BACKGROUND AND OBJECTIVE Despite the high prevalence of endometriosis, estimated at 6-10% in reproductive-age women, and the associated

economic burden, potential modifiable risk factors remain incompletely elucidated. Several studies have analyzed the association between alcohol ingestion and risk of endometriosis, with conflicting results. We conducted a systematic review and metaanalysis of available data on the relation between alcohol intake and risk for endometriosis.

MATERIALS AND METHODS We searched all case-control and cohort studies published as original articles in English through May 2012. We used the Medical Subject Heading terms diet, nutrition, alcohol, vitamin, fat, or vegetable plus endometriosis.

RESULTS Most of the 15 studies identified for review were retrospective case-control studies. One was a cohort study. In a comparison of any vs no alcohol intake, all but 2 relative risk estimates were above unity (range, 0.34 2.28) (Figure). The summary estimate was 1.24 (95% confidence interval [CI], 1.12 1.36). In analyses of infrequent, moderate/regular, and heavy alcohol intake vs no alcohol intake, summary relative risk estimates were 1.14 (95% CI, 0.86 1.52), 1.23 (95% CI, 1.08 1.40), and 1.19 (95% CI, 0.99 1.43), respectively.

COMMENT A relation between alcohol drinking and endometriosis risk is biologically plausible, since alcohol has been shown to increase levels of endogenous estrogens. The general results of this metaanalysis confirm that any alcohol intake is associated with increased risk of developing endometriosis compared to no alcohol consumption. No clear dose-risk relationship emerged. When interpreting the association between alcohol intake and risk for endometriosis, one should consider potential confounding factors. Alcohol intake has been shown to increase time to pregnancy and the risk for (subclinical) spontaneous abortion and has been associated with infertility. Thus, it is possible that the association between alcohol ingestion and endometriosis risk may be explained at least in part by the role of infertility. However, studies that have considered the potential confounding role of parity or analyzed data separately for women with a diagnosis of endometriosis due to pelvic pain or ovarian cysts have generally confirmed the association. Further, published studies have defined their populations differently regarding whether both cases and controls were selected from both fertile and infertile women and whether controls included healthy subjects or patients with conditions other than endometriosis. This heterogeneity may have affected the study results. Socioeconomic status and body mass are other confounding factors that may not have been considered. Since

only a few studies adjusted for these covariates, we cannot exclude

the possibility that confounding played a role in the association between alcohol and endometriosis that we identified

An important methodologic problem in studying the epidemiology of endometriosis is the choice of controls. In this review a direct association between alcohol intake and risk for endometriosis was observed in studies that included controls recruited in the hospital for different acute conditions as well as women without endometriosis confirmed by surgery or ultrasonography.

Endometriosis is a chronic, longlasting condition. It has been suggested that women with pelvic pain related endometriosis may drink alcohol to alleviate pain. Some studies have analyzed separately the role of alcohol drinking among women with or without pain, or considered only women without severe pain: in these studies the association between alcohol and endometriosis was consistent with the general findings of this analysis.

A limitation of this analysis is that we are not able from the published studies to evaluate whether alcohol exposure preceded the development of endometriosis. In the 3 studies that considered former and current alcohol drinkers separately, an association emerged with current, but not former, use. Thus, we cannot exclude the possibility that the observed association is explained, at least in part, by reverse causation.

Compared with metaanalysis of randomized clinical trials,

those including observational studies are potentially more subject to bias and other sources of heterogeneity. In all the studies, information regarding alcohol use was self-reported; thus, some misclassification may have occurred. Alcohol drinking, particularly heavy drinking, may be misreported in observational studies. In general, however, any misclassification should tend to reduce the odds ratio estimates.

Among other strengths of our analysis is the relatively large number of studies and total subjects considered, providing adequate statistical power to detect limited summary risk estimates. In conclusion, the present metaanalysis provides evidence for a significant positive association between alcohol consumption and endometriosis risk, although the issue of causality remains open to discussion. Further studies are needed to clarify whether alcohol consumption may exacerbate an existing disease or could be related to disease severity.

CLINICAL IMPLICATIONS - Published studies consistently show an increased risk for endometriosis among alcohol drinkers, although no clear dose risk relationship emerged. - Further studies are needed to clarify whether the association may be causal.