{"paper_id":"ea7c67b9-7195-49d6-9038-b566bf919781","body_text":"R E V I E W Open Access\nA review of the risk factors, genetics and\ntreatment of endometriosis in Chinese\nwomen: a comparative update\nYi Dai, Xiaoyan Li, Jinghua Shi and Jinhua Leng *\nAbstract\nEndometriosis is one of the major causes of economic burden and compromised quality of life in a very large\npercentage of Asian women. While it is perceived as a benign condition, recent research has shown that it may be\na significant cause of infertility and metastatic cancer. It has also been associated with other diseases linked to the\nfunctioning of the immune system. Genetic as well as environmental factors are known to affect the manifestation\nand progression of endometriosis. This review aims to summarize recent research pertaining to the risk factors,\ndiagnosis and treatment of endometriosis in Chinese women. It also provides an overview of identified genetic\nmutations and polymorphisms and their effects on the risk of developing endometriosis in the Chinese population.\nA comparison has been drawn between Asian and European-American female populations and the differences in\nrisk factors and treatment responses have been summarized. Since traditional Chinese medicine (TCM) is often used\nto treat endometriosis, wherever possible, a comparison between efficacies of Western medicine and TCM in the\nChinese population has also been provided. Although much progress has been made in the treatment and\nresolution of endometriosis, several gaps remain and this review also highlights possible areas of future research\nand advancement that can result in an improvement in patient outcomes and quality of life.\nKeywords: Endometriosis, Chinese, Risk factors, Mutations, Treatment\nPlain English summary\nEndometriosis is a disorder inwhich the stromal or glandu-\nlar tissue that normally lines the inside of the uterus grows\nin a location outside of the uterus. About 10 –15% of\nwomen in their reproductive years are affected worldwide.\nAlthough the cause of endometriosis remains unclear, gen-\netic and environmental factors are considered as risk fac-\ntors for manifestation and progression of endometriosis.\nThis study aims to summarize recent research pertaining to\nthe risk factors, diagnosis and treatment of endometriosis\nin Chinese women. Women with endometriosis generally\nsuffer from severe pain and other debilitating consequences\nwhich results in a compromised quality of life. Endometri-\nosis also has a major effect on the child-bearing ability of\nwomen. Studies show that though several strategies for the\nmanagement of affected patients have been developed,\ncomplete cure is not yet possib le. Endometriosis treatment\ngenerally involves medicationsor surgery. Traditional Chin-\nese medicine (TCM) that is often used for infertility treat-\nment has shown successful results in controlling the\nrecurrence of endometriosis following surgery thereby pro-\nviding symptomatic pain relief and improving Health Re-\nlated Quality of Life. Though several treatment regimens\nare available for the management of patients with endomet-\nrial lesions, alternative strategies are used in China. In con-\nclusion, although Western medicine has been studied and\nvalidated more extensively for the treatment of endometri-\nosis, both TCM and Western medicine are used equally in\nthe treatment of endometriosis in Chinese women.\nBackground\nEndometriosis is an estrogen-responsive, chronic condi-\ntion that arises from the extra-uterine growth of the\nstromal or glandular tissue that lines the uterus [ 1].\nWorldwide, it represents a significant cause of morbidity\nin about 10-15% of women in their reproductive years\n[2]. Although significant efforts have been made to\n* Correspondence: jinhualeng1@gmail.com\nDepartment of Obstetrics and Gynecology, Peking Union Medical College\nHospital, 1# Shuaifuyuan, Dongcheng District, Beijing 100730, China\n© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0\nInternational License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and\nreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to\nthe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver\n(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.\nDai et al. Reproductive Health  (2018) 15:82 \nhttps://doi.org/10.1186/s12978-018-0506-7\n\nenhance detection and subsequently treat endometriosis,\ndiagnosis in the majority of women is delayed on average\nby 10 years globally [ 3] and by 13 years in China [ 4].\nIdentification of risk factors is integral to diagnose endo-\nmetriosis. Moreover, early diagnosis is essential to effect-\nively treat endometriosis. This review delineates the risk\nfactors and genetic differences among Chinese women\nsuffering from endometriosis and also updates the reader\nabout the treatment of endometriosis in China.\nEndometriosis: Pathophysiology and risk factors\nThe risk of endometriosis has been linked to ethnicity and\nseveral studies have reported a nine-fold increase in risk in\nAsian women when compared to the European-American\nwhite female population [5–7].\nIt is well known that endometriosis, despite having a\nstrong genetic predisposition, is also affected by environ-\nmental exposures. Both these factors have a bearing on\nthe difference in the risk of disease occurrence observed\nbased on parameters such as race and ethnicity. While evi-\ndence for an association between genetic polymorphisms\nand risk of endometriosis is robust [ 8–11], evidence link-\ning environmental factors to endometriosis risk is some-\nwhat weaker. Environmental factors such as elevated\nlevels of phthalate esters, persistent organochlorine pollut-\nants, perfluorochemicals, and intra-uterine exposure to\ncigarette smoke among others can cause endometriosis by\ninducing oxidative stress, altering hormonal homeostasis,\nor by changing immune responses. However, further stud-\nies in different populations are required in order to meas-\nure the extent of this association [ 12–16]. Other risk\nfactors, such as the presence of lower genital tract infec-\ntions, have also been proposed as a possible cause of in-\ncreased risk [17].\nThe origin and pathophysiology of endometriosis re-\nmains incompletely understood and several hypotheses\nthat seek to explain its development and progression have\nbeen proposed (Fig. 1). The most well accepted model is\nthat of retrograde menstruation (where endometrial cells\nare refluxed through the fallopian tubes and implanted\nonto the pelvic or peritoneal organs) accompanied by the\navoidance of anoikis, wherein cells of endometrial origin\nable to survive outside the uterus have an imbalance be-\ntween pro and anti-apoptotic factors [ 18, 19]. It has been\nreported that CD147 is one such anti-apoptotic factor and\nits overexpression has been shown to lead to the survival\nof human uterine epithelial cells outside the uterus [ 20].\nThe miRNA MiR-191 has also been shown to be involved\nand inhibits tumor necrosis factor- α induced apoptosis of\novarian endometriosis and endometrioid carcinoma cells\nby targeting Death-associated Protein Kinase 1 [ 21]. Cer-\ntain molecules such as fibroblast growth factor receptor 1\nhave also been shown to be overexpressed in ectopic ver-\nsus eutopic endometrium and in patients suffering from\nFig. 1 Overview of the proposed interplay between various factors reported in the pathogenesis of endometriosis. The different factors\nare denoted by the various shapes and the arrows indicate the interplay between them. Abbreviations: CD147 – Basigin or cluster of\ndifferentiation 147, MiR-191 – Micro RNA 191, TIMP3 – Tissue Inhibitor of Metalloproteinase 3, DAPK1 – Death-associated protein kinase 1,\nTNF-α – Tumor Necrosis Factor α\nDai et al. Reproductive Health  (2018) 15:82 Page 2 of 12\n\nendometriosis versus healthy controls. One study also\ndemonstrated an overexpression of fibroblast growth fac-\ntor receptor 1 in patients with post-surgery recurrence\n[22]. In addition, studies have also revealed the involve-\nment of miRNAs and siRNAs in disease pathology. In fact,\nthe process of endometriosis associated ovarian cancer is\nthought to involve miR-191. By down-regulating and low-\nering protein expression of tissue inhibitor of metallopro-\nteinases 3, which has a pro-apoptotic function, it is\nthought to induce the survival of ectopic endometrial\ncells. Interestingly, lower tissue inhibitor of metallopro-\nteinases 3 expression has also been associated with several\nother types of cancer [ 23].\nOther theories have also been put forward to explain\nthe origin of endometriosis. Non-uterine theories propose\nthe occurrence of coleomic metaplasia, a transdifferentia-\ntion of extrauterine tissue to ectopic endometrial tissue,\nprobably due to endocrine disrupting chemicals or other\nhormonal factors [ 24]. A recently proposed theory sug-\ngests that bone marrow-derived stem cells can cause\nendometriosis. This occurs due to increased binding of\nthe stem cell chemokine CXCR4 with its ligand CXCL12,\nwhich increases matrix metalloproteinase expression and\nsubsequent extracellular matrix protein degradation, lead-\ning to metastasis. Furthermore, CXCR4-CXCL12 binding\npromotes angiogenesis through increased vascular endo-\nthelial growth factor expression [25].\nSymptomatically, endometriosis is characterized by in-\nflammation and involvement of different immune system\ncomponents. Lesions may be divided into three main\ntypes, viz., peritoneal, ovarian, and deep infiltrating\nendometriosis, depending on their location within the\nbody. Several pelvic and peritoneal organs may be in-\nvolved, and although the involvement of the urinary\ntract and kidneys are rare, a single study has reported\nthe presence of endometriosis of the renal parenchyma\nin a Chinese woman [ 26].\nIn general, a large degree of variation in disease severity\nexists amongst patients who suffer from this condition. It\nhas also been found that an increase in the number of\nendometrial lesions does not always correlate with the se-\nverity of symptoms, suggesting that endometriosis is a\nmultifaceted condition that is governed by several aspects\nof patient physiology. Based on global standards, disease is\nclassified as Stage I-IV based on revised criteria pertaining\nto extent and severity specified by the American Society\nof Reproductive Medicine (rASRM), also known as the re-\nvised American Fertility Society criteria. However, this\nmethod was not robust enough to predict post-surgery\npregnancy outcome [ 27]. To counter rASRM ’ss h o r t c o m -\ning, a new staging system called the Endometriosis Fertil-\nity Index (EFI) was developed. EFI evaluated age, duration\nof infertility, pregnancy history, extent of endometriosis,\nand the least-function score to predict pregnancy outcome\nafter surgery [ 28]. The Chinese Medical Association\n(CMA) recommends utilizing EFI to assess outcomes in\nendometriosis patients [29].\nWomen with endometriosis generally suffer from se-\nvere pain and other debilitating consequences such as\ndysmenorrhea, chronic pelvic pain, dyspareunia, and ex-\ngenital symptoms such as dyschezia, dysuria, hematuria,\nand rectal bleeding resulting in a compromised quality\nof life (QoL) [ 30, 31]. Another major effect of harboring\nthis condition is infertility and 30 –50% of the women af-\nfected by endometriosis have compromised child-\nbearing ability [ 32]. A recent systematic review analyzing\nthe outcomes of more than 1.9 million women found\nendometriosis to be associated with worsening of obstet-\nric and pregnancy related outcomes such as miscarriage,\npre-term labor, placenta previa, small for gestational age,\nand cesarean delivery as compared with healthy controls\n[33]. A Chinese study also reported similar results [ 34].\nApart from these consequences, there is also an in-\ncreased risk of diseases such as cancer (especially ovar-\nian) [ 35–37] and auto-immune diseases. Studies have\nalso shown that tumors from Chinese ovarian cancer pa-\ntients with pre-existing endometriosis have distinct\nclinico-pathological features, such as a predisposition for\novarian clear cell carcinoma, when compared to the nor-\nmal Chinese population [ 38].\nIn general, the consequences of endometriosis are\noften under-reported and underestimated [ 39] and the\ndisease represents a significant burden, both economic\nand qualitative [ 40]. Although several strategies for the\nmanagement of affected patients have been developed,\ncomplete cure is not yet possible. Even after treatment\nwith current therapeutic regimens including surgical\nintervention, endometriosis remains a frequently recur-\nring disease. The following sections of this review seek\nto summarize the state of the art in the diagnosis and\ntreatment of this disease, and wherever possible, to draw\na comparison between strategies used in China with\nthose deployed in the Western world for the effective\nresolution of disease and management of patients.\nGenetic basis of endometriosis in Chinese women\nMutations and polymorphisms in several genes have\nbeen implicated in the pathophysiological process that\nresults in endometriosis. These genes belong to diverse\ngroups, both functionally as well as spatially. However, a\nstrong association has been detected between single nu-\ncleotide polymorphisms (SNPs) in hormone receptor\nand metabolism related genes and endometriosis in Tai-\nwanese Chinese Women [ 41]. A study in Taiwanese\nwomen also showed that MUC17 polymorphisms are in-\nvolved in endometriosis development and associated in-\nfertility [ 11]. In addition, by comparing the mutational\nlandscape between normal women and Chinese\nDai et al. Reproductive Health  (2018) 15:82 Page 3 of 12\n\nendometriosis patients, a recent whole exome sequen-\ncing study implicated genes involved in biological adhe-\nsion, cell-cell junctions, and chromatin-remodeling\ncomplexes in the development of endometriosis [ 42].\nMuch research based on genetic factors that influence\nendometriosis has focused on Han Chinese women,\nsince a relatively higher rate of disease prevalence has\nbeen detected in this population. In addition, genome\nwide association studies found that polymorphisms in\nrs12700667 located within the intergenic region of 7p15.\n2 are also associated with an elevated risk of ovarian\nendometriosis in North Chinese women [ 43]. Although\nseveral studies have detected differences in genetic mu-\ntations that predispose Asian and Western populations\nto endometriosis, a recent genome wide association\nmeta-analysis revealed a significant overlap in loci linked\nwith endometriosis risk in Japanese and European popu-\nlations [ 44].\nMutation association studies conducted in different\npopulations in order to link genetic mutations to risk of\nendometriosis presents a very strong body of evidence\nsupported by a large number of meta-analyses. Some of\nthese associations related to Chinese and Asian popula-\ntions have been summarized in Table 1.\nCurrent techniques for diagnosis and biomarkers of\nendometriosis\nImaging techniques such as color Doppler ultrasounds and\nCT/ MRI scans are recommended for the initial diagnosis\nof endometriosis by the CMA, although MRI primarily vi-\nsualizes ovarian and not peritoneal endometriosis [ 39].\nHowever, due to the necessity for a histological verification\nof the presence of endometrial glands/stroma combined\nwith a laparoscopy (which is regarded as the current gold\nstandard for the confirmation of the presence of endomet-\nrial lesions) and also due to several cases of misdiagnosis,\nan accurate identification of endometriosis occurs after an\naverage of 6 years following initial onset [ 29, 45]. In con-\njunction with a laparoscopic diagnosis of endometriosis, a\nscoring system is generally used for the assessment of se-\nv e r i t yo fd i s e a s e .T h em o s tc o m m o n l yu s e do n ei st h er e -\nvised American Fertility Soci ety scoring system for the\nextent and severity of ectopic endometrial adhesions. The\nCMA guidelines also use the Endometriosis Fertility Index\n(EFI) scoring system in order to assess patient fertility re-\nlated parameters.\nThe technique of laparoscopy, however, has several draw-\nbacks of which its invasive nature and reliance on the skill\nof the surgeon for an accurate visual inspection of the pel-\nv i cc a v i t yr e p r e s e n t i n gt h em a j o ri s s u e s .I na d d i t i o n ,i ti s\nnot always capable of detecting deep infiltrating lesions,\nresulting in several undiagnosed cases. However, efforts are\nbeing made in order to devise non-invasive methods for the\ndiagnosis of endometriosis and certain studies have\ndemonstrated an association between elevated serum levels\nof CA125 in endometriosis pa tients, suggesting that they\nmay be used as biomarkers during the diagnostic process in\nboth, Asian as well as European-American populations\n[46]. Another study has also demonstrated the superiority\nof CA125 over the platelet-lymphocyte ratio in the diagno-\nsis of moderate to severe end ometriosis in Chinese women\n[47]. However, CA125 levels cannot be used as a diagnostic\nbiomarker in isolation due to a low sensitivity and specifi-\ncity for endometrial lesions. One of the major concerns of\nthe use of CA-125 as a biomarker is that elevated serum\nlevels have been detected in other gynecological pathologies\nas well. However, CMA guidelines indicate that CA-125\nelevation may be useful for the detection of advanced stage\nendometriosis, endometriosis combined with adenomyosis\nor obvious pelvic inflammation, and also in the diagnosis of\nendometrioma rupture [48, 49].\nSeveral other strategies are being developed and panels\nthat detect levels of inflammatory and non-inflammatory\nmarkers are still not very specific for endometrial lesions\n[50, 51]. Amongst inflammatory markers a systematic re-\nview identified IL-8 as the best studied, with MCP-1 and\nCCL5 coming a close second [ 50]. Another strategy for\nnon-invasive diagnosis of disease is the use of miRNA\npanels. A prospective study has also shown that the\nurine of affected patients had a distinct peptide pattern\nthat can be developed into an assay for diagnosis [ 52].\nDespite these advances, recent Cochrane reviews have\nconcluded that none of the currently available techniques,\nwhether lab-developed or already existing commercial\nplatforms, are suitable for use as a replacement for lapar-\noscopy or even as a diagnostic triage test [ 53, 54]. Thus,\nmore emphasis on targeting endometriosis-specific\nmarkers for diagnostic purposes is required in order to de-\nvelop a non-invasive diagnostic testing platform for accur-\nate and non-invasive identification of disease.\nCurrent strategies for the management of endometriosis\nin China and worldwide\nSince endometriosis is associated with debilitating pain and\na very high risk of infertility, most treatments aim to allevi-\nate symptoms of the disease such as dysmenorrhea and\ndyspareunia while simultan eously improving pregnancy\nand fertility outcomes. Thus, the use of combinatorial regi-\nmens is common, and often, surgical excision or ablation of\nlesions using laparoscopy is often done in order to reduce\nlarge ectopic endometrial masses. However, based on rec-\nommendations by international guidelines, decisions re-\ngarding the timing and aptness of surgical intervention are\ngenerally guided by patient preferences, disease severity and\nfertility goals. Surgical removal is generally followed by\nGnRHa or oral contraceptives in order to prevent disease\nrecurrence and to provide symptomatic relief. Clinical\nguidelines published by the Obstetrics and Gynecology\nDai et al. Reproductive Health  (2018) 15:82 Page 4 of 12\n\nTable 1 Genetic Mutations and Polymorphisms and their impact on the risk of Endometriosis and Infertility in Chinese women\nGene/ Protein Name Protein Function Mutation/\nPolymorphism\nRisk of Endometriosis/Infertility Population References\nESR 1 Estrogen receptor\nalpha\nHormone Receptor (TA)n Short Increased/Un-reported Mixed Wang et al., 2013 [ 86]\n(TA)n Long Decreased/Unreported Mixed Wang et al., 2013 [ 86]\nrs3798573 A/G Increased/Increased Han Chinese Wang et al., 2013 [ 86]\nESR 2 Estrogen receptor\nbeta\nHormone Receptor rs4986938 and\nrs1256049\npolymorphisms\nNo significant association detected/\nUnreported\nAsian and\nEuropean-\nAmerican\nGuo et al., 2014 [ 87]\nPR Progesterone Receptor Hormone Receptor rs104283 CT SNP Increased/Un-reported Southern Han\nChinese\nMao et al., 2015 [ 88]\nGST Glutathione-S-\ntransferases M1/T1\nMetabolic Enzyme Null genotype Increased/ Unreported Chinese Chen et al., 2015 [ 9];\nZhu et al., 2014 [ 89]\nGALT Galactose-1-\nphosphate uridyl transferase\nMetabolic Enzyme Q188R and N314D No significant association detected/\nUnreported\nChinese He et al., 2006 [ 90]\nBDNF Human brain-derived\nneurotrophic factor\nTropic factor Val66Met\npolymorphism\nIncreased/Increased Han Chinese Zhang et al.,2012 [ 91]\nFGF2 Fibroblast Growth\nFactor 2\nGrowth factor 754C/G polymorphism Increased/Un-reported North Chinese Kang et al., 2012 [ 92]\nVEGF Vascular endothelial\ngrowth factor\nGrowth factor +405G > C No significant association detected/\nUnreported\nAsian and\nEuropean-\nAmerican\nFang et al., 2015 [ 93]\n-1154A Decreased/Unreported North Chinese Liu et al., 2009 [ 94]\n-2578A Decreased/Unreported North Chinese Liu et al., 2009 [ 94]\nVEGFR-2 Vascular\nendothelial growth factor\nreceptor 2)\nGrowth factor\nreceptor\n1192C/T + T/T Decreased Han Chinese Kang et al., 2013 [ 95]\n1192C/C Increased\nTP53 Tumor suppressor codon 72\npolymorphism Pro/Pro\nand Arg/Pro\nIncreased Chinese and\nAsian\nChang et al., 2002\n[96]; Jia et al., 2012\n[97]\nMMP-2 Matrix\nmetalloproteinase-2\n1306C– > T and -735C –\n>T\nIncreased/Unreported North Chinese Kang et al., 2008 [ 98]\nTIMP-2 Tissue inhibitor of\nmetalloproteinase-2\n418G– > C Decreased/Unreported North Chinese Kang et al., 2008 [ 98]\nE-Cadherin Cell Adhesion\nMolecule\nrs8049282 SNP Increased/Increased Northern\nChinese\nKang et al., 2014 [ 99]\nCOX-2 Cyclo-oxygenase 2 Inflammatory\npathway Enzyme\nGt oAa t − 1195\n(promoter)\nIncreased/ Unreported Chinese Wang et al., 2015\n[100]\nICAM-1 Intercellular\nAdhesion Molecule 1\nCell Adhesion\nMolecule\nK469E polymorphism Further decreased in Asian populations\ncompared to European-Americans/\nUnreported\nAsian and\nEuropean-\nAmerican\nPabalan et al., 2015\n[101]\nCYP19 Aromatase\nEnzyme\nrs700518AA No significant association detected/\nIncreased upon pre-existing endometriosis\nChinese Wang et al., 2014\n[102]\nFCRL3 rs7528684 Unreported/ Increased upon pre-existing\nendometriosis\nHan Chinese Zhang et al., 2015\n[103]\nIL-16 Interleukin 16 Cytokine rs4778889 T/C\npolymorphism\nIncreased/ Unreported Chinese Gan et al., 2010 [ 104]\nFSHR Follicle Stimulating\nHormone Receptor\nHormone receptor SNP: 680Ser/Ser and\n680Ser/Asn\nDecreased/Unreported Taiwanese\nChinese\nWang et al., 2011\n[105]\nXRCC4 X-ray repair cross-\ncomplementing group 4\nDNA repair gene codon 247*A Increased/Unreported Taiwanese\nChinese\nHsieh et al.,2008\n[106]promoter-1394*T Increased/Unreported\nIntron 3 I/D\npolymorphism\nNo significant association detected/\nUnreported\nFOXP3 Transcription\nfactor\nrs2280883 No significant association detected/\nUnreported\nHan Chinese Wu et al., 2013 [ 107]\nrs3761548\nrs3761549\nDai et al. Reproductive Health  (2018) 15:82 Page 5 of 12\n\nbranch of the CMA recommend specific treatment strat-\negies based on presenting symptoms (i.e., only pain or pain\nwith infertility) [ 29]. A flowchart outlining the diagnostic\nand treatment process for these two different types of pa-\ntient populations in China are shown in Fig.2 [29].\nThe following sub-sections of this review focus on the\ndifferent types of treatment recommended for endomet-\nriosis and their advantages and drawbacks.\nSurgical treatment\nThe goal of surgical treatment for endometriosis is to en-\nable lesion resection, alleviate symptoms and improve fertil-\nity outcomes while simultan eously preserving internal\nanatomy. The decision of which type of surgery to under-\ntake depends on the extent of endometriosis related pain\nand the fertility goals of the patient. Different types of surgi-\ncal interventions can be used for the treatment of endomet-\nrial pain. However, such treatment is only recommended\nafter the diagnosis of endometriosis has been histologically\nconfirmed (after performing a laparoscopic examination).\nA large body of clinical evidence supports the use of sur-\ngical laparoscopy to remove extraneous endometrial le-\nsions. While guidelines recommend the use of ablation and\nsurgical excision for the treatment of endometrial pain,\nsuch treatment is not recommended for advanced forms of\nthe disease. Clinical guidelines also separate the type of sur-\ngical treatment to be used depending on whether ovarian\nendometriosis is detected. In general, the European Society\nof Human Reproduction and Embryology (ESHRE) guide-\nlines recommend the use of cystectomy over drainage and\ncoagulation and CO 2 ablation in women with ovarian\nendometrioma [ 55]. The CMA specifically recommends\nlaparoscopic surgery for cases in which endometriosis is ac-\ncompanied by infertility and where large ovarian cysts (>\n4 cm) are detected. In case of deep endometrial lesions, the\nCMA as well as ESHRE guidelines recommend surgical re-\nsection, with a caveat on the high complication rates arising\nfrom such treatment. In women who do not have fertility\ngoals and fail to respond to conservative treatments, a hys-\nterectomy is recommended by both sets of guidelines. In\naddition, surgical resection of nerve pathways by pre-sacral\nneurectomy is only recommended as an add on to conser-\nvative treatment, although this requires a very high degree\nof skill [29, 55].\nMedical treatment\nSeveral types of therapies have been recommended for the\ntreatment of endometriosis by different clinical guidelines\n(depending on the presenting symptoms of the patient and\nthe nature and extent of lesions), such as Non-Steroidal\nAnti-Inflammatory Drugs, oral contraceptives, progestins\nand GnRH-agonists. Guidelines also recommend the empir-\nical treatment of endometriosis based on presenting symp-\ntoms only, without the need for a laparoscopic confirmation\nof diagnosis. In this regard, both the ESHRE and rASRM\nguidelines do not distinguish between first and second line\nFig. 2 Diagnostic and treatment process for endometriosis patients in China. (EFI: Endometriosis Fert ility Index). Adapted from CMA\nguidelines, 2015\nDai et al. Reproductive Health  (2018) 15:82 Page 6 of 12\n\ntreatment and recommend the use of NSAIDS, progestins\n(such as dienogest and danzol), oral contraceptives and\nGnRH agonists. The World Endometriosis Society (WES)\nguidelines recommend the use of NSAIDs, continuous oral\ncontraceptives and progestins as first line treatment while\nGnRH agonists and the levonorgestrel intrauterine system\n(LNG-IUS) system are recommended as second line treat-\nment. CMA guidelines indicate the use of empirical treat-\nment in those cases where there is no obvious pelvic mass\nor infertility and first and second line treatment in these\ncases is aligned with the recommendations by the WES.\nThe use of second line treatment is recommended after first\nline treatment has proved ineffective. In addition, the CMA\nrecommends that surgery should be considered when sec-\nond line treatment also fails. Effectiveness of each line of\ntreatment can be checked using standard diagnostic proce-\ndures mentioned earlier.\nWhile the treatment duration of NSAIDS has not been\nexplicitly mentioned, the CMA recommends using oral\ncontraceptives for 6 months or longer, progestins for\n6 months, and GnRH agonists for 3 to 6 months or longer\n[29]. However, both the ESHRE and CMA recommend\nthe continuous use of hormonal treatment post-surgery\nfor the prevention of recurrence and previous studies have\nalso shown that the discontinuation of hormonal therapy\npost-surgery leads to a higher rate of recurrence [ 56]. Spe-\ncifically, the rASRM recommends the use of aromatase in-\nhibitors, danazol, the LNG-IUS and medroxyprogesterone\nacetate as post-operative medical treatment. After a lap-\naroscopic confirmation has been established, NSAIDs are\nrecommended as the first line of treatment if lesions are\nminor and not of the deep infiltrating type.\nIn case of major symptoms and large, deep infiltrating le-\nsions, hormonal therapy is recommended for use in com-\nbination with surgical excision by both, the CMA and\nESHRE guidelines [29, 45]. Hormonal therapy may be di-\nvided into two categories, based on molecular targets.\nBroadly, they are classified as those that affect estrogen me-\ntabolism and responsiveness and those that affect progester-\none responsiveness. A recent systematic review and meta-\nanalysis conducted to assess the efficacy of the use of oral\ncontraceptives after surgical excision of endometrial lesions\nconcluded that combinatorial treatment is more effective in\npreventing recurrence than surgery alone. However, from\ntheir analysis the authors reported that this advantage did\nnot extend to the improvement of pregnancy outcomes\n[57]. In a randomized, post-laparoscopic study of 280 Chin-\nese women with ovarian endometriosis, the authors com-\npared side effects and menopausal symptoms of leuprorelin\nand triptorelin (both GnRH antagonists) treatment. They\nreported that leuprorelin was milder than triptorelin, with a\ngradual reduction in hormone levels and fewer menopausal\nsymptoms [58]. In another study of Chinese endometriosis\npatients that evaluated the timing of GnRH agonist\nadministration (goserelin, 3.6 mg either 3 –5d a y sp o s t -\noperatively or on days 1–5 of menstruation) the authors re-\nported that although the efficacy of treatment was equal in\nwomen with stage III-IV endome triosis, uterine bleeding\nover the course of the 28 day menstrual cycle was reduced\nin the former group [59]. A new crosslinked hyaluronan gel\nwas also evaluated for its ability to reduce postoperative ad-\nhesions in a randomized study comprising of 215 Chinese\nwomen who underwent surgical laparoscopy for the initial\nremoval of existing endometrial lesions. The study found\nthat use of the gel decreased the number and severity of\npost-operative adnexal and abdominopelvic adhesions in\npatients, thus potentially reducing the incidence of disease\nrecurrence [ 60]. In this study, the authors propose that\nsince hyaluron has a sufficiently long elimination half -life\n(metabolic clearance is slowed down by its ability to cross-\nlink), it is able to persist within the body for the time win-\ndow during which new adhesions are formed.\nSince genetic factors linked to ethnicity are known to\naffect the risk of developing endometriosis, studies have\nattempted to address the question of whether genetic dif-\nferences extend to differences in responses to treatment.\nOne such meta-analysis evaluated responses to GnRH ag-\nonists and to the progestin dienogest in European versus\nJapanese populations. Although the authors reported no\ndifferences in response rates or HRQoL parameters in ei-\nther population and found both lines of treatment equally\nefficacious, dienogest treatment was found to be superior\nin terms of bone mineral density in both populations [ 61].\nSome clinical evidence for genetically influenced racial\ndisparity in endometrial cancer comes from a retrospect-\nive study which reported that African-American women\nexperienced lower recurrence-free survival after using es-\ntrogen replacement therapy, possibly due to differences in\nestrogen metabolism [62]. However, further studies are re-\nquired to understand the clinical implications of recently\ndiscovered racial differences, such as in microRNAs [ 63]\nand oncogene mutations [64].\nSeveral alternative strategies have been used in order\nto improve the quality of life in women undergoing hor-\nmonal treatment for endometriosis and to reduce side\neffects of the therapy itself. For example, techniques\nsuch as progressive muscular relaxation training have\nbeen used effectively in order to reduce anxiety and de-\npression in Chinese Han women receiving GnRH treat-\nment for endometriosis [ 65].\nIn general, guidelines by the CMA, ESHRE and the\nrASRM encourage treatment strategies which aim to re-\nduce and eliminate pain, recurrence and the use of mul-\ntiple surgeries.\nTraditional Chinese medicine (TCM)\nTCM is used in Chinese patients to control the recur-\nrence of endometriosis following surgery, provide\nDai et al. Reproductive Health  (2018) 15:82 Page 7 of 12\n\nsymptomatic pain relief, and improve Health Related\nQuality of Life (HRQoL). It is also often used to treat in-\nfertility. Some low-quality evidence from a Cochrane re-\nview showed Chinese herbal medicine to be superior to\ndanazol treatment for the alleviation of symptoms such\nas pain and dysmenorrhea [ 66]. TCM users were also\nless likely to require surgical treatment for endometriosis\nthan non-users [ 67]. Moreover, TCM was as effective as\nWestern medicine (WM) in controlling the recurrence\nof pelvic endometriosis and improving fertility outcomes\nafter conservative surgery [ 68], but better than WM at\nimproving HRQoL [ 69]. On the other hand, a single ran-\ndomized control trial demonstrated that TCM, and oral\ncontraceptives in combination with laparoscopy were\nboth non-superior to laparoscopy alone in the treatment\nof endometriosis [ 70]. Additionally, the underlying\nmechanisms of TCM remain unstudied. Furthermore, a\nmajor gap in knowledge is represented by the fact that\nChinese medicine has never been compared with a pla-\ncebo in the treatment of endometriosis symptoms, and\nhence, further research is required in order to confirm\nits effectiveness [ 66]. Thus, although Chinese medicine\nis often used for the management of endometriosis pa-\ntients, there is a lack of high quality clinical evidence\nthat supports its effectiveness in comparison with other\nmainstream treatment strategies.\nDue to the absence of rigorous clinical evidence that\nsupports the use of Traditional Chinese medicine for the\ntreatment of endometriosis, the Delphi process (which is\nused in order to synthesize expert opinion for alternative\nmedical interventions) was used in order to develop\nguidelines that govern the use of Chinese herbal medi-\ncine in the management of endometriosis patients [ 71].\nThis guideline informs practitioners about the different\nChinese herbs that are used most commonly for the\ntreatment of specific symptoms and outlines different\npatient management strategies based on an initial assess-\nment of traditional Chinese physiology and pathology.\nThus, although several treatments exist for the man-\nagement of patients with endometrial lesions, alternative\nstrategies are commonly used in China. Since such strat-\negies have not been adequately evaluated, further re-\nsearch that addresses this issue is required in order to\nimprove patient outcomes, both in terms of fertility as\nwell as quality of life.\nTreatment of infertility\nSince approximately 30% –50% of women suffering from\nendometriosis are infertile [32], its treatment constitutes a\nlarge part of the disease management plan. Previous work\nhas established that the effectiveness of fertility treatment is\ninversely proportional to the severity of disease and that fer-\ntility outcomes in response to treatment are better in\nwomen with milder forms of endometriosis [72, 73]. This is\nprobably due to poor ovarian reserve and oocyte quality\nand lower rates of implantation in women with stage III-IV\nendometriosis. Thus, the use of expectant management is\nan option only for women with less severe forms of endo-\nmetriosis, and even then, guidelines recommend the use of\ncontrolled ovarian stimulation along with intra-uterine in-\nsemination for the improvement of fertility outcomes.\nHowever, those with infertility and advanced stage disease\nmust receive effective treatment in order to improve fe-\ncundity. In general, medically assisted reproduction tech-\nniques such as ovulation induc tion and stimulation, intra-\nuterine insemination and other assisted reproduction tech-\nniques such as in-vitro fertilization (IVF) are recommended\nby most international guidelines including the CMA for the\ntreatment of endometriosis associated infertility. In general,\nIVF is known to be highly effective in such cases and a\nmeta-analysis by Barnhart et al., showed that the presence\nof endometriosis affected the f ertility outcomes in patients\nreceiving IVF only in cases of severe disease [74].\nWhile medical treatments such as NSAIDS, oral\ncontraceptives, progestins, and GnRH analogues are\nuseful for the management of endometrial symptoms\nsuch as dyspareunia and dysm enorrhea, recent litera-\nture provides no evidence of their effectiveness for\ntreating endometriosis related infertility in patients\nw h od e s i r eal i v eb i r t h .H o w e v e r ,b o t hG n R H aa n d\noral contraceptives have been shown to improve out-\ncomes in patients using IVF and assisted reproduction\ntechniques [ 75].\nSurgical treatment of endometriosis is an option for\ncases where mild to moderate disease is present as well\nas in cases where severe disease is detected along with\npoor fertility outcomes. However, the goal of surgery in\nthese cases is to limit the extent of ovarian resection.\nCumulative evidence has shown that laparoscopic sur-\ngery (by excision as well as ablation) is highly effective\nand significantly improves fertility outcomes in patients\nwith minimal to moderate endometriosis already using\nMedically Assisted Reproduction (MAR) [ 76]. However,\nalthough evidence for its use in combination with other\nMAR techniques in severe cases is lacking; an individu-\nalized decision based on specific patient characteristics\nis recommended by all guidelines.\nFertility outcomes using combinatorial therapy were\nalso evaluated in a retrospective study of 138 Chinese\nwomen. The authors concluded that GnRH agonists\ncombined with the transvaginal ultrasound-guided cyst\naspiration procedure results in improved therapeutic ef-\nfects and pregnancy outcomes in infertile patients with\novarian endometriosis who underwent IVF-ET [ 77]. This\nrepresents a significant advancement, since the use of\ntransvaginal ultrasound-guided cyst aspiration alone has\nbeen found to result in a very high rate of disease recur-\nrence [ 78]. However, since these results are from a single\nDai et al. Reproductive Health  (2018) 15:82 Page 8 of 12\n\nstudy, current guidelines do not recommend this com-\nbination for the improvement of pregnancy outcomes.\nAnother study in a group of 168 Chinese women with\nStage III-IV endometriosis demonstrated that 2-month\ntreatment with a GnRH agonist prior to IVF tended to\nincrease the implantation rate, showing that the timing\nand duration of GnRH agonist therapy can also affect\nfertility outcomes [ 79]. However, current guidelines only\nrecommend the use of GnRH agonists for the improve-\nment of fertility outcomes in patients with severe disease\n(stage III-IV endometriosis based on rASRM classifica-\ntion) when used in combination with other surgical or\nMAR procedures [ 55].\nIt is believed that endometriosis occurs due to blood\nstasis which has manifested due to kidney Yang defi-\nciency, liver Qi stagnation, or cold [ 80]. By targeting\nblood stasis, TCM aims to treat endometriosis and in-\ncrease fertility. Indeed, a recent meta-analysis which\ncompared TCM with WM found the former to improve\npregnancy rates by almost 2-fold within 3 –6 months of\ntreatment initiation [ 80]. This mechanism treats\nendometriosis-related symptoms too. In endometriosis\naffected patients, the reduction in pain and adnexal mass\nwith TCM was more than with danazol, but comparable\nwith gestrinone. Compared with WM, a significant in-\ncrease in pregnancy rate with TCM after laparoscopy\n(61.3% vs 45.5%, P < 0.05) [ 81], but not without (52.5%\nvs 37.5%, P = 0.265) was reported [ 82]. However, both\nthe studies reported that TCM increases negative con-\nversion of endometrial antibody significantly.\nEvaluation of HRQoL and clinical guidelines for the\nmanagement of Chinese women with endometriosis\nSince women with endometriosis are known to suffer\nfrom a significant deterioration in quality of life and fer-\ntility outcomes, HRQoL assessment is important during\nthe clinical evaluation of treatment efficacy in endomet-\nriosis patients. Although generic Visual Analog Scales\nsuch as Short-Form 36 or Short-Form 12 and EuroQoL\nmay be used to evaluate the efficacy of treatments in\nterms of HRQoL, several specific questionnaires that\nfocus on different endometriosis-related QoL parameters\nsuch as self-image, relationship with children, effect on\nwork life, and productivity have been developed. For ex-\nample, the Endometriosis Health Profile-30 question-\nnaire which has been translated into Chinese [ 83, 84]\nand the much shorter Endometriosis Health Profile-5\nquestionnaire are commonly used for such assessments.\nIn a study of 336 Chinese women, the authors found\nthat the translated Endometriosis Health Profile-30\nquestionnaire was internally consistent and valid for use\nas an effective scale for the assessment of HRQoL in\nChinese women [ 83].\nSeveral international societies and organizations exist\nthat regularly publish guidelines and updates for the\nmanagement of endometriosis in patients. Among these,\nguidelines by the International Society for Gynecologic\nEndoscopy, the American Association of Gynecologic\nLaparoscopists, the European Society for Gynecological\nEndoscopy and the Australian Gynecological Endoscopy\nand Surgical Society are widely consulted. The ESHRE\nguidelines represent standardized clinical guidelines for\nthe management of endometriosis worldwide [ 45, 55]. In\ngeneral, the recommendations of the CMA are in line\nwith international guidelines and discuss and propose\ndifferent patient management strategies, as summarized\nin the above sections of this article.\nRecently, the WES derived a set of consensus guide-\nlines for the management of patients with endometriosis.\nThis consensus statement was drafted after consultation\nwith an international panel of experts and is the first\nguideline that represents the views of women affected by\nendometriosis themselves [ 85]. Of particular interest is\nthe fact that these guidelines address the issue of patient\nmanagement in under-studied groups such as adoles-\ncents and post-menopausal women. They also propose\nmodels for the management of disease in low resource\nsettings, which is a significant concern in large and de-\nveloping economies like China.\nConclusions\nIn conclusion, although WM has been studied and\nvalidated more extensively for the treatment of endo-\nmetriosis, TCM and WM are both used equally in the\ntreatment of endometriosis in Chinese women. In\naddition, although guidelines recommend the use of\ndifferent disease management strategies based on the\nextent and severity of endometrial lesions, long-term\nmedical management is highly recommended in order\nto prevent exacerbation and recurrence. Guidelines by\nt h eC M Aa r ea l i g n e dw i t ht h o s eb yt h eW E Sa n d\nESHRE and in general, medical management is rec-\nommended over surgical treatment. More research is\nrequired on non-invasive diagnostic methods in order\nto accurately detect the presence of disease before a\nlaparoscopy and to enable individualized treatment of\npatients while improving patient outcomes. While\nextensive studies have been conducted on the genetic\nbasis of endometriosis in the female Chinese popula-\ntion, a clear association between the presence of\nmutations and polymorphisms and the clinical mani-\nfestation of disease has not been made. In addition,\ndata regarding the underlying mechanisms involved\nare also limited and an extensive study of these fac-\ntors is likely to allow clinicians to better manage the\naffected population.\nDai et al. Reproductive Health  (2018) 15:82 Page 9 of 12\n\nAbbreviations\nCMA: Chinese Medical Association; EFI: Endometriosis Fertility Index;\nESHRE: European Society of Human Reproduction and Embryology;\nGnRHa: Gonadotropin-releasing hormone agonist; HRQoL: Health Related\nQuality of Life; IVF: In-vitro fertilization; LNG-IUS: Levonorgestrel intrauterine\nsystem; MAR: Medically assisted reproduction; QOL: Quality of life;\nrASRM: American Society of Reproductive Medicine; SNP: Single nucleotide\npolymorphisms; TCM: Traditional Chinese medicine; WES: World\nEndometriosis Society; WM: Western Medicine\nAcknowledgements\nThe authors acknowledge Dr. Kripa Madnani (PhD), Leo J. Philip Tharappel,\nand Dr. Amit Bhat (PhD) from Indegene Pvt. Ltd. for their medical writing\nassistance and critical evaluation of the supporting literature (funded by\nBayer AG) while drafting this review article.\nAvailability of data and materials\nData sharing not applicable to this article as no datasets were generated or\nanalyzed during the current work.\nAuthors’ contributions\nAll authors have contributed equally in the development of this manuscript.\nAll authors read and approved the final manuscript.\nEthics approval and consent to participate\nNot applicable.\nCompeting interests\nThe authors declare that they have no competing interests.\nPublisher’sN o t e\nSpringer Nature remains neutral with regard to jurisdictional claims in\npublished maps and institutional affiliations.\nReceived: 24 October 2017 Accepted: 11 April 2018\nReferences\n1. Vercellini P, Vigano P, Somigliana E, Fedele L. Endometriosis: pathogenesis\nand treatment. Nat Rev Endocrinol. 2014;10:261 –75.\n2. Giudice LC, Kao LC. Endometriosis. 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