Phthalates and risk of endometriosis and leiomyomata suggests that increased menstrual cycling is a risk factor (Schwartz 2001; Wise et al. 2004). Similarly, endometriosis is associated with abnormal steroid production and activ- ity (Dizerega et al. 1980; Eskenazi and Warner 1997), with diagnoses occurring postmenarchally (Houston 1984) and symp- toms abating after menopause. Endometriotic implants are dependent on estrogen for their maintenance and growth (Dizerega et al. 1980; Gurates and Bulun 2003), and reduc- tion of estradiol production, via either surgi- cal (oophorectomy) or hormonal (GnRH agonist analogues) intervention, causes atro- phy of endometriosis lesions and is effective in treating pain symptoms. High-dose synthetic progestins are effective in the treatment of endometriosis through suppression of luteiniz- ing hormone and FSH secretion that inhib- its estradiol production, direct antiestrogenic effects on the lesions, and induction of pseudo- decidualization (Taylor and Lebovic 2009). Estradiol production is up-regulated in endo- metriotic implants, whereas estradiol metabo- lism is impaired because of a deficiency of the enzyme 17β-hydroxysteroid dehydrogenase type 2 (Gurates and Bulun 2003). Also, the progesterone receptor subtype B is deficient in endometriosis tissue (Attia et al. 2000). In epi- demiologic studies, endometriosis is positively associated with early age at menarche, shorter cycle length, decreased parity, and not breast- feeding (Missmer et al. 2004a), all of which can affect menstrual cycling and lifetime cumulative exposure to estrogens. Nonetheless, although our findings for DEHP’s oxidative metabolites provided sup- port for an inverse association between DEHP exposure and endometriosis, they raised doubts about an association with leiomyomata. In the subset of women evaluated in 2001–2004, we compared findings for urinary concentrations of MEHHP and MEOHP with findings for MEHP, and both MEHHP and MEOHP were detectable in nearly all specimens in our study, including those in which MEHP was undetectable. The associations of the two oxi- dative metabolite concentrations with endo- metriosis were inverse and remarkably similar in magnitude to the corresponding association for MEHP. However, the associations between the oxidative metabolites and uterine leio- myomata were not consistent with the inverse (albeit nonsignificant) corresponding associa- tion for MEHP. The association for MEHHP was essentially [OR = 0.97 (95% CI, 0.55– 0.71) for women in the highest quartile vs. the lowest three quartiles], and although the asso- ciations for MEOHP and MECPP suggested a positive (nonsignificant) association, further analyses at alternative threshold concentrations were more consistent with associations [e.g., OR = 0.92 (95% CI, 0.39–2.15) compar- ing highest sextile of urinary MEOHP vs. the lowest five]. Although these findings emanated from a subset of participants, they suggest that the inverse association between MEHP and leiomyomata may be a chance finding. Our study has three principal limitations that warrant consideration. First, with its cross- sectional design, the assessment of exposure to phthalates may have occurred several years after diagnosis of the outcomes. It is uncertain whether diagnosis would directly influence uri- nary phthalate concentrations by altering the metabolism of phthalates, although recent data from 60 women in the Early Pregnancy Study indicate little variation in urinary phthalate metabolite concentrations across phases of the menstrual cycle (Baird et al. 2009), suggesting that changes in a woman’s endogenous hor- monal milieu (which might occur with age, oral contraceptive use, or hysterectomy) have mini- mal effects on phthalate metabolism. However, it remains possible that diagnoses could indi- rectly affect urinary phthalate concentrations via exposures resulting from diagnosis, as described above. However, given the short half-lives of the metabolites, it seems unlikely that diagnosis- related procedures occurring more than a few days before the NHANES examination would be an important source of exposure. Moreover, although medications have recently been identi- fied as an important source of DBP and DEP exposures (Hauser et al. 2004; Hernández- Díaz et al. 2009), medications typically indi- cated for endometriosis and leiomyomata are not likely to contain these compounds because they are not coated for timed release. Even in the absence of reverse causation, the increas- ing interval between the relevant and measured exposures is a form of measurement error— nondifferential with respect to exposure or dis- ease status—that could attenuate the observed associations. The associations between MBP and uterine leiomyomata and between MEHP and endometriosis became stronger when we confined analyses to women whose diagnoses or hysterectomies occurred within 7 years of their NHANES evaluation, suggesting that this type of exposure measurement error may have affected our results. Our exposure measure is limited in that phthalates do not bioaccumulate and have short half-lives in the body. Therefore, measure- ments taken at a single point in time are less reliable indicators of typical exposures than, for example, a series of measurements taken over several weeks. Yet emerging data suggest some consistency of phthalate exposures over time among reproductive-age women. In their study of 46 women 35–49 years of age who provided first-morning urinary voids on 2 consecutive days, Hoppin et al. (2002) found intraclass correlations (ICCs) ranging from 0.53 to 0.80 for creatinine-corrected urinary concentrations of MBP, MEP, MEHP, and MBzP. Over lon- ger time intervals, these correlations may be Environmental Health Perspectives • volume 118 | number 6 | June 2010 weaker, as suggested by data from two studies: the Early Pregnancy Study, which reported ICCs for these urinary metabolites ranging from 0.36 to 0.53 for measurements taken over 2-week intervals (Baird et al. 2009); and a study of 28 pregnant women (Adibi et al. 2008), which reported ICCs for the creatinine- corrected urinary phthalate concentrations ranging from 0.21 to 0.65 for measurements taken repeatedly over 6 weeks. Therefore, it is possible that we have underestimated the true associations, where they exist, between phthalate exposures and endometriosis and uterine leiomyomata. Nonetheless, our expo- sure measures do represent an advance over measures used in previous work in that we have used urinary measures of phthalate metabolites, which are far less vulnerable to contamination than phthalate diester measurements in blood. Moreover, we have evaluated exposures to four phthalates, conferring a degree of specificity to our findings. Finally, an important limitation of our study is that measures of both outcomes were based solely on self-report of physician diag- nosis. Prevalence estimates of these conditions in our study population are similar to stud- ies based on hospital-discharge and prospec- tive cohort data (Eskenazi and Warner 1997; Missmer and Cramer 2003; Schwartz and Marshall 2000; Wise et al. 2005). Two large prospective studies of self-reported leiomyo- mata that validated the reports against medical records indicated a low proportion of false pos- itives (Marshall et al. 1997; Wise et al. 2004); therefore, specificity of diagnosis is likely to be high. False reports of endometriosis diag- nosis may occur more frequently (Missmer et al. 2004b), but the proportion of undiag- nosed endometriosis cases is likely to be smaller (Zondervan et al. 2002). For both outcomes, it seems unlikely that misclassification of disease status was influenced by degree of phthalate exposure, and such nondifferential misclas- sification would have attenuated our findings. Our findings for endometriosis may have been further influenced by phthalate effects that are specific to different types of underlying pathol- ogy. Estrogen-related risk factors appear to vary by endometriosis that is concurrent with and independent of infertility (the latter which is often accompanied by pain) (Missmer et al. 2004a, 2004b). However, in the absence of data on infertility and symptomatic pain, the findings reflect an averaged association of the phthalate measures with these two subgroups. In addition to our study’s strengths in its exposure measurements, our study also benefited from its large sample size, its con- sideration of several important potential confounders, and its representativeness of the general population of reproductive-age women living in the United States. In conclu- sion, we have identified preliminary evidence 831