Weuve et al. laparoscopy-confirmed cases were more likely than controls to have “elevated” creatinine-cor- rected urinary MEHP concentrations [above the controls’ median (4.2 ng/mg)], although this association was not significant. Findings were weaker for urinary MEHHP, MEOHP, and the molar sum of the three DEHP metab- olites. Itoh et al. also found significantly higher uncorrected concentrations of all three DEHP metabolites with increasingly severe stage of endometriosis (p < 0.02), but these trends diminished upon creatinine correction. The discrepant findings may stem from differences in exposure assessment and/or case definition. For measures of exposure to DEHP, the first two case–control studies used blood-based concentrations of DEHP, which is no longer considered a valid approach for assessing expo- sure because of concerns about contamination from laboratory equipment and other external sources. The correlation between serum DEHP and MEHP concentrations was weak in the Cobellis et al. (2003) study (r = 0.16, p ≥ 0.3), raising questions about the utility of the serum DEHP measurements, including the possibility that DEHP measurements were affected by external contamination (Hauser and Calafat 2005). Blood-based concentrations of MEHP are also prone to contamination from DEHP that is also present in the specimen, because serum enzymes can hydrolyze DEHP to MEHP during storage (Kato et al. 2003). For their case definitions, all three case–control studies enrolled women with laparoscopically confirmed endometriosis. Cases in the Cobellis et al. (2003) study underwent further histologic confirmation. However, because all participants were enrolled in clinical settings, it is possible that DEHP and MEHP concentrations were affected by supplies used in very recent medical procedures associated with the clinical condi- tions (Hauser and Calafat 2005). For example, at least some of the specimens in the Cobellis et al. (2003) study were collected immediately before anesthesia for laparoscopy, when the women were likely on an intravenous therapy line, a potential source of DEHP exposure (U.S. Food and Drug Administration 2002). This may explain why plasma MEHP concen- trations in the Cobellis et al. (2003) study were about 100 times the urinary MEHP concentra- tions among the women in our study. It is also possible that controls recruited from a clinical setting—such as those seeking treatment for infertility in the Itoh et al. (2009) study—had conditions that were themselves influenced by exposure to phthalates, leading to biased find- ings (Hernán et al. 2004). In contrast, our results for MBP agree with results from the Reddy et al. (2006) study in which women with endometriosis had signifi- cantly higher plasma concentrations of DBP (the parent compound of MBP) compared with controls (Reddy et al. 2006). Nonetheless, blood measures of DBP entail limitations as described for DEHP, and even in the absence of external contamination, there remains the possibility that some of the DBP could be missed because of its hydrolysis to MBP (Kato et al. 2003). In the study by Itoh et al. (2009), endometriosis was not significantly associated with having an “elevated” creatinine-corrected urinary MnBP concentration (above the median among the controls, 43.4 ng/mg), and there was no apparent trend in urinary MnBP across severity classes of the condition. Our findings for MBzP and endo- metriosis were consistent with those of Itoh et al. (2009) but diverged from those of Reddy et al. (2006) in which plasma BzBP concentra- tions among cases were significantly higher than those among controls. Similar to our find- ings for MEP, Itoh et al. (2009) did not find a significant association between creatinine- corrected urinary MEP and endometriosis. Our weakly inverse association between MEHP and leiomyomata agrees with the case–control study by Luisi et al. (2006), in which significantly lower serum DEHP and MEHP concentrations were found among hysterectomy-confirmed cases of leiomyomata relative to controls (confirmed by ultrasound to be free of disease). The measurement con- cerns we described above also pertain to this case–control study, but they would likely serve to overestimate DEHP exposures among the cases, rendering the estimates from this case– control study conservative. However, this study may have reduced external contamina- tion through its use of glass collection and storage materials. Our results are also consistent with animal data showing positive associations of exposure to DEHP and its metabolite MEHP with ano- vulation or delayed ovulation, longer estrous cycles, decreased synthesis of estradiol, and decreased serum progesterone levels (Davis et al. 1994a, 1994b; Lovekamp and Davis 2001), all of which would predict a protective effect on uterine leiomyomata and endometri- osis. The pathophysiology of leiomyomata is believed to depend on the biological activ- ity of the endogenous sex steroid hormones estrogen (estradiol, estrone, estriol) and pro- gesterone (Rein 2000; Rein and Nowak 1992; Rein et al. 1995), as well as locally derived growth factors (Andersen 1998). The hor- mone-dependent nature of leiomyomata is supported by the following observations: They do not occur before menarche, they have an increased concentration of estrogen and pro- gesterone receptors compared with normal myometrium (Strauss and Coutifaris 1999), and they shrink in volume after menopause or with suppression of ovarian function via gonadotropin-releasing hormone (GnRH) agonist therapy or oophorectomy (Friedman et al. 1990). The literature on the relation of endogenous sex hormones to leiomyomata is limited and mixed. Although an earlier study reported than serum estrogen levels did not differ significantly between leiomyomata cases and controls (Potgieter et al. 1995), a subsequent study reported that urinary con- centrations of many sex hormones, including 17β-estradiol, were significantly higher among leiomyomata cases than controls (Jung et al. 2004). Several epidemiologic studies show an increased risk of leiomyomata associated with reproductive and hormonal factors, including early age at menarche and nulliparity, which Table 4. Adjusteda ORs of endometriosis or uterine leiomyomata by concentration of creatinine-corrected urinary phthalate metabolites of DEHP (2001–2004). MEHP Cases/n OR 95% CI Endometriosis (n = 838) Lowest three quartilesb 45/615 Highest quartileb 12/223 Uterine leiomyomata (n = 835) Lowest three quartilesb 91/612 Highest quartileb 22/223 Endometriosis or uterine leiomyomata (n = 835) 1.00 Reference 0.60 (0.24–1.50) 1.00 Reference 0.66 (0.32–1.37) Cases/n 47/628 10/210 87/626 26/209 MEHHP OR 95% CI 1.00 Reference 0.46 (0.18–1.21) 1.00 Reference 0.97 (0.55–1.71) Cases/n 46/627 11/211 84/625 29/210 MEOHP OR 95% CI 1.00 Reference 0.62 (0.27–1.44) 1.00 Reference 1.43 (0.87–2.37) Molar sum of MEHP, MEHHP, and MEOHP Cases/n OR 95% CI 47/629 10/209 86/627 27/208 1.00 Reference 0.48 (0.18–1.25) 1.00 Reference 1.08 (0.60–1.95) Lowest three quartilesb 115/612 1.00 Reference 116/626 1.00 Reference 113/625 1.00 Reference 115/627 1.00 Reference Highest quartileb 31/223 0.69 (0.38–1.25) 30/209 0.69 (0.43–1.12) 33/210 0.96 (0.63–1.47) 31/208 0.77 (0.46–1.29) aAdjusted for age, race/ethnicity, age at menarche, and current pregnancy status. Further adjustment for current breast-feeding status created model instability. bRanges for MEHP groups (ng/mg): 0.2–6.3 (lowest three quartiles) and 6.4–538 (highest quartile); ranges for MEHHP groups (ng/mg): 0.5–31.9 (lowest three quartiles) and 32.0–1885 (highest quartile); ranges for MEOHP groups (ng/mg): 0.6–21.3 (lowest three quartiles) and 21.4–1115 (highest quartile); and ranges for molar sum of MEHP, MEHHP, and MEOHP (nmol/mg): 0.6–27.5 (lowest three quartiles) and 27.5–1094 (highest quartile). 830 ovlume 118 | number 6 | June 2010 • Environmental Health Perspectives