{"paper_id":"09226edc-a1ff-4d8d-96fc-8309106af5ce","body_text":"Endometriosis is a disease characterized by the presence of ectopic endometrial tissue outside the uterine cavity, with clinical presentations of dysmenorrhea, dyspareunia, dyschezia, and sometimes diarrhea.[ 1 2 ] Endometriosis is an estrogen-dependent disease strongly influenced by the cyclic change of steroid hormones and it causes inflammatory conditions in the pelvic cavity[ 3 4 ] and may present with subfertility, ongoing pelvic pain, and/or pelvic mass despite treatment with oral contraceptives and analgesics.[ 5 6 7 8 ] While the incidence of malignant change was rare,[ 9 10 ] endometriosis remains an important cause of morbidity impeding quality of life in women of reproductive age.[ 11 ] Although the exact etiology and pathogenesis of endometriosis are unclear,[ 12 ] environmental and genetic factors which induce complex immunological interactions within the pelvic cavity have been implicated in the disease.[ 13 ]\nIn the Western populations, endometriosis is estimated to occur in 5% to 10% of the population; however, the prevalence of endometriosis is suspected to be higher in Asian women, affecting approximately 15% of women.[ 5 14 15 ] Indeed, compared to women in the United States of America, women from Southeast Asia and Japan have a higher prevalence of endometriosis although this may be confounded by socioeconomic status, and the fact that the studies upon which these estimates were based were of poor quality and in some cases were over 40 years old.[ 11 ] Despite this, the suggestion that prevalence rates might be higher in Asian populations and the fact that these populations are numerically significantly larger than elsewhere implies that endometriosis is a significantly larger problem for Asian countries than elsewhere in the world. Furthermore, given the plethora of ethnic variations that exist among Asian populations, the epidemiological data and trends from Western countries may not always be relevant to populations in Asia. Combined, this suggested that an updated approach to determining the epidemiology of endometriosis in Asian populations is required.\nUnderstanding the epidemiology and risk factors for endometriosis in the Asian context is important to guide patient care. This includes both the diagnosis and treatment of this debilitating condition. As the clinical impact of the lifestyle and environmental factors on the development of endometriosis is a frequently asked question by the patients and the researchers, the objective of this review was to describe the epidemiology, including the associated inherited, lifestyle, and/or environmental factors with the incidence of endometriosis in the East Asian populations.\n\nWe undertook a search of English literature from Medline, PubMed, and the Cochrane Library (including the Cochrane Database of Systematic Reviews) for all articles relate to human endometriosis published between January 2000 and December 2016. The MeSH terms included all subheadings, and keywords included \"endometriosis risk,\" \"endometriosis association,\" \"endometriosis epidemiology,\" \"endometriosis gene,\" and \"endometriosis environment.\" All published works were included from the electronic database searches and cross-references pick-up was also performed during the review search if the article was not initially found. Each article was assessed on the abstract for its relevance and only those focusing on epidemiologic information, such as prevalence, incidence, and correlating risk factors, were included. Adenomyosis, which is the endometriotic disorder of the uterus,[ 16 17 18 ] was not included in this review as it is a disease different from the peritoneal or ovarian endometriosis.[ 19 ] Laboratory studies of disease mechanism were also excluded. In consideration of the ethnic similarity, only studies developed from East Asia (including ethnic groups of Chinese, Taiwanese, Japanese, and Koreans peoples) were included; however, those derived from Northern Asia (such as ethnic groups of Siberia), Central Asia (such as ethnic groups Turkic, Iranian, and Russians peoples), South Asia (including ethnic groups of India, Indochinese Peninsula, and Filipino peoples), and West Asia (such as ethnic groups of Arab peoples and Jews) were not included.\n\nA total of 65 candidate articles were identified fitting the scope of the current review, and finally, 22 eligible articles included for review [ Figure 1 ]. We found five studies of demographic and/or environmental parameters related to endometriosis [ Table 1 ], 12 studies showed positive findings for an association of a genetic polymorphism with endometriosis [ Table 2 ], and another 5 studies found negative results for a correlation of genotypes with endometriosis [ Table 3 ].\nFlow diagram of article selection process\nStudies of demographic or environmental parameters\nBMI: Body mass index\nSummary of Ggenetic polymorphism studies with significant differences\nSNP: Single -nucleotide polymorphism, TNF-: Tumor necrosis factor- alpha, GST: Glutathione-S-transferases, CI: Confidence interval, OR: Odds ratio\nSummary of genetic polymorphism studies with no association or significance\nSNP: Single- nucleotide polymorphism, TNF-: Tumor necrosis factor- alpha, GST: Glutathione-S-transferases\nThe majority of included studies were either retrospective cohort studies or case–control studies, neither of which is able to produce reliable incidence nor prevalence estimates. Indeed, there was only one study from which an estimate of prevalence was obtainable. This was a large survey of nurses from Japan, in which 1025 of 15,019 (6.8%) self-reported endometriosis.[ 20 ] The authors of this study found that 89% of women with self-reported endometriosis had a diagnosis confirmed by laparoscopy.[ 20 ]\nOnly one study reported the effect of body mass index (BMI) on the severity of endometriosis. Korean women with early or mild endometriosis have a significantly higher BMI compared to those with advanced disease even after adjusting for age, parity, and menstrual factors.[ 21 ]\nOnly one study reported the effect of parity on the development of endometriosis. Korean women with only one child experience a more severe disease than those with more than one child.[ 21 ]\nEnvironmental exposure includes cigarette smoking and exposure to industrial chemicals. One study reported that cigarette smoking is associated with an increased risk of endometriosis in women with surgically confirmed endometriosis from Japan.[ 20 ]\nA number of industrial chemicals and environmental pollutants are known to either mimic or antagonize endogenous hormones.[ 41 ] Of particular interest are the organochlorides, found in pesticides, and heavy metals. However, in two studies of infertile women from Japan, there was very little difference in the levels of these compounds in women with or without endometriosis.[ 22 23 ] Yet, given these women were infertile, the influence of such environmental toxins in an unselected group of women with endometriosis remains unclear.\nInfertility is significantly associated with increased risk of endometriosis in women with surgically confirmed endometriosis from Japan although whether endometriosis is the causal factor for infertility remains a possibility.[ 20 ] Unsurprisingly then, there appears to be an association of a diagnosis of infertility in women who are subsequently diagnosed with endometriosis.\nA short menstrual cycle length, at age 18–22 years of age, was significantly associated with an increased risk of endometriosis in women surgically confirmed endometriosis from Japan.[ 20 ] However, in Korean women, no association between menstrual cycle length and disease severity was found.[ 21 ]\nIn a Japanese study, the prevalence of endometriosis in siblings of women diagnosed with endometriosis was 8.8% compared to 1.5% of controls, suggesting that there is a familial tendency for endometriosis.[ 24 ] There may therefore be a genetic link between specific polymorphisms and the development of endometriosis.\nSeveral genes have been studied [Tables  2  and  3 ]. An increased risk of endometriosis has been reported in women with  CDKN2B-AS/rs10965253  and  WNT4/rs16826658  single-nucleotide polymorphisms (SNPs);[ 25 ]  TIMP-2  promoter region;[ 26 ] estrogen synthesis and metabolism genes (nonsynonymous SNPs rs6165, rs6166, rs2066479, and rs700519);[ 27 ]  FGF2  754C/C polymorphism;[ 30 ]-C805 or -1031T/C  TNFA  gene polymorphism;[ 31 ] A264C  HSD17B1  polymorphisms in cytochrome P450 CYP19;[ 34 ] a13 allele in interferon gamma ( IFN -γ); and  IFN -γ CA repeat polymorphisms;[ 34 ] A264C  HSD17B1  polymorphisms in cytochrome P450 CYP19;[ 35 ] and a13 allele in  IFN -γ and  IFN -γ CA repeat polymorphisms.[ 13 ]\nIn contrast, alterations in the  TIMP-2  intron 1 region and  MMP-2 ,[ 26 ]-765C allele of  COX-2  gene,[ 29 ] SNPs in the follicle-stimulating hormone receptor  FSHR  gene,[ 29 ]  FGF2  754C/G or G/G,[ 30 ]-863C/A  TNFA  gene polymorphism,[ 31 ]418C/C  TIMP-2  polymorphism,[ 32 ] and appear to be protective. Increased serum endostatin levels (but not  VEGF  levels) are negatively correlated with development of endometriosis.[ 39 ]\nOther genetic alterations have been reported to have no association with the development of endometriosis. These include  ESR1  gene polymorphisms (although the authors speculated this may be due to low sample size),[ 36 ] K469E and G241R polymorphisms in  ICAM-1 ;[ 37 ] C627T in  IL-2R  β gene;[ 38 ] G (4349) A, C (936) T, 405G,-406C>T  VEGF  polymorphisms;[ 39 ] and  GSTM1, GSTT1 , and GSTP1.[ 40 ]\nThe role of the E-cadherin gene is controversial, with several studies reporting a significant association with endometriosis risk, particularly with 160C/-347 GA and 30-UTR C/T polymorphisms,[ 33 ] while other polymorphisms are not associated with increased risk (-160C/A and -347 G/GA).[ 33 ]\nOne study[ 20 ] proposed an idea that some inherited or constitutional factors which increased the risk of endometriosis could hardly be changed, while some others which correlated to lifestyle or environmental factors could be modifiable. Collectively, for the current review, nonmodifiable risk factors include infertility, menstrual cycle length, early menarche, family history, and genetics; however, factors include diet, BMI, length of breastfeeding, physical activity, and exposure to heavy metals and pesticides could be modifiable to the development of endometriosis [ Table 4 ].\nFactors associated with increased risk of endometriosis\nBMI: Body mass index\n\nIn contrast to the abundant articles focused on the molecular biologic studies,[ 4 12 42 ] there was limited data on the epidemiology of endometriosis in the East Asian populations despite earlier reports suggesting that endometriosis is more common in women from Asia than from Western countries.[ 5 11 14 15 ] In the present review, it appears that the best characterized risk factors in the East Asian populations are the various genetic polymorphisms that have been studied. In contrast to the genetic or familial factors which are nonmodifiable, factors such as parity, smoking, and probably the BMI could be the modifiable factors for the development of endometriosis. Regretfully, almost all these found articles were limited by their low strength of evidence and lack of the strong support of causal relationship, so these factors finally could only conclude an association or correlation with endometriosis.\nEndometriosis is a dynamic and complex disorder, involving the interplay of genetic and environmental factors. The current review revealed a number of risk factors for endometriosis, including early menarche,[ 43 ] increased BMI,[ 44 45 46 ] environmental factors (including cigarette smoking),[ 47 ] and genetic factors.[ 48 49 ] It seems some of our findings were consistent with other studies that early menarche, shorter menstrual length, duration of infertility, and family history of endometriosis are strongly associated with endometriosis,[ 8 50 51 ] while higher parity and higher BMI are associated with decreased risk.[ 8 ] However, some associations have not yet been proven or disproven, such as smoking and the influence of diet.[ 8 50 52 53 ] A Japanese study in the current review found cigarette smoking significantly increased the risk of endometriosis, while another study from Boston, USA, found smoking was associated with decreased risk,[ 8 ] and a study from Sweden found no significant association between smoking and endometriosis.[ 50 ] The same study from Sweden also found no significant associations with level of education, BMI, oral contraceptive use, coffee consumption, or alcohol intake.\nBMI is significantly associated with disease severity in one Korean study,[ 21 ] those with lower BMI being more likely to have more severe disease compared to those with higher BMI. Other studies have also suggested that women with a low BMI are at greater risk of endometriosis.[ 8 44 45 46 ] This might explain the difference in the prevalence in Asian women compared to women from the United States,[ 11 ] given that average BMIs are much higher in the US population. However, a critical question is whether the low BMI is the cause or the consequence of developing endometriosis even though these studies suggested a correlation. Besides, if BMI is a potential predisposing factor of endometriosis, it is still unknown if there are any BMI-related genetic or environmental factors which could be involved.\nFactors contributing toward or against endometriosis development are far from clearly understood, and the interaction between genetic susceptibility and environmental factors is inadequately studied, despite over 50 years of hypothesis-driven research.[ 3 ] The epidemiological data reviewed in the current study suggested that the development of endometriosis in the East Asian populations is strongly driven by genetic factors; however, almost all these studies were focused on the genetic SNPs. It is still unclear the exact biological significance of these SNPs or the mechanisms of subsequent signaling.\nThere are several limitations to the current review. First, we only included articles that were published in English, which may lead to bias considering this review is specifically focused on the East Asian populations. Second, as with all reviews, there is possible publication bias and we have not formally assessed this. Third, the retrieved publications were from only several countries within East Asia (Japan, Taiwan, Korea, and China). Although we also found some available data from India[ 54 55 56 57 58 59 ] (South Asia), epidemiology-related researches from other Asian countries remains sparse. Fourth, probably because of the difficulties of epidemiologic studies, the level of evidence for lifestyle research may not be strong enough. Although these data are still worthy as a reference of an East Asian population, surely, there was no strong evidence to support if those proposed \"modifiable\" risk factors could really change the development of endometriosis. Fifth, links between the genetic and mechanistic studies of the development of endometriosis were lacking. From a cohort viewpoint, the clinical impact of the genetic polymorphism in a woman's life is unclear, and it is not clear whether those revelations would be altered after conception or not, as the incidence of endometriosis significantly declines after successful pregnancy. Obviously, there are many questions yet to be answered.\nData on the epidemiologic factors of endometriosis in the Asian populations are limited. The available data that examine potential genetic factors, however, do not reveal whether such factors directly contribute to increased risk of endometriosis. Smoking, low parity, and probably BMI could be modifiable risk factors associated with endometriosis among East Asian women. Further extensive studies on endometriosis in Asian women are required to identify other risk factors for the management of this condition.[ 60 ]\nThis study was partially supported by the research grants of National Science Council, Ministry of Science and Technology (grant no. NMRPG3G0521 (MOST 106-2314-B-182A-150-)) to Dr. C.F. Yen.\nThere are no conflicts of interest.","source_license":"CC0","license_restricted":false}