Search

Background: Maternal breast volume is determined by the quantity of glandular and adipose tissue, and it undergoes significant changes during pregnancy. These changes are intricately linked to the development of glandular tissue, which most likely reflects lactation capacity. Evidence indicates that women with overweight or obesity exhibit larger breast volume compared to those with a normal body mass index (BMI), emphasizing the close relationship between breast volume and maternal adiposity. Hence, we aim to investigate breast volume growth and maternal BMI as potential risk factors for low milk production., Methods: Lactating women (n = 609) from the Perth metropolitan area in Western Australia between 2011 and 2023 were included in the analysis. Twenty-four-hour milk production measurements were conducted using the test weighing method, and milk removal frequencies were recorded. Mothers completed questionnaires regarding demographic, obstetric and infant details. Linear and logistic regression models were used to determine maternal and infant factors associated with milk production., Results: Here we show that increasing maternal age and BMI are associated with low milk production. Moreover, larger pre-pregnancy breast volume and breast growth are associated with both higher BMI and milk production., Conclusions: Women who are older, have an obese BMI and who have minimal pre-pregnancy breast volume and breast growth should be provided with antenatal screening and breastfeeding support as they are more likely to experience low milk production.

Whether trace metals modify breast density, the strongest predictor for breast cancer, during critical developmental stages such as puberty remains understudied. Our study prospectively evaluated the association between trace metals at Tanner breast stage B1 (n = 291) and at stages both B1 and B4 (n = 253) and breast density at 2 years post-menarche among Chilean girls from the Growth and Obesity Cohort Study. Dual-energy x-ray absorptiometry assessed the volume of dense breast tissue (absolute fibroglandular volume [FGV]) and percent breast density (%FGV). Urine trace metals included arsenic, barium, cadmium, cobalt, cesium, copper, magnesium, manganese, molybdenum, nickel, lead, antimony, selenium, tin, thallium, vanadium, and zinc. At B1, a doubling of thallium concentration resulted in 13.69 cm 3 increase in absolute FGV (β: 13.69, 95% confidence interval [CI]: 2.81, 24.52), while a doubling of lead concentration resulted in a 7.76 cm 3 decrease in absolute FGV (β: -7.76, 95%CI: -14.71, -0.73). At B4, a doubling of barium concentration was associated with a 10.06 cm 3 increase (β: 10.06, 95% CI: 1.44, 18.60), copper concentration with a 12.29 cm 3 increase (β: 12.29, 95% CI: 2.78, 21.56), lead concentration with a 9.86 cm 3 increase (β: 9.86, 95% CI: 0.73, 18.98), antimony concentration with a 12.97 cm 3 increase (β: 12.97, 95% CI: 1.98, 23.79) and vanadium concentration with a 13.14 cm 3 increase in absolute FGV (β: 13.14, 95% CI: 2.73, 23.58). Trace metals may affect pubertal breast density at varying developmental stages with implications for increased susceptibility for breast cancer., (© 2024 UICC.)

Objectives: Mild breast swelling is frequently observed in newborns during the first postnatal week. Breast enlargement is also observed in a minor proportion of infants beyond the first postnatal week, leading to discussions how to deal with it. Our objective was to review a case series of infants with prolonged breast swelling., Case Presentation: We examined five infants with pronounced breast enlargement beyond the first postnatal week and measured human chorionic gonadotropin (HCG), estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), and progesterone (P4) in blood samples and analyzed breast volume by sonographic volume determination in all infants initially and across time. The regression of breast enlargement positively correlated with serum prolactin levels in infants with breast enlargement beyond the first week of life. Complete regression occurred after several weeks and was characterized by normalization of serum prolactin levels., Conclusions: The present study emphasizes the role of prolactin in neonates with pronounced breast enlargement beyond the first week of life., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Breast development in a girl 3 years of age or younger is a commonly encountered scenario. Nearly all of these cases will either regress or fail to progress during follow-up, confirming a diagnosis of premature thelarche (PT). Studies show that these girls will have onset of true puberty and menses at a normal age. The authors present evidence that laboratory testing, particularly basal and gonadotropin hormone-releasing hormone -stimulated gonadotropin levels, will show overlap between girls with PT and the rare patients with the onset of central precocious puberty before age 3, mainly of whom have hypothalamic hamartomas., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Over the decades the trends of early onset of puberty have been observed in children, particularly in girls. Research evidence has reported diet to be among the most important risk factors for puberty onset. This study evaluated the association between dietary behavior and puberty in girls., Methods: We enrolled 201 girls with the main complaints of breast development as the cases at the Endocrine Department of Nanjing Children's Hospital. The cases were divided into breast development with central priming and breast development without central priming groups and were matched with 223 normal health girls with no breast development (control group). We used the modified Child Eating Behavior Questionnaire (CEBQ) to conduct a face-to-face interview about dietary behavior. Sample t-test or Mann Whitney U test or Chi-square test, the analysis of variance or Kruskal Wallis test, and least significant difference (LSD) were used to compare differences between the groups, Bonferroni was used to correct the p-value, and logistic regression was used to analyze risk factors for puberty onset., Results: A total of 424 girls participated in this study, among them, 136 were cases with breast development with central priming, 65 were cases with breast development without central priming, and 223 were normal health girls with no breast development. Age of the participants ranged from 4.5 to 9.3 years. There were significant differences in food response (p < 0.001), dietary restriction (p < 0.001), frequencies of vegetable intake (χ 2  = 8.856, p = 0.012), drinking milk (χ 2  = 23.099, p = 0.001), and borderline statistical difference in a total score of unhealthy dietary behavior (p = 0.053) among the cases and controls. However, in the post hoc analysis, these dietary behaviors were significant differences between the girls with breast development with central priming and the control groups. Moreover, girls in the breast development with central priming group had significantly higher bone age (BA), uterine body length, ovarian volume, basal luteinizing hormone (LH), basal follicle-stimulating hormone (FSH), peak LH, peak FSH, estradiol (E2), and free triiodothyronine (FT3) compared to those in the breast development without central priming group. In the multivariate logistic regression, only uterine body length was associated with increased risk of breast development with central priming (OR = 1.516, 95%CI: 1.243-1.850)., Conclusion: There were significant differences in dietary behaviors among girls with breast development with central priming and normal health girls with no breast development, and uterine body length was associated with an increasing risk of breast development with central priming among girls with breast development., (© 2024. The Author(s).)

Transforming growth factor β (TGF-β) and HER2 signaling collaborate to promote breast cancer progression. However, their molecular interplay is largely unclear. TGF-β can activate mitogen-activated protein kinase (MAPK) and AKT, but the underlying mechanism is not fully understood. In this study, we report that TGF-β enhances HER2 activation, leading to the activation of MAPK and AKT. This process depends on the TGF-β type I receptor TβRI kinase activity. TβRI phosphorylates HER2 at Ser779, promoting Y1248 phosphorylation and HER2 activation. Mice with HER2 S779A mutation display impaired mammary morphogenesis, reduced ductal elongation, and branching. Furthermore, wild-type HER2, but not S779A mutant, promotes TGF-β-induced epithelial-mesenchymal transition, cell migration, and lung metastasis of breast cells. Increased HER2 S779 phosphorylation is observed in human breast cancers and positively correlated with the activation of HER2, MAPK, and AKT. Our findings demonstrate the crucial role of TGF-β-induced S779 phosphorylation in HER2 activation, mammary gland development, and the pro-oncogenic function of TGF-β in breast cancer progression., (© 2024 Shi et al.)

Background: Estrogen receptor (ER) signaling plays an important role in the development and functional differentiation of the breast and participates in the process of breast cancer. Activated ER can affect various aspects of the cell's behavior, including proliferation, via modulating the expression of many downstream target genes. Phosphorylation is one of the activation pathways of ER. However, the relationship between estrogen receptor phosphorylation sites and breast development and carcinogenesis is not clear., Methods: Using Crisper-Cas9 gene editing technology, we constructed ER S309A mutant mice. Using carmine staining of the mammary gland of mice at different developmental stages, we examined the breast development of ER S309A mice. Using hematoxylin-eosin (HE) staining of vaginal smears of mice at the same time for 5 consecutive days, we measured the vaginal epithelial keratinocytes., Results: We established ER S309A mutant mice and observed breast defects in ER S309A mice. In addition, we observed decreased reproductive ability, and estrous cycle disorder in ER S309A mice. The number of vaginal epithelial keratino-cytes in the estrous cycle of ER S309A mice was decreased., Conclusion: These results suggest that the phosphorylation site of ER at Serine 309 is important for ER function and breast development.

Background: Premature thelarche is the most common pubertal disorder in girls. The condition should be differentiated from central precocious puberty which may result in early epiphyseal fusion and reduced adult height, necessitating treatment., Objectives: The purpose of this article is to familiarize physicians with the clinical manifestations of premature thelarche and laboratory tests that may help distinguish premature thelarche from central precocious puberty., Methods: A search was conducted in September 2022 in PubMed Clinical Queries using the key term "Premature thelarche". The search strategy included all clinical trials, observational studies, and reviews published within the past 10 years. Only papers published in the English literature were included in this review. The information retrieved from the above search was used to compile the present article., Results: Premature thelarche denotes isolated breast development before the age of 8 years in girls who do not manifest other signs of pubertal development. The condition is especially prevalent during the first two years of life. The majority of cases of premature thelarche are idiopathic. The condition may result from an unsuppressed hypothalamic-pituitary-gonadal axis in the early years of life, an "overactivation" of the hypothalamic-pituitary axis in early childhood secondary to altered sensitivity to steroids of the hypothalamic receptors controlling sexual maturation, increased circulating free estradiol, increased sensitivity of breast tissue to estrogens, and exposure to exogenous estrogens. The cardinal feature of premature thelarche is breast development which occurs without additional signs of pubertal development in girls under 8 years of age. The enlargement may involve only one breast, both breasts asymmetrically, or both breasts symmetrically. The breast size may fluctuate cyclically. The enlarged breast tissue may be transiently tender. There should be no significant changes in the nipples or areolae and no pubic or axillary hair. The vulva, labia majora, labia minora, and vagina remain prepubertal. Affected girls have a childlike body habitus and do not have mature contours. They are of average height and weight. Growth and osseous maturation, the onset of puberty and menarche, and the pattern of adolescent sexual development remain normal. Most cases of premature thelarche can be diagnosed on clinical grounds. Laboratory tests are seldom indicated. No single test can reliably differentiate premature thelarche from precocious puberty., Conclusion: Premature thelarche is benign, and no therapy is necessary apart from parental reassurance. As enlargement of breasts may be the first sign of central precocious puberty, a prolonged follow- up period every 3 to 6 months with close monitoring of other pubertal events and linear growth is indicated in all instances., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The liver kinase B1 (LKB1) controls cellular metabolism and cell polarity across species. We previously established a mechanism for negative regulation of transforming growth factor β (TGFβ) signaling by LKB1. The impact of this mechanism in the context of epithelial polarity and morphogenesis remains unknown. After demonstrating that human mammary tissue expresses robust LKB1 protein levels, whereas invasive breast cancer exhibits significantly reduced LKB1 levels, we focused on mammary morphogenesis studies in three dimensional (3D) acinar organoids. CRISPR/Cas9-introduced loss-of-function mutations of STK11 (LKB1) led to profound defects in the formation of 3D organoids, resulting in amorphous outgrowth and loss of rotation of young organoids embedded in matrigel. This defect was associated with an enhanced signaling by TGFβ, including TGFβ auto-induction and induction of transcription factors that mediate epithelial-mesenchymal transition (EMT). Protein marker analysis confirmed a more efficient EMT response to TGFβ signaling in LKB1 knockout cells. Accordingly, chemical inhibition of the TGFβ type I receptor kinase largely restored the morphogenetic defect of LKB1 knockout cells. Similarly, chemical inhibition of the bone morphogenetic protein pathway or the TANK-binding kinase 1, or genetic silencing of the EMT factor SNAI1, partially restored the LKB1 knockout defect. Thus, LKB1 sustains mammary epithelial morphogenesis by limiting pathways that promote EMT. The observed downregulation of LKB1 expression in breast cancer is therefore predicted to associate with enhanced EMT induced by SNAI1 and TGFβ family members., (© 2023 The Authors. Journal of Cellular Physiology published by Wiley Periodicals LLC.)

Introduction: This study aimed to determine the diagnostic performance of transabdominal pelvic ultrasonography and bone age in identifying the onset of puberty in girls at the Clínica Las Américas in Medellín, Colombia., Methods: We included girls aged ≤11 years referred to our clinic between March 2016 and March 2019 for signs of puberty. We compared the findings on pelvic and breast ultrasonography and bone age versus the baseline measurement of luteinizing hormone (LH) in serum, used as the reference standard for identifying the onset of puberty. We calculated the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and positive and negative likelihood ratios, analyzing subgroups of patients of different ages., Results: We analyzed 43 patients. Ultrasound assessment of breast development had the highest sensitivity (94.1%) of all the imaging parameters evaluated, but its specificity was low. However, characteristics such as the length of the body of the uterus >3.0 cm and the presence of endometrial echoes were highly specific for identifying the onset of puberty, particularly in patients aged ≤8 years., Conclusion: Pelvic ultrasonography, ultrasonographic assessment of Tanner stage of breast development, and the evaluation of bone age are useful tools for the imaging confirmation of the onset of puberty. The results of this study support the use of these techniques in clinical practice in the workup for pubertal disorders in girls., (Copyright © 2020 SERAM. Published by Elsevier España, S.L.U. All rights reserved.)

Population studies show worrisome trends towards earlier breast development, difficulty in breastfeeding, and increasing rates of breast cancer in young women. Multiple epidemiological studies have linked these outcomes with chemical exposures, and experimental studies have shown that many of these chemicals generate similar effects in rodents, often by disrupting hormonal regulation. These endocrine-disrupting chemicals (EDCs) can alter the progression of mammary gland (MG) development, impair the ability to nourish offspring via lactation, increase mammary tissue density, and increase the propensity to develop cancer. However, current toxicological approaches to measuring the effects of chemical exposures on the MG are often inadequate to detect these effects, impairing our ability to identify exposures harmful to the breast and limiting opportunities for prevention. This paper describes key adverse outcomes for the MG, including impaired lactation, altered pubertal development, altered morphology (such as increased mammographic density), and cancer. It also summarizes evidence from humans and rodent models for exposures associated with these effects. We also review current toxicological practices for evaluating MG effects, highlight limitations of current methods, summarize debates related to how effects are interpreted in risk assessment, and make recommendations to strengthen assessment approaches. Increasing the rigor of MG assessment would improve our ability to identify chemicals of concern, regulate those chemicals based on their effects, and prevent exposures and associated adverse health effects., (© 2022. The Author(s).)

Objective: Growth-based determination of pubertal onset timing would be cheap and practical. We aimed to determine this timing based on pubertal growth markers. Secondary aims were to estimate the differences in growth between cohorts and identify the role of overweight in onset timing., Design: This multicohort study includes data from three Finnish cohorts-the Type 1 Diabetes Prediction and Prevention (DIPP, N = 2,825) Study, the Special Turku Coronary Risk Factor Intervention Project (STRIP, N = 711), and the Boy cohort (N = 66). Children were monitored for growth and Tanner staging (except in DIPP)., Methods: The growth data were analyzed using a Super-Imposition by Translation And Rotation growth curve model, and pubertal onset analyses were run using a time-to-pubertal onset model., Results: The time-to-pubertal onset model used age at peak height velocity (aPHV), peak height velocity (PHV), and overweight status as covariates, with interaction between aPHV and overweight status for girls, and succeeded in determining the onset timing. Cross-validation showed a good agreement (71.0% for girls, 77.0% for boys) between the observed and predicted onset timings. Children in STRIP were taller overall (girls: 1.7 [95% CI: 0.9, 2.5] cm, boys: 1.0 [0.3, 2.2] cm) and had higher PHV values (girls: 0.13 [0.02, 0.25] cm/year, boys: 0.35 [0.21, 0.49] cm/year) than those in DIPP. Boys in the Boy cohort were taller (2.3 [0.3, 4.2] cm) compared with DIPP. Overweight girls showed pubertal onset at 1.0 [0.7, 1.4] year earlier compared with other girls. In boys, there was no such difference., Conclusions: The novel modeling approach provides an opportunity to evaluate the Tanner breast/genital stage-based pubertal onset timing in cohort studies including longitudinal data on growth but lacking pubertal follow-up., Competing Interests: The authors have declared that no competing interests exist.

Many metabolic phenotypes in cancer cells are also characteristic of proliferating nontransformed mammalian cells, and attempts to distinguish between phenotypes resulting from oncogenic perturbation from those associated with increased proliferation are limited. Here, we examined the extent to which metabolic changes corresponding to oncogenic KRAS expression differed from those corresponding to epidermal growth factor (EGF)-driven proliferation in human mammary epithelial cells (HMECs). Removal of EGF from culture medium reduced growth rates and glucose/glutamine consumption in control HMECs despite limited changes in respiration and fatty acid synthesis, while the relative contribution of branched-chain amino acids to the TCA cycle and lipogenesis increased in the near-quiescent conditions. Most metabolic phenotypes measured in HMECs expressing mutant KRAS were similar to those observed in EGF-stimulated control HMECs that were growing at comparable rates. However, glucose and glutamine consumption as well as lactate and glutamate production were lower in KRAS-expressing cells cultured in media without added EGF, and these changes correlated with reduced sensitivity to GLUT1 inhibitor and phenformin treatment. Our results demonstrate the strong dependence of metabolic behavior on growth rate and provide a model to distinguish the metabolic influences of oncogenic mutations and nononcogenic growth., (© 2021 Federation of European Biochemical Societies.)

Objectives: In this study, we evaluated the concordance between the ultrasonographic stage of breast (US B) and Tanner stage of breast (TS B) for overweight and obese girls based on a school population study., Methods: We conducted multistage, stratified cluster, and random-proportional sampling and ultimately included 221 girls (aged 6-10 years)., Results: This study revealed that the concordance was poor (accuracy=0.19 (95% confidence interval: 0.14, 0.25)) between US B and TS B among the 221 participants. When our subjects were stratified by weight, we observed a weak association between US B and TS B in the thin/normal weight group (r=0.34, p=0.001) but not in the overweight (r=0.097, p=0.38) or obese groups (r=-0.19, p=0.206), and as the body mass index (BMI) z-score increased, the overestimation ratio of TS B increased. US B manifested a positive correlation with breast bud diameter (BD) (r=0.885, p<0.001), follicle-stimulating hormone (r=0.235, p=0.009), and luteinizing hormone (r=0.192, p=0.037), but this was not the case with TS B., Conclusions: As the BMI z-score increased, the correlation between the two methods declined, and the overestimation ratio of TS B increased. US B is an objective and quantitative method used to evaluate breast development, and whether BD might replace US B as a routine diagnostic method to evaluate breast development in clinical practice needs to be confirmed in larger-sample studies., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Substantial progress has been made in the treatment of Cystic fibrosis due to introduction of CFTR modulators. However, little is known about the long term side effects of treatment with these drugs. We here present a 7 year old girl with CF who presented with breast development as a rare dose dependent side effect of treatment with ivacaftor and we report data on the correlation between drug plasma concentration and clinical effect, bodyweight, and BSA in 16 patients. Higher plasma concentrations did not correlate with clinical effect, as change in FEV1 and sweat chloride concentration. Patients with low bodyweight or BSA tended to have higher plasma concentrations. This might indicate that the current recommended dose of ivacaftor is at the top of the dose-response curve and that some patients can be treated with lower doses of ivacaftor with similar clinical effect., Competing Interests: Declaration of Competing Interest Dr. Jeyaratnam, Dr. van der Meer, Dr. Berkers and Dr. Heijerman have nothing to disclose. Dr. Beekman reports grants from proteostasis, personal fees from proteostasis,  outside the submitted work;  In addition, Dr. Beekman is inventor on a patent related to Intestinal Organoid swelling  and received royalties paid from Hubrecht Organoid Technology. Dr. van der Ent reports grants from GSK, grants from Nutricia, grants from TEVA, grants from Gilead, grants from Vertex, grants from ProQR, grants from Proteostasis, grants from Galapagos NV, grants from Eloxx, outside the submitted work; In addition, Dr. van der Ent has a patent 10,006,904 with royalties paid., (Copyright © 2021. Published by Elsevier B.V.)

Cell fate decisions are critical for adequate tissue development, maintenance and regeneration. In the mammary gland, epithelial cell fates are tightly controlled by the microenvironment. Here, we review how cell fate decisions are regulated by components of the microenvironment during mammary gland development and how pathological changes in the microenvironment can alter cell fates, leading to malignancy. Specifically, we describe the current understanding of how mammary cell fate is controlled and directed by three elements: the extracellular matrix, the immune microenvironment, and hormones-and how these elements can converge to create microenvironments that promote a fourth element: DNA damage., Competing Interests: Declaration of interests C.K. is a co-founder, consultant, and shareholder of Naveris Inc., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Reduction mammaplasty for macromastia is one of the most common operations performed by plastic surgeons. There remains hesitancy in operating on adolescents, as there is ongoing debate about breast regrowth and potential impact on breastfeeding. The goal of this study was to analyze these concerns by reviewing the current literature., Methods: A systematic review of MEDLINE, Scopus, and Google Scholar was conducted using the following terms: "breast reduction" or "mammaplasty" or "breast reconstruction" and "adolescent" or "youth" or "pediatric" or "child" or "teen." Primary outcomes were success of breastfeeding after the procedure and procedure-related complications., Results: Twenty-three studies (87 percent retrospective), consisting of 2926 patients with preoperative cup sizes of C to KK (mean, DDD), met inclusion criteria. Mean age at the time of surgery ranged from 16 to 21 years, with the youngest patient being 12 years old. The overall complication rate was 27.3 percent (95 percent CI, 14.4 to 42.5 percent). Minor complications (22.8 percent; 95 percent CI, 10.2 to 38.5 percent) were more common than major (4.2 percent; 95 percent CI, 1.6 to 7.9 percent). Eighteen percent of patients (95 percent CI, 2.2 to 43.8 percent) reported regrowth of their breast tissue postoperatively, with 2.7 percent (95 percent CI, 0.9 to 5.5 percent) undergoing a second revision mammaplasty. Fifty-three percent of patients (95 percent CI, 36.0 to 69.3 percent) did not attempt breastfeeding. Of those who attempted, 55.1 percent (95 percent CI, 34.4 to 74.9 percent) were successful., Conclusions: Prospective data are lacking. Patient counseling should focus on encouraging a trial of breastfeeding, despite surgical history. One-fifth of adolescent patients may notice breast regrowth postoperatively; however, the amount of regrowth is likely small and unlikely to reexacerbate symptoms, as the rate of revision surgery is small., (Copyright © 2021 by the American Society of Plastic Surgeons.)

This study aimed to describe the timing and patterns of pubertal maturation of girls living in rural Bangladesh. Starting in September 2015, a total of 15,320 girls from a birth cohort, aged 9 to 15 years at initial encounter, were visited twice at about a one year interval, typically in their birth month. Participants were asked to self-report extent of pubertal maturation, including breast development, pubic hair growth and age at menarche, if applicable. Pubertal stage (abbreviated as B2 and B3-4 for breast development and PH2 and PH3-4 for pubic hair growth) was assigned. Data from both visits were pooled, yielding a total of 29,377 age-related observations per pubertal characteristic. Probit regression models were used to estimate distributions of age at which each stage of pubertal development was attained. Before age 8, <3% of the study population initiated pubertal maturation as indicated by onset of breast development (B2). The median (95% confidence interval) age of B2 and B3-4 was 11.02 (11.00-11.04) and 12.82 (12.80-12.83) years, respectively; and 12.93 (12.91-12.94) and 14.29 (14.27-14.31) years for the onset (PH2) and advanced stage (PH3-4) of pubic hair growth, respectively. Median age at menarche was 13.17 (13.15-13.19) years, with 2.15 years of timespan from B2 to menarche. Girls in rural Bangladesh progressed through puberty following a well-documented sequence of sexual maturation stages. The age at which each pubertal milestone took place was somewhat later, but the tempo from breast development to menarche was comparable to that observed elsewhere. Our findings present a current norm of pubertal maturation in a typical, rural adolescent population in South Asia, which could help inform future studies and interventions to preserve or improve early adolescent health and development., Competing Interests: The authors have declared that no competing interests exist.

Objectives: Transmasculine individuals, those assigned female sex at birth but who identify as masculine, have high rates of suicidal behavior and often suffer from chest dysphoria (discomfort and distress from unwanted breast development). Growing numbers of transmasculine youth are pursuing definitive treatment with masculinizing chest surgery (MCS), and adult studies reveal marked benefits of MCS, although little is known about the impact of chest dysphoria on transmasculine youth or the optimal timing of MCS. In this study, we aimed to explore youth experiences of chest dysphoria and the impact of MCS., Methods: Transmasculine youth aged 13 to 21 were recruited from a pediatric hospital-based gender clinic. Participants completed a semistructured qualitative interview exploring the experience of chest dysphoria and thoughts about or experiences with MCS. Interview transcripts were coded by 3 investigators employing modified grounded theory, with the median interrater reliability at κ = 0.92., Results: Subjects ( N = 30) were a mean age of 17.5 years, and 47% had undergone MCS. Youth reported that chest dysphoria triggered strong negative emotions and suicidal ideation, caused a myriad of functional limitations, and was inadequately relieved by testosterone therapy alone. All post-MCS youth reported near or total resolution of chest dysphoria, lack of regret, and improved quality of life and functioning., Conclusions: We observed consensus that chest dysphoria is a major source of distress and can be functionally disabling to transmasculine youth. MCS performed during adolescence, including before age 18, can alleviate suffering and improve functioning. Additional research is needed to develop patient-reported outcome measures to assess the impact of chest dysphoria and MCS., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Stressful environments have been associated with earlier menarche. We hypothesized that anxiety, and possibly other internalizing symptoms, are also associated with earlier puberty in girls. The Lessons in Epidemiology and Genetics of Adult Cancer From Youth (LEGACY) Girls Study (2011-2016) included 1,040 girls aged 6-13 years at recruitment whose growth and development were assessed every 6 months. Prepubertal maternal reports of daughter's internalizing symptoms were available for breast onset (n = 447), pubic hair onset (n = 456), and menarche (n = 681). Using Cox proportional hazard regression, we estimated prospective hazard ratios and 95% confidence intervals for the relationship between 1 standard deviation of the percentiles of prepubertal anxiety, depression, and somatization symptoms and the timing of each pubertal outcome. Multivariable models included age, race/ethnicity, study center, maternal education, body mass index percentile, and family history of breast cancer. Additional models included maternal self-reported anxiety. A 1-standard deviation increase in maternally reported anxiety in girls at baseline was associated with earlier subsequent onset of breast (hazard ratio (HR) = 1.22, 95% confidence interval (CI): 1.09, 1.36) and pubic hair (HR = 1.15, 95% CI: 1.01, 1.30) development, but not menarche (HR = 0.94, 95% CI: 0.83, 1.07). The association of anxiety with earlier breast development persisted after adjustment for maternal anxiety. Increased anxiety in young girls may indicate risk for earlier pubertal onset., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Breast development is important for most trans women. An important limitation of current breast development measurement methods is that these do not allow for 3D volume analyses., Objectives: To examine breast development and change in anthropometry during the first 3 years of gender-affirming hormone treatment using 3D imaging. Associations with clinical or laboratory parameters and satisfaction with the gained breast development were also studied., Design: Prospective cohort study., Setting: Specialized tertiary gender identity clinic in Amsterdam, the Netherlands., Participants: Participants were 69 adult trans women with a median age of 26 years (interquartile range, 21-38)., Interventions: Gender-affirming hormone treatment., Main Outcome Measures: Volumetric and anthropometric breast development and satisfaction., Results: Breast volume increased by 72 cc (95% confidence interval [CI], 48-97) to 100 cc (standard deviation 48). This resulted in a cup-size

Background: Poor standing posture has been reported in women with larger breasts, increasing the risk of back pain. Whilst breast reduction surgery can improve posture, conservative measures such as special bras may offer short or long-term relief of symptoms without surgical intervention., Research Question: This study aimed to utilise a multi-study intervention to investigate the short and long-term kinematic effects of wearing a posture bra., Methods: Study one utilised biomechanics and physiotherapy expertise to modify the design of a prototype bra to improve posture and breast kinematics; resulting in a second-generation posture bra. To test this bra, 24 females were randomly assigned to control and intervention groups. The control group wore their everyday bra; the intervention group wore the generation 2 posture bra in place of their everyday bra for three months. Pre and post intervention, posture (spine curvature, scapula position, whole body alignment) and breast kinematics were assessed during sitting, standing and walking. Short-term effects of the posture bra were compared to an everyday bra and no bra (study two), whilst the long-term effects were compared using the no bra condition (study three)., Results: Biomechanical intervention improved posture and breast kinematics in a prototype posture bra resulting in a second-generation prototype. Pre-intervention, the generation 2 posture bra significantly improved scapula retraction by 6° during both sitting and standing, but also increased deviation of whole body alignment compared to everyday bra and no bra conditions. During walking the posture bra reduced breast motion by 17 % compared to the everyday bra. Following the three-month wearer intervention, scapula depression significantly improved in the intervention group., Significance: A biomechanically informed posture bra was able to effectively support the breasts and improve scapula position without compromising spinal curvature, reducing the risk of musculoskeletal pain associated with poor posture., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A disorder of sex development (DSD) is defined as a congenital condition in which development of chromosomal, gonadal, or anatomical sex is atypical. Swyer syndrome is an example of 46,XY DSD with a female phenotype. It usually becomes apparent in adolescence with delayed puberty and amenorrhoea. Spontaneous breast development is very rare. A 15-year-old girl was presented due to primary amenorrhoea with breast development compatible with Tanner stage V. Hormonal tests revealed hypergonadotropic hypogonadism with low level of oestradiol. Pelvic ultrasound and magnetic resonance imaging revealed a small uterus, and no ovaries were found. In the right lower abdomen, a structure of unknown origin was visible. The chromosome analysis revealed a 46,XY karyotype. The patient was qualified for a laparoscopic bilateral gonadectomy. Postoperative histopathological examination revealed gonadoblastoma. We underline the need to consider DSD 46,XY in the presence of primary amenorrhoea, even when pubertal development is present. Germ cell tumors have a tendency to grow and metastasize rapidly. Delayed diagnosis may increase the risk of malignant transformation and cause a poor diagnosis.

Context: Application of ultrasound (US) to evaluate attainment and morphology of glandular tissue provides a new rationale for evaluating onset and progression of female puberty, but currently no hormone references complement this method. Furthermore, previous studies have not explored the predictive value of endocrine profiling to determine female puberty onset., Objective: To integrate US breast staging with hypothalamic-pituitary-gonadal hormone references and test the predictive value of an endocrine profile to determine thelarche., Design Setting and Participants: Cross-sectional sample of 601 healthy Norwegian girls, ages 6 to 16 years., Main Outcome Measures: Clinical and ultrasound breast evaluations were performed for all included girls. Blood samples were analyzed by immunoassay and ultrasensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify estradiol (E2) and estrone (E1) from the subpicomolar range., Results: References for E2, E1, luteinizing hormone, follicle-stimulating hormone, and sex hormone-binding globulin were constructed in relation to chronological age, Tanner stages, and US breast stages. An endocrine profile index score derived from principal component analysis of these analytes was a better marker of puberty onset than age or any individual hormone, with receiver-operating characteristic area under the curve 0.91 (P < 0.001). Ultrasound detection of nonpalpable glandular tissue in 14 out of 264 (5.3%) girls with clinically prepubertal presentation was associated with significantly higher median serum levels of E2 (12.5 vs 4.9 pmol/L; P < 0.05) and a distinct endocrine profile (arbitrary units; P < 0.001)., Conclusions: We provide the first hormone references for use with US breast staging and demonstrate the application of endocrine profiling to improve detection of female puberty onset., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Reduction mammaplasty effectively alleviates symptoms and restores quality of life. However, operating on adolescents remains controversial, partly because of fear of potential postoperative breast growth. This cross-sectional study provides surgeons with a method to predict the optimal timing, or biological "sweet spot," for reduction mammaplasty to minimize the risk of breast regrowth in adolescents., Methods: The authors reviewed the medical records of women aged 12 to 21 years who underwent reduction mammaplasty from 2007 to 2019. Collected data included symptomology, perioperative details, and postoperative outcomes., Results: Four hundred eighty-one subjects were included in analyses and were, on average, 11.9 years old at first menses (menarche) and 17.9 years old at surgery. Six percent of subjects experienced postoperative breast growth. Breast size appears to stabilize considerably later in obese adolescents compared to healthy-weight and overweight patients, and breast growth in obese macromastia patients may not end until 9 years after menarche. Operating on obese women before this time point increased the likelihood of glandular breast regrowth by almost 120 percent (OR, 1.18; 95 percent CI, 1.11 to 1.26). Surgery performed less than 3 years after menarche, the commonly regarded end of puberty, increased the likelihood of glandular regrowth by over 700 percent in healthy-weight and overweight subjects (OR, 7.43; 95 percent CI, 1.37 to 40.41)., Conclusions: Findings suggest that reduction mammaplasty age restrictions imposed by care providers and third-party payors may be arbitrary. Surgical readiness should be determined on an individual basis incorporating the patient's biological and psychological maturity, obesity status, potential for postoperative benefit, and risk tolerance for postoperative breast growth., Clinical Question/level of Evidence: Risk, III.

Purpose of Review: The purpose of this review is to describe epidemiologic and toxicological literature investigating how endocrine-disrupting chemicals (EDCs) affect mammary gland development and function, thereby impacting lactation duration., Recent Findings: Perfluoroalkyl and polyfluoroalkyl substances appear to reduce breastfeeding duration through impaired mammary gland development, lactogenesis, and suppressed endocrine signaling. Halogenated aromatic hydrocarbons have differing associations with lactation duration, likely because of the variety of signaling pathways that they affect, pointing to the importance of complex mixtures in epidemiologic studies. Although epidemiologic literature suggests that pesticides and fungicides decrease or have no effect on lactation duration, toxicology literature suggests enhanced mammary gland development through estrogenic and/or antiandrogenic pathways. Toxicological studies suggest that phthalates may affect mammary gland development via estrogenic pathways but no association with lactation duration has been observed. Bisphenol A was associated with decreased duration of breastfeeding, likely through direct and indirect action on estrogenic pathways., Summary: EDCs play a role in mammary gland development, function, and lactogenesis, which can affect breastfeeding duration. Further research should explore direct mechanisms of EDCs on lactation, the significance of toxicant mixtures, and transgenerational effects of EDCs on lactation.

Objective: Premature thelarche (PT) is defined as isolated breast development in girls before eight years of age. Gonadotropin-releasing hormone (GnRH) stimulation test is sometimes used to distinguish between PT and central precocious puberty (CPP), although the interpretation of the test at early ages is challenging. The objective of this study was to determine the follicle stimulating hormone (FSH) and luteinizing hormone (LH) responses to GnRH stimulation in girls with PT below 3 years of age., Methods: A standardized GnRH stimulation test, bone age and pelvic ultrasound were evaluated and those without pubertal progression after a minimum of one-year follow up were included in the study., Results: On GnRH stimulation test, the median (range) baseline LH was 0.29 (0.10-0.74) IU/L, baseline FSH was 4.96 (3.18-7.05) mIU/mL, and the peak median LH was 5.75 (3.31-8.58) IU/L with the peak mean±standard deviation FSH was 40.38±20.37 mIU/mL. Among the patients, 33.3% (n=10) had baseline LH >0.3 IU/L, 67% (n=20) had peak LH >5 IU/l and 16.6% (n=5) >10 IU/L. The mean peak LH/FSH ratio was 0.17±0.09 and was ≤0.43 in all participants., Conclusion: Although consensus statements usually define baseline LH >0.3-0.5 IU/L, peak LH >5 IU/L, and LH/FSH ratios >0.66-1.0 as diagnostic cut-offs for CPP, in children below 3 years of age, the baseline and peak LH values may be similar to pubertal values, possibly due to mini-puberty. A dominant FSH response on GnRH stimulation test is more valuable than the peak LH response in the diagnosis of PT.

There are differential risk relationships between parity and breast cancer according to estrogen receptor (ER) status, with an increased risk of ER - disease reduced by breastfeeding. This may be particularly relevant for understanding the higher incidence of ER - tumors in Black women, who are more likely to be parous and less likely to breastfeed than other U.S. groups. Potential mechanisms for these relationships may include effects of disordered breast involution on inflammatory milieu in the breast as well as epigenetic reprogramming in the mammary gland, which can affect cell fate decisions in progenitor cell pools. In normal breast tissue, parity has been associated with hypermethylation of FOXA1 , a pioneer transcription factor that promotes the luminal phenotype in luminal progenitors, while repressing the basal phenotype. In breast tumors, relationships between FOXA1 methylation and parity were strongest among women who did not breastfeed. Here, we summarize the epidemiologic literature regarding parity, breastfeeding, and breast cancer subtypes, and review potential mechanisms whereby these factors may influence breast carcinogenesis, with a focus on effects on progenitor cell pools in the mammary gland., (©2020 American Association for Cancer Research.)

Objectives: Puberty suppression (PS) is a cornerstone of treatment in youth experiencing gender dysphoria. In this study, we aim to inform prescribing professionals on the long-term effects of PS treatment on the development of sex characteristics and surgical implications., Methods: Participants received PS according to the Endocrine Society guideline at Tanner 2 or higher. Data were collected from adolescents who received PS between 2006 and 2013 and from untreated transgender controls. Data collection pre- and post-PS and before surgery included physical examination and surgical information., Results: In total, 300 individuals (184 transgender men and 116 transgender women) were included. Of these, 43 individuals started PS treatment at Tanner 2/3, 157 at Tanner 4/5, and 100 used no PS (controls). Breast development was significantly less in transgender men who started PS at Tanner 2/3 compared with those who started at Tanner 4/5 and controls. Mastectomy was more frequently omitted or less invasive after PS. In transgender women, the mean penile length was significantly shorter in the PS groups compared with controls (by 4.8 cm [Tanner 2/3] and 2.1 cm [Tanner 4/5]). As a result, the likelihood of undergoing intestinal vaginoplasty was increased (odds ratio = 84 [Tanner 2/3]; odds ratio = 9.8 [Tanner 4/5])., Conclusions: PS reduces the development of sex characteristics in transgender adolescents. As a result, transgender men may not need to undergo mastectomy, whereas transgender women may require an alternative to penile inversion vaginoplasty. These surgical implications should inform decision-making when initiating PS., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Background: Earlier age at menarche is an established risk factor for breast cancer. While age at menarche has been fairly stable over the past half-century, age at breast development (thelarche) has continued to decrease. Recently, earlier age at thelarche and a longer time between thelarche and menarche (pubertal tempo) were shown to be associated with increased breast cancer risk. Our objective was to examine how breast cancer risk was associated with pubertal timing and tempo in a prospective US cohort., Methods: Women ages 35-74 years without a history of breast cancer, but who had a sister previously diagnosed with breast cancer, were enrolled in the Sister Study from 2003 to 2009 (N = 50,884). At enrollment, participants reported their ages at thelarche and menarche. Pubertal tempo was age at menarche minus age at thelarche. We estimated adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for each pubertal milestone and risk of breast cancer (invasive or ductal carcinoma in situ) using Cox proportional hazards regression. We examined whether associations between age at thelarche and breast cancer risk were modified by birth cohort, race/ethnicity, weight at age 10, and extent of breast cancer family history, as characterized by a Bayesian score based on first-degree family structure., Results: During follow-up (mean = 9.3 years), 3295 eligible women were diagnosed with breast cancer. Early ages at thelarche (HR = 1.23, 95% CI 1.03-1.46 for < 10 vs. 12-13 years) and menarche (HR = 1.10, 95% CI 1.01-1.20 for < 12 vs. 12-13 years) were positively associated with breast cancer risk. Pubertal tempo was not associated with breast cancer risk (HR = 0.99, 95% CI 0.97-1.02 per 1-year longer tempo). When considering early thelarche (< 10 years) and early menarche (< 12 years) jointly, women with both had a 30% greater risk of breast cancer compared with women with neither risk factor (95% CI 1.07-1.57). The association between age at thelarche and breast cancer risk did not significantly vary by birth cohort, race/ethnicity, childhood weight, or Bayesian family history score., Conclusions: Earlier ages at thelarche and menarche may enhance susceptibility to breast carcinogenesis. Age at thelarche is an important risk factor to consider given secular trends towards earlier development.

Background: Systemic inflammation may play a role in shaping breast composition, one of the strongest risk factors for breast cancer. Pubertal development presents a critical window of breast tissue susceptibility to exogenous and endogenous factors, including pro-inflammatory markers. However, little is known about the role of systemic inflammation on adolescent breast composition and pubertal development among girls., Methods: We investigated associations between circulating levels of inflammatory markers (e.g., interleukin-6 (IL-6), tumor necrosis factor receptor 2 (TNFR2), and C-reactive protein (CRP)) at Tanner stages 2 and 4 and breast composition at Tanner stage 4 in a cohort of 397 adolescent girls in Santiago, Chile (Growth and Obesity Cohort Study, 2006-2018). Multivariable linear models were used to examine the association between breast composition and each inflammatory marker, stratifying by Tanner stage at inflammatory marker measurement. Accelerated failure time models were used to evaluate the association between inflammatory markers concentrations at each Tanner stage and time to menarche., Results: In age-adjusted linear regression models, a doubling of TNFR2 at Tanner 2 was associated with a 26% (95% CI 7-48%) increase in total breast volume at Tanner 4 and a 22% (95% CI 10-32%) decrease of fibroglandular volume at Tanner 4. In multivariable models further adjusted for body fatness and other covariates, these associations were attenuated to the null. The time to menarche was 3% (95% CI 1-5%) shorter among those in the highest quartile of IL-6 at Tanner 2 relative to those in the lowest quartile in fully adjusted models. Compared to those in the lowest quartile of CRP at Tanner 4, those in the highest quartile experienced 2% (95% CI 0-3%) longer time to menarche in multivariable models., Conclusions: Systemic inflammation during puberty was not associated with breast volume or breast density at the conclusion of breast development among pubertal girls after adjusting for body fatness; however, these circulating inflammation biomarkers, specifically CRP and IL-6, may affect the timing of menarche onset.

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., (Copyright © 2020 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

Background: Obesity has been associated with earlier thelarche, whereas other predictors for it remain unclear., Methods: We studied child-related and parental predictors for earlier thelarche in 195 girls aged 6-8 years followed up for 2 years. A physician evaluated breast development by inspection and palpation. Body fat percentage (BF%) was measured by dual-energy X-ray absorptiometry, diet by food records, and physical activity and sedentary time by body movement and heart rate monitors. Parental education, smoking, and alcohol consumption and household income were assessed by questionnaires. Gestational age, birth weight, and maternal prepregnancy BMI were obtained from hospital registers. Predictors for thelarche were examined using logistic regression analysis adjusted for age and follow-up time., Results: The incidence of thelarche during 2 years increased by 11% (OR 1.11, CI 1.06-1.17, p < 0.001) for 1 unit increase in baseline BF%. Girls with a smoking parent had a 2.64 (95% CI 1.21-5.77, p = 0.015) times higher incidence of thelarche than other girls. The associations of lower parental education and higher maternal prepregnancy BMI with the higher incidence of thelarche were largely explained by BF%. Other possible predictors were not associated with thelarche., Conclusions: Higher BF% and exposure to tobacco smoke are independent predictors for earlier thelarche.

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.

Adipose tissue is a complex endocrine organ, with a role in obesity and cancer. Adipose tissue is generally linked to excessive body fat, and it is well known that the female breast is rich in adipose tissue. Hence, one can wonder: what is the role of adipose tissue in the breast and why is it required? Adipose tissue as an organ consists of adipocytes, an extracellular matrix (ECM) and immune cells, with a significant role in the dynamics of breast changes throughout the life span of a female breast from puberty, pregnancy, lactation and involution. In this review, we will discuss the importance of breast adipose tissue in breast development and its involvement in breast changes happening during pregnancy, lactation and involution. We will focus on understanding the biology of breast adipose tissue, with an overview on its involvement in the various steps of breast cancer development and progression. The interaction between the breast adipose tissue surrounding cancer cells and vice-versa modifies the tumor microenvironment in favor of cancer. Understanding this mutual interaction and the role of breast adipose tissue in the tumor microenvironment could potentially raise the possibility of overcoming breast adipose tissue mediated resistance to therapies and finding novel candidates to target breast cancer.

Context: Discriminating adipose and glandular tissue is challenging when clinically assessing breast development. Ultrasound facilitates staging of pubertal breast maturation (US B), but has not been systematically compared to Tanner breast (Tanner B) staging, and no normative data have been reported., Objective: To present normative references for US B along with references for Tanner B, pubic hair (PH), and menarche., Design, Setting, and Participants: A cross-sectional sample of 703 healthy girls aged 6 to 16 years were examined., Main Outcome Measures: Breast development was determined with US B and Tanner B staging. Tanner PH and menarcheal status were recorded. The age distributions of entry in US B, Tanner B, and PH stages and menarche were estimated with generalized linear and generalized additive models with a probit link. Method agreement was tested with weighted Cohen's kappa., Results: The median (±2SD) ages for thelarche, US B2 and Tanner B2, were 10.2 (7.7, 12.8) and 10.4 (8.0, 12.7) years. The median (±2SD) ages at Tanner PH2 and menarche were 10.9 (8.5, 13.3) and 12.7 (11.0, 16.2) years. Cohen's kappa of agreement (95% confidence interval) between US B and Tanner B was 0.87 (0.85-0.88). When the methods disagreed, US B was usually more advanced., Conclusion: Thelarche occurred at a slightly younger age when assessed with ultrasound compared to clinical Tanner staging, although the 2 methods had a very good agreement when determining pubertal breast maturation. A significant decrease of 2.8 months in age at menarche was observed during the past decade in Norwegian girls., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: During the postpartum period, breast engorgement in preparation for lactation may trigger the onset of vulvar labial nodules that present with pain and discomfort. These labial nodules may originate from ectopic breast tissue and can rarely present in women during the postpartum period in the labia majora., Main Issue: A 37-year-old African American female, gravida 1 para 1, presented to the Loma Linda University Medical Center with complaints of new onset labial swelling worsening 6 days following her full term spontaneous vaginal delivery. Additionally, our respondent complained of difficulty breastfeeding due to intermittent lack of milk production. She reported bilateral breast engorgement with tenderness, despite frequent attempts at breastfeeding. The respondent's presentation did not meet the criteria for other common differentials due to the physical characteristics of the nodules. The location of the nodules along the milk line led physicians to believe that the respondent was presenting with engorged extra-mammary breast tissue in the labia majora., Management: The participant was told to observe her course over the next few days as she began to have milk production and ejection. The respondent was seen in clinic for her 6-week postpartum visit, and was no longer complaining of difficulty with breastfeeding. The labial nodules had resolved spontaneously., Conclusion: A literature search yielded no case reports that described a case of an extra-mammary vulvar mass that self-resolved with resolution of breast engorgement. The infrequent presentation of extra-mammary vulvar tissue makes it difficult to conclude a guideline for diagnosis and management.

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.

Breast cancer (BC) relapse, despite clinical advancement, remains one of the biggest issues in the field. Intercellular communication, specifically via connexin (Cx)-mediated gap junctions (GJs), play a key role in the long-term survival of these, treatment-resistant breast cancer stem cells (CSCs), allowing for relapse. Both basic and clinical evidence reveal dual roles for GJs, in tumor suppression, generally referred to as dormancy, and progression and metastasis. GJ intercellular communication (GJIC) can be mediated by multiple types of Cxs, depending on the organ to which the BC cells metastasize. This review expands on the differential expression of Cx-mediated GJIC between CSCs and niche cells within a given microenvironment., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To examine adherence to a Mediterranean-like diet at age 9-10 years in relation to onset of breast development (thelarche) and first menstruation (menarche)., Design: We evaluated the associations of adherence to a Mediterranean-like diet (measured by an adapted Mediterranean-like Diet Score, range 0-9) with thelarche at baseline, age at thelarche and time to menarche. Data were collected at baseline during a clinic visit, complemented with a mailed questionnaire and three 24 hour telephone dietary recalls, followed by annual follow-up questionnaires. Multivariable Poisson regression, linear regression and Cox proportional hazards regression were used to evaluate timing of pubertal development in relation to diet adherence., Setting: New Jersey, USA., Participants: Girls aged 9 or 10 years at baseline (2006-2014, n 202)., Results: High Mediterranean-like diet adherence (score 6-9) was associated with a lower prevalence of thelarche at baseline compared with low adherence (score 0-3; prevalence ratio = 0·65, 95 % CI 0·48, 0·90). This may have been driven by consumption of fish and non-fat/low-fat dairy. Our models also suggested a later age at thelarche with higher Mediterranean-like diet adherence. Girls with higher Mediterranean-like diet adherence had significantly longer time to menarche (hazard ratio = 0·45, 95 % CI 0·28, 0·71 for high v. low adherence). Further analysis suggested this may have been driven by vegetable and non-fat/low-fat dairy consumption., Conclusions: Consuming a Mediterranean-like diet may be associated with older age at thelarche and menarche. Further research is necessary to confirm our findings in other US paediatric populations and elucidate the mechanism through which Mediterranean-like diet may influence puberty timing.

Puberty is the process of physical changes between childhood and adulthood during which adolescents reach sexual maturity and become capable of reproduction. It is considered one of the main temporal windows of susceptibility for the influence of the endocrine-disrupting chemicals (EDCs). EDCs may act as single chemical agents or as chemical mixtures; they can be pubertal influencers, accelerating and anticipating the processing of maturation of secondary sexual characteristics. Moreover, recent studies have started to point out how exposure to EDCs during puberty may predispose to breast cancer later in life. In fact, the estrogen-mimicking endocrine disruptors (EEDs) may influence breast tissue development during puberty in two main ways: the first is the action on the proliferation of the breast stromal cells, the second concerns epigenetic mechanisms. The aim of this mini-review was to better highlight what is new and what is not completely known regarding the role of EDCs during puberty.

This study aims to investigate serum makorin ring finger protein 3 (MKRN3) levels in girls with idiopathic central precocious puberty (ICPP) and premature thelarche (PT), in order to determine whether circulating MKRN3 level is associated with ICPP and PT. A total of 90 girls were enrolled in the stud. 30 age-matched girls were allocated for each group (ICPP, PT and healthy controls [HC], respectively). The base LH (B-LH) and E2 levels were higher in ICPP girls than those in HC and PT girls. The peak LH (P-LH) levels and P-LH/P-FSH values were obviously higher in ICPP girls than those in PT girls, while higher peak FSH (P-FSH) levels were detected in PT girls when compared to those in ICPP girls. Kisspeptin levels were lower in HC girls than those in ICPP and PT girls. MKRN3 levels were the highest in HC girls among the three groups. There were relatively strong negative correlations among MKRN3, kisspeptin and P-LH/P-FSH. Circulating MKRN3 can have an important role in the onset of ICPP and PT. However, this should not be used as an independent diagnostic criterion for diagnosing ICPP or differentiating ICPP from PT, but should be used only as an adjunctive diagnostic biomarker.

Timing of breast development (or thelarche) and its endogenous and exogenous determinants may underlie global variation in breast cancer incidence. The study objectives were to characterize endogenous estrogen levels and bisphenol A (BPA) exposure using a migrant study of adolescent girls and test whether concentrations explained differences in thelarche by birthplace and growth environment. Estrogen metabolites (EM) and BPA-glucuronide (BPA-G) were quantified in urine spot samples using liquid chromatography tandem mass spectrometry (LC-MS/MS) from a cross-sectional study of Bangladeshi, first- and second-generation Bangladeshi migrants to the UK, and white British girls aged 5-16 years ( n = 348). Thelarche status at the time of interview was self-reported and defined equivalent to Tanner Stage ≥2. We compared geometric means (and 95% confidence interval (CIs)) of EM and BPA-G using linear regression and assessed whether EM and BPA-G explained any of the association between exposure to the UK and the age at thelarche using hazard ratios and 95% confidence intervals. Average EM decreased with exposure to the UK, whereas BPA-G increased and was significantly higher among white British (0.007 ng/mL, 95% CI: 0.0024-0.0217) and second-generation British-Bangladeshi girls (0.009 ng/mL, 95% CI: 0.0040-0.0187) compared to Bangladeshi girls (0.002 ng/mL, 95% CI: 0.0018-0.0034). Two of four EM ratios (16-pathway/parent and parent/all pathways) were significantly associated with thelarche. The relationship between exposure to the UK and thelarche did not change appreciably after adding EM and BPA-G to the models. While BPA-G is often considered a ubiquitous exposure, our findings suggest it can vary based on birthplace and growth environment, with increasing levels for girls who were born in or moved to the UK. Our study did not provide statistically significant evidence that BPA-G or EM concentrations explained earlier thelarche among girls who were born or raised in the UK.

Factors such as socioeconomic status, age at menarche and childbearing patterns are components that have been shown to influence mammary gland development and establish breast cancer disparity. Pubertal mammary gland development is selected as the focus of this review, as it is identified as a "window of susceptibility" for breast cancer risk and disparity. Here we recognize non-Hispanic White, African American, and Asian American women as the focus of breast cancer disparity, in conjunction with diets associated with changes in breast cancer risk. Diets consisting of high fat, N-3 polyunsaturated fatty acids, N-6 polyunsaturated fatty acids, as well as obesity and the Western diet have shown to lead to changes in pubertal mammary gland development in mammalian models, therefore increasing the risk of breast cancer and breast cancer disparity. While limited intervention strategies are offered to adolescents to mitigate development changes and breast cancer risk, the prominent solution to closing the disparity among the selected population is to foster lifestyle changes that avoid the deleterious effects of unhealthy diets., (© 2020 Elsevier Inc. All rights reserved.)

Competing Interests: Competing interests: None declared.

Study Question: What are the levels of breast development and satisfaction in women with a Disorder/Difference of Sex Development (DSD)?, Summary Answer: Compared with normative data, women with DSD reached lower Tanner stages and reported less breast satisfaction., What Is Known Already: Women with DSD may have chromosomal and hormonal variations that can impact typical breast development. While much emphasis is placed on genital development in this group, little is known about breast development, satisfaction and their association., Study Design, Size, Duration: Data collection was part of the cross-sectional European multicenter dsd-LIFE study. Fourteen recruiting sites included 1040 participants between February 2014 and September 2015., Participants/materials, Setting, Methods: A total of 695 female-identifying participants were included (Turner n = 332, 46,XY DSD n = 141 and congenital adrenal hyperplasia n = 222), with a median age of 28 years. Clinical (i.e. history of hormone and surgical treatments, Tanner breast examination) and patient-reported (i.e. breast satisfaction, relationship status, sexual satisfaction and experienced femininity) data was collected by independent trained research staff. The relationship between breast development, satisfaction and femininity was assessed. Control data on breast development and satisfaction in women without DSD was retrieved from the literature., Main Results and the Role of Chance: Of the 695 participants, 61% had received estrogen replacement and 51% puberty induction therapy, whereas 2% had received breast augmentation surgery. Approximately 65% of participants had reached Tanner breast stage 5, which is substantially less than the general population (90%). Breast satisfaction was lower than normative data as well (P < 0.001, Cohen's d = 0.45). Breast size and breast satisfaction were associated with feelings of femininity., Limitations, Reasons for Caution: Limitations include the sample representativeness (e.g. regarding the clinical heterogeneity) and the limited in-depth knowledge on (prior) hormonal regimens. Furthermore, no (matched) control data was collected as part of this study., Wider Implications of the Findings: In order to support the psychosexual well-being of women with DSD, enhancing breast development by sufficient hormone replacement and possible augmentation surgery is advocated. The scope of DSD management should be beyond genital development only and consider breasts as well., Study Funding/competing Interest(s): The study was funded by the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement no. 305 373. There are no competing interests., Trial Registration Number: German Clinical Trials Register: Registration identification number: DRKS00006072., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.)

Background: Earlier age at onset of pubertal events and longer intervals between them (tempo) have been associated with increased breast cancer risk. It is unknown whether the timing and tempo of puberty are associated with adult breast density, which could mediate the increased risk., Methods: From 1988 to 1997, girls participating in the Dietary Intervention Study in Children (DISC) were clinically assessed annually between ages 8 and 17 years for Tanner stages of breast development (thelarche) and pubic hair (pubarche), and onset of menses (menarche) was self-reported. In 2006-2008, 182 participants then aged 25-29 years had their percent dense breast volume (%DBV) measured by magnetic resonance imaging. Multivariable, linear mixed-effects regression models adjusted for reproductive factors, demographics, and body size were used to evaluate associations of age and tempo of puberty events with %DBV., Results: The mean (standard deviation) and range of %DBV were 27.6 (20.5) and 0.2-86.1. Age at thelarche was negatively associated with %DBV (p trend = 0.04), while pubertal tempo between thelarche and menarche was positively associated with %DBV (p trend = 0.007). %DBV was 40% higher in women whose thelarche-to-menarche tempo was 2.9 years or longer (geometric mean (95%CI) = 21.8% (18.2-26.2%)) compared to women whose thelarche-to-menarche tempo was less than 1.6 years (geometric mean (95%CI) = 15.6% (13.9-17.5%))., Conclusions: Our results suggest that a slower pubertal tempo, i.e., greater number of months between thelarche and menarche, is associated with higher percent breast density in young women. Future research should examine whether breast density mediates the association between slower tempo and increased breast cancer risk.

Breast cancer is one of the most common cancers diagnosed in women worldwide. Genetic predisposition, such as breast cancer 1 (BRCA1) mutations, account for a minor percentage of the total breast cancer incidences. And thus, many life style factors have also been linked to the disease such as smoking, alcohol consumption and obesity. Emerging studies show that environmental pollutants may also play a role. Bisphenol-A (BPA) has been suspected to contribute to breast cancer development, and has been shown to affect mammary gland development amongst other effects. This prompted its replacement with other bisphenol analogs such as, bisphenol-S (BPS). In this study we used the human mammary epithelial cells, MCF-12A, grown in extracellular matrix to investigate the ability of BPA and BPS to disrupt mammary epithelial cells organization. We show that both BPA and BPS were equipotent in disrupting the organization of the acinar structures, despite BPS being less oestrogenic by other assays. Further, treatment with both compounds enabled the cells to invade the lumen of the structures. This study shows that BPS and BPA are environmental pollutants that may affect mammary development and may contribute to the development of breast cancer.