Migraine and its association with pubertal maturation and behavioral traits among adolescent girls.

OBJECTIVE: To determine if the ages at pubertal milestones are associated with the prevalence of adolescent migraine. BACKGROUND: Migraine headaches are a common disease in adolescent girls. Past studies have evaluated the relationship between age of onset of menarche and migraine headache, but none have studied earlier pubertal milestones such as thelarche and pubarche. METHODS: In this cross-sectional study, a previously validated questionnaire was administered to girls (15-18 years) in Breast Cancer and the Environment Research Program puberty cohort to ascertain if they met criteria for migraine over the past year. Ages of pubertal development were ascertained by serial examinations beginning at 6-8 years of age and ending in late puberty. Logistic regression analyses determined if age of onset of each pubertal milestone (thelarche, pubarche, menarche separately) was associated with adolescent migraine after adjusting for other risk factors. RESULTS: Of 761girls, 222 (29.2%) met the criteria for migraine. Later thelarche was associated with a lower odds of adolescent migraine (OR 0.83; 95% CI 0.72-0.97, p = 0.019). In models further adjusted for BASC-2 internalizing problems (n = 490), both later thelarche (OR 0.78; 95% CI 0.64-0.96, p = 0.016) and later menarche (OR 0.81; 95%CI 0.67-0.98, p = 0.026) were associated with a lower migraine prevalence. Internalizing problems (OR 1.05; 95% CI 1.03-1.07) externalizing problems (OR 1.05; 95% CI 1.02-1.07) and behavioral symptoms (OR 1.05; 95% CI 1.03-1.08) were associated with increased prevalence of migraine in separate models. CONCLUSIONS: Age of onset of thelarche and menarche, and internalizing, externalizing, and behavioral symptoms were all associated with adolescent migraine.

Adverse Effects of Early Puberty Timing in Girls and Potential Solutions.

Given the global secular declining trends of the age at puberty and its relevant mechanisms, as illustrated in the first part of this series, the present part will discuss the public health implications of early puberty and potential clinical and public health measures. Although the major effect of earlier maturation impacts adolescents' mental health and likelihood of engaging in risky behaviors, there are also effects in adulthood on cardiometabolic health, especially type 2 diabetes, and an increased risk of certain cancers, especially hormone-related cancers such as breast cancer. The paper ends with recommendations for clinical management, especially for girls who should receive further evaluation, as well as recommendations for the patient and her family and public health considerations.

The Impact of Macronutrient Intake on Sex Steroids During Onset of Puberty.

INTRODUCTION: Increased fiber intake has been associated with decreased breast cancer risk, while increased animal protein intake with increased risk. The objective of this study is to examine the relationship of dietary fiber and protein intake to estrogen and sex hormone-binding globulin (SHBG) concentrations at puberty onset. METHODS: These analyses were conducted using the Cincinnati puberty cohort of the Breast Cancer and the Environment Research Program, with girls followed every 6 months from ages 6 and 7. The analyses included serum measurements at 6-month intervals for estrogen and SHBG concentrations, from 18 months prior to breast stage 2 (onset of puberty). Dietary intake was documented via 24-hour dietary recalls every 3 months. Dietary factors of interest included total energy intake; total and animal protein; total, soluble, and insoluble fiber; and lignan and flavanol intake. RESULTS: This study included 260 participants who generated 871 serum specimens and 3,000 days of diet intake. In longitudinal models, estradiol was associated inversely with insoluble fiber intake; estrone positively with animal protein intake; SHBG with greater insoluble fiber and lower total protein intake; and ratio of estrone to SHBG, a measure of bioavailable estrogen, positively with animal protein. CONCLUSIONS: Greater protein intake, especially animal protein, led to greater estrogen concentrations and lower SHBG; greater animal protein and greater caloric intake led to increased bioavailable estrogen. This relationship may have served an evolutionary advantage in the past for greater fertility with adequate high-quality protein; in contemporary women, a modest decrease in animal protein may be beneficial in reducing breast cancer risk.

The Association between Sex Hormones, Pubertal Milestones and Benzophenone-3 Exposure, Measured by Urinary Biomarker or Questionnaire.

Experimental studies have suggested benzophenone-3 (BP-3), a sunscreen ingredient, may have endocrine-disrupting properties. A cohort of girls were recruited at ages 6-7 years and returned semi-annually for pubertal maturation staging, provided blood for serum hormone analyses [estradiol, estrone, testosterone, dehydroepiandrosterone-sulfate (DHEA-S)], and urine to measure BP-3 concentrations. We found a significant negative linear association between amount of reported sunscreen use and testosterone levels at the onset of puberty (N = 157, adjusted ß = -0.0163, 97.5% CI:-0.0300,-0.0026). The 2nd quartile of the BP-3 biomarker had earlier thelarche compared to the 1st quartile (N = 282, adjusted HR = 1.584, 97.5% CI:1.038,2.415). Results suggest that higher report of sunscreen use may be associated with lower testosterone levels at thelarche and a non-linear relationship between the BP-3 urinary biomarker and onset of puberty, although the clinical significance of the finding is limited and may be a random effect. Improved methods of BP-3 exposure characterization are needed.

Childhood Socioeconomic Status and Menarche: A Prospective Study.

PURPOSE: The relationship between socioeconomic status (SES) and menarche has implications for understanding social level influences on early life development and adult disease, including breast cancer, but remains ill defined. We report here results from the Breast Cancer and the Environment Research Program, which permitted a longitudinal study of age at menarche in relationship to childhood SES in a diverse cohort of 1,069 girls across three urban areas of the United States. METHODS: We assessed the association of SES index quintiles with age at pubertal onset with breast budding and subsequent tempo to the age at menarche between 2004 and 2015 using multiple-event Cox regression models to estimate hazard ratios and 95% confidence intervals. RESULTS: In an unadjusted model, lower SES was predictive of both earlier pubertal onset and tempo and thus earlier age at menarche in trends across quintiles. After adjusting for the potentially mediating effects of body mass index, SES trends remained significant for both outcomes. After adjusting for both body mass index and race/ethnicity, the association with SES remained substantial for pubertal onset but was much diminished and nonsignificant for tempo and thus age at menarche. CONCLUSIONS: These results suggest that a lower SES environment and social adversity affect the age at menarche primarily by hastening pubertal onset rather than by shortening tempo.

Pubertal Growth, IGF-1, and Windows of Susceptibility: Puberty and Future Breast Cancer Risk.

PURPOSE: Risk markers for breast cancer include earlier onset of menarche (age at menarche [AAM]) and peak height velocity (PHV). Insulin-like growth factor-1 (IGF-1) is associated with pubertal milestones, as well as cancer risk. This study examined the relationships between pubertal milestones associated with breast cancer risk and hormone changes in puberty. METHODS: This is a longitudinal study of pubertal maturation in 183 girls, recruited at ages 6-7, followed up between 2004 and 2018. Measures included age at onset of puberty, and adult height attained; PHV; AAM; adult height, and serum IGF-1, and estrone-to-androstenedione (E:A) ratio. RESULTS: PHV was greatest in early, and least in late maturing girls; length of the pubertal growth spurt was longest in early, and shortest in late maturing girls. Earlier AAM was related to greater PHV. IGF-1 concentrations tracked significantly during puberty; higher IGF-1 was related to earlier age of PHV, earlier AAM, greater PHV, and taller adult height. Greater E:A ratio was associated with earlier AAM. CONCLUSIONS: Factors driving the association of earlier menarche and pubertal growth with breast cancer risk may be explained through a unifying concept relating higher IGF-1 concentrations, greater lifelong estrogen exposure, and longer pubertal growth period, with an expanded pubertal window of susceptibility.

Onset of Puberty: Mother Knows Best.

STUDY OBJECTIVE: Several strategies have been proposed to determine onset of puberty without examination by a trained professional. This study sought to evaluate a novel approach to determine onset of puberty in girls. DESIGN, SETTING, AND PARTICIPANTS: This study used the Cincinnati cohort of the Breast Cancer and the Environment Research Program. Girls were recruited at 6-7 years of age and followed every 6 months in the initial 6 years, and annually thereafter. Breast maturation and foot length were performed at each visit by health professionals certified in those methods. Mothers were asked to provide the age at which they believed that their daughter's shoe size had increased more rapidly. RESULTS: These analyses include 252 participants. Age at increase in shoe size was correlated to age at onset of puberty (r = 0.21) and increase in foot length (r = 0.24). The difference of reported age of increased shoe size was 0.46 years before breast development. CONCLUSION: Reported increase in shoe size occurred somewhat earlier and was significantly correlated to age of breast development. These preliminary results suggest that mother's report of increase in shoe size appear to be as accurate as reports of other indirect methods of determining onset of puberty, such as self- or maternal estimates of breast development.

Pubertal Development: What's Normal/What's Not.

Onset of puberty, as defined by breast stage 2, appears to be starting at younger ages since the 1940s. There is an ongoing controversy regarding what is normative, as well as what is normal, and the evaluation that is deemed necessary for girls maturing before 8 years of age. There are potential implications of earlier pubertal timing, including psychosocial consequences during adolescence, as well as longer term risks, such as breast cancer and cardiometabolic risks. There are additional consequences derived from slower pubertal tempo, for age of menarche has not decreased as much as age of breast development; these include longer interval between sexual initiation and intentional childbearing, as well as a broadened window of susceptibility to endocrine-related cancers.

Sex Hormone Phenotypes in Young Girls and the Age at Pubertal Milestones.

CONTEXT: The age of pubertal onset is influenced by many variables in young girls. Previous studies have not examined sex hormones longitudinally around the time of breast development and their relationship to pubertal onset. OBJECTIVE: We sought to use an unbiased statistical approach to identify phenotypes of sex hormones in young girls and examine their relationship with pubertal milestones. DESIGN AND SETTING: Longitudinal observational study. PARTICIPANTS AND MAIN OUTCOME MEASURES: In 269 girls, serum concentrations of steroid sex hormones [estradiol (E2), estrone, testosterone, and dehydroepiandrosterone sulfate] were measured by HPLC-mass spectrometry at time points before, at, and after thelarche. Girls were classified into four hormone phenotypes using objective principal components and cluster analyses of longitudinal hormone data. The association between the identified phenotypes and age of pubertal milestones was estimated using Cox proportional hazards modeling. RESULTS: Mean ages at thelarche, pubarche, and menarche were 9.02, 9.85, and 12.30 years, respectively. Girls with low levels of all four hormones, phenotype 3b, were youngest at thelarche (8.67 years); those in phenotype 2, with the highest E2 levels and E2 surge 6 months after thelarche, were youngest at menarche (11.87 years) with shortest pubertal tempo. When controlling for race, maternal age of menarche, caregiver education, and body mass, different phenotypes were associated with the age of pubertal events. CONCLUSIONS: Hormone phenotypic clustering can identify clinically relevant subgroups with differing ages of thelarche, pubarche, and menarche. These findings may enhance the understanding of timing of pubertal milestones and risk of adult disease.

Longitudinal study of age of menarche in association with childhood concentrations of persistent organic pollutants.

BACKGROUND: Age at female puberty is associated with adult morbidities, including breast cancer and diabetes. Hormonally active chemicals are suspected of altering pubertal timing. We examined whether persistent organic pollutants (POPs) are associated with age at menarche in a longitudinal study. METHODS: We analyzed data for females enrolled at age 6-8 years in the Breast Cancer and Environment Research Program from California and Ohio. Participants were followed annually 2004-2013 and provided serum (mean age 7.8 years) for measurement of polychlorinated biphenyl (PCB), organochlorine pesticide (OCP), and polybrominated diphenyl ether (PBDE) concentrations. Age of menarche was assigned based on parental and participant reported dates and ages of menarche. Adjusted hazard ratios (aHRs) for menarchal onset were calculated with Cox proportional regression. Body mass index (BMI), potentially on the causal pathway, was added to parallel analyses. RESULTS: Age of menarche was later with higher summed PCB levels (median 11.9 years in quartile 1 [Q1] versus 12.7 in quartile 4 [Q4]) and OCP levels (12.1 years versus 12.4, respectively). When adjusting for all covariates except BMI, higher POP concentrations were associated with later age at menarche (Q4 versus Q1 aHRs: PBDEs 0.75 [95% CI 0.58, 0.97], PCBs 0.67 [95% CI 0.5, 0.89], and OCPs 0.66 [95% CI 0.50, 0.89]). Additional adjustment for BMI attenuated aHRs; PCB aHR approached the null. CONCLUSION: Findings revealed later onset of menarche with higher concentrations of certain POPs, possibly through an association with BMI. Altered pubertal timing may have long lasting effects on reproductive health and disease risk, so continued attention is important for understanding the biological processes affected by hormonally active chemicals.

Impact of Pubertal Maturation and Chronologic Age on Sex Steroids in Peripubertal Girls.

CONTEXT: There is a 4- to 5-year variation in age of breast maturation in girls. OBJECTIVE: To examine longitudinal changes in sex hormone values relative to chronologic age and time relative to breast maturation. SETTING AND DESIGN: Longitudinal observational study into which girls were recruited at 6 to 7 years of age and followed up every 6 months. MAIN OUTCOME MEASURES: Maturation status, chronologic age, race, and fasting blood specimen data were obtained. Hormones were analyzed at 6-month intervals between 2 years before and 1 year after breast maturation, using HPLC tandem mass spectroscopy. RESULTS: Estradiol and estrone levels correlated with chronologic age (R = 0.350 and 0.444, respectively); time was correlated relative to breast maturation (R = 0.222 and 0.323, respectively; all correlations, P < 0.0001). In generalized estimating equation (GEE) models, chronologic age and time relative to pubertal onset were significantly associated with serum estradiol, with similar results for estrone. Local estimated scatterplot smoothing for estradiol and estrone, by chronologic age, demonstrated differences between black and white girls, especially between 8.5 and 11 years of age, but not by race in time relative to breast maturation. Testosterone level was correlated to chronologic age (R = 0.362) and time relative to breast maturation (R = 0.259); in the GEE model, only chronologic age was significant. CONCLUSION: Chronologic age as well as time relative to onset of puberty provided unique information regarding estradiol and estrone concentrations in peripubertal girls. Serum estrogen concentrations should be evaluated with reference to chronologic age and race.

Age of Menarche in a Longitudinal US Cohort.

STUDY OBJECTIVE: Menarche is a critical milestone in a woman's life, and historically has been determined using several approaches. The goals of this study were to: (1) determine age at menarche from multiple reports of parents and adolescent participants in a prospective study; (2) examine factors affecting age at menarche; and (3) determine correlates of menarche and pubertal tempo. DESIGN: Longitudinal observational study. SETTING: Three sites of the Breast Cancer and the Environment Research Program. PARTICIPANTS: Girls enrolled at 6-8 years of age. INTERVENTIONS AND MAIN OUTCOME MEASURES: Parental and participant reported age of menarche, and tempo of puberty. RESULTS: There were 946 girls who were assigned an age of menarche. The correlation between parent and participant reports was high (Spearman R = 0.799, P < .001), and the difference was insignificant. Median age at menarche overall was 12.25 years. Compared with black participants, Hispanic girls were more likely to have menarche earlier, whereas white and Asian girls were more likely to have menarche later. Age of menarche was highly correlated with age of breast development (Spearman R = 0.547; P < .001), and inversely with body mass index (Spearman R = -0.403; P < .001). Tempo (interval of age of breast development to menarche) was slower in those with earlier breast development. CONCLUSION: Parental and adolescent reports of menarche are highly correlated. Earlier breast maturation was associated with slower tempo through puberty. Body mass index had a greater effect on age at menarche than did race and ethnicity.

Childhood Socioeconomic Position and Pubertal Onset in a Cohort of Multiethnic Girls: Implications for Breast Cancer.

Background: Higher socioeconomic position (SEP) has been associated with increased risk of breast cancer. Its relationship with earlier age of pubertal onset, a risk factor for breast cancer, is less clear.Methods: We studied the relationship of SEP to pubertal onset in a multiethnic cohort of 1,237 girls ages 6 to 8 years at baseline. Girls in three U.S. cities were followed for 5 to 8 years with annual clinical examinations from 2004 to 2012. SEP measures were examined for associations with pubertal onset, assessed by breast budding (thelarche) and pubic hair development (adrenarche). Analyses were conducted with accelerated failure time models using a Weibull distribution, with left, right, and interval censoring.Results: Higher body mass index percentage at entry to the study and black or Hispanic race/ethnicity were the strongest predictors of age at pubertal onset. An SEP index comprising household family income, mother's education, and home ownership was an independent predictor of thelarche in adjusted models for all girls together and for white and Latina, separately, but not black girls, and the relationship varied by study site. The SEP index was not related to adrenarche in adjusted models. Overall, girls from the lowest quintile of SEP entered puberty on average 6% earlier than girls from the highest quintile (time ratio = 0.94; 95% confidence interval 0.91-0.97) in adjusted models.Conclusions: Our results suggest that early-life SEP may influence the timing of pubertal development.Impact: Factors related to lower SEP in childhood can adversely affect early development in ways that may increase the risk of breast cancer. Cancer Epidemiol Biomarkers Prev; 26(12); 1714-21. ©2017 AACR.

Phenol Concentrations During Childhood and Subsequent Measures of Adiposity Among Young Girls.

Phenolic compounds represent a class of environmental chemicals with potentially endocrine-disrupting capabilities. We investigated longitudinal associations between childhood exposure to phenols, from both manmade and natural sources, and subsequent measures of adiposity among girls enrolled in the Breast Cancer and the Environment Research Program between 2004 and 2007. Baseline (ages 6-8 years) urinary concentrations were obtained for creatinine and phenol metabolites: enterolactone, genistein, daidzein, benzophenone-3, bisphenol A, the sum of parabens (methyl, ethyl, and propyl parabens), 2,5-dichlorophenol, and triclosan. Body mass index (weight (kg)/height (m)2), waist circumference, and percent body fat were measured at annual or semiannual examinations through 2015 (n = 1,017). Linear mixed-effects regression was used to estimate how baseline concentrations of phenols (tertile groups) were related to changes in girls' adiposity measurements from ages 7 through 15 years. Enterolactone was inversely associated with body mass index, waist circumference, and percent body fat, while 2,5-dichlorophenol was positively associated with these measurements. A nonmonotonic association was observed for triclosan and girls' adiposity; however, it was due to effect modification by baseline overweight status. Triclosan was positively associated with adiposity only among overweight girls. These results suggest that exposure to specific phenols during childhood may influence adiposity through adolescence.

Amphiregulin as a Novel Serum Marker of Puberty in Girls.

STUDY OBJECTIVE: Amphiregulin is a member of the epidermal growth factor family. In breast tissue, amphiregulin is a mediator of estrogen and progesterone signaling. The objectives were to examine the relationship of amphiregulin levels during peripuberty with estrogen levels. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: The participants in this analysis were a subset from a longitudinal study of pubertal maturation, the Breast Cancer and the Environment Research Program. They were recruited between ages 3 and 7 years. Blood specimens were selected for hormone analysis between 24 months before and 6 months after breast development. Serum amphiregulin levels were analyzed using enzyme-linked immunosorbent assay. RESULTS: Amphiregulin levels were measured in 188 girls; 8.5% had a maternal history of breast cancer, and 30.9% of samples were below the limit of detection. Amphiregulin levels were greatest at 18 months before the onset of breast development (P < .006), and the rise in estrone levels between -24 and -18 months was correlated with the increase in amphiregulin levels in the same time period (P = .0002). After adjustment for time relative to breast development, amphiregulin levels were associated with maternal breast cancer (P = .024). Tracking of amphiregulin levels was highly significant (P < .0001) within a given individual. CONCLUSION: Amphiregulin levels peaked at 18 months before the onset of breast development, were temporally related to the rise in serum estrone, and were significantly associated with maternal history of breast cancer. Elevated amphiregulin levels at puberty might be a predictor of increased breast cancer risk.

Peripubertal dietary flavonol and lignan intake and age at menarche in a longitudinal cohort of girls.

BackgroundDietary phytoestrogens may alter hormonal activity in childhood. Flavonols and lignans are the most prevalent phytoestrogens in the Western diet. We examined whether higher intake of flavonols and lignans was associated with later age at menarche in a prospective study of young girls.MethodsIn all, 1,044 girls aged 6-8 years (mean 7.3 years) with two to four 24-h dietary recalls during their baseline year were followed up for 11 years until the attainment of menarche in the Breast Cancer and Environment Research Project (BCERP). Associations of age at menarche with quintiles of phytoestrogens were assessed using hazard ratios (HR) and 95% confidence intervals (CIs) from Cox proportional hazards models, controlling for body mass index and other covariates.ResultsThe highest quintile of flavonol intake was associated with a later age at menarche, compared with the lowest quintile (adjusted HR: 0.80, 95% CI: (0.66-1.00). For lignans, there was a later age in overweight girls (HR: 0.56, 95% CI=0.40-0.80).ConclusionThese dietary bioactives may reflect a healthy diet, and foods high in phytoestrogens may influence the timing of menarche.

Longitudinal Associations of Phthalate Exposures During Childhood and Body Size Measurements in Young Girls.

BACKGROUND: Phthalates are environmental chemicals that may play a role in the development of obesity. Few studies have investigated longitudinal associations between postnatal phthalate exposures and subsequent anthropometric measurements in children. METHODS: We collected data as part of The Breast Cancer and Environment Research Program at three US sites. A total of 1,239 girls, aged 6-8 years, were enrolled in 2004-2007. We categorized baseline phthalate exposures, assessed from creatinine-corrected urinary concentrations of low-molecular weight phthalate metabolites, as low, <78; medium, 78 to <194; and high, ≥194 µg/g creatinine and of high-molecular weight phthalates as low, <111; medium, 111-278; and high, ≥278 µg/g creatinine. Anthropometric measurements were collected through 2012 (n = 1,017). Linear mixed effects regression estimated how baseline low and high-molecular weight phthalate concentrations related to changes in girls' body mass index (BMI), height, and waist circumference at ages 7-13 years. RESULTS: Low-molecular weight phthalates were positively associated with gains in BMI and waist circumference. Predicted differences in BMI and waist circumference between girls with high versus low concentrations of low-molecular weight phthalates increased from 0.56 (95% confidence interval [CI]: -0.02, 1.1) to 1.2 kg/m (95% CI: 0.28, 2.1) and from 1.5 (95% CI: -0.38, 3.3) to 3.9 cm (95% CI: 1.3, 6.5), respectively. High-molecular weight phthalates were negatively associated with height but only among girls who were normal weight at baseline (BMI ≤ 85th percentile). CONCLUSION: Phthalates, specifically low-molecular weight phthalates, have small but detectable associations with girls' anthropometric outcomes. Low-molecular weight phthalates showed stronger associations than other types of phthalates.

Thyroid Antagonists (Perchlorate, Thiocyanate, and Nitrate) and Childhood Growth in a Longitudinal Study of U.S. Girls.

BACKGROUND: Perchlorate, thiocyanate, and nitrate are sodium/iodide symporter (NIS) inhibitors that block iodide uptake into the thyroid, thus affecting thyroid function. Thyroid dysfunction can adversely affect somatic growth and development in children. To our knowledge, no studies have examined effects of NIS inhibitors on body size measures. OBJECTIVE: We investigated associations between NIS inhibitors and childhood growth in 940 girls from the Puberty Study of the Breast Cancer and Environment Research Program. METHODS: Urine samples collected from girls 6-8 years of age at enrollment (2004-2007) from New York City, greater Cincinnati, Ohio, and the Bay Area in California were analyzed for NIS inhibitors and creatinine (C). The longitudinal association between NIS inhibitors and anthropometric measures [height, waist circumference, and body mass index (BMI)] during at least three visits was examined using mixed effects linear models, adjusted for race and site. RESULTS: Compared with girls in the low-exposure group (3.6, 626, and 500 mg/gC, median perchlorate, thiocyanate, and nitrate, respectively) girls with the highest NIS inhibitor exposure (9.6, 2,343, and 955 mg/gC, median perchlorate, thiocyanate, and nitrate, respectively) had slower growth in waist circumference and BMI but not height. Significant differences in the predicted mean waist circumference and BMI between the low- and high-exposure groups were observed beginning at 11 years of age. CONCLUSIONS: Higher NIS inhibitor exposure biomarkers were associated with reductions in waist circumference and BMI. These findings underscore the need to assess exposure to NIS inhibitors with respect to their influence on childhood growth. CITATION: Mervish NA, Pajak A, Teitelbaum SL, Pinney SM, Windham GC, Kushi LH, Biro FM, Valentin-Blasini L, Blount BC, Wolff MS, for the Breast Cancer and Environment Research Project (BCERP). 2016. Thyroid antagonists (perchlorate, thiocyanate, and nitrate) and childhood growth in a longitudinal study of U.S. girls. Environ Health Perspect 124:542-549; http://dx.doi.org/10.1289/ehp.1409309.

Bone Density and Timing of Puberty in a Longitudinal Study of Girls.

STUDY OBJECTIVE: Primary: To examine the relationship between relative timing of puberty with bone mineral density (BMD) in a group of adolescent girls; Secondary: To determine if family history of breast cancer was associated with bone mineral density. DESIGN/SETTING/PARTICIPANTS: Longitudinal study of girls recruited between 6 and 7 years of age seen every 6 months for 5 years, and subsequently seen annually. BMD of the lumbar spine was measured by dual-energy X-ray absorptiometry (DXA) at mean age of 12.5 years; age- and race-specific Z-scores (BMDz) were calculated. Age of pubertal onset was determined by the first occurrence of breast stage 2, and participants were categorized into race-specific early, on-time and late puberty onset groups. MAIN OUTCOME MEASURES: BMDz by timing of pubertal onset, and by family history of breast cancer. RESULTS: DXA scans were performed on 227 study participants, and a second scan was performed on 114 participants 2 years later. Age of onset of puberty was inversely correlated with BMDz, r = -0.31 (P < .0001). There was no association between BMDz and family history of breast cancer. CONCLUSIONS: Earlier timing of puberty was associated with higher BMD. The high shared variance of BMD and timing of pubertal onset implies an underlying biologic basis.

Brominated Flame Retardants and Other Persistent Organohalogenated Compounds in Relation to Timing of Puberty in a Longitudinal Study of Girls.

BACKGROUND: Exposure to hormonally active chemicals could plausibly affect pubertal timing, so we are investigating this in the Breast Cancer and the Environment Research Program. OBJECTIVES: Our goal was to examine persistent organic pollutants (POPs) in relation to pubertal onset. METHODS: Ethnically diverse cohorts of 6- to 8-year-old girls (n = 645) provided serum for measure of polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), and lipids. Tanner stages [breast (B) and pubic hair (PH)], and body mass index (BMI) were measured at up to seven annual clinic visits. Using accelerated failure time models, we calculated time ratios (TRs) for age at Tanner stages 2 or higher (2+) and POPs quartiles (Q1-4), adjusting for confounders (race/ethnicity, site, caregiver education, and income). We also calculated prevalence ratios (PRs) of Tanner stages 2+ at time of blood sampling. RESULTS: Cross-sectionally, the prevalence of B2+ and PH2+ was inversely related to chemical serum concentrations; but after adjustment for confounders, only the associations with B2+, not PH2+, were statistically significant. Longitudinally, the age at pubertal transition was consistently older with greater chemical concentrations; for example: adjusted TR for B2+ and Q4 for ΣPBDE = 1.05; 95% CI: 1.02, 1.08, for ΣPCB = 1.05; 95% CI: 1.01, 1.08, and for ΣOCP = 1.10; 95% CI: 1.06, 1.14, indicating median ages of about 6 and 11 months older than least exposed, and with similar effect estimates for PH2+. Adjusting for BMI attenuated associations for PCBs and OCPs but not for PBDEs. CONCLUSIONS: This first longitudinal study of puberty in girls with serum POPs measurements (to our knowledge) reveals a delay in onset with higher concentrations.