Urinary cadmium and endometriosis prevalence in a US nationally representative sample: results from NHANES 1999-2006.

STUDY QUESTION: Is exposure to toxic metal cadmium associated with increased endometriosis prevalence among a nationally representative sample of the US population? SUMMARY ANSWER: Concentrations of urinary cadmium, a long-term biomarker (10-30 years) of cadmium exposure, were associated with an increased prevalence of endometriosis. WHAT IS KNOWN ALREADY: Cadmium exhibits estrogenic properties and may increase the risk of endometriosis, a gynecologic condition associated with substantial morbidity, for which estrogen has a central pathogenic role. Previous epidemiological studies of cadmium and endometriosis have yielded mixed results, with null, positive, and inverse associations being reported. STUDY DESIGN, SIZE, DURATION: We conducted a cross-sectional study using data from four cycles of the National Health and Nutrition Examination Survey (NHANES) 1999-2006. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study population comprised participants aged 20-54 years who had an endometriosis diagnosis, available data on urinary cadmium, and a glomerular filtration rate ≥60 ml/min/1.73 m2 (unweighted n = 1647). Urinary cadmium was measured by inductively coupled plasma-mass spectrometry, and we used urinary creatinine concentrations and covariate-adjusted standardization to account for urinary dilution. Self-reported diagnosis of endometriosis was ascertained by interview. We examined the association between quartiles of urinary cadmium and endometriosis using log-binomial regression to estimate adjusted prevalence ratios (aPRs) and 95% CIs. MAIN RESULTS AND THE ROLE OF CHANCE: We observed twice the prevalence of endometriosis for participants with cadmium concentrations in the second quartile (versus the first quartile) (aPR 2.0, 95% CI: 1.1, 3.9) and the third quartile (versus the first quartile) (aPR 2.0, 95% CI: 1.1, 3.7). Our data also suggested a 60% increased prevalence of endometriosis with urinary cadmium concentrations in the fourth quartile (versus the first quartile) (aPR 1.6, 95% CI: 0.8, 3.2). In a sensitivity analysis, restricting the study population to premenopausal participants with an intact uterus and at least one ovary (unweighted n = 1298), stronger associations accompanied by wider CIs were observed. LIMITATIONS, REASONS FOR CAUTION: We were limited by the ascertainment of urinary cadmium and endometriosis diagnosis at a single time point, given the cross-sectional study design, and we relied on self-report of endometriosis diagnosis. However, urinary cadmium characterizes long-term exposure and findings from validation studies suggest that misclassification of self-reported endometriosis diagnosis may be minimal. WIDER IMPLICATIONS OF THE FINDINGS: This study suggests that cadmium is associated with an increased endometriosis prevalence. Given the substantial morbidity conferred by endometriosis and that the general population is ubiquitously exposed to cadmium, further research is warranted to confirm our findings. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Institute of Nursing Research (grant R00NR017191 to K.U.) of the National Institutes of Health. The authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

A prospective ultrasound study of cigarette smoking and uterine leiomyomata incidence and growth.

BACKGROUND: Uterine leiomyomata (fibroids) are common, benign neoplasms that contribute substantially to gynecologic morbidity. Some existing epidemiologic studies indicate that cigarette smoking is associated with lower uterine leiomyomata risk. However, no prospective studies have systematically screened an entire study population for uterine leiomyomata using transvaginal ultrasound or evaluated the association between cigarette smoking and uterine leiomyomata growth. OBJECTIVE: This study aimed to examine the association between cigarette smoking and uterine leiomyomata incidence and growth in a prospective ultrasound study. STUDY DESIGN: We enrolled 1693 residents from the Detroit metropolitan area into the Study of Environment, Lifestyle, and Fibroids during 2010 to 2012. Eligible participants were aged 23 to 34 years, had an intact uterus but no previous diagnosis of uterine leiomyomata, and self-identified as Black or African American. We invited participants to complete a baseline visit and 4 follow-up visits over approximately 10 years. At each visit, we used transvaginal ultrasound to assess uterine leiomyomata incidence and growth. Participants provided extensive self-reported data throughout follow-up including exposures to active and passive cigarette smoking in adulthood. We excluded participants who did not return for any follow-up visits (n=76; 4%). We fit Cox proportional hazards regression models to estimate hazard ratios and 95% confidence intervals for the association between time-varying smoking history and incidence rates of uterine leiomyomata. We fit linear mixed models to estimate the percentage difference and 95% confidence intervals for the association between smoking history and uterine leiomyomata growth. We adjusted for sociodemographic, lifestyle, and reproductive factors. We interpreted our results based on magnitude and precision rather than binary significance testing. RESULTS: Among 1252 participants without ultrasound evidence of uterine leiomyomata at baseline, uterine leiomyomata were detected in 394 participants (31%) during follow-up. Current cigarette smoking was associated with a lower uterine leiomyomata incidence rate (hazard ratio, 0.67; 95% confidence interval, 0.49-0.92). Associations were stronger among participants who had smoked for longer durations (≥15 years vs never: hazard ratio, 0.49; 95% confidence interval, 0.25-0.95). The hazard ratio for former smokers was 0.78 (95% confidence interval, 0.50-1.20). Among never smokers, the hazard ratio for current passive smoke exposure was 0.84 (95% confidence interval, 0.65-1.07). Uterine leiomyomata growth was not appreciably associated with current (percent difference, -3%; 95% confidence interval, -13% to 8%) or former (percent difference, -9%; 95% confidence interval, -22% to 6%) smoking. CONCLUSION: We provide evidence from a prospective ultrasound study that cigarette smoking is associated with lower uterine leiomyomata incidence.

Cadmium Exposure and Ovarian Reserve in Women Aged 35-49 Years: The Impact on Results From the Creatinine Adjustment Approach Used to Correct for Urinary Dilution.

Cadmium is toxic to the ovaries in animal studies, but its association with diminished ovarian reserve in women is not established. We investigated urinary cadmium, a biomarker of long-term exposure, in relation to diminished ovarian reserve, as indicated by elevated serum follicle-stimulating hormone concentrations (≥10 IU/L), in women aged 35-49 years (unweighted n = 1,681). Using data from the Third National Health and Nutrition Examination Survey (1988-1994), we conducted Poisson regression to estimate adjusted relative risks and 95% confidence intervals. Because the best approach to correcting for urinary dilution in spot samples with creatinine remains controversial, we employed 3 approaches: standardization, covariate adjustment, and covariate-adjusted standardization. Our data suggested a modest association with standardization (highest quartile vs. lowest: relative risk (RR) = 1.3, 95% confidence interval (CI): 0.8, 1.9; P for trend = 0.06) and covariate-adjusted standardization (highest quartile vs. lowest: RR = 1.3, 95% CI: 0.9, 1.9; P for trend = 0.05) and a stronger association with covariate adjustment (highest quartile vs. lowest: RR = 1.8, 95% CI: 1.2, 2.9; P for trend = 0.01). The stronger association with covariate adjustment may reflect bias from conditioning on urinary creatinine, a collider in the hypothesized causal pathway. We conclude that cadmium may contribute to ovarian aging in women and that careful consideration of the creatinine adjustment approach is needed to minimize bias.

Early-life Farm Exposure and Ovarian Reserve in a US Cohort of Women.

BACKGROUND: In a previous exploratory study, we reported lower concentrations of the ovarian reserve biomarker anti-Müllerian hormone (AMH) in adulthood with prenatal farm exposure. We now examine this association as well as childhood farm exposure using enrollment data from the Sister Study, a large US cohort of women. METHODS: We collected prenatal and childhood farm exposure data by questionnaire and telephone interview. However, serum AMH data were available only for a nested subset: premenopausal women ages 35-54 subsequently diagnosed with breast cancer (n = 418 cases) and their matched controls (n = 866). To avoid potential bias from restricting analyses to only premenopausal controls, we leveraged the available cohort data. We used data from both premenopausal cases and controls as well as postmenopausal women ages 35-54 (n = 3,526) (all presumed to have undetectable AMH concentrations) and applied weights to produce a sample representative of the cohort ages 35-54 (n = 17,799). The high proportion of undetectable AMH concentrations (41%) was addressed using reverse-scale Cox regression. An adjusted hazard ratio (HR) <1.0 indicates that exposed individuals had lower AMH concentrations than unexposed individuals. RESULTS: Prenatal exposure to maternal residence or work on a farm was associated with lower AMH concentrations (HR 0.66; 95% confidence intervals [CI] = 0.48 to 0.90). Associations between childhood farm residence exposures and AMH were null or weak, except childhood contact with pesticide-treated livestock or buildings (HR 0.69; 95% CI = 0.40 to 1.2). CONCLUSIONS: Replication of the prenatal farm exposure and lower adult AMH association raises concern that aspects of prenatal farm exposure may result in reduced adult ovarian reserve.

REPRODUCTIVE TOXICOLOGY: Pregnancy exposure to endocrine disrupting chemicals: implications for women's health.

Women are ubiquitously exposed to non-persistent endocrine disrupting chemicals (EDCs) from food contact materials and personal care products. Understanding the impacts of exposure to these chemicals on pregnancy and long-term health outcomes in women is a critical area of research that has been largely overlooked. This brief review focuses on the epidemiologic literature exploring associations of non-persistent EDCs - including phthalates, parabens, bisphenols, and triclosan - with maternal pregnancy outcomes and long-term health outcomes in women. We focus on the challenges of this research, particularly assessing non-persistent EDC exposures, aspects of study design, and statistical approaches. We conclude by reviewing the best practices for non-persistent EDC research with regards to pregnancy and women's health. Though limited, we found some evidence indicating that exposure to non-persistent EDCs is associated with pregnancy health. However, findings from these studies have been inconsistent and require corroboration. Recent studies have also proposed that non-persistent EDC exposures in pregnancy may adversely affect postnatal maternal health. To date, only a few studies have been conducted and have only focused on postpartum weight. More research is needed in this area to inform efforts to promote optimal health across the lifespan of women.

Soy-based infant formula feeding and menstrual pain in a cohort of women aged 23-35 years.

STUDY QUESTION: Is soy formula feeding during infancy associated with menstrual pain in reproductive-age women? SUMMARY ANSWER: Our data suggest that soy formula feeding during infancy is associated with several indicators of severe menstrual pain in reproductive-age women. WHAT IS KNOWN ALREADY: A prior study observed greater severity of menstrual pain in young women who as infants participated in feeding studies and were assigned to soy-based formula feeding. STUDY DESIGN, SIZE, DURATION: We used data from the Study of Environment, Lifestyle & Fibroids (SELF), a cohort of 1696 African-American women ages 23-35 years at enrollment. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Data on infant soy formula feeding was ascertained by self-administered questionnaire for 1553 participants, with 89% of participants receiving assistance from their mothers. Information on menstrual pain indicators was collected by web- and telephone-interview. We estimated the relative risk (RR) and 95% confidence interval (CI) using log-binomial regression, or log-multinomial regression, adjusting for participant age and maternal education. MAIN RESULTS AND THE ROLE OF CHANCE: Women ever fed soy formula as infants were more likely than unexposed women to report ever use of hormonal contraception for menstrual pain (RR 1.4, CI: 1.1-1.9) and moderate/severe menstrual discomfort/pain with 'most periods', but not 'every period', during early adulthood (ages 18-22 when not using hormonal contraception) (RR 1.5, CI: 1.1-2.0). LIMITATIONS, REASONS FOR CAUTION: We relied on retrospective recall to ascertain infant exposure to soy formula feeding and data on menstrual pain indicators. WIDER IMPLICATIONS OF THE FINDINGS: Our observations add to the growing body of literature from animal and human studies on the reproductive health consequences of early-life exposure to soy formula. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences and, in part, by funds allocated for health research by the American Recovery and Reinvestment Act. This research was also supported by grant K99NR017191 (KU). None of the authors has a conflict of interest. TRIAL REGISTRATION NUMBER: Not applicable.

Soy-based Infant Formula Feeding and Heavy Menstrual Bleeding Among Young African American Women.

BACKGROUND: Phytoestrogen exposure from soy formula feeding during infancy may disrupt reproductive system development, resulting in altered menstrual bleeding in adulthood. METHODS: We investigated this relationship in a cohort of 1,696 young African American women using enrollment data from the Study of Environment, Lifestyle, & Fibroids (2010-2012). Questionnaire data on soy formula feeding were available for 1,553 participants, 89% based on mother's report. Menstrual bleeding outcomes including those indicative of heavy menstrual bleeding were ascertained by interview. We estimated relative risks (RRs) and 95% confidence intervals (CI) for associations between soy formula feeding and menstrual bleeding outcomes using log-binomial regression and log-multinomial regression, comparing participants ever fed and never fed soy formula. RESULTS: We observed associations between soy formula feeding and variables indicating a history of heavy menstrual bleeding, including ever experiencing heavy, gushing-type bleeding (RR: 1.2, 95% CI: 1.0, 1.4), ever use of nonsteroidal anti-inflammatory drugs for heavy bleeding (RR: 1.3, 95% CI: 1.0, 1.6), and ever use of a contraceptive method for heavy bleeding (RR: 1.2, 95% CI, 0.9, 1.6). Among the subset of participants with menses in the past year who did not use medication that may alter menstrual flow (n = 762), our data suggested that soy formula feeding was associated with heavier flow and the adverse impact of menstrual bleeding on quality of life, but CIs were wide. CONCLUSIONS: Our data suggested that soy formula feeding is associated with heavy menstrual bleeding. Our results support the idea that infancy is a susceptible developmental window for female reproductive function.

A population-based case-control study of urinary bisphenol A concentrations and risk of endometriosis.

STUDY QUESTION: Is bisphenol A (BPA) exposure associated with the risk of endometriosis, an estrogen-driven disease of women of reproductive age? SUMMARY ANSWER: Our study suggests that increased urinary BPA is associated with an increased risk of non-ovarian pelvic endometriosis, but not ovarian endometriosis. WHAT IS KNOWN ALREADY: BPA, a high-volume chemical used in the polymer industry, has been the focus of public and scientific concern given its demonstrated estrogenic effects in vivo and in vitro and widespread human exposure. Prior studies of BPA and endometriosis have yielded inconsistent results and were limited by the participant sampling framework, small sample size or use of serum (which has very low/transient concentrations) instead of urine to measure BPA concentrations. STUDY DESIGN, SIZE, DURATION: We used data from the Women's Risk of Endometriosis study, a population-based case-control study of endometriosis, conducted among female enrollees of a large healthcare system in the US Pacific Northwest. Cases were women with incident, surgically confirmed endometriosis diagnosed between 1996 and 2001 and controls were women randomly selected from the defined population that gave rise to the cases, without a current or prior diagnosis of endometriosis. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Total urinary BPA concentrations were measured in 143 cases and 287 population-based controls using single, spot urine samples collected after disease diagnosis in cases. Total urinary BPA concentration (free and conjugated species) was quantified using a high-performance liquid chromatography-mass spectrometry method. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression, adjusting for urinary creatinine concentrations, age and reference year. We also evaluated the association by disease subtypes, ovarian and non-ovarian pelvic endometriosis, that may be etiologically distinct. MAIN RESULTS AND THE ROLE OF CHANCE: We did not observe a statistically significant association between total urinary BPA concentrations and endometriosis overall. We did observe statistically significant positive associations when evaluating total urinary BPA concentrations in relation to non-ovarian pelvic endometriosis (second versus lowest quartile: OR 3.0; 95% CI: 1.2, 7.3; third versus lowest quartile: OR 3.0; 95% CI: 1.1, 7.6), but not in relation to ovarian endometriosis. LIMITATIONS, REASONS FOR CAUTION: Given the short elimination half-life of BPA, our study was limited by the timing of collection of the single urine sample, that occurred after case diagnosis. Thus, our BPA measurements may not accurately represent the participants' levels during the etiologically relevant time period for endometriosis development. In addition, since it was not feasible in this population-based study to surgically confirm the absence of disease, it is possible that some controls may have had undiagnosed endometriosis. WIDER IMPLICATIONS OF THE FINDINGS: By using population-based data, it is more likely that the controls represented the underlying frequency of BPA exposure in contrast to prior studies that used for comparison control women undergoing surgical evaluation, where the indication for surgery may be associated with BPA exposure. The significant associations observed in this study suggest that BPA may affect the normal dynamic structural changes of hormonally responsive endometrial tissue during the menstrual cycle, promoting the establishment and persistence of refluxed endometrial tissue in cases with non-ovarian pelvic endometriosis. Further research is warranted to confirm our novel findings in endometriosis subtypes that may be etiologically distinct. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the National Institutes of Health, National Institute of Environmental Health Sciences (grant number R03 ES019976), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant number R01 HD033792); US Environmental Protection Agency, Science to Achieve Results (STAR) (grant number R82943-01-0) and National Institute of Nursing Research (grant number F31NR013092) to KU for training support. This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Institute of Child Health and Human Development, National Institute of Environmental Health Sciences, National Institute of Nursing Research or the National Institutes of Health. The authors have no actual or potential competing financial interests. TRIAL REGISTRATION NUMBER: Not applicable.

Tampons as a source of exposure to metal(loid)s.

BACKGROUND: Between 52-86% of people who menstruate in the United States use tampons-cotton and/or rayon/viscose 'plugs'-to absorb menstrual blood in the vagina. Tampons may contain metals from agricultural or manufacturing processes, which could be absorbed by the vagina's highly absorptive tissue, resulting in systemic exposure. To our knowledge, no previous studies have measured metals in tampons. OBJECTIVES: We evaluated the concentrations of 16 metal(loid)s in 30 tampons from 14 tampon brands and 18 product lines and compared the concentrations by tampon characteristics. METHODS: About 0.2 - 0.3 g from each tampon (n = 60 samples) were microwave-acid digested and analyzed by inductively coupled plasma mass spectrometry (ICP-MS) to determine concentrations of arsenic, barium, calcium, cadmium, cobalt, chromium, copper, iron, manganese, mercury, nickel, lead, selenium, strontium, vanadium, and zinc. We compared concentrations by several tampon characteristics (region of purchase, organic material, brand type) using median quantile mixed models. RESULTS: We found measurable concentrations of all 16 metals assessed. We detected concentrations of several toxic metals, including elevated mean concentrations of lead (geometric mean [GM] = 120 ng/g), cadmium (GM = 6.74 ng/g), and arsenic (GM = 2.56 ng/g). Metal concentrations differed by region of tampon purchase (US versus European Union/United Kingdom), by organic versus non-organic material, and for store- versus name-brand tampons. Most metals differed by organic status; lead concentrations were higher in non-organic tampons while arsenic was higher in organic tampons. No categoriy had consistently lower concentrations of all or most metals. DISCUSSION: Tampon use is a potential source of metal exposure. We detected all 16 metals in at least one sampled tampon, including some toxic metals like lead that has no "safe" exposure level. Future research is needed to replicate our findings and determine whether metals can leach out of tampons and cross the vaginal epithelium into systemic circulation.

Subgroups of pelvic pain are differentially associated with endometriosis and inflammatory comorbidities: a latent class analysis.

ABSTRACT: Chronic pelvic pain is heterogeneous with potentially clinically informative subgroups. We aimed to identify subgroups of pelvic pain based on symptom patterns and investigate their associations with inflammatory and chronic pain-related comorbidities. Latent class analysis (LCA) identified subgroups of participants (n = 1255) from the Adolescence to Adulthood (A2A) cohort. Six participant characteristics were included in the LCA: severity, frequency, and impact on daily activities of both menstruation-associated (cyclic) and non-menstruation-associated (acyclic) pelvic pain. Three-step LCA quantified associations between LC subgroups, demographic and clinical variables, and 18 comorbidities (10 with prevalence ≥10%). Five subgroups were identified: none or minimal (23%), moderate cyclic only (28%), severe cyclic only (20%), moderate or severe acyclic plus moderate cyclic (9%), and severe acyclic plus severe cyclic (21%). Endometriosis prevalence within these 5 LCA-pelvic pain-defined subgroups ranged in size from 4% in "none or minimal pelvic pain" to 24%, 72%, 70%, and 94%, respectively, in the 4 pain subgroups, with statistically significant odds of membership only for the latter 3 subgroups. Migraines were associated with significant odds of membership in all 4 pelvic pain subgroups relative to those with no pelvic pain (adjusted odds ratios = 2.92-7.78), whereas back, joint, or leg pain each had significantly greater odds of membership in the latter 3 subgroups. Asthma or allergies had three times the odds of membership in the most severe pain group. Subgroups with elevated levels of cyclic or acyclic pain are associated with greater frequency of chronic overlapping pain conditions, suggesting an important role for central inflammatory and immunological mechanisms.

Phthalates and risk of endometriosis.

BACKGROUND: Phthalates are ubiquitous environmental chemicals with endocrine disruptive properties. The impact of these chemicals on endocrine-related disease in reproductive-age women is not well understood. OBJECTIVE: To investigate the relationship between urinary phthalate metabolite concentrations and the risk of a hormonally-driven disease, endometriosis, in reproductive-age women. METHODS: We used data from a population-based case-control study of endometriosis, conducted among female enrollees of a large healthcare system in the U.S. Pacific Northwest. We measured urinary phthalate metabolite concentrations on incident, surgically-confirmed cases (n=92) diagnosed between 1996 and 2001 and population-based controls (n=195). Odds ratios (OR), and 95% confidence intervals (CI) were estimated using unconditional logistic regression, adjusting for urinary creatinine concentrations, age, and reference year. RESULTS: The majority of women in our study had detectable concentrations of phthalate metabolites. We observed a strong inverse association between urinary mono-(2-ethyl-5-hexyl) phthalate (MEHP) concentration and endometriosis risk, particularly when comparing the fourth and first MEHP quartiles (aOR 0.3, 95% CI: 0.1-0.7). Our data suggested an inverse association between endometriosis and urinary concentrations of other di-2-ethylhexyl phthalate (DEHP) metabolites (mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP)) and ∑DEHP, however, the confidence intervals include the null. Our data also suggested increased endometriosis risk with greater urinary concentrations of mono-benzyl phthalate (MBzP) and mono-ethyl phthalate (MEP), although the associations were not statistically significant. CONCLUSIONS: Exposure to select phthalates is ubiquitous among female enrollees of a large healthcare system in the U.S. Pacific Northwest. The findings from our study suggest that phthalates may alter the risk of a hormonally-mediated disease among reproductive-age women.

Soy-Based Infant Formula Feeding and Uterine Fibroid Development in a Prospective Ultrasound Study of Black/African-American Women.

BACKGROUND: Uterine fibroids are highly prevalent, benign tumors. They are the leading indication for hysterectomy, and Black women are disproportionally burdened. Soy-based infant formula contains phytoestrogens, and exposure during sensitive developmental windows may adversely affect the developing uterus; early phytoestrogen treatment in rodent studies led to detrimental uterine effects, including increased fibroid risk in Eker rats. Limited epidemiological studies also have suggested increased fibroid development with soy formula infant feeding. OBJECTIVE: The goal of this study was to examine the association between soy formula feeding in infancy and fibroid development in adulthood. METHODS: We evaluated this association among 1,610 Black/African-American women age 23-35 y in the Study of Environment, Lifestyle & Fibroids (SELF). Soy formula feeding data was gathered directly from the participants' mothers (89%). A standardized ultrasound examination was conducted during 4 clinic visits over 5 y to detect fibroids ≥0.5cm in diameter. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between soy formula feeding and incident fibroids adjusted for early-life and adult factors. Fibroid growth was calculated as change in log-volume for fibroids matched at successive visits. RESULTS: Of 1,121 fibroid-free participants at baseline, 150 (13%) were ever fed soy formula as infants, and 269 (24%) developed incident fibroids. We did not observe an association between ever being fed soy formula and incident fibroid risk (HR=1.08; 95% CI: 0.75, 1.54). However, participants fed soy formula within 2 months of birth and for >6 months (n=53) had an elevated risk of fibroid incidence in comparison with those never fed soy formula (HR=1.56; 95% CI: 0.92, 2.65). Fibroid growth rates did not differ. DISCUSSION: Adding support to limited human data, this prospective fibroid study found that soy-based formula feeding during infancy was associated with a suggestive increase in risk of ultrasound-identified incident fibroids in adulthood. https://doi.org/10.1289/EHP11089.

Cannabis smoking, tobacco cigarette smoking, and adenomyosis risk.

OBJECTIVE: To investigate cannabis smoking and tobacco cigarette smoking in relation to adenomyosis risk. DESIGN: We used data from a case-control study of adenomyosis conducted among enrollees ages 18-59 years of an integrated health care system in Washington State. The case-control study used 2 control groups given the challenge of selecting noncases when cases are diagnosed by hysterectomy. SUBJECTS: Cases (n = 386) were enrollees with incident, pathology-confirmed adenomyosis diagnosed between April 1, 2001, and March 31, 2006. The 2 control groups comprised hysterectomy controls (n = 233) with pathology-confirmed absence of adenomyosis and population controls (n = 323) with an intact uterus selected randomly from the health care system population and frequency matched to cases on age. EXPOSURE: Detailed data on cannabis and tobacco cigarette smoking history were ascertained through in-person structured interviews, allowing estimation of joint-years of cannabis smoking and pack-years of tobacco cigarette smoking. MAIN OUTCOME MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between cannabis smoking, tobacco cigarette smoking, and adenomyosis were estimated using multivariable unconditional logistic regression. Analyses were adjusted for age, reference year, menarche age, education, and pack-years of cigarette smoking (or joint-years of cannabis smoking). RESULTS: No association was observed between cannabis smoking history and adenomyosis risk. However, we did observe the suggestion of an association between ever tobacco cigarette smoking and adenomyosis risk, comparing cases to hysterectomy controls (OR, 1.3; 95% CI, 0.9-1.9) and population controls (OR, 1.2; 95% CI, 0.8-1.8). Our data suggested a 50% increased odds of adenomyosis with >15 pack-years of smoking (vs. never smoking), comparing cases to hysterectomy controls (OR, 1.5; 95% CI, 0.9-2.6; Ptrend=.135). The suggestion of a 40% increased adenomyosis odds was observed with smoking >5-15 pack-years (vs. never smoking), comparing cases to population controls (OR, 1.4; 95% CI, 0.8-2.4; Ptrend=0.136). CONCLUSION: In the first study of cannabis smoking and adenomyosis risk, no association was observed. However, our data suggested an increased odds of adenomyosis with history of tobacco cigarette smoking. Further research is warranted to replicate our results given the substantial morbidity with adenomyosis and frequency of cigarette smoking and recreational and medical cannabis use.

Breastfeeding history and adenomyosis risk using a novel case-control study design.

OBJECTIVE: To evaluate the association between breastfeeding history, including lifetime exclusive breastfeeding, and risk of adenomyosis. DESIGN: We used data from a case-control study designed with 2 control groups to address the challenge of selecting noncases for a valid epidemiologic study when cases are identified by hysterectomy. The case-control study was conducted among premenopausal and postmenopausal enrollees aged 18-59 years in a large, integrated health care system in western Washington state. PATIENT(S): Cases were enrollees with incident, pathology-confirmed adenomyosis diagnosed during 2001-2006 (n = 386). The 2 control groups were as follows: (1) randomly selected age-matched enrollees with intact uteri ("population controls," n = 323) and (2) hysterectomy controls (n = 233). INTERVENTION(S): Data on breastfeeding history were collected by in-person interviews. For each reported live birth, participants were asked whether they breastfed, along with infant age at supplemental feeding introduction and breastfeeding discontinuation. MAIN OUTCOME MEASURE(S): Among participants with at least 1 live birth (330 cases, 246 population controls, and 198 hysterectomy controls), we used unconditional logistic regression to estimate adjusted odds ratios and 95% confidence intervals (CIs) for the associations between the following: (1) ever breastfeeding, (2) ever breastfeeding for ≥8 weeks, (3) lifetime breastfeeding, and (4) lifetime exclusive breastfeeding and risk of adenomyosis. Analyses were adjusted for age, reference year, smoking, education, and parity. RESULT(S): In analyses comparing cases with population controls, we observed a 40% decreased odds of adenomyosis with a history of ever breastfeeding (adjusted odds ratio, 0.6; 95% CI, 0.3-1.0) and breastfeeding for ≥8 weeks (adjusted odds ratio, 0.6; 95% CI, 0.4-0.8). The strongest associations, 60%-70% decreased odds of adenomyosis, were observed with ≥12 months of lifetime breastfeeding (vs. <3 months) (adjusted odds ratio, 0.4; 95% CI, 0.2-0.6) and 9 to <12 months of lifetime exclusive breastfeeding (vs. <3 months) (adjusted odds ratio, 0.3; 95% CI, 0.2-0.6), comparing cases to population controls. In analyses using hysterectomy controls, we observed similar patterns of associations slightly attenuated in magnitude. CONCLUSION(S): Breastfeeding history was associated with a 40% decreased odds of adenomyosis, a condition that can confer substantial morbidity and requires hysterectomy for definitive treatment. The consistency of our findings with that of a previous study lends support that breastfeeding may modify risk of adenomyosis.

Biomarkers of progestin therapy resistance and endometrial hyperplasia progression.

OBJECTIVE: We sought to identify biomarkers associated with progestin therapy resistance and persistence/progression of endometrial hyperplasia. STUDY DESIGN: We performed a nested case-control study among women with complex (n = 73) and atypical (n = 41) hyperplasia treated with oral progestin, followed up 2-6 months for persistence/progression. We evaluated index endometrial protein expression for progesterone receptor isoform A, progesterone receptor isoform B (PRB), PTEN, Pax-2, and Bcl-2. Odds ratios and 95% confidence intervals (CIs) were estimated. RESULTS: Among women with atypical hyperplasia, high PRB expression was associated with 90% decreased risk of persistence/progression (95% CI, 0.01-0.8). High expression of progesterone receptor A and PRB suggested decreased risk of persistence/progression (odds ratio, 0.1; 95% CI, 0.02-1.0). These findings were not observed among women with complex hyperplasia. No associations were found with PTEN, Pax-2, and Bcl-2 protein expression. CONCLUSION: PRB expression shows promise as a biomarker of progestin response. Further research is warranted to understand how PRB expression may guide treatment decisions.

PAX2 loss by immunohistochemistry occurs early and often in endometrial hyperplasia.

Immunohistochemical markers to assist in the diagnosis and classification of hyperplastic endometrial epithelial proliferations would be of diagnostic use. To examine the possible use of PAX2 as a marker of hyperplastic endometrium, cases of normal endometrium, simple and complex hyperplasia without atypia, atypical hyperplasia, and International Federation of Gynecology and Obstetrics (FIGO) grade 1 endometrioid carcinomas were stained for PAX2. Two hundred and six endometrial samples were available for interpretation of PAX2 staining. The percentage of cases with complete PAX2 loss (0% of cells staining) increased with increasing severity of hyperplasia: 0% of normal proliferative and secretory endometrium (n=28), 17.4% of simple hyperplasia (n=23), 59.0% of complex hyperplasia (n=83), 74.1% of atypical hyperplasia (n=54), and 73.3% of FIGO grade 1 endometrioid cancers (n=15). Partial loss of PAX2 expression did occur in normal endometrium (17.9%) but in smaller proportions of tissue and was less frequent than in simple hyperplasia (47.8% with partial loss), complex hyperplasia (32.5%), atypical hyperplasia (22.2%), and FIGO grade 1 carcinomas (20.0%). Uniform PAX2 expression was rare in complex (8.4%) and atypical hyperplasia (3.7%) and carcinoma (6.7%). When evaluating loss of PAX2 in histologically normal endometrium adjacent to lesional endometrium in a given case, statistically significant differences in staining were observed for simple hyperplasia (P=0.011), complex hyperplasia (P<0.001), atypical hyperplasia (P<0.001), and FIGO grade 1 endometrioid cancer (P=0.003). In summary, PAX2 loss seems to occur early in the development of endometrial precancers and may prove useful in some settings as a diagnostic marker in determining normal endometrium from complex and atypical hyperplasia and low-grade carcinomas. However, it is not useful in distinguishing between these diagnostic categories.

An Epidemiologic Review of Menstrual Blood Loss as an Excretion Route for Per- and Polyfluoroalkyl Substances.

PURPOSE OF REVIEW: Menstrual blood loss, a common physiologic occurrence, provides an excretion route for per- and polyfluoroalkyl substances (PFAS) since these chemicals are bound to proteins in blood. To increase awareness of this relationship in environmental epidemiology, we reviewed the available epidemiologic data on menstrual bleeding and PFAS concentrations. RECENT FINDINGS: Initial epidemiologic studies reported generally higher PFAS concentrations in men, menopausal women, and those with a history of hysterectomy compared to premenopausal women. Although subsequent studies investigating menstrual cycle characteristics observed somewhat discrepant results for menstrual irregularity and cycle length, consistent associations have been observed between heavy menstrual bleeding and lower PFAS concentrations. This review highlights the important role of menstrual bleeding on the excretion of PFAS. Given the high prevalence of menstrual bleeding in the population and the implications for environmental epidemiology, we provide recommendations to move this field forward.

Menstrual Products as a Source of Environmental Chemical Exposure: A Review from the Epidemiologic Perspective.

PURPOSE OF REVIEW: Menstrual bleeding is a regular, common occurrence in a substantial portion of the population. Menstruators may use more than 10,000 menstrual products over the lifetime. Given the potential for environmental chemicals in menstrual products to be absorbed by the vulvar and vaginal epithelium into systemic circulation, we reviewed the available data on menstrual products as a source of environmental chemical exposure. RECENT FINDINGS: Nearly two dozen studies have been conducted measuring environmental contaminants in menstrual products; all have detected environmental chemicals but had discrepant conclusions on exposure risks. Only three human studies have investigated menstrual product use and environmental chemical concentrations and all observed associations. Detection of environmental chemicals in menstrual products, in combination with challenges of exposure assessment, scarcity of human studies, and the exceedingly common occurrence of menstrual bleeding, motivates the need for further research. We provide recommendations to move this field forward.

Ultrasound-Confirmed, Age-Specific Uterine Leiomyoma Incidence in a Cohort of Black Individuals.

OBJECTIVE: To estimate the age-specific incidence of uterine leiomyomas identified by transvaginal ultrasonography among participants in SELF (Study of Environment, Lifestyle & Fibroids). METHODS: SELF is a longitudinal cohort study of individuals aged 23-35 years who self-identified as Black. Participants were recruited from the Detroit, Michigan, area and underwent up to five transvaginal ultrasonograms over a period of up to 10 years to identify uterine leiomyomas. We randomly imputed incidence dates between the last ultrasonogram date in which no leiomyomas were detected and the date of the ultrasonogram in which leiomyomas were first detected. We used Poisson regression to estimate age-specific incidence rates per 1,000 person-years with 95% CIs. The rates were then compared with those of the BWHS (Black Women's Health Study) and the NHS II (Nurses' Health Study II)-two prospective cohort studies based on self-reported leiomyoma diagnoses. RESULTS: In this cohort, 1,693 participants completed a baseline interview and ultrasonogram. We excluded 385 (22.7%) participants with leiomyomas detected during baseline, seven participants whose ultrasonograms were poor quality, and 60 participants with only a baseline ultrasonogram. Among the remaining 1,241 participants, the overall incidence rate was 53.9 cases per 1,000 person-years (95% CI 48.6-59.6). The age-specific incidence rates (cases/1,000 person-years) were: younger than 30 years: 49.7, 95% CI 40.9-59.9; 30-34 years: 55.2, 95% CI 47.0-64.3; and 35-39 years: 58.2, 95% CI 47.3-70.9. Among participants aged younger than 30 years, the incidence rate in SELF was more than double that of the BWHS or the NHS II. CONCLUSION: The high age-specific leiomyoma incidence rates in this prospective ultrasound-based study indicate that many young Black individuals with leiomyomas go undiagnosed. These data suggest that individuals could benefit from ultrasound screening when they experience symptoms compatible with leiomyomas (eg, heavy menstrual bleeding, anemia, pelvic pain).

Correlates of whole blood metal concentrations among reproductive-aged Black women.

BACKGROUND: Metals may influence reproductive health, but few studies have investigated correlates of metal body burden among reproductive-aged women outside of pregnancy. Furthermore, while there is evidence of racial disparities in exposure to metals among U.S. women, there is limited research about correlates of metal body burden among Black women. OBJECTIVE: To identify correlates of whole blood metal concentrations among reproductive-aged Black women. METHODS: We analyzed cross-sectional data from a cohort of 1664 Black women aged 23-35 years in Detroit, Michigan, 2010-2012. We collected blood samples and questionnaire data. We measured concentrations of 17 metals in whole blood using inductively-coupled plasma-mass spectrometer-triple quadrupole and total mercury using Direct Mercury Analyzer-80. We used multivariable linear regression models to identify sociodemographic, environmental, reproductive, and dietary correlates of individual metal concentrations. RESULTS: In adjusted models, age was positively associated with multiple metals, including arsenic, cadmium, and mercury. Education and income were inversely associated with cadmium and lead. Current smoking was strongly, positively associated with cadmium and lead. Alcohol intake in the past year was positively associated with arsenic, barium, copper, lead, mercury, vanadium, and zinc. Having pumped gasoline in the past 24 h was positively associated with cadmium, chromium, and molybdenum. Having lived in an urban area for the majority of residence in Michigan was positively associated with arsenic, lead, and nickel. Higher water intake in the past year was positively associated with several metals, including lead. Fish intake in the past year was positively associated with arsenic, cesium, and mercury. We also observed associations with body mass index, season, and other environmental, reproductive, and dietary factors. SIGNIFICANCE: We identified potential sources of exposure to metals among reproductive-aged Black women. Our findings improve understanding of exposures to metals among non-pregnant reproductive-aged women, and can inform policies in support of reducing disparities in exposures. IMPACT STATEMENT: There are racial disparities in exposures to metals. We analyzed correlates of blood metal concentrations among reproductive-aged Black women in the Detroit, Michigan metropolitan area. We identified sociodemographic, anthropometric, lifestyle, environmental, reproductive, and dietary correlates of metal body burden. Age was positively associated with several metals. Education and income were inversely associated with cadmium and lead, indicating socioeconomic disparities. We identified potential exposure sources of metals among reproductive-aged Black women, including smoking, environmental tobacco smoke, pumping gasoline, living in an urban area, and intake of alcohol, water, fish, and rice.