{"paper_id":"2cb144c3-9923-4326-9890-4b375943989e","body_text":"Copyright@ Sanjay Kumar Sah | Biomed J Sci & Tech Res | BJSTR. MS.ID.005132.\n24352\nReview Article\nISSN: 2574 -1241\nDiscerning Endometriosis as a Multifaceted Entity: A \nComprehensive Review\nSanjay Kumar Sah1*, Amit Kumar Shrivastava2, Amin Ullah 1, Sadaf Pervej1, Yubin Ding3, and \nYing Xiong Wang3\n1Ph. D. Scholar, Department of Reproductive Medicine, Joint International Research Laboratory of Reproduction & Development, \nChongqing Medical University, People’s Republic of China\n2Assistant professor, Department of Pharmacology, Universal College of Medical Sciences, Nepal\n3Professor, Joint International Research Laboratory of Reproduction & Development, Chongqing Medical University, People’s Republic of \nChina\n*Corresponding author: Sanjay Kumar Sah, Ph. D. Scholar, Department of Reproductive Medicine, Joint International Research \nLaboratory of Reproduction & Development, Chongqing Medical University, People’s Republic of China\n      DOI: 10.26717/BJSTR.2020.31.005132\nARTICLE INFO ABSTRACT\nBackground: Endometriosis is a hormone-dependent benign inflammatory disease \nof the female reproductive system characterized by the presence of endometrium in an \nabnormal or ectopic location causing pain & infertility and affects approximately 10% of \nreproductive-age women. A more in-depth insight into the complex mechanisms involved \nin the commencement, development, and advancement is required to accomplish the \ndesired objectives of therapy effective against the symptomatic disease, associated \ninfertility, and malignancies. \nMethods: We searched the PubMed database using the following search terms in \nvarious combinations “Endometriosis and Pathogenesis, Infertility, Pregnancy, Cancer, \nBiomarkers, Risk factors, Management” and identify relevant English language studies \npublished up to June of 2020. Furthermore, articles were included within the citing \nreferences. \nResults: This review has been structured from a historical perspective that facilitates \nan up-to-date comprehension of the disease, illustrated by relatively recent molecular \nand genetic signs of progress. \nConclusion: This article will furnish the readers with up-to-date knowledge regarding \nthe biomarkers, infertility, pregnancy, and carcinoma with the ailment and also shed light \non the management of the disease.\nAbbreviations: ASRM: American Society for Reproductive Medicine; EFI: Endometriosis \nFertility Index; QoL: Quality of Life; MRI: Magnetic Resolution Image; TVUS: Transvaginal \nUltrasonography; DIE: Deep Infiltrating Endometriosis; CT: Computerized Tomography; \nMDCT-e: Multidetector CT Enema; MRI-e: MRI Enema; BMI: Body Mass Index; EAOC: \nEndometriosis-Associated Ovarian Cancer; RTKs: Receptor Tyrosine Kinase; ART: \nAssisted Reproductive Technology; NSAIDs: Non-Steroidal Anti-Inflammatory Drugs; \nCOX: Cyclooxygenase; ASA: Acetylsalicylic Acid; GnRH: Gonadotropin-Releasing \nHormone; ADR: Adverse Drug Reaction; OCP: Oral Contraceptive Pill; COC: Combined Oral \nContraceptives; CI: Confidence Interval; FDA: Food Drug Administration; CHC: Combined \nHormonal Contraceptive; Ais: Aromatase Inhibitor; VEGF: Vascular Endothelial Growth \nFactor; CPI: Cell Proliferation Index\nReceived: \n  October 17, 2020\nPublished: \n   November 04, 2020\nCitation: Sanjay Kumar Sah, Amit Kumar \nShrivastava, Amin Ullah, Sadaf Pervej, \nYubin Ding, Ying Xiong Wang. Discerning \nEndometriosis as a Multifaceted Entity: \nA Comprehensive Review. Biomed J \nSci & Tech Res 31(4)-2020. BJSTR. \nMS.ID.005132. \nKeywords: Cancer; Endometriosis; \nInfertility; Management; Pathogenesis\nIntroduction\nEndometriosis is defined as a hormone-dependent benign \ninflammatory disease of the female reproductive system  \n \ncharacterized by the implantation and growth of lesions formed \nby endometrial stromal and epithelial cells present outside the \n\n\nCopyright@ Sanjay Kumar Sah | Biomed J Sci & Tech Res | BJSTR. MS.ID.005132.\nVolume 31- Issue 4\nDOI: 10.26717/BJSTR.2020.31.005132\n24353\nuterine cavity, mainly in the peritoneum associated with abdominal \nviscera [1-3]. However, it is stated by some studies that glandular \nand stromal cells can be present outside the uterus such as on the \nsurfaces of ovaries and the pelvic [4]. Various kinds of literature \nhave suggested that endometriotic lesions are not restricted within \nthe boundaries of the abdominopelvic cavity. Still, it is also found \nin other parts of the body, such as gastrointestinal tract, lungs, \ndiaphragm, abdomen, and pericardium [5,6]. The urinary tract, the \nthorax, and the nasal mucosa [7], liver [8]. Also, endometriotic foci \nhave been found on the uterine ligaments, cervix, labia, and vagina \n[9] peripheral and axial skeleton, as well as the central nervous \nsystem [10]. Although it is benign, it happens spontaneously in \nwomen and non-human primates that menstruate, causing pain \nand infertility [11].\nPrevalence\nEndometriosis affects approximately 6% to 10% that covers \n176 million women of childbearing age, as high as 35-50% women \nwith pain or unexplained infertility [12] and becoming a substantial \nsocioeconomic burden globally [5,6]. However, an actual incidence \nof endometriosis is quite difficult to rule out due to expensive \ndiagnosis and surgical based procedures, so the estimated range \nvaries from 10%-15% [13]. The general assessment indicates \nabout 25% of all women may have endometriosis in their thirties to \nforties and after diagnoses for hospitalizations for genito-urinary \nissues result in 6.9% disease involvement [14]. The pelvic region \ncomprises three significant forms of endometriosis such as ovarian, \nperitoneal, and infiltrating endometriotic lesions. Morphologically, \nlesions are divided into three groups viz; white, red, and black \nlesions. The red lesion interprets with a high level of vascularization, \nlater followed by whitish lesion due to inflammation and fibrosis \nand classical black lesions are characterized by cyclic tissue \ndecomposition and healing with the subsequent formation of scar \ntissue [6].\nClassification (The Revised ASRM Criteria for \nEndometriosis Staging)\nThe American Fertility Society score which is presently better \nknown as American Society for Reproductive Medicine (ASRM) \nnamed based on data obtained from the operating room and \ncomparative study of therapeutic interventions which is widely \naccepted classification among clinicians [15]. ASRM classifies \nthe severeness of endometriosis based on location, number, \nmorphology, and size of the lesions found during the surgical \nprocedures into point score from Stage I (minimal) to Stage IV \n(severe) [16] (Table 1). The ASRM classification system’s major \nlimitation remained unclear for many years, whether it has any \nprognostic significance regarding the prediction of a woman’s \nfertility potential after surgery, which is paramount for patients \ntrying to conceive. Endometriosis Fertility Index (EFI) is being \nmore recent classification because it includes point scores from \nthe ASRM system combined with additional anamnestic, and post-\nsurgical information [17]. EFI is a simple, robust, and validated \nclinical tool employed for setting the management plan of \nendometriotic infertile women that predicts pregnancy rate after \nthe surgical staging of endometriosis. It furnishes reassurance to \nthose women with good predictions and avoids wastage of both \ntime and treatment for those with poor prognoses [18].\nTable 1: The staging system of endometriosis.\nStage Class Point score Remarks\nSTAGE I MINIMAL BETWEEN 1-5\nHigher Score, \nGreater Severity of \nEndometriosis\nSTAGE II MILD BETWEEN 6-15\nSTAGE III MODERATE BETWEEN 16-40\nSTAGE IV SEVERE > 40\nNote: This table explains about the staging system of \nendometriosis. ASRM classifies the severeness of endometriosis \nbased on location, number, morphology, and size of the lesions \nfound during the surgical procedures into point score from Stage \nI (minimal) to Stage IV (severe).\nClinical Features \nDespite being a common gynecological disease, endometriosis \ncan be either asymptomatic or symptomatic, and most commonly \nit is characterized by cyclic menstrual pain, chronic pelvic pain, \ndyspareunia, menorrhagia, and dyschezia [19] as well as dysuria, \nback pain and bladder or bowel problems (for instance, painful \nurination or bowel movements) [20]. The pelvic pain in women \nwith endometriosis is described as pain before the onset of menses \nand deep dyspareunia that worsens upon menstrual flow. Sacral \nand lower backaches during menses also can be present [21].\nSocietal and Financial Impacts of Endometriosis\nEndometriosis has a great impinge not only physically but \nalso on mental health, social life, and daily activities of living, \nproductivity and ultimately become a significant economic and \nsocial burden on patients, their families & relatives, and society as \na whole. Notwithstanding its increasing prevalence and expensive \ndiagnosis & management, the present understanding of the disease \nis limited due to lack of fund and advanced research causes a \nslowdown of the needed innovation in the field of diagnosis and \ntreatment [22]. The prospective study assesses the estimated \nrunning cost of endometriosis in 10 countries stated $12 419 per \nwoman (approximately €9579) annually, comprising one-third of \nthe direct health care costs with two-thirds attributed to a loss of \nproductivity. This total spending seems to be a significant factor for \ndecreased quality of life (QoL).\nThis study showed that the gradual expensive diagnosis \neconomic burden associated with endometriosis espied in \nthe referral centers is high and is similar to other chronic \ndiseases (diabetes, Crohn’s disease, Rheumatoid arthritis) [23]. \nEndometriosis is estimated to have the societal burden of more \nthan $49 billion in the USA alone with a decline in productivity per \n\nCopyright@ Sanjay Kumar Sah | Biomed J Sci & Tech Res | BJSTR. MS.ID.005132.\nVolume 31- Issue 4\nDOI: 10.26717/BJSTR.2020.31.005132\n24354\nwomen accounting twice high as expenses of healthcare [24]. In \ndefiance of advancements in the diagnosis and understanding of \nendometriosis, many women with endometriosis often associated \nwith multiple side effects, and high recurrence rates are struggling \ndue to inefficient non-invasive diagnostic methods and treatments \n[25,26]. The QoL of the patients is broadly affected with a negative \nimpact on social and family life, and high health care costs due to \nendometriosis [27,28].\nRisk Factors\nThere are several existing evidence of risk factors that may \nplay a role in the etiopathogenesis of endometriosis including age, \ngenetic factors, menstrual parameters, anthropometric measures, \nbody habitus, lifestyle factors, and environmental exposures. \nEndometriosis is one of the salient diseases seen in the reproductive \nage of women which may be explained by estrogenic atmosphere \nstrongly implicated in its pathogenesis and considered an average \nage of diagnosis being 28 years [29]. The risk of endometriosis \nhas been linked to ethnicity, and several studies have reported \na nine-fold increase in Asian women’s risk when compared to \nthe European-American white female population. A manifold of \neducation has been said the link with ethnicity as Asian women \nhave nine times greater risk than the European- American white \nfemale [30]. Nonetheless, black women appear less likely to be \ndiagnosed with endometriosis compared with white women [31].\nSome reproductive problems such as early menarche (≤11 years \nof age), short menstrual cycles (≤27 days), heavy and long-lasting \nbleeding, reduced parity and reduced lifetime duration of lactation \ncollaborate with the increased risk of endometriosis [2,15,32]. \nEndometriosis is inversely correlated with body weight, body mass \nindex, and waist-to-hip ratio. Besides, it is more common in taller \nand thinner women due to consistently elevated levels of estradiol \nin follicular phase [33]. The altered endangerment of endometriosis \nhas been reported in association with certain lifestyle factors such \nas smoking, exercise, and consumption of alcohol and caffeine [34]. \nThe risk of endometriosis appears to be increased in women who \nare associated with the following pictures [2,30,35,36] (Table 2).\nTable 2: Risk factors in association with endometriosis. \nSN Risk factors of endometriosis\n1 Asian women than American and European white women\n2 Early menarche (≤11 years of age)\n3 Taller and thinner women\n4 Advancing age up to menopause\n5 Short menstrual cycles (≤27 days)\n6 Longer duration of menstrual flow (> 7 days)\n7 Heavy menstrual bleeding\n8 Delayed childbirth\n9 Reduced or no parity\n10 First-degree relatives (mother, sister, daughter) with \nendometriosis\nNote: Table 2 explains the relationship between endometriosis \nand several risk factors. The risk of endometriosis has been \nlinked to ethnicity, race, age, body mass index, height and other \ndiseases.\nRole of Animal Model in Diagnosis\nThe conventional discovery and development of diagnostic \nmarkers & new therapeutic drugs have been handicapped due \nto the unavailability of suitable animal models for in vitro testing \nand their limited use [37]. Thus, the researcher believes that an \nappropriate model’s evolution may occupy a strong position to \nreduce the prevalence rate and provide quality life to many females \nof the younger generation. They stated that humans and non-human \nprimates are the only mammal option that spontaneously develops \nendometriosis. Still, the limitations of humans and expenses of \nprimate studies have made a boundary to the researcher to make \nuse of small animal models. Non-primates could be another \npossible option for medical research. However, unfortunately, they \nneither menstruate nor are capable of developing endometriosis. \nEven so, several researchers decided to use rabbits, rats, and mice to \ninvestigate multiple aspects of the disease. Although several studies \nhave proven valuable for studying some aspects of the disease, \nsurgical induction of endometriosis lacks the potential to address \nthe underlying cellular mechanisms of endometrial attachment \nand invasion that are critical for the initial establishment of ectopic \nlesions in women.\nTherefore, researchers moved forward to establish the best \nanimal model with similar pathophysiology of human disease [38]. \nAmong various animal models of endometriosis, rodent models have \na plethora of benefits such as; cheaper due to their small size, large \nlitters, and short gestation. Additionally, these animal models play \na significant role in the study of endometriosis because of the wide \navailability of genetic knock-out mice, antibodies against murine \nand rat proteins as well as knowledge of the murine genome. Many \ndifferent model systems have been generated in mice and rats, each \nwith specific characteristics that are consequential for the interest \nof study [39]. Females with very early stages of the endometriosis \nare rarely diagnosed, making it difficult to scrutinize the elaboration \nand progression of ectopic lesions in a large population. Numerous \nexperimental models of endometriosis have been developed to \nfulfil these crucial gaps, which can explain the pathophysiology and \nthe consequences of this [38]. More significantly, rodent models of \nendometriosis are often utilized for preclinical testing to identify \nnew therapeutic agents. The usage of experimental endometriosis \nmodels for therapeutic testing has recently been reviewed.\nPathogenesis \nEven after decades of research the exact cause of endometriosis \nis not yet fully comprehended. However, existing documents \nsuggest that combinations of hormonal, immunologic, genetic, \nand environmental factors are contributing to the origin and \ndevelopment of endometriosis [3]. There are several leading \n\nCopyright@ Sanjay Kumar Sah | Biomed J Sci & Tech Res | BJSTR. MS.ID.005132.\nVolume 31- Issue 4\nDOI: 10.26717/BJSTR.2020.31.005132\n24355\nmechanisms like retrograde menstruation, altered immunity, \ncoelomic metaplasia, and metastatic spread. Moreover, the \nother possible pathogenic elements like hormonal imbalance, \nimmunological, environmental toxin, genetic, and epigenetic \nmechanisms may occur to allow the disease establishment and \nprogression [40]. Eventually, stem cell and genetic emergence of \nthe disease are also being suggested for undergoing novel research. \nIn 1940, Sampson proposed a distinctive theory in connection with \nthe pathogenesis of endometriosis called retrograde menstruation, \nwhich is a widely accepted theory. Normally, endometrium sheds \nsloughs off through the cervix and vagina during the menstrual \nphase of the cycle, but sometimes it moves upward and backward \nthrough the fallopian tube into the peritoneal cavity known as \nretrograde menstruation.\nIt was found that approximately 90% of the subjects were \nestimated to experience a certain amount of endometrial sheds \ninto their peritoneal cavity. Still, only a small proportion of them \nhave developed endometriosis [41]. However, some authors \nexplained that retrograde menstruation in association with other \nabnormalities like eutopic anomalies of the endometrium (such \nas; the altered synthesis and secretion of proteins and gene \nexpression) and immune system abnormalities might be involved \nin the pathophysiology of endometriosis [42]. Whereas other \nresearchers have hypothesized that pathogenesis of endometriosis \nfor the development of ectopic lesions is enhanced by a replicate \ncapacity due to a surge in telomerase synthesis in the sloughed \nendometrium during retrograde [43]. Meanwhile, induction theory \nwas hypothesized by another researcher which includes: the \nsloughing endometrium gives off “factors” during menstruation, and \nthat causes changes in the surface epithelium of the ovary leading \nthe differentiation of endometrium-like tissue and migration to the \nperitoneal cavity.\nAccording to in situ  theory, the totipotent cells endure \nhomogenous from the fetus surviving into adultness and during \nthe reproductive age, get stimulated and thus differentiating into \nendometriotic lesions [44]. There might be a certain contribution of \nendometrial stem cells in the etiology of the disease which describes \ncertain rare and extreme cases of endometriosis. Pathogenesis of \nendometriosis most likely involved various factors, and extensive \ninvestigation has explored the role of genetics, environmental \nfactors, and the immune system in predisposing patients. A \nnew insight into normal physiology of uterus and pathogenesis \nof endometriosis is found to be sought by the identification of \nendometrial as well as extra uterine stem/progenitor cells that aim \nthe uterus and endometriotic implants [45].\nEpigenetics of Endometriosis\nEpigenetics describes changes to the cytosine base pairs and \nhistones remodeling that affect gene expression, however, they \nare not mutations of the DNA itself. Several mechanisms might \nchange the epigenetics of endometriosis; they are heritable \nchanges in gene expression that occur without alterations to the \nunderlying DNA sequencing [46]. As they are stable and heritable, \nthey facilitate the propagation of the transformed cell line and \ncan be preserved in cell divisions. Besides, they are reversible \ndue to which, remodeling to any future cells in that line could \nalter the epigenetic profile further or remove it together [47]. \nThe refashioning includes DNA methylation, histone methylation, \nacetylation, sumoylation, ubiquitylation, and phosphorylation, as \nwell as chromatin remodeling and RNA transcriptional alterations \n[46]. There are specific genes that are known to be overexpressed in \ndecidualization, having been seen down-regulated in endometriosis \nand vice versa. These comprise various elements like transcription \nfactors, hormones, growth factors, cytokine/chemokine’s signaling, \ncell cycle regulation, adhesion, the immune system, and proteases, \nincluding genes associated with steroidogenesis, implantation, and \nplacental development could also be affected [48].\nEndometriosis in Association with Fertility\nFertility is affected by many pathways in the case of endome -\ntriosis such as peritoneal inflammation and endocrine imbalance, \nwhich interfere with ovarian function and ultimately reduce oo -\ncyte’s competence, but minimal and mild endometriosis has been \nshown to improve fertility modestly after removal of superficial \nfoci. The chance of fertility after resection of endometriomas and \ndeep infiltrating lesions has remained undocumented [17]. As in -\nferred by women’s accounts, it may be salutary for drawing out rel-\nevant clinical guidelines for the clarification of evidence depicting \nassociation among endometriosis and Fertility and treatment of \nconditions and dissipating the shared beliefs, along with the notion \nthat pregnancy is an appropriate alternative for a cure. Besides, it \nmay be employed for developing the protocols for understanding \nand addressing the fertility concerns specific to women those who \ndo not reveal themselves as heterosexual [49].\nEndometriosis in Association with Infertility \nThe routine intricacy that is seen in women with moderate to \nsevere endometriosis is infertility [5]. A large cohort study revealed \nan increased risk of subsequent infertility by 2-fold in women age \nof fewer than 35 years with a prior history of laparoscopically \nconfirmed endometriosis [15]. During endometriosis, the \ninflammatory environment of Pelvic anatomy becomes distorted \nand results in the reduced monthly fecundity rate via mechanical \ninterruption like pelvic adhesions. These disruption imbalances the \nprocess of oocyte release or pickup alters sperm motility, interferes \nwith the myometrium contraction ability, impairs fertilization, and \nembryo transport. Also, gamete transport and embryo implantation \nare affected due to escalation in cytokine production, which reduces \nthe tubal function and decline in the tubal motility and contractility. \nThe current evidence proposed the mechanisms of endometriosis-\nassociated with infertility [50].\n\nCopyright@ Sanjay Kumar Sah | Biomed J Sci & Tech Res | BJSTR. MS.ID.005132.\nVolume 31- Issue 4\nDOI: 10.26717/BJSTR.2020.31.005132\n24356\nImpairment of the hypothalamo-pituitary-ovarian axis may kick \ninto infertility in women carrying with a prolonged follicular phase, \ndecreased serum estradiol levels, and reduced peak luteinizing \nhormone concentration [51]. The principal reason for morbidness \nin women with endometriosis is infertility. In people who have \nendometriosis, 30 to 50 percent face infertility, and consequently, \nfecundity decreases from 15 to 20 percent each month in healthy \nwomen up to 2 to 5 percent in those with endometriosis [34,52,53]. \nAccording to history, women having endometriosis-associated \ninfertility are prone to minute, exact or multidimensional \nabnormalities [51,54-57] (Figure 1).\nFigure 1: Endometriosis in association with infertility. \nNote: Endometriosis has been associated with infertility. However, this figure tries to explain the mechanisms by which \nendometriosis affects gametes and embryos, the fallopian tubes and embryo transport, implantation and the eutopic \nendometrium; these abnormalities begins from altered pituitary ovarian axis leading to infertility.\nEndometriosis in Association with Sub-Fertility\nEndometriotic lesions may vary from just a few implants to \nextensive adhesions and organ infiltration and even outside the \npelvic cavity, validated by ASRM classification into four classes: \nminimal, mild, moderate, and severe endometriosis [58]. There \nwere several pieces of evidence to support the hypothesis that \nthe presence of endometriosis causes subfertility. This evidence \nincludes an increased prevalence of endometriosis in sub fertile \n\nCopyright@ Sanjay Kumar Sah | Biomed J Sci & Tech Res | BJSTR. MS.ID.005132.\nVolume 31- Issue 4\nDOI: 10.26717/BJSTR.2020.31.005132\n24357\nwomen compared with women of proven Fertility, a reduced \nmonthly fecundity rate (MFR) in baboons with mild to severe \nendometriosis in comparison to those with minimal endometriosis \nor a normal pelvis, a trend toward a reduced MFR in infertile women \nwith minimal to mild endometriosis when compared to women with \nunexplained infertility, a reduced MFR and cumulative pregnancy \nrate after donor sperm insemination in women with minimal-\nmild endometriosis compared with those with a normal pelvis, a \nreduced implantation rate per embryo after IVF in women with \nmoderate to severe endometriosis in comparison to women with \na normal pelvis, and an increased MFR and cumulative pregnancy \nrate after surgical removal of minimal to mild endometriosis [59].\nEndometriosis and Pregnancy\n Endometriosis is a disease of women’s reproductive period. \nThe individual with a previous diagnosis of the disease had adverse \nconsequences such as an increased risk of pregnancy and neonatal \ncomplications, and this risk remained significant after adjusting for \nmaternal age. The risk of multiple pregnancies, breech presentation, \nand placenta previa was more than two-fold higher in women with \nendometriosis than in the control group. Besides, the estimated \nrisk of stillbirth was more than 1.5-fold higher in the affected \ngroup. Endometriosis does not influence fetal well-being because \nthe pregnant mothers with endometriosis are at higher risk of \nobstetric complications like miscarriages, threatened miscarriages, \npreterm labor, preterm birth, and a higher cesarean section rate \n[60]. Women with endometriosis are more vulnerable to serious \nand important adverse maternal, fetal and neonatal outcomes [61]. \nAs revealed by a large study, people with endometriosis had greater \nodds of pre-eclampsia (OR 1.13, 95% CI 1.02-1.26), antepartum \nbleeding/placental complications (OR 1.76, 95% CI 1.56-1.99), and \ncesarean delivery (OR 1.47, 95% CI 1.40-1.54) [62].\nDiagnosis \n Primarily, those suspected patients are screened by physical \nexaminations and pelvic ultrasound. Secondarily, further \ninvestigations are performed such as target pelvic examination, \ntransvaginal ultrasound, and pelvic magnetic resolution image \n(MRI) by an expert [63]. The gold standard of diagnosing the \nendometriosis clinically is a histopathological examination that is \nmany times undergone by a laparoscopy. If a woman has a thorough \nhistory of following clinical features such as; recurring or persistent \npelvic pain, dysmenorrhoea, dyspareunia, and infertility along with \nphysical symptoms like; pain during pelvic examinations, nodules \nin the uterosacral ligament, retrocervix and vaginal fornix, as well \nas vagina and rectum is advised for a diagnostic laparoscopy to \nconfirm the endometriosis [64].\nImaging technology occupies a significant position in the \ndiagnosis of the disease. However, in the case of endometriosis, \nit is imperative not only for assessing the extent of disease; but \nalso sets a guideline for surgical excision of the targeted area. The \nadvancements in radiological techniques namely; transvaginal \nultrasonography (TVUS) or Magnetic Resonance Imaging (MRI) \nare very useful clinically in symptomatic patients [65]. Pelvic \nendometriosis comprises three major separate commodities such \nas peritoneal, ovarian, and deep infiltrating endometriosis (DIE) \nwith different pathogenesis [66]. Also, the multislice computerized \ntomography (CT) enteroclysis and multidetector CT enema \n(MDCT-e) and MRI enema (MRI-e) are useful in the evaluation of \nbowel endometriosis and their sensitivity and specificity are 98.7% \nand 100%, respectively [67,68].\nBiomarkers of Endometriosis\nResearchers are exploring the utility of biomarkers for early \ndiagnosis as a noninvasive approach, but more investment in this \narea is required for it to be fruitful. Current blood-based biomarkers \nunder investigation include; regulators of gene expression (micro- \nRNAs), inflammatory markers, tumor markers, growth factors, and \nhormonal markers, proteomics, metabolomics, oxidative stress, \nautoantibodies as well as endometrial and menstrual effluent \nbiomarkers. Despite extensive research in the field of biomarkers for \nendometriosis including blood, urine, body fluids and endometrial \nbiopsy, neither a single biomarker nor a panel of biomarkers has \nbeen proven for a noninvasive diagnostic test which can provide \nsufficient sensitivity and specificity [69]. The invention of new and \nvalidated putative biomarkers are crucial for the advancement of \nthe field and are top research priorities for endometriosis proposed \nin 2009 and 2013 by highly ranked researchers [23,70].\nEndometriosis- Associated Cancer\nThe association between endometriosis and gynecological \ncancer on a molecular basis is obscure. Formation of endometrial-\nlike tissue and lesion on the surface of the uterus and fallopian \ntubes cause pelvic inflammation, severe pain, and infertility [71,72]. \nThe relationship between endometriosis and ovarian cancer was \nfirst published in 1927 [73]. No epidemiological evidence was \npublished until the end of the 20th century. After that, the first \nlarge epidemiological study popped in from Sweden along with \ntwo big studies (20,686 and 64,492 participants respectively). \nThe studies revealed that there was an increased risk of ovarian \ncancer for those women who were suffering from endometriosis \n[74,75]. Also, there are many pathological factors involved to cause \nendometriosis, which includes; early menarche, abnormal uterine \nbleeding, abnormal estrogen level, low body mass index (BMI), cell \nadhesion factors, angiogenic factors, elevated gonadotropins, and \nchronic inflammation. According to the previous pieces of evidence \nof endometriosis, the parents, siblings, children as well as twins of \nthose who have the disease, the likelihood of cancer may be up to \nten folds higher than the healthy population.\nMoreover, single nucleotide polymorphism may increase the \nrisk of endometriosis and its associated cancer [76]. The overall \nrisk of Endometriosis-associated carcinoma remains low despite \n\nCopyright@ Sanjay Kumar Sah | Biomed J Sci & Tech Res | BJSTR. MS.ID.005132.\nVolume 31- Issue 4\nDOI: 10.26717/BJSTR.2020.31.005132\n24358\nit is a common medical issue. According to a huge epidemiological \nstudy, the all-inclusive prevalence of ovarian cancer in a patient \ndiagnosed with endometriosis was 0.3-0.8 percent, which was 2-3 \ntimes perilous than the controls [77]. Endometriosis is somatically \ntaught genetic change similar to those found in cancer, leading to \nclonal expansion and genetically abnormal cells. Endometriotic \ncysts are monoclonal characterized by loss of hetrozygocity \nin 75 percent of them, and mostly affecting 9p, 11q, and 22q \nchromosomes [78]. Jiang, X et al. investigated the possibility of \nendometriosis - associated ovarian cancer. In this study, 40 cases \nof endometriosis were examined for clonal status, the functional \nalteration in TP53, RASK and, all losses is the candidate of ovarian \ntumor suppressor on chromosome arm 6q, 9p, 11q, 17p, 17q and \n22q genes were investigated [79]. The permanent and irreversible \nchanges of a nucleotide sequence in endometriotic lesions called a \nsomatic mutation, and many genetic mutations have been identified \nin endometriosis-associated ovarian cancer (EAOC).\n39 genes were identified in the association between \nendometriosis and cancer. Several studies focused on the loss of \nheterozygocity of 10q gene, chromosomal aneuploidy, genomic \nalteration PGR and, ESR1 gene were common in women cancer \n[71,80,81]. Sato, et al. investigated that the functional alteration \nof tumor suppressor gene (PTEN/MMAC) which is located on \nchromosome arm 10q, in this study 54 cases of endometrioid \ncarcinoma and endometrial cyst were included. The result was \nsuggested that LOH at this site occurs 8 of 19 endometriosis - \nassociated ovarian carcinomas (42.1%), 6 of 22 clear cell carcinoma \n(27.3%), and 13 of 23 endometriosis cyst (56.5%). Similarly, 4 out \nof 20 endometriosis - associated carcinomas having a somatic \nmutation in PTEN were identified [82]. Specific protein markers for \novarian carcinoma have been evaluated in atypical endometriosis. \nHepatocyte nuclear factor - 1 β (HNF-1β) is a transcription factor \nthat has significantly been expressed in ovarian cancer and seldom \nexpressed in non-clear cell carcinoma [83]. The data collected \nantecedent research suggested that endometriosis is a monoclonal \nneoplastic disease and also a precursor of EAOC notwithstanding \nmenopause. On one hand various types of molecular events like \nalteration of p53 gene, PTEN silencing, K-ras mutations have \nbeen discovered in EAOC. While activation of HNF-1 on the other \nhand, appears to be distinctive to clear cell carcinoma in becoming \napparent in Endometriosis [84].\nAccording to contemporary studies of whole - genome or \ntargeted sequencing ARIDIA and PIK3CA genes were identified \nas having frequent mutations while PPP2RIA and KRAS having \nmoderate mutations in ovarian cell carcinomas [85-87], mutations \nof PTEN, CTNNB1, and KRAS in endometrioid carcinoma [83,88,89]. \nActivation of oncogenic KRAS and PI3K survival pathways and \ninactivation of tumor suppressor genes PTEN and ARID1A in \ncombination with the results of gene expression profiling of these \ntwo tumor types are suggested for clear cell and endometrioid \novarian carcinomas respectively [90-92]. Besides, IP3k/AKT/\nmTOR is the most investigating signaling mechanism for many \ncellular activities like cell growth, cell survival, proliferation, protein \nsynthesis, transcription, and angiogenesis. Dysregulation of the \nsignaling pathway causes activation of other downstream signaling \nmechanisms leading oncogenesis in humans. IP3K is a lipid kinase \nof G-protein coupled receptor and receptor tyrosine kinase (RTKs) \nfamily protein according to their structure; it is categorized in three \nclasses I, II, and III. Again, Class, I of IP3K is sub-classified into two \ncategories (IA and IB).\nIt is a group of heterodimer proteins consisting of p85 and p110 \nregulatory subunit encoded in 3 distinct genes viz; PIK3CA, PIK3CB, \nand PIK3CD. Catalytic activation of p110 leads to phosphorylation \nof 3 rd carbon of the inositol that had of phosphatidylinositol 4-5 \nbiphosphate (PIP2) lead to produce phosphatidylinositol [3-5] \ntriphosphate (PIP3), for the activation of 2 nd messenger PIP3, \nthus triggering AKT in the plasma membrane. The blockade \nof this pathway leads to independent cell growth due to a lack \nof a negative regulator of PIP3K/AKT/ [93,94]. Endometriosis \nis a benign inflammatory disease however, the molecular and \ncellular features work in a similar manner like; malignancy \noccurs, including increased cell proliferation, re-expression of \nthe pluripotent transcription factor OCT4 [95], epithelial-to-\nmesenchymal transition [96] acquisition of migratory phenotype \n[95,97] development of distant foci, cell adhesion, invasion [98] \nangiogenesis, and at times, treatment resistance [99]. It is not fully \ndeclined but there is a strong association between endometriosis \nand ovarian cancer. Genetic mutation is the major factor of \novarian cancer thus many protein markers are used for advanced \ndiagnosis, prognosis, and treatment. All genomic and proteomic \nmarkers facilitate the development of the best diagnostic tool for \nendometriosis - associated ovarian cancer.\nManagement \nEndometriosis is a chronic inflammatory disease that \nrequires long term or lifelong treatment. Three major therapeutic \nmanagement types exist for endometriosis, including Medical \ntreatment, surgery, and assisted reproductive technology (ART) \n[100]. Accurate diagnosis is imperative because it provides outright \ninformation regarding severity of the disease. Many societies \nsuch as American College of Obstetricians and Gynecologists and \nAmerican Societies of Reproductive Medicine approved medical \ntreatment before definitive diagnosis [101,102]. The medical \ntreatment provides only short term pain relief but when combined \nwith surgical intervention, divulges long term relief. The main \nconcern is how endometriosis-associated pain can be managed. \nPhysicians believe in optimal management for this condition. All \nthese treatments are suppressive and do not possess curative effect.\n1) Egg preservation in young patients affected by \nendometriosis.\n\nCopyright@ Sanjay Kumar Sah | Biomed J Sci & Tech Res | BJSTR. MS.ID.005132.\nVolume 31- Issue 4\nDOI: 10.26717/BJSTR.2020.31.005132\n24359\n2) Preoperative surgical management to inhibit evolution \nand to avoid removal of cyst that might look like endometriosis.\n3) Postoperative hormonal suppression to decrease \nrecurrence of endometriosis [103].\nNon-Steroidal Anti-Inflammatory Drugs (NSAIDs)\nNon-steroidal anti-inflammatory drugs (NSAIDs) are used to \nreduce pain associated with dysmenorrhea in 80% of women. It \ninhibits cyclooxygenase (COX), a key enzyme in the biosynthesis of \nprostaglandin in endometriosis-associated pain and inflammation. \nCyclooxygenase is two types viz; COX-1 and COX-2. NSAIDs and \nacetylsalicylic acid (ASA) inhibit both COX-1 and COX-2 but have a \nselective effect to primarily inhibit COX-2. However, management \nwith NSAIDs is not significant, because endometrial pain appears \nby involving other factors in addition to prostaglandin. Ibuprofen, \nNaproxen, Mefenamic acid, Diclofenac, Meclofenamate, Ketoprofen \nare commonly seen effective in dysmenorrhea. It acts quickly within \n30 to 60 minutes and can be taken on a regular basis according \nto the score of pain. Oral contraceptives can be used as second-\nline treatment if NSAIDs fail or decrease the pain incompletely. \nIndividual NSAIDs have different types of actions depending \nupon their selective and non-selective receptor binding capacity. \nBesides, there might be specific side effects of NSAIDs, such as \ngastrointestinal (nausea, vomiting, peptic ulcer), hypersensitivity, \nrays syndrome, intestinal nephritis, etc. [104-106].\nHormonal Therapy\nGonadotropin-releasing hormone (GnRH) agonists are useful \nto deplete further synthesis of endogenous gonadotropins from \nthe pituitary gland, interrupting the menstrual cycle, eventually \nresulting to cause endometrial atrophy and amenorrhea [107]. \nProgestin is an acceptable alternative drug for first-line therapy of \nendometriosis and has been used for over 30 years. Endometrial \ncarcinoma has been treated with a more diverse method than \nthe other malignant tumors that affect intra pelvic organs in \nuntreatable cases. Radiotherapy, chemotherapy, and hormonal \ntherapy are used in cases of endometrial malignancy. Here in \nhormonal treatment is better for those who wish to remain fertile \nafter the early development of pre-menopausal endometrial cancer \n[108,109]. Progestin is effective in suppressing endometrial tumor \ngrowth in comparison to GnRH and Danazol. The cost-effectiveness \nand lower incidence of estrogen deficiency associated with adverse \ndrug reaction (ADR) are lower than GnRH and danazol in the \ntreatment of endometriosis. Thus, investigators have considered \nprogestin as more effective and useful than GnRH and Danazol. \nProgestin with hormonal contraceptives can be provided either \nalone or in combination with estrogen to prevent development \nendometriosis hyperplasia. It decreases glandular cellularity by \nincluding apoptosis and inhibits angiogenesis in the myometrium \n[109-111].\nMedroxyprogestrone Acetate (MP A)\nMPA is a synthetic and one of the most studied progestin that is \ntypically used to cure irregular menstruation and abnormal uterine \nbleeding. It has been a greater effect on pain and improving quality \nlife in placebo therapy, but the MPA and GnRH agonist dose 15-50 \nmg daily administration the efficacy has been found equivalent \n[110,112]. Ushijima K et al. conducted the Multicenter phase II \nclinical trial study. They found an 82% complete rate response in \nendometrial hyperplasia, where all the patients received 600 mg \nMPA with low dose Aspirin for 8 to 16 weeks and were monitored \nin following after 3 years. During the observation period, 12 \npregnancies and 7 normal deliveries were achieved, which proved \nthat MPA is effective in fertility-sparing treatment with a high \ndose and least toxicities for endometrial cancer and endometrial \nhyperplasia [113].\nDanazol\nIt is a synthetic steroid with strong anti-gonadotropins \nand weak androgenic properties, which inhibit estrogen and \nprogesterone receptors’ results in preventing endometriotic \natrophy and reduced menstrual cycles [114]. Selak V, et al. 2001 \nin a Cochrane systematic review, evaluated the effectiveness of \nDanazol to placebo in the treatment of endometriosis along with \ninfertility in women of reproductive age. The data represented that \ntreatment with Danazol was effective in endometriosis-associated \npain, and Laparoscopic scores were improved as compared to with \nor without placebo treatment [115]. Luisi S, et al. 2009 evaluated \nthe efficacy of Danazol in young women with menorrhagia. Total \n55 (30 had one or two miscarriages & 25 were nullipara) women \nwere selected for this study after biopsies (hysteroscopy-directed \nbiopsy) to exclude endometriosis hyperplasia, polyps. Also, they \nwere prescribed 200 mg danazol daily at night by vaginal route for \n6 months. \nThe result was useful as there was a significant reduction in \nthe severity of blood loss in all women after 2 months of treatment \n[116]. Furthermore, another investigation by Szubert M, et al. \n2014 depicted the efficacy of danazol treatment in endometriosis \nand pain management. 103 cases were selected and laparoscopy \nwas performed during follow up. Only 71 women were diagnosed \nwith having endometriosis and other women were suffering from \nminor pain in the pelvis. Treated with 2X200 mg danazol daily for \n6 months, only 35 participants completed the study (two follow up \nvisits at third and sixth months). After treatment, the pain score \nand concentration of CA-125 in plasma was significantly decreased \n[117].\nHormonal Contraceptives\nLimited studies said that oral contraceptives are useful in the \ntreatment of endometriosis-associated with chronic pain. GnRH \nis the principal regulatory hormone of FSH) and LH. All these \n\nCopyright@ Sanjay Kumar Sah | Biomed J Sci & Tech Res | BJSTR. MS.ID.005132.\nVolume 31- Issue 4\nDOI: 10.26717/BJSTR.2020.31.005132\n24360\nhormones are involved in the synthesis and regulation of estrogen \nfor ovulation and follicular development. Oral Contraceptive Pill \n(OCP) inhibits the synthesis of LH and FSH to prevent estrogen \nand progesterone synthesis by suppressing the activation of \nGnRH, resulting in the prevention of endometrial proliferation \nand produces scanty cervical mucus [109]. Estrogen - progestin \ncombination or alone progestin is one of the most common \ncontraceptives used as the first-hand treatment for chronic pain \nthe in case of endometriosis and ovarian function. These can be \nprescribed through oral contraceptive pills, transdermal patches, \nvaginal ringsEstrogen - progestin combination or alone progestin \nis one of the most common contraceptives used as the first-line \ntreatment of endometriosis-associated with chronic pain and \novarian function. These can be prescribed through oral contraceptive \npills, transdermal patches, vaginal rings [118]. According to the \ndegree of success in women who were affected by endometriosis or \nits associated pain, the cost, ease of administration, and tolerance \neffect are the key factor of these drugs to make them common.\nContinuous therapy of combined oral contraceptives (COC) is \nbetter to control chronic pain as compared to cyclic administration \n[111]. A systemic review by Vercellini P , et al. 2011 revealed that the \ncommon relative risk of 0.63 [95% confidence interval (CI), 0.47-\n0.85] for current OC users, 1.21 (95% CI, 0.94-1.56) for past users \nand 1.19 (95% CI, 0.89-1.60) forever users. This study indicated \nthat OC is effective in reducing endometriosis and its symptoms \n[119]. A study undergone by Sullivan H, et al. 1999 to rule out \nwhether the dose of COC was effective in endometriosis or ovarian \nactivities revealed that COC had positive impacts on endometriosis. \nA total of 30 healthy women were included, who were administered \n60 mcg of Gestodene and 15 mcg of Ethinyl Estradiol on 21 st and \n24th day in every 28 days menstrual cycle and were monitored \nover 5 months. The outcome was that such a regimen is an active \ntreatment for endometriosis as compared to an alone ultra-low dose \nof estrogen treatment [120]. Medroxyprogesterone acetate 10-100 \nmg of norethindrone acetate 5 mg daily is commonly prescribed to \ntreat endometriosis; this progesterone is completely suppressing \nhypothalamic-pituitary axis for preventing ovulation [121].\nGonadotropin Releasing Hormone (GnRH) Agonist\nGnRH agonists are one of the most common drugs used for \nthe treatment of endometriosis. These drugs are down-regulating \nGnRH receptors from the hypothalamic-pituitary gland, which \ndecreases gonadotropin secretion to inhibit ovulation and reduce \nserum estrogen level [122]. It is prescribed only after consultation \nwith a physician. Leuprolide is a GnRH agonist that is effective \nin endometriosis as approved by the Food Drug Administration \n(FDA) [123]. Initially, the administration of Leuprolide stimulates \nLH and FSH which leads to increment in steroidogenesis thus, \nit elevates estrogen level in females and testosterone along \nwith dihydrotestosterone (DHT) in males. Moreover, long term \nadministration of Leuprolide can decrease the hormonal level, \nwhich may ultimately inhibit gonadotropin release by inhibiting \nthe secretion of LH and FSH in both males and females [124]. \nIn comparison with combined hormonal contraceptive (CHC) \ntreatment, GnRH agonists have better efficacy in endometriosis \nand its associated chronic pain [125]. Various research have been \nconducted to improve novel treatment with GnRH agonists for \nendometriosis and its associated symptoms, to conclude how \ncurrently existing therapies work, which type of biochemical \nabnormalities are seen and how can they be minimized. All these \nstudies concluded a similar effect of GnRH agonists found effective \nin preventing endometriosis and chronic pain [126-130].\nGonadotropin Releasing Hormone Antagonist (GnRH-\nAnta.) \nGnRH antagonists have an advantage over the agonists about \ninitial flare and hypoestrogenism through a direct mechanism that \ncompletely inhibits the GnRH receptors resulting in immediate \nsuppression of LH and FSH secretion [131]. With the aid of cloning \nand high throughput peptide screening of oral human GnRH \nreceptors, antagonist Elagolix was developed. It has a high affinity \nto bind GnRH receptors and reduces the interaction with CYP450 in \ninhibiting LH and FSH [132,133]. Clinical research was conducted \nin two different doses; 150 and 200 mg. First was 150mg daily for \n24 months and second, 200 mg twice a day for 6 months. In 2018, \nUSFDA approved 150 - 200 mg Elagolix for the management of \nendometriosis [134,135]. At the moment, various formulations are \navailable but oral, and injectable preparations are widely used that \ncompetitively inhibit the GnRH secretion. The other two types of \nGnRH antagonists called Relugolix and Linzagolix are introduced, \nwhich work to prevent the advanced stage of endometriosis-\nassociated pain. Both the drugs are under clinical trials phase III. \nIn the clinical trial, 40 mg Linzagolix is used in combination with \nEthyl estradiol 0.1 mg or 0.5 mg NETA (clinical trial registration No. \nNCT03204318, NCT03204331, and NCT02778919) [135].\nAromatase Inhibitor\nThe Aromatase enzyme comprised two types of polypeptides. \nThe first one belongs to the superfamily of the cytochrome \nP450 (CYP450arom), which is the product of single gene CYP19, \nand second is flavoprotein (flavoprotein NADPH-CYP450 \nreductase). It is expressed on different body sites like ovarian \ngranulosa cells, adipose tissue, placental syncytiotrophoblast, \nosteoblasts, and brain. Aromatase’s main source is ovarian cells in \npremenopausal women, while adipose tissues in postmenopausal \nwomen [136,137]. Aromatase converts approximately 2% of \nAndrostenedione to E1. Further, it turned to E2 in postmenopausal \nwomen by 17ß-Hydroxysteroid dehydrogenase type 1 in peripheral \ntissue resulting to high level of E2 circulating in the blood to \ncause endometrial hyperplasia and carcinoma [138]. The agent \nAromatase inhibitor (AIs) was first employed to manage estrogen \nreceptor activating breast carcinoma.\n\nCopyright@ Sanjay Kumar Sah | Biomed J Sci & Tech Res | BJSTR. MS.ID.005132.\nVolume 31- Issue 4\nDOI: 10.26717/BJSTR.2020.31.005132\n24361\nAIs represent the new promising treatment of endometriosis. \nIt has the capability to reduce estrogen production by inhibiting \nthe enzyme cytochrome P450 [139]. AIs are classified into three \ngenerations. The first generation is Glutehimide, which has many \nadverse effects like lethargy, hypersensitivity, nausea, etc. The \nsecond generation is, Fadrozole and Formestancel have more \nselective and higher efficacy over the first generation and have less \nadverse effects. The third generation Aromatase inhibitors, namely; \nLetrozole, Anastrazole, and Examestande, are triazole derivatives \nthat are selective, reversible as well as more potent, making \nthem ideal for using clinically. These agents are prescribed in \npremenopausal women to decrease the estrogen level and increase \nFSH secretion from pituitary glands. Treatment with Aromatase \ninhibitors must be combined with other potent drugs to down-\nregulate [137].\nLetrozole \nLetrozole is a non-steroidal aromatase inhibitor that has been \ncommonly used for the management of endometriosis-associated \npelvic pain and breast carcinoma. It was first reported in 2004 for \nthe management of endometriosis. Letrozole has been used alone \nor in combination with other steroidal or non-steroidal analogs for \nthe treatment of [140]. In the preclinical study, the animals were \nselected and made develop endometriosis by Vernon and Wilson’s \nmethod. After the 14th day of model development, the animals \nunderwent laparoscopy to measure heterotrophic. After that, they \nwere provided 0.5 mg/kg AIs (Letrozole) daily for 3 weeks. Upon \ncompletion of treatment, the animals were re-examined, and the \nsize of heterotrophy was determined. Besides, the histopathology \nstudy was carried out in both groups (control and AIs treated group). \nThe result suggested that 0.5 mg/kg for 21 days of treatment with \nLetrozole decreases the size of heterotopies. The total percentage \nof reduction of 79.92% ± 7.89% was observed [141]. A Prospective \nnon-randomized study was carried out, including 20 patients \nwith endometriosis and its associated chronic pelvic pain. Both \nLetrozole and norethindrone were prescribed in combined form as \n2.5mg/kg for 6 months starting from the 3 rd day of the menstrual \ncycle. Besides, the pain score was recorded 30 days before starting \nthe treatment. The result showed that following the procedure, and \nall the patients showed significant improvement in pain and [142].\nRole of Micro-RNAs in Endometriosis Treatment\nMicro-RNAs (miRNAs) are the highly conserved 9-22 nucleotide \nlong non-coding RNAs that play a crucial role in cellular functions \nsuch as; cell proliferation, angiogenesis, apoptosis, and gene \nexpression. miRNAs are directly bound to the 3 untranslated regions \nof messenger RNA (mRNA [143]. miRNAs have been found in most \nbody fluids and the expression of miRNAs differs between healthy \nand diseased people however its physiological roles are obscure \n[144]. Endometriosis is a multifactorial disease characterized by the \npresence of endometrial tissue surrounding the womb. miRNAs are \nexpressed in different gynecological disorders like; malignancies, \nleiomyoma, endometriosis, etc. Ovarian carcinoma is a rampant \nlethal malignancy in developed countries [145]. As angiogenesis is \na key factor in endometriosis, several studies have reported that \nincrement in VEGF level causes endometriosis [146-148]. miRNAs \nare involved in apoptosis disease progression as a result of which, \nin endometriosis, they are used as a diagnosing tool for detecting \nthe progress of the disease and cell proliferation. Also, miRNAs are \npotential and efficient in the early detection of [143].\nAnti-Angiogenesis Factor\nPresently available medical treatment is effective to suppress \nhormonal synthesis. Oral contraceptives, androgenic agents, \nprogestin analogs, GnRH agonists and GnRH antagonists have \nbeen successfully used for the treatment of endometriosis. \nHowever, these agents are not effective in eradicating the disease \nin some cases. Long term use of these agents exhibits major \nadverse effects. Interleukins-8, vascular endothelial growth \nfactor (VGEF) receptor-2, Endoglin, Urokinase-type plasminogen \nactivator, matrix metalloproteinase-2, and 9, as well as a placental \ngrowth factor, is found in an activated endometrial cell in tumors \n[111,149-151]. Previous studies showed that soluble truncated \nfms like tyrosine kinase-1 receptor and affinity-purified VEGF \nantibody are significantly useful to inhibit the angiogenesis \nfactor in endometriosis. The blockade of VEGF signaling prevents \nendometrial lesions and associated carcinoma. Bevacizumab is \na recombinant humanized anti-VEGF monoclonal antibody that \nprevents vascular density and also leads increment in apoptotic cell \ndemise in case of surgically induced endometriosis.\nBevacizumab is in phase II clinical trial 15 mg/kg intravenous \nroute of administration every 3 weeks until the disease progression \nis effective in endometrial carcinoma [152,153]. Thalidomide is also \nused as an anti-angiogenic agent in endometriosis. The mechanism \nof action of thalidomide is suppression of phosphoinositide 3 kinases \n(P13K)/protein kinase B (AKT) signaling to inhibit the formation of \nangiogenesis-related effect [154]. Antônio LG, et al. investigated the \neffect of thalidomide in the progression of endometrial lesions. 1 \nand 10 mg/kg thalidomide was administered in Wistar rats daily \nfor 10 days. After 10 days of treatment, the tissue was isolated, \nand the cell proliferation index (CPI) was identified. The result \nproved that thalidomide had significantly reduced the lesion area \nand CPI [155]. Women who had relapsing endometriosis after \nsurgical treatment of ovarian and peritoneal endometriosis were \nmade discontinue GnRH agonist treatment, meanwhile, 300 mg/kg \nof thalidomide was prescribed for 6 months. Eventually, following \nthe anti-angiogenic treatment with thalidomide, the relapse of \nendometriosis was completely suppressed [156].\nSurgical Treatment \nSurgical management of endometriosis requires extensive \nknowledge of the disease that should be managed by a \n\nCopyright@ Sanjay Kumar Sah | Biomed J Sci & Tech Res | BJSTR. MS.ID.005132.\nVolume 31- Issue 4\nDOI: 10.26717/BJSTR.2020.31.005132\n24362\nmultidisciplinary team to lead professional gynecologists. \nLaparoscopy is a useful tool for the diagnosis of disease and \ndetermining the severity of disease before starting the surgical \ntreatment [157]. It is effective in suppressing symptoms and chronic \npain and can increase the fertility of women. Approximately, 50% \nof cases will re-develop symptoms within a few years of surgery. \nThe severity of the disease determines the successful surgical \ntreatment of Endometriosis [122]. Patients who have chronic \npelvic pain or ovarian endometrium and do not respond to medical \nmanagement need surgical treatment. There are some approaches \nfor considering surgical management viz; \n1) Egg preservation in young patients affected by \nendometriosis.\n2) Preoperative surgical management to inhibit evolution \nand to avoid removal of cyst that might look like endometriosis.\n3) Postoperative hormonal suppression to decrease \nrecurrence of endometriosis [103].\nConclusion\nIt is mandatory to understand that endometriosis is a complex, \ndebilitating disease comprising multiple factors in its origin and \ndevelopment. Researchers are comprehending the distinct clinical \nfeatures, including chronic pelvic pain and infertility, to discover \nthe significant markers or therapeutic strategies to battle the \nmysterious disease. It is significant to gain cognizance into the \ncomplex etiology of endometriosis due to different causes viz; \nthe unavailability of non-invasive diagnostic markers, delay in \ndiagnosis, high risk of recurrence of the disease following surgical \nremoval of the tissue, and lack of a definitive cure for the disease. \nThis article will furnish the readers with up-to-date knowledge \nregarding the pathogenesis, biomarkers, association of infertility, \npregnancy, and carcinoma with the ailment and also shed light on \nthe management of the disease.\nFuture Prospective \nStill, endometriosis research is lacking the exact mechanism \nfor etiology, biomarkers, and effective treatment modalities to \ngenerate convincing data with high sensitivity and specificity. \nBesides, limitations derive from small sample size and suboptimal \ncharacterization of specimens.\nAcknowledgement\nAll authors have contributed significantly, and that all authors \nare in agreement with the content of the manuscript. We would like \nto thank Mrs. Sabita shah for her great contribution in editing the \nmanuscript.\nEthical Consideration\nConflict of interest: Authors declare that they have no conflict \nof interest.\nReferences\n1. Giudice LC (2010) Clinical practice. Endometriosis. The New England \njournal of medicine 362(25): 2389-2398.\n2. Klemmt PAB, Starzinski Powitz A (2018) Molecular and Cellular \nPathogenesis of Endometriosis. Current women’s health reviews 14(2): \n106-116.\n3. Giudice LC, Kao LC (2004) Endometriosis. Lancet 364(9447): 1789-\n1799.\n4. Koger KE, Shatney CH, Hodge K, Mc Clenathan JH (1993) Surgical scar \nendometrioma. Surgery, gynecology & obstetrics 177(3): 243-246.\n5. Macer ML, Taylor HS (2012) Endometriosis and infertility: a review of \nthe pathogenesis and treatment of endometriosis-associated infertility. \nObstetrics and gynecology clinics of North America 39(4): 535-549.\n6. 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(2018) Clinical \nevaluation and management of endometriosis: guideline for Korean \npatients from Korean Society of Endometriosis 61(5): 553-564.\nSubmission Link: https://biomedres.us/submit-manuscript.php\nAssets of Publishing with us\n• Global archiving of articles\n• Immediate, unrestricted online access\n• Rigorous Peer Review Process\n• Authors Retain Copyrights\n• Unique DOI for all articles\nhttps://biomedres.us/\nThis work is licensed under Creative\nCommons Attribution 4.0 License\nISSN: 2574-1241\nDOI: 10.26717/BJSTR.2020.31.005132\nSanjay Kumar Sah. Biomed J Sci & Tech Res","source_license":"CC0","license_restricted":false}