1 Epidemiology Branch, Division of Epidemiology, Statistics & Prevention Research, National Institute of Child Health & Human Development, 6100 Executive Boulevard, Room 7B03, Rockville, MD 20852, 2 24th Century Press, 3 University at Buffalo and 4 US Environmental Protection Agency, USA
5 To whom correspondence should be addressed. Email: gb156i{at}nih.gov
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Abstract |
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Key words: endocrine disruptors/endometriosis/environment/fecundity/polychlorinated biphenyls
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Introduction |
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An evolving body of literature suggests that endometriosis may have an environmental origin. Of particular concern are hormonally active environmental agents such as dioxin and other persistent compounds that bio-accumulate and magnify within the food chain, e.g. polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs). These hormonally active environmental agents are believed to be capable of disrupting endocrine pathways by binding to estrogen and androgen receptors and mimicking or blocking hormones, or by altering hormone function, synthesis or modulation (Safe et al., 1991; DeRosa et al., 1998
). Exposure to endocrine disrupting compounds has been associated with changes in sensitive human reproductive endpoints such as menstruation (Mendola et al., 1997
; Eskenazi et al., 2002a
; b
).
The weight of evidence underlying an association between dioxin and PCBs and endometriosis includes data from experimental animal, primate and human studies. Recognition of a purported relationship between dioxin and endometriosis first emerged when Rier et al. (1993) reported a significant dose-dependent increase in the incidence and severity of endometriosis in exposed Rhesus monkeys. Subsequently, Yang et al. (2000)
investigated the effects of dioxin on survival and growth of ectopic endometrium in monkeys following autotransplantation. Additional evidence stems from experimental studies involving rodents, where associations have been reported between dioxin exposure and growth of transplanted (from humans) endometrial implants in nude mice (Bruner et al., 1997
). Moreover, endometriosis has been experimentally produced in rats and mice following surgical placement of endometriosis and repeated dioxin exposure (Cummings et al., 1996
, 1999
). These findings support dioxin's ability to promote surgically placed endometriosis in rodents (species that normally do not develop endometriosis).
Human evidence primarily comes from five published studies, although different exposures were considered. Two studies report significant positive associations between dioxin (Mayani et al., 1997) and PCBs (Gerhard and Runnebaum, 1992
) and endometriosis, while two other studies report two-fold (Eskenazi et al., 2002b
) to four-fold (Pauwels et al., 2001
) increases in risk of endometriosis, albeit the confidence intervals (CIs) were inclusive of one. One study failed to find an association between PCB congeners and endometriosis (Lebel et al., 1998
). The fact that Belgium has some of the highest breast milk dioxin concentrations in the world (World Health Organization, 1989
) and high prevalence of endometriosis (Koninckx et al., 1991
) provides ecological support for a positive association.
Definitive epidemiological investigation regarding exposure to PCBs and related chemicals and endometriosis is difficult, since it requires visual inspection of the pelvis. This operative criterion for the diagnosis of endometriosis tremendously complicates study design, which by and large is restricted to a cohort of women undergoing laparoscopy or laparotomy. Most women of reproductive age, the population at risk for developing endometriosis, do not undergo such operative procedures. To this end, symptomatic women who opt out of surgery will systematically be missed from operative sampling frameworks, along with asymptomatic women with disease. Thus, the potential for misclassification bias poses concern, especially given the relatively prevalent nature of disease, i.e. 1015% of women of reproductive age, or approximately one in 10 females aged 1850 years (Kjerulff et al., 1996). Although investigators have attempted to utilize non-surgical diagnostic approaches for classifying women by endometriosis status, such as on the basis of symptoms or medical history, low concordancy has been reported when these are compared with laparoscopic diagnosis (Duleba, 1997
; Eskenazi et al., 2001
).
The choice of comparison group for women with endometriosis is a complicated issue, and is less well discussed than is the need for laparoscopy for visual confirmation of disease. The reference population for study is women at risk of developing endometriosis, which means menstruating women. Women seeking medical attention and the much smaller proportion that undergo diagnostic laparoscopy pose methodological challenges for investigators regarding selection bias. Use of other women undergoing laparoscopy may be less than ideal for assessing the relation between PCBs and endometriosis if other gynaecological disorders also are associated with exposure; hence, differences in exposure profiles may be similar, resulting in the absence of an effect. While women undergoing tubal ligation may comprise a potential healthy comparison group, their reproductive profiles are likely to be different from women with endometriosis who seek care, e.g. higher gravidity and parity and, possibly, lactation history. The lipophilic nature of PCBs and other hormonally active environmental agents underscores the importance of considering reproductive history.
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Materials and methods |
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Data collection
Participating surgeons first informed women about the study and asked about their willingness to be contacted by the study's research assistant for further details. Consenting women were then contacted by the research assistant, who interviewed women in their home. The assistant was unaware of the women's preoperative diagnosis. Specifically, a standardized questionnaire elicited information from women on the following groups of variables: sociodemographic, reproductive and medical history, lifestyle characteristics, and limited information on diet, e.g. sport fish consumption. The questionnaire was purposefully designed to ascertain information on potential confounders, which included gravidity (number of pregnancies regardless of outcome) and parity (number of live births), body mass index, and current cigarette smoking, since all have been reported as risk factors for endometriosis (McCann et al., 1993; Batt et al., 1997
).
Following the interview, women were asked to donate 20 cc of blood draw. All venipuncture equipment was tested for and found to be free of contamination from materials in tubing or needles by our Toxicology Research Center (TRC) at the University at Buffalo. Seventy-nine (94%) women provided blood specimens, which were transported to the TRC immediately following the interview.
Laparoscopies were performed by highly trained and experienced laparoscopic surgeons, who were asked to complete standardized operative reports immediately following the surgery. The forms ascertained information on postoperative diagnosis and other pathology regardless of surgical indication. For women observed to have endometriosis, severity of disease was staged according to the American Fertility Society's revised definition (American Fertility Society, 1985) as: stage I (minimal); stage II (mild); stage III (moderate); or stage IV (severe). This system encompasses location, number, size and depth of endometriosis, along with presence/absence of adhesions. This scoring system can be affected by inter-rater variations and an anatomical orientation for pelvic exploration. We were unable to formally assess inter-rater reliability; however, surgeons were masked to exposure status. The case definition for endometriosis is controversial, especially for minimal or mild disease, since it tends to be characterized by the appearance of subtle and non-pigmented lesions (Koninckx, 1994
).
The affiliated University and participating hospitals gave Institutional Review Board approval for the conduct of this study. Consent was obtained from all participating women.
Laboratory methods
Gas chromatography with electron-capture was used to quantify serum specimens in a masked manner with regard to the 62 PCB congeners as described previously (Whitcomb et al., 2004). Briefly, to each serum sample surrogate standards of PCB IPAC isomer numbers 46 and 142 were added and allowed to equilibrate overnight. Methanol was added to precipitate serum protein and the sample mixture was then extracted with hexane at 50 r.p.m. for 20 h in a rotary extraction unit, followed by centrifugation and concentration to 2 ml under a stream of nitrogen. To separate lipids from PCBs, the mixture was passed through a deactivated Florisil column, eluted with hexane and concentrated under a stream of nitrogen using 200 µl of isooctane as a keeper solvent. Internal standards (congeners 30 and 204) were added to the extract prior to injection into an Agilent 6890 Gas Chromatograph equipped with an electron capture detector. Chromatographic data were collected electronically and analysed using Turbochrome chromatographic software. All chromatographic data were burned to CDs for permanent data archiving. Serum specimens were run in batches of 10 plus four quality control samples (i.e. reagent blank, matrix blank, matrix blank containing a mixed standard of 15 specific congeners at known values, and a duplicate participant sample). Matrix blanks consisted of sheep serum with low background levels of PCBs. Congener concentrations were calculated from standard curves for the 15 calibration standards, and the remaining congener concentrations were calculated from response factors that were generated for each congener in our laboratory. Each congener concentration was adjusted for surrogate recovery and subtraction of reagent blanks. The limit of detection was determined as 3 SD of the mean of at least 10 matrix blanks. We did not substitute values below the limits of detection to avoid missing weaker signals (Needham and Wang, 2002
).
Serum lipids were determined according to the methodology of Phillips et al. (1989), given that blood specimens were not fasting samples. This method determines concentrations of total lipids (TL) as a product of total cholesterol (TC), free cholesterol (FC), triglycerides (TG) and phospholipids (PL) as follows:
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Statistical analysis
PCB congener concentrations were the observed serum values corrected only for recovery and blanks and expressed as ng/g serum, which translates to parts per billion. All concentrations were log transformed by the formula: ln (1+).
A complete listing of PCB congeners quantified is provided in Table I. Our focus was on identifying PCB congeners most closely associated with risk of endometriosis. There was insufficient remaining blood for the quantitation of dioxin and furans. We first summed 62 individual PCB congeners into a total representing the simple sum. Next, we summed estrogenic congeners (numbers 18, 31, 44, 48, 52, 70, 99, 101, 126, 136, 153 and 188) and anti-estrogenic congeners (numbers 105, 114, 126 and 169) using a previously reported grouping for PCB congeners (Cooke et al., 2001). Subsequently, we categorized each of these sums into tertiles.
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Results |
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As Table II shows, the sample comprised mostly white, married, college-educated women with a mean age of 32 (±4) years. Significant differences in educational attainment and household income were observed between women with and without endometriosis. No differences were observed for marital status or religion, two variables that might impact fertility, by endometriosis status. Table III shows a comparison of reproductive history by endometriosis status. Women with endometriosis had fewer pregnancies and live births in comparison with unaffected women, but higher rates of lactation among parous women. Despite comparable ages at menarche, women with endometriosis reported initiating sexual intercourse at later ages than women without endometriosis.
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Discussion |
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We further explored the association between tertiles and severity of disease and choice of control population to the extent possible given our limited sample size. No significant association was seen between severity of endometriosis, as determined by surgeons using the American Fertility Society's revised definition, and risk. We recognize the potential for error in assigning severity, although laparoscopic surgeons were masked to PCB exposure status. When the analyses were restricted to women undergoing tubal sterilization as the comparison group (excluding women with other gynaecological pathology), the relation between anti-estrogenic PCBs and risk of endometriosis remained and increased in magnitude. Specifically, an approximately five-fold increase in risk of endometriosis was associated with exposure in the third tertile of anti-estrogenic PCBs when controlling for serum lipids and cigarette smoking (OR 4.78; 95% CI 1.0340.70). When parity was added to this model, risk increased, although accompanied by an increase in the width of the CI including the null (OR 7.04; 95% CI 0.42118.4). Caution is needed in interpreting these data given our limited sample size. However, this finding emphasizes the importance of the comparison group when estimating risk of endometriosis in relation to environmental exposures.
We are unable to compare directly our study with those of previous authors due to varying methodologies. Some authors have focused on dioxin or toxic equivalency factors (TEQs), while others on a subset of PCBs. Laboratory practices for lipid adjustment vary, and we a priori included serum lipids in our model as a covariate given its hypothesized causal relationship with both exposure and disease status. Cautious interpretation of our results in the context of past research supports the work of two previous authors. Mayani et al. (1997) reported significant differences in the percentage of dioxin-positive infertile women undergoing laparoscopy diagnosed with or without endometriosis, i.e. 18% and 3%, respectively. Dioxin was quantified in blood using gas chromatography and mass spectrometry, but individual PCB congeners were not quantified, precluding a direct comparison with our study. Gerhard and Runnebaum (1992)
reported higher serum concentrations of three non-dioxin-like PCB congeners (numbers 138, 153 and 180) among women with endometriosis in comparison with women without disease, although it was not clear whether endometriosis was laparoscopically or histologically confirmed. Two studies reported dioxin exposure to be associated with an increased risk of endometriosis, although CIs included one. Pauwels et al. (2001)
reported an adjusted 4.6-fold increase in the risk of endometriosis for women with 100 pg TEQ/g serum lipids in comparison with women below this arbitrary cut-off point, while Eskenazi and colleagues reported a two-fold increased risk for TCDD concentrations of 100 p.p.t. or more (Eskenazi et al., 2002b
). The authors of the latter study noted the small number of affected women (n=19) and the absence of laparoscopic confirmation of disease as two potential study limitations.
Lebel et al. (1998) did not observe significant differences in mean plasma concentrations of 14 PCB congeners and 11 chlorinated pesticides among women with or without endometriosis confirmed by laparoscopy. While not achieving statistical significance, individual concentrations for PCB congeners (and sum) including the five overlapping with our study (numbers 52, 99, 101, 105 and 153) were slightly higher for women with endometriosis than control women. Our study differs from that of Lebel et al. (1998)
in three important ways. First, we did not match women by indication for laparoscopy; rather, we relied upon laparoscopy for classification of endometriosis status. It remains plausible that matching on indication will inadvertently match on other relevant covariates and mask relationships between exposure and outcome. If PCBs are involved in gynaecological pathology and not exclusively endometriosis, differences may be masked by the lack of variation with regard to exposure. Secondly, we did not lipid adjust PCB concentrations but included serum lipids as a covariate in our model. Traditionally, toxicologists have adjusted non-fasting blood samples for lipids by simply dividing PCB concentrations for serum lipids, however they are estimated. We believe that this approach is prone to biasing results, and that addition of an independent lipid term in statistical models is a preferable method of accounting for lipids in the PCBdisease relationship. A last consideration may be attributed to the uniqueness of our geographical area. As identified by the International Joint Commission, our geographical study region comprises Areas of Concern (AOC) with regard to containing contaminated water bodies (e.g. Buffalo River, Niagara River, 18-Mile Creek). This is also an area impacted by federal National Priority Sites and Superfund sites. Carpenter et al. (2001)
reported significantly higher incidence rates of endometriosis among women aged 2544 years discharged from New York State hospitals in this area when compared with all three other groups of similarly aged women: (ii) New York State residents; (ii) Upstate New York (exclusive of New York City) residents residing outside AOC zip codes; and (iii) Upstate New York residents residing in areas with other federal or state Superfund sites. Our findings for a significant reduction in risk of endometriosis for gravidity and cigarette smoking support those of earlier investigators and underscore the veracity of sampling strategy and disease classification.
Since humans are exposed to a mixture of environmental chemicals, we recognize the potential that residual confounding may account for the relationship between anti-estrogenic PCBs and endometriosis. Our laboratory quantified seven OCPs, including DDE, but none was associated with endometriosis either individually or when summed into a single score (data not shown). Given our sample size and the absence of any observed association, we did not include DDE or other OCP concentrations into our logistic models, nor did we include other fertility-related factors such as age of first intercourse or breastfeeding history.
We recognize the absence of a uniform classification for determining biological activity of PCB congeners. Our categorization of congeners by estrogenic or anti-estrogenic activity is based on the work of Cooke et al. (2001). We are unable to determine which of the four anti-estrogenic congeners or their relative groupings or weighting drives the effect, largely due to our sample size. The anti-estrogenic actions of dioxin have been recognized (Astroff et al., 1991
; Krishnan et al., 1995
), along with its ability to induce endometriosis (Cummings et al., 1996
). Our findings may be consistent with the recent work of Ohtake et al. (2003)
, who reported adverse estrogenic-related actions of dioxin-like environmental contaminants.
These findings await corroboration, but we believe that they underscore the need for purposeful investigation to determine whether such exposures are involved in the natural history of endometriosis. The ramifications for this disease extend beyond traditional gynaecological and fecundity complaints to include increased risk of autoimmune disorders (Sinaii et al., 2002), reproductive site cancers (Brinton et al., 1997
; Obata and Hoshiai, 2000
; Chen, 2004
) and other aspects of quality of life such as disruption in sexual and physical activity, employment and mental health (Boling et al., 1988
; Carlson et al., 1994a
,b
).
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Acknowledgements |
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References |
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Submitted on June 17, 2004; accepted on September 29, 2004.