H, Fushiki S & Honjo H 2003 Gonadotropin-releasing hormone agonist and danazol normalize aromatase cytochrome P450 expression in eutopic endometrium from women with endometriosis, adenomyosis, or leiomyomas. Fertility and Sterility 79 (Supplement 1) 735–742. (https://doi.org/10.1016/ s0015-0282(02)04813-6) Jørgensen H, Hill AS, Beste MT, Kumar MP, Chiswick E, Fedorcsak P, Isaacson KB, Lauffenburger DA, Griffith LG & Qvigstad E 2017 Peritoneal fluid cytokines related to endometriosis in patients evaluated for infertility. Fertility and Sterility 107 1191.e2–1199.e2. (https://doi.org/10.1016/j.fertnstert.2017.03.013) Kaponis A, Iwabe T, Taniguchi F, Ito M, Deura I, Decavalas G, Terakawa N & Harada T 2012 The role of NF-kappaB in endometriosis. Frontiers in Bioscience 4 1213–1234. Kellenberger LD & Petrik J 2018 Hyperglycemia promotes insulin- independent ovarian tumor growth. Gynecologic Oncology 149 361–370. (https://doi.org/10.1016/j.ygyno.2018.02.003) Kim S, Millet I, Kim HS, Kim JY, Han MS, Lee MK, Kim KW, Sherwin RS, Karin M & Lee MS 2007 NF-kappa B prevents beta cell death and autoimmune diabetes in NOD mice. PNAS 104 1913–1918. (https:// doi.org/10.1073/pnas.0610690104) Kim C, Miller RS, Braffett BH, Pan Y, Arends VL, Saenger AK, Barnie A, Sarma AV & EDIC Research Group 2018 Ovarian markers and irregular menses among women with type 1 diabetes in the Epidemiology of Diabetes Interventions and Complications study. Clinical Endocrinology 88 453–459. (https://doi.org/10.1111/cen.13546) Knip M & Simell O 2012 Environmental triggers of type 1 diabetes. Cold Spring Harbor Perspectives in Medicine 2 a007690. (https://doi. org/10.1101/cshperspect.a007690) Knip M, Luopajärvi K & Härkönen T 2017 Early life origin of type 1 diabetes. Seminars in Immunopathology 39 653–667. (https://doi. org/10.1007/s00281-017-0665-6) Kocbek V , Grandi G, Blank F, Wotzkow C, Bersinger NA, Mueller MD, Kyo S & McKinnon BD 2016 TNF α-induced IKKβ complex activation influences epithelial, but not stromal cell survival in endometriosis. Molecular Human Reproduction 22 768–777. (https://doi.org/10.1093/ molehr/gaw054) Lambelet M, Terra LF, Fukaya M, Meyerovich K, Labriola L, Cardozo AK & Allagnat F 2018 Dysfunctional autophagy following exposure to pro-inflammatory cytokines contributes to pancreatic β-cell apoptosis. Cell Death and Disease 9 96. (https://doi.org/10.1038/ s41419-017-0121-5) Łebkowska A, Adamska A, Jacewicz M, Tołwi ńska J, Krentowska A, Hryniewicka J, Le śniewska M, Bossowski A, Górska M & Kowalska I 2017 Association between polycystic ovary syndrome and the risk of subclinical vascular disease in normal-weight women with type 1 diabetes. Polish Archives of Internal Medicine 127 741–748. (https://doi. org/10.20452/pamw.4116) Lee LF, Xu B, Michie SA, Beilhack GF, Warganich T, Turley S & McDevitt HO 2005 The role of TNF-alpha in the pathogenesis of type 1 diabetes in the nonobese diabetic mouse: analysis of dendritic cell maturation. PNAS 102 15995–16000. (https://doi.org/10.1073/ pnas.0508122102) Lee AW, Templeman C, Stram DA, Beesley J, Tyrer J, Berchuck A, Pharoah PP, Chenevix-Trench G, Pearce CL & Ovarian Cancer Association Consortium 2016 Evidence of a genetic link between endometriosis and ovarian cancer. Fertility and Sterility 105 35.e1–43. e1. (https://doi.org/10.1016/j.fertnstert.2015.09.023) Liaw YP, Ko PC, Jan SR, Huang JY, Nfor ON, Lung CC, Chiang YC, Yeh LT, Chou MC, Tsai HD, et al . 2015 Implications of type1/2 diabetes mellitus in breast cancer development: a general female population- based cohort study. Journal of Cancer 6 734–739. (https://doi. org/10.7150/jca.12197) Lien E & Zipris D 2009 The role of toll-like receptor pathways in the mechanism of type 1 diabetes. Current Molecular Medicine 9 52–68. (https://doi.org/10.2174/156652409787314453) Lin YH, Chen KJ, Peng YS, Chen PC & Yang YH 2018 Type 1 diabetes impairs female fertility even before it is diagnosed. Diabetes Research and Clinical Practice 143 151–158. (https://doi.org/10.1016/j. diabres.2018.07.010) Liuwantara D, Elliot M, Smith MW, Yam AO, Walters SN, Marino E, McShea A & Grey ST 2006 Nuclear factor-kappa B regulates beta- cell death: a critical role for A20 in beta-cell protection. Diabetes 55 2491–2501. (https://doi.org/10.2337/db06-0142) Ljunggren P, Maahs DM, Johansson P, Ludvigsson J, Pyle L, Sippl R, Wadwa RP & Snell-Bergeon J 2016 Reduced brachial artery distensibility in patients with type 1 diabetes. Journal of Diabetes and its Complications 30 893–897. (https://doi.org/10.1016/j. jdiacomp.2016.03.004) Ludvigsson JF, Neovius M, Söderling J, Gudbjörnsdottir S, Svensson AM, Franzén S, Stephansson O & Pasternak B 2019 Maternal glycemic control in type 1 diabetes and the risk for preterm birth: a population- based cohort study. Annals of Internal Medicine 170 691–701. (https:// doi.org/10.7326/M18-1974) Luo XZ, Zhou WJ, Tao Y, Wang XQ & Li DJ 2015 TLR4 activation promotes the secretion of IL-8 which enhances the invasion and proliferation of endometrial stromal cells in an autocrine manner via Downloaded from Bioscientifica.com at 06/09/2026 09:58:57PM via free access https://doi.org/10.1530/JOE-19-0248 https://joe.bioscientifica.com © 2019 Society for Endocrinology Published by Bioscientifica Ltd. Printed in Great Britain R56 Co-morbid endometriosis and type 1 diabetes R C M Simmen et al.243:3 Journal of Endocrinology the FAK signal pathway. American Journal of Reproductive Immunology 74 467–479. (https://doi.org/10.1111/aji.12425) Maahs DM, West NA, Lawrence JM & Mayer-Davis EJ 2010 Epidemiology of type 1 diabetes. Endocrinology and Metabolism Clinics of North America 39 481–497. (https://doi.org/10.1016/j.ecl.2010.05.011) Maffeis C, Birkebaek NH, Konstantinova M, Schwandt A, Vazeou A, Casteels K, Jali S, Limbert C, Pundziute-Lycka A, Toth-Heyn P, et al . 2018 Prevalence of underweight, overweight, and obesity in children and adolescents with type 1 diabetes: data from the international SWEET registry. Pediatric Diabetes 19 1211–1220. (https://doi. org/10.1111/pedi.12730) Mahalingaiah S, Sun F, Cheng JJ, Chow ET, Lunetta KL & Murabito JM 2017 Cardiovascular risk factors among women with self-reported infertility. Fertility Research and Practice 3 7. (https://doi.org/10.1186/ s40738-017-0034-0) Matalliotakis I, Panidis D, Vlassis G, Neonaki M & Koumantakis E 1997 Decreased sensitivity to insulin during treatment with danazol in women with endometriosis. Clinical and Experimental Obstetrics and Gynecology 24 160–162. Mier-Cabrera J, Jiménez-Zamudio L, García-Latorre E, Cruz-Orozco O & Hernández-Guerrero CQ 2011 Quantitative and qualitative peritoneal immune profiles, T-cell apoptosis and oxidative stress-associated characteristics in women with minimal and mild endometriosis. BJOG 118 6–16. (https://doi.org/10.1111/j.1471-0528.2010.02777.x) Morotti M, Vincent K, Brawn J, Zondervan KT & Becker CM 2014 Peripheral changes in endometriosis-associated pain. Human Reproduction Update 20 717–736. (https://doi.org/10.1093/humupd/ dmu021) Needell JC & Zipris D 2017 Targeting innate immunity for type 1 diabetes prevention. Current Diabetes Reports 17 113. (https://doi.org/10.1007/ s11892-017-0930-z) Nothnick WB, Falcone T, Olson MR, Fazleabas AT, Tawfik OW & Graham A 2018 Macrophage migration inhibitory factor receptor, CD74, is overexpressed in human and baboon (Papio Anubis) endometriotic lesions and modulates endometriotic epithelial cell survival and interleukin 8 expression. Reproductive Sciences 25 1557–1566. (https://doi.org/10.1177/1933719118766262) Osum KC, Burrack AL, Martinov T, Sahli NL, Mitchell JS, Tucker CG, Pauken KE, Papas K, Appakalai B, Spanier JA, et al . 2018 Interferon- gamma drives programmed death ligand 1 expression on islet β cells to limit T cell function during autoimmune diabetes. Scientific Reports 8 8295. (https://doi.org/10.1038/s41598-018-26471-9) Pabona JM, Simmen FA, Nikiforov MA, Zhuang D, Shankar K, Velarde MC, Zelenko Z, Giudice LC & Simmen RC 2012 Krüppel-like factor 9 and progesterone receptor coregulation of decidualizing endometrial stromal cells: implications for the pathogenesis of endometriosis. Journal of Clinical Endocrinology and Metabolism 97 E376–E392. (https://doi.org/10.1210/jc.2011-2562) Pencovich N, Luk J, Hantisteanu S, Hornstein MD & Fainaru O 2014 The development of endometriosis in a murine model is dependent on the presence of dendritic cells. Reproductive Biomedicine Online 28 515–521. (https://doi.org/10.1016/j.rbmo.2013.12.011) Purohit S, Sharma A, Hopkins D, Steed L, Bode B, Andersen SW, Reed JC, Steed RD, Yang T & She JX 2015 Large-scale discovery and validation studnies demonstrate significant reductions in circulating levels of IL-8, IL1Ra, MCP-1, and MIP-1B in patients with type 1 diabetes. MIP-1β in patients with type 1 diabetes. Journal of Clinical Endocrinology and Metabolism 100 E1179–E1187. (https://doi. org/10.1210/JC.2015-1388) Qiao YC, Chen YL, Pan YH, Tian F, Xu Y, Zhang XX & Zhao HL 2017 The change of serum tumor necrosis factor alpha in patients with type 1 diabetes mellitus: a systematic review and meta-analysis. PLoS ONE 12 e0176157. (https://doi.org/10.1371/journal.pone.0176157) . Rahmioglu N, Macgregor S, Drong AW, Hedman ÅK, Harris HR, Randall JC, Prokopenko I, International Endogene Consortium (IEC), The GIANT Consortium, Nyholt DR, Morris AP, et al . 2015 Genome- wide enrichment analysis between endometriosis and obesity-related traits reveals novel susceptibility loci. Human Molecular Genetics 24 1185–1199. (https://doi.org/10.1093/hmg/ddu516) Rakhila H, Girard K, Leboeuf M, Lemyre M & Akoum A 2014 Macrophage migration inhibitory factor is involved in ectopic endometrial tissue growth and peritoneal-endometrial tissue interaction in vivo: a plausible link to endometriosis development. PLoS ONE 9 e110434. (https://doi.org/10.1371/journal.pone.0110434) Rogovskaya S, Rivera R, Grimes DA, Chen PL, Pierre-Louis B, Prilepskaya V & Kulakov V 2005 Effect of a levonorgestrel intrauterine system on women with type 1 diabetes: a randomized trial. Obstetrics and Gynecology 105 811–815. (https://doi.org/10.1097/01. AOG.0000156301.11939.56) Saguyod SJU, Kelley AS, Velarde MC & Simmen RC 2018 Diet and endometriosis-revisiting the linkages to inflammation. Journal of Endometriosis and Pelvic Pain Disorders 10 51–58. (https://doi. org/10.1177/2284026518769022) Sánchez-Zamora YI, Juarez-Avelar I, Vazquez-Mendoza A, Hiriart M & Rodriguez-Sosa M 2016 Altered macrophage and dendritic cell response in Mif-/- mice reveals a role of Mif for inflammatory-Th1 response in type 1 diabetes. Journal of Diabetes Research 2016 7053963. Saraswat L, Ayansina DT, Cooper KG, Bhattacharya S, Miligkos D, Horne AW & Bhattacharya S 2017 Pregnancy outcomes in women with endometriosis: a national record linkage study. BJOG 124 444–452. (https://doi.org/10.1111/1471-0528.13920) Sasaki S, Yasuda T, Kaneto H, Kuroda A, Fujita Y, Fujisawa K, Tabuchi Y, Kasami R, Matsuoka TA, Matsuhisa M, et al . 2013 Basal insulin requirements after progesterone treatment in a type 1 diabetic pregnant woman. Internal Medicine 52 259–262. (https://doi. org/10.2169/internalmedicine.52.8675) Schreiber AK, Nones CF, Reis RC, Chichorro JG & Cunha JM 2015 Diabetic neuropathic pain: physiopathology and treatment. World Journal of Diabetes 6 432–444. (https://doi.org/10.4239/wjd.v6.i3.432) Seyfarth J, Förtsch K, Ahlert H, Laws HJ, Karges B, Deenen R, Köhrer K, Mayatepek E, Meissner T & Jacobsen M 2017 Dominant TNF α and impaired IL-2 cytokine profiles of CD4+ T cells from children with type-1 diabetes. Immunology and Cell Biology 95 630–639. (https://doi. org/10.1038/icb.2017.24) Shigiyama F, Kumashiro N, Rikitake T, Usui S, Saegusa M, Kitamura M, Uchino H & Hirose T 2016 A case of lean polycystic ovary syndrome with early stage of type 1 diabetes successfully treated with metformin. Endocrine Journal 63 193–198. (https://doi.org/10.1507/ endocrj.EJ15-0548) Shu X, Ji J, Li X, Sundquist J, Sundquist K & Hemminki K 2010 Cancer risk among patients hospitalized for type 1 diabetes mellitus: a population-based cohort study in Sweden. Diabetic Medicine 27 791–797. (https://doi.org/10.1111/j.1464-5491.2010.03011.x) Simmen RCM & Kelley AS 2018 Seeing red: diet and endometriosis risk. Annals of Translational Medicine 6 (Supplement 2) S119. (https://doi. org/10.21037/atm.2018.12.14) Sjöberg L, Kaaja R, Gissler M, Tuomilehto J, Tiitinen A & Pitkäniemi J 2017 Termination of pregnancy and sterilisation in women with childhood-onset type 1 diabetes. Diabetologia 60 2377–2383. (https:// doi.org/10.1007/s00125-017-4428-7) Stanic AK, Kim M, Styer AK & Rueda BR 2014 Dendritic cells attenuate the early establishment of endometriosis-like lesions in a murine model. Reproductive Sciences 21 1228–1236. (https://doi. org/10.1177/1933719114525267) Suda K, Nakaoka H, Yoshihara K, Ishiguro T, Tamura R, Mori Y, Yamawaki K, Adachi S, Takahashi T, Kase H, et al . 2018 Clonal expansion and diversification of cancer-associated mutations in endometriosis and normal endometrium. Cell Reports 24 1777–1789. (https://doi.org/10.1016/j.celrep.2018.07.037) Sugiura-Ogasawara M, Ebara T, Matsuki T, Yamada Y, Omori T, Matsumoto Y, Kato S, Kano H, Kurihara T, Saitoh S, et al . 2019 Downloaded from Bioscientifica.com at 06/09/2026 09:58:57PM via free access https://doi.org/10.1530/JOE-19-0248 https://joe.bioscientifica.com © 2019 Society for Endocrinology Published by Bioscientifica Ltd. Printed in Great Britain R57 Review R C M Simmen et al. Co-morbid endometriosis and type 1 diabetes 243:3 Journal of Endocrinology Endometriosis and recurrent pregnancy loss as new risk factors for venous thromboembolism during pregnancy and post-partum: the JECS Birth Cohort. Thrombosis and Haemostasis 119 606–617. (https:// doi.org/10.1055/s-0039-1677733) Swerdlow AJ, Laing SP, Qiao Z, Slater SD, Burden AC, Botha JL, Waugh NR, Morris AD, Gatling W, Gale EA, et al . 2005 Cancer incidence and mortality in patients with insulin-treated diabetes: a UK cohort study. British Journal of Cancer 92 2070–2075. (https:// doi.org/10.1038/sj.bjc.6602611) Symons LK, Miller JE, Kay VR, Marks RM, Liblik K, Koti M & Tayade C 2018 The immunopathophysiology of endometriosis. Trends in Molecular Medicine 24 748–762. (https://doi.org/10.1016/j. molmed.2018.07.004) Tai N, Wong FS & Wen L 2013 TLR9 deficiency promotes CD73 expression in T cells and diabetes protection in nonobese diabetic mice. Journal of Immunology 191 2926–2937. (https://doi.org/10.4049/ jimmunol.1300547) Takemura Y, Osuga Y, Yoshino O, Hasegawa A, Hirata T, Hirota Y, Nose E, Morimoto C, Harada M, Koga K, et al . 2007 Metformin suppresses interleukin (IL)-1beta-induced IL-8 production, aromatase activation, and proliferation of endometriotic stromal cells. Journal of Clinical Endocrinology and Metabolism 92 3213–3218. (https://doi.org/10.1210/ jc.2006-2486) Thomas NJ, Jones SE, Weedon MN, Shields BM, Oram RA & Hattersley AT 2018 Frequency and phenotype of type 1 diabetes in the first six decades of life: a cross-sectional, genetically stratified survival analysis from UK Biobank. Lancet: Diabetes and Endocrinology 6 122–129. (https://doi.org/10.1016/S2213-8587(17)30362-5) Thomas NJ, Lynam AL, Hill AV , Weedon MN, Shields BM, Oram RA, McDonald TJ, Hattersley AT & Jones AG 2019 Type 1 diabetes defined by severe insulin deficiency occurs after 30 years of age and is commonly treated as type 2 diabetes. Diabetologia 62 1167–1172. (https://doi.org/10.1007/s00125-019-4863-8) Ulukus M & Arici A 2005 Immunology of endometriosis. Minerva Ginecologica 57 237–248. Vaarala O 2011 The gut as a regulator of early inflammation in type 1 diabetes. Current Opinion in Endocrinology, Diabetes, and Obesity 18 241–247. (https://doi.org/10.1097/MED.0b013e3283488218) van Bussel BC, Soedamah-Muthu SS, Henry RM, Schalkwijk CG, Ferreira I, Chaturvedi N, Toeller M, Fuller JH, Stehouwer CD & EURODIAB Prospective Complications Study Group 2013 Unhealthy dietary patterns associated with inflammation and endothelial dysfunction in type 1 diabetes: the EURODIAB study. Nutrition, Metabolism, and Cardiovascular Diseases 23 758–764. (https://doi.org/10.1016/j. numecd.2012.04.005) Veillat V , Lavoie CH, Metz CN, Roger T, Labelle Y & Akoum A 2009 Involvement of nuclear factor-kappaB in macrophage migration inhibitory factor gene transcription up-regulation induced by interleukin- 1 beta in ectopic endometrial cells. Fertility and Sterility 91 (Supplement) 2148–2156. (https://doi.org/10.1016/j. fertnstert.2008.05.017) Veillat V , Sengers V , Metz CN, Roger T, Leboeuf M, Mailloux J & Akoum A 2012 Macrophage migration inhibitory factor is involved in a positive feedback loop increasing aromatase expression in endometriosis. American Journal of Pathology 181 917–927. (https://doi.org/10.1016/j. ajpath.2012.05.018) Wang Y, Sosinowski T, Novikov A, Crawford F, White J, Jin N, Liu Z, Zou J, Neau D, Davidson HW, et al . 2019 How C-terminal additions to insulin B-chain fragments create superagonists for T cells in mouse and human type 1 diabetes. Science Immunology 4 eaav7517. (https:// doi.org/10.1126/sciimmunol.aav7517) Waugh K, Snell-Bergeon J, Michels A, Dong F, Steck AK, Frohnert BI, Norris JM & Rewers M 2017 Increased inflammation is associated with islet autoimmunity and type 1 diabetes in the Diabetes Autoimmunity Study in the Young (DAISY). PLoS ONE 12 e0174840. (https://doi.org/10.1371/journal.pone.0174840) Wise J 2016 Type 1 diabetes is associated with increased risk of several cancers. BMJ 352 i1210. (https://doi.org/10.1136/bmj.i1210) Woo JH, Yang YI, Ahn JH, Choi YS & Choi JH 2017 Interleukin 6 secretion from alternatively activated macrophages promotes the migration of endometriotic epithelial cells. Biology of Reproduction 97 660–670. (https://doi.org/10.1093/biolre/iox118) Worley MJ Jr, Liu S, Hua Y, Kwok JS, Samuel A, Hou L, Shoni M, Lu S, Sandberg EM, Keryan A, et al . 2015 Molecular changes in endometriosis-associated ovarian clear cell carcinoma. European Journal of Cancer 51 1831–1842. (https://doi.org/10.1016/j. ejca.2015.05.011) Yilmaz B, Sucak A, Kilic S, Aksakal O, Aksoy Y, Lortlar N, Sut N & Gungor T 2010 Metformin regresses endometriotic implants in rats by improving implant levels of superoxide dismutase, vascular endothelial growth factor, tissue inhibitor of metalloproteinase-2, and matrix metalloproteinase-9. American Journal of Obstetrics and Gynecology 202 368.e1–368.e8. (https://doi.org/10.1016/j. ajog.2009.10.873) Younis A, Hawkins K, Mahini H, Butler W & Garelnabi M 2014 Serum tumor necrosis factor- α, interleukin-6, monocyte chemotactic protein-1 and paraoxonase-1 profiles in women with endometriosis, PCOS, or unexplained infertility. Journal of Assisted Reproduction and Genetics 31 1445–1451. (https://doi.org/10.1007/ s10815-014-0237-9) Zhang X & Mu L 2015 Association between macrophage migration inhibitory factor in the endometrium and estrogen in endometriosis. Experimental and Therapeutic Medicine 10 787–791. (https://doi. org/10.3892/etm.2015.2516) Zullo F, Spagnolo E, Saccone G, Acunzo M, Xodo S, Ceccaroni M & Berghella V 2017 Endometriosis and obstetrics complications: a systematic review and meta-analysis. Fertility and Sterility 108 667. e5–672.e5. (https://doi.org/10.1016/j.fertnstert.2017.07.019) Received in final form 14 August 2019 Accepted 29 August 2019 Accepted Preprint published online 29 August 2019 Downloaded from Bioscientifica.com at 06/09/2026 09:58:57PM via free access