Early Breast Development Research Articles

Evaluating breast ultrasonography as a complementary diagnostic method in girls with central precocious puberty.

Assessment of breast development by physical examination can be difficult in the early stages and in overweight girls. To investigate ultrasonography (US) for evaluation of early breast development. In a prospective study, 125 girls (age 7.1 ± 1.5years) with breast development before 8years underwent US breast staging, breast volume, and elastography, in addition to clinical/hormonal evaluation for precocious puberty. Accuracy of US for determining breast development and predicting progression to central precocious puberty was investigated. Physical examination revealed glandular breast enlargement in 100 and predominantly lipomastia in 25. Breast US in the former confirmed glandular breast development in 92 (group 1, physical examination and US positive), but not in 8 (group 2, physical examination positive, US negative). Comparison of the two groups demonstrated lower Tanner and US staging, bone age/chronological age, basal luteinizing hormone (LH), breast volume, and uterine volume in group 2. In the 25 lipomastia patients, US demonstrated no breast tissue in 19 (group 3, physical examination and US negative), but US stage ≥ II in 6 (group 4, physical examination negative, US positive) without differences in clinical parameters. After follow-up of 19.8 ± 4.2months, 46/125 subjects were diagnosed with precocious puberty. US stage, total breast volume, and shear-wave speeds were significantly higher in these 46 patients. Multivariate analyses demonstrated breast volume > 3.4cc had odds ratio of 11.0, sensitivity of 62%, and specificity of 89, in predicting progression to precocious puberty, being second only to stimulated LH for all variables. Breast US is a useful predictive tool for diagnosis of precocious puberty in girls. Higher US stages and higher breast volume on US increased the likelihood of eventual diagnosis of precocious puberty.

Early breast development in girls: the power of greyscale sonography and sonoelastography.

Accurate distinction between central pubertal precociousness (PP) and premature thelarche (PT) is important to guide treatment. Both greyscale ultrasonography (US) and sonoelastography can be used to examine breast tissue. The aim of this study is to investigate the performance of breast US and strain elastographic (SE) in the diagnosis of increased breast volume in girls. Sixty-three girls with breast development up to 8 years of age and diagnosed with PP and PT were included in the prospective study. Basal luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol (E2) values were obtained. Each bud was considered as a unit in US. Mediolateral (ML) and anteroposterior diameters (AP) were measured, and US grading was performed. Breast SE was examined, and strain index (SI) was calculated. US and laboratory findings were compared. Of the 121 buds examined, 39 (32.2%) were with PP (6.97 ± 2.44 years) and 82 (67.8%) were with PT (6.51 ± 2.52 years). Diameters were correlated with bone age, LH, FSH, and US grade. The mean AP showed a moderate difference in favour of PP between the groups (P < .06). The mean ML was higher in PP (P < .01). There was a difference in mean SI values (P < .004). Sensitivity and specificity were 71% and 61% for ML and 72% and 56% for SI, respectively. Both ML and US grading may help discriminate PP from PT. The role of sonoelastography requires further investigation. Ultrasound and SE show significant differences between PP and PT, but these are not sufficiently reliable to be of clinical use. The contribution of sonoelastography requires further study before it can be recommended. However, SI of breast tissue can be helpful in distinguishing PP and PT from other causes of early increase in breast volume.

Vaginal Bleeding In Prepubertal Girls-A Case Series in Malaysia

The etiology of prepubertal vaginal bleeding varies from isolated pubertal causes to malignant tumors and generates significant anxiety among girls and their caretakers. Hence, these cases require careful assessment and management. This is a report of five cases of prepubertal vaginal bleeding with various causes and were managed in a tertiary referral center in Malaysia. The first case was a 6-year-old girl who had no pubertal changes with 3 weeks’ history of bleeding. She underwent examination under anesthesia and found to have multiple vaginal polyps. Another 6-year-old girl noted to have a doughnut-shaped mass protruding from her urethral meatus. She was treated with estrogen cream and sitz baths. Another child had early breast development while pelvic ultrasound revealed a multiseptated ovarian cyst requiring a cystectomy. A 19-month-old toddler had a large intravaginal mass. She required further investigation, referral to the pediatric surgeon and oncologist for treatment of a malignant yolk sac tumor. Lastly, an 8-year-old girl was noted to have monthly vaginal spotting without any secondary sexual characteristics development. Prepubertal vaginal bleeding is abnormal thus requires prompt assessment to ascertain the cause and administer appropriate management. It is important to rule out sexual abuse and malignancy. Examination under anaesthesia and vaginoscopy is recommended when imaging modality is inconclusive. Referral to tertiary centres experienced in managing such cases ensures good outcomes. Thorough targeted history-taking and pediatric-specific gynecological examination skills are crucial to formulate accurate diagnosis and appropriate management.

Evaluation of Clinical and Laboratory Findings in the Differential Diagnosis of Central Precocious Puberty and Premature Thelarche.

In this study, it was aimed to examine the clinical and laboratory findings that can be used to predict central precocious puberty (CPP) in cases whose breast development started before the age of 8. The chronological age, anthropometric measurements, bone age (BA), hormone test results and pelvic ultrasonography findings of the cases were recorded. Those with a peak luteinizing hormone (LH) level of ≥5 IU/L in the gonadotropin-releasing hormone (GnRH) stimulation test were classified as CPP and those with a peak LH level of <5 IU/L were classified as prepubertal cases. A receiver operating characteristic (ROC) analysis was performed to determine the diagnostic accuracy of laboratory variables. A total of 297 female cases were included in the study. The age at the time of admission, height-standard deviation score (SDS), BA, the long axis of the uterus and the volumes of the right and left ovaries of the cases diagnosed with CPP were found to be significantly higher than those of the prepubertal group. The cut-off value providing the best sensitivity (99%) and specificity (99%) for the peak LH was found to be 4.55; the cut-off value providing the best sensitivity (94%) and specificity (85%) for the peak LH/follicle-stimulating hormone (FSH) ratio was found to be 0.32 and the cut-off value providing the best sensitivity (47%) and specificity (93%) for the basal LH was found to be 0.13. We believe that in female cases with early breast development, a peak LH level of ≥4.55 may possibly indicate CPP and a basal LH level of <0.13 can significantly rule out CPP.

Associations between body mass index and pubertal development based on the outcomes of girls with early breast development.

To investigate the associations between physical and pubertal development based on the breast development outcomes in girls. This was a retrospective study. A total of 452 girls aged 6~8 years were included. Based on their breast development outcomes, the patients were divided into an idiopathic central precocious puberty (ICPP) group and a premature thelarche (PT) group. Anthropometry included measurements of height, weight, and BMI. ICPP was diagnosed when five diagnostic criteria from the current guidelines were met. The girls with breast development at initial evaluation had a median age of 6.9 years. In total, 31.4% of patients were diagnosed with ICPP, and ICPP was rare in girls <7 years old (19%). Patients who presented with recurrence of breast development in the PT group accounted for 38.4%. At initial evaluation, the height, weight, BMI and bone age (BA) of the girls in the PT group corresponded to those of a normally developing girl at ages 7.8 years, 8.2 years, 8.6 years and 7.6 years, respectively. The girls in the ICPP group had a mean age of 7.3 years, and their mean height, weight, and BMI were 129.6cm, 28.4kg, and 17.0 kg/m2, which corresponded to the mean of a normally developing girl at ages 8.5 years, 9.1 years, and 10.5 years, respectively; these patients had BA of 9.2 years. Additionally, based on receiver operating characteristic (ROC) curve analysis, when the basal luteinizing hormone (LH) level was 0.32 IU/L and BMI reached 16.4 kg/m2, CPP was diagnosed in patients meeting all five diagnostic criteria for CPP, and the specificity and sensitivity were 71.9% and 88.2%, respectively. Girls with breast development before 8 years old had a high proportion of recurrence of breast development. The physical development of these girls at the time of breast development preceded that of normally developing girls by 1-2 years. BMI is an independent risk factor for early pubertal development, and is a simple and clear predictor of ICPP. In addition to the five classic diagnostic criteria, CPP is diagnosed when physical development corresponds to the mean for a 10.5 years old girl.

Relationship between prolactin level and puberty in girls with early breast development.

Prolactin (PRL) stimulates the mammary glands development; however, it also inhibits gonadotropin-releasing hormone (GnRH) secretion. We evaluated the relationship between PRL levels and puberty in girls with precocious breast development. This study included 244 girls with breast development < 8 years of age. Patients were categorized as central precocious puberty (CPP) [peak luteinizing hormone (LH) levels≥ 5 IU/L after GnRH stimulation] versus non-CPP (NPP) group. High PRL was defined as serum PRL > 17.9ng/mL. High PRL was more common in NPP than in CPP group (17.6 vs. 8.1%, p=0.025), although mean PRL levels did not differ. In NPP group, the high PRL group had lower peak LH/follicle-stimulating hormone (FSH) ratio, and later LH peak time after GnRH stimulation than normal PRL group (all p<0.05). PRL levels of the subgroups according to the peak LH time (15, 30, 45, 60, and 90min after GnRH stimulation) were different in NPP group, but not in CPP group. PRL levels tended to be higher as the peak LH time was delayed. High PRL was associated with decreased odds for CPP (OR=0.42, p=0.043). Girls with NPP showed higher proportion of high PRL than CPP group. High PRL group showed more features of prepubertal response in NPP group, and associated with decreased odds for CPP, suggesting the possibility of PRL role on breast development while suppressing hypothalamic-pituitary-gonadal axis activation in NPP girls.

An integrated computational approach to screening of alkaloids inhibitors of TBX3 in breast cancer cell lines

TBX3 is an ancient and evolutionarily conserved family member of T-box transcription factors that acts as a key regulator in embryonic development and organogenesis. It is often overexpressed in various epithelial and mesenchymal malignancies which has a significant impact on various hallmarks of cancer, which mainly includes senescence shunt, apoptosis, anoikis, angiogenesis, and promoting metastatic and expansion of cancer stem cells. In addition to the role of TBX3 in early breast development, a number of studies have also confirmed the amplification of TBX3 in the occurrence and development of breast cancer. To overcome a major challenge in breast cancer treatment, resistance to current anti-cancer drug, it is important to develop new drug pipeline. In this study of different alkaloid molecules, to identify potential alkaloid inhibitors of TBX3, a structure based virtual screening was done involving molecular docking, ADME, toxicity analysis, molecular dynamics simulation. From our study 5 ligands named Jervine, Diflomotecan, Camptothecin, Vincamine, and Anoniane were primarily confirmed as potential inhibitors. The followed screening manner funnels out five potential compounds that have a high scoring function that emphasizes their high binding ability along with no toxicity effects. The molecular mechanics-generalized born surface area (MM-GBSA) and molecular dynamics (MD) simulation showed that Jervine along with Diflomotecan formed the stable complexes with TBX3 which makes it obvious that these two alkaloids can be introduced into the drug development pipeline and used as a new leader to develop new effective drugs against breast cancer. Communicated by Ramaswamy H. Sarma

An Approach to the Evaluation and Management of the Obese Child With Early Puberty.

With the declining age at onset of puberty and increasing prevalence of childhood obesity, early breast development in young obese girls has become a more frequent occurrence. Here, we examine available literature to answer a series of questions regarding how obesity impacts the evaluation and management of precocious puberty. We focus on girls as the literature is more robust, but include boys where literature permits.Suggestions include: (1) Age cutoffs for evaluation of precocious puberty should not differ substantially from those used for nonobese children. Obese girls with confirmed thelarche should be evaluated for gonadotropin-dependent, central precocious puberty (CPP) to determine if further investigation or treatment is warranted. (2) Basal luteinizing hormone (LH) levels remain a recommended first-line test. However, if stimulation testing is utilized, there is a theoretical possibility that the lower peak LH responses seen in obesity could lead to a false negative result. (3) Advanced bone age (BA) is common among obese girls even without early puberty; hence its diagnostic utility is limited. (4) Obesity does not eliminate the need for magnetic resonance imaging in girls with true CPP. Age and clinical features should determine who warrants neuroimaging. (5) BA can be used to predict adult height in obese girls with CPP to inform counseling around treatment. (6) Use of gonadotropin-releasing hormone analogues (GnRHa) leads to increased adult height in obese girls. (7) Obesity should not limit GnRHa use as these agents do not worsen weight status in obese girls with CPP.

Response to Letter to the Editor from De Zegher and Ibanes: On the rising incidence of early breast development.

No abstract for a letter

On the rising incidence of early breast development: puberty as an adaptive escape from ectopic adiposity in mismatch girls

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The Relationship of Early Adiposity Rebound With Accelerated Bone Age and Breast Development in Girls: A Prospective Cohort Study

Abstract Introduction: Adiposity rebound (AR) refers to the increase in body mass index (BMI) that follows the BMI nadir in childhood. Earlier AR increases the likelihood of being overweight/obese and may lead to early pubertal advancement, especially in girls. We aimed to evaluate the longitudinal changes in anthropometrics, bone age (BA), and breast development in relation to AR timing in girls. Methods: This study included girls (n = 349) of the Environment and Development of Children (EDC) cohort, a prospective cohort of healthy children started in 2012 with biennial visits to study the effects of environmental exposures on physical and neurobehavioral development. The BMI trajectories of girls with 3 or more measurements between 2 and 8 years of age (n = 242) were visually inspected to determine AR timing. After excluding preterm and multiple births, 204 girls were included and categorized according to the age at AR: group 1 (&amp;lt;3.9 years; n = 34, 17%), group 2 (3.9-5.9 years; n = 55, 27%) and group 3 (≥6 years; n = 115, 56%). AR groups were compared for differences in anthropometric measures, BA progression, and breast development. The relationships between AR and outcomes were analyzed with adjustment for age, gestational age, birthweight, physical activity and diet. Results: At age 2, there were no differences in anthropometric measures. By age 4, group 1 showed higher mean BMI z-scores (0.87) than groups 2 (-0.19) and 3 (-0.45) (P &amp;lt;0.001). The differences in BMI z-scores were significant between all 3 groups at 6 and 8-years (P &amp;lt;0.001, for all). Height differences became significant at 8-years (P = 0.010), with greater mean height z-score in group 1 (0.80) compared to group 3 (0.30). BA progression differed significantly between groups 1, 2 and 3 at 6-years (BA 6.87 vs. 6.44 vs. 6.36 years respectively; P &amp;lt; 0.001) and at 8-years (BA 9.65 vs. 8.82 vs. 8.60 respectively; P &amp;lt; 0.001). The inverse relationship between AR timing and BA remained significant after adjusting for covariates at 6 years (B = -0.222, P = 0.040) and 8 years (B = -0.468, P &amp;lt;0.001). Breast development occurred in 49 girls (24%) by age 8 with increased occurrence in the earlier AR groups: group 1 (n = 16, 47%), group 2 (n = 17, 31%), and group 3 (n = 16, 14%) (P for trend &amp;lt;0.001). When compared to group 3, the earlier AR groups had significantly increased risk of breast development at age 8 (OR 5.1, 95%CI 2.1-12.4 for group 1 and OR 2.4, 95%CI 1.1-5.4 for group 2, P &amp;lt;0.001 for both), after adjusting for covariates (P &amp;lt;0.05, for both). Conclusions: Girls who had earlier AR showed greater BA progression starting at 6 years and continuing at 8 years along with greater height at 8 years. These girls are at risk for early breast development after adjustment for covariates. AR timing may be a predictor for BA progression and onset of breast development in girls.

Girls' Pubertal Timing and Tempo and Mental Health: A Longitudinal Examination in an Ethnically Diverse Sample

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 8 years. 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.

Bisphenol A and Puberty Onset in Female Mice: Developmental Effects of Low-Dose Exposure.

Bisphenol A and Puberty Onset in Female Mice: Developmental Effects of Low-Dose Exposure.

Abstract A14: Infancy and childhood infections and pubertal timing in the LEGACY Girls’ Study

Abstract An earlier age at pubertal development is associated with increased breast cancer risk, and Westernized countries are observing earlier ages of pubertal timing in girls. While increased rates of childhood obesity are associated with earlier ages of pubertal development, earlier ages of puberty are also observed in countries that are not experiencing high rates of childhood obesity. Prior evidence from a birth cohort in Hong Kong suggests that early life infections, as measured by hospitalizations, is associated with pubertal onset. Emerging evidence suggests that early life and childhood exposures to infection may impact pubertal development. Therefore, we aimed to assess whether indirect measures of infections in infancy (birth-12 months) and early childhood (1-5 years) are associated with the age of onset of puberty (menarche and breast and pubic hair development). We used data from the Infection Questionnaire from the multisite prospective LEGACY Girls Study where mothers/guardians reported on daughters’ indirect exposure to infection (daycare attendance, antibiotic use, physician visit due to fever, hospitalization due to infection) and specific exposure to infections (e.g., tonsillitis, cold sores). Mothers/guardians reported on daughters’ age at first menses and the onset of breast and pubic hair development using Tanner Staging (as defined as Tanner Stage 2 or higher). We used Cox Proportional Hazard Ratio (HR) models to examine the prospective association between infection history and pubertal timing. We considered site, race/ethnicity, and maternal education as possible confounders. In 615 girls (average age (SD) 9.5 (2.4) years) whose mother/guardians completed the Infection Questionnaire, 65% were white non-Hispanic, 18% were Hispanic, 5% were Black non-Hispanic, and 9% were Asian. Sixty-nine percent of mothers/guardians had a college degree or higher. We assessed frequency of infectious exposures across infancy and early childhood where 73% of girls ever used antibiotics, 59% of girls ever had an ear infection, 59% of girls ever attended daycare over 10 hours per week, 29% of girls visited a physician due to fever (measured in childhood only), 36% of mothers reported girls having 2 or more infections, and 6% of girls were ever hospitalized due to infection. In multivariable models controlled for socioeconomic and maternal factors, earlier age of pubic hair development was associated with hospitalization due to infection compared to never hospitalized (HR=1.53, 95% CI=1.07-2.21) and ever antibiotic use compared to never antibiotic use (HR=1.31, 95% CI=1.03-1.68). Compared to never, multivariable models suggested that earlier age at menarche was associated with physician visit due to fever (HR=1.30, 95% CI=1.04-1.63). We observed no association between infectious exposures and earlier breast development. These results suggest that infancy and childhood infectious exposures may be related to earlier pubertal development, but more studies are needed to confirm these findings. Citation Format: Yun Huang, Irene L. Andrulis, Angela R. Bradbury, Saundra S. Buys, Mary B. Daly, Esther M. John, Lisa A. Schwartz, Mary Beth Terry, Jasmine A. McDonald. Infancy and childhood infections and pubertal timing in the LEGACY Girls’ Study [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A14.

Sağlam Çocuk Polikliniğinde Prematür Telarş Olgularında Çevresel Maruziyet Değerlendirilmesi

Backround: Breast development, without any signs of sexual maturation, in girls younger than 8 years is almost universally accepted as premature thelarche (PT). Prevalance and etiology are clearly unknown. Objectives: We designed a study to follow up girls who had unilateral or bilateral PT and to show regression after stopping care products. Material and Methods: The design of study was retrospective Children and their parents were enrolled into the study from September 2016 to February 2017. All children had one common symptom which was unilateral or bilateral breast development not associated with pubic or axillary hair, vaginal bleeding or other sign of sexual maturation, at the well child visit. In these children with no organic causes, monitoring was taken after stopping of care products. Result: 28 girls were evaluated and mean age was 2,3 years (± 0,3). Noone had a chronic disease. All cases identified as Tanner stage-2 and continued to have early breast development on follow-up. 18 (64,2%) girls had unilateral breast development. After stopping care products, both group had regression in six months. Conclusions: Currently there are no predictive tests to show the risk of breat development of early or puberty precoccus. Children may be exposed to much more diagnostic tests because of overuse products. Physician must be aware of these products. Families may use a minimum amount of care products for their children.

Early breast development in overweight girls: does estrogen made by adipose tissue play a role?

BackgroundGirls who are overweight/obese (OB) develop breast tissue but do not undergo menarche (the first menstrual period) significantly earlier than girls of normal weight (NW). It has been proposed that estrogen synthesized by adipose tissue may be contributory, yet OB do not have higher serum estrogen levels than NW matched on breast stage. We hypothesized that estrogen synthesized locally, in mammary fat, may contribute to breast development. This hypothesis would predict that breast development would be more advanced than other estrogen-sensitive tissues as a function of obesity and body fat.Methods80 pre-menarchal girls (26 OB, 54 NW), aged 8.2–14.7 yrs, underwent dual-energy x-ray absorptiometry to calculate percent body fat (%BF), Tanner staging of the breast, breast ultrasound for morphological staging, trans-abdominal pelvic ultrasound, hand x-ray (bone age), a blood test for reproductive hormones, and urine collection to determine the vaginal maturation index (VMI), an index of estrogen exposure in urogenital epithelial cells.ResultsWhen controlling for breast morphological stage determined by ultrasound, %BF was not associated with serum estrogen or gonadotropin (LH and FSH) levels or on indices of systemic estrogen action (uterine volume, endometrial thickness, bone age advancement, and VMI). Tanner breast stage did not correlate with breast morphological stage and led to misclassification of chest fatty tissue as breast tissue in some OB.ConclusionsThese studies do not support the hypothesis that estrogen derived from total body fat or local (mammary) fat contributes to breast development in overweight/obese girls.

Breastfeeding and timing of pubertal onset in girls: a multiethnic population-based prospective cohort study

BackgroundEarly puberty is associated with higher risk of adverse health and behavioral outcomes throughout adolescence and adulthood. US girls are experiencing earlier puberty with substantial racial/ethnic differences. We examined the association between breastfeeding and pubertal timing to identify modifiable risk factors of early puberty and potential sources of racial/ethnic differences in the timing of pubertal development.MethodsA prospective cohort study of 3331 racially/ethnically diverse girls born at Kaiser Permanente Northern California (KPNC) between 2004 and 06. All data were obtained from KPNC electronic clinical and administrative datasets. Mother-reported duration of breastfeeding was obtained from questionnaires administered at each ‘well-baby’ check-up exam throughout the baby’s first year and categorized as ‘Not breastfed’, ‘Breastfed < 6 months’, and ‘Breastfed ≥6 months’. Pubertal development data used Tanner stages assessed by pediatricians during routine pediatric checkups starting at age 6. Pubertal onset was defined as transition from Tanner Stage 1 to Tanner Stage 2+ for breast (thelarche) and pubic hair (pubarche). Weibull regression models accommodating for left, right, and interval censoring were used in all analyses. Models were adjusted for maternal age, education, race/ethnicity, parity and prepubertal body mass index (BMI). We also examined race/ethnicity as a potential effect modifier of these associations.ResultsNot breastfeeding was associated with earlier onset of breast and pubic hair development compared to breastfeeding ≥6 months (adjusted hazard ratio [HR]: 1.25; 95% confidence interval [CI]: 1.07–1.46; HR: 1.24; 95% CI: 1.05–1.46, respectively). Breastfeeding for < 6 months was also associated with the risk of earlier pubic hair development (HR: 1.14; 95% CI: 1.00–1.30, compared to breastfeeding ≥6 months). Inclusion of girls’ prepubertal BMI slightly attenuated the association between breastfeeding and timing of breast onset but remained significant. The association between not breastfeeding and early breast development may be stronger among African American girls (HR: 1.92; 95% CI: 1.01–3.66, compared to breastfeeding ≥6 months) than other racial/ethnic groups.ConclusionsBreastfeeding is an independent predictor of pubertal onset in girls, and the strength of the association may vary by race/ethnicity. Providing breastfeeding support and lactation education for high risk mothers may help prevent earlier pubertal onset and promote positive health outcomes later in life.

Comparative study of GnRHa stimulation test and GnRH stimulation test

Objective To compare the results of GnRHa stimulation test and GnRH stimulation test in girls with Idiopathic central precocious puberty. Methods The girls aged 6-10 who were diagnosed with early breast development(<8 years old) from January 2016 to June 2018 were randomly divided into GnRHa stimulation test group and GnRH stimulation test group according to clinical manifestations, auxiliary examinations and follow-up.The difference in the results of the stimulation test between the two groups was compared. Results A total of 108 girls were enrolled in this study, and 40(37%) of the GnRHa stimulation tests were performed.Among them, 25(63%) patients with idiopathic central precocious puberty had the confirmed diagnosis, and the GnRH stimulation test was performed.Of the 68(63%) patients, 30(44%) had idiopathic central precocious puberty.The peaks of LH in the GnRHa challenge test group and the GnRH challenge test group were 11.33(6.81, 15.79) and 7.89(5.35, 14.21), and the FSH peaks were 15.68(10.18, 20.06) and 17.26(13.34, 21.42), showing no significant differences (U=1078.50, P=0.07; U=1617.50, P=0.10). The peak values of LH/FSH were 0.86(0.37, 1.17) and 0.52(0.31, 0.83), respectively, and there was a statistical difference(U=953.00, P=0.01). GnRH challenge test showed the ICPP sensitivity of 90.91%(81.10%-100.72%), specificity of 94.29%(86.60%-101.98%), total coincidence rate of 92.65%(86.44 %-98.85%), Yoden index of 0.85( 0.72%-0.98%). Sensitivity of the GnRHa challenge test showed the ICPP diagnosis rate of 95.24%(86.13%-104.35%), specificity of 73.68%(53.88%-93.48%), total coincidence rate of 85.00%(73.93%-96.07%), Yoden index of 0.69(0.47-0.91). Conclusion For the diagnosis of idiopathic central precocious puberty in girls, the GnRHa challenge test is more sensitive than the GnRH challenge test, and the specificity and the Yoden index are both low.Therefore, routine use of GnRHa stimulation test as the replacement of GnRH stimulation test is not recommended. Key words: Central precocious puberty; Girl; GnRHa; GnRH; Stimulation test

MON-242 Early Breast Development in Overweight Girls: Does Estrogen Made by Adipose Tissue Play a Role?

Overweight/obese girls (OB) undergo thelarche but not menarche significantly earlier than normal weight girls (NW). It has been proposed that estrogen synthesized by adipose tissue may be contributory, yet OB do not have higher serum estrogen levels than NW matched on breast stage. We hypothesized that in OB, adipose tissue overlying the breast bud may be a ready source of estrogen that is sufficient to initiate thelarche because the primitive breast bud is intimately associated with the mammary fat pad during development (Anbazhagan Am J Anat ’91, Neville J Mammary Gland Biol Neoplasia ’98). Estrogen derived from mammary fat could act locally to induce thelarche but would not be detected in the circulation and therefore would not act systemically to induce uterine maturation/menses. To address this hypothesis, we measured reproductive hormones and imaged the breast, uterus, and ovaries in 80 pubertal, pre-menarchal girls (26 OB, 54 NW) aged 8.2-14.7 yrs. We used total percent body fat (%BF), determined by DXA, as a proxy for mammary fat, taking advantage of the positive correlation between these two measures (Novotny Am J Hum Biol ’11, Schautz Eur J Clin Nutr ’11, Zhu Eur Radiol ’16). We predicted that if estrogen derived from mammary fat contributes to breast maturation, then girls with higher %BF (and thus more mammary fat) would demonstrate immaturity of other estrogen-sensitive tissues (e.g. uterus, endometrial lining, vaginal epithelium) compared with girls of the same breast morphological stage (stages A-E based on Bruni et al. Adolesc Pediatr Gynecol ‘90) with lower %BF. OB were younger than NW (10.1 ± 1.1 vs. 11.3 ± 1.3 yrs, p<0.001) and more likely to be non-Hispanic Black or Hispanic (p=0.03). %BF ranged from 13.1-53.5% (3rd-97th percentiles). The distribution of Tanner breast and pubic hair stages was similar in NW and OB, and the full spectrum of breast development (A-E) was observed with stages D and E being the most common (59%) overall. Uterine volume, endometrial thickness, sex steroids (E1, E2, T, A’dione), and gonadotropins increased (p<0.001 for all), as expected, with breast morphological stage but %BF was not associated with any index of systemic estrogen action or reproductive hormones in a linear regression model controlled for breast morphological stage. These studies suggest that neither total %BF nor local (mammary) are clinically significant sources of estrogen capable of inducing breast development in OB. Taken together with the comparable gonadotropin levels observed in girls of the same breast morphological stage across a broad range of total %BF, these findings point to earlier activation of the hypothalamic-pituitary-ovarian axis in OB as the most likely cause of earlier thelarche in OB compared with NW. Longitudinal follow-up of this cohort is underway to investigate the effect of %BF on the maturational trajectory of the central components of the female reproductive axis.

Association of Prepubertal and Adolescent Androgen Concentrations With Timing of Breast Development and Family History of Breast Cancer

Early breast development is a risk factor for breast cancer, and girls with a breast cancer family history (BCFH) experience breast development earlier than girls without a BCFH. To assess whether prepubertal androgen concentrations are associated with timing of breast development (analysis 1) and to compare serum androgen concentrations in girls with and without a BCFH (analysis 2). Prospective cohort study of 104 girls aged 6 to 13 years at baseline using data collected between August 16, 2011, and March 24, 2016, from the Lessons in Epidemiology and Genetics of Adult Cancer From Youth (LEGACY) Girls Study, New York site. Analysis 1 included serum concentrations of dehydroepiandrosterone sulfate, androstenedione, and testosterone (free and total) measured before breast development and divided at the median into high and low categories. Analysis 2 included the degree of BCFH: first-degree was defined as having a mother with breast cancer and second-degree was defined as having a grandmother or aunt with breast cancer. Analysis 1 included age at onset of breast development measured using the Pubertal Development Scale (scores range from 1-4; scores ≥2 indicate breast development), and analysis 2 included serum androgen concentrations. We also assessed breast cancer-specific distress using the 8-item Child Impact of Events Scale. Our analyses included 36 girls for the prospective model, 92 girls for the cross-sectional model, and 104 girls for the longitudinal model. Of the 104 girls, the mean (SD) age at baseline was 10.3 (2.5) years, and 41 (39.4%) were non-Hispanic white, 41 (39.4%) were Hispanic, 13 (12.5%) were non-Hispanic black, and 9 (8.7%) were other race/ethnicity. Forty-two girls (40.4%) had a positive BCFH. Girls with prepubertal androstenedione concentrations above the median began breast development 1.5 years earlier than girls with concentrations below the median (Weibull survival model-estimated median age, 9.4 [95% CI, 9.0-9.8] years vs 10.9 [95% CI, 10.4-11.5] years; P = .001). Similar patterns were observed for dehydroepiandrosterone sulfate (1.1 years earlier: age, 9.6 [95% CI, 9.1-10.1] years vs 10.7 [95% CI, 10.2-11.3] years; P = .009), total testosterone (1.4 years earlier: age, 9.5 [95% CI, 9.1-9.9] years vs 10.9 [95% CI, 10.4-11.5] years; P = .001), and free testosterone (1.1 years earlier: age, 9.7 [95% CI, 9.2-10.1] years vs 10.8 [95% CI, 10.2-11.4] years; P = .01). Compared with girls without BCFH, girls with a first-degree BCFH, but not a second-degree BCFH, had 240% higher androstenedione concentrations (geometric means: no BCFH, 0.49 ng/mL vs first-degree BCFH, 1.8 ng/mL vs second-degree, 1.6 ng/mL; P = .01), 10% higher total testosterone concentrations (12.7 ng/dL vs 14.0 ng/dL vs 13.7 ng/dL; P = .01), and 92% higher free testosterone concentrations (1.3 pg/mL vs 2.5 pg/mL vs 0.3 pg/mL; P = .14). The dehydroepiandrosterone sulfate concentration did not differ between BCFH-positive and BCFH-negative girls but was elevated in girls with breast cancer-specific distress. Our findings suggest that androgen concentrations may differ between girls with and without a BCFH and that elevated hormone concentrations during adolescence may be another factor to help explain the familial clustering of breast cancer.