Abstract
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.
Introduction
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 (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 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 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 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.
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.
Potential therapeutic complications in co-morbid T1DM and ENDO
To date, no systematic studies have addressed the question of whether treatments administered to singly 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 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.
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.
Citation: Journal of Endocrinology 243, 3; 10.1530/JOE-19-0248
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.
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