{"paper_id":"110be2da-4d05-4796-9374-2f1a58190861","body_text":"Endometriosis is a common disease characterized by the growth of endometrial tissue (which\nnormally lines the uterus) outside the uterine cavity. 1  The estimated prevalence of endometriosis in women of reproductive age is 2% to 11%\nin Europe and the United States 2 , 3  and 12% in China. 4  The symptoms of endometriosis vary among patients and disease extent 5  but usually include painful periods (dysmenorrhea), chronic pelvic pain, pain with\nintercourse (dyspareunia), and infertility. 1 , 6 , 7  Endometriosis exerts a considerable impact on health-related quality of life, 8  and the variable presentation often leads to a delay in diagnosis. 9 , 10  Currently, there are no curative treatment strategies for endometriosis other than\nlaparoscopic surgery. Although endometriotic lesions can be removed by conservative surgery,\nthe disease can recur in 30% to 50% of women. 11 , 12\nEndometriotic lesions may be characterized into 3 phenotypes based on localization and\nhistology: superficial peritoneal endometriosis (SUP), cystic ovarian endometriosis or\nendometrioma (OMA), and deep infiltrating endometriosis (DIE). 13 – 15  These 3 phenotypes can occur either individually or in combination in the same\npatient. The pathogenesis of endometriosis remains poorly understood but is thought to\ninvolve a variety of mechanisms. 16  Indeed, hormonal, inflammatory, immunologic, genetic, epigenetic, and environmental\nfactors have all been reported to be associated with endometriosis. 17 – 26  In addition, some studies have suggested that endometriosis may be related to dietary\nas well as early-life factors (including exposure to environmental toxic agents). 27 – 30  Nevertheless, the SUP, OMA, and DIE phenotypes of endometriosis may have different\norigins and pathogenetic mechanisms, and there is only limited information regarding the\nfactors associated with these phenotypes in the Chinese population.\nThe recently published FEELING (Factors associated with the development of Endometrioma and\ndEep infiLtratING endometriosis) study was a case–control study of 1008 patients in 3\ncountries (China, Russia, and France), designed to investigate the clinical, lifestyle, and\nenvironmental factors associated with OMA and DIE versus SUP and no endometriosis. 31  The FEELING study identified several factors associated with OMA and DIE, including\nprevious use of hormonal treatment for endometriosis, previous surgery for endometriosis,\nand living or working in a city or by a busy area. 31  In addition, substantial differences among regions were noted regarding the\ndiagnosis, symptomatology, and management of endometriosis. 31\nThe aim of the present study was to perform a subgroup analysis of data from women in China\nwho were enrolled in the FEELING study in order to investigate the factors associated with\ndifferent phenotypes of endometriosis, with a focus for early-life factors.\n\nThis is a subgroup analysis of the FEELING study 31  for the 546 participants in China enrolled between May 2011 and April 2013 to\nidentify early-life exposure factors associated with OMA and/or DIE. The criteria for\ninclusion and diagnosis of SUP, OMA, and DIE were described in the FEELING study ( NCT01351051 ). 13 – 15 , 31  The women who underwent gynecological surgery for a benign in the past 3 months\nwere considered for recruitment. Deep infiltrating endometriosis was considered in the\npresence of endometrial tissue infiltrating beneath the peritoneal surface for >5 mm 15  or when the muscularis was infiltrated. 14  The patients were classified according to the more severe lesion (SUP, OMA, and the DIE). 13\nAll patients provided informed written consent before participating in the study. The\nstudy was approved by the regional independent ethics committees/institutional review\nboards and was conducted in accordance with the Declaration of Helsinki.\nOne case report form and 2 questionnaires were collected from each participant in a\nface-to-face interview with the investigator at the first postsurgical routine visit. Data\nregarding symptoms and previous medical history, including endometriosis history,\npresurgical symptoms, details of surgery for endometriosis, endometriosis status,\nadditional gynecologic and medical history, and family medical history, were obtained\nretrospectively using an internet-based electronic data capture (EDC) case report form.\nInformation regarding current habits, including environment, dietary habits, and health\nand mood during the postsurgical visit, was collected prospectively using a\nparticipant-completed questionnaire. Finally, an investigator-completed EDC questionnaire\nwas used to obtain extra information regarding their age, gender, years in practice in\ngynecology, practice site information, number of newly diagnosed patients with\nendometriosis per year, total number of endometriosis cases followed per year, and number\nof assisted reproductive technologies for endometriosis per year. No safety evaluations\nwere undertaken as this was a noninterventional study.\nThe main objective of this study was to identify early-life exposure factors associated\nwith OMA and/or DIE. For the purposes of the primary analysis, SUP and non-EM were\nconsidered as control cases while OMA and DIE were considered as definite disease. The\nrationale for this was that the clinical significance of SUP remains unclear, with some\nauthors arguing that it may not represent true endometriotic disease. 16 , 32 , 33\nAs DIE is the less frequent form of endometriosis, the sample size in the original\nFEELING study was determined according to DIE 31 : assuming that the frequency of associated factors in the population is 10% and a\ndropout rate of 20%, the inclusion of 1008 participants allowed the detection of odds\nratios (ORs) ≥2 with a significance level of 5% and a power of 90%.\nA descriptive statistical analysis was applied. Continuous data were expressed as means\n(standard deviation) or medians (quartile, maximum value, and minimum value), as\nappropriate. Categorical variables were expressed as n (%).\nUnivariable logistic regression analyses were performed to screen for factors potentially\nassociated with OMA and/or DIE. Subsequently, multivariable regression analysis was\ncarried out using a significance level of 10% for entry of variables into the model and a\nsignificance level of 5% to retain variables in the model. The Hosmer-Lemeshow\ngoodness-of-fit test was applied to the final selected model, and ORs with 95% confidence\nintervals (CIs) were calculated. The ORs were considered significant when their associated\nCI excluded 1.0.  P  < .05 was considered statistically significant. Of\nnote, associations with borderline  P  values ( P  =\n.03-.05) should be interpreted with caution. All statistical analyses were performed using\nSAS software version 9.1 (SAS Institute Inc, Cary, North Carolina).\n\nA total of 546 women were enrolled in China, 156 (28.6%) in the non-EM group, 156 (28.6%)\nin the SUP group, 156 (28.6%) in the OMA group, and 78 (14.3%) in the DIE group. The\nbaseline characteristics of the enrolled participants are presented in  Table 1 .\nBaseline Characteristics of the Study Participants. a\na  Data presented as n (%) unless otherwise stated.\nb  A union that lacks any publicly recognized bond.\nc  N = 546, except N = 545 (data missing for 1 participant).\nClinical, lifestyle, and environmental factors found by univariable analyses to be\npotentially associated with endometriosis are presented in  Table 2 . Compared with participants in the non-EM\nand SUP groups, factors associated with OMA and DIE were noncyclic chronic pelvic pain (OR\n= 2.30, 95% CI: 1.40-3.78), more severe dysmenorrhea (class 1-4: OR = 2.77, 95% CI:\n1.77-4.34; class 5-7: OR = 3.31, 95% CI: 2.00-5.46; class 8-10: OR = 6.96, 95% CI:\n4.02-12.07), deep dyspareunia (OR = 3.09, 95% CI: 1.81-5.27), gastrointestinal symptoms\nduring menstruation (OR = 3.40, 95% CI: 2.23-5.19), urinary symptoms during menstruation\n(OR = 4.34, 95% CI: 1.91-9.85), previous surgical diagnosis of endometriosis (OR = 7.07,\n95% CI: 3.10-16.14), previous hormonal treatment of endometriosis (OR = 22.32, 95% CI:\n7.97-62.52), previous uterine surgery (OR = 1.57, 95% CI: 1.03-2.39), longer time since\nmenarche (OR = 1.47, 95% CI: 1.06-2.03), more regular menstrual cycle (OR = 0.37, 95% CI:\n0.17-0.84), no previous use of a progestin-only oral contraceptive (OR = 0.26, 95% CI:\n0.07-0.90), previous pregnancy (OR = 1.42, 95% CI: 1.00-2.02), not having been breastfed\n(OR = 0.48, 95% CI: 0.26-0.88), endometriosis in a first-degree relative (OR = 4.12, 95%\nCI: 1.10-15.39), and higher alcohol consumption (OR = 9.83, 95% CI: 1.02-95.06;  Table 2 ).\nUnivariable Analysis of the Factors Associated With OMA and DIE.\nAbbreviations: BMI, body mass index; CI, confidence interval; DIE, deep\ninfiltrating endometriosis; Non-EM, no endometriosis; OMA, endometrioma; OR, odds\nratio; SD, standard deviation; SUP, superficial peritoneal endometriosis.\na  Odds ratio expressed for a 10-unit increment in age.\nb  A union that lacks any publicly recognized bond.\nThe following variables were entered into the multivariable analysis: addition of salt to\ncooking, premature birth, not having been breastfed, gastrointestinal symptoms during\nmenstruation, health status, endometriosis in a first-degree relative, menstrual cycle\nregularity, living in a city or by a busy area, practicing vaginal douching, previous\nuterine surgery, progestin-only oral contraceptive pill, smoking status, stress level,\nprevious hormonal treatment for endometriosis, infertility, and previous surgical\ndiagnosis of endometriosis. The multivariable analysis identified the following factors as\nindependently associated with OMA and DIE: not having been breastfed (OR = 0.33, 95% CI:\n0.16-0.69), previous hormonal treatment for endometriosis (OR = 17.95, 95% CI:\n5.92-54.43), gastrointestinal symptoms during menstruation (OR = 3.18, 95% CI: 1.90-5.31),\nnot living in a city or by a busy area (OR = 2.14, 95% CI: 1.27-3.60), not having\ninfertility (OR = 0.55, 95% CI: 0.34-0.87), previous surgical diagnosis of endometriosis\n(OR = 3.18, 95% CI: 1.90-5.31), regular menstrual cycles (OR = 0.36, 95% CI: 0.13-0.96),\nand not practicing vaginal douching (OR = 0.39, 95% CI: 0.16-0.97;  Table 3 ). Among the identified factors, the only\none related to early-life exposure was not having been breastfed, and we subjected it to\nfurther robustness analysis to check whether it remained a significant factor when the OMA\nand DIE groups were considered separately instead of as one group.\nMultivariable Analysis of the Factors Associated With OMA and DIE. a\nAbbreviations: CI, confidence interval; DIE, deep infiltrating endometriosis;\nNon-EM, no endometriosis; OMA, endometrioma; OR, odds ratio; SUP, superficial\nperitoneal endometriosis.\na  The Hosmer-Lemeshow goodness-of-fit test yielded a  P \nvalue of .789, indicating a good fit.\nFurther subgroup multivariable analysis confirmed not having been breastfed as a\nprotective factor for DIE, when compared with non-EM (OR = 0.13, 95% CI: 0.02-0.88), and\nwith OMA + SUP (OR = 0.19, 95% CI: 0.04-0.85). Nevertheless, the univariable results did\nnot show that not having been breastfed was a protective factor for OMA, when compared\nwith non-EM (OR = 0.66, 95% CI: 0.32-1.36), and with SUP (OR = 0.63, 95% CI:\n0.31-1.30).\n\nTo the best of our knowledge, this subgroup analysis of the population of Chinese women\nfrom the FEELING study is the first multicenter case–control study to explore early-life\nfactors potentially related to different phenotypes of endometriosis. The main finding of\nthe present study was that having been breastfed was associated with OMA and DIE, as were\nprevious hormonal treatment for endometriosis, gastrointestinal symptoms during\nmenstruation, not living in a city or by a busy area, not having infertility, previous\nsurgical diagnosis of endometriosis, regular menstrual cycles, and not practicing vaginal\ndouching. As not having been breastfed was identified as a protective factor in the initial\nChinese substudy analysis, we performed further subgroup robustness analyses, and the\nresults indicated that this factor may only be a protective factor against DIE.\nOnly a small number of previous studies have reported the relationship between history of\nhaving been breastfed and endometriosis in adult life. The FEELING study, on which the\npresent analysis is based, did not find a significant association of having been breastfed\nwith OMA and/or DIE when all participants from China, Russia, and France were analyzed together. 31  The subgroup analysis suggested that not having been breastfed might be protective\nagainst DIE in participants from China but not from France or Russia, raising the intriguing\npossibility of regional differences in the impact of this factor. 31  Indeed, the FEELING study noted several intercountry differences highlighting the\ncomplex and multifactorial origins of endometriotic disease. 31\nOur observation that not having been breastfed may be a protective early-life factor\nagainst DIE in Chinese women is not in agreement with previous studies in women of other\nethnicities. Vannuccini et al investigated the influence of several intrauterine and early\nneonatal exposures and found that formula feeding and prematurity were risk factors of\ndeveloping endometriosis in adult life in women from Italy. 34  Similarly, a study in Japan determined that breast-fed infants have a lower incidence\nof endometriosis in adult life. 35  In contrast, another study found that perinatal factors, including breastfeeding,\nmight not play an important role in the pathogenesis of endometriosis. 36  The reasons for the seemingly inconsistency between our results and those of other\ninvestigations remain unknown, but there are several possibilities. One plausible\nexplanation is that, in China, breastfed infants might be exposed to higher levels of\nenvironmental toxicants (such as dioxins and related compounds) that are present in breast\nmilk and contribute to the pathogenesis of endometriosis. 30 , 37 , 38  These toxicants have been suggested to promote endometriosis development through\nvarious mechanisms, including epigenetic mechanisms that alter the expression of hormone receptors. 30 , 37 – 40  Unfortunately, being a first child or not was not collected as a variable and could\nnot be analyzed in terms of higher exposure to toxicants. Another possibility is that\nformula milk used in China may differ from that used in the other countries where the\nprevious studies were conducted. Two studies (in the United States and Europe) reported that\nhaving been fed with soy formula milk increased the risk of endometriosis, and it was\nsuggested that this effect of formula milk might involve an augmentation in the levels of\nestrogen and testosterone in the infant. 34 , 41  Thus, it is not inconceivable that lower hormone levels in formula milk in China may\nhave negated and even reversed any effect of formula milk on endometriosis risk. A third\npotential reason is that the present study analyzed different phenotypes separately and\nfound the protecting effect only for DIE, while all previous studies considered different\nphenotypes of endometriosis indifferently as a homogenous disease. The origins and\npathogeneses of the various endometriosis phenotypes likely differ, and many experts do not\nconsider SUP to represent true endometriotic disease. 16 , 32 , 33  Furthermore, studies also indicate that the potential causes for the differences\nbetween OMA and DIE might vary in several aspects such as epithelial–mesenchymal transition,\nfibroblast-to-myofibroblast transdifferentiation and smooth muscle metaplasia. 42  This variation in methodology may thus have contributed to the seemingly\ninconsistency between this study and previous investigations. In addition, it cannot be\nexcluded that selection bias in our study may have influenced our findings, since most women\nin China prefer to breastfeed their infants, and hence most participants in this study were breastfed. 43 , 44  Further research is needed to validate the association found and establish the\nunderlying mechanisms of the apparent protective effect of not having been breastfed against\nDIE in Chinese women. Since professional women and those with higher education tend to\nbreastfeed their infants less in China, thus have comparatively reduced mother–infant\ncontact, this can be one of the potential directions to be explored in future studies.\nIt is perhaps not surprising that previous surgical diagnosis of endometriosis or previous\nhormonal treatment of endometriosis was associated with OMA and DIE, as more severe or\ndeeply infiltrating disease (OMA and DIE) would be more likely to have already been\nclinically detected and treated than superficial disease (ie, SUP), explaining why a higher\nproportion of participants with OMA and DIE received a previous diagnosis or hormonal\ntherapy than participants with SUP. Furthermore, our observation that the severity of\ngastrointestinal symptoms during menstruation was associated with OMA, and DIE is consistent\nwith previous studies showing an association between advanced endometriosis and dysmenorrhea. 45 , 46  In the FEELING study, the associations of OMA and DIE with previous surgical\ndiagnosis of endometriosis and previous hormonal treatment of endometriosis were found for\nparticipants from all 3 countries, while the association with severity of gastrointestinal\nsymptoms during menstruation was observed in participants from both China and Russia. 31\nEndometriosis is known to be associated with infertility, although the underlying\nmechanisms remain unclear. 47  The observation in the present study that infertility was inversely associated with\nOMA and DIE may therefore seem somewhat unexpected. However, as noted in the FEELING study, 31  infertility may have been the main indication for surgery among the non-EM/SUP cases,\nexplaining our finding.\nIt has been suggested that the prevalence of endometriosis should be low in remote rural\nsettings that are characterized by high fertility rate, frequent teenage pregnancy, and\nprotracted breastfeeding, all of which reduce the total number of menstrual cycles. 36 , 48  However, in the current study, living in a city or by a busy area appeared to be\nprotective against OMA and DIE. In the FEELING study, such an association was not observed\nin participants from France or Russia. 31  Similarly, although the present study revealed a possible protective effect of\nvaginal douching against endometriosis, no effect was observed for participants from France\nor Russia in the FEELING study 31  or for women in the United States in another case–control study. 49  The reasons for these apparent inconsistencies are unknown and merit further\nconsideration in future research.\nThis study has some limitations. The sample size in this study was rather small; hence,\nadditional data from a larger population are needed to confirm and extend our observations.\nAs mentioned above, most participants in this study were breastfed, which may have\nintroduced a degree of selection bias. In addition, there may have been a bias against\nenrollment of women in less developed areas due to a decreased willingness to undergo\nmedical investigations for diagnosis of the disease (eg, due to economic factors) and/or a\nreduced diagnostic efficiency in rural medical centers (which have less medical expertise in\nthis field). Thus, the role of environmental factors may not have been fully explored.\nFurther prospective studies are required to confirm the conclusion of the current\nresearch.\nIn conclusion, not having been breastfed was found to be a potentially protective\nearly-life factor against DIE in Chinese women. Further studies are warranted to confirm\nthis finding from an observational study, and to explore the possible underlying\nmechanisms.","source_license":"CC0","license_restricted":false}