Endometriosis is defined as the presence of endometrial glands and stroma outside the uterine cavity, mainly in the pelvic peritoneum.1 The external endometrial fragments are influenced by ovarian hormones, and they cyclically bleed in the pelvis as they would within the uterus. This induces inflammatory reactions, scarring, and adhesion to surrounding tissues, which can lead to debilitating symptoms. A prevalence of 6–10% has been estimated in women of childbearing age.1 Despite this frequent occurrence, substantial associated costs,2 and considerable adverse effects on quality of life,3 the etiology of endometriosis is still poorly understood. There is strong evidence for the involvement of female hormones and some disruption in immunologic processes in endometriosis,4 although it is unclear whether immune dysfunction is a cause or a consequence of the disease.5 However, the only recognized risk factors to date are those reflecting increased exposure to menstruation (ie, earlier menarche, shorter menstrual cycles, and nulliparity), and modifiable risk factors remain to be identified.4
Endometriosis is diagnosed mostly in young women, with a reported peak of incidence before 30 years of age.6 Because there is a substantial delay between onset of symptoms and surgical diagnosis,3 the true onset of the disease is likely to occur at an even younger age. Indeed, case series among teenagers have suggested endometriosis onset during adolescence: endometriosis prevalence was shown to be 69–74% among adolescents with chronic pelvic pain.7,8 Because these reports date from the 1990s and laparoscopic diagnostic techniques have now considerably improved, those prevalence estimates are probably underestimated.9 Childhood and adolescent ages could thus be of particular importance in endometriosis onset, and the study of exposures occurring during these periods may help identify early predictors of endometriosis. We explored the potential relationships between several early hormonal and environmental exposures and endometriosis risk.
The E3N Cohort
E3N is a prospective cohort study involving 98,995 French women born in 1925–1950 and insured by a national health scheme mostly covering teachers. Women were enrolled in 1989–1991 after returning a baseline self-administered questionnaire on their lifestyle and medical history along with an informed consent declaration. Follow-up questionnaires were sent every 2–3 years thereafter.
Case Definition and Ascertainment
The 1992 questionnaire retrospectively asked participants whether endometriosis had been diagnosed, requesting information about age at diagnosis, type of treatment, and procedures that enabled diagnosis. Subsequent follow-up questionnaires continued to collect this information prospectively. Because endometriosis occurs mostly in women of reproductive age, we considered both prevalent cases (ie, diagnosed before the 1992 questionnaire, reported retrospectively) and incident cases (ie, diagnosed after the 1992 questionnaire, reported prospectively) to avoid including only late-diagnosed cases, and we used a case-control design for analysis. Compared with prevalent cases, women with incident endometriosis were more likely to be young at inclusion, to be parous, and to have ever used hormonal treatments. They were similar in height, body mass index at inclusion, body silhouette at 20–25 years of age, age at menarche, and menstrual cycle length before 17 years of age (data not shown).
Because laparoscopic surgery is the gold standard for endometriosis diagnosis,1 we restricted our analyses to only those cases reported as diagnosed or treated by laparoscopy or surgery. We performed a validation study by sending a specific questionnaire to 200 randomly selected women who self-reported surgical treatment or diagnosis of endometriosis. We asked women to confirm their date of diagnosis and to provide pathology or hospitalization reports and contact details for their physicians. A validation committee reviewed all documents; a mention of the presence of endometriosis was sought, and the women’s physicians were contacted in case of dubious reports until a definitive conclusion was made. Among the 183 cases who replied (92%), 75% (137 of 183) were confirmed, and the date of diagnosis was correctly reported in 82% of the validated cases (112 of 137). The self-reported diagnosis was incorrect in 17% of cases (31 of 183), and no clear conclusion could be drawn in 8% of cases (15 of 183) (ie, no information on symptoms or disease history, or no medical reports were provided). Among the 31 self-reports of endometriosis that were not confirmed, the alternative explanations were endometrial hyperplasia (55%), adenomyosis (29%), and abdominal pain of unknown cause (16%).
Assessment of Exposures
We recorded age at menarche in the 1990 and 1992 questionnaires. For women in whom data were available in both questionnaires (n = 79,282), the correlation coefficient between the two responses was 0.92. The 1992 questionnaire contained information on menstrual cycle length and cycle regularity before 17 years of age.
The 2002 questionnaire asked about childhood exposures to cats and dogs at home, whether women had lived on a farm for at least 3 successive months during childhood, and if so, the type of animals they were exposed to and their age at first pet or farm animal exposure. To further explore the potential influence of exposure to animal allergens, we used previously created ecological variables.10 Counties of birth with <5000 inhabitants were considered as rural, according to the General Agricultural Census definition. We also used a “bovine score,” which combines information on number of cattle per inhabitant and size of county of birth, calculated based on the General Agricultural Census data.10 Similar scores were constructed for horses, goats, sheep, pigs, and poultry.
The 1992 questionnaire collected data on passive smoking during childhood. We asked the women to recall whether their parents smoked when they were a child and the typical amount of time the women remained in a smoky room during their childhood. The baseline questionnaire collected level of suffering from food deprivation during World War II, county of birth, out-of-school physical activity, and walking activity at 8–15 years of age. To assess the influence of food deprivation at a young age (≤20 years), we restricted our analysis on World War II food deprivation to the women born in or before 1945.
Assessment of Covariates
Women reported their parity in 1990 and 1992. At baseline, we recorded data on body shapes at various ages using figure drawings proposed by Sørensen et al11 (eFigure, http://links.lww.com/EDE/A645), with drawings ranking from 1 to 8 corresponding to increasing body size from leanest to largest. Body shape at 20–25 years of age was chosen for the adjustment models because the association between body shape and endometriosis risk was strongest at that age (data not shown). We created three categories of body shape: lean (drawings ≤ 2), medium (drawing 3), and large (drawings ≥ 4). We calculated a body mass index at baseline as weight in kilograms divided by height in meters squared. We collected information on the use of oral contraceptives (OCs) and premenopausal progestagens in 1992 and then updated these data in each follow-up questionnaire.
Population for Analysis
We excluded from the analysis all women who did not report endometriosis as treated or diagnosed through surgery or laparoscopy (n = 1,061). We also excluded women with primary amenorrhea (n = 26) and those who reported diagnosis before menarche (n = 5) or after menopause (n = 518), because endometriosis is rare in these settings. We further excluded women with missing information on age at menarche (n = 1,567) or on age at endometriosis diagnosis (n = 691), and those who reported a personal cancer history (n = 19,209). Our final sample for analysis consisted of 75,918 women.
Statistical analyses were performed with SAS version 9.2. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models. The effect of childhood and adolescent exposures on endometriosis risk was first assessed in models adjusted for birth cohort (1925–1930, 1931–1935, 1936–1940, 1941–1945, 1946–1950), height (<160, 160–164, ≥165 cm), body shape at 20–25 years of age (lean, medium, large), parity (nulliparous, parous), age at menarche (<12, 12–14, ≥15 years), and menstrual cycle length before 17 years of age (irregular or regular cycles of ≤24, 25–31, ≥32 days). In separate models, we further adjusted for time-varying use of OCs and premenopausal progestagens, to ensure that hormonal treatment for endometriosis did not confound our findings. Tests for linear trend were performed in models where each factor of interest was entered as an ordinal variable. Because occurrence of endometriosis in our cohort was reported both retrospectively and prospectively, we conducted our analyses separately using prevalent (n = 2,126) and incident (n = 558) cases. We tested for homogeneity over strata using chi-square tests.12 Data were considered as missing if the women responded to the questionnaire but provided no information on the considered factor. A “missing” category was created for the variables of interest, and the numbers of missing values are provided as footnotes in the tables. For adjustment factors, missing values were imputed to the median or the modal category if occurring in <5% of observations; otherwise, these values were excluded. In this case, we checked that the results were not modified when values were imputed to the modal category instead of being excluded.
The final study sample consisted of 75,918 women, among whom 2684 cases of endometriosis were reported. The average age at diagnosis was 40 years (standard deviation = 8.1 years). Table 1 presents the characteristics of the participants.
Regarding hormonal factors, we observed in fully adjusted models an increased risk of endometriosis in women with earlier menarcheal age (Table 2). Shorter menstrual cycles before 17 years of age were associated with an increase in endometriosis risk (OR = 1.15 [95% CI = 0.98–1.35]). There was no overall association between regularity of menstrual cycles before 17 years of age and endometriosis.
We observed a 12% increase in endometriosis risk in women who were exposed at home to cats and dogs during their childhood (Table 3). Exposures to either cats or dogs were not associated with risk, whereas exposure to both was (1.18 [1.07–1.31]). There was no heterogeneity among these three categories, however (test for homogeneity, P = 0.17), and the association between pet exposure and endometriosis risk did not differ according to age at first exposure. Women who reported having lived on a farm for at least 3 consecutive months during childhood had a 12% increased endometriosis risk (2–24%), and there was no heterogeneity according to age at first exposure (test for homogeneity, P = 0.68). When considering type of farm animal, women who reported having been exposed to cows, pigs, and sheep while living on a farm for ≥3 months had no risk, whereas those reporting exposure to other (not further specified) animals had a 24% increased endometriosis risk (8–43%). To better understand this finding, we used the ecologic variables described above10: there was no association between endometriosis risk and size of county of birth (<5000 vs. ≥5000 inhabitants) and no association with any of the derived animal scores (number of cattle, horses, goats, sheep, pigs, and poultry per capita in women’s county of birth) (data not shown).
Although parental smoking per se during the women’s childhood was not associated with endometriosis, the reported level of indoor exposure to passive smoking during childhood was linearly associated with a higher endometriosis risk (test for trend, P = 0.0008; Table 4). To assess whether these associations differed according to the participants’ own smoking habits, we stratified the analyses according to the women’s smoking at the time of the questionnaire. Although ever-smokers were more likely to report passive smoking in childhood, ORs were reduced in this stratum, whereas they were higher in never-smokers. We detected heterogeneity in the category “a few hours per week,” but not in the other passive-smoking categories (data not shown).
We found a linear relationship between level of World War II food deprivation before 20 years of age and endometriosis risk (test for trend, P = 0.0008; Table 4). Because age at menarche is associated with both early food deprivation13 and endometriosis risk,4 we investigated a potential interaction or mediation effect of menstrual cycle characteristics in the relation of food deprivation to endometriosis risk. There was no interaction between food deprivation from World War II and menstrual cycle length before 17 years of age (P = 0.86), menstrual cycle regularity before 17 years of age (P = 0.83), or age at menarche (P = 0.14). The results were almost identical with or without these menstrual characteristics in the model, thus dismissing a mediation effect in the relationship between food deprivation and endometriosis risk.
Although out-of-school physical activity at 8–15 years of age was unrelated to endometriosis, there was a modest dose-response relationship between walking activity at 8–15 years of age and endometriosis risk (test for trend, P = 0.008; Table 4).
For all studied factors, results were almost identical when additionally adjusted for use of OCs or premenopausal progestagens (data not shown). In addition, we found no evidence of heterogeneity in analyses stratified according to the prevalent or incident status of cases. To assess whether our results differed according to diagnosis method, we performed a sensitivity analysis by repeating analyses according to three case definitions: (1) all reported cases; (2) cases reported as treated or diagnosed by a physician through any procedure; and (3) cases reported as treated or diagnosed by laparoscopy or surgery only; most associations were stronger with increasing level of endometriosis ascertainment (data not shown).
We found that earlier menarcheal age and shorter menstrual cycle length were associated with a higher risk of endometriosis. Endometriosis risk modestly increased with childhood exposure to pets at home and with living on a farm for 3 consecutive months or more, although through no specific type of farm animal exposure. We observed positive linear relationships among frequency of indoor exposure to passive smoking during childhood, level of World War II food deprivation, and endometriosis risk. There was also a modest dose-response association between weekly walking activity at 8–15 years of age and endometriosis risk, but no association with out-of-school physical activity at those ages.
The distribution of self-reported age at endometriosis diagnosis in the E3N cohort is unusual, as it peaks around 45–49 years of age,14 whereas the most recent data show a peak of incidence before 30 years of age.6 However, as we have previously discussed,14 age at endometriosis diagnosis in our cohort is assessed over an unusually long period of time (1942–2003), with a distribution that reflects both the shift in diagnostic procedures in the 1990s and a decline of endometriosis diagnosis with age.14 E3N women were born between 1925 and 1950, and considering the early onset of endometriosis that we know today, the period during which these women were at risk for diagnosis likely started around 1935–1960. During those decades, laparoscopy was not yet the standard diagnostic procedure for endometriosis, and diagnosis is likely to have been even more delayed at that time; hence, the unusually late age at endometriosis diagnosis in our cohort.
The higher endometriosis risk with earlier menarche is consistent with prospective15 and case-control studies,16–19 although a previous case-control study in infertile women reported higher risk associated with later menarche.20 Only two studies evaluated early menstrual cycle characteristics,15,19 and their results are consistent with reports of a higher endometriosis risk with shorter menstrual cycles in adulthood.17,18,20–22 Our findings are in line with those reports and could suggest either that endometriosis risk is increased with increased exposure to menstruation and female sex hormones or that endometriosis modifies the hormonal milieu, resulting in disruption of menstrual cycling onset and characteristics.
To our knowledge, this investigation is the first to assess associations between endometriosis and early exposure to environmental factors that may modify immunologic and inflammatory processes (such as pet or farm animals, living on a farm, passive smoking, and food deprivation). Our results regarding exposure to pet or farm animals or farm dwelling were expected in the opposite direction. Indeed, endometriosis has been associated with immune dysfunction and hyperstimulation of the immune system4 and, in particular, with atopic diseases or allergy.23–25 Because early exposure to pet or farm animal allergens has been suggested to protect from asthma and allergic manifestations10,26,27 (including in our cohort),10 we anticipated a similar association with endometriosis. The modest positive associations may suggest a deleterious influence of other factors related to early animal exposure (such as microbial, virus, or endotoxin exposure) on immune function and endometriosis. Because we could not determine any specific type of farm animal involved in the association between early farm dwelling and endometriosis risk, the association may be due to factors unrelated to the presence of animals, such as exposure to pesticides, fertilizers, or other pollutants. Increasing experimental evidence suggests an influence of environmental toxicants on endometriosis development, such as dioxin or dioxin-like compounds,28–30 which are known to disrupt endocrine and immune functions.5 Recently, persistent organochlorine pesticides have also been shown to increase endometriosis risk in a laparoscopic cohort of U.S. women,31 and other studies have reported increased risks with higher concentration of phthalates,32,33 polychlorinated dibenzodioxins and polychlorinated dibenzofurans,34 and polychlorinated biphenyls.35 Considering the small magnitude of our associations, however, we cannot rule out a spurious association owing to unknown residual confounders. Further research is required to confirm associations of endometriosis with exposure to animals and with farm dwelling during childhood and to understand the underlying mechanisms.
Active cigarette smoking in adulthood or adolescence has generally been associated with decreased endometriosis risk in previous research,6,16,21,36 in line with the known antiestrogenic effect of inhaled tobacco smoke.37 Our findings suggest a linear association in the opposite direction for indoor exposure to passive smoking during childhood. Our sensitivity analyses according to the women’s own smoking status suggest that ever-smokers may have reported less accurately their passive smoking exposure than did never-smokers, which could have underestimated the association in ever-smokers. However, the inverse relation between active smoking and endometriosis likely diluted the positive association between passive smoking and endometriosis risk, whereas the stronger association observed in never-smokers reinforces our hypothesis of a deleterious effect of passive smoking on endometriosis risk. Smoke products that are passively absorbed differ in quantities and quality from those absorbed through active smoking. The antiestrogenic effect may be minimal through passive smoking, whereas a deleterious effect on endometriosis risk through exposure to some toxic compounds in tobacco smoke, such as polycyclic aromatic hydrocarbons38 or dioxins,39,40 may dominate. Early exposure to these toxic compounds could also have an impact on immune functions during early life, in that alterations of the immune system have been observed in endometriosis.5 This is the first study showing a negative effect of passive smoking during childhood on endometriosis risk; further research is needed to confirm this intriguing relationship.
Considering that endometriosis risk increases with exposure to menstruation,4 and because women exposed to World War II food deprivation as children experience later menarche,41 early famine exposure could be expected to reduce endometriosis risk. In addition, early exposure to famine has been associated with development of metabolic syndrome,42,43 diabetes,44 and hyperglycemia45 in adulthood; because insulin resistance is associated with reduced ovulation,46 this could lead to reduced endometriosis risk. However, we found a higher endometriosis risk with World War II food deprivation. One hypothesis for this finding is that early food deprivation may irreversibly alter women’s reproductive or immune functions. Indeed, famine exposure during childhood has been suggested to impair the adult female reproductive function in a Dutch study, in which severe childhood famine was associated with lower chances of childbirth at any given time after marriage, and risk of a medical reason (including endometriosis)47,48 for having no or fewer children than wanted was higher in women exposed to severe famine.47 In addition, malnutrition has deleterious effects on immunity.49 Experimental studies have shown that glucose deprivation compromises the activity of the immune system in female rodents50 and that intrauterine growth restriction in mice is associated with a smaller thymus,51 a key organ of the immune system. The potential association between early food deprivation and endometriosis risk deserves further investigation.
Although adult physical activity has been associated with lower endometriosis risk and improvement of symptoms,21,52–55 little is known about the influence of childhood or adolescent physical activity on endometriosis. Herein, we found a positive dose-response relationship between walking activity at 8–15 years of age and endometriosis. Only two previous studies have investigated adolescent physical activity in relation to adult endometriosis risk. The first study reported a 27% increased endometrioma risk for any physical activity at 12–21 years of age, but with no evidence of linear trends with activity intensity, frequency, or duration.52 The Nurses’ Health Study II found a positive linear relationship between physical activity at 12–13 years of age and endometriosis risk. Specifically, risk increased in those reporting strenuous physical activity at those ages, although other types of physical activity and activity at any other adolescent age were unrelated to risk.56 We were not able to examine multiple types of physical activity during childhood or adolescence, and our positive findings focused on walking, an activity of mild intensity. However, walking may be the activity that women remember the most from their childhood, at a time when people used to walk frequently. These results might suggest that the early adolescent period is a critical window of exposure for the initiation or the implantation of endometriosis lesions, which physical activity might promote at that age. The results should nonetheless be interpreted with caution relative to the association between body shapes during childhood or adolescence and endometriosis57; although we adjusted for this factor, we cannot rule out residual confounding in the association between childhood or adolescent physical activity and endometriosis risk.
Strengths of our study include the large sample size, regularly available information on endometriosis diagnosis and treatment, and detailed data on childhood and adolescent exposures. As to limitations, although it has been suggested that fertile and infertile women with endometriosis have different risk factor profiles,58 our data on infertility were not sufficiently reliable to assess potential interactions according to this factor. Future studies should include accurate infertility data allowing for stratified analyses, as this may help identify differential associations. A limitation that is inherent to the study design is the long time-frame between the studied exposures and disease occurrence. We cannot rule out possible confounding due to unmeasured factors in adulthood that may mediate the relationships between childhood or adolescent exposures and endometriosis risk. Prospective studies including young populations will be needed to confirm our findings. In our study, endometriosis diagnosis was self-reported, which could have induced misclassification; however, restricting the outcome definition to endometriosis reported as treated or diagnosed by surgery or laparoscopy is likely to have substantially decreased misclassification, as supported by the high confirmation rate of endometriosis cases in our validation study and by validation data in the Nurses’ Health Study II.58 Because endometriosis can be asymptomatic, in the absence of a systematic surgical assessment, some endometriosis cases may have been misclassified in the noncases group. However, although endometriosis is not a rare disease, the impact of false negatives in such a large population of noncases is likely to be low and would mostly result in diluting associations. Most cases were reported retrospectively, which could lead to recall bias. However, conducting the analysis separately in prevalent and incident cases did not substantially modify our findings and yielded no heterogeneity between subgroups. In addition, covariates were reported retrospectively and are thus subject to recall bias. Although reproducibility could not be tested for all covariates, previous repeatability studies on various self-reported factors in our cohort showed high agreement levels,14,59,60 suggesting reasonable quality of the cohort data. Moreover, because any recall bias in exposure assessment is likely to be nondifferential between cases and noncases, it would probably result in underestimating the associations.
In conclusion, this large study confirms reported associations between endometriosis risk and earlier menarcheal age or childhood or adolescent physical activity, and it also potentially identified novel endometriosis predictors among exposures occurring in childhood or adolescence. Although the size of the associations was modest and not always in the expected direction, a large number of novel associations was detected. Therefore, these findings call for further research to explore the underlying mechanisms for endometriosis development.
We are grateful to the study subjects for their continued participation and to Nicolas Chopin, Hervé Foulot, and Charles Chapron for reviewing endometriosis cases for the validation study. We warmly thank Nicole Mathieu (CNRS, UMR Ladyss [Social Dynamics and Reconstruction of Spaces], Paris, France), Francine Kauffmann, Marie-Pierre Oryszczyn, Nicole Le Moual, and Raphaëlle Varraso (Inserm, CESP Centre for Research in Epidemiology and Population Health, U1018, Respiratory and Environmental Epidemiology Team, Villejuif, France; Univ. Paris Sud 11, UMRS 1018, Villejuif, France) for the design of the questions on animal exposure and farm dwelling and for the creation of the ecological variables on rurality and animal scores. We also thank Rafika Chaït, Marie Fangon, Lyan Hoang, Céline Kernaleguen, and Maryvonne Niravong for managing the data.
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