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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.

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.

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.

This is the first of two installments examining early puberty in girls. The first paper will discuss secular trends in onset of puberty and the possible mechanisms to explain these developments. The potential etiologies examined will include the role of endocrine-disrupting chemicals and obesogens, the impact of body mass index and obesity, genetic and biologic pathways, and the influence of lifestyle behaviors. The second paper of the two-part series will examine the potential health impacts of early puberty on young and adult women and offer suggestions for clinical management and public health prevention.

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 β = −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.

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.

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.

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.

Background: Polybrominated diphenyl ethers (PBDEs) are flame retardants, exposing humans primarily though diet, dust and inhalation. Higher levels of PBDEs have been associated with adverse health ...

PurposeEarlier timing and faster tempo of puberty have been linked to adolescents' poor mental health. Previous research rarely adjusted for childhood mental health, did not use physical examination to assess puberty, and excluded Latinas and Asian Americans. This study addressed these limitations.MethodsWe followed 822 girls, recruited at ages 6-8, for 8years. Breast and pubic hair development and anxiety and depressive symptoms were assessed prospectively and repeatedly. Structural equation models tested whether pubertal timing and tempo were associated with adolescent mental health symptoms and whether associations varied by ethnicity. Models were adjusted for childhood mental health symptoms, body mass index, and family income.ResultsEarlier breast development was associated with higher depressive symptoms among whites (β=-.19; p < .01) and higher anxiety symptoms among Latinas (β=-.26; p < .05), but lower depressive symptoms among Asians (β= .24, p < .05). Later pubic hair development (b= .24; p < .05) and faster pubic hair tempo (β= .26; p < .01) were associated with higher anxiety symptoms among Latinas. Faster pubic hair tempo was associated with lower depressive symptoms among Asians (β=-.34; p < .05). Tempo of breast development showed no associations.ConclusionsFindings confirmed that earlier breast development was associated with higher mental health symptoms for Latina and white girls but was protective among Asians. Results for pubic hair and pubertal tempo were inconsistent, requiring future examination. While targeted interventions to prevent mental health problems among early-maturing girls are critical, there is variability among who might benefit most.

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.

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.

Importance The initial clinical sign of pubertal onset in girls is breast gland development (thelarche). Although numerous studies have used recalled age at menarche (first menstruation) to assess secular trends of pubertal timing, no systematic review has been conducted of secular trends of thelarche. Objectives To systematically evaluate published data on pubertal timing based on age at thelarche and evaluate the change in pubertal onset in healthy girls around the world. Data Sources A systematic literature search was performed in PubMed and Embase of all original peer-reviewed articles published in English before June 20, 2019. Study Selection Included studies used clinical assessment of breast development in healthy girls and used adequate statistical methods, including the reporting of SEs or CIs. The quality of the articles was evaluated by assessing study design, potential sources of bias, main characteristics of the study population, and methods of statistical analysis. Data Extraction and Synthesis In accordance with PRISMA guidelines, all articles were assessed for eligibility independently by 2 authors. Weighted regression analysis was performed using a random-effects model. Main Outcomes and Measures Studies examining age at thelarche (development of Tanner breast stage 2) in healthy girls. Results The literature search resulted in a total of 3602 studies, of which 30 studies fulfilled the eligibility criteria. There was a secular trend in ages at thelarche according to race/ethnicity and geography. Overall, the age at thelarche decreased 0.24 years (95% CI, −0.44 to −0.04) (almost 3 months) per decade from 1977 to 2013 (P = .02). Conclusions and Relevance The age at thelarche has decreased a mean of almost 3 months per decade from 1977 to 2013. A younger age at pubertal onset may change current diagnostic decision-making. The medical community needs current and relevant data to redefine “precocious puberty,” because the traditional definition may be outdated, at least in some regions of the world.

Screening for sexually transmitted infections (STIs) outside of traditional health-care facilities is limited by the privacy needed for sample collection. We explored the acceptability of privacy shelters for the self-collection of genital swabs and tested the use of privacy shelters during mobile STI screening. Attendees ≥14 years old at two outdoor community events completed a questionnaire that assessed participant characteristics, health-care access, and rating of acceptability of self-collecting penile or vaginal swabs in a privacy shelter and four other private spaces: portable restroom, health van, home, and doctor’s office. A privacy shelter was used during mobile STI screening. The majority (65%) of the 95 participants reported that using a privacy shelter was somewhat or very acceptable. No participant characteristics or health-care access factors were associated with the acceptability of privacy shelters. Women rated a privacy shelter more acceptable than a portable restroom or health van. Men rated a privacy shelter more acceptable than a portable restroom. During mobile STI screening, all 13 men and women who requested STI testing used the privacy shelter for self-sampling. Rating of acceptability before and after privacy shelter use was the same. Privacy shelters may enable STI screening without using a building or vehicle for sample collection.

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.

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.

To study potential environmental influences on puberty in girls, we investigated urinary biomarkers in relation to age at menarche. Phenols and phthalates were measured at baseline (6–8 years of age). Menarche was ascertained over 11 years for 1051 girls with menarche and biomarkers. Hazards ratios were estimated from Cox models adjusted for race/ethnicity and caregiver education (aHR, 95% confidence intervals [CI] for 5th vs 1st quintile urinary biomarker concentrations). 2,5-Dichlorophenol was associated with earlier menarche (aHR 1.34 [1.06–1.71]); enterolactone was associated with later menarche (aHR 0.82 [0.66–1.03]), as was mono-3-carboxypropyl phthalate (MCPP) (aHR 0.73 [0.59–0.91]); the three p-trends were

Methods We conducted a study of per- and polyfluoroalkyl substance biomarkers, including PFOA, in girls from Greater Cincinnati (CIN, N = 353) and the San Francisco Bay Area (SFBA, N = 351). PFOA was measured in the baseline serum sample collected in 2004–2007 of 704 girls at age 6–8 years. Mixed effects models were used to derive the effect of PFOA on BMI, waist-to-height and waist-to-hip ratios over increasing age in this longitudinal cohort. Results Median PFOA serum concentrations were 7.3 (CIN) and 5.8 (SFBA) ng/mL, above the U.S. population median for children 12–19 years in 2005–2006 (3.8 ng/mL). Log-transformed serum PFOA had a strong inverse association with BMIz in the CIN girls (p = 0.0002) and the combined two-site data (p = 0.0008); the joint inverse effect of PFOA and Age*PFOA weakened at age at 10–11 years. However, in the SFBA group alone, the relationship was not significant (p = 0.1641) with no evidence of changing effect with age. The effect of PFOA on waist:height ratio was similar to BMIz at both sites, but we did not find a significant effect of PFOA on waist:hip ratio in either the CIN or SFBA girls. Conclusions PFOA is associated with decreased BMI and waist:height ratio in young girls, but the strength of the relationship decreases with age. Site heterogeneity may be due to greater early life exposure in Cincinnati. Disclaimer The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Use of trade names is for identification only and does not imply endorsement by the CDC, the Public Health Service, or the US Department of Health and Human Services.

BACKGROUND: Perfluorooctanoate (PFOA) has been used extensively in the manufacture of both commercial and household products. PFOA serum concentrations have been associated with adverse health effects, including lower body mass in children and infants. OBJECTIVE: To determine if there is an association between PFOA and body mass, insulin and lipid profile in exposed young girls. METHODS: We conducted a cross-sectional study of PFAS environmental biomarkers and insulin resistance in 6 to 8 year-old girls from Greater Cincinnati (n=353). In 2004–2006, blood samples were obtained to measure polyfluoroalkyl substances (PFAS), fasting insulin, glucose and lipids. Clinical exams included anthropometric measurements and pubertal maturation staging. Linear regression and mediation analyses, specifically structural equation modeling (SEM), were used to determine the strength and direction of the relationships between PFAS, pubertal maturation status, body mass index (BMI), cholesterol and insulin resistance. RESULTS: The median PFOA (7.7ng/ml) was twice the National Health and Nutrition Examination Survey (2005–2006). Only PFOA, a PFAS sub-species, showed statistically significant relationships with the outcomes. In regression models, PFOA was associated with decreased BMI and waist-to-height ratio (p=0.0008; p=0.0343), HDL-cholesterol (p=0.0046) and had a borderline inverse association with the HOMA Index of insulin resistance (p=0.0864). In SEM, PFOA retained an inverse relationship with BMI (p

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

Lead may alter growth and development, but prospective studies on menarche are lacking. Among girls enrolled at 6-8 years of age in the Breast Cancer and Environment Research Program cohort during ...

Introduction: Cross-sectional studies suggest that postnatal blood lead (PbB) concentrations are negatively associated with child growth. Few studies prospectively examined this association in populations with lower PbB concentrations. We investigated longitudinal associations of childhood PbB concentrations and subsequent anthropometric measurements in a multi-ethnic cohort of girls. Methods: Data were from The Breast Cancer and the Environment Research Program at three sites in the United States (U.S.): New York City, Cincinnati, and San Francisco Bay Area. Girls were enrolled at ages 6–8 years in 2004–2007. Girls with PbB concentrations collected at ≤10 years old (mean 7.8 years, standard deviation (SD) 0.82) and anthropometry collected at ≥3 follow-up visits were included (n = 683). The median PbB concentration was 0.99 μg/d (10th percentile = 0.59 μg/dL and 90th percentile = 2.00 μg/dL) and the geometric mean was 1.03 μg/dL (95% Confidence Interval (CI): 0.99, 1.06). For analyses, PbB concentrations were dichotomized as

Complementary and alternative health care approaches are prevalent in the patients and families served by practitioners in pediatric and adolescent gynecology. This article addresses gaps in knowledge, including new terminology, prevalence of use, rates of and reasons behind nondisclosure, and potential interactions of herbal products with prescribed medication. It closes with practical complementary health approaches to the adolescent with dysmenorrhea.

STUDY OBJECTIVES: Menarche is a critical milestone in a woman’s life, and historically has been determined through 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 impacting 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. MAIN OUTCOME MEASURES: Parental and participant reported age of menarche, 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< 0.001), and the difference was insignificant. Median age at menarche overall was 12.25 years. Compared to Black participants, Hispanic girls were more likely to have menarche earlier, while 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 BMI (Spearman R= −0.403, p< .001). Tempo (interval of age of breast development to menarche) was slower in those with earlier breast development. CONCLUSIONS: Parental and adolescent reports of menarche are highly correlated. Earlier breast maturation was associated with slower tempo through puberty. BMI had a greater impact on age at menarche than did race and ethnicity.

Early menarche is linked to higher incidence of adult asthma, suggesting that earlier puberty may influence type 2 immune response characteristics of allergic diseases. We examined the hypothesis that timing of breast and pubic hair development, which precede menarche, is associated with increased childhood atopic conditions.Girls were enrolled at 6-8 yr of age (2004-2007) in the Breast Cancer and the Environment Research Program Puberty Study and were followed through 2011. Pubertal stages were assessed and atopic conditions were queried annually. Associations of age at pubertal stage 2 for breast or pubic hair development with atopic conditions were assessed using prevalence ratios (PR) or odds ratios (OR) and 95% confidence intervals (CI) from log-binomial regression and generalized estimating equation models, controlling for body mass index and other covariates. A total of 1055 girls with medical and pubertal stage data were included.Asthma (ever vs. never) was associated with younger pubarche (≤10 vs.10 yr, PR = 1.15, CI: 1.04-1.28 adjusted for race/ethnicity and site; PR = 1.13, CI: 1.01-1.25 further adjusted for BMI), but not thelarche. In longitudinal models, risk of developing allergies increased with younger age at pubarche (adjusted OR = 1.60, CI: 1.10-2.34; ≤10 vs.10 yr). Risks were highest among black girls with earlier pubarche (n = 248/326); for allergies, their fully adjusted OR was 2.35, CI: 1.06-5.19 for pubarche ≤10 vs.10 yr.Atopic conditions during childhood are associated with younger age at pubarche, independent of obesity, and these relationships may vary by racial/ethnic groups.

Background Understanding readiness to transfer from pediatric to adult healthcare is important for all youth; however, research and implementation guidelines in this area have emphasized youth seen in pediatric subspecialty settings. The purpose of this study was to develop an approach for evaluating transition readiness in a primary care setting, collect pilot data that examined the transition readiness of teens in that program, and implement assessments as part of clinical care. Method Forty boys and girls aged 12–22 were recruited from an adolescent medicine outpatient program in a large children’s hospital. The first 10 adolescents provided responses to questions and participated in cognitive interviewing. Questions changed minimally and responses from all 40 participants were combined. After the study visit, a researcher compared participant responses to electronic medical records and coded responses for accuracy. The survey consisted of 41 transition readiness items from previously published measures. Results The research team was able to develop a tool to assess transition readiness within a clinical setting. When administered to participants from that program, participants demonstrated poor transition readiness. Modifications were made based on participant feedback and implementation in the clinical setting. Clinicians were successful with administering transition readiness assessments. Conclusions It appears that even in youth who are generally well, transition readiness is low. Transition readiness assessments can be implemented in the primary care setting, and have been useful for guiding clinical care. Additional barriers and next steps will be discussed.

Studies of hormone changes in the peripubertal period note increases in adrenal hormones prior to increases in sex steroids. It is unclear how these processes are related to each other, except through this temporal relationship.Examine relationships in adrenal and sex hormones in 252 peripubertal girls.Longitudinal observation study. School districts, at the Cincinnati site of the Breast Cancer and the Environment Research Centers, between 2004-2010. Participants were recruited between ages 6 and 7 years of age and were seen every 6 months. Main outcome measures included height, weight, maturation status, and fasting blood specimen. Serum was analyzed for selected hormones every six months, beginning 30 months prior to, and extending to 6 months after, breast development. Androstenedione, estradiol, estrone, and T were measured by high-performance liquid chromatography (HPLC) with tandem mass spectrometry. Dehydroepiandrosterone-sulfate (DHEA-S) and SHBG also were measured.DHEA-S concentrations increased 24 months before breast development; androstenedione and estrone between 12 to 18 months before breast development; whereas estradiol and T increased, and SHBG fell between 6 and 12 months before breast development. Girls with greater body mass index had lower estradiol concentrations at onset of breast development as well as 6 months after pubertal onset.Serum estrone and DHEA-S increased prior to estradiol concentrations, and the increase in estradiol occurred prior to breast development. Heavier peripubertal girls have lower estradiol levels at puberty, suggesting peripheral conversion of adrenal androgens to estrone.

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.

Background Tobacco smoke contains known hormonally active chemicals and reproductive toxicants. Several studies have examined prenatal maternal smoking and offspring age at menarche, but few examined earlier pubertal markers, nor accounted for exposure during childhood. Our objective was to examine pre- and postnatal smoke exposure in relation to timing of early pubertal events. Methods An ethnically diverse cohort of 1239 girls was enrolled at age 6-8 years old for a longitudinal study of puberty at three US sites. Girls participated in annual or semi-annual exams to measure anthropometry and Tanner breast and pubic hair stages. Prenatal and current tobacco smoke exposures, as well as covariates, were obtained from parent questionnaire. Cotinine was measured in urine collected at enrollment. Using accelerated failure time models, we calculated adjusted time ratios for age at pubertal onset (maturation stages 2 or higher) and smoke exposure. Results Girls with higher prenatal (≥5 cigarettes per day) or secondhand smoke exposure had earlier pubic hair development than unexposed (adjusted time ratio: 0.92 [95% CI = 0.87, 0.97] and 0.94 [95% CI = 0.90, 0.97], respectively). Including both exposures in the same model yielded similar associations. Higher urinary cotinine quartiles were associated with younger age at breast and pubic hair onset in unadjusted models, but not after adjustment. Conclusions Greater prenatal and childhood secondhand smoke exposure were associated with earlier onset of pubic hair, but not breast, development. These exposures represent modifiable risk factors for early pubertal development that should be considered for addition to the extensive list of adverse effects from tobacco smoke.

PurposeThis study aims to examine the longitudinal association between puberty and sleep in a diverse sample of girls and explore racial/ethnic differences in this association.MethodsUsing latent growth curve modeling, the present study measured pubertal development (timing and rate) and sleep (wake time and bedtime) in 1,239 socioeconomically and ethnically diverse girls starting when they were 6-8 years old and followed longitudinally for up to 8 years. Pubertal assessment was conducted annually in clinic by physical examination, classified by sexual maturation stage for breast and pubic hair development by trained raters.ResultsIn line with previous research, black girls had the earliest pubertal development, followed by Hispanic, white, and Asian girls. Black girls, on average, reported significantly shorter sleep duration than Hispanic (β = -.20, p

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

Background Industrial discharges of perfluorooctanoic acid (PFOA) to the Ohio River, contaminating water systems near Parkersburg, WV, were previously associated with nearby residents' serum PFOA concentrations above US general population medians. Ohio River PFOA concentrations downstream are elevated, suggesting Mid-Ohio River Valley residents are exposed through drinking water. Objectives Quantify PFOA and 10 other per- and polyfluoroalkyl substances (PFAS) in Mid-Ohio River Valley resident sera collected between 1991 and 2013 and determine whether the Ohio River and Ohio River Aquifer are exposure sources. Methods We measured eleven PFAS in 1608 sera from 931 participants. Serum PFOA concentration and water source associations were assessed using linear mixed-effects models. We estimated between-sample serum PFOA using one-compartment pharmacokinetics for participants with multiple samples. Results In serum samples collected as early as 1991, PFOA (median = 7.6 ng/mL) was detected in 99.9% of sera; 47% had concentrations greater than US population 95th percentiles. Five other PFAS were detected in greater than 82% of samples; median other PFAS concentrations were similar to the US general population. Serum PFOA was significantly associated with water source, sampling year, age at sampling, tap water consumption, pregnancy, gravidity and breastfeeding. Serum PFOA was 40–60% lower with granular activated carbon (GAC) use. Repeated measurements and pharmacokinetics suggest serum PFOA peaked 2000–2006 for participants using water without GAC treatment; where GAC was used, serum PFOA concentrations decreased from 1991 to 2012. Conclusions Mid-Ohio River Valley residents appear to have PFOA, but not other PFAS, serum concentrations above US population levels. Drinking water from the Ohio River and Ohio River Aquifer, primarily contaminated by industrial discharges 209–666 km upstream, is likely the primary exposure source. GAC treatment of drinking water mitigates, but does not eliminate, PFOA exposure.

© 2014, Springer Science+Business Media New York. To examine the association of breastfeeding or its duration with timing of girls’ pubertal onset, and the role of BMI as a mediator in these associations. A population of 1,237 socio-economically and ethnically diverse girls, ages 6–8 years, was recruited across three geographic locations (New York City, Cincinnati, and the San Francisco Bay Area) in a prospective study of predictors of pubertal maturation. Breastfeeding practices were assessed using self-administered questionnaire/interview with the primary caregiver. Girls were seen on at least annual basis to assess breast and pubic hair development. The association of breastfeeding with pubertal timing was estimated using parametric survival analysis while adjusting for body mass index, ethnicity, birth-weight, mother’s education, mother’s menarcheal age, and family income. Compared to formula fed girls, those who were mixed-fed or predominantly breastfed showed later onset of breast development [hazard ratios 0.90 (95 % CI 0.75, 1.09) and 0.74 (95 % CI 0.59, 0.94), respectively]. Duration of breastfeeding was also directly associated with age at onset of breast development (p trend = 0.008). Associations between breastfeeding and pubic hair onset were not significant. In stratified analysis, the association of breastfeeding and later breast onset was seen in Cincinnati girls only. The association between breast feeding and pubertal onset varied by study site. More research is needed about the environments within which breastfeeding takes place in order to better understand whether infant feeding practices are a potentially modifiable risk factor that may influence age at onset of breast development and subsequent risk for disease in adulthood.

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.

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.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.BMDz by timing of pubertal onset, and by family history of breast cancer.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.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.

Purpose Early life exposures during times of rapid growth and development are recognized increasingly to impact later life. Epidemiologic studies document an association between exposures at critical windows of susceptibility with outcomes as diverse as childhood and adult obesity, timing of menarche, and risk for hypertension or breast cancer. Methods This article briefly reviews the concept of windows of susceptibility for providers who care for adolescent patients. Results The theoretical bases for windows of susceptibility is examined, evaluating the relationship between pubertal change and breast cancer as a paradigm, and reviewing the underlying mechanisms, such as epigenetic modification. Conclusions The long-term sequela of responses to early exposures may impact other adult morbidities; addressing these exposures represents an important challenge for contemporary medicine.

To examine whether the known association between early pubertal breast maturation and insulin sensitivity (SI) is mediated by adiposity.Cross-sectional analyses.Observational study examining the roles of environment, diet, and obesity on puberty.379 girls with a mean age, 7.03 years; 62% were white and 29% black.Pubertal development was assessed via physical examination and adiposity by body mass index Z score (BMI Z) and waist-to-height ratio. Fasting blood samples were obtained for insulin and glucose concentrations. SI was calculated with the quantitative insulin sensitivity check index (QUICKI). Analysis of variance and Sobel's test was used to assess mediation.Fifty-five girls were pubertal (Tanner 2 breast). Breast maturation was inversely associated with SI (P = .005) and positively associated with BMI Z (P.001) and waist-to-height ratio (P.001). The effect of breast maturation on SI was no longer significant (P = .41) after adjusting for the effect of BMI Z, which remained significant (P.001). Similar results were obtained when waist-to-height ratio replaced BMI Z in the models. Mediation analyses demonstrated that 75% of the association between breast maturation and SI is mediated by adiposity.In girls, decreased SI during early puberty is largely mediated by total and visceral adiposity.

Hormonally active environmental exposures may alter timing of puberty. We investigated urinary biomarkers of 9 phthalates and 13 phenols including 3 phytoestrogens in relation to menarche among girls enrolled at 6-8 years of age during 2004-2007 in the Breast Cancer and Environment Research Program. This multi-ethnic cohort study of 1239 girls at three US sites was followed through 2015. For urinary metabolites assayed in baseline samples, age at menarche was available on 1051 girls. Associations of biomarker quintiles with menarche were estimated from Cox proportional hazards models adjusted for race, ethnicity, and caregiver education (aHR, 95% confidence intervals [CI]). Urinary enterolactone was associated with later age at menarche (aHR 0.82 [0.66-1.03] for 5th vs 1st quintile, p-trend 0.028). Effects were stronger in girls with below-median body mass index (aHR 0.75 [0.59-0.95], 3rd vs 1st enterolactone tertile) compared to higher body mass (aHR 1.04 [0.82-1.33]). 2,5-Dichlorophenol was associated w...

Introduction: We investigated longitudinal associations between phenol exposures and subsequent adiposity measurements in a multi-ethnic cohort of girls. Methods: Data were collected as part of The...

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. 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

Primiparity has been associated with 3 to 4 mg/dL lower high-density lipoprotein cholesterol concentrations in black and white adult women that persist several years after delivery.To examine the lasting effects of adolescent pregnancy on blood lipids, an early risk factor for future cardiometabolic diseases.The National Heart Lung and Blood Institute's Growth and Health Study is a multicenter prospective cohort that measured fasting blood lipids for 1013 (513 black, 500 white) participants at baseline (1987-1988) ages 9-10, and again at follow-up (1996-1997) ages 18-19.Change in fasting plasma total cholesterol, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol, defined as the difference between baseline and follow-up measurements, was compared among 186 (145 black, 41 white) primi- or multiparas, 106 (55 black, 51 white) nulliparous, gravidas versus 721 (313 black, 408 white) nulligravidas. Fully adjusted multiple linear regression models estimated blood lipid changes among these pregnancy groups adjusted for race, age at menarche, baseline lipids, physical inactivity, body mass index, and family sociodemographics.In the 10-year study period, adolescent paras compared with nulligravidas had greater decrements in high-density lipoprotein cholesterol (mg/dL; fully adjusted mean [95% confidence interval] group differences in black -4.3 [-6.7, -2.0]; P.001 and white: -4.5 [-8.2, -0.7]; P = .016) and greater increments in fasting triglycerides (mg/dL; adjusted mean [95% confidence interval] group differences in black: 10.4 [3.9, 16.8]; P.001, and white: 11.6 [-3.6, 26.8]; P = .167).Adolescent pregnancy contributes to pro-atherogenic lipid profiles that persist after delivery. Further research is needed to assess whether adolescent pregnancy has implications for future cardiovascular disease risk in young women.

Recent studies have documented earlier pubertal maturation in both girls and boys. Several factors have been proposed to account for earlier maturation. Epidemiologic studies have indicated that genetic factors are the most important influence contributing to the variability in the onset of puberty. Studies have also noted the association of elevated BMI with earlier puberty in girls, although the relationship between BMI and onset of puberty in boys is less consistent. The relationship of BMI and onset of puberty may be mediated by several factors, including leptin and kisspeptin, changes in bioavailable sex hormones, and environmental exposures. Recently, there have been genome-wide meta-analyses examining onset of puberty and anthropometric traits that may provide insight into the relationships of BMI, height velocity, and pubertal timing. Newer fields of investigation include examination of epigenetic modification.

Recent studies have documented earlier pubertal maturation in both girls and boys. Several factors have been proposed to account for earlier maturation. Epidemiologic studies have indicated that genetic factors are the most important influence contributing to the variability in the onset of puberty. Studies have also noted the association of elevated BMI with earlier puberty in girls, although the relationship between BMI and onset of puberty in boys is less consistent. The relationship of BMI and onset of puberty may be mediated by several factors, including leptin and kisspeptin, changes in bioavailable sex hormones, and environmental exposures. Recently, there have been genome-wide meta-analyses examining onset of puberty and anthropometric traits that may provide insight into the relationships of BMI, height velocity, and pubertal timing. Newer fields of investigation include examination of epigenetic modification.

© 2015, Public Health Services, US Dept of Health and Human Services. All rights reserved. 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. Citation: Windham GC, Pinney SM, Voss RW, Sjödin A, Biro FM, Greenspan LC, Stewart S, Hiatt RA, Kushi LH. 2015. Brominated flame retardants and other persistent organohalogenated compounds in relation to timing of puberty in a longitudinal study of girls.

The proportion of child and adolescent obesity in the United States has dramatically increased over the past few decades, challenging public health strategies and medical needs of the individual. The medical consequences of obesity include metabolic syndrome, polycystic ovary syndrome, and cardiovascular disease. There is no definite diagnostic criterion of metabolic syndrome in children and adolescents; commonly noted features are central adiposity, insulin resistance, dyslipidemia, and hypertension. To prevent negative health outcomes and early recognition for those at risk for overweight and obesity, healthcare providers should screen BMI in children and adolescents at least annually, as well as provide anticipatory guidance to all families during health maintenance visit. This review will address the epidemiology and consequences of obesity in children and adults, and issues for health care providers and public health officials to consider. These issues include increasing physical activity, decreasing sedentary activities, and promoting healthy eating behaviors.