Abstract
Background:
This study aimed to investigate potential factors, especially early-life exposures, associated with endometrioma (OMA) and/or deep infiltrating endometriosis (DIE) in Chinese women.
Methods:
This is a subgroup analyses of the FEELING study, which was a case–control study that investigated the clinical, lifestyle, and environmental factors associated with OMA and/or DIE in China, Russia, and France. In this subgroup analysis, the data for the Chinese participants were further analyzed using logistic regression model.
Results:
All women (N = 546) had fully completed the questionnaire. The mean age of the participants was 31.8 (range: 18-41) years. Univariable analysis showed that noncyclic chronic pelvic pain, dysmenorrhea intensity class, and whether breastfed during infancy were distributed differently between patients with OMA or DIE and those with no endometriosis (non-EM) or superficial peritoneal endometriosis (SUP; P < .05). Multivariable analysis revealed that not having been breastfed was a protective factor against OMA and DIE (odds ratio [OR] = 0.33, 95% confidence interval [CI]: 0.16-0.69). Further analysis indicated not having been breastfed was a protective factor for DIE compared with non-EM (OR = 0.13, 95% CI: 0.02-0.88) and with OMA + SUP (OR = 0.19, 95% CI: 0.04-0.85) but was not a protective factor for OMA compared with non-EM (OR = 0.66, 95% CI: 0.32-1.36) and with SUP (OR = 0.63, 95% CI: 0.31-1.30).
Conclusion:
This is the first study suggesting that not having been breastfed might protect against DIE in Chinese women.
Keywords: endometriosis, early-life exposure, risk factor, breastfeeding
Introduction
Endometriosis is a common disease characterized by the growth of endometrial tissue (which normally lines the uterus) outside the uterine cavity.1 The estimated prevalence of endometriosis in women of reproductive age is 2% to 11% in Europe and the United States2,3 and 12% in China.4 The symptoms of endometriosis vary among patients and disease extent5 but usually include painful periods (dysmenorrhea), chronic pelvic pain, pain with intercourse (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 laparoscopic surgery. Although endometriotic lesions can be removed by conservative surgery, the disease can recur in 30% to 50% of women.11,12
Endometriotic lesions may be characterized into 3 phenotypes based on localization and histology: superficial peritoneal endometriosis (SUP), cystic ovarian endometriosis or endometrioma (OMA), and deep infiltrating endometriosis (DIE).13–15 These 3 phenotypes can occur either individually or in combination in the same patient. The pathogenesis of endometriosis remains poorly understood but is thought to involve a variety of mechanisms.16 Indeed, hormonal, inflammatory, immunologic, genetic, epigenetic, and environmental factors have all been reported to be associated with endometriosis.17–26 In addition, some studies have suggested that endometriosis may be related to dietary as 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 origins and pathogenetic mechanisms, and there is only limited information regarding the factors associated with these phenotypes in the Chinese population.
The recently published FEELING (Factors associated with the development of Endometrioma and dEep infiLtratING endometriosis) study was a case–control study of 1008 patients in 3 countries (China, Russia, and France), designed to investigate the clinical, lifestyle, and environmental factors associated with OMA and DIE versus SUP and no endometriosis.31 The FEELING study identified several factors associated with OMA and DIE, including previous use of hormonal treatment for endometriosis, previous surgery for endometriosis, and living or working in a city or by a busy area.31 In addition, substantial differences among regions were noted regarding the diagnosis, symptomatology, and management of endometriosis.31
The aim of the present study was to perform a subgroup analysis of data from women in China who were enrolled in the FEELING study in order to investigate the factors associated with different phenotypes of endometriosis, with a focus for early-life factors.
Methods
Study Design
This is a subgroup analysis of the FEELING study31 for the 546 participants in China enrolled between May 2011 and April 2013 to identify early-life exposure factors associated with OMA and/or DIE. The criteria for inclusion 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 were considered for recruitment. Deep infiltrating endometriosis was considered in the presence of endometrial tissue infiltrating beneath the peritoneal surface for >5 mm15 or when the muscularis was infiltrated.14 The patients were classified according to the more severe lesion (SUP, OMA, and the DIE).13
All patients provided informed written consent before participating in the study. The study was approved by the regional independent ethics committees/institutional review boards and was conducted in accordance with the Declaration of Helsinki.
Assessments
One case report form and 2 questionnaires were collected from each participant in a face-to-face interview with the investigator at the first postsurgical routine visit. Data regarding symptoms and previous medical history, including endometriosis history, presurgical symptoms, details of surgery for endometriosis, endometriosis status, additional gynecologic and medical history, and family medical history, were obtained retrospectively using an internet-based electronic data capture (EDC) case report form. Information regarding current habits, including environment, dietary habits, and health and mood during the postsurgical visit, was collected prospectively using a participant-completed questionnaire. Finally, an investigator-completed EDC questionnaire was used to obtain extra information regarding their age, gender, years in practice in gynecology, practice site information, number of newly diagnosed patients with endometriosis per year, total number of endometriosis cases followed per year, and number of assisted reproductive technologies for endometriosis per year. No safety evaluations were undertaken as this was a noninterventional study.
Objectives
The main objective of this study was to identify early-life exposure factors associated with OMA and/or DIE. For the purposes of the primary analysis, SUP and non-EM were considered as control cases while OMA and DIE were considered as definite disease. The rationale for this was that the clinical significance of SUP remains unclear, with some authors arguing that it may not represent true endometriotic disease.16,32,33
Statistical Analysis
As DIE is the less frequent form of endometriosis, the sample size in the original FEELING study was determined according to DIE31: assuming that the frequency of associated factors in the population is 10% and a dropout rate of 20%, the inclusion of 1008 participants allowed the detection of odds ratios (ORs) ≥2 with a significance level of 5% and a power of 90%.
A descriptive statistical analysis was applied. Continuous data were expressed as means (standard deviation) or medians (quartile, maximum value, and minimum value), as appropriate. Categorical variables were expressed as n (%).
Univariable logistic regression analyses were performed to screen for factors potentially associated with OMA and/or DIE. Subsequently, multivariable regression analysis was carried out using a significance level of 10% for entry of variables into the model and a significance level of 5% to retain variables in the model. The Hosmer-Lemeshow goodness-of-fit test was applied to the final selected model, and ORs with 95% confidence intervals (CIs) were calculated. The ORs were considered significant when their associated CI excluded 1.0. P < .05 was considered statistically significant. Of note, associations with borderline P values (P = .03-.05) should be interpreted with caution. All statistical analyses were performed using SAS software version 9.1 (SAS Institute Inc, Cary, North Carolina).
Results
Participants
A total of 546 women were enrolled in China, 156 (28.6%) in the non-EM group, 156 (28.6%) in the SUP group, 156 (28.6%) in the OMA group, and 78 (14.3%) in the DIE group. The baseline characteristics of the enrolled participants are presented in Table 1.
Table 1.
Baseline Characteristics of the Study Participants.a
| Characteristic | Value |
|---|---|
| Age on visit day (years), mean (range) | 31.80 (18-41) |
| Body mass index (kg/m2), mean (SD) | 21.37 (3.27) |
| Ethnicity | |
| Asian | 546 (100%) |
| Other | 0 (0%) |
| Marital status | |
| Single | 80 (14.7%) |
| Married | 450 (82.4%) |
| Free unionb | 14 (2.6%) |
| Divorced/separated | 2 (0.4%) |
| Widowed | 0 (0%) |
| Educational levelc | |
| Primary school | 20 (3.7%) |
| High school | 112 (20.6%) |
| Vocational or professional school | 59 (10.8%) |
| Polytechnic or equivalent (+2 years) | 38 (7.0%) |
| University or business school (+4 to 5 years) | 316 (58.0%) |
| Data missing | 1 (0.2%) |
| Smoking status | |
| Current smoker | 12 (2.2%) |
| Ex-smoker | 4 (0.7%) |
| Never smoked | 530 (97.1%) |
| Endometriosis group | |
| No endometriosis | 156 (18.6%) |
| Superficial peritoneal endometriosis | 156 (28.6%) |
| Endometrioma | 156 (28.6%) |
| Deep infiltrating endometriosis | 78 (14.3%) |
a Data presented as n (%) unless otherwise stated.
b A union that lacks any publicly recognized bond.
c N = 546, except N = 545 (data missing for 1 participant).
Univariable Analyses of Factors Associated With OMA and DIE
Clinical, lifestyle, and environmental factors found by univariable analyses to be potentially associated with endometriosis are presented in Table 2. Compared with participants in the non-EM and SUP groups, factors associated with OMA and DIE were noncyclic chronic pelvic pain (OR = 2.30, 95% CI: 1.40-3.78), more severe dysmenorrhea (class 1-4: OR = 2.77, 95% CI: 1.77-4.34; class 5-7: OR = 3.31, 95% CI: 2.00-5.46; class 8-10: OR = 6.96, 95% CI: 4.02-12.07), deep dyspareunia (OR = 3.09, 95% CI: 1.81-5.27), gastrointestinal symptoms during menstruation (OR = 3.40, 95% CI: 2.23-5.19), urinary symptoms during menstruation (OR = 4.34, 95% CI: 1.91-9.85), previous surgical diagnosis of endometriosis (OR = 7.07, 95% CI: 3.10-16.14), previous hormonal treatment of endometriosis (OR = 22.32, 95% CI: 7.97-62.52), previous uterine surgery (OR = 1.57, 95% CI: 1.03-2.39), longer time since menarche (OR = 1.47, 95% CI: 1.06-2.03), more regular menstrual cycle (OR = 0.37, 95% CI: 0.17-0.84), no previous use of a progestin-only oral contraceptive (OR = 0.26, 95% CI: 0.07-0.90), previous pregnancy (OR = 1.42, 95% CI: 1.00-2.02), not having been breastfed (OR = 0.48, 95% CI: 0.26-0.88), endometriosis in a first-degree relative (OR = 4.12, 95% CI: 1.10-15.39), and higher alcohol consumption (OR = 9.83, 95% CI: 1.02-95.06; Table 2).
Table 2.
Univariable Analysis of the Factors Associated With OMA and DIE.
| Characteristic | Non-EM + SUP | OMA + DIE | OR (95% CI) | P |
|---|---|---|---|---|
| n/N or mean (SD) | n/N or mean (SD) | |||
| Age on visit day (years) | 31.44 (5.38; n = 312) | 32.27 (5.07; n = 234) | 1.35 (0.98-1.87)a | .070 |
| BMI on visit day (kg/m2) | .735 | |||
| <18.5 | 45/312 | 41/234 | 1.24 (0.76-2.02) | |
| 18.5-21.9 | 155/312 | 114/234 | Reference | |
| 22.0-24.9 | 74/312 | 55/234 | 1.01 (0.66-1.55) | |
| ≥25.0 | 38/312 | 24/234 | 0.86 (0.49-1.51) | |
| Weight change >±5 kg in previous 3 months | .758 | |||
| Yes | 5/312 | 3/234 | 0.80 (0.19-3.37) | |
| No | 307/312 | 231/234 | Reference | |
| Marital status | .797 | |||
| Single | 50/312 | 30/234 | 0.78 (0.48-1.27) | |
| Married | 254/312 | 196/234 | Reference | |
| Free unionb | 8/312 | 6/234 | 0.97 (0.33-2.85) | |
| Divorced/separated | 0/312 | 2/234 | – | |
| Education | .109 | |||
| Primary or high school | 87/311 | 45/234 | 0.61 (0.40-0.93) | |
| Vocational or professional school | 34/311 | 25/234 | 0.87 (0.49-1.52) | |
| Polytechnic or equivalent | 19/311 | 19/234 | 1.18 (0.60-2.31) | |
| University or business school | 171/311 | 145/234 | Reference | |
| Smoking status | .062 | |||
| Current or ex-smoker | 13/312 | 3/234 | 0.30 (0.08-1.06) | |
| Never smoked | 299/312 | 231/234 | Reference | |
| Noncyclic chronic pelvic pain | <.001 | |||
| Yes | 30/312 | 46/234 | 2.30 (1.40-3.78) | |
| No | 282/312 | 188/234 | Reference | |
| Dysmenorrhea intensity class | <.001 | |||
| 0 | 177/312 | 61/234 | Reference | |
| 1-4 | 67/312 | 64/234 | 2.77 (1.77-4.34) | |
| 5-7 | 43/312 | 49/234 | 3.31 (2.00-5.46) | |
| 8-10 | 25/312 | 60/234 | 6.96 (4.02-12.07) | |
| Pain at time of ovulation | .236 | |||
| Yes | 14/312 | 16/234 | 1.56 (0.75-3.27) | |
| No | 298/312 | 218/234 | Reference | |
| Deep dyspareunia | <.001 | |||
| Yes | 23/312 | 46/233 | 3.09 (1.81-5.27) | |
| No | 289/312 | 187/233 | Reference | |
| Infertility | .179 | |||
| Yes | 95/312 | 59/234 | 0.77 (0.53-1.13) | |
| No | 217/312 | 175/234 | Reference | |
| Gastrointestinal symptoms during menstruation | <.001 | |||
| Yes | 42/312 | 81/234 | 3.40 (2.23-5.19) | |
| No | 270/312 | 153/234 | Reference | |
| Urinary symptoms during menstruation | <.001 | |||
| Yes | 8/312 | 24/234 | 4.34 (1.91-9.85) | |
| No | 304/312 | 210/234 | Reference | |
| Previous surgical diagnosis of endometriosis | <.001 | |||
| Yes | 7/246 | 40/233 | 7.07 (3.10-16.14) | |
| No | 239/246 | 193/233 | Reference | |
| Previous hormonal treatment for endometriosis | <.001 | |||
| Yes | 4/263 | 60/234 | 22.32 (7.97-62.52) | |
| No | 259/263 | 174/234 | Reference | |
| Associated diseases | .232 | |||
| Yes | 24/311 | 12/234 | 0.65 (0.32-1.32) | |
| No | 287/311 | 222/234 | Reference | |
| Allergic rhinitis, asthma, eczema or anaphylaxis | .204 | |||
| Yes | 18/311 | 8/234 | 0.58 (0.25-1.35) | |
| No | 293/311 | 226/234 | Reference | |
| Previous uterine surgery | .037 | |||
| Yes | 52/311 | 56/234 | 1.57 (1.03-2.39) | |
| No | 259/311 | 178/234 | Reference | |
| Time since menarche (years) | 18.08 (5.45; n = 311) | 19.16 (5.14; n = 234) | 1.47 (1.06-2.03) | .020 |
| Menstrual cycle regularity | .017 | |||
| Always or usually regular | 284/311 | 226/234 | Reference | |
| Irregular | 27/311 | 8/234 | 0.37 (0.17-0.84) | |
| Tampon use during menstruation | .466 | |||
| Yes | 41/311 | 36/234 | 1.20 (0.74-1.94) | |
| No | 270/311 | 198/234 | Reference | |
| Practices vaginal douching | .075 | |||
| Yes | 27/311 | 11/234 | 0.52 (0.25-1.07) | |
| No | 284/311 | 223/234 | Reference | |
| Ovulatory disorders, amenorrhea or menorrhagia | .466 | |||
| Yes | 28/311 | 17/234 | 0.79 (0.42-1.48) | |
| No | 283/311 | 217/234 | Reference | |
| Combined oral contraceptive pill | .922 | |||
| Currently or previously | 5/312 | 4/234 | 1.07 (0.28-4.02) | |
| Never | 307/312 | 230/234 | Reference | |
| Progestin-only oral contraceptive | .033 | |||
| Yes | 15/312 | 3/234 | 0.26 (0.07-0.90) | |
| No | 297/312 | 231/234 | Reference | |
| Intrauterine device | .795 | |||
| Currently or previously | 39/312 | 31/234 | 1.07 (0.65-1.77) | |
| Never | 273/312 | 203/234 | Reference | |
| Barrier contraception on a regular basis | .601 | |||
| Yes | 173/312 | 135/234 | 1.10 (0.78-1.54) | |
| No | 139/312 | 99/234 | Reference | |
| Prior pregnancy | .047 | |||
| Yes | 175/312 | 151/234 | 1.42 (1.00-2.02) | |
| No | 137/312 | 83/234 | Reference | |
| Premature birth | .054 | |||
| Yes | 10/312 | 16/234 | 2.22 (0.99-4.98) | |
| No | 302/312 | 218/234 | Reference | |
| Born from a twin pregnancy | .219 | |||
| Yes | 9/312 | 3/234 | 0.44 (0.12-1.63) | |
| No | 303/312 | 231/234 | Reference | |
| Having been breastfed | .018 | |||
| Yes | 269/310 | 218/234 | Reference | |
| No | 41/310 | 16/234 | 0.48 (0.26-0.88) | |
| Siblings | .870 | |||
| Yes | 222/312 | 168/234 | 1.03 (0.71-1.50) | |
| No | 90/312 | 66/234 | Reference | |
| Age of mother at birth | 27.27 (4.55; n = 271) | 26.73 (3.99; n = 222) | 0.75 (0.49-1.13) | .170 |
| Family history of obesity | .471 | |||
| Yes | 13/312 | 7/234 | 0.71 (0.28-1.81) | |
| No | 299/312 | 227/234 | Reference | |
| Family history of early menopause | 1.000 | |||
| Yes | 4/312 | 3/234 | 1.00 (0.22-4.51) | |
| No | 308/312 | 231/234 | Reference | |
| Endometriosis in a first-degree relative | .035 | |||
| Yes | 3/312 | 9/234 | 4.12 (1.10-15.39) | |
| No | 309/312 | 225/234 | Reference | |
| Malignancy in a first-degree relative | .565 | |||
| Yes | 24/312 | 15/234 | 0.82 (0.42-1.60) | |
| No | 288/312 | 219/234 | Reference | |
| Malignancy in a second-degree relative | .911 | |||
| Yes | 39/312 | 30/234 | 1.03 (0.62-1.71) | |
| No | 273/312 | 204/234 | Reference | |
| Lives in a city or busy area | .099 | |||
| Yes | 259/312 | 181/234 | Reference | |
| No | 53/312 | 53/234 | 1.43 (0.94-2.19) | |
| Lives or works in a smoky atmosphere | .631 | |||
| Yes | 68/311 | 55/233 | 1.10 (0.74-1.65) | |
| No | 243/311 | 178/233 | Reference | |
| Usually drinks filtered/bottled water | .903 | |||
| Never or rarely | 69/312 | 55/234 | Reference | |
| Sometimes | 99/312 | 75/234 | 0.95 (0.60-1.51) | |
| Often or always | 144/312 | 104/234 | 0.91 (0.59-1.40) | |
| Number of days exposed to sun for >1 hour | 135.4 (121.5; n = 292) | 139.7 (123.2; n = 222) | 1.00 (0.99-1.02) | .694 |
| Use of indoor tanning bed | .980 | |||
| Yes | 2/311 | 0/233 | – | |
| No | 309/311 | 233/233 | Reference | |
| Use of thermal facilities | .526 | |||
| Yes | 75/311 | 62/234 | 1.13 (0.77-1.67) | |
| No | 236/311 | 172/234 | Reference | |
| Employment status | .738 | |||
| Employed | 239/310 | 188/232 | Reference | |
| Housewife | 40/310 | 26/232 | 0.83 (0.49-1.40) | |
| Retired | 0/310 | 1/232 | – | |
| Unemployed | 8/310 | 3/232 | 0.48 (0.12-1.82) | |
| Not working due to present health status | 23/310 | 14/232 | 0.77 (0.39-1.54) | |
| Salt added to cooking | .114 | |||
| Yes | 301/310 | 232/234 | Reference | |
| No | 9/310 | 2/234 | 0.29 (0.06-1.35) | |
| Units of alcohol per week | 0.12 (0.51; n = 298) | 0.30 (1.34; n = 229) | 9.83 (1.02-95.06) | .048 |
| Regular exercise | .628 | |||
| Yes | 135/311 | 106/233 | 1.09 (0.77-1.53) | |
| No | 176/311 | 127/233 | Reference | |
| Number of hours of sleep per night | .339 | |||
| >8 hours | 61/312 | 56/233 | 1.34 (0.88-2.03) | |
| 6-8 hours | 227/312 | 156/233 | Reference | |
| <6 hours or does not sleep well | 24/312 | 21/233 | 1.27 (0.68-2.37) | |
| Stress level | .112 | |||
| Not at all stressed | 16/312 | 20/233 | Reference | |
| Mild, moderate, marked, or extreme stress | 296/312 | 213/233 | 0.58 (0.29-1.14) | |
| Irritable or short-tempered | .612 | |||
| Never or rarely | 74/312 | 49/233 | Reference | |
| Sometimes | 151/312 | 111/233 | 1.11 (0.72-1.72) | |
| Often or always | 87/312 | 73/233 | 1.27 (0.79-2.04) | |
| Lack of motivation to take part in social activities | .212 | |||
| Never | 30/311 | 34/233 | Reference | |
| Rarely or sometimes | 225/311 | 159/233 | 0.62 (0.37-1.06) | |
| Often or always | 56/311 | 40/233 | 0.63 (0.33-1.19) | |
| Difficulty controlling anxieties or worries | .685 | |||
| Yes | 98/312 | 77/233 | 1.08 (0.75-1.55) | |
| No | 214/312 | 156/233 | Reference | |
| Nonconsensual sexual contact | .872 | |||
| Yes | 6/288 | 5/218 | 1.10 (0.33-3.67) | |
| No | 282/288 | 213/218 | Reference | |
| Health status | .056 | |||
| Excellent, very good, or good | 154/312 | 91/232 | Reference | |
| Fair | 144/312 | 126/232 | 1.48 (1.04-2.11) | |
| Poor | 14/312 | 15/232 | 1.81 (0.84-3.93) |
Abbreviations: BMI, body mass index; CI, confidence interval; DIE, deep infiltrating endometriosis; Non-EM, no endometriosis; OMA, endometrioma; OR, odds ratio; SD, standard deviation; SUP, superficial peritoneal endometriosis.
a Odds ratio expressed for a 10-unit increment in age.
b A union that lacks any publicly recognized bond.
Multivariable Analysis of Factors Associated With OMA and DIE
The following variables were entered into the multivariable analysis: addition of salt to cooking, premature birth, not having been breastfed, gastrointestinal symptoms during menstruation, health status, endometriosis in a first-degree relative, menstrual cycle regularity, living in a city or by a busy area, practicing vaginal douching, previous uterine surgery, progestin-only oral contraceptive pill, smoking status, stress level, previous hormonal treatment for endometriosis, infertility, and previous surgical diagnosis of endometriosis. The multivariable analysis identified the following factors as independently associated with OMA and DIE: not having been breastfed (OR = 0.33, 95% CI: 0.16-0.69), previous hormonal treatment for endometriosis (OR = 17.95, 95% CI: 5.92-54.43), gastrointestinal symptoms during menstruation (OR = 3.18, 95% CI: 1.90-5.31), not living in a city or by a busy area (OR = 2.14, 95% CI: 1.27-3.60), not having infertility (OR = 0.55, 95% CI: 0.34-0.87), previous surgical diagnosis of endometriosis (OR = 3.18, 95% CI: 1.90-5.31), regular menstrual cycles (OR = 0.36, 95% CI: 0.13-0.96), and not practicing vaginal douching (OR = 0.39, 95% CI: 0.16-0.97; Table 3). Among the identified factors, the only one related to early-life exposure was not having been breastfed, and we subjected it to further robustness analysis to check whether it remained a significant factor when the OMA and DIE groups were considered separately instead of as one group.
Table 3.
Multivariable Analysis of the Factors Associated With OMA and DIE.a
| Characteristic | Non-EM + SUP | OMA + DIE | OR (95% CI) | P |
|---|---|---|---|---|
| n/N | n/N | |||
| Infertility | .011 | |||
| Yes | 80/238 | 59/233 | 0.55 (0.34-0.87) | |
| No | 158/238 | 174/233 | Reference | |
| Gastrointestinal symptoms during menstruation | <.001 | |||
| Yes | 38/238 | 81/233 | 3.18 (1.90-5.31) | |
| No | 200/238 | 152/233 | Reference | |
| Previous surgical diagnosis of endometriosis | .018 | |||
| Yes | 7/238 | 40/233 | 3.06 (1.21-7.73) | |
| No | 231/238 | 193/233 | Reference | |
| Previous hormonal treatment for endometriosis | <.001 | |||
| Yes | 4/238 | 60/233 | 17.95 (5.92-54.43) | |
| No | 234/238 | 173/233 | Reference | |
| Menstrual cycle regularity | .041 | |||
| Always or usually regular | 219/238 | 225/233 | Reference | |
| Irregular | 19/238 | 8/233 | 0.36 (0.13-0.96) | |
| Practices vaginal douching | .043 | |||
| Yes | 21/238 | 11/233 | 0.39 (0.16-0.97) | |
| No | 217/238 | 222/233 | Reference | |
| Breastfed | .003 | |||
| Yes | 205/238 | 217/233 | Reference | |
| No | 33/238 | 16/233 | 0.33 (0.16-0.69) | |
| Lives in a city or busy area | .004 | |||
| Yes | 202/238 | 181/233 | Reference | |
| No | 36/238 | 52/233 | 2.14 (1.27-3.60) |
Abbreviations: CI, confidence interval; DIE, deep infiltrating endometriosis; Non-EM, no endometriosis; OMA, endometrioma; OR, odds ratio; SUP, superficial peritoneal endometriosis.
a The Hosmer-Lemeshow goodness-of-fit test yielded a P value of .789, indicating a good fit.
Further Prespecified Subgroup Analysis on Not Having Been Breastfed
Further subgroup multivariable analysis confirmed not having been breastfed as a protective factor for DIE, when compared with non-EM (OR = 0.13, 95% CI: 0.02-0.88), and with OMA + SUP (OR = 0.19, 95% CI: 0.04-0.85). Nevertheless, the univariable results did not show that not having been breastfed was a protective factor for OMA, when compared with non-EM (OR = 0.66, 95% CI: 0.32-1.36), and with SUP (OR = 0.63, 95% CI: 0.31-1.30).
Discussion
To the best of our knowledge, this subgroup analysis of the population of Chinese women from the FEELING study is the first multicenter case–control study to explore early-life factors potentially related to different phenotypes of endometriosis. The main finding of the present study was that having been breastfed was associated with OMA and DIE, as were previous hormonal treatment for endometriosis, gastrointestinal symptoms during menstruation, not living in a city or by a busy area, not having infertility, previous surgical diagnosis of endometriosis, regular menstrual cycles, and not practicing vaginal douching. As not having been breastfed was identified as a protective factor in the initial Chinese substudy analysis, we performed further subgroup robustness analyses, and the results indicated that this factor may only be a protective factor against DIE.
Only a small number of previous studies have reported the relationship between history of having been breastfed and endometriosis in adult life. The FEELING study, on which the present analysis is based, did not find a significant association of having been breastfed with 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 against DIE in participants from China but not from France or Russia, raising the intriguing possibility of regional differences in the impact of this factor.31 Indeed, the FEELING study noted several intercountry differences highlighting the complex and multifactorial origins of endometriotic disease.31
Our observation that not having been breastfed may be a protective early-life factor against DIE in Chinese women is not in agreement with previous studies in women of other ethnicities. Vannuccini et al investigated the influence of several intrauterine and early neonatal exposures and found that formula feeding and prematurity were risk factors of developing endometriosis in adult life in women from Italy.34 Similarly, a study in Japan determined that breast-fed infants have a lower incidence of endometriosis in adult life.35 In contrast, another study found that perinatal factors, including breastfeeding, might not play an important role in the pathogenesis of endometriosis.36 The reasons for the seemingly inconsistency between our results and those of other investigations remain unknown, but there are several possibilities. One plausible explanation is that, in China, breastfed infants might be exposed to higher levels of environmental toxicants (such as dioxins and related compounds) that are present in breast milk and contribute to the pathogenesis of endometriosis.30,37,38 These toxicants have been suggested to promote endometriosis development through various 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 not be analyzed in terms of higher exposure to toxicants. Another possibility is that formula milk used in China may differ from that used in the other countries where the previous studies were conducted. Two studies (in the United States and Europe) reported that having been fed with soy formula milk increased the risk of endometriosis, and it was suggested that this effect of formula milk might involve an augmentation in the levels of estrogen and testosterone in the infant.34,41 Thus, it is not inconceivable that lower hormone levels in formula milk in China may have negated and even reversed any effect of formula milk on endometriosis risk. A third potential reason is that the present study analyzed different phenotypes separately and found the protecting effect only for DIE, while all previous studies considered different phenotypes of endometriosis indifferently as a homogenous disease. The origins and pathogeneses of the various endometriosis phenotypes likely differ, and many experts do not consider SUP to represent true endometriotic disease.16,32,33 Furthermore, studies also indicate that the potential causes for the differences between OMA and DIE might vary in several aspects such as epithelial–mesenchymal transition, fibroblast-to-myofibroblast transdifferentiation and smooth muscle metaplasia.42 This variation in methodology may thus have contributed to the seemingly inconsistency between this study and previous investigations. In addition, it cannot be excluded that selection bias in our study may have influenced our findings, since most women in 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 underlying mechanisms of the apparent protective effect of not having been breastfed against DIE in Chinese women. Since professional women and those with higher education tend to breastfeed their infants less in China, thus have comparatively reduced mother–infant contact, this can be one of the potential directions to be explored in future studies.
It is perhaps not surprising that previous surgical diagnosis of endometriosis or previous hormonal treatment of endometriosis was associated with OMA and DIE, as more severe or deeply infiltrating disease (OMA and DIE) would be more likely to have already been clinically detected and treated than superficial disease (ie, SUP), explaining why a higher proportion of participants with OMA and DIE received a previous diagnosis or hormonal therapy than participants with SUP. Furthermore, our observation that the severity of gastrointestinal symptoms during menstruation was associated with OMA, and DIE is consistent with 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 diagnosis of endometriosis and previous hormonal treatment of endometriosis were found for participants from all 3 countries, while the association with severity of gastrointestinal symptoms during menstruation was observed in participants from both China and Russia.31
Endometriosis is known to be associated with infertility, although the underlying mechanisms remain unclear.47 The observation in the present study that infertility was inversely associated with OMA 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, explaining our finding.
It has been suggested that the prevalence of endometriosis should be low in remote rural settings that are characterized by high fertility rate, frequent teenage pregnancy, and protracted 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 protective against OMA and DIE. In the FEELING study, such an association was not observed in participants from France or Russia.31 Similarly, although the present study revealed a possible protective effect of vaginal douching against endometriosis, no effect was observed for participants from France or Russia in the FEELING study31 or for women in the United States in another case–control study.49 The reasons for these apparent inconsistencies are unknown and merit further consideration in future research.
This study has some limitations. The sample size in this study was rather small; hence, additional data from a larger population are needed to confirm and extend our observations. As mentioned above, most participants in this study were breastfed, which may have introduced a degree of selection bias. In addition, there may have been a bias against enrollment of women in less developed areas due to a decreased willingness to undergo medical investigations for diagnosis of the disease (eg, due to economic factors) and/or a reduced diagnostic efficiency in rural medical centers (which have less medical expertise in this field). Thus, the role of environmental factors may not have been fully explored. Further prospective studies are required to confirm the conclusion of the current research.
In conclusion, not having been breastfed was found to be a potentially protective early-life factor against DIE in Chinese women. Further studies are warranted to confirm this finding from an observational study, and to explore the possible underlying mechanisms.
Acknowledgments
Medical writing support was provided by Zhiwei Guo of Shanghai Meisi Medical Technology Co, Ltd, with funding from Ipsen.
Authors’ Note: Y.D. conceived and coordinated the study, designed, performed and analyzed the experiments, wrote the article. X.M.Z., M.X., Y.F.Z., and P.R.S. carried out the data collection, data analysis, and revised the article. J.H.L. designed the study, carried out the data analysis, and revised the article. All authors reviewed the results and approved the final version of the manuscript.
Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Pengran Sun is an employee of Ipsen.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Sponsorship, article processing charges, and the open access fee for this study were funded by Ipsen.
References
- 1. Greene AD, Lang SA, Kendziorski JA, Sroga-Rios JM, Herzog TJ, Burns KA. Endometriosis: where are we and where are we going? Reproduction. 2016;152(3):R63–R78. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Buck Louis GM, Hediger ML, Peterson CM, et al. ; ENDO Study Working Group. Incidence of endometriosis by study population and diagnostic method: the ENDO study. Fertil Steril. 2011;96(2):360–365. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Morassutto C, Monasta L, Ricci G, Barbone F, Ronfani L. Incidence and estimated prevalence of endometriosis and adenomyosis in Northeast Italy: a data linkage study. PLoS One. 2016;11(4):e0154227. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Chu KK, Chen FP, Chang SD. Prevalence of endometriosis among women undergoing laparoscopic procedures. Diagn Ther Endosc. 1995;2(1):35–37. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Sinaii N, Plumb K, Cotton L, et al. Differences in characteristics among 1,000 women with endometriosis based on extent of disease. Fertil Steril. 2008;89(3):538–545. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Brawn J, Morotti M, Zondervan KT, Becker CM, Vincent K. Central changes associated with chronic pelvic pain and endometriosis. Hum Reprod Update. 2014;20(5):737–747. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. de Ziegler D, Borghese B, Chapron C. Endometriosis and infertility: pathophysiology and management. Lancet. 2010;376(9742):730–738. [DOI] [PubMed] [Google Scholar]
- 8. Jia SZ, Leng JH, Shi JH, Sun PR, Lang JH. Health-related quality of life in women with endometriosis: a systematic review. J Ovarian Res. 2012;5(1):29. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Nnoaham KE, Hummelshoj L, Webster P, et al. ; World Endometriosis Research Foundation Global Study of Women’s Health consortium. Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertil Steril. 2011;96(2):366–373. e368. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Hudelist G, Fritzer N, Thomas A, et al. Diagnostic delay for endometriosis in Austria and Germany: causes and possible consequences. Hum Reprod. 2012;27(12):3412–3416. [DOI] [PubMed] [Google Scholar]
- 11. Guo SW. Recurrence of endometriosis and its control. Hum Reprod Update. 2009;15(4):441–461. [DOI] [PubMed] [Google Scholar]
- 12. Kikuchi I, Takeuchi H, Kitade M, Shimanuki H, Kumakiri J, Kinoshita K. Recurrence rate of endometriomas following a laparoscopic cystectomy. Acta Obstet Gynecol Scand. 2006;85(9):1120–1124. [DOI] [PubMed] [Google Scholar]
- 13. Chapron C, Souza C, Borghese B, et al. Oral contraceptives and endometriosis: the past use of oral contraceptives for treating severe primary dysmenorrhea is associated with endometriosis, especially deep infiltrating endometriosis. Hum Reprod. 2011;26(8):2028–2035. [DOI] [PubMed] [Google Scholar]
- 14. Chapron C, Chiodo I, Leconte M, et al. Severe ureteral endometriosis: the intrinsic type is not so rare after complete surgical exeresis of deep endometriotic lesions. Fertil Steril. 2010;93(7):2115–2120. [DOI] [PubMed] [Google Scholar]
- 15. Koninckx PR, Martin DC. Deep endometriosis: a consequence of infiltration or retraction or possibly adenomyosis externa? Fertil Steril. 1992;58(5):924–928. [DOI] [PubMed] [Google Scholar]
- 16. Vercellini P, Vigano P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol. 2014;10(5):261–275. [DOI] [PubMed] [Google Scholar]
- 17. Burney RO, Talbi S, Hamilton AE, et al. Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinology. 2007;148(8):3814–3826. [DOI] [PubMed] [Google Scholar]
- 18. Santulli P, Borghese B, Noel JC, et al. Hormonal therapy deregulates prostaglandin-endoperoxidase synthase 2 (PTGS2) expression in endometriotic tissues. J Clin Endocrinol Metab. 2014;99(3):881–890. [DOI] [PubMed] [Google Scholar]
- 19. Santulli P, Chouzenoux S, Fiorese M, et al. Protein oxidative stress markers in peritoneal fluids of women with deep infiltrating endometriosis are increased. Hum Reprod. 2015;30(1):49–60. [DOI] [PubMed] [Google Scholar]
- 20. Leconte M, Nicco C, Ngo C, et al. The mTOR/AKT inhibitor temsirolimus prevents deep infiltrating endometriosis in mice. Am J Pathol. 2011;179(2):880–889. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Ngo C, Nicco C, Leconte M, et al. Protein kinase inhibitors can control the progression of endometriosis in vitro and in vivo. J Pathol. 2010;222(2):148–157. [DOI] [PubMed] [Google Scholar]
- 22. Borghese B, Tost J, de Surville M, et al. Identification of susceptibility genes for peritoneal, ovarian, and deep infiltrating endometriosis using a pooled sample-based genome-wide association study. Biomed Res Int. 2015;2015:461024. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Nyholt DR, Low SK, Anderson CA, et al. Genome-wide association meta-analysis identifies new endometriosis risk loci. Nat Genet. 2012;44(12):1355–1359. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Pagliardini L, Gentilini D, Vigano P, et al. An Italian association study and meta-analysis with previous GWAS confirm WNT4, CDKN2BAS and FN1 as the first identified susceptibility loci for endometriosis. J Med Genet. 2013;50(1):43–46. [DOI] [PubMed] [Google Scholar]
- 25. Borghese B, Barbaux S, Mondon F, et al. Research resource: genome-wide profiling of methylated promoters in endometriosis reveals a subtelomeric location of hypermethylation. Mol Endocrinol. 2010;24(9):1872–1885. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Umezawa M, Sakata C, Tanaka N, et al. Pathological study for the effects of in utero and postnatal exposure to diesel exhaust on a rat endometriosis model. J Toxicol Sci. 2011;36(4):493–498. [DOI] [PubMed] [Google Scholar]
- 27. Crain DA, Janssen SJ, Edwards TM, et al. Female reproductive disorders: the roles of endocrine-disrupting compounds and developmental timing. Fertil Steril. 2008;90(4):911–940. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Benagiano G, Brosens I. In utero exposure and endometriosis. J Matern Fetal Neonatal Med. 2014;27(3):303–308. [DOI] [PubMed] [Google Scholar]
- 29. Mahalingaiah S, Winter MR, Aschengrau A. Association of prenatal and early life exposure to tetrachloroethylene (PCE) with polycystic ovary syndrome and other reproductive disorders in the cape cod health study: a retrospective cohort study. Reprod Toxicol. 2016;65:87–94. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Bruner-Tran KL, Osteen KG. Dioxin-like PCBs and endometriosis. Syst Biol Reprod Med. 2010;56(2):132–146. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Chapron C, Lang JH, Leng JH, et al. Factors and regional differences associated with endometriosis: a multi-country, case-control study. Adv Ther. 2016;33(8):1385–1407. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Holt VL, Weiss NS. Recommendations for the design of epidemiologic studies of endometriosis. Epidemiology. 2000;11(6):654–659. [DOI] [PubMed] [Google Scholar]
- 33. Koninckx PR. Is mild endometriosis a condition occurring intermittently in all women? Hum Reprod. 1994;9(12):2202–2205. [DOI] [PubMed] [Google Scholar]
- 34. Vannuccini S, Lazzeri L, Orlandini C, Tosti C, Clifton VL, Petraglia F. Potential influence of in utero and early neonatal exposures on the later development of endometriosis. Fertil Steril. 2016;105(4):997–1002. [DOI] [PubMed] [Google Scholar]
- 35. Tsutsumi O, Momoeda M, Takai Y, Ono M, Taketani Y. Breast-fed infants, possibly exposed to dioxins in milk, have unexpectedly lower incidence of endometriosis in adult life. Int J Gynaecol Obstet. 2000;68(2):151–153. [DOI] [PubMed] [Google Scholar]
- 36. Somigliana E, Vigano P, Abbiati A, et al. Perinatal environment and endometriosis. Gynecol Obstet Invest. 2011;72(2):135–140. [DOI] [PubMed] [Google Scholar]
- 37. Kunisue T, Watanabe M, Iwata H, et al. Dioxins and related compounds in human breast milk collected around open dumping sites in Asian developing countries: bovine milk as a potential source. Arch Environ Contam Toxicol. 2004;47(3):414–426. [DOI] [PubMed] [Google Scholar]
- 38. Zhao B, Zheng M, Jiang G. Dioxin emissions and human exposure in China: a brief history of policy and research. Environ Health Perspect. 2011;119(3):a112–a113. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39. Bruner-Tran KL, Resuehr D, Ding T, Lucas JA, Osteen KG. The role of endocrine disruptors in the epigenetics of reproductive disease and dysfunction: potential relevance to humans. Curr Obstet Gynecol Rep. 2012;1(3):116–123. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40. Bruner-Tran KL, Gnecco J, Ding T, Glore DR, Pensabene V, Osteen KG. Exposure to the environmental endocrine disruptor TCDD and human reproductive dysfunction: Translating lessons from murine models. Reprod Toxicol. 2017;68:59–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41. Upson K, Sathyanarayana S, Scholes D, Holt VL. Early-life factors and endometriosis risk. Fertil Steril. 2015;104(4):964–971 e965. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42. Liu X, Zhang Q, Guo SW. Histological and immunohistochemical characterization of the similarity and difference between ovarian endometriomas and deep infiltrating endometriosis. Reprod Sci. 2018. Mar;25(3):329–340. [DOI] [PubMed] [Google Scholar]
- 43. Qiu L, Zhao Y, Binns CW, Lee AH, Xie X. A cohort study of infant feeding practices in city, suburban and rural areas in Zhejiang Province, PR China. Int Breastfeed J. 2008;3:4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44. Tu P. The effects of breastfeeding and birth spacing on child survival in China. Stud Fam Plann. 1989;20(6 pt 1):332–342. [PubMed] [Google Scholar]
- 45. Apostolopoulos NV, Alexandraki KI, Gorry A, Coker A. Association between chronic pelvic pain symptoms and the presence of endometriosis. Arch Gynecol Obstet. 2016;293(2):439–445. [DOI] [PubMed] [Google Scholar]
- 46. Mishra VV, Gaddagi RA, Aggarwal R, Choudhary S, Sharma U, Patel U. Prevalence; characteristics and management of endometriosis amongst infertile women: a one year retrospective study. J Clin Diagn Res. 2015;9(6):Qc01–Qc03. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47. Macer ML, Taylor HS. Endometriosis and infertility: a review of the pathogenesis and treatment of endometriosis-associated infertility. Obstet Gynecol Clin North Am. 2012;39(4):535–549. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48. Somigliana E, Vigano P, Benaglia L, Crovetto F, Vercellini P, Fedele L. Endometriosis in a rural remote setting: a cross-sectional study. Gynecol Endocrinol. 2012;28(12):979–982. [DOI] [PubMed] [Google Scholar]
- 49. Meaddough EL, Olive DL, Gallup P, Perlin M, Kliman HJ. Sexual activity, orgasm and tampon use are associated with a decreased risk for endometriosis. Gynecol Obstet Invest. 2002;53(3):163–169. [DOI] [PubMed] [Google Scholar]