Discussion
We observed two previously unreported POPs (γ-HCH and β-HCH) to be associated with an increased odds of an endometriosis diagnosis in the operative and population cohorts, respectively. Our findings for HCH isomers were robust to adjustment, although with some reduction in magnitude. All remaining POPs varied by cohort and biological medium. Also of note is the observation that three POPs (i.e., PBDE-47, PCB-74, and PCB-156) measured in fat were inversely associated with the odds of an endometriosis diagnosis in the operative cohort.
The novel use of a matched cohort design allowed us to assess the consistency of findings by study cohort, diagnostic method, and biological medium. Our inconsistent findings across study cohorts and biological media suggest the importance of such factors when attempting to weigh available evidence. Because women in the population cohort did not undergo laparoscopies, we cannot assess chemical profiles of fat across cohorts. We did attempt to compare our omental fat concentrations with the sole previous study that quantified PCBs in serum and fat and noted lower concentrations for our cohort (Louis et al. 2005). This may reflect more nulligravid women coupled with a limited (n = 15) number of omental fat samples analyzed in the earlier study relative to ours, along with different laboratory analytic methods. Our findings do corroborate higher concentrations in fat relative to lipid-adjusted serum concentrations consistent with their lipophilicity (Allam and Lucena 2001; Johnson-Restrepo et al. 2005; Whitcomb et al. 2005). Fat concentrations reflect steady-state concentrations that integrate lipophilic chemicals accumulated over time. They reflect body burdens that are less affected by factors that may affect serum concentrations. Use of proxy biospecimens for lipophilic chemicals may mask or minimize health effects, as suggested by the lack of consistent findings across biological media irrespective of cohort, and may account for equivocal findings published to date.
We assessed the impact of diagnostic method for endometriosis in relation to the inconsistency of study findings across cohorts. MRI-diagnosed endometriosis may have limited sensitivity and specificity relative to visualization depending upon the presence of classical or atypical lesions and disease severity (Stratton et al. 2003). Therefore, we conducted sensitivity analyses to restrict endometriosis to stages 3 and 4 and observed no association with β-HCH in the operative cohort (AOR = 0.68; 95% CI: 0.28, 1.66). Also of note was the change in direction for γ-HCH (AOR = 0.86; 95% CI: 0.57, 1.28) when diagnosis was restricted to histologic and visualized disease. These findings suggest that γ-HCH may be associated with milder rather than more severe disease, or they may reflect the fragility of models given the reduction in power and bidirectional errors in clinical staging of endometriosis. Further study of HCH is warranted, given the relatively consistent findings for its positive association with endometriosis across cohorts, although with different isomers emerging for each cohort. Such differences may reflect the toxicologic properties (γ-HCH is more toxic than β-HCH) or bioaccumulation potential (β-HCH is more bioaccumulative than γ-HCH) of HCH isomers. The findings await future corroboration.
The emergence of two other POPs—PBDE-183 and PCB-151—when restricting the referent group to women with a postoperative report of a normal pelvis as a part of our sensitivity analyses is intriguing. This finding underscores the importance of ensuring that the comparison group undergoes surgical visualization to identify women with no endometriosis or other gynecologic pathology. This finding may suggest a possible shared etiology for endometriosis and other gynecologic disorders for some POPs, although a more complete understanding is not possible without purposefully designed research aimed at addressing this question.
We present novel findings of an association between lipophilic HCH isomers and endometriosis. HCH production and sale ceased in the United States in 2007, with earlier restrictions for agriculture use (Agency for Toxic Substances and Disease Registry 2005). γ-HCH has a shorter half-life than does β-HCH (~2 weeks and 7 years, respectively) resulting in human exposure, which may be declining except for select subpopulations (Becker et al. 2002; Centers for Disease Control and Prevention 2009; Stehr-Green 1989). Further interpretation of our findings in the context of past literature is challenging, because no two studies are directly comparable. Pregnancy and breast-feeding history affects internal dose of POPs and may result in concentration differences for women with and without visualized endometriosis. This is particularly true if the former group has fewer pregnancies and breast-feeding intervals relative to unaffected women. Because some POPs were associated with reduced fecundity (Harley et al. 2010; Meeker et al. 2011), we included a conditional breast-feeding variable in our models to adjust for reproductive histories and observed little change in the estimates. Also, serum PCB concentrations are reported to decline throughout pregnancy (Glynn et al. 2011), particularly when modeled as a function of women's baseline exposures (Bloom et al. 2007).
We were able to locate reports of some studies that focused on OCPs but not PBDEs. Lebel et al. (1998) reported higher geometric mean concentrations for six of nine measured OCPs, including β-HCH, for women with endometriosis (n = 86) compared with women without endometriosis (n = 70), although none of the differences achieved significance, possibly a function of overmatching the comparison women on surgical indication. Trabert et al. (2010) reported comparable median serum DDE concentrations by endometriosis status consistent with our observation. Lastly, Cooney et al. (2010) reported that women in the third versus first tertile of serum HCB were significantly more likely to have surgically visualized endometriosis.
The exact mechanisms by which POPs may influence the development of endometriosis remain unknown, although several pathways have been suggested, such as potent modulation of immune and endocrine function (Rier and Foster 2002). Human endometrium is a known site for estrogen, and many POPs or their metabolites have been detected there (Schaefer et al. 2000). POPs may exert effects on estrogen or other hormonal production, or induce inflammation and the chronic stimulation of proinflammatory cytokines. Both PCBs and DDE have been associated with immunologic changes, such as the down-regulation of natural killer cells or interleukin-1β and interleukin-12 (Quaranta et al. 2006).
Our study has important limitations, including a relatively limited population cohort size, of which 11% of women were found to have endometriosis, and possible selection bias arising from the use of telephone directories for defining the population cohort recruited from California. The extent to which such directories represent the female populations for the referent population is unknown. The lack of major differences between cohorts may simply reflect who participates in research irrespective of sampling framework rather than selection factors per se. Other study limitations include the lack of quantified dioxin exposure, given its suggestive association with endometriosis (Eskenazi et al. 2002), and our inability to establish the timing and temporal ordering of fat and serum concentrations relative to development of disease, including a possible in utero origin (Buck Louis et al. 2010; Signorile et al. 2010). We are unaware of any human data specifying the interval between exposure and disease onset, although it was estimated to be 7–10 years in rhesus monkeys (Rier et al. 1993). The dynamic nature of endometriosis, often characterized by periods of disease progression and regression, further challenges our ability to delineate initiating events or to diagnosis truly incident disease (D'Hooghe et al. 1992; Redwine 1987).