1 Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.
2 Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle, WA.
Received for publication August 16, 2002; accepted for publication January 22, 2003.
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ABSTRACT |
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case-control studies; endometriosis; exercise
Abbreviations: Abbreviations: CI, confidence interval; MET, metabolic equivalent; OR, odds ratio.
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INTRODUCTION |
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The etiology and pathogenesis of endometriosis are not well understood, and prevalence estimates vary according to the study population, underlying the difficulty in determining risk factors for the disease. Nonetheless, the role of endogenous characteristics in the growth and maintenance of endometriosis has been widely reported (7). These characteristics include factors related to menstruation, such as early age at menarche (814) and shorter cycle length (8, 9, 1116), and hormonal factors such as circulating estrogen (17). Environmental and behavioral factors that can potentially influence endogenous factors are of particular interest in preventing and controlling this disease. Regular exercise, which is associated with reduced cumulative exposure to menstrual flow, decreased ovarian stimulation, and estradiol production (18), is one such factor.
Prior studies of the association between endometriosis and physical activity did not distinguish between different forms of the disease (superficial vs. deep infiltrating lesions, site of disease, etc.) and yielded mixed results (8, 13, 14). A population-based, cross-sectional survey in a Norwegian county found no association (13), whereas two case-control studies in the United States reported a decreased endometriosis risk associated with strenuous exercise for at least 3 hours a week (8, 14). The previous studies were based on self-reported or infertile cases of all types of endometriosis combined and considered only current, regular, and strenuous exercise. Our study focused on one specific type of significant endometriotic disease (endometriomas), captured all newly diagnosed medically confirmed cases within a defined population, and examined a broad range of physical activity over two time periods of possible etiologic relevance as well as varying levels of intensity, duration, and frequency. In this study, we evaluated the risk of endometriomas associated with physical activity, both in the recent past and during adolescence and early adulthood.
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MATERIALS AND METHODS |
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We obtained the participation of 83.9 percent of eligible benign neoplasm cases (n = 162) and 82.2 percent of eligible controls (n = 755) through written informed consent. The current analysis was based on the subset of benign neoplasm cases with cystic ovarian endometriosis, which consisted of 77 women with a surgically confirmed endometrioma diagnosis (International Classification of Diseases, Ninth Revision, code 617.1) and 735 controls without a history of endometriosis. The study was approved by the Group Health Cooperative and the Fred Hutchinson Cancer Research Center human subjects review committees.
Physical activity
In-person interviews were conducted to collect information on demographic characteristics as well as medical, menstrual, reproductive, contraceptive, and physical activity histories prior to the reference date. Women were asked to report their physical activity during the 2 years prior to the reference date and between the ages of 12 and 21 years according to the following question: "During this time, did you do any strenuous physical activities, exercise or sports on a regular basis, that is, at least 24 times a year? Include walking for pleasure to and from work/school, if at least 1 mile [1.61 km]. Include indoor and outdoor sports." The questions were based in part on the Minnesota Leisure Time Physical Activity Questionnaire, which has been widely used and evaluated in the exercise science and public health fields (19, 20). Women reported up to four activities; for each, the ages at which they started and stopped, the time spent per episode, the frequency, and the number of months per year that they engaged in the activity were recorded.
To account for varying levels of energy expenditure, a metabolic equivalent (MET) was assigned to each activity. A MET is the ratio of the metabolic rate for a specific activity to a standard resting metabolic rate of 1.0 kcal per kilogram of body weight per hour; one MET is defined as the rate during quiet sitting. Therefore, a 3.0-MET activity would require three times the metabolic energy expenditure of sitting quietly. Intensity codes (in METs) are available in the updated version of the Compendium of Physical Activities (21), which includes 605 specific activities with intensity codes ranging from 1.0 (sitting) to 15.0 (speed skating). In the present study, all activities were categorized as low, medium, or high intensity. On the basis of previous studies (20, 22, 23) and on data indicating that conditioning or heavy activities require more than 50 percent of the average maximal oxygen intake (19), we defined high-intensity activities as those with intensity codes of ≥6.0 METs, such as running, bicycling, and tennis. Activities of moderate intensity (4.05.9 METs) consisted of those such as gardening, dancing, and softball; low/light activities (<4.0 METs) included golf, bowling, and walking for pleasure. For a complete list of activities and intensity codes, refer to the Appendix.
Statistical analysis
Unconditional logistic regression analysis was used to calculate odds ratios as an estimate of the relative risk and 95 percent confidence intervals for the association between physical activity and the risk of endometrioma (24). Separate analyses were conducted for the 2-year period prior to the reference date and the period between the ages of 12 and 21 years. The analyses were based on five different measurements of physical activity during each period: 1) any physical activity versus none; 2) the highest intensity level of activity defined as low intensity, moderate intensity, or high intensity versus none (four mutually exclusive categories); 3) the total number of hours spent engaging in high-intensity activity (in tertiles) versus no high-intensity activity; 4) the total number of episodes of high-intensity activity (in tertiles) versus no high-intensity activity; and 5) high-intensity physical activity ≥three times/week, ≥30 minutes/episode, and ≥10 months/year for 2 years (for the 2-year period) or for ≥5 years (for the period between the ages of 12 and 21 years) versus no high-intensity activity during the relevant period. Tertiles were used to compare the distribution of number of hours and episodes, and the cutpoints were based on the distribution of these exposures among the controls.
To account for the difference in age between cases and controls, we adjusted the proportion of controls to the age distribution for endometrioma cases based on the following groups: ≤24 years, 2529 years, 3034 years, and 3539 years. Age standardization was conducted for the univariate presentation of results shown in table 1.
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RESULTS |
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Physical activity during the 2 years prior to the reference date
We found no association between "any physical activity" during the 2 years prior to the reference date and risk of endometrioma after controlling for age, number of livebirths, oral contraceptive use, and cigarette smoking (odds ratio (OR) = 0.90, 95 percent confidence interval (CI): 0.54, 1.52; table 2). A nonsignificant decreased risk was found for women who reported any high-intensity activity (OR = 0.74, 95 percent CI: 0.42, 1.31; table 2), whereas those who engaged in exclusively low and/or moderate activities had no difference in risk relative to those who reported no physical activity.
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Physical activity between 12 and 21 years of age
After we controlled for age, physical activity between the ages of 12 and 21 years was not associated with risk of endometrioma ("any physical activity"; OR = 1.27, 95 percent CI: 0.75, 2.15; table 3). The risk did not differ significantly by the intensity level of activity. When we focused on high-intensity activity, no significant reduction in risk was associated with increased duration or frequency of activity, although a lower risk was observed for women in the highest tertile (105 minutes per week) of high-intensity hours (OR = 0.82, 95 percent CI: 0.38, 1.77). A similar trend was observed for women reporting the highest frequency of activity (>1.5 times per week) of physical activity during adolescence (OR = 0.47, 95 percent CI: 0.18, 2.23). We found no significant interaction between age at the reference date and physical activity during this period (data not shown).
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DISCUSSION |
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One advantage of the current study is that the intensity level of physical activity was based on the determination of METs for specific activities by using the recently updated Compendium of Physical Activities (21) and not on a study subjects interpretation of "vigorous" or "regular" exercise. We were also able to evaluate the combined effects of duration, frequency, and intensity level of physical activity and consequently activity levels suggested in public health recommendations (26). The inverse associations between physical activity and endometriotic disease in the current study are similar to those found in the two previous studies (8, 14) even though cases in our study were women with more severe disease and cases in previous studies had infertility-associated endometriosis, often a mild or moderate form of disease. In a cross-sectional study in Norway (13), investigators compared women with and without a self-reported diagnosis of endometriosis and did not find a reduced risk associated with "regular" exercise (OR = 0.7, 95 percent CI: 0.3, 1.5). In that study, the investigators did not define "regular" exercise or specify exercise prior to diagnosis as the relevant exposure period. In none of the three studies (8, 13, 14) did the authors address whether the presence of preexisting disease may have influenced the levels of recent physical activity reported by endometriosis cases. Our study was able to address this issue by obtaining exercise patterns during adolescence, a time when activity would unlikely be affected by undiagnosed disease.
This population-based study was designed to include a representative sample of defined cases with one type of serious endometriotic disease (endometriomas) as opposed to previous studies, which were based on self-reported or infertility-associated endometriosis. The majority of cases in our study (96.1 percent) had no prior history of ovarian endometriosis, and all cases of disease were confirmed surgically, increasing diagnostic validity. Although cases were limited to a subset of women with more severe disease, they represented a homogeneous group etiologically, which enabled a more precise evaluation of potential risk factors. Controls were randomly selected and thus considered representative of the defined source population (female enrollees in the Group Health Cooperative). Although controls were considered disease free, without a diagnostic evaluation confirming the absence of disease, one cannot exclude the possibility that some of them may have harbored undiagnosed endometriosis. One would expect routine and strenuous activity to take place less often among these women, which would result in bias toward the null.
A potential explanation for the decreased endometrioma risk we observed in relation to strenuous physical activity is a reverse temporal sequence of events whereby cases did not engage in physical activity because of symptoms indicative of preexisting, undiagnosed disease. To address this possibility, we conducted two additional analyses to assess the impact of symptoms on consistent, high-intensity physical activity during the 2 years prior to diagnosis. In one such analysis, we excluded women who reported severe pain or heavy bleeding associated with menstruation (n = 65). We found a similar reduction in risk associated with regular, high-intensity activity for the remaining women (OR = 0.32, 95 percent CI: 0.13, 0.80). Although we did not have information on chronic pelvic pain, we asked cases whether a symptomincluding pelvic pain, pressure, fullness; vaginal bleeding heavier than during a period; delayed or irregular menstruation; and other symptomsprompted the visit that ultimately led to diagnosis. In an additional analysis, we excluded cases who reported having a symptom for more than 3 months (n = 24) and found a slightly attenuated effect consistent with a 61 percent reduction in endometrioma risk (OR = 0.39, 95 percent CI: 0.14, 1.07). We were unable to assess the presence of chronic pelvic pain, which might have led to a reduced pattern of physical activity among some women with endometriomas prior to their diagnosis, contributing to the observed decrease in risk associated with current activity. However, past research has found that only 7 percent of women with ovarian endometriosis report severe pelvic pain (27), reassuring us that this factor is unlikely to fully explain our results. Moreover, we found a trend toward reduced risks for women reporting consistent and strenuous activity between the ages of 12 and 21 years, a time when temporal ambiguity is unlikely, supporting the plausibility of a true inverse association.
We did not find an association between endometrioma risk and exclusively low- to medium-intensity activity in either of the two periods. This may reflect varying effects of different levels of exercise intensity on the female reproductive system. In some women, routine and athletic activity results in suppressing the hypothalamic release of gonadotropin-releasing hormone, which limits pituitary secretion of luteinizing hormone and follicle-stimulating hormone, in turn reducing ovarian stimulation and estradiol production (18). By disrupting the hypothalamic-pituitary-ovarian axis, regular and strenuous exercise can prolong the follicular phase and lead to interruption or suppression of menstrual cycles (18). If physical activity at higher intensity levels results in an altered hormonal milieu, a womans risk of endometriosis may be reduced because of lower levels of hormonal stimuli (e.g., endogenous estrogen levels), which influence both growth and development. This situation may be more apparent in the current study since cases were defined as women with endometriomas, which occur in the ovaries, a microenvironment with very high steroid hormone concentrations (28). In addition, to the extent that retrograde menstruation plays a role in development of endometriosis, exercise-related menstrual irregularities could lower a womans risk of ovarian endometriosis by reducing the amount of menstrual reflux over time. Activities of moderate intensity may not correlate to similar changes in risk because of transient or clinically insignificant hormonal changes or because of no measurable disturbances in the menstrual cycle.
Definitive diagnosis of endometriosis requires direct visualization of lesions through an operative intervention, so women with a surgical diagnosis of the disease represent a subset of all women harboring the disease. The possibility of asymptomatic disease and the absence of sensitive screening tests that are noninvasive limited our ability to draw conclusions about the etiologic relevance of factors such as strenuous physical activity, which is associated with the clinical incidence of disease. Although its role in the pathogenesis of endometriosis needs to be explored further, the effects of strenuous exercise on circulating hormone levels and on the menstrual cycle are supported by studies that have found delayed menarche as well as primary and secondary amenorrhea in female athletes (2932).
We explored the effects of strenuous activity on characteristics of the menstrual cycle in controls. Women who reported routine, high-intensity activity during the 2 years prior to the reference date had a shorter "period" length (34.7 vs. 30.6 percent with 4 or fewer days) and a lighter volume of menstrual flow (11.6 vs. 5.6 percent experienced "light" bleeding) than those who did not participate in high-intensity activity. For activity between 12 and 21 years of age, regular exercisers were more likely to have a later (age ≥14 years) menarche (28.0 vs. 19.6 percent) and onset of regular periods (46.0 vs. 33.1 percent).
In our study, physical activity data were derived from self-reports, which are subject to more misclassification than measurements based on physical activity logs or exercise tests. In one validity study, subject responses on the Minnesota Leisure Time Physical Activity Questionnaire were compared with those from six 48-hour records and a 4-week version of the questionnaire (20). The authors noted a strong correlation in heavy activities reported by the three methods but weak or no associations for moderate and light activities. The lack of an association for lower-intensity activities in our study may stem from a greater degree of nondifferential misclassification of these activities.
At least two explanations are possible for the absence of a significant association between physical activity at ages 1221 years and endometrioma risk in our study. First, exercise patterns during adolescence and early adulthood often fluctuate widely from year to year, so any summary estimate is a crude measure of activity during this highly variable period. To address this issue, we separated the period into two segments, 1216 years and 1721 years, and conducted the same set of analyses; the overall conclusions remained the same (data not shown). Second, self-reports of physical activity between the ages of 12 and 21 years are subject to more recall error than activities performed in the recent past. If cases and controls inaccurately recall past activity to a similar extent, then measurement of physical activity during that period can result in bias toward the null.
In summary, our study findings suggest a reduced endometrioma risk associated with regular, high-intensity physical activity during adulthood and, to a lesser extent, adolescence. Endometriosis constitutes a wide spectrum of pathologic and clinical disease, and this study was based on a relatively homogeneous subgroup of women diagnosed with cystic ovarian endometriosis. Although the ovaries are the most common site for endometriotic implants, the etiology of ovarian endometriosis may differ from disease that develops at other sites, especially when its unique endocrine environment is considered. Different microenvironments may imply differing causal pathways for the development and maintenance of endometriosis. There is a need to investigate whether the potential benefits of vigorous and consistent physical activity extend to other affected sites and types of this disease as well.
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ACKNOWLEDGMENTS |
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The authors thank Dr. Noel Weiss for his valuable comments.
APPENDIX
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NOTES |
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REFERENCES |
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