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Bisphenol A and phthalates and endometriosis: the Endometriosis: Natural History, Diagnosis and Outcomes Study

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Bisphenol A and phthalates and endometriosis: the Endometriosis: Natural History, Diagnosis and Outcomes Study
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  Bisphenol A and phthalates andendometriosis: the Endometriosis:Natural History, Diagnosis andOutcomes Study Germaine M. Buck Louis, Ph.D., a C. Matthew Peterson, M.D., b Zhen Chen, Ph.D., a Mary Croughan, Ph.D., c Rajeshwari Sundaram, Ph.D., a Joseph Stanford, M.D., d Michael W. Varner, M.D., b Anne Kennedy, M.D., e Linda Giudice, M.D., Ph.D., c Victor Y. Fujimoto, M.D., c Liping Sun, M.S., a Lei Wang, Ph.D., f Ying Guo, Ph.D., f and Kurunthachalam Kannan, Ph.D. f a Division of Epidemiology, Statistics and Prevention Research,  Eunice Kennedy Shriver   National Institute of Child Healthand Human Development, National Institutes of Health, Rockville, Maryland;  b Department of Obstetrics andGynecology,  d Department of Family Medicine, and  e Department of Radiology, University of Utah, Salt Lake City, Utah; c Department of Obstetrics, Gynecology and Reproductive Sciences, University of California at San Francisco, SanFrancisco, California; and  f Division of Environmental Health Sciences, Wadsworth Center, New York State Departmentof Health and Department of Environmental Health Sciences, The University at Albany, Albany, New York Objective:  To explore the relation between bisphenol A and 14 phthalate metabolites and endometriosis. Design:  Matched cohort design. Setting:  Fourteen clinical centers. Patient(s):  The operative cohort comprised 495 women undergoing laparoscopy/laparotomy, whereas the population cohort comprised 131women matched on age and residence. Intervention(s):  None. Main Outcome Measure(s):  Surgically visualized or pelvic magnetic resonance imaging diagnosed endometriosis in the two cohorts,respectively. Result(s):  Oddsratios(OR)and95%con fi denceintervals(CIs)wereestimatedusinglogisticregressionadjustingforage,bodymassindex,andcreatinine. In the population cohort, six phthalate metabolites — mono- n -butyl phthalate, mono-[(2-carboxymethyl) hexyl] phthalate, mono (2-ethyl-5-carboxyphentyl) phthalate, mono (2-ethylhexyl) phthalate, mono (2-ethyl-5-hydroxyhexyl) phthalate, and mono (2-ethyl-5-oxohexyl) phthalate — were signi fi cantly associated with an approximately twofold increase in the odds of an endometriosis diagnosis. Twophthalates were associated with endometriosis in the operative cohort when restricting to visualized and histologic endometriosis(monooctyl phthalate; OR 1.38; 95% CI 1.10 – 1.72) or when restricting comparison women to those with a postoperative diagnosis of a normal pelvis [mono (2-ethylhexyl) phthalate; OR 1.35; 95% CI 1.03 – 1.78]. Conclusion(s):  Selectphthalateswereassociatedwithhigheroddsofanendometriosisdiagnosisfor women with magnetic resonance imaging – diagnosed endometriosis. The lack of consistency of  fi nd-ings across cohorts underscores the impact of methodology on  fi ndings. (Fertil Steril  2013;100:162 – 9.  2013 by American Society for Reproductive Medicine.) Key Words:  Bisphenol A, endometriosis, endocrine disrupting chemicals, epidemiology, phthalates Discuss:  You can discuss this article with its authors and with other ASRM members at  http://fertstertforum.com/louisgmb-bisphenol-a-phthalates-endometriosis/ Use your smartphoneto scan this QR codeand connect to thediscussion forum for this article now.* * Download a free QR code scanner by searching for   “ QR scanner  ”  in your smartphone ’ s app store or app marketplace. Received November 21, 2012; revised March 7, 2013; accepted March 12, 2013; published online April 8, 2013.G.M.B.L.hasnothingtodisclose.C.M.P.hasnothingtodisclose.Z.C.hasnothingtodisclose.M.C.hasnothingtodisclose.R.S.hasnothingtodisclose.J.S.reportsa consultancy with Swiss Diagnostics and grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and theWomen's Reproductive Health Foundation. M.W.V. has nothing to disclose. A.K. reports a grant from the University of Utah Department of Radiology;honoraria from the University of California-Davis and Siemens; and royalties and payment for development of educational materials from Amirsys Inc.L.G. reports board membership in the World Endometriosis Research Foundation and royalties from the textbook Endometriosis: Science and Practice.V.Y.F. has nothing to disclose. L.S. has nothing to disclose. L.W. has nothing to disclose. Y.G. has nothing to disclose. K.K. has nothing to disclose.This study was funded by the Intramural Research Program,  Eunice Kennedy Shriver   National Institute of Child Health and Human Development, NationalInstitutes of Health (contracts NO1-DK-6-3428, NO1-DK-6-3427, and 10001406-02). Ethicon Endo-Surgery donated the HARMONIC ACE 36P scalpelblades for use in the study through a signed Materials Transfer Agreement with the University of Utah and the  Eunice Kennedy Shriver   National In-stitute of Child Health and Human Development.Reprint requests:GermaineM.BuckLouis,Ph.D.,Division ofEpidemiology,Statistics andPreventionResearch, EuniceKennedyShriver  NationalInstituteofChild Health and Human Development, 6100 Executive Bvld., Room 7B03, Rockville, Maryland 20852 (E-mail: louisg@mail.nih.gov).Fertility and Sterility® Vol. 100, No. 1, July 2013 0015-0282/$36.00Copyright ©2013 Published by Elsevier Inc. on behalf of American Society for Reproductive Medicinehttp://dx.doi.org/10.1016/j.fertnstert.2013.03.026 162  VOL. 100 NO. 1 / JULY 2013  E ndometriosisisagynecologicdisordercharacterizedby endometrial glands and stroma that grow outside theuterine cavity. This ectopic endometrium responds tohormonal signaling and may manifest as dysmenorrhea, in-fertility, and pain (1). Although a plethora of mechanismshavebeeninvestigated,itsetiologyremainsunknown.Duringthe past decade, an evolving body of evidence suggests a pos-sible role for endocrine disrupting chemicals (EDCs), whichare exogenous chemicals that interfere with hormonal ho-meostasis, including alterations in estrogen (E) signaling (2).The Endocrine Society published a Statement on EDCs inwhich they noted strong evidence for adverse reproductiveoutcomes after exposure, including some evidence that early exposures may be associated with epigenetic changes and,possibly, transgenerational effects (3, 4). However, datagaps remain for human exposure and fecundity endpointssuch as gynecologic disorders, including endometriosis.Much of the available evidence on environmentalchemicals and endometriosis focuses on persistent environ-mental pollutants, or chemicals with long half-lives or lipo-philic properties that promote their bioaccumulation andbiomagni fi cation in ecosystems and the food chain (5, 6).For example, positive associations have been reported for endometriosis and select organochlorine pesticides, such asaromatic fungicides and hexachlorocyclohexane (7, 8),polychlorinated biphenyls (8 – 11), per  fl uorochemicals (12),and dioxins (13, 14). Still, other researchers have notobserved relations between these chemicals andendometriosis (15, 16), underscoring remaining critical datagaps.In contrast to the body of evidence on persistent environ-mental chemicals and endometriosis, limited research has fo-cused on short-lived environmental chemicals despiteexperimental animal evidence suggestive of reproductiveand developmental toxicity  (17, 18). Two such compounds — bisphenol A (BPA) and phthalates — are of particular concernas possible reproductive and/or developmental toxicants,including for humans as recently summarized (3). Bisphenol A is a high-production-volume phenolic chemical used inthe manufacture of polycarbonate plastics and epoxy resincoatings in canned food containers (19), and its widespreadexposure for human populations poses important publichealth challenges (20). Initial controversy regarding the po-tential reproductive and developmental toxicity of BPA haswanedgiventherapidlyevolvingbodyofevidenceinanimalsand humans suggesting adverse implications for a range of effects, as recently summarized (21, 22). Given its similarity to endogenous Es, BPA has the ability to interact with Ereceptors and stimulate E production and also alter gonadotrophin hormone secretion (23, 24). Another emerging class of short-lived chemicals is phthalates, or so-called plasticizers because they are added to plastics to en-hance  fl exibility and resilience (25). Like BPA, phthalatesare high-volume production chemicals that are metabolizedquickly and excreted in urine without evidence of accumula-tion within the body  (25 – 27). Phthalates produceantiandrogenic effects largely through the reduction in T production and, possibly, reduced E production at highdoses (28, 29). Despite their relatively short half-lives, ubiqui-tous occurrence of BPA and phthalates may produce contin-ual exposures for humans. Available data on BPA and phthalates and endometriosisareemerging,including fi  veofsevenhumanstudiesreportinghigher phthalate concentrations in women with endometri-osis than in those without endometriosis (30 – 36) and twoequivocal studies focusing on BPA  (37, 38). These early studies are important contributions to the literature butrequire cautious interpretation of the  fi ndings in light of important methodologic limitations including themeasurement of phthalates in plasma rather than urine (30 – 32, 36); self-reported endometriosis (34); uncertain timing of biospecimen collection relative to timing of surgery  (30 – 32, 35) or after surgery and diagnosis (35); categorizing women with stage 1 endometriosis with unaffected women(33, 37); and the absence of multivariable analysis to adjustfor potential confounders (30 – 32, 37). Although the fi ndings on phthalates and BPA are intriguing, it isimportant to note the relatively limited number of womendiagnosed with endometriosis in past research, rangingfrom sample sizes comprising 28 (35) to 97 women (36). In light of these suggestive data for phthalates, and to a lesser extent BPA, coupled with the continual nature of humanexposure (39, 40), we analyzed banked urine samples fromthe Endometriosis: Natural History, Diagnosis andOutcomes (ENDO) Study  (41). MATERIALS AND METHODS Study Design and Populations TheENDOStudywasdesignedwiththespeci fi caimofassess-ing the relation between persistent environment chemicalsand endometriosis, and used a matched cohort design to es-tablish both an operative and population cohort (41). Allwomen scheduled for laparoscopy or laparotomy at one of 14 participating clinical centers in the Salt Lake City, Utahand San Francisco, California geographic areas in 2007 – 2009 were screened for eligibility: currently menstruating,aged 18 – 44 years, not breastfeeding for  R 6 months, no in- jectable hormonal treatment within the past 2 years, and nocancer history save for nonmelanoma skin cancer. The oper-ativecohort(n ¼ 495)wasthenmatchedonageandresidencewithin a 50-mile radius to women in the surrounding geo-graphic areas served by the clinical centers using the UtahPopulation Database or a telephone white pages directory for the Utah and California sites, respectively. This latter group of women comprised the population cohort (n ¼ 131)and was further screened to ensure they were at risk for endo-metriosis and being diagnosed (i.e., currently menstruatingandresidingingeographiccatchmentareas,respectively).Be-cause women in the population cohort were not having sur-gery, they underwent standardized pelvic magneticresonanceimaging(MRI)fortheassessmentofendometriosis. Womenwithahistoryofsurgicallyvisualizeddiseaseorprev-alent disease were ineligible for participation. A priori power calculations for the size of the two cohorts were based on re-ported differences in concentrations of polychlorinated bi-phenyls by endometriosis status at the time the Study wasunder development (42). VOL. 100 NO. 1 / JULY 2013  163 Fertility and Sterility®  Data Collection  An introductory package was mailed to all women, followedby telephone screening. In-person standardized interviewswere conducted with women before surgery or MRI, followedby anthropometric assessment (43). Upon enrollment, womenprovided nonfasting urine (approximately 120 mL) samplesthat were collected in containers determined to be free of the chemicals under analysis. Surgeons completed standard-ized operative reports regarding primary and secondary diag-noses and other operative fi ndings; endometriosis was stagedusing the Revised American Fertility Society's classi fi cation(44). One radiologist read all MRIs using either a Siemens Avanto or Espree 1.5 Tesla scanner using a US Food andDrug Administration – approved protocol for pelvic imaging,and all diagnoses were corroborated by a second radiologist.Full human subjects' approval was awarded by all participat-ing research institutions for the conduct of this study. Add-tionally, all participating women provided written, informedconsent before any data collection. Endometriosis Diagnosis The clinical gold standard of surgically visualized disease wasused to de fi ne endometriosis in the operative cohort (45, 46),and MRI visualized endometriosis for the population cohort.Disease staging (44) was only assigned for the operativecohort, given the limited sensitivity of MRIs for diagnosingminimal/mild disease (47, 48). Speci fi cally, scores for stages1 – 4 ranged from 1 to 5, 6 to 15, 16 to 40, and  > 40,respectively. Statistical Analysis The completeness of data and the distributions of all chemi-cals were assessed in the descriptive phase of research.Creatinine-adjusted geometric means along with 95% con fi -dence intervals (CIs) were calculated, then strati fi ed by endo-metriosis status and cohort. Statistical signi fi cance wasevaluatedusing theStudent  t  test orWilcoxon nonparametrictest for continuous data. Logistic regression was used in theanalytic phase to estimate the odds ratio (OR) for an endome-triosis diagnosis for each chemical and by cohort along withcorresponding 95% CIs. Chemicals were log (x þ 1) trans-formed and standardized by their SDs to aid in the interpreta-tion of the effect before inclusion in models. A priori, wede fi nedpotentialconfoundersasage(years),bodymassindex(BMI,weightinkilograms/heightinmeters 2 ),andurinarycre-atinine (ng/mL). Four percent of women in each cohort wereexcluded from the analysis either because of surgical cancel-lation (n ¼ 22) or unreadable MRIs for diagnostic purposes (n ¼ 4). We conducted various sensitivity analyses for the oper-ative cohort to assessthe robustnessof our  fi ndings, given re-maininguncertaintiesabouthowbesttomodelchemicalsandendometriosis: [1] restricting endometriosis to stages 3 and 4or moderate/severe disease in the operative cohort for com-parison with MRI-diagnosed endometriosis in the populationcohort; [2] restricting endometriosis to visualized and histo-logically con fi rmed disease; and [3] restricting the compari-son women in the operative cohort to those with a primary postoperative diagnosis of a normal pelvis to minimize a pos-sible shared etiology with other gynecologic pathology. Wealso re-ran adjusted models to include parity conditional ongravidity (never pregnant, pregnant without births, pregnantwith births) (49), because uncertainty remains how best tomodel parity. Toxicologic Analysis Fourteen phthalate metabolites were analyzed in urine (0.5mL) samples after enzymatic deconjugation followed by solidphase extraction (50). These included the following:  fi  ve me-tabolites of di (2-ethyl hexyl) phthalate (DEHP), namely,mono (2-ethyl-5-carboxyphentyl) phthalate (mECPP),mono-[(2-carboxymethyl) hexyl] phthalate (mCMHP), mono(2-ethyl-5-oxohexyl) phthalate (mEOHP), mono (2-ethyl-5-hydroxyhexyl) phthalate (mEHHP), and mono (2-ethylhexyl) phthalate (mEHP); mono (3-carboxypropyl)phthalate (mCPP), monomethyl phthalate (mMP), monoethylphthalate (mEP), mono (2-isobutyl phthalate) (miBP), mono- n -butyl phthalate (mBP), monocyclohexyl phthalate(mCHP), monobenzyl phthalate (mBzP), monoisonoyl phtha-late (mNP), and monooctyl phthalate (mOP). For instrumentalanalysis, seven isotopically labeled phthalate metabolites( 13 C 4 -mMP,  13 C 4 -mEP,  13 C 4 -mBP,  13 C 4 -mECPP,  13 C 4 -mEHP, 13 C 4 -mBzP, and D 4 -miBP) and  13 C 4 -4-methylumbelliferonewere used as internal standards. Total BPA concentrationswere quanti fi ed using high-performance liquid chromatogra-phy coupled with an API 2000 electrospray triple-quadrupolemass spectrometer  (51). Ongoing quality assurance and con-trolproceduresincludedineachbatchof25samplesamethodblank, a spiked blank, and a pair of matrix-spiked sample/du-plicates. Trace levels of mBP, miBP, and mEHP were detectedin procedural blanks (water passed through the entire analyt-ical procedure), and sample concentrations for these com-pounds were subtracted from blank values. This resulted ina few negative values. The regression coef  fi cient of calibra-tion standards, injected at concentrations ranging from 0.05ng/mL to 20 ng/mL, was  > 0.999. The limit of quantitationof phthalate metabolites and BPA was 0.1 – 0.5 and 0.1 ng/mL,respectively,whichwasdeterminedaccording tothelow-est point of the calibration standard and a nominal sample volume of 0.5 mL, used in this study. RESULTS  As previously reported, the incidence of endometriosis was41% and 11% in the operative and population cohorts, re-spectively, of which 71% of women in the operative cohorthad minimal/mild disease (41). As Table 1 re fl ects, few dif-ferences were observed for study characteristics across co-horts or by endometriosis status, except that affectedwomen in the operative cohort were signi fi cantly younger,of lower parity, leaner, and resided in smaller householdsthan unaffected women. No signi fi cant differences were ob-served for these characteristics in the population cohort by endometriosis status. Table 2 re fl ects a pattern of higher creatinine-adjusted geometric mean concentrations for allphthalates and BPA for women with than without endome-triosis, but only in the population cohort. Mean differences 164  VOL. 100 NO. 1 / JULY 2013 ORIGINAL ARTICLE: ENVIRONMENT AND EPIDEMIOLOGY  were signi fi cantly higher for women with than withoutendometriosis for eight phthalates: mCPP, mBP, miBP,mECPP, mCMHP, mEHHP, mEHP, and mEOHP. However,all con fi dence intervals overlapped for women with andwithout endometriosis except for mECPP (54.15 [95% CI26.81 – 109.4] and 20.7 [95% CI 17.30 – 23.76], respectively),which is a major metabolite of the widely used plasticizer DEHP. No association was observed between creatinineand endometriosis (OR 1.00 [95% CI 0.82 – 1.22] and OR0.68 [95% CI 0.39 – 1.20], respectively). A range of correla-tions was observed for each cohort between select phthalatesbut not with BPA (Supplemental Tables 1 and 2, availableonline). For example, correlations ranged from 0.07 (mNP-mEP and mOP_mEP) to 0.94 (mEOHP and mECPP) in theoperative cohort, and from   0.01 (mCHP_mEP) to 0.94(mEHHP_mEOHP) in the population cohort, respectively.Logistic regression results are presented in Table 3 andre fl ect no signi fi cant increased ORs for BPA or any phtha-lates and endometriosis in the operative cohort, even after adjusting for age, BMI, and creatinine. Contrarily in thepopulation cohort, four phthalates (mECPP, mEHHP,mEOHP, and mEHP) consistently re fl ected an approximately 1.7-fold or higher odds of endometriosis per 1 SD increase inconcentration in unadjusted models. After adjustment,a twofold or higher increase in the ORs were observed for these phthalates in the population cohort. Of note, mBPand mCMHP were signi fi cantly associated with endometri-osis in the population cohort, but only after adjustment (ad- justed OR [AOR] 2.62 [95% CI 1.14 – 6.05] and AOR 2.65[95% CI 1.33 – 5.31], respectively). Inclusion of parity in  fi nalphthalate-adjusted models did not change the ORs in any models irrespective of cohort, except for BPA (AOR 1.97 TABLE 1 Mean comparison of cohorts by endometriosis status, the ENDO Study (n [ 600).CharacteristicOperative cohort (n [ 473) Population cohort (n [ 127)Endometriosis (n [ 190) None (n [ 283) Endometriosis (n [ 14) None (n [ 113) Age at menarche (y) 13.0  1.8 12.8  1.6 13.2  1.5 12.7  1.5Age at enrollment (y) 32.0  6.8 b 33.6  7.1 33.1  8.3 32.1  7.8Menstrual cycle length (d) 28.1  8.7 31.6  31.7 27.4  3.5 30.3  11.1Parity (no. live births) a 1.8  1.3 b 2.2  1.4 2.6  1.6 2.2  1.5Body mass index (kg/m 2 ) 26.3  7.2 c 29.2  8.4 27.4  9.0 27.0  6.7Household size (no. persons) 3.2  1.5 c 3.7  1.7 3.5  1.9 3.7  1.9 Note:  Excludes 22 women in the operative cohort whose surgeries were cancelled and 4 women in the population cohort whose MRIs were unreadable. Values are mean  SD. a Restricted to 394 gravid women. b P  < .05;  c P  < .01 comparison of endometriosis status within cohort. Buck Louis. BPA, phthalates, and endometriosis. Fertil Steril 2013. TABLE 2 Geometric mean comparison of urinary phthalate and BPA by cohort and endometriosis status, the ENDO Study, 2005 – 2009 (n [ 600).ChemicalsOperative cohort (n [ 473) Population cohort (n [ 127)Endometriosis (n [ 190) None (n [ 283) Endometriosis (n [ 14) None (n [ 113) Phthalates (ng/mL)mMP (range 0.003 to 93.865) 2.12 (1.71 – 2.62) 2.35 (2.03 – 2.72) 3.67 (1.80 – 7.47) 2.71 (2.14 – 3.44)mEP (range 3.075 to 1,202.4) 107.2 (88.73 – 129.4) 109.6 (93.64 – 128.3) 152.0 (59.11 – 390.8) 138.2 (107.1 – 178.4)mCPP (range 0.001 to 99.653) 2.71 (2.29 – 3.22) 3.41 (3.02 – 3.84) 5.75 (3.38 – 9.80) 4.06 (3.41 – 4.83) a mBP (range  4.683 to 572.068) 12.07 (10.67 – 13.66) 11.01 (10.02 – 12.10) 19.13 (12.53 – 29.22) 11.24 (9.74 – 12.97) a miBP (range  11.931 to 365.692) 7.28 (6.39 – 8.30) 6.82 (6.16 – 7.55) 13.32 (7.67 – 23.15) 7.59 (6.37 – 9.05) b mECPP (range 1.874 to 1,196.57) 24.68 (21.31 – 28.60) 24.98 (22.23 – 28.07) 54.15 (26.81 – 109.4) 20.27 (17.30 – 23.76) b mCMHP (range 2.401 to 698.372) 29.34 (25.46 – 33.81) 29.19 (25.92 – 32.88) 53.54 (25.93 – 110.5) 22.51 (19.00 – 26.66) a mEHHP (range 0.042 to 796.609) 16.34 (13.68 – 19.53) 14.40 (12.51 – 16.56) 32.37 (11.97 – 87.53) 11.86 (9.83 – 14.32) a mEOHP (range 0.4480 to 599.763) 10.98 (9.37 – 12.86) 10.12 (8.90 – 11.50) 23.03 (9.85 – 53.84) 8.29 (6.86 – 10.02) a mCHP (range 0.001 to 81.903) 0.03 (0.03 – 0.04) 0.04 (0.03 – 0.04) 0.04 (0.02 – 0.08) 0.03 (0.02 – 0.04)mBzP (range  0.390 to 338.335) 6.96 (6.10 – 7.94) 7.82 (6.98 – 8.76) 9.85 (5.96 – 16.27) 6.46 (5.33 – 7.84)mEHP (range  19.865 to 224.851) 4.75 (3.78 – 5.97) 4.12 (3.40 – 5.01) 8.32 (4.00 – 17.28) 3.07 (2.09 – 4.49) b mOP (range 0.000 to 56.639) 0.06 (0.05 – 0.07) 0.06 (0.05 – 0.07) 0.06 (0.03 – 0.11) 0.05 (0.04 – 0.07)mNP (range 0.004 to 52.380) 0.16 (0.13 – 0.18) 0.16 (0.14 – 0.18) 0.22 (0.11 – 0.46) 0.16 (0.12 – 0.21)BPA (ng/mL)Range (  1.802 to 497.966) 1.45 (1.14 – 1.84) 1.66 (1.40 – 1.97) 4.19 (2.18 – 8.03) 1.65 (1.23 – 2.23) b Creatinine (mg/dL)Range (9.130 to 488.600) 87.85 (78.83 – 97.89) 89.39 (81.85 – 97.62) 57.21 (35.50 – 92.21) 79.03 (68.03 – 91.80) Note:  Excludes 22 women in the operative cohort whose surgeries were cancelled, and 4 women in the population cohort whose MRIs were unreadable. Phthalates and BPA concentrations werestandardized by creatinine only for the calculation of geometric means for comparison purposes and rounded to three decimal places. Values are geometric means (95% CIs).  P   values comparegeometric means for women with and without endometriosis for each cohort. a P  < .05. b P  < .01. Buck Louis. BPA, phthalates, and endometriosis. Fertil Steril 2013. VOL. 100 NO. 1 / JULY 2013  165 Fertility and Sterility®  [95% CI 1.04 – 3.72]) in the population cohort. Our   fi ndingswere upheld when using bootstrap methods inclusive of 1,000 resamples to assess the robustness of the underlyingdistributional assumptions, estimated standard errors, andparameters to corroborate  fi nding, given the size of the pop-ulation cohort.Our sensitivity analyses for the operative cohort demon-strated no signi fi cant ORs for any of the chemicals when re-stricting endometriosis to stages 3 – 4, which we consideredthe closest analysis to the population cohort (Table 4). When restricting the analysis to women with visualized andhistologically con fi rmeddisease,mOP wassigni fi cantlyasso-ciatedwithahigherodds(AOR1.38[95%CI1.10 – 1.72])ofdi-agnosis. When women without endometriosis were restrictedto women with a postoperative diagnosis of a normal pelvis,mEHP was signi fi cantly associated with endometriosis (AOR1.35 [95% CI 1.03 – 1.78]), corroborating the signi fi cant asso-ciation seen in the population cohort. TABLE 3 Phthalates and BPA and the odds of an endometriosis diagnosis by cohort and model, the ENDO Study, 2007 – 2009 (n [ 600).ChemicalOperative cohort (n [ 473)OR (95% CI)Population cohort(n [ 127)OR (95% CI)Operative cohort (n [ 473)AOR a (95% CI)Population cohort(n [ 127)AOR a (95% CI)Bootstrap method(n [ 127)AOR PhthalatesmMP 1.00 (0.84 – 1.21) 0.96 (0.55 – 1.69) 0.98 (0.78 – 1.24) 1.25 (0.66 – 2.37) 1.39 (0.68 – 2.86)mEP 0.97 (0.81 – 1.17) 0.87 (0.49 – 1.54) 1.01 (0.82 – 1.24) 1.07 (0.56 – 2.04) 1.19 (0.51 – 2.40)mCPP 0.83 (0.69 – 1.01) 1.05 (0.60 – 1.82) 0.78 (0.63 – 0.98) 1.27 (0.71 – 2.26) 1.33 (0.63 – 2.36)mBP 1.08 (0.90 – 1.30) 1.23 (0.70 – 2.15) 1.11 (0.86 – 1.43) 2.62 (1.14 – 6.05) b 3.61 (1.17 – 11.0) b miBP 1.02 (0.85 – 1.22) 1.35 (0.72 – 2.56) 1.02 (0.80 – 1.29) 2.22 (0.98 – 5.04) 3.26 (0.99 – 10.2)mECPP 0.98 (0.81 – 1.17) 1.78 (1.02 – 3.11) b 0.99 (0.79 – 1.25) 2.92 (1.46 – 5.84) b 3.53 (1.54 – 8.07) b mCMHP 0.99 (0.82 – 1.19) 1.56 (0.89 – 2.73) 0.98 (0.77 – 1.26) 2.65 (1.33 – 5.31) b 3.34 (1.25 – 8.27) b mEHHP 1.09 (0.91 – 1.31) 1.74 (1.03 – 2.92) b 1.10 (0.89 – 1.36) 2.20 (1.23 – 3.94) b 2.61 (0.99 – 6.23)mEOHP 1.05 (0.87 – 1.26) 1.70 (1.00 – 2.88) b,c 1.06 (0.85 – 1.32) 2.33 (1.26 – 4.29) b 2.65 (1.15 – 5.50) b mCHP 1.08 (0.89 – 1.30) 0.63 (0.09 – 4.57) 1.07 (0.87 – 1.32) 0.74 (0.23 – 2.45) 1.89 (0.16 – 4.02)mBzP 0.89 (0.74 – 1.08) 1.04 (0.60 – 1.80) 0.84 (0.65 – 1.07) 1.47 (0.76 – 2.85) 1.63 (0.75 – 3.28)mEHP 1.18 (0.97 – 1.44) 2.18 (1.05 – 4.56) b 1.20 (0.97 – 1.49) 2.59 (1.17 – 5.75) b 3.06 (1.60 – 6.22) b mOP 1.03 (0.86 – 1.23) 0.79 (0.25 – 2.53) 1.06 (0.87 – 1.29) 0.84 (0.40 – 1.78) 0.97 (0.003 – 3.95)mNP 0.86 (0.69 – 1.07) 0.91 (0.48 – 1.72) 0.85 (0.68 – 1.06) 0.90 (0.50 – 1.63) 0.90 (0.40 – 1.54)BPA 0.93 (0.77 – 1.12) 1.62 (0.93 – 2.80) 0.96 (0.79 – 1.19) 1.68 (0.96 – 2.92) 1.82 (1.01 – 3.36) b Note:  Concentrations were log transformed and rescaled by their SDs for analysis. a AOR adjusted for age (years), BMI (continuous), and creatinine (continuous). b Signi fi cant OR. c CI before rounding (1.0002 – 2.8769). Buck Louis. BPA, phthalates, and endometriosis. Fertil Steril 2013. TABLE 4 Phthalates and BPA and the odds of an endometriosis diagnosis: sensitivity analyses for operative cohort (n [ 339).ChemicalSensitivity modelEndometriosis diagnosisstages 3 and 4 (n [ 339)Visualized and histologicallycon fi rmed endometriosis (n [ 473)Comparison women with postoperativediagnosis normal pelvis (n [ 320)OR (95% CI) AOR a (95% CI) OR (95% CI) AOR a (95% CI) OR (95% CI) AOR a (95% CI) PhthalatesmMP 1.09 (0.81 – 1.47) 1.18 (0.81 – 1.72) 1.09 (0.85 – 1.41) 1.08 (0.78 – 1.50) 1.01 (0.81 – 1.26) 0.99 (0.75 – 1.31)mEP 0.99 (0.74 – 1.31) 1.04 (0.75 – 1.43) 1.04 (0.80 – 1.34) 1.04 (0.78 – 1.39) 1.00 (0.80 – 1.24) 1.05 (0.81 – 1.35)mCPP 0.83 (0.61 – 1.12) 0.83 (0.59 – 1.16) 0.90 (0.69 – 1.18) 0.86 (0.63 – 1.18) 0.82 (0.66 – 1.03) 0.75 (0.57 – 0.99)mBP 0.98 (0.74 – 1.30) 1.04 (0.71 – 1.53) 0.98 (0.76 – 1.27) 0.91 (0.64 – 1.31) 1.10 (0.88 – 1.38) 1.13 (0.84 – 1.52)miBP 0.93 (0.71 – 1.24) 0.96 (0.67 – 1.38) 1.08 (0.83 – 1.41) 1.08 (0.77 – 1.51) 1.05 (0.84 – 1.32) 1.09 (0.82 – 1.46)mECPP 0.89 (0.66 – 1.20) 0.91 (0.63 – 1.33) 1.02 (0.79 – 1.33) 1.03 (0.75 – 1.42) 1.09 (0.87 – 1.38) 1.18 (0.87 – 1.60)mCMHP 0.91 (0.68 – 1.21) 0.91 (0.62 – 1.34) 1.02 (0.78 – 1.32) 0.98 (0.70 – 1.38) 1.10 (0.87 – 1.38) 1.14 (0.84 – 1.55)mEHHP 0.97 (0.72 – 1.30) 0.99 (0.71 – 1.38) 1.06 (0.82 – 1.37) 1.03 (0.77 – 1.38) 1.26 (0.99 – 1.60) 1.32 (1.01 – 1.75)mEOHP 0.95 (0.71 – 1.27) 0.98 (0.69 – 1.39) 1.08 (0.84 – 1.39) 1.08 (0.79 – 1.46) 1.19 (0.94 – 1.51) 1.27 (0.95 – 1.70)mCHP 1.21 (0.95 – 1.55) 1.24 (0.93 – 1.65) 1.02 (0.80 – 1.30) 1.00 (0.78 – 1.28) 1.01 (0.83 – 1.23) 0.99 (0.81 – 1.21)mBzP 0.82 (0.61 – 1.10) 0.77 (0.52 – 1.14) 1.01 (0.78 – 1.31) 1.02 (0.72 – 1.42) 0.89 (0.71 – 1.11) 0.79 (0.59 – 1.07)mEHP 1.20 (0.88 – 1.63) 1.23 (0.88 – 1.72) 1.22 (0.93 – 1.61) 1.21 (0.90 – 1.62) 1.35 (1.05 – 1.74) b 1.35 (1.03 – 1.78) b mOP 1.12 (0.88 – 1.43) 1.16 (0.89 – 1.50) 1.30 (1.05 – 1.60) b 1.38 (1.10 – 1.72) b 0.97 (0.79 – 1.19) 0.99 (0.80 – 1.22)mNP 0.99 (0.77 – 1.29) 0.99 (0.76 – 1.28) 0.94 (0.70 – 1.26) 0.93 (0.70 – 1.25) 0.84 (0.65 – 1.09) 0.84 (0.64 – 1.11)BPA 0.91 (0.67 – 1.23) 0.94 (0.68 – 1.28) 0.93 (0.71 – 1.22) 0.94 (0.71 – 1.26) 1.11 (0.87 – 1.40) 1.21 (0.93 – 1.58) Note:  All chemicals were log transformed then rescaled by their SDs for analysis. a AOR adjusted for age (years), BMI (continuous), and creatinine (continuous). b Signi fi cant OR. Buck Louis. BPA, phthalates, and endometriosis. Fertil Steril 2013. 166  VOL. 100 NO. 1 / JULY 2013 ORIGINAL ARTICLE: ENVIRONMENT AND EPIDEMIOLOGY
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