Increased risk of rheumatoid arthritis in patients with endometriosis: genetic aspects

Abstract

Introduction

RA is a prototypic inflammatory autoimmune disease with a poorly understood aetiopathogenesis, where genetic, immune and environmental factors contribute to the development and progression of its clinical manifestations [1]. It affects ∼1% of the population and leads to significant morbidity and mortality, thus shortening the lifespan up to 10 years [2]. RA affects women, who represent ≥60% of RA cases [3]. A characteristic of RA is the presence of serum autoantibodies, including antibodies directed against RF and citrullinated peptides (ACPA) [4], while two anti-acetylated peptide antibodies (AAPAs)—anti-acetylated lysine (AcLys) and anti-acetylated ornithine (AcOrn)—have been examined recently regarding their potential role in the improvement of RA classification [5]. Another type of autoantibodies has been detected with activity against carbamylated proteins (anti-CarPs), which may have a diagnostic value in RA, measuring the joint damage, especially in RF- and ACPA-negative patients [6]. Interestingly, it has been reported that rhesus monkeys develop anti-CarP antibodies upon induction of collagen-induced arthritis but not RF or ACPA [7]. Most importantly, triple positivity for ACPA, RF and anti-CarP antibodies was found to provide interesting information on individuals at risk to develop RA [8]. Moreover, various reproductive and hormonal factors have been associated with an increased risk of RA as well [9].

Endometriosis is one of the most common benign gynaecological diseases, defined as the presence of ectopic endometrial glands and stroma outside of the uterine cavity on other organs, such as the ovaries, fallopian tubes and bowel, with an unknown aetiology and poorly understood pathogenesis, affecting up to 10% of the women and representing a major cause of pain and infertility [10]. Its pathophysiology stems from a broad spectrum of risk factors, including aberrations in oestrogen production and its metabolism, exposure to environmental toxins and pollution and genetic background [11, 12]. There is strong evidence suggesting that an aberrant immunologic response contributes to its pathogenesis. In some of these women with endometriosis, there is also a chronic local inflammatory process and the presence of autoantibodies. It has been suggested that the combined effect of several gene polymorphisms related to the immune system can alter immune homeostasis at some level, thus contributing to the establishment of endometrial cells in ectopic sites and, as a consequence, to progression of the disease [13, 14]. In women of reproductive age, ∼10–15% suffer from endometriosis and their clinical symptoms include severe pelvic pain, heavy menstrual pain, irregular menstrual bleeding and pain during intercourse or exercise. According to the literature, immune cell dysfunctions as well as an inflammatory environment characterize all forms of endometriosis [10].

Although the mechanisms leading to endometriosis are still unclear, a number of different studies have described changes in immune parameters in women with endometriosis and infertility. Moreover, various epidemiological studies demonstrated that patients with endometriosis were associated with an increased risk for developing RA compared with unaffected controls [15–19]. The aim of this review is the analysis of the observed increased risk of RA among women with endometriosis, thus pointing to the potential underlying shared genetic factors that deserve further study.

Genetics of RA and endometriosis

Advances in human genetics have led to a dramatic increase in the number of RA risk alleles identified in patients with this disease. The overall heritability of RA had been estimated to be ∼50–60% in twin studies, but recently it was suggested that the detected RA loci account for <50% of the total genetic heritability [6]. Many lines of evidence indicate that expansion of existing genome-wide association studies (GWASs) enhances the power to detect additional loci. Notably, a large number of novel genes associated with this disease have been identified with the use of the Immunochip in the last decade, which initially brought the number of RA susceptibility loci in Caucasians to 48 [20] and in all populations to 110 [21–23]. However, the heritability explained by the identified variants was estimated to be only ∼20% [21]. Recently, Kwon et al. [24] identified six new RA risk loci that reached the genome-wide significance threshold (P = 5 × 10⁻⁸) through a meta-analysis of newly generated GWAS results, while Ha et al. [23] discovered 11 novel RA-associated loci surpassing the genome-wide significance level in a large-scale meta-analysis integrating genetic associations in East Asians and Europeans.

The majority of the loci associated with RA susceptibility have been found to code for proteins strongly linked to immune function [20, 25]. Understanding the genetic component of susceptibility to RA has increased our knowledge of the disease process and directed new approaches to disease management, leading to the identification of disease-associated genetic variants that were assumed to cause modified immune responses and precede the onset of disease symptoms [26]. There is also considerable variation across populations worldwide in terms of the existing data on the factors associated with the pathogenesis of the disease.

Endometriosis exhibits a high complexity, as genetic, epigenetic and environmental influences seem to interact in order to formulate the disease phenotype. Apart from involvement of aberrant immunologic responses, angiogenesis processes and biochemical alterations in disease development, it also has a strong genetic predisposition, as shown by monozygotic twin–based and family [27, 28] gene association studies that took into account candidate genes and single nucleotide polymorphisms (SNPs) [29, 30] as well as GWASs [31–35]. Interestingly, the number of novel endometriosis-associated loci has increased due to developments in high-throughput genotyping technology and new GWASs and meta-analyses that are presently in progress. Thus an analysis of eight GWASs in women of European and East Asian descent identified 19 distinct disease-associated signals harboured in 14 loci [35]. Furthermore, in the largest GWAS and replication meta-analysis of endometriosis to date, including 762 600 individuals (60 674 cases, 701 926 controls) of European and East Asian descent, 42 loci (31 novel) comprising 59 distinct association signals were identified. These loci explained 5.5% of the disease variance and were enriched for transcription factor binding sites with roles in progesterone resistance, cell cycle regulation, oncogenesis and ovarian tissue enhancers [36]. Apart from the progress thus far in the identification of SNPs exhibiting an association with endometriosis, many studies show controversial results, due largely to poor study design, with small populations and poorly defined ethnicity [29].

The influence of autoimmunity in endometriosis

Detailed studies have been conducted aimed at elucidating the influence of autoimmunity in endometriosis, thus facilitating better knowledge of the pathogenetic mechanisms leading to both autoimmune diseases and endometriosis. To this end, >40 years ago, Weed and Arquembourg [37] suggested a possible autoimmune mechanism that might explain the infertility characterizing some women with endometriosis, based on their observation of IgG and complement deposition in the eutopic endometrium of patients with this disorder. Further identification of autoantibodies against endometrial antigens or other types of antigens have associated endometriosis with autoimmunity [38, 39]. More recently, an influence of autoimmunity in endometriosis has been hypothesized due to its association with the presence of anti-nuclear, anti-phospholipid and anti-endometrial autoantibodies, elevated levels of inflammatory cytokines, decreased apoptosis and cell-mediated abnormalities [13, 40, 41]. This decreased apoptosis explains the reason why ectopically implanted cells survive [42, 43]. However, it has to be clarified whether the formation of antibodies in endometriosis patients reflects a natural response to the destruction of the chronic local tissue or a pathologic response leading, as a consequence, to a more generalized autoimmune dysfunction [44]. Of interest, natural killer (NK) cells, which have been suggested to play a role in the clearance of regurgitated endometrial cells from the peritoneal cavity of most healthy women, appear a decrease in local NK-mediated cytotoxicity in the peripheral and peritoneal fluid in both autologous and heterologous endometrium in endometriosis patients [45]. This decrease is more pronounced in the moderate and severe stages of the disorder. Moreover, peritoneal macrophages were found to be increased in total number, concentration and status of activation in women with endometriosis [46]. It has also been suggested that an alteration or defect in immune surveillance in women with endometriosis may lead to autoimmune diseases [15].

Several studies in patients with endometriosis have shown aberrant function of immune cells, suggesting an important role of immunological factors in the development of this disorder. The theory that endometriosis may be considered as an autoimmune disease was first introduced in 1987 [47]. Although endometriosis itself is not an autoimmune disease, previous cohort-based studies have suggested that women with endometriosis may be susceptible to develop various autoimmune diseases, including SLE [15, 48, 49], SS [15, 49], multiple sclerosis [15, 49], RA [15, 17], scleroderma [15, 49], coeliac disease [50], autoimmune thyroid disorder [51, 52], Crohn’s disease and ulcerative colitis [53]. Of note, endometriosis shares similarities with several autoimmune diseases, including elevated levels of inflammatory cytokines, decreased apoptosis and cell-mediated abnormalities [13]. Importantly, some case reports have previously suggested comorbidity of endometriosis with autoimmune disorders such as alopecia universalis, autoimmune thyroiditis and autoimmune progesterone dermatitis [54, 55].

Interestingly, various studies suggest that a comorbidity relationship can be observed between endometriosis and other pathological but non-autoimmune diseases. These comorbidities include migraines [56], irritable bowel syndrome [57], endometrial cancer [58], diabetes mellitus [59], obesity [60], pelvic inflammatory disease [58], chronic liver disease [58], depression, hypertension, hyperlipidaemia and cardiovascular disease [57].

Shared susceptibility loci between RA and endometriosis

Previous findings suggested an association between endometriosis and the risk for RA in different populations from the USA [15–17] and Taiwan [18, 19]. This observation posed the intriguing question concerning the putative role of a shared genetic background as regards the co-occurrence of endometriosis and RA. Interestingly, according to the existing data, various genes involved in inflammation and autoimmunity are significantly associated with both endometriosis and RA and, as a consequence, shared genetic components between these diseases appear biologically plausible. Therefore, aiming to elucidate this situation, we attempted to provide a comprehensive update on the current understanding of the potential shared genetic component of these diseases by performing an extensive, critical search of the current literature in order to gain insights regarding genetic polymorphism associated with both conditions.

In this framework, the results of our literature research showed that the Fc receptor-like 3 (FCRL3) rs7528684 [61–65], protein tyrosine phosphatase non-receptor type 22 (PTPN22) rs2476601 (C1885T) [20, 66–68], signal transducer and activator of transcription 4 (STAT4) rs7574865 and rs7582694 [68–70] intronic SNPs, human leucocyte antigen (HLA) DRB1 rs660895 [71, 72], forkhead box protein 3 (FOXP3) rs3761548 (−3279G/T) SNP [73, 74], VEGF rs1570360 SNP [75, 76], IL-6 rs18001796 [75–79], IL-10 rs1800871 [80, 81], C-C motif chemokine ligand 21 (CCL21) rs2812378 [20, 71] and interferon regulatory factor 5 (IRF5) rs10488631 [26, 69, 82] SNPs are associated with both diseases under investigation (Table 1).

The FCRL3 gene encodes a member of the Ig receptor superfamily and is one of several Fc receptor-like glycoproteins clustered on the long arm of chromosome 1 (1q21-23). This protein is present in a surface cell receptor that has homology to the Fc immunoreceptors and is expressed predominantly in B lymphocytes and exhibits dual-signalling properties, mediating B cell receptor signalling as well as plasma B cell maturation and antibody production [83]. The functional promoter polymorphism rs7528684 (–169T/C) in FCRL3 has been previously shown in RA patients to enhance expression levels of FCRL3 via both more efficient nuclear factor κB binding and increased promoter activity [61, 65, 75, 83, 84]. Furthermore, given that a higher expression of FCRL3 and augmented autoantibody production were associated with the disease-associated allele and/or genotype, FCRL3 appears to be a functional and potentially pathogenic molecule in more autoimmune diseases apart from RA, as presented already for SLE, Graves’ disease and Hashimoto’s thyroiditis [61, 85]. As regards endometriosis, the aforementioned increased FCRL3 expression in B cells and the subsequent disturbance of particular signalling pathways may affect normal B cell functions [83], thus contributing to pelvic pain and infertility, which represent two major manifestations of endometriosis [86].

The PTPN22 gene is located on chromosome 1 (1p13.3-13.1) and encodes a lymphoid-specific phosphatase known as Lyp that is an important down-regulator of T cell activation [87]. The PTPN22 rs2476601 SNP, which corresponds to the A620W polymorphism, results in a variant that does not bind kinases efficiently, encoding a gain-of-function enzyme that increases the inhibition of T cell receptor signalling. Therefore it could have profound effects on the function of the immune system and the development of RA. Interestingly, this SNP shows the second strongest association with RA, right after HLA-DRB1. The immune system is supposed to play a role in the onset and development of endometriosis, given that various theories have suggested that in women with endometriosis alterations in T cell–mediated immunity may facilitate implantation of endometrial fragments or cells in ectopic regions [88]. Thus the rs2476601 SNP probably leads to immunological alterations occurring in endometriosis, due to abnormalities in the function and levels of T lymphocytes [40].

STAT4, encoded by the STAT4 gene located at 2q32.2-q32.3, represents a transcription factor involved in the transduction of IL-12, IL-23 and type 1 IFN-mediated signals into Th1 and Th17 differentiation, monocyte activation and IFN-γ production [89]. The requirement for STAT4-dependent cytokine regulation has been well established regarding the pathogenesis of various autoimmune diseases, including RA [69], thus highlighting the critical role for STAT4 in autoimmune diseases. Considering that immunological deregulation is involved in the pathogenesis of endometriosis, it can be assumed that STAT4 gene polymorphisms may be linked to the development of the disease. While the exact molecular mechanism by which STAT4 is enrolled in the pathogenesis of endometriosis has not yet been determined, it has been assumed that the two intronic polymorphisms rs7574865 and rs7582694 can affect the gene expression or mRNA splicing and may induce strong Th1 and Th17 cytokine responses as well as IFN signalling [68].

HLA-DRB1 is a member of the HLA class II, presenting peptides derived from extracellular proteins to Th cells [90]. The HLA-DRB1 rs660895 SNP is a tag SNP for the HLA-DRB1*0401 allele, which was associated initially with RA, and the risk for RA may be higher for individuals carrying one copy of the HLA-DRB1*0401 allele, if they also carry a different HLA-DRB1 risk allele [91]. Several studies have suggested that the HLA locus DRB1 represents the largest predisposing genetic factor conferring risk to RA. HLA molecules are critical in restricting the recognition of antigenic peptides by T cells, while HLA polymorphisms are involved in mechanisms shaping the T cell repertoire [92]. It has been assumed that RA-associated DRB1 alleles may play a critical role in the disease process, either by shaping the T cell receptor repertoire and/or by presenting an inducing microbial or autoantigenic peptide to self-reactive T cells [93]. Furthermore, ectopic endometrium contains an increased proportion of HLA-DR-positive stromal and glandular epithelial cells compared with eutopic endometrium [94, 95]. Thus it is likely that this aberrant expression of HLA-DR antigen in these cells of eutopic and ectopic endometria in endometriosis is deeply involved in various immunological abnormalities observed in endometriosis [71].

The FOXP3 rs3761548 (-3279G/T) SNP was found to be associated with RA and endometriosis [73, 74]. It has been suggested that mutations or SNPs of this gene may modify its functional role, thus leading to the absence of functional CD4⁺CD25⁺ Tregs that prevent autoimmunity and maintain immune homeostasis and, as a consequence, to the development of some autoimmune diseases [95]. Accumulated evidence suggests that Tregs may function as important regulators of immune response in RA, determining if RA will develop [96]. It has also been observed that Foxp3 serum levels are significantly higher in patients with RA than in controls, thus indicating that an ongoing inflammatory process is in progress in RA patients [74]. Of note, it has been reported that rs3761548 is associated with an increased risk for endometriosis, regardless of the stage of the disease [97]. Interestingly, Song et al. [98] showed that this SNP, located in the promoter region, changes gene expression through modification of the binding efficiency of the Sp1 transcription factor and alteration of the kinetics of FOXP3 gene transcription initiation.

The VEGF rs1570360 SNP has been associated with both RA and endometriosis [75, 76]. VEGF is strongly induced by hypoxia and represents a potent endothelial cell-specific angiogenic factor. Furthermore, it also acts as a pro-inflammatory cytokine [99]. Angiogenesis is considered to be an essential process in the proliferative synovitis, which characterizes RA, occurring in the early stage of RA, and is believed to be crucial for the progression of the arthritic lesions [100]. Various polymorphisms within the VEGF gene have been analysed thus far and associated with the production of VEGF protein. Many of these polymorphisms are associated with an increased susceptibility to several disorders in which angiogenesis is critical regarding disease development [101, 102]. Moreover, it is well known that angiogenesis is implicated in endometriosis. Thus VEGF, as an angiogenic factor, promotes neovascularization, which is an important process involved in the implantation of endometrial cells in ectopic sites [103]. Therefore it can be suggested that alterations in VEGF production may play a crucial role in the initiation of RA as well as endometriosis [104].

The IL-6 gene is located on chromosome 7p21 and encodes the multifunctional cytokine IL-6, which is involved in the inflammatory response, serving as a physiologic link between the endocrine and immune systems. It represents a well-studied pro-inflammatory cytokine, with its levels being elevated in serum and synovial fluid of RA [105]. IL-6 has been found to be associated with both the differentiation of Th17 cells and the balance between pathogenic Th17 and protective Treg cells in RA patients and therefore may play a role in RA pathogenesis [106]. An association of the IL-6 promoter region rs1800796 (-572G/C) SNP with the increased susceptibility to both RA and endometriosis has been reported [78–80]. This SNP appears to influence IL-6 transcription rates in vitro and basal IL-6 levels in vivo [107]. Of interest, the levels of IL-6 have been found to be elevated in both peritoneal fluid and serum of women with endometriosis [108].

IL-10 is an important immunomodulatory cytokine, with an ability to inhibit the activation and function of T cells, macrophages and monocytes, thus contributing to the final termination of inflammatory responses [109]. Several studies have shown that the rs1800871 (-819 C/T) SNP, which is located within the functional promoter, can influence IL-10 mRNA levels as well as the production of IL-10 [110]. Regarding endometriosis, women carrying allele C of this SNP of the IL-10 gene were associated with a 2-fold reduced risk of the disease compared with those of the common TT genotype. The C allele has also been associated with higher levels of IL-10 compared with the T allele in women with endometriosis [111], thus representing a mechanism resulting in down-regulation of peritoneal cavity cell inflammation [81].

CCL21 is a chemokine that is responsible for recruiting CCR7-expressing lymphocytes and dendritic cells to secondary lymphoid tissues [112]. Angiogenesis, dependent on endothelial cell activation, migration and proliferation, is involved in the development of RA and CCL21 plays an important role in this pathology [113]. The potential role of CCL21 in endometriosis is still unknown, although a shift toward a Th1 response may contribute to the increased cytokine/inflammatory profile that has been observed in endometriosis [114]. Notably, both RA and endometriosis are associated with variants of the CCL21 gene, but with opposite alleles (G and A, respectively), thus suggesting a differentiated functional role of the alleles in each disease [71, 81].

IRF5 is a transcription factor expressed in lymphocytes, macrophages and dendritic cells that is involved in the transcriptional activation of type I interferon (IFN-responsive genes. Moreover, it mediates Toll-like receptor (TLR) signal transduction, thus leading to production of various pro-inflammatory cytokines [115, 116], and it has been suggested that it also acts as a molecular switch controlling inflammatory mechanisms mediated by macrophage cells [117]. Several studies have shown that polymorphisms in the IRF5 gene are associated with an increased risk of developing RA and functional experiments have confirmed that IRF5 contributes to disease pathogenesis in inflammatory arthritis [118]. Furthermore, the formation of type I IFN and pro-inflammatory cytokines promotes inflammation by triggering immune responses related to altered T cell profiles and B cell development, an observation associated with endometriosis [119].

Conclusions

In this study, analysis of the observed increased risk of RA among women with endometriosis showed that most of the aforementioned shared gene polymorphisms have been associated with at least one other autoimmune disease apart from RA, an observation that was expected given that the clinical co-occurrence of various autoimmune diseases is based on shared biochemical pathways. Of note, and just as in autoimmune diseases, in endometriosis, similar immunologic alterations appear concerning an increase in the number and cytotoxicity of macrophages, abnormalities in the functions and concentrations of B and T lymphocytes and a reduction in the number or activity of NK cells [76]. Considering that endometriosis is associated with RA risk, and this association is similarly influenced by hysterectomy (removal of the uterus), oophorectomy (removal of the ovaries) and analgesic use [17], it remains to be understood whether and how endometriosis itself, or hysterectomy or other factors associated with endometriosis, is related to this increased risk for RA [17].

Aiming to unravel the mechanisms underlying the risk association between RA and endometriosis, various possible explanations can be suggested. Thus it can be hypothesized that endometriosis may cause chronic inflammation and trigger immunity dysregulation that leads to RA, considering that inflammation is the precursor to a lot of different disease pathologies. The ectopic endometrial cells and lesions developed may provoke an increased immune response, given that the inflammation is systemic and is not restricted just locally at these lesions. An alternative hypothesis, suggesting that autoimmunity may be the underlying condition of endometriosis, cannot be excluded. Furthermore, stress caused by chronic endometriosis-related pain, dyspareunia, infertility and sexual dysfunction may trigger the onset of RA [18].

The data presented provide evidence for various genetic factors that are shared between endometriosis and RA, thus demonstrating apparent genetic links between these conditions. Furthermore, these data support the suggestion that, due to the shared risk variants, shared pathways may cause common immune dysregulation in both diseases, thus representing a significant contributor to the onset and/or worsening of them. A lot of clinicians still treat endometriosis as a simple endocrine disorder caused by a hormonal imbalance without looking at what impact it has on the immune system. It should be noted that clinicians should be aware of the possibility of a co-occurrence of endometriosis and RA, considering that early diagnosis and treatment are warranted. A deeper understanding of these shared associations is needed, as they may provide new leads into the causes or consequences of both conditions, thus helping in the development of non-hormonal medication and the potential use of immunomodulators, which can inhibit endometriosis development and alleviate pain or infertility in these women [13]. Importantly, research on existing autoimmune disease medications (anti-TNF and pentoxifylline) until now has shown that these drugs were not effective in reducing endometriosis symptoms. However, a pilot study is currently in progress to determine whether the anti-inflammatory IL-1 inhibitor anakinra reduces pelvic pain due to endometriosis without altering menstrual cycles, which is an indicator of ovulatory function (Agarwal SK, La Jolla, CA, USA, personal communication). It remains to be understood whether and how endometriosis itself, or other factors associated with endometriosis, is related to the risk of RA. Therefore new studies focusing on the activities of numerous cells involved in immune reactions and/or the shared endometriosis and RA risk variants may provide new therapeutic targets for the establishment of endometrial cells in ectopic sites as well as the progression of endometriosis.

Although the association between RA and endometriosis has only been recently examined, the identification of involvement of certain well-known signalling pathways such as those involving IL-6 or JAK/STAT and their structurally and biochemically defined components may be a starting point for drug repurposing since many relevant inhibitors are already in existence. In the framework of the present review article, we identified gene variants that exhibit a genetic overlap for both RA and endometriosis, which are related to IL-6, B cell or JAK/STAT pathways. Interestingly, there are various reports in the literature suggesting a therapeutic benefit for women with endometriosis upon using IL-6 or JAK/STAT inhibitors. According to the literature, IL-6 promotes the occurrence and development of endometriosis as an important pro-inflammatory molecule by interfering with cellular immune function through the cytokine network [108]. In addition, IL-6 also plays a crucial role in the pathogenesis of endometriosis. Furthermore, it has been suggested that conditions involving IL-6 and IL-6R are correlated with the aetiology of endometriosis. An increase in sIL-6R in peritoneal fluid promotes the development of endometriosis by enhancing the bioactivity of IL-6 [120]. In this context, tocilizumab, which is bound specifically to both soluble and transmembrane IL-6 receptors (sIL-6R and mIL-6R), may be a good choice for the treatment of endometriosis. Based on experimental data, it has been suggested that in rats with induced endometriosis, anti-IL-6R monoclonal antibodies could offer a new horizon of use of this immunomodulatory biologic drug in the treatment of endometriosis [121]. Moreover, the JAK/STAT3 pathway is upregulated in endometriosis and is a therapeutic target. Thus it has been reported that inhibition of JAK/STAT signalling using tofacitinib may be a viable method for the treatment of endometriosis [122]. Similarly, tanshinone I, which modulates the expression of JAK/STAT signalling pathway proteins by antiproliferative activity due to induction of apoptosis [123], may prove beneficial for the development of a therapy for endometriosis and deserves further research. A further evaluation of current evidence investigating the association between endometriosis and RA from population-based studies will facilitate the understanding of the causes and consequences of endometriosis and provide a reference for better healthcare practices population-wide [52].

Current research on the genetics of endometriosis has shown advances in identifying specific genetic loci and associations that can be used in clinical practice. As the percentage of women affected by endometriosis is noteworthy, sequencing data, expression data and other omics data are accumulating along with recent GWASs that can be exploited by artificial intelligence technologies and state-of-the-art machine learning algorithms. Notably, a large number of clinical trials are being conducted in order to identify genetic biomarkers for endometriosis. The association between endometriosis and RA increases relevant data, but guides their processing and evaluation in a hypothesis-based way. In conclusion, information that can be derived from the studies at the intersection between inflammation and shared genetic factors may be important not only for the analysis of molecular and cellular mechanisms underlying RA and endometriosis pathogenesis, but also for the development of novel therapeutic alternatives in endometriosis, where curative treatment is largely lacking [124].

Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.

Disclosure statement: The authors have declared no conflicts of interest.

References