{"paper_id":"435e8754-c5e8-4110-b67d-61ed03005e70","body_text":"49\nIntroduction\nEndometriosis is an oestrogen dependent debilitating \ngynaecological condition that is underdiagnosed in women and \nis characterized by the implantation and successful adaptation of \nendometrial tissue in extrapelvic sites. This can include the bowel, \nlungs, ureters and ovaries with a wide spectrum of severity noted. \nThis chronic condition is thought to affect 7-10% of women of \nreproductive age and up to half of all infertile women [1]. Currently, \ndue to the insidious presentations of endometriosis in women \nof childbearing age it is unsurprising that on average it takes \n10.4 years from first symptom to diagnosis and even with the \nimprovements made in imaging modalities this remains a lengthy \n8 years. Indeed this can cause several issues including the need \nfor future oophorectomy and hysterectomy as a result of lesion \nprogression [2]. Unfortunately in the majority many women are \nturned away and their symptoms considered functional in nature \nmany years before this diagnosis is made. This inevitably leads \nto major disability and impaired quality of life. Indeed due to the \nnature of this condition many women may mistakenly think the \nsymptoms they suffer are normal [3].\nMethods \nPapers were identified by searching medical databases \nincluding Pubmed, Cochrane and Google Scholar.\nAll papers identified were published in peer reviewed journals \nbetween 2008-2017. All selected papers were of high quality \nand dealt with either screening of endometriosis through either \nadaptation of existing techniques or novel biomarkers. \nResults and Discussion\nAt present, there are three types of endometriosis recognised; \nsuperficial, ovarian and deep infiltrating4. Superficial lesions \nare likely pelvic in nature and can be identified as blue-black on  \n \ndirect observation. Ovarian endometriosis deposits also known \nas endometriomas (‘chocolate cysts’) are psuedocystswhich are \nmuch more likely to form adhesions to surrounding structures. \nDeep infiltrating endometriosis however is defined as extension of \nendometrial glands >5mm beneath the peritoneal surface and most \nfrequently involves the uterosacral ligaments and is associated with \nunderlying adenomyosis. These lesions are classically related to the \ncyclical pain patients report and are solid masses of endometrial \ntissue with associated fibrous and smooth muscle proliferation [4]. \nThe initial symptoms of endometriosis include, dysmenorrhoea, \ndyspareunia, lower abdominal pain, dysuria and altered bowel \nhabit. Of these dysmenorrhoea is the most common symptom and \ncompounding this up to 20% of affected women will have other \nchronic pain conditions including fibromyalgia, migraine and \nirritable bowel syndrome4.It is due to this varied presentation \nthat clinicians often have to rely on a good history of the clinical \nsigns and symptoms in order to make the diagnosis. One systematic \nreview addressing the usefulness of signs/symptoms in diagnosing \nendometriosis showed that dysmenorrhoea and dyspareunia are \nuniversally present in endometriosis particularly in early stage \ndisease5. Key points within the history include the presence of \nsymptoms and their timing within the women’s menstrual cycle, \nthe length of the womens menstrual cycle and the regularity of \ntheir periods. However while essential clinical examination of \nthe patient often provides little information with findings such as \ncervical deviation, cervical tenderness; fixed retroverted uterus or \nadnexal mass often not found. But when found is more likely to be \npresent when the examination is performed during menstruation \n[5]. \nCurrent understanding is that this condition has both a genetic \nand environmental components with patients who have an affected \nfirst degree relative themselves having 6 times the relative risk of \nDominic Adam Worku* \nMedical Doctor, University of Birmingham, UK\n*Corresponding author: Dominic Adam Worku, Medical Doctor, University of Birmingham, UK\nSubmission: \n  October 17, 2017; Published: \n  November 14, 2017   \nThe Role of Biomarkers in the Early Diagnosis of \nEndometriosis\nMini Review                                                                                           \nCopyright © All rights are reserved by Dominic Adam Worku.\nCRIMSONpublishers\nhttp://www.crimsonpublishers.com\nAbstract\nEndometriosis is a chronic gynecological problem which is frequent within the general population. Due to its varied presentations there is often a \nvast delay in diagnosis incurring a large amount of psychological and physical harm with infertility being unfortunate sequelae. Whilst improvements \nhave been made with regards to the treatment of endometriosis, diagnosis remains challenging for clinicians with traditional investigations yielding \npoor results. This review will consider potential biomarkers and investigations for the early diagnosis of endometriosis.\nISSN: 2577-2015\n\nHow to cite this article: Dominic A W. The Role of Biomarkers in the Early Diagnosis of Endometriosis. Invest Gynecol Res Women’s Health. 1(3). IGRWH.000512: \n2017. DOI: 10.31031/IGRWH.2017.01.000512\n 50\nInvest Gynecol Res Women’s HealthInvestigations in Gynecology Research & Womens Health\ndeveloping the condition versus controls [1]. Indeed current opinion \nis that 51% of the variation in endometriosis risk is heritable. \nHowever, studies looking into the genetic basis of endometriosis \nhave failed to reproduce candidate genes. Recently however \nGenome Wide Association Studies (GWAS) utilising patients with \nendometriosis from three continents have shown there to be 10 loci \nwhich together only account for ~5% of underlying endometriosis \nheritability [6]. As such much more work with regards to DNA \nmethylation and histone modification are required. \nHistorically, the pathophysiology of endometriosis has been \nexplained by Sampsons theory of retrograde menstruation \nsecondary to fallopian tube reflux, [7]. While this has formed \nmuch of the basis of endometrial research and understanding the \nfact that a paucity of diagnostic techniques for this condition exist \nremains evident. Indeed even after several decades of research the \ngold standard remains laparoscopy which incurs great cosmetic, \npsychological and physical harm but can identify all types of \nendometriosis [7]. However even this gold standard has potential \nflaws with visual diagnosis of endometriosis by this process proving \nto be suboptimal. It is thought that up to half of all positive findings \non laparoscopy will be incorrect with differentials including benign \ninflammatory changes [4]. \nAs laparoscopy represents an extreme method of diagnosing \ndisease given its high frequency within the population, physicians \nwill often initially rely on common and easily accessible imaging \nmodalities such as transvaginal ultrasound (TVUS). TVUS is a \ncommon modality used within gynaecology to diagnose a myriad \nof problems. In a recent systematic review looking at the accuracy \nof this modality it was found to have a sensitivity of 53%, 49% \nand 58% in uterinesacral, rectovaginal septum and vaginal \nendometriosis respectively [8]. Indeed the problem with TVUS is \nthat often the detail it provides is suboptimal particularly for deep \ninfiltrating endometrial lesions and is not sensitive for large areas \nof disease [9]. As such MRI is increasingly being used for this reason \nas well as to diagnose endometriomas, stage disease and confirm \nthe presence of adhesions. This can all be achieved at magnetic \nfield strengths of ~3.0T . The general consensus at present is that \nMRI is most sensitive when performed during the first half of the \nmenstrual cycle with a full bladder to remove the anteversion of \nthe uterus. Utilising diffusion weighted imaging alongside apparent \ndiffusion coefficient (ADC) values radiologists have been able to \nidentify with great accuracy endometriomas and solid implants. \nThis is because they demonstrate restricted diffusion patterns \nversus other pelvic pathologies including haemorrhagic cysts and \ndermoid cysts [9]. At present most imaging protocols suggest that \nT1-weighted sequences be used to detect endometrial lesions \nof<1cm with fat suppression sequences allowing for differentiation \nof haemorrhagic and cystic lesions10. In comparison pure fibrous \nlesions will exhibit low T1/T2 imaging intensity while most \nendometrial lesions exhibit low intensity on T2 imaging. As such \nthe reported specificity of MRI can be as high as 97% [10].\nHowever as MRI remains a difficult and expensive means of \ndiagnosing such a common condition it remains the hope that a \nnon-invasive test can be made utilising urine, blood, peritoneal fluid \netc which with high sensitivity identifies early endometrial disease \nin the presence of a normal TVUS. Indeed through the development \nof such a test, it could be sought to prognosticate women based \non their levels of said biomarkers. One biomarker which has \nhad a lot of attention is CA-125. This mucinous glycoprotein is \nexpressed by derivatives of coelomic and mullerian epithelium and \nmay be upregulated in both serum and peritoneal fluid in many \ngynaecological conditions, both benign and malignant in nature \nwhere peritoneal inflammation occurs [11]. Early studies of CA-\n125 in this setting has shown that the sensitivity of this marker \ndecreases with more advanced stages of disease and that patients \nwith endometriosis have significantly increased concentrations of \nCA-125 in the peritoneal fluid versus controls irrespective of the \nphase of menstruation [12]. A metanalysis of CA-125 performance \nin this setting revealed that the sensitivity of this marker ranges \nfrom 4-100% with a specificity of 38-100% [13]. Indeed much \nlike in ovarian cancer where this biomarker is used, it is thought \nthat it may be best utilised when used as part of a biomarker \npanel, with the sensitivity of this marker improving to 74-94% \nwith a specificity of 55-75% when combined with VEGF, Annexin \nV and sICAM1 [7]. However, while promising these results need \nto be ratified according to age and ethnicity of female cohorts, \nboth of which are known to influence CA-125 values. In addition \nthe use of this biomarker remains suboptimal in the diagnosis of \nendometriosis due to its low specificity. Other serum biomarkers \nthat hold promise in the future include key factors that mediate \nangiogenesis and include fibroblast growth factor 2 (FGF2) and \nEndoglin which may also have uses in monitoring progression of \nendometriosis and its response to treatment [12].\nUnlike other tissues of the body the human endometrium is \none which in a coordinated manner changes its composition and \narchitecture on a monthly basis. This process is one which sees \ngreat cellular proliferation and hormone secretion and eventual \nhormone withdrawal and apoptosis. Underpinning this process \nis angiogenesis, which is a key process within endometriosis \npathogenesis. In studying this process it has been revealed that \nmicroRNAs (miRNAs) are pivotal in this. MicroRNAs are intronic \ncoded genes implicated in regulating gene expression and thus \nfundamentally control biological systems through gene silencing \nof several mRNAs simultaneously [14]. Through improvements in \nnext generation sequencing and microarray technology we are now \nable to study the effects of miRNAs at a genomic scale. Furthermore, \nthe presence of circulating miRNA in the blood has led to research \ninto their application as biomarkers in several conditions including \nsepsis and myocardial infarction [14]. Early research in this field \nhas revealed differential miRNA expressions between endometrial \npatients and controls with downregulation of miR-34C-5p, miR-9 \nand mir-34b, let-7d etc. Let-7d was the first miRNA discovered to \npromote cellular differentiation with reduced expression of let-\n7 family members well known to be associated with malignancy \nwhich has shown to have in endometriosis sensitivity and \nspecificity of 83.3% and 100% respectively [14]. Understandably \nthe downregulation of a miRNA leads to a rise of its corresponding \n\nInvestigations in Gynecology Research & Womens Health\nHow to cite this article: Dominic A W. The Role of Biomarkers in the Early Diagnosis of Endometriosis. Invest Gynecol Res Women’s Health. 1(3). IGRWH.000512: \n2017. DOI: 10.31031/IGRWH.2017.01.000512\n51\nInvest Gynecol Res Women’s Health\nmRNAtarget gene product it regulates, many of which have been \nimplicated in inflammation, mitosis, cell signalling, angiogenesis \nand extracellular remodelling.\nCurrently, miR-125-5P is considered the single most effective \ndiagnostic marker in endometriosis which is upregulated in this \nsetting when measured by quantitative real-time PCR and analysed \nusing receiver operating characteristics. In addition it had the \ngreatest sensitivity and specific of any single miRNA in surgically \ndiagnosed patients. Indeed when combined with miR-451a and \nmIR-3613-5p a maximum AUC score 1.00 was achieved [15]. \nA key question remains what causes this dysregulation in the \nfirst place. This is because miRNA expression is known to be affected \nby age, ethnicity, and underlying disease activity. The latter of these \nis an important point as each of the three types of endometriosis \nexhibits a different miRNA profile which is affected by the point of \nthe menstrual cycle in which they are measured with a circadian \nrhythm of expression thought to exist [16]. Due to this and the small \nstudy sizes used to date as well as the paucity of establishedmodels \nin which miRNA research can be conducted in vivo there is much to \ndo before any translations into the clinic can be made [17]. \nDue to the presence of ectopic endometrial tissue it’s of \nno surprise that there may be an immunological component \nto this disease. It has been considered that endometriosis may \ndevelop as a result of inadequate removal of ectopic tissue due \nto underlying immune cell alterations including decreased CD36 \nand LFA-1 expression and decreased T-lymphocyte cytotoxicity \n[18]. Indeed hormonal alterations in endometriosis are thought \nto perpetuate this pro-inflammatory state. Moreover, it has been \nrecognised that affected patients demonstrate altered immune \nresponses and often have an increased prevalence of autoimmune \ndisease including systemic lupus erythematosus (SLE). Presently, \nseveral autoantibodies have been demonstrated in the serum of \nendometrial patients including anti-α-enolase, anti-PDKI1L, anti-\nsyntaxin 5 auto antibodies [19]. Indeed antiendometrial antibody \nessay has shown to have a positive predictive value of 88% when \nused before laparoscopy in the diagnosis of endometriosis [20]. \nHowever while measuring the immunological titres is useful, \nthe concern is the fact that these autoantibodies can be found in \nunaffected women and men. In addition no cut-offs have been \nassigned to discriminate between active and inactive disease \nmeaning they offer little information or prognostication of affected \nindividuals.\nWhile serum markers remain important, changes to the \nultrastructure of the endometrium could offer important \ninsights into early endometrial disease. In recent years there \nhas been considerable interest with regards to nerve biopsy \nof the endometrium. Over a decade ago it was first noted that \nendometriosis patients have multiple small unmyelinated C- \nnerve fibres which can be identified in histological samples of \nboth endometrial lesions and of the endometrium itself through \nimmune histochemistry staining. In contrast in unaffected female \npatients there are no nerve fibres within the mucosal layers of the \nendometrium. While this clear distinction sounds perfect for a \nproposed diagnostic test there have been conflicting reports with \nsome finding that biopsy is neither sensitive or specific with one \nretrospective study finding that of 29 patients with adenomyosis \nwith no endometriosis at laparoscopy, 69.2% had positive neuronal \nimmunohistochemistry staining [21,22], However the presence of \nneuronal fibres is not found routinely pelvic inflammatory disease \n(PID) or endometrial polyps. Irrespective of this the presence \nof these new nerve fibres are as of yet unknown however are \nconsidered key in the cyclical pain that affected women feel as \nthey are sensitized to endogenous oestrogens during menstruation \nwhere at a tissue level inflammation is occurring [22]. Current \nmanagement of endometriosis involves use of the combined oral \ncontraceptive (COCP) and indeed GnRH agonists confirming that \nendometriosis is a hormone responsive disease. However, these \nare plagued with side effects and are not ideal in those women \nwho wish to conceive [4]. It is a result of this that efforts have been \nmade to detect local aromatase activity, which may reflect early \nstage disease. While this would be a very useful test, early works \nhave identified that aromatase expression in infertile women is \nno different irrespective of whether endometriosis is the cause. \nHowever as there are many steroid regulating proteins which may \nbe implicated, it may be that measuring enzyme levels locally within \nthe endometrium may be a future diagnostic tool as will mapping \nlocal oestrogen receptor expression in symptomatic women [23]. \nConclusion\nAt present endometriosis remains a highly disabling condition \nthat affects a great number of women. While much has been achieved \nwith regards to treatment, diagnosis of this condition remains \nunchanged from decades past with many women waiting years for a \ndiagnosis. Currently, several new methods of identifying early stage \ndisease have been identified although their significance remains \nunknown. Furthermore, while much work has been undertaken in \nidentifying biomarkers in endometriosis ,one major problems is \nfew have been sufficiently studied to allow for meta-analysis and \nthus any conclusions to be made. In order to improve the utility of \nproposed biomarkers, larger studies must be conducted in patients \naccording to disease subtype and patient presentation to allow for \nmeaningful translation of experimental data to the clinic.\nReferences\n1. Grande G, Vincenzoni F, Milardi D, Pompa G, Ricciardi D, et al. (2017) \nCervical mucus proteome in endometriosis. Clin Proteomics 14: 7.\n2. Oliveria MAP , Raymundo TS, Soares LC, Pereira TRD, Demôro AVE, et \nal. (2017) How to use CA-125 more effectively in the diagnosis of deep \nendometriosis. BioMed Research International 2017: 6. \n3. Zhao L, Gu C, Ye M, Zhang Z, Han W, et al. 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Expert Rev Clin Immunol 7(5): 611-626.\n18. Gajbhiye R, Sonawani A, Khan S, Suryawanshi A, Kadam S, et al. (2012) \nIdentification and validation of novel serum markers for early diagnosis \nof endometriosis. Hum Reprod 27(2): 408-417.\n19. Randall GW, Gantt PA, Poe Zeigler RL, Bergmann CA, Noel ME, et al. (2007) \nSerum antiendometrial antibodies and diagnosis of endometriosis. Am J \nReprod Immunol 58(4): 374-382.\n20. Zhang X, Lu B, Huang X, Xu H, Zhou C, et al. (2010) Innervation of \nendometrium and myometrium in women with painful adenomyosis \nand uterine fibroids. Fertil Steril 94(2): 730-737.\n21. Miller EJ, Fraser IS (2015) The importance of pelvic nerve fibres in \nendometriosis. Women’s health 11(5): 611-618.\n22. May KE, Villar J, Kirtley S, Kennedy SH, Becker CM (2011) Endometrial \nalterations in endometriosis: a systematic review of putative biomarkers. \nHum Reprod Update 17(5): 637-653.","source_license":"CC0","license_restricted":false}