Reproductive and Lifestyle Factors Associated with Endometriosis in a Large Cross-Sectional Population Sample

Abstract

Objectives:

Despite the high prevalence of endometriosis among women of reproductive age, risk factors or markers for developing the condition remain largely unknown. Many of the published studies are based on small selected samples. We therefore investigated the relationships of reproductive and lifestyle factors with endometriosis in a large sample of Swedish female twins.

Material and methods:

This cross-sectional study included 28,822 women. Among these, endometriosis was reported by 1,228 women and the self-reported diagnosis was confirmed by medical records. Potential risk factors or markers for risk considered were age at menarche, level of education, body mass index (BMI), parity, oral contraceptive (OC) use, infertility, coffee consumption, smoking, and alcohol intake, which were investigated using logistic regression with crude and adjusted analyses. We performed within-pair analysis to examine the sensitivity of the results.

Results:

Late age at menarche and higher parity showed an inverse association and infertility showed a strong association with endometriosis. We observed positive associations with coffee consumption and smoking and an inverse association with OC use in crude analysis but not in adjusted analysis. There were no significant associations between level of education, BMI, or alcohol intake and endometriosis. Within-pair analysis showed persistent inverse association of parity and association of infertility with endometriosis.

Conclusions:

Our study suggests that late age at menarche and higher parity are inversely associated and infertility is strongly associated with endometriosis. Future studies are needed to explore the significance of these factors in the diagnosis of endometriosis and understanding of its etiology.

Introduction

Endometriosis is a chronic, inflammatory, estrogen-dependent disease defined by the presence of endometrial-like tissue outside the uterus.¹ Endometriosis is most frequently associated with dysmenorrhea, chronic pelvic pain, menorrhagia, dyspareunia, and infertility. It is a complex trait with significant environmental and genetic influences that are likely to affect disease expression.^2,3

A number of menstrual and reproductive factors are suggested as risk factors or markers for endometriosis, such as earlier age at menarche, shorter menstrual cycle length, heavier menstrual volume, and nulliparity.^4

–11 A link between use of oral contraceptives (OCs) and endometriosis is still uncertain. Researchers have observed an increased risk,¹² a protective effect,¹³ and even no association¹⁴ between OC and endometriosis. It has been suggested that up to 50% of infertile women have endometriosis; however, a causal link has not yet been demonstrated.^7,15

Environmental and lifestyle factors are also suggested as risk factors or markers for risk. Although studies have indicated an inverse relationship between endometriosis and body mass index (BMI),^16

–19 there is no consensus as to whether a lean body type is a cause of, or a result of, the disease. Furthermore, one recent study has suggested a positive association between endometriosis and BMI during late childhood.²⁰ Coffee consumption and smoking have also shown diverse associations with endometriosis. One study reported an increased risk²¹ whereas another failed to show any association between coffee and endometriosis.²² Smoking has shown to be either protective^23,24 or not to be associated with the disease.^25,26 A meta-analysis indicated an association between alcohol consumption and endometriosis.²⁷

Study Aim and Objective

Despite the high prevalence of morbidity and healthcare costs, risk factors or markers for endometriosis remain largely unknown. Many studies are limited by design or sample size and have limitations in interpretability of results. Therefore, the objective of this study was to investigate the relationships between reproductive and lifestyle factors and endometriosis in a large sample of female twins aged 20–65 years using data from the population-based Swedish Twin Registry (STR).

Materials and Methods

Study population and data collection

The study population included a cohort of 28,822 female twins aged 20–65 years at interview (mean age 44.45, standard deviation ±12.30)² who participated in two cross-sectional surveys of STR, Screening Across the Lifespan Twin²⁸ with 74% response rate in a cohort born during 1926–1958 and the Swedish Twin Study of Adults’ Genes and Environments²⁹ with 60% response rate in a cohort born during 1959–1985. The data collection process included a detailed set of questions regarding incident diseases, demographical, reproductive, and lifestyle factors. There were 3,595 MZ and 3,601 DZ female twin pairs, where both twins had answered the question on endometriosis. Of the 28,822 women, 1,228 were reported to be diagnosed with endometriosis which was validated with medical records. Medical records from 442 women were scrutinized and the self-reported diagnosis could be validated in 362 cases (82%). In the remaining 18% of the cases, we had received either no information about endometriosis or only information about adenomyosis without endometriosis from the medical records. Potentially, these women were diagnosed in a hospital other than the one from where we requested medical records from, or they might have mistaken adenomyosis for endometriosis. Among all confirmed cases, 80% were diagnosed surgically and 20% clinically.² We confirmed clinically diagnosed cases based on symptoms (severe dysmenorrhea, pelvic pain, dyspareunia, and infertility), physical examination, and sonography, since Ferrero et al.³⁰ have shown that clinically suspected endometriosis (based on symptoms, physical examination, and sonography) could be confirmed by magnetic resonance imaging and/or surgery in 90% of the cases. Thus, self-reported endometriosis had acceptable validity, and we proceeded to perform analyses using the self-reported data.

Assessment of exposures

Potential risk factors or markers of risk were assessed by questionnaires. The women were asked “Have you ever been diagnosed with endometriosis, also called chocolate cysts?” and information on age at interview and age at menarche “How old were you when you had your first menstrual period” at the time of data collection. Question concerning level of education was “What is the highest education you have undergone/are undergoing, how many years in total.” Weight and height were reported at interview and these measures were used to calculate BMI (kg/m²). Information on parity (“Number of children”) was also requested. Regular use of OC pills solely for contraception was questioned and this variable was used in analysis. We also investigated “Do you take hormones as the pill because of menstrual pain” to distinguish from the use for contraceptive purpose. Information on infertility was ascertained with the question, “Have you been investigated or treated for infertility?”

Coffee consumption was assessed by the question, “How many cups of coffee do you drink on average per day?” (do not drink/drink sometime, 1–2 cups, 3–4 cups, or 5 or more cups per day). Cigarette smoking and use of snuff were calculated according to an algorithm based on survey questions, whether they smoked or used snuff regularly, sometimes, or did not use. Exposure of alcohol was assessed using a variable with weekly consumption of alcohol units (i.e., number of drinks per week). Total number of drinks per week was estimated to the sum of the number of glasses of beer (35.5 cL), wine (14.8 cL), and liquor (4.4 cL) per week. These represent the National Institute on Alcohol Abuse and Alcoholism³¹ standard units.

Ethics approval

The study was reviewed and approved by the Regional Ethics Committee in Stockholm, Sweden (diary number 2009/1676-31/2).

Statistical methods

Descriptive information of potential risk factors or markers for subjects with and without endometriosis and also with no response was calculated as absolute numbers and percentage. We performed logistic regression analyses to calculate both crude odds ratios (ORs), where each potential risk factor or marker for endometriosis was analyzed separately and adjusted OR, where all potential risk factors or markers were included in one model simultaneously, together with age at interview. To account for dependencies between twins in pairs, we used cluster robust standard errors and calculated 95% confidence intervals (CIs) based on these. Among the statistically significant risk factors, we also performed within-pair analyses among MZ twins, also called “fixed effect” or “co-twin control,” adjusting confounding factors that are completely shared by both twins in a pair by conditional logistic regression. By conditioning on the twin pair id each twin with endometriosis, the case, is compared with her co-twin, the control, that is, the twin and her co-twin.³² An example of shared factors is genetic factors (MZ twins are genetically identical) and estimates may be interpreted as closer to a potential causal effect. We considered these analyses as a sensitivity test.

Statistical analysis has been conducted using STATA IC 12.

Results

Our study consisted of 28,822 female twins aged 20–65 years at interview. Among them, 1,228 reported that they had received an endometriosis diagnosis. The distribution of demographic profile and response rate of endometriosis cases and noncases is presented in Table 1. We investigated eight potential risk factors or markers for endometriosis. The nonresponses were minimal among those who also answered the question about endometriosis, except for snuff, where the nonresponse was 63.2%. Details are presented in Table 1. Because of the low response rate for snuff, we did not consider this variable in any further analysis. Typically, responding women were more than 40 years old with menarche at 13 years of age. The majority of women had a normal BMI, with parity of two or more children and did not use OC regularly. Infertility was more common among cases than among noncases. Almost 80% of women consumed coffee daily, less than 50% smoked regularly, and alcohol consumption was moderate.

Table 1.

Descriptive Statistics of Subject Characteristics Including Response Rate, Potential Risk Factors, or Markers for Endometriosis

Potential risk factors	With endometriosis (total cases n = 1228), n (%)	Without endometriosis (total cases n = 27 594), n (%)	No response, n (%)
Age at interview, year
<30	50 (4.1)	4387 (16.2)	0
30–40	212 (17.3)	5072 (18.7)
41–50	497 (40.5)	7678 (28.3)
>50	469 (38.2)	10 457 (38.0)
Age at menarche, year
≤11	170 (13.8)	2932 (10.8)	1103 (3.8)
12	261 (21.3)	5682 (21.0)
13	343 (28.0)	7317 (27.0)
14	247 (20.1)	5940 (21.9)
15 or more	171 (14.0)	4656 (17.2)
Level of education, year
≤10	378 (30.8)	7969 (29.0)	453 (1.6)
11–13	405 (33.0)	9039 (33.0)
14 or more	426 (34.7)	10 152 (37.0)
Body mass index (kg/m²)
<18.5	25 (2.0)	756 (2.7)	881 (3.1)
18.5–24.9	757 (61.6)	17 864 (64.7)
25–29.9	321 (26.1)	6304 (22.8)
30 or more	89 (7.2)	1825 (6.6)
Parity
0	305 (24.8)	7210 (26.1)	0
1	234 (19.1)	4019 (15.0)
2 or more	689 (56.1)	16 365 (59.3)
OC as contraceptive
Nonuser	1030 (83.9)	22 325 (81.0)	0
Regular user	198 (16.1)	5269 (19.1)
Infertility
No	853 (69.5%)	25 803 (93.5%)	0
Yes	374 (30.5%)	1785 (6.5%)
Coffee/day
Sometime	254 (20.7)	6904 (25.0)	91 (0.03)
1–2 cups	338 (27.5)	7666 (28.0)
3–4 cups	448 (36.5)	9494 (34.4)
5 cups or more	186 (15.1)	3441 (12.4)
Smoking
Nonsmoker/sometime	638 (52.0)	16 106 (58.3)	148 (0.05)
Regular smoker	582 (47.4)	11 348 (41.1)
Snuff
Nonuser/sometime	388 (31.6)	9423 (34.1)	17 917 (63.2)
Regular user	63 (5.1)	1031 (3.7)
Alcohol intake (drinks/week), unit cL
Nonuser	170 (13.8)	3367 (12.2)	1209 (4.3)
>0–≤4.5	799 (65.1)	17 521 (63.5)
>4.5–9	145 (11.8)	4034 (14.6)
>9 or more	58 (4.7)	1519 (5.5)

OC, oral contraceptive pill.

Late age at menarche was significantly associated with a decreased risk for endometriosis with an OR of 0.75 (CI: 0.60, 0.93) at 14 years and an OR of 0.63 (CI: 0.50, 0.81) at 15 years after adjusting for all considered risk factors or markers. There was no statistically significant association between endometriosis and BMI. Parity of two or more children was inversely associated with endometriosis with an OR of 0.70 (CI: 0.59, 0.83) compared with having no children, in the adjusted analysis. Our analysis showed an inverse association of regular use of OC, but it did not remain significant in the adjusted analysis. Infertility was significantly associated with endometriosis with an OR of 5.04 (CI: 4.35, 5.83) in the adjusted analysis. We also observed a significantly higher risk of endometriosis with daily consumption of coffee and smoking in crude analysis but not in adjusted analysis. Neither level of education with a crude OR of 0.94 (CI: 0.82, 1.09) at education level 11–13 years and crude OR of 0.88 (0.77, 1.02) at education level 14 years or more nor alcohol intake showed any meaningful, statistically significant associations with endometriosis. Details of results are presented in Table 2.

Table 2.

Odds Ratios for Probable Risk Factors or Markers for Endometriosis

Potential risk factors	OR (95% CI)	OR ^a (95% CI)
Age at menarche, year
≤11	Ref	Ref
12	0.79 (0.65, 0.97)	0.82 (0.66, 1.01)
13	0.81 (0.67, 0.98)	0.83 (0.67, 1.01)
14	0.72 (0.59, 0.88)	0.75 (0.60, 0.93)
15 or more	0.63 (0.51, 0.79)	0.63 (0.50, 0.81)
Body mass index (kg/m²)
<18.5	0.78 (0.52, 1.17)	1.30 (0.82, 2.22)
18.5–24.9	Ref	Ref
25–29.9	1.20 (1.05, 1.37)	1.49 (0.93, 2.37)
30 or more	1.15 (0.92, 1.44)	1.36 (0.82, 2.26)
Parity
0	Ref	Ref
1	1.38 (1.15, 1.64)	0.86 (0.70, 1.05)
2 or more	0.99 (0.86, 1.15)	0.70 (0.59, 0.83)
OC as contraceptive
Nonuser	Ref	Ref
Regular user	0.81 (0.70, 0.95)	0.88 (0.74, 1.04)
Infertility
No	Ref	Ref
Yes	6.34 (5.56, 7.23)	5.04 (4.35, 5.83)
Coffee/day
Sometime	Ref	Ref
1–2 cups	1.20 (1.01, 1.41)	1.10 (0.91, 1.32)
3–4 cups	1.28 (1.09, 1.51)	1.04 (0.88, 1.24)
5 cups or more	1.47 (1.21, 1.79)	1.09 (0.88, 1.39)
Smoking
Nonsmoker/sometime	Ref	Ref
Regular smoker	1.29 (1.15, 1.46)	1.11 (0.97, 1.27)
Alcohol intake (drinks/week), unit cL
Nonuser	Ref	Ref
>0–≤4.5	0.90 (0.76, 1.07)	0.94 (0.78, 1.13)
>4.5–9	0.71 (0.57, 0.89)	0.88 (0.70, 1.12)
>9 or more	0.76 (0.56, 1.03)	0.91 (0.65, 1.28)

Adjusted for age at interview (20–65 years), age at menarche, body mass index, parity, OC as contraceptive, infertility, coffee, smoking and alcohol intake.

CI, confidence interval; OC, oral contraceptive pill; OR, odds ratio.

As sensitivity analyses, we performed within-twin-pair analyses among MZ twins, investigating the OR in discordant twin pairs, among factors that were statistically significant in the mentioned adjusted analyses. The results showed a persistent inverse association of endometriosis with parity of two or more children with an OR of 0.31 (CI: 0.16, 0.59) compared with having no children; this means that we could confirm the result in the adjusted analysis. Furthermore, the OR for infertility was 2.65 (CI: 1.58, 4.44) compared with no history of infertility, and as such could confirm the significance of association between infertility and endometriosis. Furthermore, the OR for age at menarche at 14 years was 1.68 (CI: 0.66, 4.31) and at 15 years was 1.21 (CI: 0.45, 3.27) compared with age at menarche <11; thus the significance of the association could not be confirmed.

Discussion

Findings and interpretation

Our cross-sectional study with a large population-based twin sample revealed inverse associations between late age at menarche and higher parity with endometriosis and a strong association between infertility and endometriosis, which were statistically significant after adjusting for all considered risk factors or markers for risk. An inverse association between OC and endometriosis was found, however, not statistically significant in the adjusted analysis.

The findings of an inverse relationship between late age at menarche and endometriosis are in line with findings from previous published studies.^8,10 The majority of previous studies have reported that early menarche (<11 years) increases the risk of endometriosis.^4,7,33
–35 Most of these studies have been based on small sample sizes, and they did not find a linear trend always. In some studies higher levels of estradiol^36,37 and estrone³⁷ have been observed among adult women who had early age at menarche. Evidence shows that estradiol plays an important role in the development of endometriosis,^38
–40 which may explain that higher early exposure to estrogen caused by early age at menarche may cause an increased risk for endometriosis.

Consistent with other published studies, an inverse association with endometriosis was shown for parity with two or more children^7,9,11,40,41 and also a strong association between infertility and endometriosis.^41,42 Parity may be inversely associated with endometriosis in this study because of reverse causation. We speculate that women who have endometriosis are less fertile and are thus less likely to end up having two or more children. The hypothesis that endometriosis causes infertility or a decrease in fecundity remains, however, controversial. It is not clear whether endometriosis and infertility share a common cause or whether infertility is in the etiological pathway to endometriosis.⁴¹

During the use of OC, ovulation is suppressed and the amount of menstrual bleeding is reduced, making OC an effective treatment option for endometriosis. Considering this mechanism, the use of OC might have the potential to also prevent the development of endometriosis; however, this could not be shown in our study. The possibility of a link between use of OC and endometriosis has long been a matter of debate. Studies have shown previous use of OC to be associated with endometriosis later in life,^12,43 whereas others have reported a protective effect^13,44 or could not find any association between use of OC and endometriosis.^5,14 The diversity of findings can be explained by several factors. In previous studies, the indications for OC use as well as the durations of treatment vary between individuals, making interpretation difficult. In our study, only women using OC solely for contraceptive purpose were considered as OC users in the analysis. Although our results pointed toward a protective effect, the association did not remain significant when other risk factors/markers were considered. Our results thus neither support nor oppose the use of OC for primary prevention of endometriosis.

Among women in our study, we could not find an association between smoking and the risk for endometriosis. Our study is in line with a previous large meta-analysis²⁵ and other studies^6,17,26,45 and further strengthens that there is no association between smoking and endometriosis.

We observed no association between BMI and endometriosis, which is inconsistent with previous studies. Others have observed a positive²⁰ or inverse^16,17,19,46 association between BMI and endometriosis. This discrepancy could be because of lack of information regarding BMI before the onset of the disease. Nagle et al.²⁰ collected data on BMI when women were 10–16 years of age, whereas Shah et al.¹⁸ in their large prospective study used the BMI reported by women both at the time of data collection and when they were 18 years of age. In our study, we asked for the information of BMI at the time of interview, and most women probably had a lower BMI at younger age, since BMI usually increases with age.⁴⁷ We are concerned about the possibility of recall bias and reverse causation because of our study design. That may be a reason why we did not observe association between BMI and endometriosis. However, the biological mechanisms behind a possible association are not clear and further work should focus on elucidating underlying biological relationships that contribute directly to the initiation and promotion of endometriosis in association with different BMIs.

This study showed no association between consumption of coffee and endometriosis, after adjustment for other risk factors/markers. Our result is consistent with the result of a recent meta-analysis²² and further strengthens the result of no association between coffee consumption and endometriosis. We observed no meaningful association between alcohol consumption and risk for endometriosis. One recent meta-analysis concluded that alcohol consumption is associated with an increased risk for endometriosis.²⁷ The limitation of this is that it is impossible to evaluate whether alcohol exposure preceded the development of endometriosis. Thus, they could not exclude that the observed association is explained, at least in part, by reverse causation.

Strength and weaknesses

To our knowledge, this is one of the largest studies to date on investigation of reproductive and life style factors or markers as risk factors for endometriosis. Previous large studies have examined in total 116,678 females with 1,766 endometriosis cases⁷ and 17,032 women with 313 endometriosis cases.⁴⁴ Other studies were small including a total of 512–976 women with 168–410 endometriosis cases.^10,12

This study also has limitations, which should be considered. It is a cross-sectional study where information was collected at one time point with no follow-up, which probably affected the prevalence of endometriosis. Reverse causality bias may be introduced in cross-sectional studies because exposure is ascertained at the same time point as the outcome. As the delay in diagnosis of endometriosis can be 7–10 years, it is difficult to report the timing of exposure in a retrospective survey. Consequently, because the true time sequence of events is unknown, we cannot ascertain that the exposure preceded the outcome. Furthermore, diagnostics criteria for endometriosis have varied during the years, a fact that might have contributed to underdiagnoses especially among women who were diagnosed before surgical confirmation became a requirement for the diagnosis of endometriosis. Self-reported age at menarche may be uncertain, but it would have the same impact also on the control group. One problem with all studies on endometriosis is to assure that the nondiseased group is free of endometriosis and the impossibility of knowing the exact onset of disease, as opposed to the date of diagnosis.⁷ There is also a possibility of recall bias, even if we tried to limit recall bias through the use of a highly structured questionnaire.

Conclusion

Our cross-sectional study of a large population-based twin sample revealed inverse association of endometriosis with reproductive factors such as late age at menarche and parity with two or more children. This study also reported a strong association between infertility and endometriosis. It is not known so far whether infertility causes endometriosis or is a consequence of endometriosis. It is also not clear whether endometriosis and infertility share a common cause. Further research is needed to find out the causality. This study highlights the need for well-designed prospective studies with more information about confounders and the need to understand the significance of these factors in the diagnosis of the endometriosis and understanding of its etiology. Future studies should also focus on other potential risk factors or markers for endometriosis not previously extensively studied such as exposure to drugs or other environmental factors with special focus on childhood and adolescent women.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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